[ CAS No. 1159599-99-1 ]

Name: 1159599-99-1|2-Oxa-6-azaspiro[3.3]heptane oxalate|97%
Brand: Ambeed
SKU: A161934
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Quality Control of [ 1159599-99-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1159599-99-1 ]

Product Details of [ 1159599-99-1 ]

CAS No. :	1159599-99-1	MDL No. :	MFCD11976178
Formula :	C₇H₁₁NO₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KOUVDKDABFOPIG-UHFFFAOYSA-N
M.W :	189.17	Pubchem ID :	53308464
Synonyms :

Calculated chemistry of [ 1159599-99-1 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.71
Num. rotatable bonds :	1
Num. H-bond acceptors :	6.0
Num. H-bond donors :	3.0
Molar Refractivity :	44.73
TPSA :	95.86 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-9.74 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.71
Log Po/w (XLOGP3) :	-3.22
Log Po/w (WLOGP) :	-1.62
Log Po/w (MLOGP) :	-1.43
Log Po/w (SILICOS-IT) :	1.4
Consensus Log Po/w :	-0.83

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	1.08
Solubility :	2280.0 mg/ml ; 12.1 mol/l
Class :	Highly soluble
Log S (Ali) :	1.78
Solubility :	11300.0 mg/ml ; 59.9 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.96
Solubility :	20.7 mg/ml ; 0.109 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.66

Safety of [ 1159599-99-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1159599-99-1 ]

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

Upstream synthesis route of [ 1159599-99-1 ]
Downstream synthetic route of [ 1159599-99-1 ]

[ 1159599-99-1 ] Synthesis Path-Upstream 1~8

1
[ 13573-28-9 ]
[ 144-62-7 ]
[ 1159599-99-1 ]

Yield	Reaction Conditions	Operation in experiment
51.1%	Stage #1: With magnesium In methanolSonication; Inert atmosphere Stage #2: for 0.0833333 h; Inert atmosphere	To a solution of 9 (7.5 g, 29.6 mmol) in 500 mL MeOH, magnesium turnings (5.04 g, 207 mmol) were added and reaction mass was sonicated for 1 h. Then solvent was evaporated and 1 L of diethyl ether was added along with sodium sulphate decahydrate (4.21 g, 29.6 mmol) and stirred for 1 h at RT. The reaction mixture was filtered through celite and dried over anhyd. Na2SO4 and then oxalic acid (1.33 g, 14.80 mmol) dissolved in 2 mL EtOH added and stirred for 5 min to get oxalate salt of amine (10) (1.5 g). Yield: 51.1percent; off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 4.65 (s, 4H, 2CH_2, spiro morpholine), 4.16 (s, 4H, 2CH_2, spiro morpholine); LC-MS (ESI + ve) m/z 100.0 [M+H]⁺.

Reference： [1] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 475 - 487
[2] Patent: WO2017/15106, 2017, A1, . Location in patent: Page/Page column 138; 139

2
[ 174-78-7 ]
[ 144-62-7 ]
[ 1159599-99-1 ]

Reference： [1] Organic Process Research and Development, 2016, vol. 20, # 3, p. 675 - 682
[2] Fitoterapia, 2014, vol. 92, p. 111 - 115

3
[ 1522-92-5 ]
[ 1159599-99-1 ]

Reference： [1] Fitoterapia, 2014, vol. 92, p. 111 - 115
[2] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 475 - 487
[3] Patent: WO2017/15106, 2017, A1,
[4] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401

4
[ 144-62-7 ]
[ 1159599-99-1 ]

Reference： [1] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401

5
[ 13573-28-9 ]
[ 1159599-99-1 ]

Reference： [1] Fitoterapia, 2014, vol. 92, p. 111 - 115

6
[ 78-71-7 ]
[ 1159599-99-1 ]

Reference： [1] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401

7
[ 2402-83-7 ]
[ 1159599-99-1 ]

Reference： [1] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401

8
[ 46246-91-7 ]
[ 1159599-99-1 ]

Reference： [1] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401

[ 1159599-99-1 ] Synthesis Path-Downstream 1~68

1
[ 1159599-99-1 ]
[ 1240402-76-9 ]
[ 1240402-44-1 ]

Yield	Reaction Conditions	Operation in experiment
8%		b) {3-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazol-5-yl}-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone Trimethylaluminum (1.0 mL of a 2 M solution in hexane, 2 mmol) was slowly added to a solution of 2-oxa-6-azonia-spiro[3.3]heptane oxalate salt (100 mg, 0.53 mmol) in toluene (2 mL) at 0 C. and the resulting mixture stirred for 2 h at room temperature. Then a solution of 3-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (200 mg, 0.6 mmol) in toluene (8 mL) was added dropwise and the resulting mixture heated at 110 C. for 3 h. After cooling to room temperature and extractive workup (ethyl acetate/aqueous saturated Seignette's salt solution) the organic phase was dried (Na2SO4) and filtered. Purification by chromatography (silica, dichloromethane:methanol=95:5 to 7:3) afforded the title compound (19 mg, 8%) as a colourless oil. MS: m/e=400.1 [M+H]+.

Reference： [1]Patent: US2010/210651,2010,A1 .Location in patent: Page/Page column 28

2
[ 13573-28-9 ]
[ 144-62-7 ]
bis(2-oxa-6-azaspiro[3.3]heptan-6-ium) ethanedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%		<strong>[13573-28-9]6-tosyl-2-oxa-6-azaspiro[3.3]heptane</strong>s (155; 7.30 g, 28.8 mol) and magnesium (4.9 g, 0.2 mol) were sonicated for one hour in methanol (500 ml). Almost all sol vent was removed from the grey reaction mixture on a rotary evaporator to give a viscous grey residue. Diethyl ether (500 ml) and sodium sulfate ( 15.0 g) were added and the resulting l ight grey m ixture was stirred vigorously for 30 min before filtration .The fi ltrate was dried over anhydrous sodium sul fate and anhydrous oxalic acid ( 1.3 g, 1 4.4 mol) dissolved in ethanol (~1 ml) was added to the organic phase. A thick white precipitate formed instantly. It was fi ltered off and dried under vacuum to give 2-oxa-6-azaspiro[3.3]heptane oxalate (156; 3.37 g, 81 %) as amorphous white solid. MS (ESI) calcd for C10H20N2O2-C4O8 376.28.
81%		<strong>[13573-28-9]6-tosyl-2-oxa-6-azaspiro[3.3]heptane</strong>s (7.30 g, 28.8 mol) and magnesium(4.9 g, 0.2 mol) were sonicated for one h in methanol (500 mL). Almost all solvent was removed from the grey reaction mixture on a rotary evaporator to give a viscous grey residue. Diethyl ether(500 mL) and sodium sulfate (15.0 g) were added and the resulting light grey mixture was stirred vigorously for 30 min before filtration. The filtrate was dried over anhydrous sodium sulfate and anhydrous oxalic acid (1.3 g, 14.4 mol) dissolved in ethanol (~1 mL) was added to the organic phase. A thick white precipitate formed instantly. It was filtered off and dried under vacuum to give 2-oxa-6-azaspiro[3.3]heptane oxalate 3.37 g (81%) as amorphous white solid
73.6%		A mixture of <strong>[13573-28-9]6-(toluene-4-sulfonyl)-2-oxa-6-aza-spiro[3.3]heptane</strong> (128) (1.27 g,5 mmol) in MeOH(10 mL) was added magnesium chips. The mixture was reacted using ultrasound at RT for 20 mins. Oxalic acid was added and the mixture was stirred for 15 min, then concentrated to give oxalate salt (129) (1.06 g, 3.68mmol, yield: 73.6%).1H NMR: (D20, 400 MHz): delta (ppm) 4.76 (s, 4H), 4.23 (s, 4H). ESI-MS (M+l): 101 calc. forC5H9NO 100.

37%

Step 2 2-Oxa-6-azaspiro[3.3]heptane hemioxalate Procedure: <strong>[13573-28-9]6-(Toluene-4-sulfonyl)-2-oxa-6-azaspiro[3.3]heptane</strong> (510 mg, 2 mmol) and magnesium granular (336 mg, 14 mmol) were sonicated for one hour in methanol (100 ml). Almost all solvent was removed from the grey reaction mixture on a rotary evaporator to give a viscous grey residue. Diethyl ether (10 ml) and sodium sulfate decahydrate (1 g) were added and the resulting light grey mixture was stirred vigorously for 30 minutes before filtration. The filtrate was dried over anhydrous sodium sulfate and anhydrous oxalic acid (90 mg, 1 mmol) dissolved in Ethanol (~0.5 mL) was added to the organic phase. A thick white precipitate formed instantly. It was filtered off and dried under vacuum to give 2-oxa-6-azaspiro[3.3]heptane hemioxalate (140 mg, 37%) off-white solid. 1H NMR (300 MHz, CDCl3) delta 4.64 (s, 4H), 4.11 (s, 4H).

Reference： [1]Patent: WO2011/59839,2011,A1 .Location in patent: Page/Page column 143
[2]Patent: WO2013/59587,2013,A1 .Location in patent: Page/Page column 212
[3]Patent: WO2011/143365,2011,A1 .Location in patent: Page/Page column 192
[4]Patent: US2012/252777,2012,A1 .Location in patent: Page/Page column 83-84

3
[ 1159599-99-1 ]
[ 1323407-86-8 ]
[ 1323403-80-0 ]

Yield	Reaction Conditions	Operation in experiment
10%		5.98 3-{4-[4-(2-OXA-6-AZA-SPIRO[3.3]HEPT-6-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE To the dichloromethane (10 ml) suspension of 2-oxa-6-azaspiro[3.3]heptane oxalate (0.124 g, 0.857 mmol) was added N-ethyl-N-isopropylpropan-2-amine (0.425 ml, 2.57 mmol). The mixture was stirred at room temperature for 5 min. Then 3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.380 g, 0.857 mmol) was added, which was still a suspension. About 3 ml of acetonitrile was added and the mixture was stirred at room temperature overnight. The mixture was purified by preparative HPLC (MeCN/water in 0.1% HCOOH) to give 3-{4-[4-(2-Oxa-6-aza-spiro[3.3]hept-6-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione (39 mg, 10% yield); mp, not determined. HPLC: Waters Symmetry C-18, 3.9*150 mm, 5 mum, 1 mL/min, 240 nm, gradient from 10/90 to 90/10 in 5 min, isocratic at 90/10 in 5 min (CH3CN/0.1% H3PO4), 4.32 min (95.2%). 1H NMR (DMSO-d6) delta 1.93-2.04 (m, 1H, CHH), 2.36-2.48 (m, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.84-2.99 (m, 1H, CHH), 3.30 (s, 3H, CH2CH2), 3.51 (s, 1H, CH2), 4.20-4.47 (m, 2H, CH2), 4.59 (s, 3H, CH2CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 1H, CH2), 7.23-7.36 (m, 4H, Ar), 7.38-7.53 (m, 31-1, Ar), 10.97 (br. s., 1H, NH). 13C NMR (DMSO-d6) delta 22.39, 31.21, 38.54, 45.13, 51.66, 61.97, 62.85, 69.47, 79.96, 115.05, 115.26, 127.62, 128.35, 129.79, 130.00, 133.35, 135.23, 137.96, 153.51, 167.99, 170.92, 172.76. LC/MS m/e=462.

Reference： [1]Patent: US2011/196150,2011,A1 .Location in patent: Page/Page column 114

4
[ 1159599-99-1 ]
[ 7697-28-1 ]
[ 1352621-28-3 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate Example Int23.014-bromo-3-methylphenyl)(2-oxa-6-azaspiro[3.3]hept-6-yl)methanoneTo a stirred solution of 4-bromo-3-methylbenzoic acid (1.5 g) in DMF (55 mL) was added molecular sives (1.9 g) and the mixture was stirred for 1 h. TBTU (4.0 g) was added and the mixture was stirred for 30 minutes. Potassium carbonate (4.8 g) and <strong>[1159599-99-1]2-oxa-6-azaspiro[3.3]heptane ethanedioate</strong> (2:1 ) (1.5 g) were added and the mixture was stirred at r.t. for 16 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 1.77 g of the title compound.
	In N,N-dimethyl-formamide; at 20℃; for 17.5h;	Intermediate Example Int23.014-bromo-3-methylphenyl)(2-oxa-6-azaspiro[3.3]hept-6-yl)methanoneTo a stirred solution of 4-bromo-3-methylbenzoic acid (1.5 g) in DMF (55 mL) was added molecular sives (1.9 g) and the mixture was stirred for 1 h. TBTU (4.0 g) was added and the mixture was stirred for 30 min. Potassium carbonate (4.8 g) and <strong>[1159599-99-1]2-oxa-6-azaspiro[3.3]heptane ethanedioate</strong> (2:1 ) (1.5 g) were added and the mixture was stirred at r.t. for 16 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 1.77 g of the title compound.

Reference： [1]Patent: WO2011/157688,2011,A1 .Location in patent: Page/Page column 140-141
[2]Patent: WO2012/160029,2012,A1 .Location in patent: Page/Page column 114-115

5
[ 1159599-99-1 ]
[ 1008769-87-6 ]
[ 1352621-31-8 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate Example Int24.05[4-bromo-3-(trifluoromethoxy)phenyl](2-oxa-6-azaspiro[3.3]hept-6- yl)methanone To a stirred solution of Int24.03 (900 mg) in DMF (24 mL) was added molecular sives ( 1 .0 g) and the mixture was stirred for 1 h. TBTU (1 .32 g) was added and the mixture was stirred for 30 minutes. Potassium carbonate (2.18 g) and 2- oxa-6-azaspiro[3.3]heptane ethanedioate (2: 1 ) (454 mg) were added and the mixture was stirred at r. t. for 1 6 h . Further TBTU (500 mg) and 2-oxa-6- azaspiro[3.3]heptane ethanedioate (2: 1 ) (225 mg) were added and the mixture was stirred at r.t. for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 386 mg of the title compound.1H-NMR (400MHz, DMSO-d6): delta [ppm]= 4.18 (s, 2H), 4.46 (s, 2H), 4.63 (s, 4H), 7.53 (dd, 1 H), 7.61 - 7.67 (m, 1 H), 7.89 (d, 1 H).
	With potassium carbonate; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 20℃; for 18.5h;	Intermediate Example Int24.05[4-bromo-3-(trifluoromethoxy)phenyl](2-oxa-6-azaspiro[3.3]hept-6-yl)- methanoneTo a stirred solution of Int24.03 (900 mg) in DMF (24 mL) was added molecular sives ( 1.0 g) and the mixture was stirred for 1 h. TBTU (1.32 g) was added and the mixture was stirred for 30 min. Potassium carbonate (2.18 g) and 2-oxa-6- azaspiro[3.3]heptane ethanedioate (2:1 ) (454 mg) were added and the mixture was stirred at r.t. for 16 h. Further TBTU (500 mg) and 2-oxa-6- azaspiro[3.3]heptane ethanedioate (2:1 ) (225 mg) were added and the mixture was stirred at r.t. for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 386 mg of the title compound.1H-NMR (400MHz, DMSO-d6): delta [ppm]= 4.18 (s, 2H), 4.46 (s, 2H), 4.63 (s, 4H), 7.53 (dd, 1 H), 7.61 - 7.67 (m, 1 H), 7.89 (d, 1 H).

Reference： [1]Patent: WO2011/157688,2011,A1 .Location in patent: Page/Page column 143-144
[2]Patent: WO2012/160029,2012,A1 .Location in patent: Page/Page column 117-118

6
[ 893761-44-9 ]
[ 1159599-99-1 ]
[ 1394241-82-7 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 7746 - 7758

7
[ 1159599-99-1 ]
C₃₀H₃₈ClNO₃ [ No CAS ]
C₃₅H₄₆N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With triethylamine; In dichloromethane; at 20℃; for 5h;	Compound TX64007: Compound 11 (0.3 mmol) and 2-oxa-6- azaspiro[3,3]heptanes oxalate (124.7 mg, 0.66 mmol) were taken up in CH2CI2 (5 mL). Et3N (418 mu, 3 mmol) was added and the mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with HC1 (5 mL) and extracted with CH2CI2 (2x 10 mL). The combined organic phase was washed by NaCl (Sat.), dried over Na2S04, then directly loaded on a silica gel column and purified by column chromatography (silica gel, 0-75% EtOAc in Hexanes) to give the compound TX64007 as a white foam (56.8 mg, 34%>) (only the pure fractions were collected, purification was not optimized). 1H NMR (500 MHz, CDC13) delta 8.01 (s, 1H), 6.01 (s, 1H), 4.79 (s, 4H), 4.33 (s, br, 4H), 2.90-3.01 (m, 2H), 2.41-2.51 (m, 1H), 1.83-1.96 (m, 2H), 1.13-1.82 (m, 13H), 1.44 (s, 3H), 1.32 (s, 3H), 1.25 (d, 3H, J= 6.4 Hz), 1.01 (s, 3H), 1.01 (s, 3H), 0.91 (s, 3H); m/z 559 (M+l).

Reference： [1]Patent: WO2012/125488,2012,A1 .Location in patent: Page/Page column 164

8
[ 1159599-99-1 ]
[ 1370447-63-4 ]
[ 1370444-27-1 ]

Yield	Reaction Conditions	Operation in experiment
13 mg	With sodium tris(acetoxy)borohydride; acetic acid; In chloroform; at 20℃; for 72h;	A suspension of the compound (150 mg) prepared in Reference Example P-J1, 2-oxa-6-azaspiro[3.3]heptane oxalate (2:1) (157 mg), and acetic acid (0.1 mL) in CHCl3 (3 mL) was stirred at room temperature for a while, and then sodium triacetoxyborohydride (231 mg) was added thereto, followed by stirring for 3 days. A saturated NaHCO3 solution was added to the reaction solution, followed by extraction with CHCl3. The organic layer was filtered through a phase separator, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (PTLC) (1.0 mm silica gel 60F254 plate, mobile phase: CHCl3/MeOH=90/10 (v/v)) and column chromatography (SNAP Cartridge KP-NH: 11 g, mobile phase: EtOAc/MeOH=100/0 to 95/5 (v/v)). The resulting crude product was washed with a solvent mixture of EtOAc and n-hexane (EtOAc/n-hexane=1/6 (v/v)) with stirring to yield the title compound (13 mg, colorless solid). MS (ESI pos.) m/z: 496 ([M+H]+). 1H-NMR (600 MHz, CDCl3) delta (ppm); 1.19 (6H, d, J=6.9 Hz), 2.59-2.72 (4H, m), 3.36 (4H, br. s.), 4.06-4.13 (1H, m), 4.35 (2H, s), 4.74 (4H, s), 6.36-6.43 (1H, m), 7.23-7.29 (2H, m), 7.49 (1H, d, J=7.8 Hz), 7.51-7.54 (1H, m), 7.75 (1H, d, J=9.2 Hz), 7.85-7.88 (1H, m), 7.93 (2H, d, J=8.3 Hz).

Reference： [1]Patent: US2013/197217,2013,A1 .Location in patent: Paragraph 0604; 0605; 0606; 0607

9
[ 1159599-99-1 ]
[ 1449712-49-5 ]
[ 1449710-19-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; 1-hydroxy-1H-benzotriazol hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dimethyl sulfoxide; at 20℃; for 16h;	General procedure: 4-{7-[3-Cyano-4-(tetrahydro-pyran-4-yloxy)-phenyl]-furo[3,2-b]pyridin-2-yl}-benzoic acid (100 mg, 0.23 mmol) and N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (47.5 mg, 0.27 mmol) are dissolved in DMSO (2 ml). N-(3-Dimethylamino- propyl)-N'-ethylcarbodiimidhydrochloride (DAPECI) (87.0 mg, 0.45 mmol), 1- hydroxybenzotriazole hydrate (HOBt) (34.8 mg, 0.15 mmol) and N-methyl- morpholine (49.9 muIota, 0.45 mmol) are added to the solution. The mixture is stirred at room temperature for 16 h. DMSO is evaporated and the product is isolated by chromatography; yield: 61 mg [2-(4-{7-[3-cyano-4-(tetrahydro-pyran-4-yloxy)- phenyl]-furo[3,2-b]pyridin-2-yl}-benzoylamino)-ethyl]-methyl-carbamic acid tert-butyl ester; HPLC/MS: 2.37 min, [M+H] = 597; 1H NMR (500 MHz, DMSO-d6/TFA-di) delta [ppm] 8.84 (d, J = 6.5 Hz, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.55 (dd, J = 9.0, 2.3 Hz, 1H), 8.25 - 8.17 (m, 3H), 8.11 - 7.97 (m, 3H), 7.62 (d, J = 9.2 Hz, 1 H), 5.02 - 4.87 (m, 1 H), 3.96 - 3.81 (m, 2H), 3.65 - 3.49 (m, 3H), 3.47 - 3.29 (m, 4H), 2.80 (s, 3H), 2.10 - 2.02 (m, 2H), 1.79 - 1.70 (m, 2H), 1.28 (s, 9H).

Reference： [1]Patent: WO2013/117285,2013,A1 .Location in patent: Page/Page column 69; 77; 78

10
[ 1159599-99-1 ]
[ 1537168-68-5 ]

Reference： [1]Patent: WO2014/9296,2014,A1

11
[ 1003845-06-4 ]
[ 1159599-99-1 ]
C₉H₁₂BN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1,4-dioxane; at 100℃; for 1h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (150 mg, 0.95 mmol) and 2-oxa-6-azaspiro- [3.3]heptane oxalate (239 mg, 1.26 mmol) were suspended in 1,4-dioxane (6 mL) and triethylamine (0.18 mL, 1.26 mmol) was added. The mixture was heated at 100C under microwave irradiation for 1 h. The mixture was diluted with MeOH (20 mL), then concentrated. To the resulting orange oil were added Intermediate 6 (228 mg, 0.62 mmol), 2M aqueous potassium carbonate solution (1.4 mL) and 1,4-dioxane (5 mL). The mixture was thoroughly degassed before the addition of bis[3-(diphenylphosphanyl)- cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (36 mg, 0.04 mmol), then the mixture was heated at 100C for 15 h. EtOAc (10 mL) was added, then the mixture was washed with water (2 x 10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with a gradient of 0-7% MeOH in DCM. The resulting material was further purified by preparative HPLC, to afford the title compound (21.2 mg, 5%) as a white solid. deltaEta (500 MHz, CDC13) 9.04 (d, J 4.5 Hz, IH), 8.74 (s, 2H), 7.93 (s, IH), 7.28 (t, J 7.9 Hz, IH), 7.17 (d, J 8.2 Hz, IH), 7.12 (t, J 7.5 Hz, IH), 6.94 (d, J 7.6 Hz, IH), 6.63 (t, J 73.5 Hz, IH), 4.87 (s, 4H), 4.35 (s, 4H), 4.32 (s, 2H), 2.57 (s, 3H). Method A HPLC-MS: MH+ mlz 465, RT 3.59 minutes

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 116; 117

12
[ 13573-28-9 ]
[ 1159599-99-1 ]

Reference： [1]Fitoterapia,2014,vol. 92,p. 111 - 115

13
[ 1159599-99-1 ]
[ 1449279-91-7 ]

Reference： [1]Fitoterapia,2014,vol. 92,p. 111 - 115

14
[ 1159599-99-1 ]
[ 1449279-92-8 ]

Reference： [1]Fitoterapia,2014,vol. 92,p. 111 - 115

15
[ 1159599-99-1 ]
(4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylic acid [ No CAS ]
[ 1449279-89-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; at 20℃; for 24h;	General procedure: Commercial (4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid (7, paclitaxel side chain,2 g, 0.005 mol, 1.00 equiv) and HATU (3 g, 0.0079 mol, 1.50equiv)were added to a solution of compound 6 (1 g, 0.0052 mol,1.00 equiv) in THF (50 mL), and the reaction mixturewas stirredat room temperature for 24 h. Then 150 mL water and CH2Cl2was added. The organic layer was washed with brine, driedover MgSO4, and evaporated to give a residue which waschromatographed over silica gel (Petroleumether:EtOAc = 1:3)to afford compound 9 as a white amorphous powder (2.252 g,86%) as a pair of diastereoisomers

Reference： [1]Fitoterapia,2014,vol. 92,p. 111 - 115

16
[ 1159599-99-1 ]
[ 196404-55-4 ]
[ 1449279-90-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; at 20℃; for 24h;	General procedure: Commercial (4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid (7, paclitaxel side chain,2 g, 0.005 mol, 1.00 equiv) and HATU (3 g, 0.0079 mol, 1.50equiv)were added to a solution of compound 6 (1 g, 0.0052 mol,1.00 equiv) in THF (50 mL), and the reaction mixturewas stirredat room temperature for 24 h. Then 150 mL water and CH2Cl2was added. The organic layer was washed with brine, driedover MgSO4, and evaporated to give a residue which waschromatographed over silica gel (Petroleumether:EtOAc = 1:3)to afford compound 9 as a white amorphous powder (2.252 g,86%) as a pair of diastereoisomers. Compound 10 was prepared through the coupling ofcompounds 6 and commercial (4S,5R)-3-tert-butoxycarbony-2-(4-methoxpheny)-4-phenyl-5-oxazolidinecarboxylic acid(8, docetaxel side chain) in 95% yields by similar procedures.Compound 10 is also a pair of diastereoisomers

Reference： [1]Fitoterapia,2014,vol. 92,p. 111 - 115

17
[ 174-78-7 ]
[ 144-62-7 ]
[ 1159599-99-1 ]

Yield	Reaction Conditions	Operation in experiment
3.22 g	In diethyl ether; ethanol;	To the filtrate was added under stirringa solution of anhydrous oxalic acid (4.5 g, 0.05 mol) in EtOH(10 mL), which immediately formed a white precipitate. Thesolid was filtered and dried under reduced pressure to givepure 2-oxa-6-azaspiro[3.3]heptane (3.22 g, 73%) of oxalatemono-salt as an amorphouswhite powder. 1H NMR(400 MHz,CDCl3): delta 4.65 (s, 4H), 4.12 (s, 4H); 13C NMR (100 MHz, CDCl3)delta 79.2, 54.1, 39.3.

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 675 - 682
[2]Fitoterapia,2014,vol. 92,p. 111 - 115

18
[ 1522-92-5 ]
[ 1159599-99-1 ]

Reference： [1]Fitoterapia,2014,vol. 92,p. 111 - 115
[2]European Journal of Medicinal Chemistry,2016,vol. 122,p. 475 - 487
[3]Patent: WO2017/15106,2017,A1
[4]Synthesis,2017,vol. 49,p. 2394 - 2401

19
[ 1159599-99-1 ]
[ 1527513-49-0 ]

Reference： [1]Patent: US2014/5167,2014,A1

20
[ 1159599-99-1 ]
[ 1527515-29-2 ]

Reference： [1]Patent: US2014/5167,2014,A1

21
[ 1159599-99-1 ]
[ 1588523-07-2 ]
[ 1549706-61-7 ]

Yield	Reaction Conditions	Operation in experiment
51 mg	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	A solution of crude triazole (182 mg, 0.53mmol, 1.00 equiv) in DMF (17.00mL) was treated successively with N,N-diisopropylethylamine (0.40mL, 2.30mmol, 4.37 equiv) and <strong>[1159599-99-1]2-oxa-6-azaspiro[3.3]heptan-6-ium oxalate</strong>34 (311mg, 1.08mmol, 2.05 equiv) and the resulting mixture was stirred at 20C for 16h, then concentrated to dryness under reduced pressure. The residue was re-suspended in MeOH, filtered through a pad of Celite, and the filtrate was purified by column column chromatography on silica gel, eluting with 0-50% EtOAc/hexanes followed by re-precipitation (twice) from EtOAc/hexanes, to give 17 (51 mg, 24%) as an amorphous white solid: mp 238-240C; 1H NMR (CDCl3): delta 8.30 (s, 1H), 7.50 (m, 5H), 7.41 (m, 1H), 4.67 (br s, 4H), 4.51 (q, J=7.15Hz, 2H), 4.31 (br s, 4H), 1.47 (t, J=7.14Hz, 3H); HRESIMS calcd for C20H20N6NaO4 m/z [M+Na]+ 431.1438, found 431.1433, calcd for C20H21N6O4 m/z [M+H]+ 409.1619, found 409.1622; TLC Rf=0.13 (50% EtOAc/hexanes); HPLC purity: 97.1%.

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1029 - 1039

22
[ 14305-08-9 ]
[ 1159599-99-1 ]
[ 1549705-95-4 ]

Yield	Reaction Conditions	Operation in experiment
45%	With caesium carbonate; In N,N-dimethyl-formamide; at 50 - 100℃; for 20h;	Following a general literature method,34 a solution of 30 (540mg, 1.64mmol, 1.00 equiv) in DMF (50mL) was treated with anhydrous Cs2CO3 (824 mg, 2.51mmol, 1.53 equiv) and 2-oxa-6-azaspiro[3.3]heptan-6-ium oxalate35 (720mg, 2.50mmol, 1.53 equiv) and the mixture was stirred at 50C for 16h, then at 100C for 4h. The cooled reaction mixture was diluted with brine and extracted with EtOAc (×5). The combined organic extracts were washed with water (×3) and brine, dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with EtOAc/hexanes to give 10 (246 mg, 45% yield) as fine off-white crystals: mp 214-217C; 1H NMR (CDCl3): delta 7.54 (m, 2H), 7.43 (m, 2H), 7.34 (m, 1H), 7.23 (s, 1H), 4.85 (s, 4H), 4.62 (s, 4H); HRESIMS calcd for C15H1481BrN3NaO2 m/z [M+Na]+ 372.0412, found 372.0155; calcd for C15H1479BrN3NaO2 m/z [M+Na]+ 370.0162, found 370.0157. TLC Rf=0.05 (50% EtOAc/hexanes); HPLC purity: 98.1%.

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1029 - 1039

23
[ 624-38-4 ]
[ 1159599-99-1 ]
[ 1527515-05-4 ]

Yield	Reaction Conditions	Operation in experiment
37%		6-(4-Iodophenyl)-2-oxa-6-azaspiro[3.3]heptane The title compound was synthesized according to General Method D, utilizing 1,4-diiodobenzene (2.5 g, 7.6 mmol), <strong>[1159599-99-1]2-oxa-6-azaspiro[3.3]heptane oxalic acid salt</strong> (1.0 g, 6.9 mmol), CuI (0.26 g, 1.4 mmol), BINOL (0.40 g, 1.4 mmol), and K3PO4 (4.4 g, 21 mmol) in DMF (15 mL). The mixture was diluted with EtOAc, filtered through Celite and the filtrate was concentrated. Purification by flash chromatography (Biotage Isolera, 100 g HP-SIL, 10-50% EtOAc in hexanes) gave the title compound as a yellow solid (0.78 g, 37%). 1H NMR (400 MHz, CDCl3) delta ppm 7.47 (d, J=8.8 Hz, 2H), 6.22 (d, J=8.8 Hz, 2H), 4.82 (s, 4H), 3.98 (s, 4H); MS ESI 301.9 [M+H]+, calcd for [C11H12INO+H]+ 302.0.

Reference： [1]Patent: US2014/5167,2014,A1 .Location in patent: Paragraph 0229; 0230

24
[ 1159599-99-1 ]
[ 1527513-53-6 ]

Reference： [1]Patent: US2014/5167,2014,A1

25
[ 1159599-99-1 ]
(S)-3-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-N-(cyclopentyl(pyridin-2-yl)methyl)-1H-indazole-5-carboxamide p-toluenesulfonate [ No CAS ]

Reference： [1]Patent: US2014/5167,2014,A1

26
[ 1159599-99-1 ]
(S)-3-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-N-(cyclopentyl(pyridin-2-yl)methyl)-1H-indazole-5-carboxamide benzenesulfonate [ No CAS ]

Reference： [1]Patent: US2014/5167,2014,A1

27
[ 13206-46-7 ]
[ 1159599-99-1 ]
[ 1575590-88-3 ]

Yield	Reaction Conditions	Operation in experiment
0.49 g	With triethylamine; In methanol; dichloromethane; at 20℃; for 48h;	To a solution of 2-methylpropanal (5.6 mL, 61.8 mmol) in DCM (75mL) cooled with an ice bath was added bromine (3.2 mL, 61.8 mmol) dropwise. After 1 hr, the resulting 2- bromo-2-methylpropanal solution was evaporated to a weight of 8.5 g. This material was stirred in DCM (8 ml) at room temperature and 6-oxa-2-azaspiro[3.3]heptane; 1/2 oxalate (1.57mL, 7.19mmol) was added along with TEA (10 mL) and MeOH (3 mL). After stirring 2 days, the mixture was diluted with brine (30 mL) and the layers separated. The organic layer was washed with 1M HC1 (50 mL) and then the aqueous layer was basified with KOH to pH = 10-11. This was then extracted with DCM and the organic layers were combined, dried (MgS04), filtered and concentrated to isolate 2-methyl-2-(6-oxa-2-azaspiro[3.3]heptan-2- yl)propanal as an oil used directly in the next step.

Reference： [1]Patent: WO2014/39899,2014,A1 .Location in patent: Page/Page column 78

28
[ 1159599-99-1 ]
[ 1446358-48-0 ]
C₂₂H₁₈F₂N₆O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With triethylamine; In tetrahydrofuran; at 40℃; for 48h;	General procedure: General procedure B A solution of amino nucleophile (3 equiv.), triethylamine (10 equiv.), and Intermediate 1 (1 equiv.) was stirred in dioxane and water (2:1 ratio) at 90 C until complete consumption of starting material was observed by LC/MS. The solution was diluted withiN hydrochloric acid and dichloromethane. The layers were then separated and thelayer was extracted with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification yielded theproduct The title compound was prepared following general procedure B, except 2-oxa-6-azaspiro[3.3]heptane oxalate (2 equiv.) was the amine reactant, 6 equivalents of triethylamine was used, and contents were heated to 40 C for 2 d as a solution in THF. The reaction was cooled and concentrated to yield a solid, which was dissolved in ethyl acetate. The organic layer was washed with iN HC1 solution, dried, filtered, and concentrated in vacuo to deliver the desired compound, Compound 1-32 (19 mg, 33% yield) as a white solid.1H NMR (500 MHz, METHANOL-d4) oe ppm 8.83 (s, 1 H) 8.24 (br. s, 1 H) 7.57 (br. s., 1 H)7.29-7.33 (m, 1 H) 7.03 -7.16 (m, 2 H) 6.91 -7.01 (m, 2 H) 5.99-6.05 (m, 2 H) 4.28 -4.61 (m, 4 H) 3.99 (s, 2 H) 3.88 (s, 2 H).

Reference： [1]Patent: WO2014/144100,2014,A2 .Location in patent: Paragraph 00274

29
[ 1159599-99-1 ]
1-((S)-sec-butyl)-6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine [ No CAS ]
1-((S)-sec-butyl)-6-chloro-3-(2-oxa-6-azaspiro[3.]hept-6-yl)-1H-pyrazolo[4,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	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 100℃; for 16h;Sealed tube;	A mixture of l-((S)-i,ec-butyl)-6-chloro-3-iodo-lH-pyrazolo[4,3-c]pyridine (0.985 g, 2.935 mmol), <strong>[1159599-99-1]2-oxa-6-azaspiro[3.3]heptane oxalic acid salt</strong> (0.555 g, 2.935 mmol), 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene (0.17 g, 0.294 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.0672 g, 0.073 mmol), cesium carbonate (2.87 g, 8.81 mmol), and 1,4-dioxane (19 mL) was heated in a sealed vial at 100 C. After 16 h the cooled reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with additional ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica (solvent gradient: 20- 70% ethyl acetate in cyclohexane) to afford the title compound (0.657 g, 73%) as a yellow solid. [a]D +7.0 (c 2.55, methanol). 1H NMR (400 MHz, CDC13) delta 8.53 (1H, d, J= 1.0 Hz), 7.11 (1H, d, J= 1.0 Hz), 4.88 (4H, s), 4.34 (4H, s), 4.25-4.16 (1H, m), 2.04-1.93 (1H, m), 1.84-1.73 (1H, m), 1.47 (3H, d, J= 6.7 Hz), 0.75 (3H, t, J= 7.4 Hz).

Reference： [1]Patent: WO2014/210354,2014,A1 .Location in patent: Page/Page column 112; 113

30
[ 1159599-99-1 ]
[ 1578244-55-9 ]
[ 1578244-77-5 ]

Reference： [1]Organic and Biomolecular Chemistry,2015,vol. 13,p. 893 - 904

31
[ 1159599-99-1 ]
[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate [ No CAS ]
C₂₁H₂₉N₃OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;	Example 126 A mixture of [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate (100 mg), 2-oxa-6-azaspiro[3.3]heptaneoxalate (67 mg), K2CO3 (94 mg), and DMF (1.0 mL) was stirred at 80 C. for 12 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/MeOH), and fumaric acid (10 mg) was added thereto to form a salt, followed by washing with EtOAc, thereby obtaining 6-(4,4-dimethylcyclohexyl)-2-methyl-4-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)thieno[2,3-d]pyrimidinefumarate (23 mg).

Reference： [1]Patent: US2015/111876,2015,A1 .Location in patent: Paragraph 0314

32
[ 1159599-99-1 ]
4-(benzyloxy)-3,5-diisopropylbenzoic acid [ No CAS ]
(4-(benzyloxy)-3,5-diisopropylphenyl)(2-oxa-6-azaspiro[3.3]heptan-6-yI)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium carbonate; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; for 1h;	[00137] To a solution of 4-(benzyloxy)-3,5-diisopropylbenzoic acid (100 mg, 0.32 mmol) in DMF (5 mL) was added HATU (180, 0.48 mmol), K2C03 (220 mg, 1.6 mmol) and 2- oxa-6- azaspiro[3.3]heptan-6-ium carboxyformate (101 mg, 0.35 mmol). The resulting solution was allowed to stir for ihour. Upon completion the reaction mixture was quenched with H20 (20mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with H20 (3 x 30 mL), brine (20 mL), dried over MgSO4 and the solvent was removed under vacuum. The crude product was purified by column chromatography (EtOAc/n-Hexane) to afford the product as a white solid (62 mg, 50% yield). 1H NMR (400 MHz, CDCI3) O 7.54 - 7.31 (m, 7H), 4.83 (d, J = 11.7 Hz, 6H), 4.40 (d, J = 42.4 Hz, 4H), 3.39 (hept, J = 6.8 Hz,2H), 1.25 (d, J = 6.8 Hz, 12H). 130 NMR (101 MHz, CDCI3) O 170.82, 157.83, 142.63,128.66, 128.31, 127.37, 126.60, 125.44, 72.92, 60.89, 53.37, 26.39, 24.02. MS [M+Na]:C25H31NO3 requires: 416.2202, found: 416.2186.

Reference： [1]Patent: WO2015/97475,2015,A1 .Location in patent: Paragraph 00137

33
[ 1159599-99-1 ]
[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-4-yl]acetic acid [ No CAS ]
2-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-4-yl]-1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200 mg	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 20℃; for 3h;	Example 3B Preparation of 2-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-4-yl]-1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethanone A solution of 200 mg of [6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-4-yl]acetic acid (Example 3A), 312 mg of HATU, 0.3 ml of triethylamine and 158 mg of 2-oxa-6-azaspiro[3.3]heptane oxalate (2:1) (CAS 174-78-7 for the free base) in 10 ml of DMF was stirred at room temperature for 3 hours. The mixture was partitioned between semiconcentrated brine and ethyl acetate, the organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, dichloromethane/methanol gradient). Yield: 200 mg of 2-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-4-yl]-1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethanone. _: 1H NMR (400 MHz, RT, DMSO-d6): delta=2.50 (s, 3H); 2.82 (dd, 1H); 3.05 (dd, 1H); 3.44 (q, 1H); 4.01 (d, 1H); 4.05 (d, 1H); 4.43 (d, 1H); 4.49 (d, 1H); 4.65-4.75 (m, 4H); 6.19 (d, 1H); 7.13-7.29 (m, 3H); 7.41 (d, 2H); 7.47 (dt, 1H); 7.60 (dt. 1H); 7.74 (d, 1H).

Reference： [1]Patent: US2015/299201,2015,A1 .Location in patent: Paragraph 0556; 0557; 0558; 0559

34
[ 1159599-99-1 ]
[ 1415899-20-5 ]
6-(cyclopropylmethoxy)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridine-2-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃;Inert atmosphere;	Under a nitrogen atmosphere a mixture of compound methyl 5-bromo-6- (0208) (cyclopropylmethoxy)pyridine-2-carboxylate (CAN 1415899-20-5, 0.51 g, 1.8 mmol), 2- oxa-6-azaspiro[3.3]heptane ethanedioate (CAN 1254966-66-9, 0.29 mg, 1.8 mmol), Pd2(dba)3 (33 mg, 0.035 mmol), BINAP (45 mg, 0.07 mmol) and Cs2C03 (1.76 mg, 5.4 mmol) in toluene (50 mL) was stirred at 110 C overnight. After concentration, the residue was partitioned between water (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (2x20 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated to give a residue which was purified by column chromatography eluting with petroleum ether - ethyl acetate (1: 1) to give the target compound (0.4 g, 73%) as yellow solid, LC-MS: 305.1 [MH+] .

Reference： [1]Patent: WO2015/150438,2015,A1 .Location in patent: Page/Page column 30

35
[ 1159599-99-1 ]
[ 1415899-20-5 ]
6-(cyclopropylmethoxy)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridine-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/150438,2015,A1

36
[ 1159599-99-1 ]
N,N'-bis{4-[(2-chloro-4-fluorobenzoyl)amino]phenyl}-5,10-dioxo-5H,10H-diimidazo[1,5-a:1',5'-d]pyrazine-1,6-dicarboxamide [ No CAS ]
N-{4-[(2-chloro-4-fluorobenzoyl)amino]phenyl}-5-(2-oxa-6-azaspiro[3.3]hept-6-ylcarbonyl)-1H-imidazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7 mg	With N-ethyl-N,N-diisopropylamine; at 20℃; for 120h;	To the crude mixture of N,N?-bis{4-[(2-ch[oro-4-f[uorobenzoy[)amino]pheny[1-5,10-dioxo-5H,1OH-diimidazo[1 ,5-a:1?,S?-d]pyrazine-l ,6-dicarboxamide (0.160 mmo[,Intermediate 005), were added 61 mg (0.32 mmo[) 2-oxa-6-azaspiro[3.3]heptane oxa[ate and 0.278 mL (1 .6 mmo[) N-ethy[-N-isopropy[propan-2-amine and the mixture was stirred for 5 d at room temperature.The reaction mixture was concentrated in vacuo and the residue was purified bypreparative HPLC chromatography to give 7 mg of the tit[e compound as a so[idmateria[.1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 13.60 (br. s., 1H), 10.51 (s, 1H), 7.91 (s,1H), 7.75-7.64 (m, 5H), 7.59 (dd, 1H), 7.36 (td, 1H), 4.83 (s, 2H), 4.77-4.68 (m,4H), 4.33 (s, 2H).LC-MS (Method 1): R = 0.97 mm; MS (ESIpos) m/z = 484 [M+H].

Reference： [1]Patent: WO2015/150449,2015,A2 .Location in patent: Page/Page column 329

37
[ 1159599-99-1 ]
phenyl 5-({4-[(2-chloro-4,5-difIuorobenzoyl)amino]phenyl}carbamoyl)-1H-imidazole-4-carboxylate [ No CAS ]
N-{4-[(2-chloro-4,5-difluorobenzoyl)amino]phenyl}-4-(2-oxa-6-azaspiro[3.3]hept-6-ylcarbonyl)-1H-imidazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40 mg	at 20℃; for 20h;	To the crude reaction mixture of pheny[ 5-({4-[(2-ch[oro-4,5-dif[uorobenzoy[)amino]pheny[lcarbamoy[)-1H-imidazo[e-4-carboxy[ate (0.40 mmo[,Intermediate 022) were added 69.1 mg (0.24 mmo[) 2-oxa-6-azaspiro[3.3]heptaneethanedioate (2:1)and the mixture was stirred for 20 hours at room temperatur. The reaction was di[uted with water and the resu[ting precipitate was fi[tered off and was washed with water. The crude product was purified by f[ash co[umn chromatography (dich[oromethane/methano[-gradient) to give after washing withdich[oromethane and drying under vacuum at 50 C 40 mg of the tit[e compound as a so[id materia[.1H-NMR (400 MHz, DMSO-d6), 6 [ppm] = 13.58 (s, 1H), 13.44 (br. s., 1H), 10.54 (s,1H), 8.06-7.80 (m, 3H), 7.75-7.47 (m, 4H), 4.81 (s, 2H), 4.75-4.56 (m, 4H), 4.32 (s,2H).LC-MS (Method 5): Rt = 0.92 mm; MS (ESIpos) m/z = 502.0 [M+H].

Reference： [1]Patent: WO2015/150449,2015,A2 .Location in patent: Page/Page column 256

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[ 1159599-99-1 ]
[6-(3-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-4-yl]acetic acid [ No CAS ]
2-[6-(3-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-4-yl]-1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
190 mg	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 20℃; for 3h;	Example 10 Preparation of 2-[6-(3-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-4-yl]-1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethanone A solution of 215 mg of ethyl [6-(3-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-4-yl]acetate (Example 7) and 0.6 ml of aqueous sodium hydroxide solution (1M) in 36 ml of THF was stirred at room temperature for 18 hours. The solution was concentrated fully under reduced pressure. This gave 199 mg of [6-(3-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-4-yl]acetic acid. This was dissolved in 10 ml of DMF and admixed with 310 mg of HATU, 0.3 ml of triethylamine and 157 mg of 2-oxa-6-azaspiro[3.3]heptane oxalate (2:1) and stirred at room temperature for 3 hours. The mixture was partitioned between semiconcentrated brine and ethyl acetate, the organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, dichloromethane/methanol gradient). (0599) Yield: 190 mg of 2-[6-(3-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-4-yl]-1-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethanone. (0600) 1H NMR (400 MHz, RT, CDCl3): delta=2.59 (s, 3H); 2.78 (dd, 1H); 3.24 (dd, 1H); 3.75 (dt, 1H); 4.18 (bs, 2H); 4.42 (d, 1H); 4.74-4.89 (m, 5H); 6.01 (d, 1H); 7.06 (d, 1H); 7.18 (bs, 1H); 7.21-7.31 (m, 3H); 7.34-7.42 (m, 2H); 7.50 (dt, 1H).

Reference： [1]Patent: US2015/299201,2015,A1 .Location in patent: Paragraph 0597; 0598; 0599; 0600

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(4aR)-N-[2-(6-chloro-5-cyanopyridin-3-yl)-4-(trifluoromethyl)phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide [ No CAS ]
(4aR)-N-[2-[5-cyano-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]-4-(trifluoromethyl)phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 60℃; for 48h;Inert atmosphere;	Example 111 (4aR)-N-[2-[5-Cyano-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]-4-(trifluoromethyl)phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (4aR)-N-[2-(6-Chloro-5-cyanopyridin-3-yl)-4-(trifluoromethyl)phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 68) (20 mg, 0.032 mmol) was dissolved in 1,2-dichloroethane (0.32 mL) under nitrogen atmosphere, 2-oxa-6-azaspiro[3.3]heptane oxalate (24.5 mg, 0.129 mmol) and N,N-diisopropylethylamine (0.068 mL, 0.388 mmol) were added, and the mixture was stirred at room temperature overnight and at 60 C. for 2 days. A 0.37 M aqueous potassium dihydrogenphosphate solution and dichloromethane were added to the reaction mixture, the mixture was intensely stirred, and subsequently, the water layer was separated by a phase separator, and the organic layer was concentrated at reduced pressure. The resultant residue was purified by C18 reverse-phase column chromatography (30-95% acetonitrile/water) to obtain the title compound (19.7 mg, 89%). LCMS: m/z 681[M+H]+ HPLC retention time: 0.99 minutes (analysis condition SMD-TFA50)

Reference： [1]Patent: US2016/2251,2016,A1 .Location in patent: Paragraph 1506-1508

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[ 1159599-99-1 ]
C₁₈H₁₇NO₄ [ No CAS ]
C₂₃H₂₆N₂O₄ [ No CAS ]

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 675 - 682

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[ 1361019-05-7 ]
6-(3-bromo-1-methyl-1H-pyrazol-5-yl)-2-oxa-6-azaspiro[3.3]heptane [ No CAS ]