392338-15-7|(R)-tert-Butyl methyl(pyrrolidin-3-yl)carbamate| Ambeed

Structure of 392338-15-7

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Quality Control of [ 392338-15-7 ] Purity: 97% SDS Specification

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Product Details of [ 392338-15-7 ]

CAS No. :	392338-15-7
Formula :	C₁₀H₂₀N₂O₂
M.W :	200.28
SMILES Code :	CN([C@@H]1CCNC1)C(=O)OC(C)(C)C
MDL No. :	MFCD09263387
InChI Key :	XYKYUXYNQDXZTD-MRVPVSSYSA-N
Pubchem ID :	7019173

Safety of [ 392338-15-7 ]

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

Computational Chemistry of [ 392338-15-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	0
Fraction Csp3	0.9
Num. rotatable bonds	4
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	59.39
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	41.57 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.63
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.88
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.83
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.86
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.48
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.14

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.37
Solubility	8.5 mg/ml ; 0.0424 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.34
Solubility	9.21 mg/ml ; 0.046 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	-1.44
Solubility	7.29 mg/ml ; 0.0364 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.9 cm/s

Druglikeness

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

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.74

Application In Synthesis of [ 392338-15-7 ]

* 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 [ 392338-15-7 ]

[ 392338-15-7 ] Synthesis Path-Downstream 1~35

1
[ 762286-32-8 ]
[ 392338-15-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonium formate;palladium 10% on activated carbon; In methanol; water; for 5h;Heating / reflux;	(b) Title compoundA solution of the compound obtained above (14.5 g, 50.14 mmol), Pd/C (10%, 50% in water) (3g) and ammonium formate (12.7 g, 200.5 mmol) in a mixture of MeOH (390 ml_) and water (45 ml_) was heated at reflux for 5 hours. The reaction was filtered through Celite and the filtrate was washed with AcOEt and MeOH. The solvent was evaporated to dryness to afford 10.6 g of the title compound as an oil(yield: 100%).1H NMR (300 MHz, CDCI3) delta: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H), 3.11 (m, 2H), 4.58 (m, 1 H).
100%	With ammonium formate;palladium 10% on activated carbon; In methanol; water; for 5h;Heating / reflux;	A solution of the compound obtained above (14.5 g, 50.14 mmol), Pd/C (10%, 50% in water) (3 g) and ammonium formate (12.7 g, 200.5 mmol) in a mixture of MeOH (390 mL) and water (45 mL) was heated at reflux for 5 hours. The reaction was filtered through CeI ite and the filtrate was washed with EtOAc and MeOH. The solvent was concentrated to dryness, to afford 10.6 g of the title compound as an oil (yield: 100%).1H NMR (300 MHz, CDCI3) delta: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H), 3.11 (m, 2H), 4.58 (m, 1 H).
100%	With ammonium formate;palladium 10% on activated carbon; In methanol; water; for 5h;Heating / reflux;	(b) Title compoundA mixture of the compound obtained above (14.5 g, 50.14 mmol), Pd/C (10%, 50% in water) (3 g) and ammonium formate (12.7 g, 200.5 mmol) in MeOH (390 mL) and water (45 mL) was heated under reflux for 5 hours. The reaction mixture was filtered through Celite and the filter was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 10.6 g of the title compound as an oil (yield: 100%). <n="103"/>1H RMN (300 MHz, CDCI3) delta: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H), 3.11 (m, 2H), 4.58 (m, 1 H).

100%	With ammonium formate;palladium 10% on activated carbon; In methanol; water; for 5h;Heating / reflux;	(b) Title compound; A solution of the compound obtained above (14.5 g, 50.14 mmol), Pd/C (10%, 50% in water) (3 g) and ammonium formate (12.7 g, 200.5 mmol) in a mixture of MeOH (390 mL) and water (45 mL) was heated under reflux for 5 hours. The reaction was filtered through Celite and the filter aid was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 10.6 g of the title compound in the form of an oil (yield: 100%).1H RMN (300 MHz, CDCI3)delta: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H), 3.11 (m, 2H), 4.58 (m, 1 H).
100%	With ammonium formate;palladium 10% on activated carbon; In methanol; water; for 5h;Heating / reflux;	A mixture of the compound obtained above (14.5 g, 50.14 mmol), Pd/C (10%, 50% in water) (3 g) and ammonium formate (12.7 g, 200.5 mmol) in MeOH (390 mL) and water (45 mL) was heated under reflux for 5 hours. The reaction was filtered through CeI ite and the filter cake was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 10.6 g of the title compound in the form of an oil (yield: 100%). 1H NMR (300 MHz, CDCI3) ?: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H), 3.11 (m, 2H), 4.58 (m, 1 H).
100%	With ammonium formate;palladium 10% on activated carbon; In methanol; water; for 5h;Reflux;	A mixture of the compound obtained above (14.5 g, 50.14 mmol), Pd/C (10%, 50% in water) (3 g) and ammonium formate (12.7 g, 200.5 mmol) in MeOH (390 mL) and water (45 mL) was heated under reflux for 5 hours. The reaction was filtered through Celite and the filter was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 10.6 g of the title compound as an oil (yield: 100%).1H NMR (300 MHz, CDCI3)delta: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H), 3.1 1 (m, 2H), 4.58 (m, 1 H).
100%	With ammonium formate;palladium 10% on activated carbon; In methanol; water; for 5h;Reflux;	(b) Title compound; A solution of the compound previously obtained (14.5 g, 50.14 mmol), Pd/C (10%, 50% in water) (3 g) and ammonium formate (12.7 g, 200.5 mmol) in MeOH (390 mL) and water (45 mL) was heated under reflux for 5 hours. The reaction was filtered through Celite and the filtrate was washed with EtOAc and MeOH. The solvent was concentrated to dryness, providing 10.6 g of the title compound as an oil (yield: 100%).1H NMR (300 MHz, CDCI3) delta: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H), 3.11 (m, 2H), 4.58 (m, 1 H).
100%	With ammonium formate; In methanol; water; for 5h;Reflux;	A mixture of the compound obtained above (14.5 g, 50,14 mmol), Pd/C (10%, 50% in water) (3 g) and ammonium formate (12.7 g, 200.5 mmol) in MeOH (390 mL) and water (45 mL) was heated under reflux for 5 hours. The reaction mixture was filtered through Celite and the iter was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 10.6 g of the title compound as an oil (yield: 100%).1H NMR (300 MHz, CDC ) delta: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H}, 3.11 (m, 2H)s 4.58 (m, 1H).
100%	With ammonium formate;palladium 10% on activated carbon; In methanol; water; for 5h;Reflux;	(b) Title compound; A mixture of the compound obtained above (14.5 g, 50.14 mmol), Pd/C (10%, 50% in water) (3 g) and ammonium formate (12.7 g, 200.5 mmol) in MeOH (390 mL) and water (45 mL) was heated under reflux for 5 hours. The reaction was filtered <n="81"/>through CeI ite and the filter was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 10.6 g of the title compound as an oil (yield: 100%).1H RMN (300 MHz, CDCI3)delta: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H), 3.11 (m, 2H), 4.58 (m, 1 H).
	With formic acid;palladium(II) hydroxide/carbon; In methanol; at 60℃; for 16h;	Example 1 E (RVMbetathyl-pyrrolidin-S-yl-carbamic acid tert-butyl esterTo a solution of Example 1 D (285 mg, 0.98 mmol) in 4.4% HCO2HYMeOH (20 mL) under a nitrogen atmosphere was added Pd(OH)2 on carbon (20%, 40 mg) and the resulting mixture was heated at 60 0C for 16 hours. The mixture was cooled to room temperature, filtered through a layer of diatomaceous earth, washed with extra MeOH (30 mL) and concentrated under reduced pressure. The residue was diluted with CH2CI2 (30 mL), washed with 1 M NaOH, dried (MgSO4), filtered and concentrated under reduced pressure to provide the title compound. 1H NMR (CD3OD): delta 1.46 (s, 9H), 1.79 (m, 1H), 1.99 (m, 1H), 2.76 (m, IH), 2.79 (s, 3H), 2.87 (m, 1 H), 3.03 (m, 2H), 4.57 (p, J = 6 Hz, 1 H). MS (DCl-NH3) m/z 201 (M+H)+.
	With formic acid;Pd(OH)2/C; In methanol; at 60℃; for 16h;Inert atmosphere;	To a solution of Example 1E (285 mg, 0.98 mmol) in 4.4% HCO2H/MeOH (20 mL) under a nitrogen atmosphere was added Pd(OH)2 on carbon (20%, 40 mg), and the resulting mixture was heated at 60 C. for 16 hours. The mixture was cooled to room temperature and filtered through a layer of diatomaceous earth, the filter pad was washed with extra MeOH (30 mL), and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (30 mL) and washed with 1 M NaOH, then the organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CD3OD) delta 4.57 (d, J=6 Hz, 1H), 3.03 (m, 2H), 2.87 (m, 1H), 2.79 (s, 3H), 2.76 (m, 1H), 1.99 (m, 1H), 1.79 (m, 1H), 1.46 (s, 9H). MS (DCI+) m/z 201 (M+H).
	With formic acid;Pearlman catalyst; In methanol; at 60℃; for 16h;Inert atmosphere;	Example 2B tert-butyl methyl[(3R)-pyrrolidin-3-yl]carbamate To a solution of the product of Example 2A (285 mg, 0.98 mmol) in 4.4% formic acid/methanol (20 mL) under a nitrogen atmosphere was added palladium hydroxide on carbon (20%, 40 mg) and the resulting mixture was heated at 60 C. for 16 hours. The mixture was cooled to room temperature, filtered through a layer of diatomaceous earth, washed with extra methanol (30 mL) and concentrated under reduced pressure. The residue was diluted with dichloromethane (30 mL), washed with 1 M sodium hydroxide, dried (magnesium sulfate), filtered and concentrated under reduced pressure to provide the title compound: 1H NMR (CD3OD) delta 1.46 (s, 9H), 1.79 (m, 1H), 1.99 (m, 1H), 2.76 (m, 1H), 2.79 (s, 3H), 2.87 (m, 1H), 3.03 (m, 2H), 4.57 (p, J=6 Hz, 1H); MS (DCl/NH3) m/z 201 (M+H)30 .
	With hydrogen;20% Pd(OH)2 on carbon; In methanol; under 760.051 Torr;	To a stirred solution of benzyl (3R)-3-[(tert-butoxycarbonyl) (methyl) amino] pyrrolidine- 1-carboxylate 34a (1.5 g, 5.17 mmole) in MeOH (10 ml) was added Pd (OH) 2 on carbon (150 mg). The reaction mixture was under 1 atmosphere of H2 overnight, filtered through celite and concentrated, in vacuo. The residue obtained was used directly in the subsequent reaction without any further purification, [VIDE INFRA. 1H NMR] (300 MHz, CD30D) 6 4.47 [(1H,] m), 3.20 (1H, m), 2.91 (2H, m), 2.76 (1H, m), 2.69 (3H, s), 1.89 (1H, m), 1.68 [(1 H,] m), 1.35 (9H, s).
	With hydrogen;palladium(II) hydroxide/carbon; In isopropyl alcohol; at 20℃; under 2327.23 Torr;	To compound 20b in i-PrOH (100 mL) was added Pd (OH) 2 (8 g, 20% on carbon, 50% wet) prior to hydrogenation (40 psi) overnight with shaking at room temperature. The reaction mixture was filtered through Celite, the solvent was removed under vacuum, and the resulting solid was washed with ether to give 20c (11.07 g. ) The mother liquor was further concentrated to yield 18. 8 g oil. LC-MS: 201. 1 (MH+).

References: [1]Patent: WO2007/31529,2007,A1 .Location in patent: Page/Page column 24.
[2]Patent: WO2009/56551,2009,A1 .Location in patent: Page/Page column 54.
[3]Patent: WO2009/77608,2009,A1 .Location in patent: Page/Page column 101-102.
[4]Patent: WO2009/80721,2009,A2 .Location in patent: Page/Page column 72.
[5]Patent: WO2009/68512,2009,A1 .Location in patent: Page/Page column 54.
[6]Patent: WO2010/43633,2010,A1 .Location in patent: Page/Page column 91-92.
[7]Patent: WO2010/94721,2010,A1 .Location in patent: Page/Page column 68.
[8]Patent: WO2011/76878,2011,A1 .Location in patent: Page/Page column 52.
[9]Patent: WO2009/115496,2009,A1 .Location in patent: Page/Page column 78-79.
[10]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4450 - 4457.
[11]Patent: WO2008/60767,2008,A2 .Location in patent: Page/Page column 121.
[12]Journal of Medicinal Chemistry,2008,vol. 51,p. 6547 - 6557.
[13]Patent: US2009/233904,2009,A1 .Location in patent: Page/Page column 78.
[14]Patent: US2009/270364,2009,A1 .Location in patent: Page/Page column 27.
[15]Patent: WO2003/106462,2003,A1 .Location in patent: Page 71.
[16]Patent: WO2004/81005,2004,A1 .Location in patent: Page 66.

2
[ 7693-46-1 ]
[ 392338-15-7 ]
[ 910220-79-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4450 - 4457.

3
[ 1018442-84-6 ]
[ 392338-15-7 ]
tert-Butyl {(3R)-1-[4-(benzyloxy)-2-oxo-2H-1,2'-bipyridin-5'-yl]pyrrolidin-3-yl}methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 12.5h;Heating / reflux;	A suspension of 4-(Benzyloxy)-5'-iodo-2H-1,2'-pyridin-2-one from Preparation 2a (100 mg, 0.24 mmol), tert-butyl methyl[(3R)-pyrrolidin-3-yl]-carbamate (60 mg, 0.29 mmol; see Example 34b in WO2003/106462), Pd(OAc)2 (2.5 mg, 0.009 mmol), BINAP (6.1 mg, 0.009 mmol) and NaOtBu (33 mg, 0.35 mmol) in toluene (5 ml) was purged with nitrogen for 30 mins. Reaction mixture was heated under reflux condition for 12 h. After cooling to room temperature, water was added and reaction mixture was extracted with ethyl acetate (3*20 ml). Organic layer was washed with water (30 ml), brine (30 ml) and dried (Na2SO4). Concentration and column purification (silica, 30% EtOAc/hexane) provided the title compound as a light yellow solid (100 mg, 84%) 1H NMR (400 MHz, CDCl3) delta ppm 1.47 (s, 9H), 2.13-2.22 (m, 2H), 2.80 (s, 3H), 3.23-3.33 (m, 2H), 3.46-3.52 (m, 2H), 5.02 (s, 2H), 6.02 (d, 1H), 6.06 (dd, 1H), 6.94 (dd, 1H), 7.34-7.40 (m, 5H), 7.59-7.65 (m, 2H), 7.80 (d, 1H). LRMS m/z (FIA) 477 [MH+]

References: [1]Patent: US2008/85884,2008,A1 .Location in patent: Page/Page column 67.

4
[ 1018442-84-6 ]
[ 392338-15-7 ]
tert-butyl {(3R)-1-[4-(benzyloxy)-2-oxo-2H-1,3'-bipyridin-6'-yl]pyrrolidin-3-yl}methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 14h;	A mixture of 4-(benzyloxy)-6'-fluoro-2H-1,3'-bipyridin-2-one from Preparation 2 (500 mg, 1.69 mmol), (R)-methyl-pyrrolidinyl-3-yl-carbamic acid tert-butyl ester (372 mg, 1.86 mmol; see Example 34b in WO2003/106462) and potassium carbonate (700 mg, 5.06 mmol) in N,N-dimethylformamide (15 ml) was heated to 110 C. After 14 hours the reaction mixture was concentrated and the crude product mixture was purified by column chromatography eluting with ethyl acetate, followed by 9:1 ethyl acetate:methanol which gave the desired product as a white powder (693 mg, 86%). 1H NMR (400 MHz, CD3OD) delta ppm 1.45 (s, 9H), 2.21 (m, 2H), 2.81 (s, 3H), 3.43 (m, 2H), 3.84 (m, 2H), 4.82 (b, 1H), 5.15 (s, 2H), 6.08 ((s, 1H), 6.25 (d, 1H), 6.05 (d, 1H), 7.31-7.45 (m, 7H), 8.02 (s, 1H). LRMS m/z 477 [MH+]

References: [1]Patent: US2008/85884,2008,A1 .Location in patent: Page/Page column 23.

5
[ 392338-15-7 ]
4'-Trifluoromethyl-biphenyl-4-carboxylic acid [(S)-1-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-pyrrolidin-3-yl]-methyl-amide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4450 - 4457.

6
[ 392338-15-7 ]
[ 910220-80-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4450 - 4457.

7
[ 392338-15-7 ]
Methyl-((R)-1-{(S)-3-[methyl-(4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-pyrrolidine-1-carbonyl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4450 - 4457.

8
[ 392338-15-7 ]
4'-Trifluoromethyl-biphenyl-4-carboxylic acid {(S)-1-[(R)-3-(cyclobutylmethyl-methyl-amino)-pyrrolidine-1-carbonyl]-pyrrolidin-3-yl}-methyl-amide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4450 - 4457.

9
[ 75677-02-0 ]
[ 392338-15-7 ]
[ 762285-62-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In DMF (N,N-dimethyl-formamide); at 70℃; for 20h;	Amine 20c (17.4 g, 86.9 MMOL,) compound 20a (30.8 g, 86. 7 MMOL,) and TEA (48.6 mL, 0. 35 mol) were dissolved in DMF (110 mL) and heated (70 C) in an oil-bath (20 hr.) After removal of solvent under vacuum, the residual mixture was diluted with DCM : I-PROH (3: 1,1600 mL, ) washed 3 times with aliquots (200 mL) OF NAOH/H20 (0.5 N, ) washed once with brine (200 mL, ) dried over MGS04, filtered and concentrated. To the residue was added ether (50 mL, ) and this mixture was kept at 4 C overnight prior to filtration and washing with cold ether to give 20d (19. 25 g. ) The mother liquor was concentrated and purified via flash chromatography to afford a second batch of crystals. The combined yield of 20d was 24.8 g. LC-MS: 417.1 (MH+).

References: [1]Patent: WO2004/81005,2004,A1 .Location in patent: Page 66.

10
[ 56-05-3 ]
[ 392338-15-7 ]
[ 929716-71-2 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In ethanol; at 80℃; for 1h;Product distribution / selectivity;	Alternative method for preparation 15: tert-Butyl [(3R)-1-(2-amino-6-chloropyrimidin-4-yl)pyrrolidin-3-yl]methylcarbamate A suspension of 2-amino-4,6-dichloropyrimidine (3.62 g, 22.1 mmol) and the amine of preparation. 47 (5.40 g, 27.0 mmol) in ethanol (45 ml) was treated with TEA (4.62 ml, 33.1 mmol) and the resulting mixture heated at 80 C. for 1 hour. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was separated and the aqueous extracted with further ethyl acteate. The combined organic extracts were dried (magnesium sulphate) and the solvent removed in vacuo to give an orange oil. Trituration with di-isopropyl ether gave a pale yellow solid which was filtered and dried in vacuo to give the title compound (7.0 g, 87%). 1H NMR (400 MHz, DMSOd6): delta 5.77 (1H, s), 4.60 (1H, br m), 3.27 (4H, br m), 2.70 (3H, s), 2.02 (2H, br m), 1.39 (9H, s) ppm. MS (ESI) m/z 327 [M+H]+
52%	With N-ethyl-N,N-diisopropylamine; In ethanol; for 3h;Heating / reflux;	REFERENCE EXAMPLE 8 tert-Butyl [(3/?)-1-(2-amino-6-chloropyrimidin-4-yl)pyrrolidin-3- yl]methylcarbamate To a solution of 2-amino-4,6-dichloropyrimidine (1 g, 6.09 mmol) and DIEA (1.6 ml_, 9.1 mmol) in EtOH (8 ml_) under argon atmosphere, the compound obtained in reference example 5 was added (1.2 g, 6.09 mmol) and the resulting mixture was stirred at reflux for 3 hours. It was allowed to cool to room temperature, the solid obtained was filtered and the mother liquors were concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane/AcOEt mixtures of increasing polarity as eluent, to afford 1.04 g of the title compound (yield: 52%). LC-MS (Method 1 ): tR = 7.12 min; m/z = 328 (MH+).

References: [1]Patent: US2007/185075,2007,A1 .Location in patent: Page/Page column 18.
[2]Patent: WO2007/31529,2007,A1 .Location in patent: Page/Page column 26.
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 2429 - 2439.

Yield	Reaction Conditions	Operation in experiment
		Example 34(b) tert-Butyl methyl[(3R)-pyrrolidin-3-yl]carbamate To a stirred solution of benzyl (3R)-3-[(tent-butoxycarbonyl)(methyl)amino]pyrrolidine-1-carboxylate 34a (1.5 g, 5.17 mmole) in MeOH (10 ml) was added Pd(OH)2 on carbon (150 mg). The reaction mixture was under 1 atmosphere of H2 overnight, filtered through celite and concentrated, in vacuo. The residue obtained was used directly in the subsequent reaction without any further purification, vide infra. 1H NMR (300 MHz, CD3OD) delta4.47 (1H, m), 3.20 (1H, m), 2.91 (2H, m), 2.76 (1H, m), 2.69 (3H, s), 1.89 (1H, m), 1.68 (1H, m), 1.35 (9H, s).

12
[ 1193-21-1 ]
[ 392338-15-7 ]
[ 929716-71-2 ]

References: [1]Patent: US2007/185075,2007,A1 .Location in patent: Page/Page column 18.

13
[ 596793-57-6 ]
[ 392338-15-7 ]
[ 638217-50-2 ]

Yield	Reaction Conditions	Operation in experiment
0.30%	With thionyl chloride; triethylamine;	Example 34(c) tert-Butyl (3R)-1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl(methyl)carbamate This material was prepared from 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (1.05 g, 4.94 mmole), SOCl2 (10 ml), tert-butyl methyl[(3R)-pyrrolidin-3-yl]carbamate 34b (0.989 g, 4.94 mmole) and Et3N (0.689 ml, 4.94 mmole) in a manner as previously described for example 9d to give a brown oil (0.723g, 0.30%). 1H NMR (300 MHz, CDCl3) delta8.62 (1H, d, J=5.1 Hz), 7.85 (1H, s), 7.35 (1H, d, J=5.1 Hz), 4.82 (1H, m), 3.93 (3H, m), 3.63 (1H, m), 2.82 (3H, s), 2.12 (2H, m), 1.47 (9H, s); ESIMS (MH+): 396.05.

References: [1]Patent: US2004/9965,2004,A1 .

14
[ 638217-49-9 ]
[ 392338-15-7 ]

Yield	Reaction Conditions	Operation in experiment
62%	With hydrogen;5% palladium over charcoal; In ethanol; at 20℃; under 2585.81 Torr; for 44h;	Preparation 47: tert-Butyl methyl[(3R)-pyrrolidin-3-yl]carbamate; A solution of the carbamate of preparation 46 (15.58 g, 46.6 mmol) in ethanol (150 ml) was hydrogenated in the presence of 5% Pd/C (1 g) at 50 psi at room temperature for a period of 18 hours. Further Pd/C (500 mg) was added and the resulting mixture hydrogenated under the same conditions for a further 26 hours. The catalyst was filtered off and the filtrate concentrated in vacuo. Purification by chromatography (DCM:MeOH:0.880 ammonia (100:0:0 changing to 90:10:1 by volume) gave the title compounds as a pale yellow oil (5.85 g, 62%). 1H NMR (400 MHz, CDCl3): delta 4.56 (1H, m), 3.06 (2H, m), 2.87 (1H, m), 2.79 (1H, m), 2.78 (3H, s), 2.54 (1 H, s), 1.95 (1H, m), 1.73 (1H, m), 1.43 (9H, s) ppm. MS (ESI) m/z 201 [M+H]+
	With hydrogen;palladium 10% on activated carbon; In methanol; for 2h;Inert atmosphere;	Step 2: tert-butyl methyl[(3R)-pyrrolidm-3-yl]carbamate; HN O- N' o /-Pd/C (wt. 10%, 400 mg) was added to a solution of benzyl (3R)-3-[(tert- butoxycarbonyl)(methyl)arnino]pyrrolidine-l-carboxylate (1.4 g, 4.2 mmol) in methanol (10.0 mL) under nitrogen. The mixture was stirred under hydrogen ballon for 2 h., and filtered. The filtrate was concentrated under reduced pressure to give the desired product which was directly used in the next step reaction without further purification. LCMS (M+Na)+: m/z = 201.3.

References: [1]Patent: US2007/185075,2007,A1 .Location in patent: Page/Page column 23-24.
[2]Patent: WO2010/75270,2010,A1 .Location in patent: Page/Page column 179.

15
[ 1027332-69-9 ]
[ 392338-15-7 ]
[ 1031817-76-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; at 80℃;	Example 45E 10-chloro-4-rf3R)-3-fmethylamino)pyrrolidin-1-yl1-5,6-dihvdrori1benzoxepinor5,4- alphafipymidin-2-amineTo a mixture of Example 45D (48 mg, 0.17 mmol) in EtOH (1 mL) was added Example 1 E (51 mg, 0,25 mmol) followed by triethylamine (0.17 mL, 1 ,2 mmol) and the resulting mixture heated at 80 0C overnight, cooled, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of CH2Cl2: EtOAc (5:1 , 2:1 and 1.1 ) to provide the intermediate Boc-protected product. This intermediate Boc-protected product was taken up in CH2CI2 (2 mL), treated with trifluoroacetic acid (2 mL), heated at 60 C for 1 minute, cooled, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of 2, 10 and 20 % (9:1 MeOH: saturated aqueous NH4OH) in CH2CI2 to provide the title compound. 1H NMR (CDCI3) delta 184 (m, 1 H), 2.11 (m, 1 H), 2.49 (s, 3 H), 2.73 (dt, J=6.02, 1.86 Hz, 2 H), 3.32 (m, 1 H), 3.43 (dd, J=10.85, 4.75 Hz, 1 H), 3,61 (m, 1 H), 3.72 - 3.81 (m, 2 H), 4.51 (t, J=5.93 Hz, 2 H), 4.70 (s, 2 H), 7.01 (d, J=8.82 Hz, 1 H), 7..31 (dd, J=8.48, 2.71 Hz, 1 H), 7.86 (d, J=2.71 Hz, 1 H); MS (M+H)+ m/z 346.

References: [1]Patent: WO2008/60767,2008,A2 .Location in patent: Page/Page column 151.

16
[ 1031817-94-3 ]
[ 1031817-96-5 ]
[ 392338-15-7 ]
[ 1027332-92-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; at 80℃;	Exampje 1,1.,1.,B tert-butyl f3R)-1-f2-amino-5,5-dioxo-6.7-dihvdro-5H-5l6-thia-1.3-diaza- dibenzora.clcvclohepten^-vDpyrrolidin-S-vK methyl CarbamateThe products from Example 1 1 1A (40 mg) were treated with the product from Example 1 E (42.7 mg, 0.213 mmol) and triethylamine (139 mul, 0.995 mrnoi), in ethanol (0.57 ml_), heated at 80 0C for overnight, cooled, diluted with CH2CI2 (25 ml_) and washed with 1 M NaOH (5 m._). The layers were separated and the aqueous was extracted with CH2CI2 (2 x 25 rnL). The combined CH2CI2 layers were dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel eluting with 1 :1 :0 hexane:EtOAc:EtOH, then a gradient to 0:1 :0 over 10 minutes followed by a gradient to 0:1 :9 over 10 minutes to provide the title compound as the faster moving less polar product. 1H NMR (CDCI3) delta 1.49 (s, 9 H), 2.03 - 2.13 (m, 2 H), 2.84 (s, 3 H), 3.16 (dd, J=14.2, 5.1 Hz, 1 H), 3.33 - 3.44 (m, 1 H), 3.57 - 3.67 (m, 1 H), 3-70 - 3.77 (m, 3 H), 3.78 - 3.89 (m, 2 H), 4.67 - 4.81 (m, 1 H), 5.18 (s, 2 H), 7.23 - 7.28 (m, 1 H), 7.38 - 7.47 (m, 2 H), 7.95 - 8.01 (m, 1 H), MS (M+H)+ m/z 460.

References: [1]Patent: WO2008/60767,2008,A2 .Location in patent: Page/Page column 193.

17
[ 1027332-49-5 ]
[ 392338-15-7 ]
[1-(2-amino-6-methyl-5,6-dihydro-benzo[h]quinazolin-4-yl)-pyrrolidinyl-3-yl]-methyl-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile; at 110℃; for 16h;	Example 1 F [1j:(2-Amino-6-methyl-5,6-dihvdro-be?zofh]quina2olin-4-yl)-pyrrolidi?-3-yl1-methyl- carbamic acid tert-butyl esterA solution consisting of Example 1C (80 mg, 0.28 mmol) , Example 1E (89 mg, 0.45 mmol) and triethylamine (0.2 mL) in anhydrous acetonitrile (3 mL) was placed in a screw capped vial, and heated at 110 0C for 16 hours. The mixture was cooled, concentrated under reduced pressure, and the resulting residue chrarnatographed on silica gel eluting with EtOAc to provide the titfe compound. 1H NMR (CD3OD) delta 1.24 (d, J=6 Hz, 3H), 1.45 (s, 9H)1 1.83 (m, 1 H), 2.07 (m, 1 H), 2.47 (s, 3H), 2.66 (m, 1 H), 2.95 (m, 1 H), 3.28 (m, 1 H), 3.44 (m, 1 H), 3.65 (m, 1 H), 3.77 (m, 2H)1 4.65 (m, 1 H), 473 (s, 2H), 7.22 (m, 1 H), 7.33 (m, 2H), 8.13 (m, 1 H). MS (M+H)+ m/z 410.

References: [1]Patent: WO2008/60767,2008,A2 .Location in patent: Page/Page column 121.

18
[ 945975-19-9 ]
[ 392338-15-7 ]
[ 945975-85-9 ]

Yield	Reaction Conditions	Operation in experiment
93.7%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 20℃;	Example 9; Synthesis of tert-Butyi [(R)-l-(2-amino-8-chlorobenzo[4,5]furo[3,2- d]pyrimidin-4-yl)pyrrolidin-3-yl] N-methyl carbamate; A suspension of 2-amino-4,8-dichlorobenzo[4,5]furo[3,2-d]pyrimidine (34.79 g, 136.92 mmol, 1.0 eq) in IPA (550 ml) is treated with N,N-diisopropylethylamine (47.70 ml, 35.39 g, 273.83 mmol, 2.0 eq) followed by a solution of (R)-3-[(N-tert-butoxycarbonyl)-N-methyl] aminopyrrolidine (31.53 g, 137.90 mmol, 1.0 eq, 87.6%) and stirred at room temperature overnight. The reaction mixture is evaporated to dryness, the residue is dissolved in DCM (300 ml) and washed with water (200 ml), saturated NaHCOs solution (200 ml) and water (200 ml), the organic layer is dried over Na2S(M and evaporated to give a reddish solid (53.60 g, 128.26 mmol, 93. 7%).1H NMR (CDCl3): d 1.5 (s, 9H), 2.1 (m, IH), 2.2 (m, IH), 2.85 (s, 3H), 3.75 (br, 2H), 4.1 (br, 2H), 4.8-5.0 (br, 3H), 7.45 (d, IH), 7.5 (dd, IH), 8.0 (d, IH).

References: [1]Patent: WO2008/62013,2008,A1 .Location in patent: Page/Page column 16.

19
[ 1111201-40-1 ]
[ 392338-15-7 ]
[ 1111201-43-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethanol;Microwave irradiation;	The following preferred compounds are prepared according to the route given below: [Show Image] [Show Image] i) Dihydropyran, HCl in dioxan, CH2Cl2, RT; ii)TMEDA, hexane, n-BuLi, DMF, -10C; to RT then cHCl RT; iii) Hydroxylamine.HCl, NaOAc, MeCN, H2O reflux;iv) Ac2O, 190C microwave; v)EtOH, aq NaOH, RT 16h; vi) Ethyl bromoacetate, K2CO3, MeCN, refluxvii) KOtBu, THF, 5C, viii) formamidineHCl, sulfolane 150C; ix) POCl3, MeCN, BnMe3N+Cl-, 100C, microwavex) DIPEA, Boc-NMe pyrrolidine, EtOH, microwave; xi) NalO4, EtOH; xii) TFA, DCM.

References: [1]Patent: EP2020412,2009,A1 .Location in patent: Page/Page column 11-13.

20
[ 1132690-71-1 ]
[ 392338-15-7 ]
[ 1148116-17-9 ]

Yield	Reaction Conditions	Operation in experiment
59%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In 1,4-dioxane; at 20℃; for 72h;	To a suspension of the compound obtained in reference example 7 (1 g, 4.88 mmol) in 1 ,4-dioxane (50 mL), triethylamine (12.5 mL), PyBOP (2.54 g, 4.88 mmol) and reference example 1 (1.47 g, 7.34 mmol) were added. The resulting suspension was stirred at room temperature for 72 hours and was then concentrated to dryness. The crude product obtained was partitioned between dichloromethane and 0.5 N NaOH. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using EtOAc/MeOH mixtures of increasing polarity as eluent, to afford 1.12 g of the desired compound (yield: 59%).LC-MS (Method 2): tR = 2.38 min; m/z 388 (MH+)

References: [1]Patent: WO2009/56551,2009,A1 .Location in patent: Page/Page column 60.

21
C₈H₁₂ClN₃ [ No CAS ]
[ 1164116-14-6 ]
[ 392338-15-7 ]
[ 1164116-43-1 ]

Yield	Reaction Conditions	Operation in experiment
32%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 100℃;	EXAMPLE 1; 2-lsobutyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine; The compound obtained in reference example 1 (144 mg, 0.72 mmol) was added to a solution of reference example 3 (89 mg as an approx 50% mixture of the two regioisomers, 0.48 mmol equivalents to 0.24 mmol of the intended regioisomer) and DIEA (0.25 ml_, 1.44 mmol) in n-BuOH (6 ml_), and the resulting mixture was heated overnight in a sealed tube at 100 C. Additional reference example 1 (96 mg, 0.48 mmol) and DIEA (0.25 ml_) were added and it was heated at 100 0C for one more day. It was allowed to cool and the solvent was evaporated to dryness. The crude product obtained was purified by preparative HPLC-MS (column X- Terra PREP MS C18 5 mum (100 mm x 19 mm), rate: 20 mL/min, eluent: A = AcN, B = NH4HCO3 75 mM, gradient: 0 min A at 25%; 1 min A at 25%; 11 min A at 90%; 12 min A at 90%) and the fractions containing the product were evaporated to dryness, providing 26.9 mg of the Boc-protected intermediate (yield: 32%). ,HCI (4 M solution in 1 ,4-dioxane, 1.5 mL) and MeOH (1 mL) were added to this intermediate, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness. The residue was dissolved in water, 1 N NaOH solution was added until basic pH and it was extracted three times with chloroform. The combined organic phases were dried over anhydrous Na2SO4 and it was concentrated to dryness. The crude product obtained was purified by preparative HPLC-MS (column X-Terra PREP MS C18 5 mum (100 mm x 19 mm), <n="83"/>rate: 20 ml_/min, eluent: A = AcN, B = NH4HCO3 75 mM, gradient: 0 min A at 10%; 1 min A at 10%; 8 min A at 90%) and the fractions containing the product were evaporated to dryness, providing 5.2 mg of the title compound (yield: 27%). LC-MS (Method 2): tR = 1.20 min; m/z 250 (MH+).

References: [1]Patent: WO2009/80721,2009,A2 .Location in patent: Page/Page column 81-82.

22
C₁₁H₁₂ClN₃ [ No CAS ]
[ 1164116-31-7 ]
[ 392338-15-7 ]
[ 1164116-36-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 100℃;	REFERENCE EXAMPLE 29; 2-(2-Cyclopentylethynyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4- amine; (a) terf-Butyl (R)-1 -^-amino^-^-cyclopentylethynylJpyrimidin-beta- yl)pyrrolidin-3-yl(methyl)carbamate; The compound obtained in reference example 1 (0.16 g, 0.8 mmol) was added to a mixture of the compound obtained in reference example 28 (0.15 g as a mixture of regioisomers, 0.67 mmol) and DIEA (0.13 g, 1.0 mmol) in n-BuOH (2 ml_) and the resulting mixture was heated overnight in a sealed tube at 100 C. It was allowed to cool and the solvent was evaporated to dryness. The crude product obtained was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing 85.5 mg of the title compound (yield: 18% from 2,6-dichloropyhmidin-4-amine). LC-MS (Method 2): tR = 2.65 min; m/z = 386 (MH+).

References: [1]Patent: WO2009/80721,2009,A2 .Location in patent: Page/Page column 78-79.

23
[ 1157869-95-8 ]
[ 392338-15-7 ]
[ 1157871-26-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In 1,4-dioxane; at 20℃; for 120h;	A mixture of the compound obtained in reference example 6 (1.0 g, 6.06 mmol), the amine obtained in reference example 1A (1.95 g, 9.7 mmol) and PyBOP (4.1 g, 7.9 mmol) in a mixture of TEA (37 mL) and 1 ,4-dioxane (63 mL) was stirred at room temperature for 4 days, after which more of the compound obtained in reference example 1A (1.95 g, 9.7 mmol), PyBOP (4.1 g, 7.9 mmol) and TEA (19 mL) were added and it was stirred at room temperature for one more day. The reaction mixture was evaporated to dryness, the residue was diluted with water and chloroform and 2 N NaOH solution was added until basic pH. The phases were separated and the aqueous phase was extracted twice with chloroform. The combined organic phases were dried over anhydrous Na2SO4 and it was concentrated to dryness. The crude product obtained was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as an eluent, providing 2.5 g of the desired compound. LC-MS (Method 2): tR = 2.17 min; m/z 348 (MH+).

References: [1]Patent: WO2009/68512,2009,A1 .Location in patent: Page/Page column 64.

24
[ 1157870-22-8 ]
[ 392338-15-7 ]
[ 1157870-43-3 ]

Yield	Reaction Conditions	Operation in experiment
56%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 100℃; for 24h;	The compound obtained in reference example 1A (0.18 g, 0.9 mmol) was added to a mixture of the compound obtained in reference example 17 (0.2 g, 0.9 mmol) and DIEA (0.16 g, 0.9 mmol) in EtOH (4 mL) and the resulting mixture was heated in a sealed tube at 100 C for 24 hours. It was allowed to cool and the solvent was evaporated to dryness. The crude product obtained was purified bychromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing 0.19 g of the desired compound (yield: 56%). LC-MS (Method 2): tR = 2.53 min; m/z = 386 (MH+).

References: [1]Patent: WO2009/68512,2009,A1 .Location in patent: Page/Page column 59-60.

25
[ 1027332-70-2 ]
[ 392338-15-7 ]
C₂₃H₃₁N₅O₂ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6547 - 6557.

26
[ 1188283-74-0 ]
[ 392338-15-7 ]
[ 1188283-83-1 ]

Yield	Reaction Conditions	Operation in experiment
82%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 80℃;	REFERENCE EXAMPLE 8a(R)-tert-Butyl 1-(2-amino-7-isopropylfuro[3,2-c(]pyrimidin-4-yl)pyrrolidin-3- yl(methyl)carbamate; To a suspension of the compound obtained in reference example 6d (1.3 g, 6.7 mmol) in acetonitrile (26 mL), triethylamine (26 mL), PyBOP (3.85 g, 7.4 mmol) and reference example 1 (2.15 g, 10.8 mmol) were added. The resulting suspension was heated at 80 0C overnight. The solvent was evaporated to dryness and the residue was diluted with dichloromethane and water. pH was adjusted to 9-10 with 1 N NaOH and the phases were separated. The aqueous phase was extracted again with dichloromethane, and the combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using EtOAc as eluent, to afford 2.08 g of the desired compound (yield: 82%)LC-MS (Method 2): tR = 2.39 min; m/z 376 (MH+).

References: [1]Patent: WO2009/115496,2009,A1 .Location in patent: Page/Page column 85.

27
[ 1187305-58-3 ]
[ 392338-15-7 ]
[ 1187305-67-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile; at 150℃; for 0.166667h;Microwave irradiation;	A microwave reaction vessel was charged with Example 1D (40 mg, 0.11 mmol), Example 1F (45 mg, 0.16 mmol), acetonitrile (3 mL), and triethylamine (0.1 mL), then the mixture was heated under microwave irradiation at 150 C. for 10 minutes. The mixture was cooled to ambient temperature and concentrated under reduced pressure, and the resulting residue was chromatographed on silica gel (100% EtOAc to 95-5 MeOH/EtOAc, eluant) to provide the title product.

References: [1]Patent: US2009/233904,2009,A1 .Location in patent: Page/Page column 78.

28
trans-2-amino-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-4-yl 4-nitrobenzenesulfonate [ No CAS ]
[ 392338-15-7 ]
tert-butyl (3R)-1-[trans-2-amino-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-4-yl]pyrrolidin-3-yl(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; at 80℃;	Example 16A tert-butyl (3R)-1-[trans-2-amino-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-4-yl]pyrrolidin-3-yl(methyl)carbamate In a capped vial, a mixture of the product of Example 12C (100 mg, 0.25 mmol), <strong>[392338-15-7](R)-tert-butyl methyl(pyrrolidin-3-yl)carbamate</strong> (74 mg, 0.37 mmol), triethylamine (0.12 mL, 0.88 mmol) and ethanol (0.5 mL) was heated overnight at 80 C. The mixture was cooled and partitioned between 1 M sodium hydroxide (5 mL) and dichloromethane (25 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (25 mL). The combined dichloromethane layers were dried (magnesium sulfate), filtered, concentrated and chromatographed on an Analogix IntelliFlash 280 using a SF10-4 g column eluding with 9:1 (5 minutes), 9:1 to 0:1 (10 minutes) and 0:1 (10 minutes) dichloromethane:ethyl acetate to provide the title compound: 1H NMR (CDCl3) delta 0.97-1.21 (m, 2H), 1.22-1.42 (m, 4H), 1.47 (s, 9H), 1.67-2.18 (m, 8H), 2.49-2.75 (m, 3H), 2.80 and 2.83 (s and s, 3H), 3.34-3.44 (m, 1H), 3.46-3.73 (m, 2H), 3.89-3.99 (m, 1H), 4.50 (s, 2H); MS (DCl/NH3) m/z 402 (M+H)+.

References: [1]Patent: US2009/270364,2009,A1 .Location in patent: Page/Page column 30-31.

29
[ 1195073-42-7 ]
[ 392338-15-7 ]
[ 1195073-44-9 ]

Yield	Reaction Conditions	Operation in experiment
	at 160℃; for 1.5h;Microwave irradiation;	Example HE tert-butyi (3i?)-l-(2-amino-8-phenyl-5,6,7,8-tetrahydropyrazolo[3',4':6,71cyclohepta[l,2- ?pyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate A solution of the product from the Example 1 ID (20 mg, 0.45 mmol ) and (R)- methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester (12 mg, 0.6 mmol) was heated in a microwave at 160 0C for 1.5 hours. The reaction mixture was concentrated and chromatographed on silica gel, eluting with 5% methanol/dichloromethane to yield the title compound: 1H NMR (300 MHz, CDCl3) delta 8.26 (s, 1 H), 7.47 (m, 5 H), 4.63 (m, 2 H), 3.58 (m, 3 H), 2.90 (m, 4 H), 2.70 (m, 2 H), 2.06 (m, 4 H), 1.48 (m, 9 H); MS (ESI+) m/z 476 (M+H)+.

References: [1]Patent: WO2009/137492,2009,A1 .Location in patent: Page/Page column 65.

30
[ 1222956-10-6 ]
[ 392338-15-7 ]
[ 1222953-69-6 ]

Yield	Reaction Conditions	Operation in experiment
59%		To a suspension of the compound obtained in reference example 1 1 a (0.15 g, 0.72 mmol) in acetonitrile (8 ml_), triethylamine (4.4 ml_), PyBOP (0.49 g, 0.94 mmol) and reference example 1 (0.24 g, 1.16 mmol) were added. The resulting mixture was heated at 80 5C overnight. The reaction mixture was concentrated to dryness and the residue was diluted with water and EtOAc, pH was brought to basic with 1 N NaOH solution and the phases were separated. The aqueous phase was re-extracted with EtOAc, and the combined organic phases were dried over Na2SO4 and concentrated to dryness, providing the intermediate precursor. HCI (4 M solution in 1 ,4-dioxane, 5 ml_) and 1 ,4-dioxane (20 ml_) were added to this intermediate and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The residue was dissolved in water and washed twice with EtOAc, that was discarded. 1 N NaOH solution was added to the acidic aqueous phase until basic pH and it was extracted three times with chloroform. The combined organic phases were dried over anhydrous Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography over silica gel using mixtures of chloroform/MeOH/NH3 COnc of increasing polarity as eluent, providing 122.6 mg of the title compound (yield: 59%). LC-MS ( Method 2): tR = 1.19 min; m/z 290 (MH+).

References: [1]Patent: WO2010/43633,2010,A1 .Location in patent: Page/Page column 106.

31
[ 1222956-61-7 ]
[ 392338-15-7 ]
[ 1222954-90-6 ]

Yield	Reaction Conditions	Operation in experiment
24%		To a suspension of the compound obtained in reference example 18 (1.81 g, 8.79 mmol) in acetonitrile (64.5 mL), triethylamine (43 mL), PyBOP (5.95 g, 11.4 mmol) and reference example 1 (2.82 g, 14.1 mmol) were added. The resulting mixture was heated at 80 5C overnight. Additional reference example 1 (1.41 g, 7.04 mmol) and PyBOP (3 g, 5.76 mmol) were added and the mixture heated at 80Q C for another 24 hours. The reaction mixture was concentrated to dryness, the residue was diluted with 1 N NaOH solution and EtOAc, and the phases were separated. The aqueous phase was re-extracted with EtOAc, and the combined organic phases were dried over Na2SO4 and concentrated to dryness. The residue was purified by chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, providing the intermediate precursor. HCI (4 M solution in 1 ,4-dioxane, 30 ml_) and EtOH (15 ml_) were added to this intermediate and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness. The residue was dissolved in water and washed with EtOAc, that was discarded. 1 N NaOH solution was added to the acidic aqueous phase until basic pH and it was extracted three times with chloroform. The combined organic phases were dried over anhydrous Na2SO4 and concentrated to dryness. The crude product thus obtained was purified by chromatography over silica gel using mixtures of chloroform/MeOH/NH3 cone of increasing polarity as eluent, and then further purified by chromatography over neutral alumina gel using mixtures of EtOAc/MeOH/NH3 conc of increasing polarity as eluent, providing 607 mg of the title compound (yield: 24%). LC-MS (Method 2): tR = 0.97 min; m/z 288 (MH+).

References: [1]Patent: WO2010/43633,2010,A1 .Location in patent: Page/Page column 111-112.

32
[ 1115491-17-2 ]
[ 392338-15-7 ]
[ 1240421-97-9 ]

Yield	Reaction Conditions	Operation in experiment
79%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In acetonitrile;Reflux;	REFERENCE EXAMPLE 4a; Benzyl 4-(2-amino-6-((3/?)-3-(fert-butoxycarbonyl(methyl)amino)pyrrolidin-1- yl)pyrimidin-4-yl)piperidin-1-carboxylate; A mixture of the compound obtained in reference example 3 (2.0 g, 6.09 mmol), the amine obtained in reference example 1 (1.95 g, 9.7 mmol), PyBOP (4.1 g, 7.9 mmol), TEA (0,9 ml_) and acetonitrile (61 ml_) was heated at reflux overnight, and then further amount of compound obtained in reference example 1 (0.61 g) and PyBOP (1.6 g) were added and it was stirred at reflux for 2 further hours. The reaction mixture was concentrated to dryness and the residue was diluted with water and ethyl acetate and 2 N NaOH aqueous solution was added until basic pH. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with a saturated solution of NaCI, they were dried over anhydrous Na2SO4 and concentrated to dryness. The crude obtained was purified by chromatography over silica gel using EtOAc as eluent, providing 2.46 g of the desired compound (yield: 79%) LC-MS (Method 2): tR = 2.43 min; m/z 511 (MH+)

References: [1]Patent: WO2010/94721,2010,A1 .Location in patent: Page/Page column 70.

33
[ 1837-55-4 ]
[ 392338-15-7 ]
[ 1201176-22-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	In tetrahydrofuran; at 23℃; for 18h;Inert atmosphere;	Example 95: 5-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(2- methylpropyl)pyridazin-3-arnine. [1 -(delta-Chloro-pyridazin-^yO-pyrrolidin-S-yO-methyl-carbamic acid tert-butyl ester. A solution of 3,5-dichloropyridazine (149 mg, 1.0 mmol) in THF (3 ml_) at 23 0C was treated with (RJ-methyl-pyrrolidin-S-yl-carbamic acid tert-butyl ester (440 mg, 2.2 mmol) and the reaction stirred at 23 0C for 18 h. The reaction diluted with EtOAc (30 ml) and solution washed with water (2 x 5 ml) and combined organic solution dried and concentrated and crude material purified on 16 g SiO2 (O to 30% EtOAc : Hex) to yield 283 mg (91 % yield) of the desired regioisomer and 17 mg (5% yield) of the undesired regioisomer. MS (ESI): mass calcd. for Ci4H2iCIN4O2, 312.5 m/z found, 313.5 [M+H]+. [1 -(delta-lsobutylamino-pyhdazin^-yO-pyrrolidin-S-yO-methyl-carbamic acid tert- butyl ester. A solution of [1-(6-chloro-pyhdazin-4-yl)-pyrrolidin-3-yl]-methyl- carbamic acid tert-butyl ester (32 mg, 0.1 mmol) in isobutylamine (1.0 ml) in a sealed tube was heated to 120 0C for 72 h. The resulting solution was purified directly on 12 g SiO2 (0 to 5% NH3/Me0H:CH2CI2) to yield 20 mg (55% yield). lsobutyl-[5-(3-methylamino-pyrrolidin-1 -yl)-pyhdazin-3-yl]-amine dihydrochlohde. To a stirring solution of [1-(6-isobutylamino-pyhdazin-4-yl)- pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (19 mg, 0.06 mmol) in 96% formic acid (0.5 ml_) was added 0.05 ml of aqueous 6N HCI. The mixture was stirred for 2 hr, diluted with MeOH and concentrated under reduced pressure (repeat 3X) to give the desired product as a white solid (101 mg, >99%). MS (ESI): mass calcd. for Ci3H23N5, 249.4 m/z found, 250.2 [M+H]. 1H NMR (400 MHz, CD3OD): 8.12 (d, J = 2.5, 1 H), 6.08 (s, 1 H), 4.1 1 - 4.01 (m, 1 H), 4.04 - 3.47 (m, 4H), 3.35 (s, 1 H), 3.15 (d, J = 7.0, 2H), 2.82 (s, 3H), 2.65 - 2.53 (m, 1 H), 2.43 - 2.31 (m, J = 5.6, 1 H), 1.96 (dt, J = 13.4, 6.7, 1 H), 1.03 (d, J = 6.7, 6H).

References: [1]Patent: WO2009/152325,2009,A1 .Location in patent: Page/Page column 81.
[2]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 956 - 959.

34
[ 24424-99-5 ]
[ 392338-15-7 ]

References: [1]Patent: WO2011/76878,2011,A1 .
[2]Patent: WO2009/115496,2009,A1 .

35
[ 1313412-62-2 ]
[ 392338-15-7 ]
[ 1313412-63-3 ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; In ethanol;Reflux;	REFERENCE EXAMPLE 6a(R)-ferf-Butyl 1-(2-amino-6-(benzyloxymethyl)pyrimidin -yl)pyrrolidin-3-yl(methyl)carbamateA mixture of the compound obtained in reference example 5 (6.37 g, 25.5 mmol), the compound obtained in reference example 1 (5.11 g, 25.5 mmol) and DIPEA (4.4 mL, 25.5 mmol) in EtOH (64 mL) was heated at reflux overnight. The reaction mixture was evaporated to dryness and the residue was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing 6.61 g of the title compound (yield: 63%),LC-MS (Method 2): R = 2.32 min; m/z 414 (MH+).

References: [1]Patent: WO2011/76878,2011,A1 .Location in patent: Page/Page column 53.

Historical Records

Technical Information

• Acyl Group Substitution • Bouveault-Blanc Reduction • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Catalytic Hydrogenation • Chan-Lam Coupling Reaction • Complex Metal Hydride Reductions • Ester Cleavage • Hydride Reductions • Lawesson's Reagent • Leuckart-Wallach Reaction • Mannich Reaction • Petasis Reaction • Preparation of Amines • Reactions of Amines • Reactions with Organometallic Reagents • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Ketenes • Specialized Acylation Reagents-Vilsmeier Reagent • Ugi Reaction

Related Functional Groups of
[ 392338-15-7 ]

Amides

A137902 [454712-26-6]

tert-Butyl 3-(methylamino)pyrrolidine-1-carboxylate

Similarity: 1.00

A138042 [172478-00-1]

tert-Butyl methyl(pyrrolidin-3-yl)carbamate

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A145018 [169750-01-0]

(S)-tert-Butyl methyl(pyrrolidin-3-yl)carbamate

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A200376 [1004538-33-3]

(R)-1-Boc-3-(Dimethylamino)pyrrolidine

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A898773 [199336-83-9]

tert-Butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate

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Amines

A137902 [454712-26-6]

tert-Butyl 3-(methylamino)pyrrolidine-1-carboxylate

Similarity: 1.00

A138042 [172478-00-1]

tert-Butyl methyl(pyrrolidin-3-yl)carbamate

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A145018 [169750-01-0]

(S)-tert-Butyl methyl(pyrrolidin-3-yl)carbamate

Similarity: 1.00

A200376 [1004538-33-3]

(R)-1-Boc-3-(Dimethylamino)pyrrolidine

Similarity: 1.00

A898773 [199336-83-9]

tert-Butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate

Similarity: 1.00

Related Parent Nucleus of
[ 392338-15-7 ]

Pyrrolidines

A137902 [454712-26-6]

tert-Butyl 3-(methylamino)pyrrolidine-1-carboxylate

Similarity: 1.00

A138042 [172478-00-1]

tert-Butyl methyl(pyrrolidin-3-yl)carbamate

Similarity: 1.00

A145018 [169750-01-0]

(S)-tert-Butyl methyl(pyrrolidin-3-yl)carbamate

Similarity: 1.00

A200376 [1004538-33-3]

(R)-1-Boc-3-(Dimethylamino)pyrrolidine

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A898773 [199336-83-9]

tert-Butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate

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