1218935-59-1|(R)-2-(2,5-Difluorophenyl)pyrrolidine| Ambeed

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Quality Control of [ 1218935-59-1 ] Purity: 97% SDS Specification

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Product Details of [ 1218935-59-1 ]

CAS No. :	1218935-59-1
Formula :	C₁₀H₁₁F₂N
M.W :	183.20
SMILES Code :	FC1=CC=C(F)C([C@@H]2NCCC2)=C1
MDL No. :	MFCD07772701
InChI Key :	NCXSNNVYILYEBC-SNVBAGLBSA-N
Pubchem ID :	7176290

Safety of [ 1218935-59-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1218935-59-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.4
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	50.35
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	12.03 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.34
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.01
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.52
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.93
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.3
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.62

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.52
Solubility	0.556 mg/ml ; 0.00304 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.89
Solubility	2.36 mg/ml ; 0.0129 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.89
Solubility	0.0238 mg/ml ; 0.00013 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	Yes
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.99 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	2.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.16

Application In Synthesis of [ 1218935-59-1 ]

* 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 [ 1218935-59-1 ]

[ 1218935-59-1 ] Synthesis Path-Downstream 1~35

1
[ 1218935-59-1 ]
[ 18087-76-8 ]
[ 1218935-61-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	In butan-1-ol; at 140℃;sealed in a pressure reaction tube;	A suspension of 6-chloro-3-nitroimidazo[l,2-b]pyridazine (1.0 g, 5.0 mmol) and <strong>[1218935-59-1](R)-2-(2,5-difluorophenyl)pyrrolidine</strong> (Prepared as described in Preparation A; 1.9 g, 11 mmol) in n-butanol (4.6 mL, 50 mmol) was sealed in a pressure reaction tube and stirred in a 140 0C oil bath overnight. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (250 mL), then washed with water (2 x 150 mL) and brine (150 mL), filtered through a Biotage Phase Separator filter paper and concentrated. The crude material was purified by silica gel chromatography, eluting with 2:1 EtOAc/hexanes to yield the product as a foamy yellow powder (1.3 g, 75% yield).

References: [1]Patent: WO2010/33941,2010,A1 .Location in patent: Page/Page column 35-36.

2
[ 1218935-60-4 ]
[ 1218935-59-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water; ethyl acetate;	To (R)-tert- butyl 2-(2,5-difluorophenyl)pyrrolidine-l-carboxylate (23.9 g, 84.4 mmol) was added 56.2 mL 4N HCl (dioxane). After stirring at ambient temperature for 2 hours, 200 mL of ether was added and the mixture was stirred for 10 minutes. The resulting slurry was filtered, yielding the hydrochloride salt of the product as a white solid (17.2 g). To obtain the free base, the HCl salt product was dispersed in a mixture of EtOAc (200 mL) and NaOH solution (100 mL, 2 N aq.) The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were filtered and concentrated to give the desired product as a liquid (13.2g, 85% yield).
	With sodium hydroxide; In water; ethyl acetate;	Step B: Preparation of (RV2-(2.5-difluorophenyl>pyrrolidine; To (R)-tert- butyl 2-(2,5-difluorophenyl)pyrrolidine-l-carboxylate (23.9 g, 84.4 mmol) was added 56.2 mL 4N HCl (dioxane). After stirring at ambient temperature for 2 hours, 200 mL of ether was added and the mixture was stirred for 10 minutes. The resulting slurry was filtered, yielding the hydrochloride salt of the product as a white solid (17.2 g). To obtain the free base, the HCl salt product was dispersed in a mixture of EtOAc (200 mL) and NaOH solution (100 mL, 2 N aq.) The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were filtered and concentrated to give the desired product as a liquid (13.2g, 85% yield).
	With sodium hydroxide; In water; ethyl acetate;	Step B: Preparation of (R)-2-(2.5-difluorophenyl)pyrrolidine.; To (R)-tert- butyl 2-(2,5-difluorophenyl)pyrrolidine-l-carboxylate (23.9 g, 84.4 mmol) was added 4N HCl in dioxane (56.2 mL). After stirring at ambient temperature for 2 hours, ether (200 mL) was added and the mixture was stirred for 10 minutes. The resulting slurry was filtered, yielding the title compound hydrochloride salt as a white solid (17.2 g). To obtain the free base, the HCl salt product was dispersed in a mixture of EtOAc (200 mL) and NaOH solution (100 mL, 2 N aq.) The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were filtered and concentrated to give the desired product as a liquid (13.2 g, 85% yield).[00418] The enantiomeric excess (% ee) of (R)-2-(2,5-difluorophenyl)pyrrolidine was determined as follows: To an ethanol solution of (R)-2-(2,5-difluorophenyl)pyrrolidine was added excess N-(2,4-dinitro-5-fluorophenyl)-L-alanine amide (FDAA, Marfey's reagent). The mixture was heated to reflux for approximately two minutes. After cooling to ambient temperature, the reaction mixture was diluted with acetonitrile and analyzed by HPLC (YMC ODS-AQ 4.6 x 50 mm 3 mum 12thetaA column; mobile phase: 5-95% solvent B in A; solvent A: H2O/1% iPrOH/10 mM ammonium acetate, and solvent B: ACN/1% iPrOH /10 mM ammonium acetate; flow rate: 2 mL/min). The enantiomeric excess (ee%) was determined from the peak areas of the two diastereomeric derivatives formed. A 1 : 1 racemic standard was prepared according the same procedure described herein, replacing (R)-2-(2,5- difluorophenyl)pyrrolidine with (rac)-2-(2,5-difluorophenyl)pyrrolidine. The ee% of the title compound obtained as described above was determined to be > 93%.

References: [1]Patent: WO2010/33941,2010,A1 .Location in patent: Page/Page column 34.
[2]Patent: WO2010/48314,2010,A1 .Location in patent: Page/Page column 45.
[3]Patent: WO2011/6074,2011,A1 .Location in patent: Page/Page column 69-70.

3
[ 1218935-59-1 ]
[ 29274-24-6 ]
[ 1223404-89-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium fluoride; In dimethyl sulfoxide; at 180℃; for 2h;	A mixture of 5-chloropyrazolo[1,5-a]pyrimidine (1.18 g, 7.68 mmol), <strong>[1218935-59-1](R)-2-(2,5-difluorophenyl)pyrrolidine</strong> (1.51 g, 8.22 mmol) and KF (2.32 g, 39.1 mmol) in DMSO (26 mL) was heated at 180 C. for 2 hours. The reaction mixture was cooled to room temperature and poured into water. The mixture was stirred for additional 30 min at room temperature. A precipitated solid was collected by filtration and dried under vacuum to afford (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (1.70 g, 74%) as a yellow solid. 1H-NMR (DMSO-d6, Varian, 400 MHz): delta 1.88-2.06 (3H, m), 2.33-2.45 (1H, m), 3.56-3.70 (1H, m), 3.90-4.00 (1H, m), 5.38 (1H, s), 5.98 (1H, s), 6.10-6.50 (1H, m), 6.85-6.91 (1H, m), 7.10-7.15 (1H, m), 7.26-7.32 (1H, m), 7.81 (1H, d, J=1.6 Hz), 8.60 (1H, s).
68%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 160℃;Sealed tube;	Preparation B; Preparation of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo?,5-alpyrimidin-3- amine; [00381] Step A: Preparation of (RV5-(2-(2.5-difluorophenyr)pyrrolidin-l- yPpyrazolo [ 1 ,5 -a"\|pyrimidine; In a pressure reaction tube was added 5-chloropyrazolo[l,5- a]pyrimidine (4.2 g, 27 mmol), <strong>[1218935-59-1](R)-2-(2,5-difluorophenyl)pyrrolidine</strong> (Preparation A; 5.3 g, 29 mmol), anhydrous n-butanol (5 ml, 55 mmol), and DIEA (9.5 ml, 55 mmol). The yellowish suspension was sealed and heated in an oil bath (160 0C) overnight. The reaction was cooled to ambient temperature, diluted with EtOAc (250 mL), and filtered, rinsing the solid with EtOAc. The filtrate (330 mL) was washed with water (2 x 150 mL), brine (100 mL), concentrated, and purified by silica chromatography, eluting with 2:1 EtOAc/hexanes to give the product as a bright yellowish solid (5.6 g, 68% yield).

References: [1]Patent: US2016/168156,2016,A1 .Location in patent: Paragraph 0462; 0464; 0465.
[2]Patent: WO2010/48314,2010,A1 .Location in patent: Page/Page column 45-46.

4
[ 139601-90-4 ]
[ 1218935-59-1 ]
C₁₉H₁₉F₂N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; for 0.0333333h;Reflux;	Step C: Determination of Enantiomeric Excess (ee%) of (RV2-(2.5- difluorophenvDpyrrolidine : To an ethanol solution of <strong>[1218935-59-1](R)-2-(2,5-difluorophenyl)pyrrolidine</strong> was added excess N-(2,4-dinitro-5-fluorophenyl)-L-alanine amide (FDAA, Marfey's reagent). The mixture was heated to reflux for approximately two minutes. After cooling to ambient temperature, the reaction mixture was diluted with acetonitrile and injected onto HPLC (YMC ODS-AQ 4.6 x 50 mm 3 mum 12thetaA column; mobile phase: 5-95% solvent B in A; solvent A: H2O/ 1% IPA/ 10 mM ammonium acetate, and solvent B: ACN/1% IP A/10 mM ammonium acetate; flow rate: 2 mL/min) to determine the enantiomeric excess of the product by calculating the peak areas of the two diastereomeric derivatives formed. A 1 : 1 racemic sample was prepared according the same procedure described herein, replacing (R)- 2-(2,5-difluorophenyl)pyrrolidine with (rac)-2-(2,5-difluorophenyl)pyrrolidine. The ee% of the product obtained as described above was determined to be > 93%.

References: [1]Patent: WO2010/48314,2010,A1 .Location in patent: Page/Page column 45.

5
[ 399-94-0 ]
[ 1218935-59-1 ]

References: [1]Patent: WO2011/6074,2011,A1 .
[2]Patent: US2017/281632,2017,A1 .
[3]Patent: CN108101820,2018,A .
[4]Patent: EP3533796,2019,A1 .

6
[ 1218935-59-1 ]
[ 1260840-74-1 ]

References: [1]Patent: WO2011/6074,2011,A1 .

7
[ 1218935-59-1 ]
[ 1260842-01-0 ]

References: [1]Patent: WO2011/6074,2011,A1 .

8
[ 1218935-59-1 ]
[ 1260846-92-1 ]

References: [1]Patent: WO2011/6074,2011,A1 .

9
[ 1218935-59-1 ]
[ 1260845-56-4 ]

References: [1]Patent: WO2011/6074,2011,A1 .
[2]Patent: US2016/168156,2016,A1 .

10
[ 1218935-59-1 ]
[ 1260840-05-8 ]

References: [1]Patent: WO2011/6074,2011,A1 .

11
[ 1218935-59-1 ]
[ 1260840-10-5 ]

References: [1]Patent: WO2011/6074,2011,A1 .

12
[ 1218935-59-1 ]
[ 1224944-77-7 ]
[ 1260845-57-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium fluoride; In dimethyl sulfoxide; at 180℃; for 2h;	A mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.30 g, 5.76 mmol), <strong>[1218935-59-1](R)-2-(2,5-difluorophenyl)pyrrolidine</strong> (Intermediate 5, 1.13 g, 6.6 mmol) and KF (1.67 g, 28.8 mmol) in DMSO (19 mL) was stirred at 180 C. for 2 hours. After being cooled to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to afford ethyl (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (2.11 g, 98%) as a yellow solid. MS: 372.90 [MH+]
79.7%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 100℃; for 15h;	Preparation C; (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolori,5-alpyrimidine-3-carboxylic acid; Step A: Preparation of (R)-ethyl 5-(2-(2.5-difluorophenv0pyrrolidin-l- yl)pyrazolo[ 1 ,5-a"\|pyrimidine-3-carboxylate.; A mixture of ethyl 5-chloropyrazolo[l,5- a]pyrimidine-3-carboxylate (Preparation B, 2.00 g, 8.86 mmol), (R)-2-(2,5- difluorophenyl)pyrrolidine (Preparation A, 1.62 g, 8.86 mmol), diisopropylethylamine (3.09 mL, 17.7 mmol) and butan-1-ol (2.95 ml, 8.86 mmol) was heated at 100 0C for 15 hours. The reaction mixture was cooled to ambient temperature and was diluted with EtOAc (30 mL) and water (10 mL). Undissolved solid was filtered and washed with Et2O to afford the title compound as a light orange solid (2.13 g). The organic layer was separated from the filtrate, washed with brine (10 mL) and dried over MgSO4. The solution was filtered and concentrated to provide additional solid that was purified by silica chromatography using gradient elution with 50-100% EtOAc/hexanes. This afforded the title compound (0.50 g) as a light yellow solid. The combined yield was 2.63 g, 79.7 %. MS (apci) m/z = 373.1 (M+H).

References: [1]Patent: US2016/168156,2016,A1 .Location in patent: Paragraph 0340; 0341.
[2]Patent: WO2011/6074,2011,A1 .Location in patent: Page/Page column 71.

13
[ 1218935-59-1 ]
[ 1224288-95-2 ]
[ 1260846-28-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step B: Preparation of (R)-5-(2-(2.5-difluorophenyl)pyrrolidin-l- vDpyrazolor 1 ,5-alpyrimidine-3-carbonitrile.; A flask was charged with the product from Step A (2.80 g, 17.5 mmol), benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (9.28 g, 21.0 mmol) and dry DMF (35 mL). The suspension was stirred at ambient temperature for 2 minutes and <strong>[1218935-59-1](R)-2-(2,5-difluorophenyl)pyrrolidine</strong> (Preparation A, 3.84 g, 21.0 mmol) and diisopropylethylamine (6.78 g, 62.5 mmol) were sequentially added (mild exotherm). The mixture was stirred at ambient temperature for 3 hours and poured into H2O (175 mL). The mixture was extracted with 50% EtOAc-hexanes and the combined organic fractions were washed sequentially with IM HCl, H2O, IM Na2CO3 and saturated NaCl. The solution was dried over MgStheta4/activated carbon and filtered through a short SiO2 plug (350 mL course frit funnel, 1/4 full of SiO2, capped with a layer of MgSO4) using 50% EtOAc-hexanes for elution. The solution was concentrated to give the title compound as a brittle white foam that was crushed to a flowing white solid and dried in vacuum (5.50 g, 97%). MS (apci) m/z = 326.2 (M+H).

References: [1]Patent: WO2011/6074,2011,A1 .Location in patent: Page/Page column 93-94.

14
[ 1218935-59-1 ]
[ 1224288-95-2 ]
[ 1260840-77-4 ]

References: [1]Patent: WO2011/6074,2011,A1 .

15
[ 1218935-58-0 ]
[ 1218935-59-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogenchloride; In tetrahydrofuran; water; for 2h;	20 mmol of the intermediate A-3 was dissolved in tetrahydrofuran 50 mL, Add 100mmol35% hydrochloric acid solution stirring, after 2 hours of reaction, the reaction solution was alkalized to basic with 2M NaOH. Extracted twice with ethyl acetate, After recovering ethyl acetate, 3.6 g of product was obtained, and the yield was 98%.HPLC purity ? 96%, HPLC chiral purity ? 99%.

References: [1]Patent: CN109354578,2019,A .Location in patent: Paragraph 0045; 0086-0087.
[2]Patent: WO2011/6074,2011,A1 .

16
[ 1218935-59-1 ]
[ 171178-21-5 ]
[ 1400633-18-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; toluene; for 30h;Inert atmosphere; Reflux;	6-[(2^)-2-(2,5-difluorophenyl)pyffolidi^ (4-3); 6-Chloro-3-nitropyridme-2~carboxamide (700 mg, 3.47 mmol), (2J?)-2-(2,5- difluorophenyl)pyrrolidine (636 mg, 3.47 mmol) was added to Toluene (1.29 mL) and DMF (6.4 mL). Hunig's Base (3.033 mL, 17.36 mmol) was added and the solution was stirred under nitrogen at reflux for 30 h. The mixture was cooled, aqueous sodium hydrogen carbonate (saturated, 40 mL) was added and the mixture was extracted with diethyl ether (3 x 40 mL). The combined organic fractions were washed with brine (saturated, 30 mL), dried, filtered and the solvent was evaporated under reduced pressure. The residue was purified by columnchromatography to give the title compound.

References: [1]Patent: WO2012/125668,2012,A1 .Location in patent: Page/Page column 41.

17
[ 1218935-59-1 ]
[ 171178-33-9 ]
[ 1400633-16-0 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 150℃; for 2h;Microwave irradiation;	6-[(2i?)-2-(2,5-difluorophenyl)pyrroUdin-l^ (2-3); 6-Chloropyrido[3,2-ii]pyrimidin-4(3H)-one (200 mg, 1.101 mmol), (2Lambda)-2-(2,5- difluorophenyl)pyrrolidine (400 mg, 2.203 mmol) was added in a 2 mL EtOH. The vial was irradiated in a microwave reactor at 150 C for 2hr. The reaction was concentrated and the crude product was purified by HPLC to give the title compound; MS (ES) m/z M+H calc'd:329, found: 329.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5800 - 5816.
[2]Patent: WO2012/125668,2012,A1 .Location in patent: Page/Page column 38.

18
[ 1218935-59-1 ]
[ 1400633-10-4 ]

References: [1]Patent: WO2012/125668,2012,A1 .

19
[ 1218935-59-1 ]
[ 1400633-11-5 ]

References: [1]Patent: WO2012/125668,2012,A1 .

20
[ 1218935-59-1 ]
[ 1400632-57-6 ]

References: [1]Patent: WO2012/125668,2012,A1 .

21
[ 1218935-59-1 ]
[ 1400633-17-1 ]

References: [1]Patent: WO2012/125668,2012,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5800 - 5816.

22
[ 1218935-59-1 ]
[ 1400633-05-7 ]

References: [1]Patent: WO2012/125668,2012,A1 .

23
[ 1218935-59-1 ]
[ 1400632-89-4 ]

References: [1]Patent: WO2012/125668,2012,A1 .

24
[ 1218935-59-1 ]
[ 1400633-19-3 ]

References: [1]Patent: WO2012/125668,2012,A1 .

25
[ 1218935-59-1 ]
[ 1400633-20-6 ]

References: [1]Patent: WO2012/125668,2012,A1 .

26
[ 1218935-59-1 ]
[ 1400632-62-3 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5800 - 5816.

27
[ 1218935-59-1 ]
[ 1256162-94-3 ]
(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium fluoride; In dimethyl sulfoxide; at 180℃; for 2h;	A mixture of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (4.70 g, 25.9 mmol), <strong>[1218935-59-1](R)-2-(2,5-difluorophenyl)pyrrolidine</strong> (Intermediate 5, 5.07 g, 27.7 mmol) and KF (7.52 g, 129 mmol) in DMSO (86 mL) was heated at 180 C. for 2 hours. After being cooled to room temperature, the reaction mixture was poured into water. The mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrate in vacuo. The residue was purified by column chromatography on SiO2 (EtOAc only to DCM:MeOH=20:1) to afford 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (8.50 g, 100%) as a yellow solid. 1H-NMR (CDCl3, Varian, 400 MHz): delta 1.90-2.28 (3H, m), 2.38-2.60 (1H, m), 3.60-4.18 (2H, m), 5.14-5.28 (0.6H, m), 5.54-5.72 (0.4H, m), 5.84-6.02 (0.6H, m), 6.35-6.46 (0.4H, m), 6.68-6.78 (1H, m), 6.82-7.20 (2H, m), 8.10-8.36 (2H, m), 9.77 and 10.11 (1H, s+s).

References: [1]Patent: US2016/168156,2016,A1 .Location in patent: Paragraph 0350; 0358; 0359; 0554; 0556; 0557.

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[ 1218935-59-1 ]

References: [1]Patent: US2016/168156,2016,A1 .
[2]Patent: CN108003161,2018,A .
[3]Patent: CN108101820,2018,A .
[4]Patent: CN108484361,2018,A .
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[6]Patent: CN108484361,2018,A .
[7]Patent: CN108484361,2018,A .
[8]Patent: CN108484361,2018,A .
[9]Patent: CN108484361,2018,A .
[10]Patent: CN108484361,2018,A .
[11]Patent: CN108484361,2018,A .
[12]Patent: CN108484361,2018,A .
[13]Patent: CN108484361,2018,A .
[14]Patent: CN108484361,2018,A .
[15]Patent: CN108484361,2018,A .
[16]Patent: CN108484361,2018,A .
[17]Patent: CN108484361,2018,A .
[18]Patent: CN108484361,2018,A .
[19]Patent: CN108484361,2018,A .
[20]Patent: EP3533796,2019,A1 .

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(R)-5-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1,3,4-oxadiazol-2-amine [ No CAS ]