[ CAS No. 149771-44-8 ]

Name: 149771-44-8|tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate|96%
Brand: Ambeed
SKU: A136543
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Quality Control of [ 149771-44-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 149771-44-8 ]

CAS No. :	149771-44-8	MDL No. :	MFCD17016708
Formula :	C₁₁H₂₀N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HNINFCBLGHCFOJ-UHFFFAOYSA-N
M.W :	212.29	Pubchem ID :	15740908
Synonyms :

Calculated chemistry of [ 149771-44-8 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.91
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	66.0
TPSA :	41.57 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.83 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.68
Log Po/w (XLOGP3) :	1.08
Log Po/w (WLOGP) :	0.6
Log Po/w (MLOGP) :	1.15
Log Po/w (SILICOS-IT) :	0.65
Consensus Log Po/w :	1.23

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.64
Solubility :	4.88 mg/ml ; 0.023 mol/l
Class :	Very soluble
Log S (Ali) :	-1.54
Solubility :	6.05 mg/ml ; 0.0285 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.37
Solubility :	8.97 mg/ml ; 0.0423 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.73

Safety of [ 149771-44-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 149771-44-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 149771-44-8 ]
Downstream synthetic route of [ 149771-44-8 ]

[ 149771-44-8 ] Synthesis Path-Upstream 1~11

1
[ 149771-43-7 ]
[ 149771-44-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrogen In ethanol	3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (Intermediate); A mixture of 3-benzyl-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid te/if-butyl ester (13.0 g, 43.0 mmol), palladium on carbon (4.0 g, 5percent) and ethanol (100 ml, 99percent) was stirred under hydrogen. The mixture was filtered on celite, dried and evaporated. A white powder was isolated. Yield 8.4 g (92percent). Mp 103.4-106°C.

Reference： [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 5, p. 674 - 681
[2] Patent: US2002/128271, 2002, A1,
[3] Patent: EP1213289, 2002, A1, . Location in patent: Page 13
[4] Patent: WO2006/106090, 2006, A1, . Location in patent: Page/Page column 16
[5] Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902
[6] Farmaco, 1993, vol. 48, # 3, p. 387 - 396
[7] Farmaco, 1998, vol. 53, # 8-9, p. 557 - 562
[8] Patent: US9404081, 2016, B2, . Location in patent: Page/Page column 179

2
[ 824982-19-6 ]
[ 149771-44-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate In methanol; water at 20℃; for 16 h;	EXAMPLE 1I 3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic Acid Tert-Butyl Ester To the product of Example 1H (2.0 g, 6.5 mmol) in 57 mL CH₃OH and 11 mL H₂O was added 2.8 g K₂CO₃ (20.3 mmol). The mixture stirred for 16 h at ambient temperature then was filtered, concentrated under reduced pressure and purified via column chromatography (SiO₂, 50percent hexanes-EtOAc) to give 1.2 g of the title compound (5.65 mmol, 87percent yield). MS (DCI/NH₃) m/z 213 (M+H)⁺.
87%	With water; potassium carbonate In methanol at 20℃; for 16 h;	Example 1I 3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester To the product of Example 1H (2.0 g, 6.5 mmol) in 57 mL CH₃OH and 11 mL H₂O was added 2.8 g K₂CO₃ (20.3 mmol). The mixture stirred for 16 h at ambient temperature then was filtered, concentrated under reduced pressure and purified via column chromatography (SiO₂, 50percent hexanes-EtOAc) to give 1.2 g of the title compound (5.65 mmol, 87percent yield). MS (DCl/NH₃) m/z 213 (M+H)⁺.

Reference： [1] Patent: US2005/65178, 2005, A1, . Location in patent: Page/Page column 18
[2] Patent: US2005/101602, 2005, A1, . Location in patent: Page/Page column 26
[3] Patent: US2005/9841, 2005, A1, . Location in patent: Page/Page column 15
[4] Patent: US2005/80095, 2005, A1, . Location in patent: Page/Page column 17

3
[ 67571-90-8 ]
[ 149771-44-8 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902
[2] Farmaco, 1998, vol. 53, # 8-9, p. 557 - 562
[3] Journal of Medicinal Chemistry, 1998, vol. 41, # 5, p. 674 - 681
[4] Farmaco, 1993, vol. 48, # 3, p. 387 - 396
[5] Patent: US9404081, 2016, B2,

4
[ 24424-99-5 ]
[ 149771-44-8 ]

Reference： [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 5, p. 674 - 681
[2] Farmaco, 1993, vol. 48, # 3, p. 387 - 396

5
[ 54221-37-3 ]
[ 149771-44-8 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902
[2] Patent: US9404081, 2016, B2,

6
[ 52321-06-9 ]
[ 149771-44-8 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902
[2] Patent: US9404081, 2016, B2,

7
[ 96483-83-9 ]
[ 149771-44-8 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902
[2] Patent: US9404081, 2016, B2,

8
[ 37061-44-2 ]
[ 149771-44-8 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902
[2] Patent: US9404081, 2016, B2,

9
[ 24424-99-5 ]
[ 67571-90-8 ]
[ 149771-44-8 ]

Reference： [1] Patent: WO2006/106090, 2006, A1,

10
[ 1384448-78-5 ]
[ 149771-44-8 ]

Reference： [1] Patent: US9404081, 2016, B2,

11
[ 100-52-7 ]
[ 149771-44-8 ]
[ 149771-43-7 ]

Reference： [1] Patent: US9404081, 2016, B2, . Location in patent: Page/Page column 179

[ 149771-44-8 ] Synthesis Path-Downstream 1~68

1
[ 149771-43-7 ]
[ 149771-44-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	Pd(OH)2-C; In methanol;	G. tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate A mixture of tert-butyl 3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, Pd(OH)2-C (1.1 g) in MeOH (22 mL) was stirred under hydrogen atmosphere (4 atm) for 10 h at room temperature. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give a product (1.45 g, 94%) as a white solid. This product was used for next step without purification.
92%	With hydrogen;5%-palladium/activated carbon; In ethanol;	3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (Intermediate); A mixture of 3-benzyl-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid te/if-butyl ester (13.0 g, 43.0 mmol), palladium on carbon (4.0 g, 5%) and ethanol (100 ml, 99%) was stirred under hydrogen. The mixture was filtered on celite, dried and evaporated. A white powder was isolated. Yield 8.4 g (92%). Mp 103.4-106C.
	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 4h;	To a stirred solution of compound LXVIII (0.00028 mol, 85 mg) in MeOH (5 mL) was hydrogenated with 10% Pd-C (15 mg) for 4 h at room temperature. After completion of the reaction (checked by TLC), the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 60-120 mesh; MeOH-DCM, 1:9) to afford Compound LXIX in 85% yield.

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 674 - 681
[2]Patent: US2002/128271,2002,A1
[3]Patent: EP1213289,2002,A1 .Location in patent: Page 13
[4]Patent: WO2006/106090,2006,A1 .Location in patent: Page/Page column 16
[5]Tetrahedron Letters,2002,vol. 43,p. 899 - 902
[6]Il Farmaco,1993,vol. 48,p. 387 - 396
[7]Il Farmaco,1998,vol. 53,p. 557 - 562
[8]Patent: US9404081,2016,B2 .Location in patent: Page/Page column 179

2
[ 501-53-1 ]
[ 149771-44-8 ]
[ 415979-31-6 ]
[ 67571-90-8 ]

Yield	Reaction Conditions	Operation in experiment
		3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid, phenylmethyl ester and 3-(phenylmethyl)-3,8-diazabicyclo[3.2.1]octane. Triethylamine (1.44 mL, 10.363 mmol) was added to a solution of 8-boc-3,8-diaza-bicyclo[3.2.1]ocatane (2.0 g, 9.421 mmol) in CH2Cl2 (20 mL), Benzyl chloroformate (1.46 mL, 10.363 mmol) was added dropwise at 0 C. and the reaction mixture was stirred at 0 C. for 0.5 hr, then allowed to warm to rt. and stirring was continued for 3 days. The reaction mixture was then quenched with water and acidified with 1N HCl solution. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to give a colorless thick oil as the crude product. 70 mg of this material was then dissolved in 1,2-dichloroethane (2 mL) and TFA (0.5 mL) was added. The reaction mixture was stirred at rt. for 2 hr. The solvent and TFA were then evaporated to give a mixture of the two title compounds as a colorless thick oil.
		Intermediates 29 and 30; <n="70"/>3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid, phenylmethyl ester and 3- (phenylmethyl)-3,8-diazabicyclo [3.2.1] octane. Triethylamine (1.44 mL, 10.363 mmol) was added to a solution of 8-boc-3,8-diaza-bicyclo[3.2. l]ocatane (2.0 g, 9.421 mmol) in CH2CI2 (20 mL), Benzyl chloroformate (1.46 mL, 10.363 mmol) was added dropwise at 00C and the reaction mixture was stirred at 00C for 0.5 hr, then allowed to warm to rt. and stirring was continued for 3 days. The reaction mixture was then quenched with water and acidified with IN HCl solution. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to give a colorless thick oil as the crude product. 70 mg of this material was then dissolved in 1,2- dichloroethane (2mL) and TFA (0.5 mL) was added. The reaction mixture was stirred at rt. for 2 hr. The solvent and TFA were then evaporated to give a mixture of the two title compounds as a colorless thick oil.

Reference： [1]Patent: US2007/270405,2007,A1 .Location in patent: Page/Page column 50
[2]Patent: WO2009/67108,2009,A1 .Location in patent: Page/Page column 68-69

3
[ 149771-44-8 ]
(+/-)-3-[[8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxycycloprop[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid 1,1-dimethylethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%		EXAMPLE 2; 3,8-Diazabicyclo[3.2.1]octane-8-carboxylic acid, 3-[[8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxycycloprop[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl]carbonyl]-1,1-dimethylethyl ester, (+/-)-. TBTU (131 mg, 0.408 mmol) and DIPEA (0.237 mL, 1.36 mmol) were added to a solution of (+/-) cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid, 8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy- (150 mg, 0.272 mmol) in DMSO (4.0 mL). The reaction mixture was stirred at rt for 15 min. 8-Boc-3,8-diaza-bicyclo[3.2.1]octane (86.7 mg, 0.408 mmol) was then added and the reaction mixture was stirred at rt overnight. It was then concentrated and the residue was purified by preparative reverse phase HPLC to give the title product as a light yellow solid, (110 mg, 54% yield). MS m/z 746(MH+), Retention time: 3.040 min. 1H NMR (300 MHz, MeOD) delta ppm 0.17 (m, 0.25 H) 1.08 (m, 0.25 H) 1.17-2.28 (m, 24.5 H) 2.38-3.12 (m, 8 H) 3.43-4.43 (m, 10 H) 4.76-4.85 (m, 0.25 H) 4.96-5.19 (m, 0.75 H) 7.02 (dd, J=8.60, 2.38 Hz, 1 H) 7.17 (d, J=2.19 Hz, 0.25 H) 7.20 (d, J=2.20 Hz, 0.75 H) 7.26-7.39 (m, 1 H) 7.49-7.70 (m, 1 H) 7.80-8.00 (m, 1.75 H) 8.12 (s, 0.25 H).

Reference： [1]Patent: US2007/270405,2007,A1 .Location in patent: Page/Page column 53

4
[ 501-53-1 ]
[ 149771-44-8 ]
[ 415979-30-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In dichloromethane; at 20℃; for 22h;	INTERMEDIATE 61; 3-Benzyl 8-tert-butyl 3,8-diazabicyclo[3.2.11octane-3,8-dicarboxylate; A mixture of 8-ter/~butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane (238 mg, 1.12 mmol), benzyl chloroformate (160 muL, 1.12 mmol) and triethylamine (280 muL, 2.0 mmol) in DCM (20 mL) was stirred at room temperature for 22 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (25 mL). The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo to give the title compound(336 mg, 87%) as a clear oil. deltaH (DMSO-d6) 7.45-7.28 (5H, m), 5.17-5.03 (2H, m), 4.18- 4.06 (2H, m), 3.79-3.69 (2H, m), 3.10-2.90 (2H, m), 1.85-1.72 (2H, m), 1.60-1.49 (2H, m), 1.41 (9H, s).

Reference： [1]Patent: WO2007/141504,2007,A1 .Location in patent: Page/Page column 68
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 1855 - 1879

5
[ 1012317-17-7 ]
[ 149771-44-8 ]
C₂₇H₃₃F₂N₇O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.666667h;	The 4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(2-difluoromethylbenzimidazol-l-yl)- 6-morpholinopyrimidine used as a starting material was prepared as follows :-; A mixture of 4-chloro-2-(2-difluoromethylbenzimidazol- 1 -yl)-6-morpholinopyrimidine (0.15 g), f°rt-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.109 g), sodium carbonate (0.071 g) and DMF (4 ml) was heated to 1000C under nitrogen in a sealed vessel in a microwave oven for 40 minutes. The reaction mixture was cooled to ambient temperature and diluted with water (50 ml). The resultant solid was isolated by filtration. There was thus obtained 4-(8-tert-butoxycarbonyl-3 ,8-diazabicy clo [3.2.1 ]oct-3 -yl)- 2-(2-difluoromethylbenzimidazol-l-yl)-6-morpholinopyrimidine which was used without further purification.

Reference： [1]Patent: WO2008/32064,2008,A1 .Location in patent: Page/Page column 101

6
[ 54221-37-3 ]
[ 149771-44-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: toluene / 85 °C 2: xylene / Heating 3: 230 °C 4: H₂; HCl / Pd/C / H₂O / 85 h / 760 Torr 5: LiAlH₄ / diethyl ether / Heating 6: CH₂Cl₂ / 20 °C 7: 72 percent / H₂ / Pd/C / methanol / 760 Torr
	Multi-step reaction with 7 steps 1: toluene / 16 h / 85 °C 2: 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Inert atmosphere; Reflux 3: 3 h / 210 - 220 °C / 760.05 Torr 4: hydrogenchloride; palladium 10% on activated carbon; hydrogen / methanol; water / 4 h / 20 °C 5: lithium aluminium tetrahydride / diethyl ether / 30 h / 0 - 20 °C / Inert atmosphere 6: dichloromethane / 16 h / 20 °C 7: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C

Reference： [1]Smith, Stephen C; Bentley, Philip D [Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902]
[2]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US9404081, 2016, B2

7
[ 67571-90-8 ]
[ 149771-44-8 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 899 - 902
[2]Il Farmaco,1998,vol. 53,p. 557 - 562
[3]Journal of Medicinal Chemistry,1998,vol. 41,p. 674 - 681
[4]Il Farmaco,1993,vol. 48,p. 387 - 396
[5]Patent: US9404081,2016,B2

8
[ 96424-68-9 ]
[ 149771-44-8 ]
[ 201162-50-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 120℃; for 48h;	tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (435 mg, 2.26 mmol), <strong>[96424-68-9]2-bromo-3-chloropyridine</strong> (400 mg, 1.88 mmol), and potassium carbonate (390 mg, 2.83 mmol) were combined in dry dimethylformamide (10 mL) and stirred at 120 C. for 48 hours. The mixture was allowed to cool room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (85:15 hexanes:ethyl acetate) to provide the title compound. MS (ESI) m/z: 268 (100%), 324.0 (M+H)+; 1H NMR (CDCl3) delta 1.48 (s, 9H), 1.92 (m, 2H), 2.07 (m, 2H), 3.13 (d, 2H), 3.59 (br, 2H), 4.30 (br, 2H), 6.84 (dd, 1H), 7.58 (dd, 1H), 8.17 (dd, 1H).
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 120℃; for 48h;	Example 23J tert-butyl 3-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (435 mg, 2.26 mmol), <strong>[96424-68-9]2-bromo-3-chloropyridine</strong> (400 mg, 1.88 mmol), and potassium carbonate (390 mg, 2.83 mmol) were combined in dry dimethylformamide (10 mL) and stirred at 120 C. for 48 hours. The mixture was allowed to cool room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (85:15 hexanes:ethyl acetate) to provide the title compound. MS (ESI) m/z: 268 (100%), 324.0 (M+H)+; 1H NMR (CDCl3) delta1.48 (s, 9H), 1.92 (m, 2H), 2.07 (m, 2H), 3.13 (d, 2H), 3.59 (br, 2H), 4.30 (br, 2H), 6.84 (dd, 1H), 7.58 (dd, 1H), 8.17 (dd, 1H).

Reference： [1]Patent: US2005/9841,2005,A1 .Location in patent: Page/Page column 15
[2]Patent: US2005/80095,2005,A1 .Location in patent: Page/Page column 17

9
[ 20375-65-9 ]
[ 149771-44-8 ]
[ 848591-63-9 ]

Yield	Reaction Conditions	Operation in experiment
22%	With caesium carbonate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 85℃; for 72h;	EXAMPLE 1J 3-(6-Phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic Acid Tert-Butyl Ester To the product of Example 11 (1.2 g, 5.65 mmol) in 50 mL toluene was added <strong>[20375-65-9]3-chloro-6-phenylpyridazine</strong> (Aldrich, 1.62 g, 8.48 mmol), 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (Strem, 0.144 g, 0.34 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, Strem, 0.104 g, 0.113 mmol), and Cs2CO3 (2.03 g, 6.2 mmol). This mixture was degassed three times with N2 backflushing then was warmed to 85 C. and stirred for 72 h. The reaction was cooled to ambient temperature, filtered, concentrated under reduced pressure and purified via column chromatography (SiO2, 50% hexanes-EtOAc) to give 0.45 g of the title compound (1.2 mmol, 22% yield). MS (DCI/NH3) m/z 367 (M+H)+.
	With 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride; caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 85℃; for 12 - 72h;	Method (A): The bicyclic secondary amine (5 mmol) was combined with <strong>[20375-65-9]3-chloro-6-phenylpyridazine</strong> (Aldrich, 7.5 mmol) in toluene (50 mL). Cesium carbonate (5.5 mmol), 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (Strem, 0.3 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, Strem, 0.2 mmol) were added, and the mixture was evacuated, then purged with N2 (three times). The mixture was warmed under N2 to 85 C. for 12-72 h. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide respective aminopyridazine.

Reference： [1]Patent: US2005/65178,2005,A1 .Location in patent: Page/Page column 18
[2]Patent: US2005/101602,2005,A1 .Location in patent: Page/Page column 37; 38

10
[ 824982-19-6 ]
[ 149771-44-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate; In methanol; water; at 20℃; for 16h;	EXAMPLE 1I 3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic Acid Tert-Butyl Ester To the product of Example 1H (2.0 g, 6.5 mmol) in 57 mL CH3OH and 11 mL H2O was added 2.8 g K2CO3 (20.3 mmol). The mixture stirred for 16 h at ambient temperature then was filtered, concentrated under reduced pressure and purified via column chromatography (SiO2, 50% hexanes-EtOAc) to give 1.2 g of the title compound (5.65 mmol, 87% yield). MS (DCI/NH3) m/z 213 (M+H)+.
87%	With water; potassium carbonate; In methanol; at 20℃; for 16h;	Example 1I 3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester To the product of Example 1H (2.0 g, 6.5 mmol) in 57 mL CH3OH and 11 mL H2O was added 2.8 g K2CO3 (20.3 mmol). The mixture stirred for 16 h at ambient temperature then was filtered, concentrated under reduced pressure and purified via column chromatography (SiO2, 50% hexanes-EtOAc) to give 1.2 g of the title compound (5.65 mmol, 87% yield). MS (DCl/NH3) m/z 213 (M+H)+.
	With ammonia; water; In methanol; at 20℃;	tert-Butyl 3-(trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.54 mmol) in methanol (85 mL) was treated with ammonium hydroxide (8.5 mL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure and purified by chromatography on silica gel (5% MeOH, 0.5% NH4OH in CH2Cl2; then 10% MeOH, 1% NH4OH in CH2Cl2) to provide the title compound. MS (DCI/NH3) m/z: 213 (M+H)+; 1H NMR (CDCl3) delta 1.47 (s, 9H), 1.81 (m, 2H), 1.94 (m, 2H), 2.65 (dd, 2H), 3.00 (br, 2H), 4.11 (br, 2H).

With ammonium hydroxide; In methanol; at 20℃;

Example 23I tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-(trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.54 mmol) in methanol (85 mL) was treated with ammonium hydroxide (8.5 mL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure and purified by chromatography on silica gel (5% MeOH, 0.5% NH4OH in CH2Cl2; then 10% MeOH, 1% NH4OH in CH2Cl2) to provide the title compound. MS (DCI/NH3) m/z: 213 (M+H)+; 1H NMR (CDCl3) delta 1.47 (s, 9H), 1.81 (m, 2H), 1.94 (m, 2H), 2.65 (dd, 2H), 3.00 (br, 2H), 4.11 (br, 2H).

Reference： [1]Patent: US2005/65178,2005,A1 .Location in patent: Page/Page column 18
[2]Patent: US2005/101602,2005,A1 .Location in patent: Page/Page column 26
[3]Patent: US2005/9841,2005,A1 .Location in patent: Page/Page column 15
[4]Patent: US2005/80095,2005,A1 .Location in patent: Page/Page column 17

11
N-[5-chloro-1-(2-ethoxyethyl)-3-methoxymethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-methylpyridin-2-ylamine [ No CAS ]
[ 149771-44-8 ]
tert-butyl 3-[1-(2-ethoxyethyl)-3-methoxymethyl-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 18h;	The MONOCHLORO compound of preparation 159 (100MG, 0. 27MOL), tert-butyl 3, 8-diazabicyclo [3.2. 1] octane-8-carboxylate (Tet. Lett. 43 (2002), 899-902) (229mg, 1. 08MMOL) and N-ETHYIDIISOPROYLAMINE (232, UL, 1. 33mmol) were dissolved in DIMETHYLSULFOXIDE (3mL) and the reaction mixture heated to 120C for 18 hours in a sealed vessel. The reaction mixture was diluted with dichloromethane and washed with water (x2), 10% aqueous citric acid solution and brine. The organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with DICHLOROMETHANE : methanol (100: 0 to 95: 5) to yield the title product. 1H NMR (CD30D, 400MHZ) 8 : 1.11 (t, 3H), 1.50 (s, 9H), 1.79 (m, 2H), 1.92 (m, 2H), 2.39 (s, 3H), 3.14 (m, 2H), 3.43 (s, 3H), 3.58 (q, 2H), 3.87 (t, 2H), 4.33 (m, 2H), 4.39 (m, 2H), 4.67 (m, 4H), 6.91 (d, 1H), 8.13 (d, 1H), 8.18 (s, 1H). LRMS: M/Z APCI+ 553 [MH] +

Reference： [1]Patent: WO2004/96810,2004,A1 .Location in patent: Page 236-237

12
N-[5-chloro-3-methyl-1-(2-propoxyethyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-6-methylpyridin-2-ylamine [ No CAS ]
[ 149771-44-8 ]
C₂₈H₄₀N₈O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With cesium fluoride; In dimethyl sulfoxide; at 110℃; for 18h;	A mixture of the chloro compound from preparation 171 (150mg, 0. 42MOL), TERT-BUTYL 3, 8-DIAZABICYCLO [3.2. 1] OCTANE-8-CARBOXYLATE (Tet. Lett. 43 (2002), 899- 902) (446mg, 2. 1 MMOL), and caesium fluoride (63. 8mg, 0. 42MMOL) in dimethylsulfoxide (3mL) was heated at 110C for 18 hours in a sealed vessel. The reaction was poured into water, and the resulting precipitate filtered off. This solid was dissolved in dichloromethane, and the solution evaporated in vacuo. The solid was REDISSOLVED in DICHLOROMETHANE (6mL), trifluoroacetic acid (2mL) added, and the solution stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue partitioned between DICHLOROMETHANE and 2N hydrochloric acid and the layers separated. The aqueous solution was basified using solid sodium carbonate and then extracted with DICHLOROMETHANE (3x). These organic extracts were dried over magnesium sulphate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using an elution gradient of DICHLOROMETHANE : methanol : 0.88 ammonia (100: 0: 0 to 98: 2: 0.25) to give the title compound as a yellow solid, 65mg. H NMR (CD30D, 400MHZ) 8 : 0.73 (t, 3H), 1.57 (m, 2H), 1.75-1. 86 (m, 4H), 2.40 (s, 3H), 2.44 (s, 3H), 3.11 (m, 2H), 3. 48 (t, 2H), 3.60 (m, 2H), 3.84 (t, 2H), 4.27 (m, 2H), 4.65 (t, 2H), 6.90 (d, 1H), 7.66 (m, 1H), 8.10 (BRD, 1H). LRMS: M/Z APCI+ 437 [MH] +

Reference： [1]Patent: WO2004/96810,2004,A1 .Location in patent: Page 155-156

13
C₁₇H₁₈ClF₃N₆O₂ [ No CAS ]
[ 149771-44-8 ]
C₂₈H₃₇F₃N₈O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 18h;	A mixture of the chloro compound from preparation 193 (150mg, 0. 35MMOL), ter-butyl 3, 8-DIAZABICYCLO [3.2. 1] OCTANE-8-CARBOXYLATE (J. Med. Chem. 1998,41, 674) (160mg, 0. 72MMOL) and N-ETHYIDIISOPROPYLAMINE (244RL, 1. 4MMOL) in DIMETHYLSULFOXIDE (3mL) were heated at 120C for 18 hours in a REACTIVIAL . The mixture was poured into water, and extracted with dichloromethane (2x). The combined organic fractions were washed with water, dried over magnesium sulphate and evaporated in vacuo The residual oil was dissolved in DICHLOROMETHANE (6mL), trifluoroacetic acid (2mL) added, and the solution stirred at room temperature 3 hours. The reaction was concentrated in vacuo, the residue partitioned between DICHLOROMETHANE and 2N hydrochloric acid and the layers separated. The aqueous phase was washed with DICHLOROMETHANE, then basified using solid sodium bicarbonate. This solution was extracted with dichloromethane (3x), these combined organic extracts dried over magnesium sulphate and evaporated in vacuo The crude product was purified by column chromatography on silica gel using an elution gradient of DICHLOROMETHANE : methanol : 0.88 ammonia (98: 2: 0.25 to 96: 4: 0.5) to afford the title compound as a yellow foam, 80MG. 1H NMR (CD30D, 400MHZ) 8 : 1.76-1. 84 (m, 4H), 2.39 (s, 3H), 3.15 (m, 2H), 3.42 (s, 3H), 3.59 (m, 2H), 4.02 (q, 2H), 4.10 (t, 2H), 4.28 (m, 2H), 4.68 (s, 2H), 4.77 (t, 2H), 6.92 (m, 1 H), 8.13 (m, 2H). LRMS: M/Z APCI 507 [MH] +

Reference： [1]Patent: WO2004/96810,2004,A1 .Location in patent: Page 165

14
[ 39856-50-3 ]
[ 149771-44-8 ]
[ 286946-26-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 10A tert-butyl 3-(6-nitro-3-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.4 g; 1.9 mmol), prepared as described in (J. Med. Chem., (1998) 41, 674), 5-bromo-2-nitropyridine (0.43 g; 2.27 mmol), prepared as described in (J. Am. Chem. Soc., (1945) 67, 668), and triethylamine (0.23 g; 2.27 mmol) in toluene (10 mL) were heated at reflux for 14 hours. After evaporation of the solvent, additional triethylamine (0.23 g) was added and the mixture further heated at 140 C for 2 hours. The residue was purified on SiO2 (CH2Cl2:EtOAc 9:1) to provide the title compound.
	With triethylamine; In dimethyl sulfoxide; at 110℃; for 16h;Inert atmosphere;	Step I tert-butyl 3-(6-nitro-3-pyridyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (1.00 g, 4.71 mmol, 1.00 equivalent) in dimethylsulfoxide (20.00 mL) were added triethylamine (1.43 g, 14.13 mmol, 3.00 equivalents) and 5-bromo-2-nitro-pyridine (1.15 g, 5.65 mmol, 1.20 equivalents). The mixture was stirred at 100C for 16 hours. LC/MS showed completion of the reaction. 40 mL of water was added to the mixture until the mixture was cooled to 20C. The aqueous phase was subjected to extraction using dichloromethane (50 mL2), washed with saturated brine (50 mL1), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by being beaten in methanol (2 mL*3) to give the title compound (639.00 mg, crude product) as a yellow solid. 1H NMR (400MHz, CDCl3) delta 8.18 (d, J = 9.2 Hz, 1H), 8.09 (d, J = 3.0 Hz, 1H), 7.15 (dd, J = 9.2 Hz, 3.0 Hz, 1H), 4.47 (br. s., 2H), 3.58 (d, J = 10.0 Hz, 2H), 3.27 (br. s., 2H), 2.12-1.99 (m, 2H), 1.86-1.76 (m, 2H), 1.49 (s, 9H). LC/MS (ESI) m/z: 335.2 (M+1).

Reference： [1]Patent: EP1147112,2003,B1 .Location in patent: Page/Page column 17-18
[2]Patent: EP3269715,2018,A1 .Location in patent: Paragraph 0061; 0248; 0249

15
C₁₈H₂₂ClNO₆S [ No CAS ]
[ 149771-44-8 ]
C₂₉H₄₀ClN₃O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; for 5h;	To a mixture of hydroxycarboxylic acid product from Step 5 (60 mg, 0.144mmol) and <strong>[149771-44-8]3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester</strong> (61 mg,0.29 mmol) in DCM (1.0 mL) was added BOP reagent (65 mg, 0.144 mmol) followedby N-methylmorpholine (47 pL, 0.43 mmol). The mixture was stirred at RT for 5 h.The mixture was quenched with brine, extracted with EtOAc and DCM. Combinedorganic phases were dried over magnesium sulfate and concentrated. The residue was purified by flash-chromatography over silica gel (eluted with 4% MeOH in DCM)to furnish 60 mg of hydroxyamide.

Reference： [1]Patent: WO2006/4880,2006,A2 .Location in patent: Page/Page column 112-113

16
[ 1722-12-9 ]
[ 149771-44-8 ]
[ 914807-96-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With triethylamine; In tetrahydrofuran; at 180℃; for 0.166667h;	3-Pyrimidin-2-yl-<strong>[149771-44-8]3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester</strong> A solution of 3,8-diaza-bicyclo[3,2,1]octane-8-carboxyli acid tert-butyl ester (50 mg, 0.24 mmol), 2-chloropyrimidine (27 mg, 0.24 mmol), triethylamine (0.1 ml, 0.72 mmol) and THF (2.5 ml) was heated at 180 C. for 10 minutes. The solution was concentrated to afford a solid residue that was dissolved in dichloromethane, which was washed sequentially with sat. aq. sodium bicarbonate and brine, dried (Na2SO4), filtered, and concentrated to afford 50 mg (71 %) of the product as a brown solid: 1H NMR (400 MHz, CDCl3): delta 8.30 (d, J=12.0 Hz, 2H), 6.52 (t, J=12.0 Hz, 1 H), 4.38-4.29 (m, 4H), 3.13 (sb, 2H), 2.42 (m, 2H), 1.69 (q, J=18.0 Hz, 2H), 1.49 (s, 9H); MS (M+1)=291.

Reference： [1]Patent: US2006/258672,2006,A1 .Location in patent: Page/Page column 21-22

17
[ 501-53-1 ]
[ 149771-44-8 ]
(1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane [ No CAS ]
3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid phenylmethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid, phenylmethyl ester and 3-(phenylmethyl)-3,8-diazabicyclo[3.2.1]octane. ; Triethylamine (1.44 mL, 10.363 mmol) was added to a solution of 8-boc-3,8-diaza-bicyclo[3.2.1]ocatane (2.0 g, 9.421 mmol) in CH2Cl2 (20 mL), Benzyl chloroformate (1.46 mL, 10.363 mmol) was added dropwise at 0 C. and the reaction mixture was stirred at 0 C. for 0.5 hr, then allowed to warm to rt. and stirring was continued for 3 days. The reaction mixture was then quenched with water and acidified with 1N HCl solution. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to give a colorless thick oil as the crude product. 70 mg of this material was then dissolved in 1,2-dichloroethane (2 mL) and TFA (0.5 mL) was added. The reaction mixture was stirred at rt. for 2 hr. The solvent and TFA were then evaporated to give a mixture of the two title compounds as a colorless thick oil.
	With triethylamine; In dichloromethane; at 0 - 20℃; for 72.5h;	Intermediate 14 and 15 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid, phenylmethyl ester and 3-(phenylmethyl)-3,8-diazabicyclo[3.2.1]octane. Triethylamine (1.44 mL, 10.363 mmol) was added to a solution of 8-boc-3,8-diaza-bicyclo[3.2.1]ocatane (2.0 g, 9.421 mmol) in CH2Cl2 (20 mL), Benzyl chloroformate (1.46 mL, 10.363 mmol) was added dropwise at 0 C. and the reaction mixture was stirred at 0 C. for 0.5 hr, then allowed to warm to rt. and stirring was continued for 3 days. The reaction mixture was then quenched with water and acidified with 1N HCl solution. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to give a colorless thick oil as the crude product. 70 mg of this material was then dissolved in 1,2-dichloroethane (2 mL) and TFA (0.5 mL) was added. The reaction mixture was stirred at rt. for 2 hr. The solvent and TFA were then evaporated to give a mixture of the two title compounds as a colorless thick oil.

Reference： [1]Patent: US2008/188458,2008,A1 .Location in patent: Page/Page column 32
[2]Patent: US2008/171015,2008,A1 .Location in patent: Page/Page column 23

18
[ 902148-42-9 ]
[ 149771-44-8 ]
3-[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo-[2,1-a][2]benzazepin-6-yl]-3,8-diazabicyclo[3.2.1]octane-8 carboxylic acid 1,1-dimethylester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With 2-(1H-9-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;	3,8-Diazabicyclo[3.2.1]octane-8-carboxylic acid, 3-[[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]carbonyl]-, 1,1-dimethylethyl ester. To a stirred solution of 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxamide-6-carboxylic acid (300 mg, 0.56 mmol), <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (150 mg, 0.71 mmol) and triethylamine (0.25 mL) in DMF (2.5 mL) was added HATU (250 mg, 0.66 mmol). The reaction mixture was stirred at rt for 1 h, diluted with H2O (10 mL), acidified with 1M HCl (aq.). (0.5 mL) and the precipitate was collected by filtration and flushed with H2O. The solids were dissolved into MeOH/DMF (1:1) and purified by preparative HPLC (CH3CN/H2O with 10 mM NH4OAc) to yield 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid, 3-[[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]carbonyl]-, 1,1-dimethylethyl ester (130 mg, 0.18 mmol, 32%) as a yellow solid. 1HNMR (300 MHz, CDCl3) delta 8.85 (br s, 1H), 8.08 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.03 (dd, J=2.6, 8.8 Hz, 1H), 6.86 (d, J=2.6 Hz, 1H), 6.75 (s, 1H), 5.25-5.00 (m, 1H), 4.49-4.01 (m, 3H), 3.88 (s, 3H), 3.35-2.90 (m, 2H), 3.03 (s, 6H), 2.86-2.72 (m, 1H), 2.12-1.12 (m, 16H), 1.41 (s, 9H). LCMS: m/e 730 (M-H)-, ret time 3.41 min, column A, 4 minute gradient.

Reference： [1]Patent: US2008/171015,2008,A1 .Location in patent: Page/Page column 29

19
[ 1013402-30-6 ]
[ 149771-44-8 ]
C₂₇H₃₃F₂N₇O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 90 - 105℃; for 1.25h;	The l-[6-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-morpholin-4-yl-pyrimidin-4-yl]-2-(difluoromethyl)benzoimidazole used as a starting material was prepared as follows:-; A mixture of l-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-2- (difluoromethyl)benzoimidazole (0.147 g), tert-bvyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.090 g), sodium bicarbonate (0.222 g) and DMF (2 ml) was heated under nitrogen to 90C for 15 minutes and then at 105C for 1 hour. The resultant mixture was cooled, filtered and evaporated. The residue was taken into dichloromethane (1.0 ml) and trifluoroacetic acid (1.0 ml), shaken at ambient temperature for 1 hour and evaporated. The residue was dissolved in methanol (5 ml), filtered and added to an Isolute SCX-3 cation exchange cartridge (5 g), followed by methanol (30 ml). The product was then eluted by addition of a 7M solution of ammonia in methanol (10 ml) and the eluent evaporated. There was thus obtained l-[6-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-morpholin-4-yl-pyrimidin-4-yl]-2- (difluoromethyl)benzoimidazole (0.15Og); Mass Spectrum: M+H+ 422. HPLC: method Al, Retention Time 2.11 minutes.

Reference： [1]Patent: WO2008/32033,2008,A1 .Location in patent: Page/Page column 95-96

20
[ 1618-36-6 ]
[ 149771-44-8 ]
[ 1116570-98-9 ]

Yield	Reaction Conditions	Operation in experiment
66%	With triethylamine; In isopropyl alcohol; at 180℃; for 0.5h;Microwave irradiation;	6.3. Example 3N-(3-bromophenyl)-3-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide A. Preparation of tert-butyl 3-(5-methyl-7H-pyrrolo [23-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a solution of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (25 mg, 0.15 mmol) and <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (30 mg, 0.14 mmol) in isopropanol (2 ml) was added triethylamine (36 muL, 0.26 mmol). The reaction was heated at 180 C. for 30 min in the microwave, then concentrated under vacuum. The residue was purified by prep HPLC (Sunfire C18 30×50 mm, 10-90% H2O/MeOH w/0.01% TFA, 15 min, 35 ml/min, 220 nm) to give tert-butyl 3-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 0.10 mmol, 66%).

Reference： [1]Patent: US2009/42893,2009,A1 .Location in patent: Page/Page column 8; 9

21
[ 1118-02-1 ]
[ 149771-44-8 ]
[ 1146692-36-5 ]

Yield	Reaction Conditions	Operation in experiment
99%		Step D: 3,8-Diaza-bicyclo[3.2.1]octane-3-carboxylic acid amide hydrochloride. A solution of <strong>[149771-44-8]3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester</strong> (2.5 g, 11.7 mmol) in CH2Cl2 (50 mL) was treated with trimethylsilyl isocyanate (14 mL, 117 mmol). The resultant mixture was stirred at rt for 4 h., concentrated and redissolved in CH2Cl2 (50 mL). To this solution was added HCl (4.0 N in 1,4-dioxane, 12 mL), and the resultant mixture was stirred at rt for 3 h. Concentration afforded the title compound as a white powder (2.4 g, 99%). MS (ESI): mass calcd. for C7H13N3O, 155.1; m/z found, 156.2 [M+H]+.

Reference： [1]Patent: US2009/111794,2009,A1 .Location in patent: Page/Page column 33

22
[ 149771-44-8 ]
[ 407-25-0 ]
[ 824982-19-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0℃; for 2h;	To a solution of <strong>[149771-44-8]3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester</strong> (212 mg, 1.0 mmol) in DCM (4 mL) were added triethylamine (208 muL, 1.5 mmol) and trifluoroacetic anhydride (169 muL, 1.2 mmol) at 0 C and the mixture stirred at 0 C for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue was purified by column chromatography to give 3-(2,2,2-trifluoro-acetyl)-3,8-diaza-bicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester as a colourless oil.
	With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;	Step 1: Into a 10 mL round bottom flask containing a solution of tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.33 mmol) in dichloromethane (2 mL) at 0 oC were added triethylamine (0.14 mL, 0.99 mmol) and trifluoroacetic anhydride (0.1 mL, 0.49 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was treated with water (3 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography (silica gel) eluting with 20-30% ethyl acetate in petroleum ether to afford tert-butyl 3-(2,2,2-trifluoroacetyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a liquid. MS calc?d [M-Boc+H]+ 209.1, found 209.4

Reference： [1]Patent: WO2009/53715,2009,A1 .Location in patent: Page/Page column 78
[2]Patent: WO2016/144847,2016,A1 .Location in patent: Page/Page column 79

23
[ 28920-43-6 ]
[ 149771-44-8 ]
[ 1225063-21-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; for 1h;	Step 1: 3-(9H-Fluoren-9-yl)methyl 8-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate[00682] A solution of <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (105 mg, 0.5 mmol) in dichloromethane (3 niL) and triethylamine (100 mg, 138 muL, 1.0 mmol) was treated with 9H-fluoren-9-ylmethyl carbonochloridate (128.0 mg, 0.5 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was washed with 1 N HCl, water, 50% saturated bicarbonate and brine. The organic layer was dried over Na2SO4, filtered and concentrated to obtain a solution of 3-(9H-fluoren-9-yl)methyl 8-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate in DCM (2 mL), which was used directly for the next step. LC/MS m/z 435.5 [M+H]+.
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25℃; for 10h;Inert atmosphere;	Intermediate M: Preparation of 3,8-Diaza-bicyclo[3.2.1]octane-3-carboxylic acid 9H- fluoren-9-ylmethyl ester · TFA (M) To a chilled solution of M-1 (1.00 g, 4.71 mmol) in DCM (50 mL) is added M-2 (1.22 g, 4.71 mmol) followed by DIPEA (900muL·, 5.17 mmol). After 10 h, the reaction is poured into water (100 mL) and extracted with DCM (100 mL). The organic layer is washed with 10% aqueous citric acid (100 mL), saturated aqueous NaHCC>3 (100 mL) and brine (100 mL), dried over MgS04, filtered and concentrated. The residue is purified on Si02 (0-50% EtOAc in heptane) to afford M-3. To a stirred solution of the M-3 (1.90 g, 4.37 mmol) in DCM (10 mL) is added TFA (10 mL). After 20 h, the mixture is concentrated to give the title product (M).

Reference： [1]Patent: WO2010/54398,2010,A1 .Location in patent: Page/Page column 195
[2]Patent: WO2015/9611,2015,A1 .Location in patent: Page/Page column 43

24
[ 59772-58-6 ]
[ 149771-44-8 ]
[ 1331846-76-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Step 1Preparation of 3-(6-Amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1 joctane-8- carboxy.ic acid tert-butyl ester. To a solution of 6-amino-pyridazine-3-carboxylic acid (212 mg, 1.0 mmol) in DMF (5 mL) was added 3,8-diaza-bicyclo[3.2.1 joctane-8- carboxylic acid tert-butyl ester (139 mg, 1.0 mmol), HATU (456 mg, 1.2 mmol) and N,N- diisopropylethylamine (0.52 mL, 3.0 mmol). The mixture was stirred at room temperature overnight after which it was diluted with EtOAc, washed with brine, dried over Na2S04, concentrated and purified over normal silica with 0-20% MeOH/DCM which gave a white solid (169 mg, 0.51 mmol). MS m/z 334.4 (M+H)+.

Reference： [1]Patent: WO2011/101409,2011,A1 .Location in patent: Page/Page column 165

25
[ 1403676-64-1 ]
[ 149771-44-8 ]
[ 1403676-76-5 ]

Yield	Reaction Conditions	Operation in experiment
95.7%	With triethylamine; In tetrahydrofuran; at 90℃; for 44h;Inert atmosphere; sealed tube;	To a solution of tert-bv yl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (67.1 mg, 0.316 mmol) and l-(trifluoromethyl)cyclobutyl lH-imidazole-l-carboxylate (88.8 mg, 0.379 mmol) in THF (2 mL) under nitrogen in a sealed tube was added triethylamine (88.0 muEpsilon, 0.632 mmol). The mixture was heated at 90 C for 20 h. The reaction was not complete and thus more 1- (trifluoromethyl)cyclobutyl lH-imidazole-l-carboxylate (88.8 mg, 0.379 mmol) andtriethylamine (88.0 muEpsilon, 0.632 mmol) were added and the reaction was continued to heat at 90 C for an additional day. The mixture was concentrated under reduced pressure and purified by Biotage column chromatography to afford the title compound as colorless oil (114.4 mg, 95.7%). Exact mass calculated for C17H25F3N2O4: 378.2, found: LCMS mlz = 379.2 [M+H]+; lU NMR (400 MHz, CDC13) delta ppm 1.47 (s, 9H), 1.61-1.77 (m, 2H), 1.79-2.05 (m, 4H), 2.45-2.64 (m, 2H), 2.67-2.80 (m, 1H), 2.80-2.93 (m, 1H), 3.03 (bs, 1H), 3.16 (bs, 1H), 3.69 (d, 1H), 3.83 (d, J = 12.88 Hz, 1H), 4.21 (bs, 2H).

Reference： [1]Patent: WO2012/145361,2012,A1 .Location in patent: Page/Page column 197

26
[ 1276676-86-8 ]
[ 149771-44-8 ]
[ 1276677-06-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; N,N-dimethyl acetamide;bis(tri-t-butylphosphine)palladium(0); at 100℃; for 18h;	Anhydrous dimethylacetamide (4.75 mL, degassed prior to use) was added to a mixture of 5-chloro-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2- one (1-4, 1.0 g, 3.94 mmol), potassium phosphate tribasic (1.67 g, 7.88 mmol), bis(tri-t- butylphosphine)palladium(O) (81 mg, 0.158 mmol), and tert-butyl 3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (1.26 g, 5.91 mmol). The resulting suspension was heated to 100 C for 18 h. Following this duration, the reaction contents were cooled to room temperature, filtered, and washed with acetonitrile. Purification using reverse-phase chromatography (20-100%, 0.1% TFA in H20: acetonitrile) afforded tert-butyl 3-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3- dihydro-lH-imidazo[4,5-¾]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (26-1) as a white solid. MS m/z (Mu+Eta): calculated = 430.2813; observed = 430.2817.

Reference： [1]Patent: WO2011/34741,2011,A1 .Location in patent: Page/Page column 110-111

27
[ 75-36-5 ]
[ 149771-44-8 ]
[ 1454648-82-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at -20 - 25℃; for 24h;	Preparation of l-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-ethanone hydrochloride (U) To a solution of <strong>[149771-44-8]3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester</strong> (1.00 g, 4.71 mmol) and triethylamine (1.41 mL, 10.0 mmol) in DCM (20 mL) cooled to -20C is added acetyl chloride (0.36 mL, 5.0 mmol) and the reaction stirred at about 25C for 24 hours. The reaction is concentrated, suspended in EtOAc (125 mL) then washed with 0.1M HCI (100 mL), sat. NaHC03 (100 mL) and brine (50 mL). The organic layer is dried (Na2S04) and concentrated to give (U-1) as an oil.
	With triethylamine; In dichloromethane; at -20 - 25℃; for 24h;	To a solution of <strong>[149771-44-8]3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester</strong> (1.00 g, 4.71 mmol) and triethylamine (1.41 mL, 10.0 mmol) in DCM (20 mL) cooled to -20 C. is added acetyl chloride (0.36 mL, 5.0 mmol) and the reaction stirred at about 25 C. for 24 hours. The reaction is concentrated, suspended in EtOAc (125 mL) then washed with 0.1M HCl (100 mL), sat. NaHCO3 (100 mL) and brine (50 mL). The organic layer is dried (Na2SO4) and concentrated to give (U-1) as an oil.

Reference： [1]Patent: WO2013/134226,2013,A1 .Location in patent: Page/Page column 93
[2]Patent: US2013/236468,2013,A1 .Location in patent: Paragraph 0328

28
rac-benzyl ((2S,3R,4R)-1-acetyl-6-bromo-2,3-dimethyl-1,2,3,4-tetrahydrociuinolin-4-yl)carbamate [ No CAS ]
[ 149771-44-8 ]
rac-tert-butyl 3-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.4%	With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In 1,4-dioxane; at 100℃; for 23h;Inert atmosphere;	A mixture of rac-benzyl ((2S,3R,4R)- I -acetyl-6-bromo-2,3-dimethyl- I ,2,3,4-tetrahydroq uinolin-4- yl)carbamate (for a preparation see Intermediate 3, (74.8 mg, 0.173 mmol), tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (43.1 mg, 0.203 mmol), sodium-tert-butoxide (50.8 mg,0.529 mmol), DavePhos (14.0 mg, 0.036 mmol) and Pd2(dba)3 (16.3 mg, 0.018 mmol) had 1,4- dioxane (2 mL) added and were heated with stirring under nitrogen at 100 C for 23 h. The reaction mixture was allowed to cool to rt and filtered through a celite cartridge which was flushed with ethyl acetate. The filtrate was concentrated and purified by MDAP (Formic) to give the product (5.5 mg, 0.013 mmol, 7.40%) as a yellow gum. LCMS (2 mm Formic): Rt = 0.80 mi [MH] = 429.

Reference： [1]Patent: WO2014/140076,2014,A1 .Location in patent: Page/Page column 94; 95

29
[ 350-46-9 ]
[ 149771-44-8 ]
tert-butyl 3-(4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;Inert atmosphere;	A suspension of 1-fluoro-4-nitrobenzene (0.266 g, 1.884 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.4 g, 1.884 mmol) and potassium carbonate (0.39 g, 2.83 mmol) in anhydrous DMF (5 mL) was heated to50 C under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool to room temperature, partitioned between water (50 mL) and ethyl acetate (50 ml) . The ethyl acetate was separated and washed with water (3 x 20 ml), dried (anhydrous sodium sulfate),filtered and reduced in vacuo. The residue was purified by flash chromatography (0-100% ethyl acetate in cyclohexane) to afford the title compound (0.62 g, 100 %) . LCMS (Method A) : = 1.61 mi m/z = 334 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 181

30
[ 27996-87-8 ]
[ 149771-44-8 ]
tert-butyl 3-(2-formyl-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
360 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;Inert atmosphere;	A suspension of 2-fluoro-5-nitrobenzaldehyde (0.358 g,2.120 mmol) tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.45 g, 2.120 mmol) and potassium carbonate(0.439 g, 3.18 mmol) in anhydrous DMF (2 mL) was heatedto 50 C under a nitrogen atmosphere for 16 h. Thereaction mixture was allowed to cool to room temperature, partitioned between water (50 mL) and ethyl acetate (50 mL) . The ethyl acetate was separated and washed with water (3 x 20 mL), dried (anhydrous sodium sulfate),filtered and reduced in vacuo. The residue was purified by flash chromatography (0-100% ethyl acetate in cyclohexane) to afford the title compound (360 mg, 0.996 mmol) . LCMS (Method C) : = 1.69 mi m/z = 384 [M+Na].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 202

31
[ 116834-64-1 ]
[ 149771-44-8 ]
C₂₇H₃₀N₄O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a stirred solution of acid VIII (0.001179 mol, 1 eq) in DMF (5 mL), EDCI (0.248 g, 0.00129 mol, 1.1 eq), HOBt (0.198 g, 0.00129 mol, 1.1 eq) and DIPEA (0.30 g, 0.00235 mol, 2 eq) were added at 0 C. and stirred for 15 minutes. A solution of amine LXIX from Example 11 (0.00117 mol, 1 eq) was then added at 0 C. and then the resulting mixture was allowed to stir at room temperature for overnight. After completion of the reaction, water (20 mL) was added and extracted with ethyl acetate (2×30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 60-120 mess, 70% ethyl acetate in hexane) to give LXXII in 57% yield.

Reference： [1]Patent: US9404081,2016,B2 .Location in patent: Page/Page column 182

32
[ 149771-44-8 ]
[ 69034-12-4 ]
tert-butyl 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.8%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 80℃; for 5h;	General procedure: To a solution of 12 (1000 mg, 4.71 mmol) in NMP (9.4 ml) was acdded ethyl 2-chloropyrimidine-5-carboxylate (967 mg,5.18 mmol) and diisopropyl ethylamine (913 mg, 7.07 mmol) at room temperature. The reaction mixture was stirred at 80 C for 5 h. The reaction mixture was diluted with water to afford the white precipitation. The resulting solid was collected by filtration to afford 13c (1627 mg, 95.3%) as the white solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2177 - 2190
[2]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 4936 - 4941

33
[ 100-52-7 ]
[ 149771-44-8 ]
[ 149771-43-7 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a solution of amine LXIX (0.00023 mol) and appropriate aldehyde (0.00023 mol) in DCM (5 mL), acetic acid (0.1 mL) was added at room temperature and the resulting mixture was allowed to stir for 30 min. Then STAB (0.100 gm, 0.00047 mol) was added to reaction mixture and the resulting mixture was allowed to stir at room temperature for 16 h. After completion of reaction, the crude mixture was diluted with DCM washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 60-120 mesh; EtOAc-Hexane, 2:8) to afford product LXX in 70-75% yield.

Reference： [1]Patent: US9404081,2016,B2 .Location in patent: Page/Page column 179

34
3-(3-chloropropyl)-1H-indole-5-carbonitrile [ No CAS ]
[ 149771-44-8 ]
3-(3-(5-cyano-1H-indol-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.1%	With sodium hydrogencarbonate; potassium iodide; In acetonitrile;Reflux;	3- (3-chloropropyl) -1H-indole-5-carbonitrile(2.80 g, 12.80 mmol),3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester(2.72 g, 12.80 mmol),Sodium carbonate (2.04g, 19.21mmol) and potassium iodide (213mg, 1.28mmol) were sequentially added to acetonitrile (30 mL), and then the reaction temperature was raised, the reaction was refluxed overnight. (PE / EA (v / v) = 3/2) to give the title compound as a white solid (3.54 g, 70.1%).

Reference： [1]Patent: CN106065018,2016,A .Location in patent: Paragraph 0208; 0209; 0210; 0211

35
[ 22536-66-9 ]
[ 149771-44-8 ]
3-(4-carbamoylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.8%	In acetonitrile;Reflux;	A mixture of <strong>[22536-66-9]2-chloropyrimidine-4-carboxamide</strong> (0.74 g, 4.70 mmol), 3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (1.00 g, 4.71 mmol) and sodium carbonate(0.75 g, 7.05 mmol) was added to acetonitrile (15 mL) and the reaction was then raised in temperature and refluxed overnight. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1/1) to give the title compound as a red solid (1.30 g, 82.8%).

Reference： [1]Patent: CN106065018,2016,A .Location in patent: Paragraph 0236; 0237; 0238; 0239

36
[ 149771-44-8 ]
[ 459-46-1 ]
tert-butyl 3-(4-fluorobenzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In acetonitrile; at 20 - 25℃; for 16h;	A solution of 1-(bromomethyl)-4-fluorobenzene (134 mg, 0.709 mmol) in acetonitrile (3 mL) was slowly added to a room temperature mixture of fe/f-butyl 3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (150 mg, 0.706 mmol) and potassium carbonate (293 mg, 2.12 mmol) in acetonitrile (12 mL) and the reaction mixture was stirred at 25 C for 16 hours. It was then filtered, and the filtrate was concentrated in vacuo; silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) afforded the product as a colorless gum. Yield: 226 mg, 0.705 mmol, quantitative. 1 H NMR (400 MHz, CDCI3) delta 7.30-7.24 (m, 2H), 6.99 (br dd, J=8.8, 8.7 Hz, 2H), 4.26-4.03 (m, 2H), 3.43 (s, 2H), 2.58 (dd, J=10.7, 2.3 Hz, 2H), 2.36-2.16 (m, 2H), 1.93-1.78 (m, 4H), 1.47 (s, 9H).

Reference： [1]Patent: WO2017/21805,2017,A1 .Location in patent: Page/Page column 117; 118

37
[ 402-43-7 ]
[ 149771-44-8 ]
tert-butyl 3-(4-(trifluoromethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium tert-pentoxide; bis(dibenzylideneacetone)-palladium(0); ruphos; In 1,4-dioxane; at 100℃; for 2h;Microwave irradiation;	A mixture of 12 (100 mg, 0.471 mmol), 1-bromo-4-(trifluoromethyl)benzene (117 mg, 0.518 mmol), Pd(dba)2 (13.54 mg,0.024 mmol), RuPhos (21.98, 0.024 mmol) and NaOt-Pen (130 mg,1.178 mmol) in 1,4-dioxane (1.0 ml) was heated at 100 C for 2 hunder microwave irradiation. After cooling to room temperature,the reaction mixture was diluted with water. The aqueous layer was separated and then extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel: EtOAc/hexane = 1/10) toafford 13a (157 mg, 94.0%) as the pale brown solid. 1H NMR (CDCl3)d 1.48 (s, 9H), 1.81 (d, J = 7.0 Hz, 2H), 1.98 (t, J = 4.5 Hz, 2H), 3.06 (s,2H), 3.47 (d, J = 11.3 Hz, 2H), 4.39 (s, 2H), 6.83 (d, J = 8.5 Hz, 2H),7.47 (d, J = 8.3 Hz, 2H). MS-ESI (m/z) = 357 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2177 - 2190

38
[ 799557-86-1 ]
[ 149771-44-8 ]
tert-butyl 3-(2-(trifluoromethyl)pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium tert-pentoxide; bis(dibenzylideneacetone)-palladium(0); ruphos; In 1,4-dioxane; at 100℃; for 2h;Microwave irradiation;	General procedure: A mixture of 12 (100 mg, 0.471 mmol), 1-bromo-4-(trifluoromethyl)benzene (117 mg, 0.518 mmol), Pd(dba)2 (13.54 mg,0.024 mmol), RuPhos (21.98, 0.024 mmol) and NaOt-Pen (130 mg,1.178 mmol) in 1,4-dioxane (1.0 ml) was heated at 100 C for 2 hunder microwave irradiation. After cooling to room temperature,the reaction mixture was diluted with water. The aqueous layer was separated and then extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel: EtOAc/hexane = 1/10) toafford 13a (157 mg, 94.0%) as the pale brown solid

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2177 - 2190

39
[ 89793-12-4 ]
[ 149771-44-8 ]
tert-butyl 3-(5-(ethoxycarbonyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.3%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 80℃; for 5h;	To a solution of 12 (1000 mg, 4.71 mmol) in NMP (9.4 ml) was acdded ethyl 2-chloropyrimidine-5-carboxylate (967 mg,5.18 mmol) and diisopropyl ethylamine (913 mg, 7.07 mmol) at room temperature. The reaction mixture was stirred at 80 C for 5 h. The reaction mixture was diluted with water to afford the white precipitation. The resulting solid was collected by filtration to afford 13c (1627 mg, 95.3%) as the white solid. 1H NMR (CDCl3)d 1.37 (t, J = 7.2 Hz, 3H), 1.49 (s, 9H), 1.65 (dd, J = 14.0, 6.6 Hz, 2H),1.92 (t, J = 4.6 Hz, 2H), 3.21 (br, 2H), 4.34 (q, J = 7.2 Hz, 2H), 4.35(br, 2H) 4.56 (d, J = 12.8 Hz, 2H), 8.84 (d, J = 5.8 Hz, 2H). MS-ESI(m/z) = 363 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2177 - 2190

40
6-((2',4'-dimethyl-[4,5'-bithiazol]-2-yl)amino)nicotinic acid [ No CAS ]
[ 149771-44-8 ]
tert-butyl 3-(6-((2',4'-dimethyl-[4,5'-bithiazol]-2-yl)amino)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51.8%	With 1-[(1-(cyano-?2-?ethoxy-?2-?oxoethylidenaminooxy)?dimethylamino-?morpholino)]-uronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1.5h;	General procedure: The mixture of 13a (151 mg, 0.423 mmol) and 4 N HCl in 1,4-dioxane solution (1.38 ml) was stirred at room temperature overnight. After concentration, the residue was crystalized with etherto afford the white precipitation. The resulting solid was collected by filtration to afford 14a (121 mg, 98.0%) as the white solid. MSESI (m/z) = 257 [M+H]+. To a solution of 4a (116 mg, 0.35 mmol)in DMF (2.3 ml) was added 14a (120 mg, 0.42 mmol), COMU (225 mg, 0.525 mmol) and Et3N (177 mg, 1.75 mmol) at room temperature.The reaction mixture was stirred at same temperature for 1.5 h. The reaction mixture was diluted with sat. NaHCO3 solution to afford the pale yellow precipitation. The resulting solid was collected by filtration to 16a

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2177 - 2190

41
7-(bromomethyl)-6-methoxybenzofuran-3(2H)-one [ No CAS ]
[ 149771-44-8 ]
tert-butyl 3-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With potassium carbonate; In dichloromethane; at 20℃; for 15h;Inert atmosphere;	(a) Step 1 Potassium carbonate (0.163 g, 1.18 mmol) was added to 5 mL of a methylene chloride solution of the 7-(bromomethyl)-6-methoxybenzofuran-3(2H)-one (0.303 g, 1.18 mmol) described in [WO2011/136319]. Two milliliters of a methylene chloride solution of 8-Boc-3,8-diazabicyclo[3.2.1]octane (0.250 g, 1.18 mmol) was added dropwise to the reaction solution, and stirring was continued for 15 hours at room temperature. The reaction solution was filtered, and the residue obtained by concentrating the filtrate was purified by silica gel chromatography (ethyl acetate/hexane) to obtain tert-butyl 3-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.182 g, 39%). 1H NMR (300 MHz, CDCl3) delta 1.43 (s, 9H), 1.77 (m, 4H), 2.37 (m, 2H), 2.60 (dd, J=2.1, 11.1 Hz, 2H), 3.65 (s, 2H), 3.91 (s, 3H), 4.08-4.16 (m, 2H), 4.61 (s, 2H), 6.68 (d, J=9.0 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H).

Reference： [1]Patent: US2017/145005,2017,A1 .Location in patent: Paragraph 0338; 0339; 0340; 0341

42
[ 364-83-0 ]
[ 149771-44-8 ]
tert-butyl 3-(4-acetyl-3-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With N,N,N,N,N,N-hexamethylphosphoric triamide; potassium carbonate; at 70℃;	Into a 100-mL round-bottom flask was added l-(2,4-difluorophenyl)ethan-l-one (2.65 g, 17.0 mmol), ferf-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.00 g, 14.1 mmol), potassium carbonate (5.86 g, 42.4 mmol), and HMPA (30 raL). The resulting solution was stirred overnight at 70 C in an oil bath and then cooled to RT and quenched by the addition of water (30 mL), The resulting solution was extracted with ethyl acetate (3 x 30 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography and eluted with ethyl acetate/petroleum ether (1 :5) to afford ferf-hutyl 3-(4-acetyl-3-fluorophenyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a brown oil (1.8 g, 30%), LCMS (ESI, m/z): 349[M+H]+
30%	With N,N,N,N,N,N-hexamethylphosphoric triamide; potassium carbonate; at 70℃;	(1503) [00477] Into a 100-mL round-bottom flask was added l-(2,4-difluorophenyl)ethan-l-one (2.65 g, 17.0 mmol), <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (3.00 g, 14.1 mmol), potassium carbonate (5.86 g, 42,4 mmol), and HMPA (30 mL). The resulting solution was stirred overnight at 70 C in an oil bath and then cooled to RT and quenched with water (30 mL). The resulting solution was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were concentrated in vacuo to provide a crude product that was purified via silica gel chromatography and eiuted with ethyl acetate/petroleum ether (1 :5) to afford fer/-butyl 3-(4- acetyl-3-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as brown oil (1.8 g, 30%). LCMS (ESI, m/z): 349

Reference： [1]Patent: WO2017/139779,2017,A1 .Location in patent: Paragraph 00286
[2]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00477

43
[ 1007-15-4 ]
[ 149771-44-8 ]
tert-butyl 3-(4-acetyl-2-bromophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 4h;Microwave irradiation;	Into a 20-mL microwave tube was added l-(3-bromo-4-fluorophenyl)ethan-l-one (3.00 g, 13.8 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.67 g, 17.3 mmol), DIEA (5,48 g, 7.39 mL, 42.4 mmol), and DMSO (8 niL). The resulting solution was heated at 120 C for 4 h under microwave irradiation. The reaction mixture was cooled to RT and then poured into water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography and eluted with ethyi acetate/petroleum ether (1 :5) to afford tert-bvXyl 3-(4-acetyl-2-bromophenyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (1.5 g, 27%). LCMS (ESI, m/z): 409,411[M+H]+
27%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 4h;Microwave irradiation;	(1519) [00481] Into a 20-mL microwave tube was added l-(3-bromo-4-fluorophenyl)ethan-l-one (3.00 g, 13.8 mmol), fert-butyl 3,8-diazabicyclo[3.2. I ]octane-8-carboxyiate (3.67 g, 17.3 mmol), DIEA (5.48 g, 7.39 mL, 42.4 mmol), and DMSO (8 mL). The resulting solution was heated to 120 C for 4 h under microwave irradiation. The reaction mixture was cooled to RT and then quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 rnL). and the combined organic layers were then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide a crude product that was purified via silica gel chromatography and eluted with ethyl acetate/petroleum ether (1 :5) to afford fer -butyl 3-(4- acetyl-2-bromophenyl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate as a yello oil (1 .5 g, 27%). LCMS (ESI, m/z) 409, 411 [ I- H I .

Reference： [1]Patent: WO2017/139779,2017,A1 .Location in patent: Paragraph 00290
[2]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00481

44
[ 149771-44-8 ]
[ 191170-76-0 ]
tert-butyl 3-(4-(2-(((benzyloxy)carbonyl)amino)ethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; XPhos; In toluene; at 100℃;Inert atmosphere;	Into a 50-mL 3-necked round-bottom flask, purged and maintained under an atmosphere of nitrogen, was added <strong>[191170-76-0]benzyl N-[2-(4-bromophenyl)ethyl]carbamate</strong> (0.692 g, 2.07 mmol), toluene (10 mL), ieri-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.400 g, 1.88 mmol), s CC (1.85 g, 5.68 mmol), Pd(dppf)Ch(0.078 g, 0.10 mmol), and XPhos (0.090 g, 0.20 mmol). The resulting solution was stirred overnight at 100 C in an oil bath and then cooled to RT and concentrated in vacuo. The crude product was purified via silica gel chromatography and eluted with ethyl acetate/petroleum ether (1 : 10) to afford fert-butyl 3-[4-(2- [[(benzyloxy)carbonyl]amino]ethyl)phenyl]-3 ,8-diazabicyclo[3.2.1 ]octane-8-carboxylate as a yellow oil (440 mg, 50%). LCMS (ESI, m/z): 466[M+H]+
27%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos; In toluene; at 100℃;Inert atmosphere;	(1255) (1256) CS2CO3 (1257) Intermediate 3 (1258) Toluene, 100 C (1259) [00415] Into a 50-mL round-bottom flask, purged and maintained under an inert atmosphere of nitrogen, was added benzyl 7Y-[2-(4-bromophenyl)ethyl]carbamate (3.15 g, 9.43 mmol), tert- butyl 3,8-diazabicyclo[3.2.1 ]octatie-8-carboxylate (2.00 g, 9.43 mmol), Pd2(dba (0,800 g, 1.09 mmol), RuPhos (0.800 g, 1.71 mmol), CS2CO3 (9.00 g, 27.6 mmol) and toluene (50 mL). The reaction mixture was stirred at 100 C overnight in an oil bath. The resulting mixture was concentrated in vacuo to remove most of the solvent and then diluted with DCM (50 mL). The solids were removed by filtration, the filtrate was concentrated in vacuo, and the crude product that was purified via silica gel chromatography and eiuted with petroleum ether/ethyl acetate (3 : 1) to afford fer -Butyl 3-(4-(2-(((benzyloxy)carbonyl)amino)ethyl) phenyl)-3,8- diazabicyclo[3.2.1 ]octane-8-carboxylate as a yellow oil (1.2 g, 27%). LCMS (ESI, m/z) 466

Reference： [1]Patent: WO2017/139779,2017,A1 .Location in patent: Paragraph 00264
[2]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00415

45
[ 327-51-5 ]
[ 149771-44-8 ]
tert-butyl-3-(4-bromo-2,5-difluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 70℃; for 0.75h;Inert atmosphere;	Into a 1-L round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was added l ,4-dibromo-2,5-difluorobenzene (15,0 g, 55.0 mmol), fert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (10.6 g, 49.9 mmol), Pd2(dba)3-CHC13 (2.59 g, 2.50 mmol), XantPhos (2.89 g, 5.00 mmol), sodium fert-butoxide (9.60 g, 99.9 mmol), and toluene (500 mL). The resulting solution was stirred for 45 min at 70 C and then cooled to RT and quenched by the addition water (100 mL). The resulting solution was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column and eluted with ethyl acetate/petroleum ether (1 : 10) to afford fe/f-butyl 3-(4-bromo-2,5- difluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as light yellow oil (15 g, 67%). LCMS (ESI, m/z). 403,405 [M+H)+
	With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 70℃; for 4h;Inert atmosphere;	(1019) (1020) intermediate 31-1 (1021) [00354] Into a 100-mL round-bottom flask that purged and maintained under an inert atmosphere of nitrogen was added 4-bromo-2-chloro-l-iodobenzene (1.20 g, 3.78 mmol), benzyl piperazine-l -carboxylate (0.924 g, 4, 19 mmol), NaOtBu (1.10 g, 1 1.4 mmol), XantPhos (0.695 g, 1.20 mmol), Pd2(dba)3 (0.393 g, 0.430 mmol), and toluene (10 mL). The reaction mixture was stirred for 4 h at 60 C and then concentrated in vacuo to provide a crude product that was purified by FCC eluting with ethyl acetate/petroleum ether (1 : 10) to afford benzyl 4-(4-bromo-2- chlorophenyl)piperazine-l -carboxylate as a colorless oil (713 mg, 46%). LCMS (ESI, m/z) 409, 41 1 [ M 1 [ j .The Intermediates in Table 1 below were synthesized according to the procedures (palladium caialyzed C-N coupling) outlined above for Example 31-1, Intermediate 31-1, using the appropriate synthetic precursors.
	With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 70℃; for 0.75h;Inert atmosphere;	A mixture of <strong>[327-51-5]1,4-dibromo-2,5-difluorobenzene</strong> (15.0 g, 55.0 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10.6 g, 49.9 mmol), Pd2(dba)3.CHCh (2.59 g, 2.50 mmol), XantPhos (2.89 g, 5.00 mmol), and sodium /ert-butoxide (9.60 g, 99.9 mmol) in toluene (500 mL) under nitrogen was stirred for 45 min at 70 C. After cooling to 25 C, the resulting mixture was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (eluting with 1 : 10 ethyl acetate/petroleum ether) to afford tert-butyl 3-(4- bromo-2,5-difluorophenyl)-3,8-diazabicyclo[3.2.l]octane-8-carboxylate as light yellow oil. LCMS: (ESI, m/z): 403, 405 [M+H]+

Reference： [1]Patent: WO2017/139779,2017,A1 .Location in patent: Paragraph 00268
[2]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00354; 00355
[3]Patent: WO2020/33709,2020,A1 .Location in patent: Paragraph 0068

46
[ 149771-44-8 ]
[ 179897-89-3 ]
tert-butyl 3-(4-bromo-2-cyanophenyl)-3,8-diazabicycio[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 80℃; for 24h;	Into a 100-mL round-bottom flask was added tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 4.71 mmol), 5-bromo-2-fluorobenzonitrile1.88 g, 9.40 mmol), DIEA (1.83 g, 2.47 mL, 14.2mmol), and DMSO (25 mL). The resulting mixture was stirred for 24 h at 80 C in an oil bath and then cooled to RT and quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (2 x 20 mL). and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography and eluted with ethyl acetate/petroleum ether (1 :5) to afford ferf-butyl 3-(4-bromo-2-cyanophenyl)-3,8- diazabicyclo[3.2.1 ]oetane-8-carboxylate as a yellow oil (550 mg, 30%). LCMS (ESI, m/z): 392, 394 [M+H]+
11%	In N,N-dimethyl acetamide; at 100℃; for 3h;	(1355) (1356) iniemsediate S3 (1357) Into a 50-mL round-bottom flask was added 5-bromo-2~fluorobenzonitrile (1.03 g, 5.17 mmol), tert-butyl 3,8-diazabicyco[3.2.1]octane-8-carboxylate (1 .00 g, 4.71 mmol), potassium carbonate (1.30 g, 9.43 mmol), and DMA (10 mL). The reaction mixture was stirred for 3 h at 100 C and then cooled and extracted with ethyl acetate (3 15 mL). The combined organic layers were then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by FCC eluting with ethyl acetate/petroleum ether (1 :3) to afford tert-butyl 3-(4-bromo-2-cyanophenyl)-3,8-diazabicycio[3.2.1]octane-8- carboxylate as a light yellow oil (196 nig. 11%). LCMS (ESI, m/z) 392, 394 j M I I ] .

Reference： [1]Patent: WO2017/139779,2017,A1 .Location in patent: Paragraph 00272
[2]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00440

47
[ 369-34-6 ]
[ 149771-44-8 ]
tert-butyl 3-(2-fluoro-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;Inert atmosphere;	Into a 100-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was added l,2-difluoro-4-nitrobenzene (1.00 g, 6.29 mmol), tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.47 g, 6.92 mmol), potassium carbonate (2.60 g, 18.8 mmol), and DMF (10 rnL). The resulting mixture was stirred for 4 h at 90 C and then cooled to RT and quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (3 10 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography and eluted with ethyl acetate/petroleum ether (1 : 10) to afford fert-butyl 3-(2- fluoro-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (1.93 g, 87%). LCMS (ESI, m/z): 352

Reference： [1]Patent: WO2017/139779,2017,A1 .Location in patent: Paragraph 00273

48
benzyl N-[2-(4-bromo-2-fluorophenyl)ethyl]carbamate [ No CAS ]
[ 149771-44-8 ]
tert-butyl 8-[4-(2-[[(benzyloxy)carbonyl]amino]ethyl)-3-fluorophenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With palladium diacetate; caesium carbonate; ruphos; In toluene; at 100℃; for 2h;Inert atmosphere;	Into a 50-mL 3 -necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was added benzyl N-[2-(4-bromo-2-fluorophenyl)ethyl]carbamate (0,500 g, 1.42 mmol), er -butyl 3 , 8-diazabicy clo[3.2.1 ]octane-3 -carboxyl ate (0.320 g, 1.51 mmol), Cs ··( (); (1.40 g, 4.30 mmol), Pd(OAc)?. (0.032 g, 0.14 mmol), RuPhos (0.13 g, 0.29 mmol), and toluene (10 mL). The resulting mixture was stirred for 2 h at 100 C in an oil bath and then cooled to RT and quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography and eluted with ethyl acetate/petroleum ether (PE/EA = 100: 1 to 3 : 1) to afford ffert-butyl 8-[4-(2-[[(benzyloxy)carbonyl]amino]ethyl)-3-fluorophenyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate as light yellow oil (220 mg, 32%). LCMS (ESI, m/'z): 484[M+H]+
15%	With palladium diacetate; caesium carbonate; ruphos; In toluene; at 100℃; for 17h;	(1270) [00418] Into a 100-mL round-bottom flask was placed benzyl (4-bromo-2- fluorophenethyl)carbamate (0.825 g, 2.34 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.500 g, 2,36 mmol), Pd(OAc (0.050 g, 0.22 mmol), RuPhos (0.050 g), CsiCC (2.23 g, 6.84 mmol), and toluene (10 mL). The resulting solution was stirred for 17 h at 1.00 C in an oil bath and then concentrated in vacuo to afford the crude product. To the crude product was added DCM (50-mL) and then the inorganic solids were removed by filtration. The filtrate was concentrated in vacuo to afford the crude product that was purified by FCC eluting with petroleum ether : ethyl acetate (1 : 1) to afford tert-butyl 3-(4~(2-(((benzyloxyjcarbonyl)amino) ethyl)-3-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (15%). LCMS (ESI, m/z): 484 [M+Fl ,

Reference： [1]Patent: WO2017/139779,2017,A1 .Location in patent: Paragraph 00279
[2]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00418

49
[ 57381-41-6 ]
[ 149771-44-8 ]
tert-butyl 3-(4-bromo-3-cyanophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; for 4h;Inert atmosphere;	(1019) (1020) intermediate 31-1 (1021) [00354] Into a 100-mL round-bottom flask that purged and maintained under an inert atmosphere of nitrogen was added 4-bromo-2-chloro-l-iodobenzene (1.20 g, 3.78 mmol), benzyl piperazine-l -carboxylate (0.924 g, 4, 19 mmol), NaOtBu (1.10 g, 1 1.4 mmol), XantPhos (0.695 g, 1.20 mmol), Pd2(dba)3 (0.393 g, 0.430 mmol), and toluene (10 mL). The reaction mixture was stirred for 4 h at 60 C and then concentrated in vacuo to provide a crude product that was purified by FCC eluting with ethyl acetate/petroleum ether (1 : 10) to afford benzyl 4-(4-bromo-2- chlorophenyl)piperazine-l -carboxylate as a colorless oil (713 mg, 46%). LCMS (ESI, m/z) 409, 41 1 [ M 1 [ j .The Intermediates in Table 1 below were synthesized according to the procedures (palladium caialyzed C-N coupling) outlined above for Example 31-1, Intermediate 31-1, using the appropriate synthetic precursors.

Reference： [1]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00354; 00355

50
[ 84194-36-5 ]
[ 149771-44-8 ]
tert-butyl 3-(3-chloro-4-formylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h;	(1441) [00460] Into a 100-mL round-bottom flask was added <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (0.743 g, 4.69 rnmol), tert-h tyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 .00 g, 4.71 mmoi), potassium carbonate (1.30 g, 9.41 mmol), and DMF (15 mL). The reaction mixture was stirred for 3 h at 100 °C and then cooled to RT and quenched with water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were dried over anhydrous sodium sulfate. The solids were removed by filtration over Celite and the filtrate was concentrated in vacuo. The resulting crude product was purified by FCC eluting with ethyl acetate/petroleum ether (1 :3) to afford fe/ -butyl 3-(3-chloro-4-formylphenyl)-3,8- (1442) 190 (1443) 144628010 vl diazabicyclo[3.2.1 ]octane-8-carboxyiate as a white solid (640 rag, 39percent). LCMS (ESI, m/z): 351

Reference： [1]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00460

51
[ 16681-70-2 ]
[ 149771-44-8 ]
tert-butyl 3-(1H-1,2,3-triazol-4-ylcarbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With N-ethyl-N,N-diisopropylamine; HATU; In 1-methyl-pyrrolidin-2-one; at 20℃;	To a stirred solution of 500 mg (2.36 mmol) tert-butyl 3,8-diazabicyclo[3.2.1 ]octane-8- carboxylate in 12 mL NMP were added 532 mg 1 H-1 ,2,3-triazole-4-carboxylic acid (4.71 mmol, 2 eq), 1 .23 mL DIPEA (7.07 mmol, 3 eq) and 1 .791 g HATU (4.71 mmol, 2 eq). After stirring overnight at RT, the solution was subjected to preparative HPLC to yield 378 mg (52 %) tert-butyl 3-(1 H-1 ,2,3-triazol-4-ylcarbonyl)-3,8-diazabicyclo[3.2.1 ]octane- 8-carboxylate. (0433) LC-MS (Method 3): Rt = 0.91 min; MS (ESIpos): m/z = 308 [M+H]+ (0434) 1 H-NMR (500 MHz, DMSO-d6) delta [ppm]: 1.43 (9H), 1 .53 - 1 .72 (2H), 1 .83 (2H), 2.92 (1 H), 3.33 (1 H), 4.14 (1 H), 4.21 (1 H), 4.30 (1 H), 4.40 (1 H), 8.29 (1 H), 15.22 (1 H).

Reference： [1]Patent: WO2017/202817,2017,A1 .Location in patent: Page/Page column 52-53

52
[ 1059735-34-0 ]
[ 149771-44-8 ]
tert-butyl 3-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 60℃; for 1h;	To a mixture of 7-benzyl-2,4-dichloro-6,8- dihydro-5H-pyrido[3,4-d]pyrimidine (920 mg, 3.13 mmol, 1.00 eq) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (677 mg, 3.19 mmol, 1.02 eq) in DMSO (18.0 mL) was added DIEA (1.21 g, 9.39 mmol, 1.64 mL, 3.00 eq). The reaction mixture was stirred at 60 C for 1 hour. The mixture was diluted with extracted with EtOAc (3 x 20 mL), washed with water (10 mL), IN HC1 (5 mL), NaHCCb (15 mL), and brine (15 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under vacuum to give tert-butyl 3-(7- benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.30 g, 2.41 mmol, 76.9 % yield, 87.0 % purity) as a brown oil which was used directly in the next step without further purification. ESI MS m/z 470.2 [M+H]+.
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 60℃; for 1h;	To a mixture of 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (920 mg, 3.13 mmol, 1.00 eq) and <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (677 mg, 3.19 mmol, 1.02 eq) in DMSO (18.0 mL) was added DIEA (1.21 g, 9.39 mmol, 1.64 mL, 3.00 eq). The reaction mixture was stirred at 60° C. for 1 hour. The mixture was diluted with extracted with EtOAc (3 20 mL), washed with water (10 mL), 1N HCl (5 mL), NaHCO 3 (15 mL), and brine (15 mL). The combined organic layers were dried over Na 2SO 4, filtered and concentrated under vacuum to give tert-butyl 3-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3,8-diaz- abicyclo[3.2.1]octane-8-carboxylate (1.30 g, 2.41 mmol, 76.9% yield, 87.0% purity) as a brown oil which was used directly in the next step without further purification. ESI MS m/z 470.2 [M+H] +.

Reference： [1]Patent: WO2017/201161,2017,A1 .Location in patent: Paragraph 0353
[2]Patent: US2019/144444,2019,A1 .Location in patent: Paragraph 0626-0627

53
methyl 4-[2-[4-[[2-[[3-(chloromethyl)benzoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carbonyl]amino]-2,6-difluorophenyl]ethyl]benzoate [ No CAS ]
[ 149771-44-8 ]
tert-butyl 3-[[3-[[3-[[3,5-difluoro-4-[2-(4-methoxycarbonylphenyl)ethyl]phenyl]carbamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]carbamoyl]phenyl]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 110℃; for 1h;	A 2OmL microwave reaction vessel is charged with methyl 4-[2-[4-[[2-[[3-(chioromethy l)benzoyi]aminoj-4, 5,6,7-tetrahydrobenzothiophene-3 -carbonyijarninoj-2,6- difiuoro-phenyl]ethyijhenzoate (1 .80 g, 2.89 mmol) and a solution of tert-butyl 3,8- diazabicyclo [3.2.1]octane-8-carboxyiate (760 mg, 3.47 mmoi) and DIPEA (1.01 mL, 5.78 mmol) in ACN (12 mL). The resulting yellow suspension is heated in a BIOTAGE Initiatormicrowave synthesizer at 110 C for 1 hr. The reaction mixture is concentrated in vacuo and the residue is partitioned between 5% aqueous NaHCO3 (150 mL) and DCM (50 ml.). The organic layer is separated, the aqueous layer is extracted with DCM (2 x 50 mL). The combined organic layers are washed with saturated aqueous NaC1 (50 mL), dried over anhydrous Na2SO4. filtered, and concentrated to dryness under reduced pressure. Theresulting residue is purified by chromatography over silica, eluting with a gradient of 15-45% of EtOAc in hexanes to afford the title compound as a light yellow solid (223 g, 97% yield) after solvent evaporation. ?HMvR (400.1 MHz, DMSO-d6): oe 1.38 (s, 9H), 1.95-1.60 (m, 8H), 2.16 (d, J= 10.0 Hz, 2H), 2.57 (d, J= 10.0 Hz, 1H), 2.70 (br s, 4H), 2.92 (s, 4H), 3.51 (s, 2H), 3.84 (s, 3H), 4.08-3.96 (m, 2H), 7.35-7.26 (in, 2H). 7.45-7.35 (m, 2H), 758-745 (m,2H), 7.79-7.72 (m, IH), 7.92-7.79 (m, 3H), 10.00 (s, IH), 11.41 (s, III),. LC-ES/MS (m/z)799 [Mi]

Reference： [1]Patent: WO2018/34883,2018,A1 .Location in patent: Page/Page column 49; 50

54
[ 65873-72-5 ]
[ 149771-44-8 ]
tert-butyl 3-((6-methoxypyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 48h;	A solution of tert-butyl 3 ,8-diazabicyclo[3 .2.1 ]octane-8-carboxylate (1.0 g, 4.71 mmol) in DCE (23.6 mL) was treated sequentially with 6- methoxynicotinaldehyde (711 mg, 5.18 mmol) and NaBH(AcO)3 (1.50 g, 7.07 mmol). The mixture was stirred for 1 day at ambient temperature, then additional 6-methoxynicotinaldehyde (711 mg, 5.18 mmol) and NaBH(AcO)3 (1.50 g, 7.07 mmol) were added. After stirring for 1 day at ambient temperature, the resulting mixture was concentrated in vacuo. The residue was purified by silica chromatography (0-100% EtOAc/ Hexanes as the gradient eluent to afford the title compound in sufficient purity for subsequent use (1.50 g, 96% yield). MS (apci) m/z = 334.2(M+H).

Reference： [1]Patent: WO2018/71447,2018,A1 .Location in patent: Paragraph 001239

55
[ 4387-36-4 ]
[ 149771-44-8 ]
tert-butyl 3-(2-cyanophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43.5%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 16h;Inert atmosphere;	A solution of <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (106 mg, 0.5 mmol), 2-iodobenzonitrile (229 mg, 1 mmol), CS2CO3 (326 mg, 1 mmol), XantPhos (23 mg, 0.04mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol) in dioxane (10 mL) was stirred under N2 at 110C for 16 hrs. The reaction mixture was concentrated and purified by chromatography (silica, EtOAc/PE = 1/5) to afford tert-butyl-3-(2-cyanophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (68 mg, 0.217 mmol, 43.5%) as a yellow oil. ESI-MS (EI+, m/z): 314.2 [M+H]+.
43.5%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 16h;Inert atmosphere;	Step 2: tert-Butyl 3-(2-cyanophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A solution of <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (106 mg, 0.5 mmol), 2-iodobenzonitrile (229 mg, 1 mmol), Cs2CO3 (326 mg, 1 mmol), XantPhos (23 mg, 0.04 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol) in dioxane (10 mL) was stirred under N2 at 110 C. for 16 hrs. The reaction mixture was concentrated and purified by chromatography (silica, EtOAc/PE=1/5) to afford tert-butyl-3-(2-cyanophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (68 mg, 0.217 mmol, 43.5%) as a yellow oil. ESI-MS (EI+, m/z): 314.2 [M+H]+.

Reference： [1]Patent: WO2018/89493,2018,A1 .Location in patent: Paragraph 00340
[2]Patent: US2019/389843,2019,A1 .Location in patent: Paragraph 0612

56
[ 98349-22-5 ]
[ 149771-44-8 ]
tert-butyl-3-(2-cyano-4,5-difluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 16h;	The mixture of 2,4,5-trifluorobenzonitrile (300 mg, 1.91 mmol), tert-butyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (486 mg, 2.92 mmol) and K2C03 (396 mg, 2.86 mmol) in DMSO (20 mL) was stirred at 100 C for 16 h. The mixture was purified by chromatography (silica, PE/EtOAc = 3/1) to afford tert-butyl-3 -(2-cyano-4, 5 -difluorophenyl)-3 , 8- diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.343 mmol, 18 %) as yellow solid. ESI-MS (Erb, m/z): 350.2 [M+H]t

Reference： [1]Patent: WO2018/89433,2018,A1 .Location in patent: Paragraph 00695

57
[ 50-00-0 ]
[ 149771-44-8 ]
tert-butyl 3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200 mg		To a solution of <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (200 mg, 942.1 umol) and paraformaldehyde (254 mg, 2.8 mmol) in methanol (2 mL) was added AcOH (2 mg, 47. lumol, 2.7 uL) (pH = 5). The mixture was stirred at 45C for 2 h. Then NaBH3CN (296 mg, 4.7 mmol) was added and stirred at 45C for 12 h. The mixture was concentrated, diluted with NaHC03 (5 mL) and extracted with dichloromethane (5 mL x 3). The combined organic layers were washed with brine (5 mL chi 2), dried over Na2S04, filtered and concentrated. The residue was purified by prep-TLC (Si02) to afford compound 19-2 (200 mg). 1H NMR (CDC13, 400MHz): delta 4.28 - 4.00 (m, 2H), 2.63 (dd, J= 2.2, 10.5 Hz, 2H), 2.23 (s, 5H), 1.94 - 1.76 (m, 4H), 1.47 (s, 9H).
	With sodium tris(acetoxy)borohydride; In tetrahydrofuran; methanol; water;Inert atmosphere;	General procedure: A general route to obtain compounds 16a and 16b follows the synthesis illustrated below. The preparation of each compound is also provided. Scheme 14: General synthetic scheme for compounds 16a and 16b. The Boc-protected bicyclic piperazine (14a-b; 250 mg, 1 .18 mmol, 1.0 eq) was dissolved in a mixture of THF/MeOH (1 :1 ). Formaldehyde (37% in H20, 287 pL, 3.53 mmol, 3.0 eq) was added, followed by addition of Na(OAc)sBH (274.5 mg, 1.30 mmol, 1 .1 eq), and the reaction mixture was stirred overnight. The solvent was evaporated and the crude product purified by column chromatography on silica (0 - 20% MeOH in DCM). The product was visualized on the TLC plate using a KMn04 stain.

Reference： [1]Patent: WO2018/102751,2018,A1 .Location in patent: Paragraph 00231
[2]Patent: WO2019/169306,2019,A1 .Location in patent: Paragraph 0321; 0416-0417

58
[ 149771-44-8 ]
[ 32779-38-7 ]
tert-butyl 3-(5-iodopyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In 1-methyl-pyrrolidin-2-one; at 85℃;	General procedure: A solution of tert-butyl 3-oxa-7,9-diazabicyclo [3.3.1 jnonane-9-carboxylate(1 g, 4.38 mmol) 2-fluoro-5-iodopyridine (1.12 g, 5.04 mmol), and sodium carbonate (0.84 g,7.88 mmol) in 1-Methyl-2-pyrrolidinone (4 ml) was heated at 85 C overnight. The mixture wascooled to room temperature, diluted with water and extracted into DCM. The organic extract was dried over Na2SO4 filtered and concentrated under reduced pressure. The residue waspurified by silica chromatography to yield Sia (1.57 g, 62.3%). MS (ESI) mlz 431.9 [M+Hj . 1HNMR (400 MHz, Chloroform-d) oe 8.30 (dd, J = 2.4, 0.7 Hz, 1H), 7.66 (dd, J = 9.0, 2.3 Hz, 1H), 6.44 (d, J = 9.0 Hz, 1H), 4.25 (d, J = 12.7 Hz, 1H), 4.21 - 4.00 (m, 3H), 3.97 - 3.86 (m,2H), 3.80 (t, J= 11.9 Hz, 2H), 3.26 (t, J= 15.1 Hz, 2H), 1.48 (s, 9H).

Reference： [1]Patent: WO2018/145021,2018,A1 .Location in patent: Page/Page column 90; 91; 115

59
N-(5-oxopentyl)-5-(thiophen-2-yl)isoxazole-3-carboxamide [ No CAS ]
[ 149771-44-8 ]
tert-butyl 3-(5-(5-(thiophen-2-yl)isoxazole-3-carboxamido)pentyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.2%	With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 6℃; for 14h;	Step 1: Preparation of tert-Butyl 3-(5-(5-(thiophen-2-yl)isoxazole-3-carboxamido)pentyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate NaBH(OAc)3 (342.67 mg, 1.62 mmol, 1.5 eq) was added to a stirred solution of Intermediate B (300 mg, 1.08 mmol, 1.0 eq), <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (343.2 mg, 1.62 mmol, 1.5 eq) and HOAc (64.73 mg, 1.08 mmol, 1.0 eq) in 1,2-dichloroethane (12 mL) at 6 C. Then the mixture was stirred at 6 C. for 14 hours. The mixture was basified with saturated NaHCO3 aqueous solution to pH 8. The water phase was extracted with CH2Cl2 (3*3 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/EtOAc from 20/1 to 1/1 to afford the title compound (450 mg, 81.2% yield) as a colorless oil. MS (ESI) m/z 475.2 [M+H]+. 1H NMR (400 MHz, CDCl3) delta ppm 7.56 (d, J=3.2 Hz, 1H), 7.52 (d, J=4.8 Hz, 1H), 7.18-7.16 (m, 1H), 6.84 (s, 1H), 4.19-4.10 (m, 2H), 3.50-3.45 (m, 2H), 2.64-2.62 (m, 2H), 2.33-2.29 (m, 2H), 2.25-2.18 (m, 2H), 1.85-1.82 (m, 4H), 1.65-1.61 (m, 4H), 1.48 (s, 9H), 1.44-1.42 (m, 2H).

Reference： [1]Patent: US2018/271837,2018,A1 .Location in patent: Paragraph 0200

60
[ 1493-27-2 ]
[ 149771-44-8 ]
3-(2-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 5h;Inert atmosphere;	General procedure: will1-fluoro-2-nitro-4-(trifluoromethyl)benzene (2.0 g, 9.56 mmol),<strong>[149771-44-8]3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester</strong> (2.03 g, 9.56 mmol),Diisopropylethylamine (2.5 ml, 14.3 mmol) was added to 100 mL in sequenceIn a single-mouth bottle,Dissolved with N,N-dimethylformamide (20 mL),The temperature was gradually raised to 90 C under a nitrogen atmosphere for 15 hours.The reaction solution is cooled to room temperature and poured into tap water.Extracted with dichloromethane (60 mL×3),The organic phase is followed by tap water,Saturated brine and washed with anhydrous sodium sulfate.Filtered and evaporated to dryness to give a crude product.Column chromatography (petroleum ether / ethyl acetate (v / v)=20/1-10/1) purification,The title compound was obtained as a yellow liquid(3.56g, 93%).

Reference： [1]Patent: CN108727393,2018,A .Location in patent: Paragraph 0139; 0140; 0182; 0184; 0185

61
[ 446-11-7 ]
[ 149771-44-8 ]
tert-butyl 3-(4-methyl-2-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 5h;Inert atmosphere;	will1-fluoro-2-nitro-4-(trifluoromethyl)benzene (2.0 g, 9.56 mmol),3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.03 g, 9.56 mmol),Diisopropylethylamine (2.5 ml, 14.3 mmol) was added to 100 mL in sequenceIn a single-mouth bottle,Dissolved with N,N-dimethylformamide (20 mL),The temperature was gradually raised to 90 ° C under a nitrogen atmosphere for 15 hours.The reaction solution is cooled to room temperature and poured into tap water.Extracted with dichloromethane (60 mL×3),The organic phase is followed by tap water,Saturated brine and washed with anhydrous sodium sulfate.Filtered and evaporated to dryness to give a crude product.Column chromatography (petroleum ether / ethyl acetate (v / v)=20/1-10/1) purification,The title compound was obtained as a yellow liquid(3.56g, 93percent).

Reference： [1]Patent: CN108727393,2018,A .Location in patent: Paragraph 0139; 0140; 0205; 0207; 0208

62
[ 100-39-0 ]
[ 149771-44-8 ]
[ 149771-43-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In acetonitrile; at 50℃; for 5h;Inert atmosphere;	<strong>[149771-44-8]3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester</strong> (0.5 g, 2.4 mmol),Benzyl bromide (0.31 mL, 2.6 mmol) and triethylamine (0.5 ml, 3.6 mmol) were sequentially added to a 100 mL single-mouth bottle.Dissolved in acetonitrile (20 mL),The temperature was gradually raised to 50 C for 5 hours under nitrogen protection.The reaction solution was cooled to room temperature and poured into tap water.Ethyl acetate extraction (60 mL × 3), and the organic phase was reused with tap water.The mixture was washed with brine and dried over anhydrous sodium sulfate.Filtered and evaporated to dryness to give a crude product.Purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 40/1-20/1)The title compound was obtained as a white solid(0.68g, 90%).

Reference： [1]Patent: CN108727393,2018,A .Location in patent: Paragraph 0228; 0230; 0231

63
[ 367-86-2 ]
[ 149771-44-8 ]
3-(2-nitro-4-(trifluoromethyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 15h;Inert atmosphere;	will1-fluoro-2-nitro-4-(trifluoromethyl)benzene (2.0 g, 9.56 mmol),<strong>[149771-44-8]3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester</strong> (2.03 g, 9.56 mmol),Diisopropylethylamine (2.5 ml, 14.3 mmol) was added to 100 mL in sequenceIn a single-mouth bottle,Dissolved with N,N-dimethylformamide (20 mL),The temperature was gradually raised to 90 C under a nitrogen atmosphere for 15 hours.The reaction solution is cooled to room temperature and poured into tap water.Extracted with dichloromethane (60 mL×3),The organic phase is followed by tap water,Saturated brine and washed with anhydrous sodium sulfate.Filtered and evaporated to dryness to give a crude product.Column chromatography (petroleum ether / ethyl acetate (v / v)=20/1-10/1) purification,The title compound was obtained as a yellow liquid(3.56g, 93%).

Reference： [1]Patent: CN108727393,2018,A .Location in patent: Paragraph 0137; 0139; 0140

64
5-chloro-2-methyl-3-nitrobenzaldehyde [ No CAS ]
[ 149771-44-8 ]
C₁₉H₂₆ClN₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.8%		At room temperature, to the containing 5-chloro-2-methyl-3-nitrobenzaldehyde (5 g, 25 mmol) <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (5.8 g, 27.5 mmol) in anhydrous dichloromethane (100 ml) solution, dropping glacial acetic acid (1.5 g, 25 mmol), after the completion of the dropping, stirring at room temperature the reaction 1 hour, then, 0 C in batches under fed into three-acetoxy borohydride (10.6 g, 50 mmol), after finishing the adding, temperature to room temperature naturally reaction 10 hours, after the reaction, slowly dripping methanol solution (20 ml), the majority of the solvent is removed under reduced pressure, the residue through silica gel column chromatography (petroleum ether: ethyl acetate 5:1 - 1:1) to obtain the white solid 6.2 g, yield 62.8%.

Reference： [1]Patent: CN109134476,2019,A .Location in patent: Paragraph 0075; 0084; 0085

65
[ 136516-64-8 ]
[ 149771-44-8 ]
tert-butyl 3-(3-fluoro-4-formyl-5-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 2h;	A solution of <strong>[136516-64-8]2,4-difluoro-6-hydroxybenzaldehyde</strong> (600 mg, 3.80 mmol), tert-butyl3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 3.75 mmol), and DIEA (700 mg, 5.42 mmol) in DMSO (10 mL) was stirred for 2 h at 100 C. After cooling to room temperature the reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:4 EtOAc/pet. ether) afforded tert-butyl 3-(3-fluoro-4-formyl-5-hydroxyphenyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: (ESI, m/z): 351 [M+H]t

Reference： [1]Patent: WO2019/32863,2019,A1 .Location in patent: Paragraph 00202

66
5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridine [ No CAS ]
[ 149771-44-8 ]
3-[6-(2,5-dimethylpyrrol-1-yl)-4-methoxypyridin-3-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With methanesulfonato(2-dicyclohexylphosphino-2?,6?-bis(dimethylamino)-1,1?-biphenyl)(2?-amino-1,1?-biphenyl-2-yl)palladium(II); sodium t-butanolate; In 1,4-dioxane; at 80℃; for 18h;Inert atmosphere;	To 5-bromo-2-(2,5-dimethyl-pyrrol-1 -yl)-4-methoxy-pyridine (1 .00 g, 3.56 mmol) and 3,8- diaza-bicyclo[3.2.1 ]octane-8-carboxylic acid ie f-butyl ester (830 mg, 3.91 mmol) in 1 ,4- dioxane (13 mL) is added sodium fe/t-butoxide (3.48 g, 10.7 mmol) and CPhos-G3- palladacycle methane sulfonate (287 mg, 0.36 mmol). The mixture is degassed with nitrogen for 5 min, and stirred for 18h at 80C. The reaction mixture is extracted with EtOAc, washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound. (0512) Yield: 760 mg (52%) ESI-MS: m/z = 412 (M+H)+ Rt(HPLC): 1.23 min (Method 1 )

Reference： [1]Patent: WO2019/81637,2019,A1 .Location in patent: Page/Page column 67; 68

67
[ 446273-59-2 ]
[ 149771-44-8 ]
tert-butyl 3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 130℃; for 3h;	Into a 100-mL round-bottom flask, was placed a solution of <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (2.0 g, 9.42 mmol, 1.00 equiv) in dimethyl sulfoxide (40 mL), N,N-diisopropylethylamine (714.0 mg, 5.52 mmol, 4.00 equiv), 4-bromo-6-chloropyridazin-3-amine (3.0 g, 14.39 mmol, 1.50 equiv). The resulting solution was stirred for 3 hours at 130 C. in an oil bath. The reaction was then quenched by the addition of water (90 mL). The resulting solution was extracted with ethyl acetate (80 mL3) and the organic layers combined. The resulting mixture was washed with brine (100 mL1). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10/1). The collected fractions were combined and concentrated under vacuum. This resulted in 1.7 g (53%) of tert-butyl 3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid.

Reference： [1]Patent: US2019/300521,2019,A1 .Location in patent: Paragraph 0838-0839

68
[ 501-53-1 ]
[ 149771-44-8 ]
8-benzyl 3-(tert-butyl) 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine; In dichloromethane; at 20℃;	To a solution of <strong>[149771-44-8]tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate</strong> (10 g, 47.11 mmol, 1 eq) in dichloromethane (140 mL) was added CbzCl (9.64 g, 56.53 mmol, 8.04 mL, 1.2 eq) and triethylamine (8.58 g, 84.79 mmol, 11.80 mL, 1.8 eq). The mixture was stirred at 20 C. for 20 hours. TLC (dichloromethane:methanol=10:1) showed reactant 1 was not consumed completely, so CbzCl (1.61 g, 9.42 mmol, 1.34 mL, 0.2 eq) was added again. The reaction mixture was stirred at 20 C. for 2 hours. The reaction mixture was washed with water (80 mL) two times, the organic layer was dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:0 to 4:1). Compound 8-benzyl 3-(tert-butyl) 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (11.48 g, 33.14 mmol, 70% yield) was obtained as colorless oil.

Reference： [1]Patent: US2019/300521,2019,A1 .Location in patent: Paragraph 0982-0983

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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

[ CAS No. 149771-44-8 ]

Quality Control of [ 149771-44-8 ]

Related Doc. of [ 149771-44-8 ]

Product Details of [ 149771-44-8 ]

Calculated chemistry of [ 149771-44-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 149771-44-8 ]

Application In Synthesis of [ 149771-44-8 ]

[ 149771-44-8 ] Synthesis Path-Upstream 1~11

[ 149771-44-8 ] Synthesis Path-Downstream 1~68

Similar Product of [ 149771-44-8 ]

Related Functional Groups of [ 149771-44-8 ]

Amides

Related Parent Nucleus of [ 149771-44-8 ]

Aliphatic Heterocycles

Other Aliphatic Heterocycles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Similar Product of
[ 149771-44-8 ]

Related Functional Groups of
[ 149771-44-8 ]

Related Parent Nucleus of
[ 149771-44-8 ]