[ CAS No. 1041026-70-3 ] {[proInfo.proName]}

Name: 1041026-70-3|tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate|95%
Brand: Ambeed
SKU: A300058
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Quality Control of [ 1041026-70-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1041026-70-3 ]

Product Details of [ 1041026-70-3 ]

CAS No. :	1041026-70-3	MDL No. :	MFCD11226963
Formula :	C₁₀H₁₈N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KVOUHLVOTMOJBS-UHFFFAOYSA-N
M.W :	198.26	Pubchem ID :	40151981
Synonyms :

Calculated chemistry of [ 1041026-70-3 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.9
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	60.94
TPSA :	41.57 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.26 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.57
Log Po/w (XLOGP3) :	0.35
Log Po/w (WLOGP) :	0.07
Log Po/w (MLOGP) :	0.86
Log Po/w (SILICOS-IT) :	0.78
Consensus Log Po/w :	0.93

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.09
Solubility :	16.1 mg/ml ; 0.081 mol/l
Class :	Very soluble
Log S (Ali) :	-0.79
Solubility :	32.4 mg/ml ; 0.163 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.54
Solubility :	5.69 mg/ml ; 0.0287 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.6

Safety of [ 1041026-70-3 ]

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 [ 1041026-70-3 ]

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

Downstream synthetic route of [ 1041026-70-3 ]

[ 1041026-70-3 ] Synthesis Path-Downstream 1~88

1
[ 1041026-67-8 ]
[ 1041026-70-3 ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium; In methanol; for 6h;Sonication;	The above product lg-5 (3.50 g, 10.0 mmol) was dissolved in MeOH (30 mL). Mg powder (1.92 g, 80.0 mmol) was added, and the mixture was sonicated for 6 h. The reaction mixture was concentrated in vacuo to afford a dark gray solid, which can be used for the further reaction without purification.

Reference： [1]Organic Letters,2008,vol. 10,p. 3525 - 3526
[2]Patent: WO2017/15106,2017,A1 .Location in patent: Page/Page column 43; 45

2
[ 1041026-70-3 ]
[ 144-62-7 ]
2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate [ No CAS ]

Reference： [1]Organic Letters,2008,vol. 10,p. 3525 - 3526

3
[ 1227259-15-5 ]
[ 1041026-70-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With ammonium formate;palladium 10% on activated carbon; In methanol; at 65℃; for 3h;Inert atmosphere;	A flask containing 6-(1-phenyl-ethyl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (200 mg, 0.66 mmol), ammonium formate (4.22 g, 67 mmol), 10% palladium on carbon (40 mg) and methanol (10 mL) was evacuated and filled with argon. The resulting mixture was stirred at 65 C. for 3 hours, then filtered and concentrated in vacuo to afford 2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (130 mg, 99%) as a brown viscous oil which was used for the next step without further purification.

Reference： [1]Patent: US2010/125061,2010,A1 .Location in patent: Page/Page column 20

4
[ 1041026-70-3 ]
[ 1332455-32-9 ]
[ 1332455-23-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 4h;	Example 4: tert-butyl 6-[6-(biphenyl-4-ylcarbonyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yl]- 2,6-diazaspiro [3.3] heptane-2-carboxylateStep ATo a solution of Intermediate 1 (300 mg, 0.86 mmol) and the amine (371 mg, 1.29 mmol) in 4 mL of DMSO was added K2C03 (593 mg, 4.29 mmol), then the mixture was stirred at 80C for 4 hours. The cooled reaction mixture was purified by HPLC to give the desired product (300 mg). *H NMR (MeOD): delta 8.45 (s, 1H), 7.75 (d, J=7.4Hz, 2H), 7.66 (d, J=7.5Hz, 2H), 7.56 (d, J=5.6Hz, 2H), 7.45 (t, J=7.6Hz, 2H), 7.37 (t, J=7.3Hz, 1H), 4.8 (br, 3H), 4.01-4.46 (m, 7H), 3.60~3.75(m, 2H), 2.89 (s, 2H), 1.42 (s, 9H). MS (m/z): 512 (M+H)+ .
	With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 4h;	To a solution of Intermediate 1 (300 mg, 0.86 mmol) and the amine (371 mg. 1.29 mmol) in 4 mL of DMSO was added K2C03 (593 mg, 4.29 mmol), then the mixture was stirred at 80C for 4 hours. The cooled reaction mixture was purified by HPLC to give the desired product (300 mg). ¾ NMR (MeOD): 5 8.45 (s, 1H), 7.75 (d, J=7.4Hz, 2H), 7.66 (d, J=7.5Hz, 2H), 7.56 (d, J=5.6Hz, 2H), 7.45 (t, J=7.6Hz, 2H), 7.37 (t, J=7.3Hz, 1H), 4.8 (br, 3H), 4.01-4.46 (m, 7H), 3.60~3.75(m, 2H), 2.89 (s, 2H), 1.42 (s, 9H). MS (ra/z): 512 (M+H)+ .

Reference： [1]Patent: WO2011/103715,2011,A1 .Location in patent: Page/Page column 44
[2]Patent: WO2011/106276,2011,A1 .Location in patent: Page/Page column 44

5
[ 475111-38-7 ]
[ 1041026-70-3 ]
[ 1334724-08-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;	Example P5: Tert-butyl-6-(4-(2-(difluoromethyl)-1 H-benzo[dlimidazol-1 -yl)-6-morpholino- 1 ,3,5-triazin-2-yl)-2,6-diazaspiro[3.31heptane-2-carboxylate (31 )4-(4-Chloro-6-(2-(difluoromethyl)-1 H-benzo[c ]imidazol-1 - yl)-1 ,3,5-triazin-2-yl)morpholine 25 (30.0 mg, 81 .8 mol, 1 .0eq.) was dissolved in DMF (3 mL). Potassium carbonate(36.2 mg, 262 mol, 3.2 eq.) and ie f-butyl 2,6-diazaspiro- [3.3]heptane-2-carboxylate (23.6 mg, 49.1 mol, 0.6 eq.)were added and the resulting reaction mixture was stirredfor 3 h at RT. The solvent was removed under high vacuum and the remaining residue was purified directly by flash column chromatography (Si02, gradient 0% to 1 % MeOH in DCM) to provide the title compound as a colourless solid (41.0 mg, 77.6 muetaiotaomicronIota, 95%). RF: 0.44 (DCM/MeOH 95:5 v/v); 1H NMR (CDCI3, 400 MHz): delta 8.39 (d, J = 8.0 Hz, 1 H), 7.86 (d, J = 7.2 Hz, 1 H), 7.62 (t, J = 54.0 Hz, 1 H), 7.39-7.37 (m, 2H), 4.28 (d, J = 32.0 Hz, 4H), 4.13 (s, 4H); 3.85 (t, J = 4.4 Hz, 4H), 3.76 (sbr, 4H), 1.44 (s, 9H); 19F-NMR (CDCI3, 376 MHz): delta -1 17.9 (d, J = 53.4 Hz, 2F); ESI-MS(C25H3oF2N803): Calc'd. 551.23 [M+Na]+, Found 551 .30.
95%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere;	Example P5 Tert-butyl-6-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (31) 4-(4-Chloro-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine 25 (30.0 mg, 81.8 mumol, 1.0 eq.) was dissolved in DMF (3 mL). Potassium carbonate (36.2 mg, 262 mumol, 3.2 eq.) and <strong>[1041026-70-3]tert-butyl 2,6-diazaspiro-[3.3]heptane-2-carboxylate</strong> (23.6 mg, 49.1 mumol, 0.6 eq.) were added and the resulting reaction mixture was stirred for 3 h at RT. The solvent was removed under high vacuum and the remaining residue was purified directly by flash column chromatography (SiO2, gradient 0% to 1% MeOH in DCM) to provide the title compound as a colourless solid (41.0 mg, 77.6 mumol, 95%). RF: 0.44 (DCM/MeOH 95:5 v/v); 1H NMR (CDCl3, 400 MHz): delta 8.39 (d, J=8.0 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.62 (t, J=54.0 Hz, 1H), 7.39-7.37 (m, 2H), 4.28 (d, J=32.0 Hz, 4H), 4.13 (s, 4H); 3.85 (t, J=4.4 Hz, 4H), 3.76 (sbr, 4H), 1.44 (s, 9H); 19F-NMR (CDCl3, 376 MHz): delta -117.9 (d, J=53.4 Hz, 2F); ESI-MS (C25H30F2N8O3): Calc'd. 551.23 [M+Na]+. Found 551.30.

Reference： [1]Patent: WO2011/114275,2011,A1 .Location in patent: Page/Page column 77-78
[2]Patent: US2013/40934,2013,A1 .Location in patent: Paragraph 0247-0248

6
[ 1041026-70-3 ]
[ 108-24-7 ]
[ 1349875-71-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium hydroxide; In dichloromethane; at 20℃; for 1h;	To a solution of 2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (130) (purchased from WUXI APPTEC} ((500 mg, 2.73 mmol) in CH2C12 (10 mL) were added KOH (459 mg, 8.19 mmol) and Ac20 (279 mg, 2.73 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with CH2C12 (20 mL), washed with H20 (20 mL). The organic layer was washed with brine (20 mL), dried over Na2S04, and filtered, evaporated to give the product (131) (510 mg, 2.13 mmol, yield: 78%). ESI-MS (M+l): 241 calc. for Ci2H2oN203 240.

Reference： [1]Patent: WO2011/143365,2011,A1 .Location in patent: Page/Page column 193

7
[ 39856-50-3 ]
[ 1041026-70-3 ]
[ 1360056-47-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dimethyl sulfoxide; at 90℃; for 40h;	Step 1. Preparation of 6-(6-Nitro-pyridin-3-yl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester In a 25 mL pear-shaped flask, <strong>[1041026-70-3]tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate</strong> (2.81 g, 14.2 mmol), 5-bromo-2-nitropyridine (2.88 g, 14.2 mmol), and TEA (1.58 g, 2.17 ml, 15.6 mmol) were combined with DMSO (12 ml) to give a light yellow solution. The reaction mixture was heated to 90 C. and stirred for 40 h. Cooled to 25 C. and the reaction mixture was diluted with 50 mL H2O and extracted with EtOAc (350 mL). The organic layers were combined, washed with sat NaCl (150 mL), dried over Na2SO4 and concentrated in vacuo. The purple oil was used crude in the subsequent reduction. (M+H)+=321 m/e.

Reference： [1]Patent: US2012/40949,2012,A1 .Location in patent: Page/Page column 86

8
[ 1041026-70-3 ]
[ 1360055-22-6 ]

Reference： [1]Patent: US2012/40949,2012,A1

9
[ 1041026-70-3 ]
[ 1360056-49-0 ]

Reference： [1]Patent: US2012/40949,2012,A1

10
[ 1041026-70-3 ]
[ 1360056-48-9 ]

Reference： [1]Patent: US2012/40949,2012,A1

11
[ 1041026-70-3 ]
[ 1360056-51-4 ]

Reference： [1]Patent: US2012/40949,2012,A1

12
[ 1041026-70-3 ]
[ 1360056-50-3 ]

Reference： [1]Patent: US2012/40949,2012,A1

13
[ 1041026-70-3 ]
[ 1360056-52-5 ]

Reference： [1]Patent: US2012/40949,2012,A1

14
[ 1041026-70-3 ]
2-bromo-1-chloro-4-fluorobenzene [ No CAS ]
[ 1246749-62-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 980 - 984

15
[ 1041026-70-3 ]
[ 1336911-04-6 ]
[ 1303470-34-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5326 - 5329

16
[ 1041026-70-3 ]
[ 1336911-04-6 ]
C₂₇H₃₄N₈O₂S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5326 - 5329

17
[ 1041026-70-3 ]
[ 1453836-28-6 ]
[ 1453836-37-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0℃;	50 mg (132 muiotatauiotaomicronIota) 8-lsopropyl-4-(2-pyrazol-1 -yl-benzylamino)-pyrazolo[1 ,5- a][1 ,3,5]triazine-2-carboxylic acid, 20 mg (141 muiotatauiotaomicronIota, 1 .07 eq) 6-(tert-butoxycarbonyl)-6- aza-2-azoniaspiro[3.3]heptane oxalate and 64 mg (168 muiotatauiotaomicronIota, 1 .28 eq) HATU were dissolved in 1 .8 ml DMF and cooled to 0 C. 52 mg (512 muiotatauiotaomicronIota, 3.89 eq) triethylamine were added. The reaction mixture was stirred over night and allowed to warm to room temperature. The mixture was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and brine. The organic phase was dried and evaporated. The residue was purified on silica gel, eluting with 10/30 cyclohexane/ethyl acetate to give the Boc-protected intermediate of (XII-7). MS (ES) C29H35N9O3 requires 557.29, found 558 (M+H)+ and 580 (M+Na)+.

Reference： [1]Patent: WO2013/128028,2013,A1 .Location in patent: Page/Page column 216

18
[ 1041026-70-3 ]
[ 69770-20-3 ]
C₂₃H₂₇ClN₂O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 737 - 741

19
[ 1041026-70-3 ]
[ 17738-06-6 ]
C₁₆H₂₂N₄O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 737 - 741

20
[ 1041026-70-3 ]
C₁₈H₁₉ClN₂O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 737 - 741

21
[ 1041026-70-3 ]
[ 1257881-93-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 737 - 741

22
[ 1041026-70-3 ]
[ 1257881-94-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 737 - 741

23
[ 1041026-70-3 ]
C₁₁H₁₄N₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 737 - 741

24
[ 1041026-70-3 ]
[ 3107-19-5 ]
6-(2,6-dichloro-4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 18h;Inert atmosphere;	In a 50 ml round-bottomed flask, <strong>[3107-19-5]1,3-dichloro-2-fluoro-5-nitrobenzene</strong> (467 mg, 2.22 mmol, Eq:1.00), tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate (529 mg, 2.67 mmol, Eq: 1.2) andCs2C03 (1.81 g, 5.56 mmol, Eq: 2.5) were combined with DMF (10 ml) to give a yellow suspension. The mixture was heated to 90 oc and stirred under argon for 18 hours. TLCindicated total conversion. Cooled and the reaction mixture was diluted with H20 and EtOAc. The aqueous layer was washed with EtOAc (2 x 40 ml). The organic layers were combined, washed with H20 (2 x 25 mL), brine (1 x 25 mL), dried over Na2S04 and concentrated in vacuo to afford the desired product in quantitative yield as a bright yellow powder.MS -m/z: 386.9/389.0. (M-1)

Reference： [1]Patent: WO2014/135471,2014,A1 .Location in patent: Page/Page column 55

25
[ 1041026-70-3 ]
6-[4-(5-amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichlorophenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: WO2014/135471,2014,A1

26
[ 1041026-70-3 ]
{3-aminomethyl-1-[4-(5-amino-2H-[1,2,4]triazol-3-ylamino)-2,6-dichlorophenyl]-azetidin-3-yl}-methanol [ No CAS ]

Reference： [1]Patent: WO2014/135471,2014,A1

27
[ 1041026-70-3 ]
6-(4-amino-2,6-dichlorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: WO2014/135471,2014,A1

28
[ 1041026-70-3 ]
6-(2,6-dichloro-4-isothiocyanato-phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: WO2014/135471,2014,A1

29
[ 1041026-70-3 ]
tert-butyl 6-(2,6-dichloro-4-(cyanamido(methylthio)methyleneamino)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/135471,2014,A1

30
[ 50-00-0 ]
[ 1041026-70-3 ]
C₁₁H₂₀N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate hydrochloride (300 mg, 1.21 mmol) in THF (5 mL) is added tetrahydrofuran-3-one (114.21 mg, 1.33 mmol) and sodium triacetoxyborhydride (349.78 mg, 1.57 mmol) and stirred at r.t. for 0.5 h. Sodium acetate (148.40 mg, 1.81 mmol) is added and stirred at r.t. overnight. The reaction mixture is diluted with aq. sodiumhydrogen carbonate solution and extracted with ethyl acetate. The organic layer is separated, dried and concentrated. The crude residue is purified by reversed phase HPLC. Yield 61%, m/z 283 [M+H]+, rt 0.61 min, LC-MS Method V011_S01.

Reference： [1]Patent: US2014/275025,2014,A1 .Location in patent: Paragraph 0674 - 0679

31
[ 1041026-70-3 ]
6-chloro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide [ No CAS ]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)nicotinamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Example 1 Preparation of N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide To a solution of N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-fluorobenzamide (Example A.1)(20 mg, 70.4 mumol) in N,N-dimethylacetamide (200 mul) under nitrogen at room temperature, was added piperazine (60.6 mg, 704 flmol). The reaction mixture was microwaved at 160C for 90 minutes. The mixture was cooled to room temperature. The resulting precipitate was filtered, rinsed with diethyl ether and dried to provide 4 mg (16.2%) of the title as an off-white solid. MS(m/e): 351.4 (M+H+)

Reference： [1]Patent: WO2014/209841,2014,A2 .Location in patent: Page/Page column 57; 58; 60; 61

32
[ 1041026-70-3 ]
(5aR,6S,6aS)-ethyl 3-((2’,4-difluoro-6-(trifluoromethyl)-4’-(((trifluoromethyl)-sulfonyl)oxy)-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate [ No CAS ]
(5aR,6S,6aS)-ethyl 3-((4’-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3,3]heptan-2-yl)-2’,4-difluoro-6-(trifluoromethyl)-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa-[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); oxalic acid; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tetrahydrofuran; at 90℃; for 16h;Inert atmosphere;	Step D: (5aR, 6S, 6a5)-ethyl 3 -((4?-(6-(tert-butoxycarbonyl)-2 ,6-diazaspiro F3 .3 ]heptan-2-yl)-2?.4-difluoro-6- (trifluoromethyl-F 1.1 ?-biphenyll-3 -ylmethoxy-5.5a.6.6a-tetrahydrocyclopropa- F4,5 icyclopentaF 1 ,2-c]pyridine-6-carboxylate To a solution of (5aR, 6S, 6aS)-ethyl 3 -((2?,4- difluoro-6-(trifluoromethyl)-4?-(((trifluoromethyl)-sulfonyl)oxy) - [1,1 ?-biphenyl] -3 -yl)methoxy)5 ,5a,6,6a-tetrahydrocyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyridine-6-carboxylate (70 mg, 0.110 mmol,1.0 eq) in THF (2 mL) was added Xant-phos (12.7 mg, 0.022 mmol, 0.2 eq), tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate oxalic acid (47.5 mg, 0.165 mmol, 1.5 eq), Pd2(dba)3 (10.0 mg, 0.0110 mmol, 0.1 eq) and Cs2CO3 (107 mg, 0.3 30 mmol, 3.0 eq) at room temperature under nitrogen atmosphere. The mixture was heated up to 90 C and stirred for 16 hours. After cooling to room temperature, the mixture was mixed with water (50 mL) and extracted with EtOAc (50mLx3). The combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated in vacuo to give the crude product, which was purified by preparative TLC (EtOAc: PE= 5: 1) to give the title compound as a white solid. ?HNMR (400 MHz, CDC13) oe:8.07 (s, 1H), 7.46-7.43 (m, 2H), 7.03 (t, J= 8.4 Hz, 1H), 6.61 (s, 1H), 6.23-6.16 (m, 2H), 5.46 (s,2H), 4.16 (q, J= 7.2 Hz, 2H), 3.22 (dd, J= 6.8 Hz&18.4 HZ, 1H), 3.00 (d, J 18.4 Hz, 1H), 2.93 (d, J= 6.8 Hz, 1H), 2.47-2.43 (m, 1H), 1.46 (s, 9H), 1.27-1.26 (m, 4H). MS (ESI) m/e (M+H+):686.2.

Reference： [1]Patent: WO2015/73342,2015,A1 .Location in patent: Page/Page column 93; 94

33
[ 1041026-70-3 ]
C₁₁H₈BrN₃ [ No CAS ]
C₂₁H₂₅N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 12h;Schlenk technique; Inert atmosphere;	An oven dried Schlenk flask was evacuated and back filled with argon gas. The procedure was repeated 3-4 times and the flask was cooled to room temperature. Then tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate (0.283 g, 0.228 mmol), the title compound from Preparative Example 1 (0.312 g, 1.19 mmol), palladium(ll)-acetate (0.027 g, 0.1 19 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.206 g, 0.357 mmol), cesium carbonate (1.10 g, 3.57 mmol) and 1 ,4-dioxane (8 ml_) were added and the reaction mixture was heated at 110 C in a sand-bath for 12 hours. The reaction mixture was cooled and diluted with water (20 ml) and the aqueous phase was extracted with ethyl acetate several times. The combined organics were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified on HP-Sil SNAP cartridges using a Biotage Isolera One purification system using 2 to 10% methanol in dichloromethane to afford the title compound (0.380 g, 84 %). 1H-NMR (400 MHz, DMSO-d6) delta = 9.09 (s, 1 H), 8.37 (d, 1 H), 8.29 (d, 1 H), 7.50 (d, 1 H), 6.31 (d, 1 H), 4.18 (s, 4H), 4.06 (s, 4H), 3.77 (s, 3H), 1.38 (s, 9H) MS (ESI): m/z = 380.36 [M+H]+
84%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 12h;Schlenk technique; Inert atmosphere;	(1239) Step A (1240) An oven dried Schlenk flask was evacuated and back filled with argon gas. The procedure was repeated 3-4 times and the flask was cooled to room temperature. Then <strong>[1041026-70-3]tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate</strong> (0.283 g, 0.228 mmol), the title compound from Preparative Example 1 (0.312 g, 1.19 mmol), palladium(II)-acetate (0.027 g, 0.119 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.206 g, 0.357 mmol), cesium carbonate (1.10 g, 3.57 mmol) and 1,4-dioxane (8 mL) were added and the reaction mixture was heated at 110 C. in a sand-bath for 12 hours. The reaction mixture was cooled and diluted with water (20 ml) and the aqueous phase was extracted with ethyl acetate several times. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on HP-Sil SNAP cartridges using a Biotage Isolera One purification system using 2 to 10% methanol in dichloromethane to afford the title compound (0.380 g, 84%). (1241) 1H-NMR (400 MHz, DMSO-d6) delta=9.09 (s, 1H), 8.37 (d, 1H), 8.29 (d, 1H), 7.50 (d, 1H), 6.31 (d, 1H), 4.18 (s, 4H), 4.06 (s, 4H), 3.77 (s, 3H), 1.38 (s, 9H). (1242) MS (ESI): m/z=380.36 [M+H]+.

Reference： [1]Patent: WO2015/110263,2015,A1 .Location in patent: Page/Page column 298
[2]Patent: US2017/2005,2017,A1 .Location in patent: Paragraph 1238; 1239; 1240; 1241; 1242

34
[ 1041026-70-3 ]
C₁₆H₁₇N₅ [ No CAS ]

Reference： [1]Patent: WO2015/110263,2015,A1

35
[ 1041026-70-3 ]
C₁₈H₂₀FN₅ [ No CAS ]

Reference： [1]Patent: WO2015/110263,2015,A1

36
[ 1041026-70-3 ]
[ 350-46-9 ]
tert-butyl 6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	A suspension of 1-fluoro-4-nitrobenzene (356 mg, 2.52 mmol), <strong>[1041026-70-3]tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate</strong> (500 mg, 2.52 mmol) and potassium carbonate(523 mg, 3.78 mmol) in anhydrous DMF (3 mL) was heated to50 C under a nitrogen atmosphere overnight. The reactionmixture was allowed to cool to room temperature, dilutedwith water (30 mL) and stirred at room temperature for 15minutes. The precipitated solid was isolated byfiltration, washed with water, sucked dry and purified by Biotage chromatography (silica 25g cartridge, cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the title compound as a yellow solid (400mg, 50%). ?H NMR (300 MHz, CDC13) : 3 8.10 (dt, 2H), 6.31 (dt, 2H), 4.15 (s, 4H), 4.13 (s, 4H), 1.45 (s, 9H) . LCMS(Method C) : = 1.64 mi m/z = 320 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 149; 150

37
[ 1041026-70-3 ]
[ 540-51-2 ]
[ 1383473-14-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In acetonitrile; at 90℃;Inert atmosphere;	A mixture of <strong>[1041026-70-3]tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate</strong> (200 mg, 1.01 mmol), 2-bromoethanol (251 mg, 2.02 mmol), and K2CO3(558 mg, 4.04 mmol) in 30 mL of CH3CN was stirred at 90oC under N2overnight. TLC test showed that the reaction was completed. Solid was removed by filtration and solvent was removed under vacuum. The resulting residue was purified by silica gel column chromatography (eluted with 2.5% MeOH in dichloromethane) to give tert-butyl 6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate as a yellow oil (193 mg, yield: 80%).
80%	With potassium carbonate; In acetonitrile; at 90℃;Inert atmosphere;	Representative procedure for synthesis of compound C-174 [00208] A mixture of <strong>[1041026-70-3]tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate</strong> (200 mg, 1.01 mmol), 2-bromoethanol (251 mg, 2.02 mmol), and K2CO3 (558 mg, 4.04 mmol) in 30 mL of CH3CN was stirred at 90 oC under N2 overnight. TLC test showed that the reaction was completed. Solid was removed by filtration and solvent was removed under vacuum. The resulting residue was purified by silica gel column chromatography (eluted with 2.5% MeOH in dichloromethane) to give tert-butyl 6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a yellow oil (193 mg, yield: 80%).
	With potassium carbonate; In acetonitrile; for 16h;Reflux;	1.441 g (5 mmol) 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tei?t-butyl ester hemioxylate was dissolved in 10 ml ACN, then 1.25 g (10 mmol) 2-bromoethanol and 2.073 g (15 mmol) K2C03 were added and the mixture was heated to reflux for 16 hours.Mixture was then filtered and concentrated in vacuo and purified via flash chromatographyusing DCM and MeOFI as eluents.MS (El, 70 eV) mlz (% relative intensity, [ion]):55 (35), 56 (37), 57 (70), 82 (33), 155(100), 169 (17), 211(56), 242 (2, [Mi).

Reference： [1]Patent: WO2016/40330,2016,A1 .Location in patent: Paragraph 00480
[2]Patent: WO2018/106818,2018,A1 .Location in patent: Paragraph 00208
[3]Patent: WO2015/97123,2015,A1 .Location in patent: Page/Page column 214; 215

38
[ 1041026-70-3 ]
(2R)-2-[(5Sa)-5-{3-chloro-2-methyl-4-[2-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid [ No CAS ]

Reference： [1]Patent: WO2015/97123,2015,A1

39
[ 1041026-70-3 ]
(2R)-2-[(5S)-5-{3-chloro-2-methyl-4-[2-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid [ No CAS ]

Reference： [1]Patent: WO2015/97123,2015,A1

40
[ 1041026-70-3 ]
[ 1383473-16-2 ]

Reference： [1]Patent: WO2015/97123,2015,A1

41
[ 1041026-70-3 ]
2-(pyrimidin-2-yl)-2,6-diazaspiro[3.3]heptane bis(2,2,2-trifluoroacetate) [ No CAS ]

Reference： [1]Patent: US2015/284411,2015,A1

42
[ 1722-12-9 ]
[ 1041026-70-3 ]
tert-butyl 6-(pyrimidin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 100 - 105℃; for 0.333333h;	A 2 L round-bottom flask was charged with <strong>[1041026-70-3]tert-butyl 2,6-diazaspiro[3,3]heptane-6-carboxylate</strong> (64.3 g, 0.32 mol), cesium carbonate (317.0 g, 0.97 mol), 2-chloropyrimidine (45.5 g, 0.4 mol), and DMF (759.0 mL). The reaction mixture was heated to 100-105 C. for 20 min. The reaction mixture was cooled to ambient temperature, diluted with water (759.0 mL) and EtOAc (759.0 mL). The organic layer was washed with water (2×500.0 mL) and brine (500.0 mL). The organic layer was dried over sodium sulfate and filtered through Celite. The filtrate was concentrated under reduced pressure. Column chromatography of the resulting crude product on silica gel, eluting with EtOAc and heptane (50-100%) afforded the desired product.

Reference： [1]Patent: US2015/284411,2015,A1 .Location in patent: Paragraph 0609

43
[ 1041026-70-3 ]
3-chloro-3-(2-ethoxy-5-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile [ No CAS ]
6-[5-cyano-3-(2-ethoxy-5-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		dl .3) 6-[5-Cyano-3-(2-ethoxy-5-methoxy-phenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]- 2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester To the solution of <strong>[1041026-70-3]tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate</strong> compound with 1,2-dihydroperoxyethyne (1 : 1) (14.2 g, 49.3 mmol) in DCM (600 mL) was added DI- PEA (60.8 mL, 348 mmol) at room temperature. After stirring for 5 min, 3-chloro-3-(2- ethoxy-5-methoxy-phenyl)-2-oxo-2,3-dihydro-lH-indole-5-carbonitrile (25 g, 58.3 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was slowly poured into cold water with stirring. The mixture was extracted with DCM 3 times. The combined organic phase was washed with water 3 times and dried over Na2S04, concentrated under reduced pressure to a residue. EtOAc was added to the residue and stirred for 30 min. The precipitate was collected by filtration and washed with cold EtOAc and MTBE. The solvent was removed under reduced pressure to give the title compound (25 g, yield 85%) as a white solid. 1H NMR (400 MHz, CDC13): delta 8.39 (s, 1H), 7.51-7.49 (m, 1H), 7.39-7.38 (d, J= 3.2 Hz, 1H), 7.17-7.16 (d, J= 1.6 Hz, 1H), 6.92-6.90 (d, J = 8.4 Hz, 1H), 6.78-6.77 (d, J = 5.6 Hz, 1H), 6.70-6.67 (d, J= 9.2 Hz, 1H), 4.00-3.98 (m, 2H), 3.83 (s, 3H), 3.81-3.68 (m, 3H), 3.34 (m, 2H), 1.41 (s, 9H), 1.09-1.06 (t, J= 7.2 Hz, 3H).

Reference： [1]Patent: WO2015/173393,2015,A1 .Location in patent: Page/Page column 72

44
[ 1041026-70-3 ]
6-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-2-vinylbenzo[d]oxazole [ No CAS ]
2-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazole [ No CAS ]

Reference： [1]Patent: WO2015/140717,2015,A1

45
[ 1041026-70-3 ]
6-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-2-vinylbenzo[d]oxazole [ No CAS ]
tert-butyl 6-(2-(6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200 mg	With methanol; at 50℃;	To a stirred solution of 6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-2- vinylbenzo[d]oxazole (Intermediate 128, 100 mg, 0.24 mmol) in dry MeOH (10 mL) at 50 C was added 2,6-diaza-spiro[3.3]heptane-2-carboxylic acid terf-butyl ester (146 mg, 0.6 mmol; made according to the procedures reported by Org. lett, 2008, 10, 3525 ). The mixture was stirred at 50 C overnight. The solvent was removed. The residue was diluted with water (30 mL) and extracted with EA (10 mLx3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated to afford 200 mg of the title compound as a white solid, which was used for next step without further purification.

Reference： [1]Patent: WO2015/140717,2015,A1 .Location in patent: Page/Page column 169; 170

46
[ 1041026-70-3 ]
(2R)-1-(4-chloro-3-(4-(3,5-dimethylisoxazol-4-yl)-5-methyl-6-(6-(2,2,2-trifluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-2-yl)phenoxy)-3-(methylamino)propan-2-ol [ No CAS ]