[ CAS No. 227940-71-8 ] {[proInfo.proName]}

Name: 227940-71-8|tert-Butyl 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate|95%
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Quality Control of [ 227940-71-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 227940-71-8 ]

Product Details of [ 227940-71-8 ]

CAS No. :	227940-71-8	MDL No. :	MFCD08274937
Formula :	C₁₉H₂₈N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JFLCCGFMLBSXBA-UHFFFAOYSA-N
M.W :	316.44	Pubchem ID :	22490266
Synonyms :

Calculated chemistry of [ 227940-71-8 ]

Physicochemical Properties

Num. heavy atoms :	23
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.63
Num. rotatable bonds :	5
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	100.2
TPSA :	32.78 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.45
Log Po/w (XLOGP3) :	3.06
Log Po/w (WLOGP) :	2.46
Log Po/w (MLOGP) :	2.9
Log Po/w (SILICOS-IT) :	2.4
Consensus Log Po/w :	2.85

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.59
Solubility :	0.0808 mg/ml ; 0.000255 mol/l
Class :	Soluble
Log S (Ali) :	-3.41
Solubility :	0.122 mg/ml ; 0.000385 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.83
Solubility :	0.0465 mg/ml ; 0.000147 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.91

Safety of [ 227940-71-8 ]

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

Application In Synthesis of [ 227940-71-8 ]

* 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 [ 227940-71-8 ]
Downstream synthetic route of [ 227940-71-8 ]

[ 227940-71-8 ] Synthesis Path-Upstream 1~4

1
[ 227940-70-7 ]
[ 227940-71-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: With hydrazine hydrate In diethylene glycol at 60℃; for 0.166667 h; Stage #2: With potassium hydroxide In diethylene glycol at 160℃; for 8 h;	A mixture of compound 2 (660 mg, 2 mmol), hydrazine monohydrate (0.472 mL, 10 mmol) and diethylene glycol was stirred at 60 C. After 10 min, KOH (828 mg, 14.8 mmol) was added and refluxed at 160 C for 8 hrs. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with dichloromethane(3 x 200 mL).The organic layer was dried over anhydrous Na₂SO₄, filtered and evaporated to yield 540 mg of the compound 3.Yield: 85 percent. ¹H NMR (CDCl₃, 300 MHz) 1.52 (br s, 9H), 1.56-1.72 (br m, 2H), 1.78 (br s, 1H), 1.87 (br s, 1H), 2.12-2.26 (br m, 2H), 2.84-3.14 (br m, 4H), 3.29 (d, 1H, J = 13.5 Hz), 3.44 (d, 1H, J = 13.5 Hz), 3.99 (d, 1H, J = 13.2 Hz), 4.16 (d, 1H, J = 13.2 Hz), 7.26 (br m, 5H). ¹³C NMR (CDCl₃, 75 MHz) 28.6, 28.8, 31.0, 47.4, 48.2, 58.6, 58.8, 63.3, 78.5, 126.4, 127.9, 128.4, 138.8, 154.8. IR (KBr): 3428 (br), 3058, 2974, 2920, 2857, 2805, 2768, 1681, 1453, 1422, 1362, 1329, 1241, 1176, 1128 cm^-1. (HRMS): calcd for C₁₉H₂₉N₂O₂ m/z 317.2229,found m/z 317.2229
66%	With hydrazine hydrate; potassium hydroxide In diethylene glycol dimethyl ether at 140℃; for 6 h;	A stirred mixture of compound 4 (12.1 g, 0.037 mol), hydrazine hydrate (9 mL, 0.184 mol), and diglyme (60 mL) was heated to 70 °C, treated with KOH (14.5 g, 0.259 mol), and heated at 140 °C for 6 h. After cooling to 80 °C, the mixture was diluted with water (150 mL), stirred for 15 mL, cooled to room temperature, extracted with hexane, dried with Na2SO4, and filtered through a short silica gel layer (elution with AcOEt—hexane, 1 : 4) to give 7.7 g (66percent) of product 5. 1H NMR (400 MHz, CDCl3), δ: 1.54 (s, 9 H); 1.61—1.70 (m, 2 H); 1.81 (br.s, 1 H); 1.89 (br.s, 1 H); 2.17—2.25 (m, 2 H); 2.91—3.17 (m, 4 H); 3.32 (d, 1 H, J = 13.6 Hz); 3.46 (d, 1 H, J = 13.5 Hz); 4.02 (d, 1 H, J = 13.1 Hz); 4.18 (d, 1 H, J = 13.1 Hz); 7.21—7.36 (m, 5 H). 13C NMR (75 MHz, CDCl3), δ: 28.60; 28.86; 31.05; 47.45; 48.28; 58.60; 58.90; 63.38; 78.59; 126.49; 127.93; 128.44; 138.89; 154.94.
66%	With hydrazine hydrate; potassium hydroxide In diethylene glycol dimethyl ether at 70 - 150℃; for 6 h;	To a stirring at 70°C solution of 3 (12.1g, 0.037mol), hydrazine monohydrate (9ml, 0.184mol) and diglyme (60ml) was added KOH (14.5g, 0.259mol). The mixture was stirred at 150°C 6h, cooled to 80°C, diluted with water (150ml) and stirred for 30min. The resulting mixture was extracted with petroleum ether (3×150ml). The combined organic layers were washed with water, brine, dried over Na₂SO₄ and evaporated. The residue was purified by SiO₂ column chromatography with AcOEt/petroleum ether (1/9) to afford 4 (7.7g, 66percent) as a colorless oil. IR (thin film, ν, cm ⁻¹): 1689 (OC=O), 736, 699 (C₆H₅). EI-MS, m/z (RI, percent): 317 [M+H]⁺ (21), 259 [M-t-Bu]⁺ (100), 215 [M-Boc]⁺ (39). ¹H NMR (400MHz, CDCl₃) δ 7.36–7.22 (m, 5H, Ph), 4.19 (d, J=13.0Hz, 1H, CH₂NBoc), 4.02 (d, J=13.1Hz, 1H, CH₂NBoc), 3.47 (d, J=13.6Hz, 1H, CH₂Ph), 3.32 (d, J=13.6Hz, 1H, CH₂Ph), 3.20–2.97 (m, 3H, CH₂NBoc, CH₂NBn), 2.91 (d, J=10.8Hz, 1H, CH₂NBn), 2.25 (d, J=10.8Hz, 1H, CH₂Bn), 2.18 (d, J=10.8Hz, 1H, CH₂Bn), 1.90 (br s, 1H, CH), 1.81 (br s, 1H, CH), 1.68 and 1.62 (d, AB system, J=12.2Hz, 2H, CH₂), 1.55 (s, 9H, CMe₃). ¹³C NMR (101MHz, CDCl₃) δ 155.08 (C=O), 139.03 (ipso-Ph), 128.59 (o-Ph), 128.07 (m-Ph), 126.63 (p-Ph), 78.73 (CMe₃), 63.51 (CH₂Ph), 59.03 and 58.74 (CH₂NBn), 48.42 and 47.59 (CH₂NBoc), 31.18 (CH₂), 29.00 (CH), 28.73 (CMe₃).

60%	Stage #1: With toluene-4-sulfonic acid hydrazide In isopropyl alcohol for 2 h; Heating / reflux Stage #2: With sodium cyanoborohydride; acetic acid In isopropyl alcohol for 2 h; Heating / reflux	[0268] A mixture of 4-toluenesulfonehydrazide (12.4 mmol; 2.30 g) and tert-butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (10.1 mmol; 4.00 g; 83.3percent; from step (a) above) were dissolved in iso-propanol (30 mL) and heated at reflux for 2 hours. Acetic acid (2.5 mmol; 0.15 g) and sodium cyanoborohydride (12.1 mmol, 0.76 g) were added and the mixture was again heated at reflux for 2 hours. The slurry was cooled to ambient temperature and filtered. The filtrate was concentrated and an extractive work-up was performed in toluene:water. The toluene solution was concentrated to give 0.95 g of sub-title compound, with a purity of 90 area percent (GC) in a yield of 60percent. [0269] MS (EI; 70 eV): m/z 259 (100percent), m/z 91 (95percent), m/z 169 (45percent), m/z 57 (35percent), m/z 316 (25percent) [0270] 13C NMR (CDCl3): δ 28.67, 28.95, 31.11, 47.55, 48.38, 58.70, 58.96, 63.46, 78.71, 126.57, 128.00, 128.53, 138.94, 155.20 (using TMS as a reference)
57.54%	With hydrazine hydrate; potassium hydroxide In diethylene glycol at 60 - 160℃; for 8 h;	To a mixture of 4-Oxo-piperidine-l -carboxylic acid tert-butyl ester (2g, 1 eq, 6.1 mmol) hydrazine monohydrate (0.33 g, 1.1 eq, 6.6mmol) and diethylene glycol (27.83ml) was added. At 60°C, powdered KOH (2.504g) was added to the reaction mixture and again heated at 160°C for 8 hrs. Then the mixture was cooled and water (40ml) was added and allowed to stir. The reaction mixture was extracted with dichloromethane and combined organics were dried with anhydrous Na₂S0₄ concentrated to obtain oily residue (2.33 l g). The crude product was purified by column chromatography on silica gel (n-hexane/ethyl acetate =9/1 ) to obtain pure product. Yield = 57.54percent; IR (Neat): 3016.3, 2922.7, 1672.4, 1427.3, 1217.4, 1 174.6 cm^"1; NMR (300MHz, CDCI3 , ppm) 87.36-7.23 (m, 5H, Ph-H); 4.19-4.13 (br d, J=18Hz, 1H, CONCH); 4.03- 3.99 (br d, J=12Hz, I H, CONCH); 3.48-3.44 (d, J=12Hz, I H, CH_2APh);3.34-3.30 (d, J=12Hz, IH, CH_2BPh); 3.13-3.09 (m, 2H, 2 x CONH); 3.03-2.98 (br d, J= 15Hz, I H, NCH); 2.92-2.89 (br d, J=9Hz, 1 H.NCH); 2.25-2.17 (m, 2H, 2 X NCH); 1 .89 (br s, IH, CH); 1.81 (br s, IH, CH); 1.68 (m, 2H, bridge CH₂); 1.54 (s, 9H, CMe₃); ¹³C NMR (50 MHz, CDC1₃, ppm) 6155.15(C=0), 128.68 (Ph), 128.10(Ph), 126.68 (Ph), 78.83 (CMe₃), 63.49 (CH₂Ph), 58.77 (NCH₂), 48.43 (CONCH₂), 47.65 (CONCH₂), 37.63 (bridge-CH₂), 31.10 (2XCH), 28.72 (CH₃); MS (ESI):317.3(M+H)⁺
27%	Stage #1: With toluene-4-sulfonic acid hydrazide In ethanol at 20℃; for 2 h; Heating / reflux Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 0 - 20℃; for 3.58333 h; Heating / reflux	To a stirring solution of title compound 228 (3.6 g, 10.90 mmol) in EtOH (100 mL) was added /?-toluenesulfanhydrazine (2.435 g, 13.07 mmol) at room temperature then the reaction mixture was heated at reflux for 2h. The mixture was cooled to room temperature and concentrated. The residue was dissolved in THF (60 mL) and water (15 mL) and NaBH₄(4.12 g, 109 mmol) was added portionwise at 0 ⁰C over 5 min (effervescence). The reaction mixture was stirred for 30 minutes at room temperature then 3h at reflux. The mixture was cooled, water was added and the mixture was extracted with Et₂O (4 times). The organic extracts were dried over Na₂SO₄, filtered and concentrated. Purified residue by flash chromatography: 4Og SiO₂, 0percent to 50percent EA / hexanes over 30 min. to afford title compound229 (1.35 g, 27percent). LRMS(ESI): (calc.) 316.22 (found) 317.5 (MH)+.
27%	Stage #1: With toluene-4-sulfonic acid hydrazide In ethanol at 20℃; Reflux Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 0 - 20℃; for 3.58166 h; Reflux	To a stirring solution of title compound 228 (3.6 g, 10.90 mmol) in EtOH (100 mL) was added /?-toluenesulfanhydrazine (2.435 g, 13.07 mmol) at room temperature then the reaction mixture was heated at reflux for 2h. The mixture was cooled to room temperature and concentrated. The residue was dissolved in THF (60 mL) and water (15 mL) and NaBH4 (4.12 g, 109 mmol) was added portionwise at 0 0C over 5 min (effervescence). The reaction mixture was stirred for 30 minutes at room temperature then 3h at reflux. The mixture was cooled, water was added and the mixture was extracted with Et2O (4 times). The organic extracts were dried over Na2SO4, filtered and concentrated. Purified residue by flash chromatography: 4Og SiO2, 0percent to 50percent EA / hexanes over 30 min. to afford title compound 229 (1.35 g, 27percent). LRMS(ESI): (calc.) 316.22 (found) 317.5 (MH)+.
27%	Stage #1: With toluene-4-sulfonic acid hydrazide In ethanol for 2 h; Reflux Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 0℃; for 3.5 h; Reflux	To a stirring solution of title compound 228 (3.6 g, 10.90 mmol) in EtOH (100 mL) was added p-toluenesulfanhydrazine (2.435 g, 13.07 mmol) at room temperature then the reaction mixture was heated at reflux for 2 h. The mixture was cooled to room temperature and concentrated. The residue was dissolved in THF (60 mL) and water (15 mL) and NaBH₄(4.12 g, 109 mmol) was added portionwise at 0° C. over 5 min (effervescence). The reaction mixture was stirred for 30 minutes at room temperature then 3 h at reflux. The mixture was cooled, water was added and the mixture was extracted with Et₂O (4 times). The organic extracts were dried over Na₂SO₄, filtered and concentrated. Purified residue by flash chromatography: 40 g SiO₂, 0percent to 50percent EA/hexanes over 30 min. to afford title compound 229 (1.35 g, 27percent). LRMS(ESI): (calc.) 316.22 (found) 317.5 (MH)+.

Reference： [1] Tetrahedron Letters, 2012, vol. 53, # 6, p. 623 - 626
[2] Physical Chemistry Chemical Physics, 2016, vol. 18, # 22, p. 15046 - 15053
[3] Journal of the American Chemical Society, 2008, vol. 130, # 17, p. 5654 - 5655
[4] Advanced Synthesis and Catalysis, 2008, vol. 350, # 13, p. 2001 - 2006
[5] Russian Chemical Bulletin, 2016, vol. 65, # 10, p. 2479 - 2484[6] Izv. Akad. Nauk, Ser. Khim., 2016, vol. 65, # 10, p. 2479 - 2484,5
[7] Journal of Organometallic Chemistry, 2017, vol. 846, p. 169 - 175
[8] Patent: US2004/229900, 2004, A1, . Location in patent: Page 14
[9] Patent: WO2015/44951, 2015, A1, . Location in patent: Page/Page column 16; 17
[10] Chemical communications (Cambridge, England), 2002, # 7, p. 673 - 675
[11] Patent: WO2008/55068, 2008, A2, . Location in patent: Page/Page column 229
[12] Patent: WO2009/137503, 2009, A1, . Location in patent: Page/Page column 58
[13] Patent: US2017/749, 2017, A1, . Location in patent: Paragraph 0059
[14] Chemistry - A European Journal, 2002, vol. 8, # 20, p. 4767 - 4780
[15] Patent: WO2013/50938, 2013, A1,
[16] Biochemical Journal, 2017, vol. 474, # 1, p. 123 - 147

2
[ 24424-99-5 ]
[ 69407-32-5 ]
[ 227940-71-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 20℃;	(iv) tert-Butyl 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate Di-tert-butyl dicarbonate was added slowly to a solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (see Example 9(ii) above; 60 g; 277 mmol) in THF (600 ML).. The reaction was stirred at rt until all of the starting material had been consumed (as indicated by tlc).. The solvent was then removed under reduced pressure to give a quantitative yield of the sub-title compound.

Reference： [1] Patent: EP1192154, 2004, B1, . Location in patent: Page 28
[2] Patent: US6465481, 2002, B1,

3
[ 69407-32-5 ]
[ 227940-71-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran	Di-tert-butyl dicarbonate was added slowly to a solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (from step (iii) above; 60 g; 277 mmol) in THF (600 mL). The reaction was stirred at n until all of the starting material had been consumed (as indicated by tlc). The solvent was then removed under reduced pressure to give a quantitative yield of the sub-title compound.

Reference： [1] Patent: EP1192156, 2004, B1, . Location in patent: Page 24

4
[ 1576-35-8 ]
[ 227940-70-7 ]
[ 227940-71-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium cyanoborohydride; acetic acid In water; isopropyl alcohol; toluene	(b) tert-Butyl 7-benzyl-3.7-diazabicyclo[3,3,1]-nonane-3-carboxylate A mixture of 4-toluenesulfonehydrazide (12.4 mmol; 2.30 g) and tert-butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (10.1 mmol; 4.00 g; 83.3percent; from step (a) above) were dissolved in isopropanol (30 mL) and heated at reflux for 2 hours. Acetic acid (2.5 mmol; 0.15 g) and sodium cyanoborohydride (12.1 mmol, 0.76 g) were added and the mixture was again heated at reflux for 2 hours. The slurry was cooled to ambient temperature and filtered. The filtrate was concentrated and an extractive work-up was performed in toluene:water. The toluene solution was concentrated to give 0.95 g of sub-title compound, with a purity of 90 area percent (GC) in a yield of 60percent. MS (EI; 70 eV): m/z 259 (100percent), m/z 91 (95percent), m/z 169 (45percent), m/z 57 (35percent), m/z 316 (25percent); ¹³C NMR (CDCl₃): 28.67, 28.95, 31.11, 47.55, 48.38, 58.70, 58.96, 63.46, 78.71, 126.57, 128.00, 128.53, 138.94, 155.20 ppm using TMS as a reference
60%	With sodium cyanoborohydride; acetic acid In water; isopropyl alcohol; toluene	(c) tert-Butyl 7-benzyl-3,7-diazabicyclo[3.3. 1]-nonane-3-carboxylate A mixture of 4-toluenesulfonehydrazide (12.4 mmol; 2.30 g) and tert-butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (10.1 mmol; 4.00 g; 83.3percent; from step (a) above) were dissolved in isopropanol (30 mL) and heated at reflux for 2 hours. Acetic acid (2.5 mmol; 0.15 g) and sodium cyanoborohydride (12.1 mmol, 0.76 g) were added and the mixture was again heated at reflux for 2 hours. The slurry was cooled to ambient temperature and filtered. The filtrate was concentrated and an extractive work-up was performed in toluene:water. The toluene solution was concentrated to give 0.95 g of sub-title compound, with a purity of 90 area percent (GC) in a yield of 60percent. MS (EI; 70 eV): m/z 259 (100percent), m/z 91 (95percent), m/z 169 (45percent), m/z 57 (35percent), m/z 316 (25percent). ¹³C NMR (CDCl₃): δ 28.67, 28.95, 31.11, 47.55, 48.38, 58.70, 58.96, 63.46, 78.71, 126.57, 128.00, 128.53, 138.94, 155.20 ppm using TMS as a reference.

Reference： [1] Patent: US6492382, 2002, B1,
[2] Patent: US6291475, 2001, B1,

[ 227940-71-8 ] Synthesis Path-Downstream 1~59

1
[ 227940-71-8 ]
[ 227940-72-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With hydrogen;palladium(II) hydroxide/carbon; In methanol; at 50℃; under 2844.39 Torr; for 2h;	Example 8: Synthesis of 3,7-diazabicyclo[3.3.1]nonane-3-carboxyIic acid tert-butyl esterExample 8 relates to the synthesis of 3,7-diazabicyclo[3.3.1]nonane-3- carboxylic acid tert-butyl ester (or N-(tert-butoxycarbonyl)-3,7- diazabicyclo[3.3.1]nonane), which was prepared according to the following techniques:7-Benzyl-3,7-diazabicyclo [3.3.1 ] nonane-3-carboxylic acid tert-butyl ester (or N-benzyl-N'-(tert-butoxycarbonyI)-3,7- diazabicyclo[3.3.1]nonane); 7-Benzyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxylic acid tert-butyl ester was prepared according to procedures set forth by Stead et al. in Org. Lett. 7(20): 4459 (2005).3,7-Diazabicyclo[3.3.1]-3-carboxyIic acid tert-butyl ester 7-Benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester(0.49 g, 1.6 mmol) was dissolved in methanol (20 mL) and 20% Pd(OH)2/C (wet) (~ 2 g) was added under a nitrogen atmosphere. This mixture was warmed to about 5O0C and shaken for 2 h under 55 psi of hydrogen. The resulting mixture was EPO <DP n="35"/>filtered and concentrated to give 0.32 g (94% yield) of the title compound (MS m/z 227 (M+H)).
94%	With hydrogen;20% palladium hydroxide-activated charcoal; In methanol; at 50℃; under 2844.39 Torr; for 2h;	7-Benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (0.49 g, 1.6 mmol) was dissolved in methanol (20 ml.) and 20% Pd(OH)2/C (wet) (~ 2 g) was added under a nitrogen atmosphere. This mixture was warmed to about 50 0C and shaken for 2 h under 55 psi of hydrogen. The resulting mixture was filtered and concentrated to give 0.32 g (94% yield) of the title compound (MS m/z 227 (M+H)).
93.33%	With 10 wt% Pd(OH)2 on carbon; hydrogen; In methanol; at 55℃;	Palladium hydroxide (0.5g),(Pearlman's catalyst), was added portion wise to a suspension of compound 12 (1.102g, 0.0367 mol) in methanol (25ml) in steel parr. The I reaction mixture was hydrogenated at 55C and 150 psi for about 17 hrs. Then it was 2 allowed to cool and filtered over sintered funnel with the aid of vacuum and concentrated to get pale yellow solid. Yield = 93.33%; MP:75C; IR ( Br): 2979.2, 2919.7, 2858.5, 1679.6, 1402.4, 1240.4, 1 172.3 1 131.9 cm"' ; IH NMR (300MHz, CDC13, ppm): 64.13-4.09 (brd, J= 12Hz, 2H, 2 x CONCH); 3.14-3.10 (m, 3H, 2 x CONCH, NCH); 3.01-2.96 (brd, J= 15Hz, I H, NCH); 2.25 (s, 2H, 2 x NH); 1.92- 1 .88 (d, J=12Hz, I H, CH); 1.80- 1 .76 (d, J= 12Hz, I H, CH); 1 .67 (s, bridge CH2); 1.48 (s,9H,CMe3); 13C NMR (50 MHz, CDCI3, ppm): 6155.49 (C=0), 79.78 (CMe3), 51 .50 (NCH2), 48.94 (C(0)NCH2), 31.39 (CH), 28.52 (CMe3), 28.15 (CMe3); MS (ESI):227.1481(M+H)+

93.33%	With hydrogen; palladium(II) hydroxide; In methanol; at 55℃; under 7757.43 Torr; for 10h;	6.1.3 3,7-Diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (10) Palladium hydroxide (0.5 g) was added portion wise to a suspension of 8 (1.102 g, 36.7 mmol) in methanol (25 ml) in steel parr under nitrogen atmosphere. The reaction mixture was hydrogenated at 55 C and 150 psi for about 10 h. Then it was allowed to cool and filtered over sintered funnel with the aid of vacuum and concentrated to get pale yellow solid. Yield = 93.33%; MP: 75 C; IR (KBr): 2979.2, 2919.7, 2858.5, 1679.6, 1402.4, 1240.4, 1172.31131.9 cm-1; 1H NMR (300 MHz, CDCl3, ppm): delta 4.13-4.09 (d, J = 12 Hz, 2H, 2 * CONCH); 3.14-3.10 (m, 3H, 2 * CONCH, NCH); 3.01-2.96 (d, J = 15 Hz, 1H, NCH); 2.25 (s, 2H, 2 * NH); 1.92-1.88 (d, J = 12 Hz, 1H, CH); 1.80-1.76 (d, J = 12 Hz, 1H, CH); 1.67 (s, 2H, bridge CH2); 1.48 (s, 9H, CMe3); 13C NMR (50 MHz, CDCl3, ppm): delta155.49, 79.78, 51.50, 48.94, 31.39, 28.52, 28.15; MS (ESI): 227.1481(M+H)+.
92%	With palladium 10% on activated carbon; hydrogen; In ethanol; for 4h;	To a solution of 3 (350 mg, 1.11 mmol) in 30mL of dry ethanol was added 28 % of the Pd, 10 wt. % on activated carbon, and H2 was bubbled through the reaction mixture for 4 hrs. The reaction was monitored by TLC. The solution was filtered through a sintered funnel and evaporated to yield 230 mg of the product 4. Yield: 92 %. (HRMS): calcd for C12H23N2O2 m/z 227.1760, found m/z 227.1750
85%		A mixture of 4 (20g, 0.063mol), ammonium formate (16g, 0.254mol) and 5% Pd/C (contains 50% H2O, 4g) in MeOH (350ml) was refluxed with stirring for 1h, cooled and filtered through celite. The solution was evaporated to the volume of 100ml and 10N NaOH (100ml) was added. The mixture was refluxed with stirring for 1h, extracted with CHCl3, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by SiO2 column chromatography with CHCl3/MeOH (9/1) to afford 5 (12.2g, 85%) as a colorless oil. IR (thin film,nu, cm -1): 1691 (OC=O). EI-MS, m/z (RI, %): 227 [M+H]+ (68), 169 [M-t-Bu]+ (72), 126 [M-Boc+H]+ (48). 1H NMR (600MHz, CDCl3) delta 4.14-4.05 (m 2H, CH2NBoc), 3.19-3.02 (m, 4H, CH2NBoc, CH2NH), 2.97 (d, J=13.1Hz, 2H, CH2NH), 1.89 and 1.77 (d, AB system, J=12.6Hz, 2H, CH2), 1.72-1.55 (m, 3H, 2CH+NH), 1.47 (s, 9H, CMe3). 13C NMR (151MHz, CDCl3) delta 155.43 (C=O, Boc), 79.61 (CMe3), 51.82 (CH2NH), 49.46 and 48.42 (CH2NBoc), 31.57 (CH2), 28.51 (CMe3), 28.28 (CH).
		(v) tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate The sub-title compound was prepared in quantitative yield according to the procedure described in step (iii) above, using <strong>[227940-71-8]tert-butyl 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate</strong> (from step (iv) above) in place of 3,7-dibenzyl-3,7-diazabicyclo[3.3.1]nonane. 13C NMR in CDCl3: delta 28.05, 28.29, 31.33, 48.35, 49.11, 51.53, 79.34, 155.16
	With palladium 10% on activated carbon; hydrogen; In ethanol; water; at 20℃; under 760.051 Torr; for 16h;	Tert-butyl 7-benzyl-3,7-diazabicyclo[3.3.1 ]nonane-3-carboxylate (7 g; 21 .3 mmol), dissolved in 20 ml EtOH was carefully added to a suspension of Palladium 10% on charcoal 50% water in EtOH (180 ml): The reaction mixture was evacuated and put under hydrogen (1 atm) three times then stirring was continued under a hydrogen pressure (1 atm) at RT for 16 h. The reaction mixture was filtered over celite and the solvent was evaporated under reduced pressure to give tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate. LC-MS: tR = 0.42 min; [M+H]+ = 227.15. Method (B)

Reference： [1]Physical Chemistry Chemical Physics,2016,vol. 18,p. 15046 - 15053
[2]Patent: WO2008/57938,2008,A1 .Location in patent: Page/Page column 33-34
[3]Patent: WO2009/111550,2009,A1 .Location in patent: Page/Page column 38
[4]Patent: WO2015/44951,2015,A1 .Location in patent: Page/Page column 17; 18
[5]European Journal of Medicinal Chemistry,2016,vol. 110,p. 1 - 12
[6]Tetrahedron Letters,2012,vol. 53,p. 623 - 626
[7]Journal of Organometallic Chemistry,2017,vol. 846,p. 169 - 175
[8]Journal of the American Chemical Society,2008,vol. 130,p. 5654 - 5655
[9]Advanced Synthesis and Catalysis,2008,vol. 350,p. 2001 - 2006
[10]Chemical Communications,2002,p. 673 - 675
[11]Chemistry - A European Journal,2002,vol. 8,p. 4767 - 4780
[12]Patent: US6465481,2002,B1
[13]Patent: EP1192154,2004,B1 .Location in patent: Page 28
[14]Patent: WO2013/50938,2013,A1 .Location in patent: Page/Page column 56
[15]Chemical Communications,2013,vol. 49,p. 10980 - 10982

2
[ 227940-70-7 ]
[ 227940-71-8 ]

Yield	Reaction Conditions	Operation in experiment
85%		A mixture of compound 2 (660 mg, 2 mmol), hydrazine monohydrate (0.472 mL, 10 mmol) and diethylene glycol was stirred at 60 C. After 10 min, KOH (828 mg, 14.8 mmol) was added and refluxed at 160 C for 8 hrs. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with dichloromethane (3 x 200 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to yield 540 mg of the compound 3. Yield: 85 %. 1H NMR (CDCl3, 300 MHz) 1.52 (br s, 9H), 1.56-1.72 (br m, 2H), 1.78 (br s, 1H), 1.87 (br s, 1H), 2.12-2.26 (br m, 2H), 2.84-3.14 (br m, 4H), 3.29 (d, 1H, J = 13.5 Hz), 3.44 (d, 1H, J = 13.5 Hz), 3.99 (d, 1H, J = 13.2 Hz), 4.16 (d, 1H, J = 13.2 Hz), 7.26 (br m, 5H). 13C NMR (CDCl3, 75 MHz) 28.6, 28.8, 31.0, 47.4, 48.2, 58.6, 58.8, 63.3, 78.5, 126.4, 127.9, 128.4, 138.8, 154.8. IR (KBr): 3428 (br), 3058, 2974, 2920, 2857, 2805, 2768, 1681, 1453, 1422, 1362, 1329, 1241, 1176, 1128 cm-1. (HRMS): calcd for C19H29N2O2 m/z 317.2229, found m/z 317.2229
66%	With hydrazine hydrate; potassium hydroxide; In diethylene glycol dimethyl ether; at 140℃; for 6h;	A stirred mixture of compound 4 (12.1 g, 0.037 mol), hydrazine hydrate (9 mL, 0.184 mol), and diglyme (60 mL) was heated to 70 C, treated with KOH (14.5 g, 0.259 mol), and heated at 140 C for 6 h. After cooling to 80 C, the mixture was diluted with water (150 mL), stirred for 15 mL, cooled to room temperature, extracted with hexane, dried with Na2SO4, and filtered through a short silica gel layer (elution with AcOEt-hexane, 1 : 4) to give 7.7 g (66%) of product 5. 1H NMR (400 MHz, CDCl3), delta: 1.54 (s, 9 H); 1.61-1.70 (m, 2 H); 1.81 (br.s, 1 H); 1.89 (br.s, 1 H); 2.17-2.25 (m, 2 H); 2.91-3.17 (m, 4 H); 3.32 (d, 1 H, J = 13.6 Hz); 3.46 (d, 1 H, J = 13.5 Hz); 4.02 (d, 1 H, J = 13.1 Hz); 4.18 (d, 1 H, J = 13.1 Hz); 7.21-7.36 (m, 5 H). 13C NMR (75 MHz, CDCl3), delta: 28.60; 28.86; 31.05; 47.45; 48.28; 58.60; 58.90; 63.38; 78.59; 126.49; 127.93; 128.44; 138.89; 154.94.
66%	With hydrazine hydrate; potassium hydroxide; In diethylene glycol dimethyl ether; at 70 - 150℃; for 6h;	To a stirring at 70C solution of 3 (12.1g, 0.037mol), hydrazine monohydrate (9ml, 0.184mol) and diglyme (60ml) was added KOH (14.5g, 0.259mol). The mixture was stirred at 150C 6h, cooled to 80C, diluted with water (150ml) and stirred for 30min. The resulting mixture was extracted with petroleum ether (3×150ml). The combined organic layers were washed with water, brine, dried over Na2SO4 and evaporated. The residue was purified by SiO2 column chromatography with AcOEt/petroleum ether (1/9) to afford 4 (7.7g, 66%) as a colorless oil. IR (thin film, nu, cm -1): 1689 (OC=O), 736, 699 (C6H5). EI-MS, m/z (RI, %): 317 [M+H]+ (21), 259 [M-t-Bu]+ (100), 215 [M-Boc]+ (39). 1H NMR (400MHz, CDCl3) delta 7.36-7.22 (m, 5H, Ph), 4.19 (d, J=13.0Hz, 1H, CH2NBoc), 4.02 (d, J=13.1Hz, 1H, CH2NBoc), 3.47 (d, J=13.6Hz, 1H, CH2Ph), 3.32 (d, J=13.6Hz, 1H, CH2Ph), 3.20-2.97 (m, 3H, CH2NBoc, CH2NBn), 2.91 (d, J=10.8Hz, 1H, CH2NBn), 2.25 (d, J=10.8Hz, 1H, CH2Bn), 2.18 (d, J=10.8Hz, 1H, CH2Bn), 1.90 (br s, 1H, CH), 1.81 (br s, 1H, CH), 1.68 and 1.62 (d, AB system, J=12.2Hz, 2H, CH2), 1.55 (s, 9H, CMe3). 13C NMR (101MHz, CDCl3) delta 155.08 (C=O), 139.03 (ipso-Ph), 128.59 (o-Ph), 128.07 (m-Ph), 126.63 (p-Ph), 78.73 (CMe3), 63.51 (CH2Ph), 59.03 and 58.74 (CH2NBn), 48.42 and 47.59 (CH2NBoc), 31.18 (CH2), 29.00 (CH), 28.73 (CMe3).

60%		[0268] A mixture of 4-toluenesulfonehydrazide (12.4 mmol; 2.30 g) and tert-butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (10.1 mmol; 4.00 g; 83.3%; from step (a) above) were dissolved in iso-propanol (30 mL) and heated at reflux for 2 hours. Acetic acid (2.5 mmol; 0.15 g) and sodium cyanoborohydride (12.1 mmol, 0.76 g) were added and the mixture was again heated at reflux for 2 hours. The slurry was cooled to ambient temperature and filtered. The filtrate was concentrated and an extractive work-up was performed in toluene:water. The toluene solution was concentrated to give 0.95 g of sub-title compound, with a purity of 90 area % (GC) in a yield of 60%. [0269] MS (EI; 70 eV): m/z 259 (100%), m/z 91 (95%), m/z 169 (45%), m/z 57 (35%), m/z 316 (25%) [0270] 13C NMR (CDCl3): delta 28.67, 28.95, 31.11, 47.55, 48.38, 58.70, 58.96, 63.46, 78.71, 126.57, 128.00, 128.53, 138.94, 155.20 (using TMS as a reference)
57.54%	With hydrazine hydrate; potassium hydroxide; In diethylene glycol; at 60 - 160℃; for 8h;	To a mixture of 4-Oxo-piperidine-l -carboxylic acid tert-butyl ester (2g, 1 eq, 6.1 mmol) hydrazine monohydrate (0.33 g, 1.1 eq, 6.6mmol) and diethylene glycol (27.83ml) was added. At 60C, powdered KOH (2.504g) was added to the reaction mixture and again heated at 160C for 8 hrs. Then the mixture was cooled and water (40ml) was added and allowed to stir. The reaction mixture was extracted with dichloromethane and combined organics were dried with anhydrous Na2S04 concentrated to obtain oily residue (2.33 l g). The crude product was purified by column chromatography on silica gel (n-hexane/ethyl acetate =9/1 ) to obtain pure product. Yield = 57.54%; IR (Neat): 3016.3, 2922.7, 1672.4, 1427.3, 1217.4, 1 174.6 cm"1; NMR (300MHz, CDCI3 , ppm) 87.36-7.23 (m, 5H, Ph-H); 4.19-4.13 (br d, J=18Hz, 1H, CONCH); 4.03- 3.99 (br d, J=12Hz, I H, CONCH); 3.48-3.44 (d, J=12Hz, I H, CH2APh);3.34-3.30 (d, J=12Hz, IH, CH2BPh); 3.13-3.09 (m, 2H, 2 x CONH); 3.03-2.98 (br d, J= 15Hz, I H, NCH); 2.92-2.89 (br d, J=9Hz, 1 H.NCH); 2.25-2.17 (m, 2H, 2 X NCH); 1 .89 (br s, IH, CH); 1.81 (br s, IH, CH); 1.68 (m, 2H, bridge CH2); 1.54 (s, 9H, CMe3); 13C NMR (50 MHz, CDC13, ppm) 6155.15(C=0), 128.68 (Ph), 128.10(Ph), 126.68 (Ph), 78.83 (CMe3), 63.49 (CH2Ph), 58.77 (NCH2), 48.43 (CONCH2), 47.65 (CONCH2), 37.63 (bridge-CH2), 31.10 (2XCH), 28.72 (CH3); MS (ESI):317.3(M+H)+
27%		To a stirring solution of title compound 228 (3.6 g, 10.90 mmol) in EtOH (100 mL) was added /?-toluenesulfanhydrazine (2.435 g, 13.07 mmol) at room temperature then the reaction mixture was heated at reflux for 2h. The mixture was cooled to room temperature and concentrated. The residue was dissolved in THF (60 mL) and water (15 mL) and NaBH4(4.12 g, 109 mmol) was added portionwise at 0 0C over 5 min (effervescence). The reaction mixture was stirred for 30 minutes at room temperature then 3h at reflux. The mixture was cooled, water was added and the mixture was extracted with Et2O (4 times). The organic extracts were dried over Na2SO4, filtered and concentrated. Purified residue by flash chromatography: 4Og SiO2, 0% to 50% EA / hexanes over 30 min. to afford title compound229 (1.35 g, 27%). LRMS(ESI): (calc.) 316.22 (found) 317.5 (MH)+.
27%		To a stirring solution of title compound 228 (3.6 g, 10.90 mmol) in EtOH (100 mL) was added /?-toluenesulfanhydrazine (2.435 g, 13.07 mmol) at room temperature then the reaction mixture was heated at reflux for 2h. The mixture was cooled to room temperature and concentrated. The residue was dissolved in THF (60 mL) and water (15 mL) and NaBH4 (4.12 g, 109 mmol) was added portionwise at 0 0C over 5 min (effervescence). The reaction mixture was stirred for 30 minutes at room temperature then 3h at reflux. The mixture was cooled, water was added and the mixture was extracted with Et2O (4 times). The organic extracts were dried over Na2SO4, filtered and concentrated. Purified residue by flash chromatography: 4Og SiO2, 0% to 50% EA / hexanes over 30 min. to afford title compound 229 (1.35 g, 27%). LRMS(ESI): (calc.) 316.22 (found) 317.5 (MH)+.
27%		To a stirring solution of title compound 228 (3.6 g, 10.90 mmol) in EtOH (100 mL) was added p-toluenesulfanhydrazine (2.435 g, 13.07 mmol) at room temperature then the reaction mixture was heated at reflux for 2 h. The mixture was cooled to room temperature and concentrated. The residue was dissolved in THF (60 mL) and water (15 mL) and NaBH4 (4.12 g, 109 mmol) was added portionwise at 0 C. over 5 min (effervescence). The reaction mixture was stirred for 30 minutes at room temperature then 3 h at reflux. The mixture was cooled, water was added and the mixture was extracted with Et2O (4 times). The organic extracts were dried over Na2SO4, filtered and concentrated. Purified residue by flash chromatography: 40 g SiO2, 0% to 50% EA/hexanes over 30 min. to afford title compound 229 (1.35 g, 27%). LRMS(ESI): (calc.) 316.22 (found) 317.5 (MH)+.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 623 - 626
[2]Physical Chemistry Chemical Physics,2016,vol. 18,p. 15046 - 15053
[3]Journal of the American Chemical Society,2008,vol. 130,p. 5654 - 5655
[4]Advanced Synthesis and Catalysis,2008,vol. 350,p. 2001 - 2006
[5]Russian Chemical Bulletin,2016,vol. 65,p. 2479 - 2484
Izv. Akad. Nauk, Ser. Khim.,2016,vol. 65,p. 2479 - 2484,5
[6]Journal of Organometallic Chemistry,2017,vol. 846,p. 169 - 175
[7]Patent: US2004/229900,2004,A1 .Location in patent: Page 14
[8]Patent: WO2015/44951,2015,A1 .Location in patent: Page/Page column 16; 17
[9]Chemical Communications,2002,p. 673 - 675
[10]Patent: WO2008/55068,2008,A2 .Location in patent: Page/Page column 229
[11]Patent: WO2009/137503,2009,A1 .Location in patent: Page/Page column 58
[12]Patent: US2017/749,2017,A1 .Location in patent: Paragraph 0059
[13]Chemistry - A European Journal,2002,vol. 8,p. 4767 - 4780
[14]Patent: WO2013/50938,2013,A1
[15]Biochemical Journal,2017,vol. 474,p. 123 - 147

3
tert-butyl 7-benzyl-9-(2-tosylhydrazono)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]
[ 227940-71-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tetrahydroborate; water; In tetrahydrofuran; at 0 - 20℃;Reflux;	Tert-butyl 7-benzyl-9-(2-tosylhydrazono)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (10.875 g; 21.8 mmol) was dissolved in a 4/1 -mixture of THF / water (150 ml) and cooled to 0C followed by NaBH4 (8.25 g; 218 mmol) in portions. Stirring was continued over night while at the same time the reaction mixture was allowed to very slowly warm to RT followed by heating to reflux for 2 h. The reaction mixture was cooled again to RT. Water (50 ml) was slowly added to destroy potential excess of NaBH4. Then again water (250 ml) was added and the product was extracted with EtOAc (3 x 250 ml). The combined organic layers were washed with brine (100 ml), dried over MgS04, filtered and the solvent was evaporated under reduced pressure to give 16.75 g of crude product which was purified by flashmaster chromatography (silicagel; heptane / EtOAc = 4 / 1 ) to give tert-butyl 7-benzyl-3,7-diazabicyclo[3.3.1 ]nonane-3-carboxylate. LC-MS: tR = 1.10 min; [M+H]+ = 317.09. Method (A)

Reference： [1]Chemistry - A European Journal,2002,vol. 8,p. 4767 - 4780
[2]Patent: WO2013/50938,2013,A1 .Location in patent: Page/Page column 55

4
[ 227940-71-8 ]
3-(toluene-4-sulfonyl)-3,7-diaza-bicyclo[3.3.1]nonane [ No CAS ]

Reference： [1]Chemistry - A European Journal,2002,vol. 8,p. 4767 - 4780
[2]Chemical Communications,2002,p. 673 - 675

5
[ 227940-71-8 ]
[ 454695-26-2 ]

Reference： [1]Chemistry - A European Journal,2002,vol. 8,p. 4767 - 4780
[2]Chemical Communications,2002,p. 673 - 675

6
[ 227940-71-8 ]
3-(toluene-p-sulfonyl)-3,7-diazabicyclo[3.3.1]nonane-7-[(R)-binaphthyl-2,2'-diyl]phosphite [ No CAS ]

Reference： [1]Chemistry - A European Journal,2002,vol. 8,p. 4767 - 4780
[2]Chemical Communications,2002,p. 673 - 675

7
[ 227940-71-8 ]
3-(toluene-p-sulfonyl)-3,7-diazabicyclo[3.3.1]nonane-7-[(R)-(3,3'-dimethyl)binaphthyl-2,2'-diyl]phosphite [ No CAS ]

Reference： [1]Chemistry - A European Journal,2002,vol. 8,p. 4767 - 4780

8
[ 227940-71-8 ]
N-(2,2-dimethylpropanoyl)-3,7-diazabicyclo[3.3.1]nonane [ No CAS ]

Reference： [1]Chemical Communications,2002,p. 673 - 675

9
[ 227940-71-8 ]
C₁₂H₂₁Cl₂N₂OP [ No CAS ]

Reference： [1]Chemical Communications,2002,p. 673 - 675

10
[ 227940-71-8 ]
[ 454695-25-1 ]

Reference： [1]Chemical Communications,2002,p. 673 - 675

11
[ 227940-71-8 ]
C₁₄H₁₉Cl₂N₂O₂PS [ No CAS ]

Reference： [1]Chemical Communications,2002,p. 673 - 675

12
[ 227940-71-8 ]
C₃₄H₃₇N₂O₃P [ No CAS ]

Reference： [1]Chemical Communications,2002,p. 673 - 675

13
[ 227940-71-8 ]
C₃₆H₃₅N₂O₄PS [ No CAS ]

Reference： [1]Chemical Communications,2002,p. 673 - 675

14
[ 24424-99-5 ]
[ 69407-32-5 ]
[ 227940-71-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	In tetrahydrofuran; at 20℃;	(iv) tert-Butyl 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate Di-tert-butyl dicarbonate was added slowly to a solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (see Example 9(ii) above; 60 g; 277 mmol) in THF (600 ML).. The reaction was stirred at rt until all of the starting material had been consumed (as indicated by tlc).. The solvent was then removed under reduced pressure to give a quantitative yield of the sub-title compound.
	In tetrahydrofuran;	(iv) tert-Butyl 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate Di-tert-butyl dicarbonate was added slowly to a solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (from step (iii) above; 60 g; 277 mmol) in THF (600 mL). The reaction was stirred at rt until all of the starting material had been consumed (as indicated by tlc). The solvent was then removed under reduced pressure to give a quantitative yield of the sub-title compound.

Reference： [1]Patent: EP1192154,2004,B1 .Location in patent: Page 28
[2]Patent: US6465481,2002,B1

15
[ 69407-32-5 ]
[ 227940-71-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With di-tert-butyl dicarbonate; In tetrahydrofuran;	Di-tert-butyl dicarbonate was added slowly to a solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (from step (iii) above; 60 g; 277 mmol) in THF (600 mL). The reaction was stirred at n until all of the starting material had been consumed (as indicated by tlc). The solvent was then removed under reduced pressure to give a quantitative yield of the sub-title compound.

Reference： [1]Patent: EP1192156,2004,B1 .Location in patent: Page 24

16
[ 1576-35-8 ]
[ 227940-70-7 ]
[ 227940-71-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium cyanoborohydride; acetic acid; In water; isopropyl alcohol; toluene;	(b) tert-Butyl 7-benzyl-3.7-diazabicyclo[3,3,1]-nonane-3-carboxylate A mixture of 4-toluenesulfonehydrazide (12.4 mmol; 2.30 g) and tert-butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (10.1 mmol; 4.00 g; 83.3%; from step (a) above) were dissolved in isopropanol (30 mL) and heated at reflux for 2 hours. Acetic acid (2.5 mmol; 0.15 g) and sodium cyanoborohydride (12.1 mmol, 0.76 g) were added and the mixture was again heated at reflux for 2 hours. The slurry was cooled to ambient temperature and filtered. The filtrate was concentrated and an extractive work-up was performed in toluene:water. The toluene solution was concentrated to give 0.95 g of sub-title compound, with a purity of 90 area % (GC) in a yield of 60%. MS (EI; 70 eV): m/z 259 (100%), m/z 91 (95%), m/z 169 (45%), m/z 57 (35%), m/z 316 (25%); 13C NMR (CDCl3): 28.67, 28.95, 31.11, 47.55, 48.38, 58.70, 58.96, 63.46, 78.71, 126.57, 128.00, 128.53, 138.94, 155.20 ppm using TMS as a reference
60%	With sodium cyanoborohydride; acetic acid; In water; isopropyl alcohol; toluene;	(c) tert-Butyl 7-benzyl-3,7-diazabicyclo[3.3. 1]-nonane-3-carboxylate A mixture of 4-toluenesulfonehydrazide (12.4 mmol; 2.30 g) and tert-butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (10.1 mmol; 4.00 g; 83.3%; from step (a) above) were dissolved in isopropanol (30 mL) and heated at reflux for 2 hours. Acetic acid (2.5 mmol; 0.15 g) and sodium cyanoborohydride (12.1 mmol, 0.76 g) were added and the mixture was again heated at reflux for 2 hours. The slurry was cooled to ambient temperature and filtered. The filtrate was concentrated and an extractive work-up was performed in toluene:water. The toluene solution was concentrated to give 0.95 g of sub-title compound, with a purity of 90 area % (GC) in a yield of 60%. MS (EI; 70 eV): m/z 259 (100%), m/z 91 (95%), m/z 169 (45%), m/z 57 (35%), m/z 316 (25%). 13C NMR (CDCl3): delta 28.67, 28.95, 31.11, 47.55, 48.38, 58.70, 58.96, 63.46, 78.71, 126.57, 128.00, 128.53, 138.94, 155.20 ppm using TMS as a reference.

Reference： [1]Patent: US6492382,2002,B1
[2]Patent: US6291475,2001,B1

17
[ 77-78-1 ]
[ 227940-71-8 ]
tert-butyl 7-benzyl-2-methyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%		(v) tert-Butyl 7-benzyl-2-methyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate N,N,N',N'-Tetramethylethylenediamine (0.98 g; 8.4 mmol) and subsequently s-BuLi in cyclohexane (8.46 mL; 1.3 M; 11.0 mmol) was added to a cooled (-70C), stirred solution of <strong>[227940-71-8]tert-butyl 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate</strong> (from step (iv) above; 2.65 g; 8.4 mmol) in THF (17 mL) under an inert atmosphere (N2). The reaction mixture was then allowed to warm to -40C, at which temperature it was stirred for 1 h. The temperature was lowered again to -70C, and a solution of dimethyl sulfate (1.64 g; 13.0 mmol) in THF (5 mL) was added. The temperature was then allowed to reach rt before the solvent was evaporated and the residue partitioned between diethyl ether and water. The organic layer was separated, dried (Na2SO4), concentrated and subjected to column chromatography (CH2Cl2:MeOH; 40:1) to give the sub-title compound in a 30% yield.

Reference： [1]Patent: EP1192156,2004,B1 .Location in patent: Page 23

19
[ 227940-71-8 ]
[ 280-74-0 ]

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 623 - 626

20
[ 227940-71-8 ]
[ 1429776-76-0 ]

Reference： [1]Patent: WO2013/50938,2013,A1

21
[ 227940-71-8 ]
3,7-diazabicyclo[3.3.1]nonan-3-yl(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)-methanone hydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/50938,2013,A1

22
[ 227940-71-8 ]
[ 1429773-09-0 ]

Reference： [1]Patent: WO2013/50938,2013,A1

23
[ 227940-71-8 ]
[ 1429776-79-3 ]

Reference： [1]Patent: WO2013/50938,2013,A1

24
[ 227940-71-8 ]
[ 1485122-44-8 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 10980 - 10982

25
[ 227940-71-8 ]
[ 1485122-49-3 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 10980 - 10982

26
[ 227940-71-8 ]
[ 1485122-24-4 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 10980 - 10982

27
[ 227940-71-8 ]
[ 1485122-26-6 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 10980 - 10982

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[ 227940-71-8 ]
[ 1485122-61-9 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 10980 - 10982

29
[ 227940-71-8 ]
[ 1485122-79-9 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 10980 - 10982

30
[ 227940-71-8 ]
[ 1485123-00-9 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 10980 - 10982

31
[ 227940-71-8 ]
[ 1485123-08-7 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 10980 - 10982

32
[ 227940-71-8 ]
[ 1485123-09-8 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 10980 - 10982

33
[ 227940-71-8 ]
7-(1-benzyl-5-oxo-pyrrolidine-2-carbonyl)-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: WO2015/44951,2015,A1

34
[ 227940-71-8 ]
7-[1-(2-bromo-benzyl)-5-oxo-pyrrolidine-2-carbonyl]-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: WO2015/44951,2015,A1
[2]European Journal of Medicinal Chemistry,2016,vol. 110,p. 1 - 12

35
[ 227940-71-8 ]
1-benzyl-5-(7-benzyl-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyrrolidin-2-one [ No CAS ]

Reference： [1]Patent: WO2015/44951,2015,A1
[2]European Journal of Medicinal Chemistry,2016,vol. 110,p. 1 - 12

36
[ 227940-71-8 ]
(5S)-5-(7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)-1-(2-bromobenzyl)pyrrolidin-2-one [ No CAS ]

Reference： [1]Patent: WO2015/44951,2015,A1
[2]European Journal of Medicinal Chemistry,2016,vol. 110,p. 1 - 12

37
[ 227940-71-8 ]
7-[1-(4-methylbenzyl)-5-oxo-pyrrolidine-2-carbonyl]-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert butyl ester [ No CAS ]

Reference： [1]Patent: WO2015/44951,2015,A1
[2]European Journal of Medicinal Chemistry,2016,vol. 110,p. 1 - 12

38
[ 227940-71-8 ]
(5S)-5-(7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)-1-(4-methylbenzyl)pyrrolidin-2-one [ No CAS ]

Reference： [1]Patent: WO2015/44951,2015,A1
[2]European Journal of Medicinal Chemistry,2016,vol. 110,p. 1 - 12

39
[ 227940-71-8 ]
benzyl N-[(2S)-1-{7-benzyl-3,7-diazabicyclo[3.3.1]nonan-3-yl}-3-methyl-1-oxobutan-2-yl]carbamate [ No CAS ]

Reference： [1]Patent: WO2015/44951,2015,A1

40
[ 227940-71-8 ]
benzyl (2S)-1-(7-benzyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)-1-oxo-3-phenylpropan-2-ylcarbamate [ No CAS ]

Reference： [1]Patent: WO2015/44951,2015,A1

41
[ 227940-71-8 ]
benzyl (2S)-1-(7-benzyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)-4-methyl-1-oxopentan-2-ylcarbamate [ No CAS ]

Reference： [1]Patent: WO2015/44951,2015,A1

42
[ 227940-71-8 ]
[ 69407-32-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With trifluoroacetic acid; In dichloromethane; at 0 - 35℃; for 4h;	Trifluoro acetic acid (TFA) (2.25ml, 5eq, 0.03 mol) was injected to the stirring suspension of compound 12 (2.0g, l eq, 0.006mol) in DCM at 0C and allowed to stir at 25C (25-35C). Then reaction mixture was made alkaline by adding 20% aq. solution of Na2C03 and resulting mixture was extracted with dichloromethane (3 chi 50ml) and organics were washed with brine. The combined organics were dried with anhydrous Sodium sulphate and concentrated to obtain yellow oily liquid ( 1.641 g). Yield: 90% ; IR(Neat): 3451.4, 2924.6, 1610.0, 1450.4 cm'' ;1H NMR (300MHz, CDC13, ppm): 87.37-7.27 (m, 5H, Ph-H); 3.49-3.41 (m, 4H, ChbPh, 2xNCH); 3.31-3.27 (d, J=12Hz, 2H, 2NCH); 3.19-3.1 1 (m, 2H, 2> NCH); 2.49-2.45 (d, J=12Hz, 2H, 2xNCH); 2.12-2.07 (m, 2H, 2CH); 1.93- 1.89 (d, J= 12Hz, I H, bridge CH); 1.79- 1.75 (d, J=12Hz, IH, bridge CH); MS (ESI):m/z = 217 (M+H)+
90%	With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;	6.1.2 3-Benzyl-3,7-Diaza-bicyclo [3,3,1]nonane (9) TFA (2.25 ml, 5eq, 30 mmol) was added to the stirring suspension of 8 (2.0 g, 1eq, 60 mmol) in DCM at 0 C and allowed to stir at room temperature. Then reaction mixture was made alkaline by adding 20% aq. solution of Na2CO3 and resulting mixture was extracted with DCM (3 * 50 ml) and organics were washed with brine. The combined organics were dried with an. Na2SO4 and concentrated to obtain yellow oily liquid (1.641 g). Yield: 90%; IR(Neat): 3451.4, 2924.6, 1610.0, 1450.4 cm-1; 1H NMR (300 MHz, CDCl3, ppm): delta 7.37-7.27 (m, 5H, Ph-H); 3.49 (s, 2H, CH2Ph), 3.36-3.41 (d, 2H, J = 12 Hz, 2 * NCH); 3.31-3.27 (d, J = 12 Hz, 2H, 2 * NCH); 3.19-3.11 (d, J = 12 Hz, 2H, 2 * NCH); 2.49-2.45 (d, J = 12 Hz, 2H, 2 * NCH); 2.12-2.07 (m, 2H, 2 * CH); 1.93-1.89 (d, J = 12 Hz, 1H, bridge CH); 1.79-1.75 (d, J = 12 Hz, 1H, bridge CH); MS (ESI): m/z = 217 (M+1)+
	With hydrogenchloride; In isopropyl alcohol; for 5h;	A solution of compound 5 (3.3 g, 10 mmol) in PriOH (30 mL) was carefully treated with concentrated HCl (15 mL). The mixture was stirred for 5 h, diluted with water, treated with a NaOH solution to pH 12, extracted with CHCl3, dried with Na2SO4, and the solvent was removed in vacuo. The residue was dissolved in THF (50 mL) and 37% aqueous formaldehyde (1.5 mL, 20 mmol) was added followed by portionwise addition of sodium triacetoxyborohydride (6.4 g, 30 mmol). After 5 h stirring, the reaction mixture was diluted with water, treated with aqueous NaOH to pH 12, extracted with diethyl ether, and the solvent was removed in vacuo. The residue was dissolved in diethyl ether and dried with Na2SO4. Removal of the solvent and drying under vacuum afforded 2.3 g (97%) of product 1. 1H and 13C NMR spectral data are summarized in Table 1.

Reference： [1]Patent: WO2015/44951,2015,A1 .Location in patent: Page/Page column 17
[2]European Journal of Medicinal Chemistry,2016,vol. 110,p. 1 - 12
[3]Russian Chemical Bulletin,2016,vol. 65,p. 2479 - 2484
Izv. Akad. Nauk, Ser. Khim.,2016,vol. 65,p. 2479 - 2484,5

43
[ 227940-71-8 ]
tert-butyl 7-((S)-1-(4-methoxybenzyl)-5-oxopyrrolidine-2-carbonyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]