1237535-78-2|5-Fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one| Ambeed

CAS No. :	1237535-78-2
Formula :	C₈H₇FN₂O
M.W :	166.15
SMILES Code :	O=C1NC2=C(C(F)=CC=N2)CC1
MDL No. :	MFCD19703686
InChI Key :	NOGFPJHXTCXVDA-UHFFFAOYSA-N
Pubchem ID :	46853239

Safety of [ 1237535-78-2 ]

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

Application In Synthesis of [ 1237535-78-2 ]

* 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 [ 1237535-78-2 ]

[ 1237535-78-2 ] Synthesis Path-Downstream 1~55

1
[ 1237535-78-2 ]
[ 220640-10-8 ]
[ 1237535-80-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 3h;	Method 1 A mixture of (7R)-7-amino-5,6,7,8-tetrahydronaphthalen-2-ol hydrobromide (16.7 g, 68.2 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (11.36 g, 64.95 mmol), and cesium carbonate (63.49 g, 194.9 mmol) in DMF (216 mL) was stirred at 140 C. for 2 h. The reaction was not complete, so additional (7R)-7-amino-5,6,7,8-tetrahydronaphthalen-2-ol hydrobromide (1.70 g, 6.82 mmol) was added. After an additional 1 h at 140 C., the reaction mixture was cooled to rt, and carefully treated with a solution of HCl (1 M). The reaction mixture was then diluted with DCM and filtered through Celite. The phases were separated and the aqueous phase was brought to pH 7 by the addition of a solution of NaOH (1.0 M). The brown precipitate was then removed by filtration through Celite, and the filtrate was washed with DCM. The aqueous phase was then brought to pH 14 by addition of a solution of NaOH (1.0 M) and an off-white precipitate formed. This suspension was treated with solid NaCl and stirred for 1 h. The solid was isolated by filtration and dried under vacuum to give a 17.7 g of an off-white solid (88% yield). LC/MS: (AA) ES+ 310. 1H NMR (400 MHz, d6 DMSO) delta: 10.47 (s, 1H), 7.94 (d, 1H), 7.12 (d, 1H), 6.85-6.81 (m, 2H), 6.26 (d, 1H), 3.03-2.96 (m, 1H), 2.89 (t, 2H), 2.85-2.79 (m, 1H), 2.76-2.66 (m, 1H), 2.51 (t, 2H), 2.44-2.38 (m, 1H), 1.90-1.84 (m, 1H), 1.65 (br s, 2H), and 1.50-1.40 (m, 1H).

References: [1]Patent: US2010/197924,2010,A1 .Location in patent: Page/Page column 13.

2
[ 3054-95-3 ]
[ 1237535-77-1 ]
[ 1237535-78-2 ]

Yield	Reaction Conditions	Operation in experiment
47%	With N-ethyl-N,N-diisopropylamine;di-mu-chlorobis[5-hydroxy-2-[1-(hydroxyimino)ethyl]phenyl]palladium(II) dimer; In water; N,N-dimethyl-formamide; at 140℃; for 5h;	Step 3 Preparation of 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one A round bottom flask was charged with tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (20.0 g, 59.2 mmol), 3,3-diethoxy-1-propene (13.5 mL, 88.7 mmol), DMF (150 mL), water (50 mL), DIPEA (15.4 mL, 88.7 mmol) and Pd catalyst 1 (Corma, A.; Garcia, H.; Leyva, A. Tetrahedron 61, 9848, 2005) (480 mg, 0.827 mmol) and the reaction mixture was stirred in an oil bath at 140 C. After 5 h, the reaction mixture was cooled in a refrigerator for 2 days. The precipitate was isolated by filtration, washed with diethyl ether, and dried to give 3.25 g of pink needles. The filtrate was concentrated to give a reddish semi-solid. This material was redissolved in DCM, and the solution was passed through 200 g of SiO2. Concentration of the resulting solution provided a red/orange residue which was recrystallized from 2-propanol (150 mL) to give 9.4 g of a pink solid. Purification of this pink solid by column chromatography (SiO2, elution with 0-75% EtOAc/DCM) provided 1.41 g of a white powder. Overall, 4.66 g of final productproduct was isolated (47% yield). LC/MS: (FA) ES+ 167. 1H NMR (300 MHz, d6 DMSO): delta 10.67 (s, 1H), 8.13-8.08 (m, 1H), 6.93-6.88 (m, 1H), 2.87 (t, 2H), and 2.51 (t, 2H). This reaction may also be carried out under the same conditions using Pd(OAc)2 as catalyst, both in the presence or absence of tri-o-tolylphosphine as ligand. In a method analogous to that described for 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one, 5-chloro-3,4-dihydro-1,8-naphthyridin-2(1H)-one was prepared from 2,4-dichloropyridine. LC/MS: (AA) ES+ 183. 1H NMR (400 MHz, d6 DMSO): delta 10.68 (s, 1H), 8.07-8.06 (m, 1H), 7.13-7.11 (m, 1H), 2.96 (t, 2H), and 2.55 (t, 2H).
47%	With N-ethyl-N,N-diisopropylamine;Pd catalyst; In N,N-dimethyl-formamide; at 140℃; for 5h;	Step 3: 5-fluoro-3,4-dihydro-l,8-naphthyridin-2(lH)-one Intermediate-28 [00201] A round bottom flask was charged with f erf-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (Int-27, 20 g, 59.2 mmol), 3,3-diethoxy-l-propene (13.5 mL, 88.7 mmol), NN-dimethylformamide (150 mL), water (50 mL), NN-diisopropylethylamine (15.4 mL, 88.7 mmol) and the Pd catalyst ("Palladacyle 1" from Corma et. al. Tetrahedron 2005, 61(41):9848; 480 mg, 0.827 mmol) and the reaction mixture was warmed to 140 C. After 5 h, the reaction mixture was cooled in a refrigerator for 2 days. The resulting precipitate was isolated by suction filtration, washed with diethyl ether, and dried to give 3.25 g of pink needles. The filtrate was concentrated to give a reddish semi-solid. This material was redissolved in methylene chloride and the solution was passed through 200 g of silica. Concentration of the resulting solution provided a red/orange residue which was recrystallized from 2-propanol (150 mL) to give 9.4 g of a pink solid. Purification of this pink solid by column chromatography (Si02} elution with 0-75% ethyl acetate in methylene chloride) provided 1.41 g of a white powder, Overall, 4.66 g of 5-fluoro-3,4- dihydro-l,8-naphthyridin-2(lH)-one was isolated (47% yield). LC-MS: (FA) ES+ 167; NMR (400 MHz, <¾-DMSO) 5 ppm 10.7 (s, 1 H), 8.1 1 (dd, J = 8.5, 5.7 Hz, 1 H), 6.91 (dd, J = 8.8, 5.7 Hz, H), 2.91- 2.85 (m, 2 H), 2.55-2.50 (m, 2 H).
47%	With N-ethyl-N,N-diisopropylamine;Palladacyle 1; In N,N-dimethyl-formamide; at 140℃; for 5h;	Step 3: 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one Intermediate 31 A round bottom flask was charged with tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (Int-30, 20 g, 59.2 mmol), 3,3-diethoxy-1-propene (13.5 mL, 88.7 mmol), N,N-dimethylformamide (150 mL), water (50 mL), N,N-diisopropylethylamine (15.4 mL, 88.7 mmol) and the Pd catalyst ("Palladacyle 1? from Corma et. al., Tetrahedron 2005, 61(41):9848; 480 mg, 0.827 mmol) and the reaction mixture was warmed to 140 C. After 5 h, the reaction mixture was cooled in a refrigerator for 2 days. The resulting precipitate was isolated by suction filtration, washed with diethyl ether, and dried to give 3.25 g of pink needles. The filtrate was concentrated to give a reddish semi-solid. This material was redissolved in methylene chloride and the solution was passed through 200 g of silica. Concentration of the resulting solution provided a red/orange residue which was recrystallized from 2-propanol (150 mL) to give 9.4 g of a pink solid. Purification of this pink solid by column chromatography (SiO2, elution with 0-75% ethyl acetate in methylene chloride) provided 1.41 g of a white powder. Overall, 4.66 g of 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one was isolated (47% yield). LC-MS: (FA) ES+ 167; 1H NMR (400 MHz, d6-DMSO) delta ppm 10.7 (s, 1H), 8.11 (dd, J=8.5, 5.7 Hz, 1H), 6.91 (dd, J=8.8, 5.7 Hz, 1H), 2.91-2.85 (m, 2H), 2.55-2.50 (m, 2H).

References: [1]Patent: US2010/197924,2010,A1 .Location in patent: Page/Page column 11-12.
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.
[3]Patent: WO2011/146591,2011,A1 .Location in patent: Page/Page column 76.
[4]Patent: US2012/15942,2012,A1 .Location in patent: Page/Page column 54.

3
[ 1237535-78-2 ]
(2S)-N-[3-[(isopropylamino)methyl]-5-(trifluoromethyl)-phenyl]-7-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.

4
[ 1237535-78-2 ]
C₃₅H₃₉F₃N₄O₅ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.

5
[ 1237535-78-2 ]
(2S)-N-[3-(2-aminopropan-2-yl)-5-(trifluoromethyl)phenyl]-7-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.

6
[ 1237535-78-2 ]
C₃₄H₃₇F₃N₄O₅ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.

7
[ 1237535-78-2 ]
[ 1274816-87-3 ]
[ 1274816-88-4 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.

8
[ 1237535-76-0 ]
[ 1237535-78-2 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.
[2]Patent: WO2011/146591,2011,A1 .
[3]Patent: US2012/15942,2012,A1 .

9
[ 34941-91-8 ]
[ 1237535-78-2 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.
[2]Patent: WO2011/146591,2011,A1 .
[3]Patent: US2012/15942,2012,A1 .

10
[ 1137826-05-1 ]
[ 1237535-78-2 ]
[ 1350750-76-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step 4: 6-(7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-4-yloxy)quinoline-3-carboxylic acidIntermediate-29 [00202] 5-fluoro-3,4-dihydro-l,8-naphthyridin-2(lH)-one (Int-28, 120 mg, 0.72 mmol), 6- hydroxyquinoline-3-carboxylic acid (1.5 mg, 0.794 mmol), and cesium carbonate (706 mg, 2.17 mmol) were weighed into a microwave vial. N,N-Dimethylformamide (3.5 mL) was added and the vial was sealed and heated in a microwave at 150 C for 4 h. The vial was opened and water was added (5 mL). The resulting clear solution was neutralized by the addition of IN HC1 and washed with ethyl acetate. The washed aqueous phase was acidified to pH 3 and pure product was collected by suction filtration. LC-MS: (FA) ES+ 336; ]H NMR (400 MHz, i/6-DMSO) delta ppm 13.55 (s, 1 H), 10.60 (s, 1 H), 9.27 (d, J = 2.1 Hz, 1 H), 8.94 (d, J = 1.9 Hz, 1 H), 8.17 (d, J = 9.1 Hz, 1 H), 8.07-8.02 (m, 1 H), 7.85 (d, J = 2.7 Hz, I H), 7.74 (dd, J = 9.1, 2.8 Hz, 1 H), 6.52 (d, J = 5.7 Hz, 1 H), 2.92 (t, J = 7.7, 7.7 Hz, 2 H), 2.54 (dd, J = 8.3, 7.1 Hz, 2 H).

References: [1]Patent: WO2011/146591,2011,A1 .Location in patent: Page/Page column 76-77.

11
[ 1237535-78-2 ]
[ 1274816-87-3 ]
(S)-7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yloxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With caesium carbonate; In ISOPROPYLAMIDE; at 150℃; for 1h;Microwave irradiation; Sealed vial;	Step 4: (S)-7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yloxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid Intermediate 325-Fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one (Int-31, 50 mg, 0.301 mmol), (2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (63.6 mg, 0.331 mmol), and cesium carbonate (294 mg, 0.903 mmol) were weighed into a microwave vial (2-5 mL) followed by N,N-dimethylacetamide (1.4 mL). The vial was sealed and the resulting mixture was stirred for 1 h at 150 C. under microwave irradiation. The contents of the vial were cooled to room temperature, water (5 mL) was added and the resulting mixture was stirred for a few minutes. The clear solution was neutralized by addition of 1N HCl and the resulting suspension was filtered through a Celite pad. The solid residue was washed with methanol then the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (2-10% methanol in methylene chloride gradient) to provide 52 mg of product as a colorless solid (41%). The enantiomeric purity of this product was assessed by chiral HPLC (85% ee). Column: IA 4.6×250 mm Elute: 100/0.1 EtOH/TFA; 0.5 mL/min 10 uL injection 50 min. LC-MS: (FA) ES+ 339; 1H NMR (400 MHz, d6-DMSO) delta ppm 12.33 (s, 1H), 10.49 (s, 1H), 8.00-7.90 (m, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.87 (dd, J=8.2, 2.5 Hz, 1H), 6.28 (d, J=5.8 Hz, 1H), 2.98-2.74 (m, 5H), 2.71-2.61 (m, 1H), 2.57-2.51 (m, 3H), 2.14-2.06 (m, 1H), 1.73 (dddd, J=13.0, 10.0, 9.9, 6.7 Hz, 1H).

References: [1]Patent: US2012/15942,2012,A1 .Location in patent: Page/Page column 54-55.

12
[ 1237535-78-2 ]
[ 1274816-87-3 ]
C₂₄H₂₉N₃O₅ [ No CAS ]

References: [1]Patent: US2012/15942,2012,A1 .

13
[ 1237535-78-2 ]
(±)-exo-ethyl 5-hydroxy-3-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]
(±)-exo-ethyl 3-methyl-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The mixture of the product from step H (90 mg, 0.38 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (64 mg, 0.38 mmol) and cesium carbonate (188 mg, 0.58mmol) in DMF (5 mL) was stirred at 120 C for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2x20 mL). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was used in next step without further purification.
	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of the product from step H (90 mg, 0.38 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (64 mg, 0.38 mmol) and cesium carbonate (188 mg, 0.58 mmol) in DMF (5 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2*20 mL). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was used in next step without further purification.

References: [1]Patent: WO2013/97224,2013,A1 .Location in patent: Page/Page column 75.
[2]Patent: US2015/45355,2015,A1 .Location in patent: Paragraph 0378; 0395-0396.

14
[ 1237535-78-2 ]
(±)-exo-ethyl 4-chloro-5-hydroxy-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]
(±)-exo-ethyl 4-chloro-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
320 mg	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The mixture of the product from step A (577 mg, 2.3 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (377 mg, 2.3 mmol) and cesium carbonate (1.1 g, 3.4 mmol) in DMF (20 mL) was stirred at 120 C for 2 hrs. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (2x30 mL). The combined organic phase was washed with brine (40 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE = 1 :5 ~ 1 : 1) to afford the title compound (320 mg, 80%) as a white solid
320 mg	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of the product from step A (577 mg, 2.3 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (377 mg, 2.3 mmol) and cesium carbonate (1.1 g, 3.4 mmol) in DMF (20 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (2*30 mL). The combined organic phase was washed with brine (40 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=1:5-1:1) to afford the title compound (320 mg, 80%) as a white solid.

References: [1]Patent: WO2013/97224,2013,A1 .Location in patent: Page/Page column 77.
[2]Patent: US2015/45355,2015,A1 .Location in patent: Paragraph 0402; 0405-0406.

15
[ 1237535-78-2 ]
(±)-exo-ethyl 3-hydroxy-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate [ No CAS ]
(±)-exo-ethyl 3-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The mixture of the product from step E (2.0 g, 9 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (1.5 g, 9 mmol) and cesium carbonate (6 g, 18mmol) in DMF (30 mL) was stirred at 120 C for 2hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2x40 mL). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE = 1 :5 ~ 1 : 1) to obtain the title compound (1.4 g, 42%) as a white solid.
42%	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of the product from step E (2.0 g, 9 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (1.5 g, 9 mmol) and cesium carbonate (6 g, 18 mmol) in DMF (30 mL) was stirred at 120 C. for 2 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2*40 mL). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=1:5-1:1) to obtain the title compound (1.4 g, 42%) as a white solid.

References: [1]Patent: WO2013/97224,2013,A1 .Location in patent: Page/Page column 36.
[2]Patent: US2015/45355,2015,A1 .Location in patent: Paragraph 0216; 0227-0228.

16
[ 1237535-78-2 ]
(±)-exo-5-((1-(6-hydroxy-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

17
[ 1237535-78-2 ]
(±)-exo-5-((1-(6-((tert-butyldimethylsilyl)oxy)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

18
[ 1237535-78-2 ]
(±)-exo-N-((hydroxyimino)(phenyl)methyl)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxamide [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

19
[ 1237535-78-2 ]
(±)-exo-5-((1-(3-phenyl-1,2,4-oxadiazol-5-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

20
[ 1237535-78-2 ]
(±)-exo-5-((1-(4-phenyl-1H-imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

21
[ 1237535-78-2 ]
(±)-exo-2-oxo-2-phenylethyl 5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

22
[ 1237535-78-2 ]
(±)-exo-5-((1-(4-(trifluoromethyl)-1H-imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

23
[ 1237535-78-2 ]
(±)-exo-5-((1-(hydroxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

24
[ 1237535-78-2 ]
(±)-exo-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carbaldehyde [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

25
[ 1237535-78-2 ]
(±)-exo-5-((1-(1-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

26
[ 1237535-78-2 ]
(±)-exo-3-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

27
[ 1237535-78-2 ]
(±)-exo-N-(2-aminophenyl)-3-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxamide [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

28
[ 1237535-78-2 ]
(±)-exo-5-((1-(1H-benzo[d]imidazol-2-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]inden-3-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

29
[ 1237535-78-2 ]
(±)-exo-5-((1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]inden-3-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .
[3]Patent: JP2016/196446,2016,A .

30
[ 1237535-78-2 ]
[ 1446091-31-1 ]
[ 1446091-30-0 ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: CN105348299,2016,A .
[3]Patent: JP2016/196446,2016,A .

31
[ 1237535-78-2 ]
(±)-exo-N-(2-mercaptophenyl)-3-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxamide [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

32
[ 1237535-78-2 ]
(±)-exo-5-((1-(benzo[d]thiazol-2-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]inden-3-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

33
[ 1237535-78-2 ]
(±)-exo-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylic acid [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

34
[ 1237535-78-2 ]
(±)-exo-N-(2-aminophenyl)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxamide [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

35
[ 1237535-78-2 ]
(±)-exo-5-((1-(1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

36
[ 1237535-78-2 ]
(±)-exo-5-((1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .
[3]Patent: JP2016/196446,2016,A .

37
[ 1237535-78-2 ]
[ 1446090-78-3 ]
[ 1446090-79-4 ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .
[3]Patent: CN105348299,2016,A .
[4]Patent: CN105348299,2016,A .
[5]Patent: JP2016/196446,2016,A .
[6]Patent: JP2016/196446,2016,A .

38
[ 1237535-78-2 ]
[ 1446090-79-4 ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

39
[ 1237535-78-2 ]
[ 1446091-46-8 ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .
[3]Patent: CN105348299,2016,A .
[4]Patent: JP2016/196446,2016,A .

40
[ 1237535-78-2 ]
(±)-exo-5-((1-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .
[3]Patent: JP2016/196446,2016,A .

41
[ 1237535-78-2 ]
[ 1446090-82-9 ]
[ 1446090-81-8 ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .
[3]Patent: CN105348299,2016,A .
[4]Patent: JP2016/196446,2016,A .

42
[ 1237535-78-2 ]
(±)-exo-5-((1-(5-fluoro-6-methyl-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .
[3]Patent: JP2016/196446,2016,A .

43
[ 1237535-78-2 ]
[ 1446090-85-2 ]
[ 1446090-84-1 ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .
[3]Patent: CN105348299,2016,A .
[4]Patent: JP2016/196446,2016,A .

44
[ 1237535-78-2 ]
(±)-exo-5-((1-(5-chloro-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .
[3]Patent: JP2016/196446,2016,A .

45
[ 1237535-78-2 ]
[ 1446090-88-5 ]
[ 1446090-87-4 ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .
[3]Patent: CN105348299,2016,A .
[4]Patent: JP2016/196446,2016,A .

46
[ 1237535-78-2 ]
(±)-exo-5-((1-(7-chloro-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]

References: [1]Patent: WO2013/97224,2013,A1 .
[2]Patent: US2015/45355,2015,A1 .

47
[ 1237535-78-2 ]
(±)-exo-ethyl 5-hydroxy-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]
(±)-exo-ethyl 5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of the product from step C (3.8 g, 0.017 mol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (2.85 g, 0.017 mol) and cesium carbonate (11.2 g, 0.034 mol) in DMF (50 mL) was stirred at 120 C for 2hrs. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (2^30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE = 1 :5 ~ 1 : 1) to obtain the title compound (2.8 g, 44%) as a white solid. -NMR (400 MHz, CDC13) delta 9.99 (s, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.10 (s, 1H), 6.90 - 6.82 (m, 2H), 6.23 (d, J = 5.8 Hz, 1H), 5.10 (d, J = 5.4 Hz, 1H), 4.22 - 4.07 (m, 2H), 3.24 (s, 1H), 3.03 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.9 Hz, 2H), 1.36 - 1.30 (m, 1H), 1.29 - 1.17 (m, 3H) ppm. MS: M/e 367 (M+l)+.
44%	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of the product from step C (3.8 g, 0.017 mol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (2.85 g, 0.017 mol) and cesium carbonate (11.2 g, 0.034 mol) in DMF (50 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (2*30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=1:5-1:1) to obtain the title compound (2.8 g, 44%) as a white solid. 1H-NMR (400 MHz, CDCl3) delta 9.99 (s, 1H), 8.06 (d, J=5.8 Hz, 1H), 7.10 (s, 1H), 6.90-6.82 (m, 2H), 6.23 (d, J=5.8 Hz, 1H), 5.10 (d, J=5.4 Hz, 1H), 4.22-4.07 (m, 2H), 3.24 (s, 1H), 3.03 (t, J=7.8 Hz, 2H), 2.67 (t, J=7.9 Hz, 2H), 1.36-1.30 (m, 1H), 1.29-1.17 (m, 3H) ppm. MS: M/e 367 (M+1)+.

References: [1]Patent: WO2013/97224,2013,A1 .Location in patent: Page/Page column 42-43.
[2]Patent: US2015/45355,2015,A1 .Location in patent: Paragraph 0244; 0252-0253.

48
[ 1237535-78-2 ]
[ 1446091-43-5 ]
[ 1446091-45-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The mixture of the product of Step G (66.3 g, 0.3 mol) and 5-fluoro-3,4-dihydro- 1,8-naphthyridin-2(1H)-one (50 g, 0.3 mol) in DMF (850 mL) was added Potassium tert-butoxide(35.4 g, 0.32 mol) and the mixture was stirred at 120 C under nitrogen for 2hrs. The reaction was cooled to room temperature and filtered through a celite pad and the filtrate was removed half of the solvent. The residue was added into stirred 2L water in drops. A solid was precipitated out of the solution. The solid was filtered, washed with water and dried in air. Thedried title compound (108.2 g, 98%) as a gray solid was used into next step directly. ?H NMR(400 IVIFIz, DMSO-d6) 10.43 (s, 1H), 7.92 (d, J= 5.8 Hz, 1H), 7.30 (d, J 2.4 Hz, 1H), 6.98 (d,J= 8.8 Hz, 1H), 6.94 (dd, J= 8.8, 2.4 Hz, 1H), 6.21 (d, J= 5.8 Hz, 1H), 5.26 (dd, J 5.4, 1.0 Hz,1H), 4.08 (q, J= 7.0 Hz, 2H), 3.34 (dd, J= 5.4, 3.2 Hz, 1H), 2.89 (t, J 7.8 Hz, 2H), 2.51 (t, J7.8 Hz, 2H), 1.34 (dd, J 3.2, 1.0 Hz, 1H), 1.18 (t, J= 7.0 Hz, 3H) ppm. MS: M/e 367 (M+1).
98%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	To the mixture of the product of Step G (66.3 g, 0.3 mol) and 5-fluoro-3,4-dihydro- 1,8- naphthyridin-2(lH)-one (50 g, 0.3 mol) in DMF (850 mL) was added Potassium tert-butoxide (35.4 g, 0.32 mol) and the mixture was stirred at 120 C under nitrogen for 2hrs. The reaction was cooled to room temperature and filtered through a celite pad and the filtrate was removed half of the solvent. The residue was added into stirred 2L water in drops. A solid was precipitated out of the solution. The solid was filtered, washed with water and dried in air. The dried title compound (108.2 g, 98%) as a gray solid was used into next step directly. XH NMR (400 MHz, DMSO-^6) delta 10.43 (s, 1H), 7.92 (d, J= 5.8 Hz, 1H), 7.30 (d, J= 2.4 Hz, 1H), 6.98 (d, J= 8.8 Hz, 1H), 6.94 (dd, J= 8.8, 2.4 Hz, 1H), 6.21 (d, J= 5.8 Hz, 1H), 5.26 (dd, J= 5.4, 1.0 Hz, 1H), 4.08 (q, J= 7.0 Hz, 2H), 3.34 (dd, J= 5.4, 3.2 Hz, 1H), 2.89 (t, J= 7.8 Hz, 2H), 2.51 (t, J= 7.8 Hz, 2H), 1.34 (dd, J= 3.2, 1.0 Hz, 1H), 1.18 (t, J= 7.0 Hz, 3H) ppm. MS: M/e 367 (M+l)+.
54.6%	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of Intermediate III (400 mg, 1.8 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) in DMF (20 mL) was stirred at 120 C for 2hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2x 10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE = 3: 1) to obtain the title compound (360 mg, 54.6%) as a white solid.

54.6%	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of Intermediate III (400 mg, 1.8 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) in DMF (20 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2*10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=3:1) to obtain the title compound (360 mg, 54.6%) as a white solid.
54.6%	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	Example 2: Synthesis of compounds 2.1-2.37 Step A: (1S,1aS,6bR)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylic acid ethyl ester Intermediate III (400mg, 1.8mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (250mg, 1.5mmol), and cesium carbonate (801mg, 2.3mol) in DMF (20mL) was stirred at 120C for 2 hours. The reaction mixture was washed with water (10mL). The reaction was diluted and extracted with ethyl acetate (2 × 10mL). The combined organic extracts were washed with brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (PE:EtOAc = 3:1 elution) to give the target compound as a white solid (360mg, 54.6%).
54.6%	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of Intermediate III (400 mg, 1.8 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) in DMF (20 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=3:1) to obtain the title compound (360 mg, 54.6%) as a white solid.

References: [1]Patent: WO2014/206343,2014,A1 .Location in patent: Page/Page column 50.
[2]Patent: WO2014/206344,2014,A1 .Location in patent: Page/Page column 56; 59; 60.
[3]Patent: WO2013/97224,2013,A1 .Location in patent: Page/Page column 47.
[4]Patent: US2015/45355,2015,A1 .Location in patent: Paragraph 0268-0270.
[5]Patent: CN105348299,2016,A .Location in patent: Paragraph 0358; 0396; 0397; 0398; 0399; 0400.
[6]Patent: JP2016/196446,2016,A .Location in patent: Paragraph 0151; 0152.

49
[ 1237535-78-2 ]
(1R,1aR,6bS)-ethyl 5-hydroxy-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]
(1R,1aR,6bS)-ethyl 5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 5h;	The mixture of (1 R, 1 aR, 6b S)-ethyl 5 -hydroxy- 1 a,6b-dihydro- 1 H-cyclopropa [b]benzofuran-1-carboxylate (2.2 g, 0.01 mol) which was separated the product from Step F in synthesis of Compound 1.1 by Chiral SFC (column: Chiralpak AD-H), 5-fluoro-3,4-dihydro- 1,8- naphthyridin- 2(1H)-one (1.67 g, 0.01 mol) and t-BuOK (1.45 g, 0.013 mol) in DMF (10 mL)was stirred at 100 C for 5 hours. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated to half of original volume. Water (30 mL) was added dropwise and a solid was precipitated out of the solution. The solid was filtered and dried in air. The title compound (3.5 g, crude) was obtained as a black solid. MS: M/e 367 (M+1).
	With potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 5h;Inert atmosphere;	The mixture of (lR,laR,6bS)-ethyl 5-hydroxy-la,6b-dihydro-lH-cyclopropa [b]benzofuran-l-carboxylate (2.2 g, 0.01 mol) which was the product from Step G in synthesis of Intermediate I by Chiral SFC (column: Chiralpak AD-H), 5-fluoro-3,4-dihydro-l,8- naphthyridin- 2(lH)-one (1.67 g, 0.01 mol) and t-BuOK (1.45 g, 0.013 mol) in DMF (10 mL) was stirred at 100 C for 5 hours. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated to half of original volume. Water (30 mL) was added dropwise and a solid was precipitated out of the solution. The solid was filtered and dried in air. The title compound (3.5 g, crude) was obtained as a black solid. MS: M/e 367 (M+l)+.

References: [1]Patent: WO2014/206343,2014,A1 .Location in patent: Page/Page column 77.
[2]Patent: WO2014/206344,2014,A1 .Location in patent: Page/Page column 88; 89.

50
[ 1237535-78-2 ]
(1R,1aR,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylic acid [ No CAS ]

References: [1]Patent: WO2014/206343,2014,A1 .
[2]Patent: WO2014/206344,2014,A1 .

51
[ 1237535-78-2 ]
(1R,1aR,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carbonyl azide [ No CAS ]

References: [1]Patent: WO2014/206343,2014,A1 .
[2]Patent: WO2014/206344,2014,A1 .

52
[ 1237535-78-2 ]
1-((1R,1aR,6bR)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(3-(trifluoromethyl)phenyl)urea [ No CAS ]

References: [1]Patent: WO2014/206343,2014,A1 .

53
[ 1237535-78-2 ]
tert-butyl ((1R,1aR,6bR)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)carbamate [ No CAS ]

References: [1]Patent: WO2014/206344,2014,A1 .

54
[ 1237535-78-2 ]
5-(((1R,1aR,6bR)-1-amino-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one monohydrochloride [ No CAS ]

References: [1]Patent: WO2014/206344,2014,A1 .

55
[ 1237535-78-2 ]
4-((4-ethylpiperazin-1-yl)methyl)-N-((1R,1aR,6bR)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(trifluoromethyl)benzamide [ No CAS ]

References: [1]Patent: WO2014/206344,2014,A1 .

Historical Records

Technical Information

• Acyl Group Substitution • Alkyl Halide Occurrence • Chan-Lam Coupling Reaction • Complex Metal Hydride Reductions • Hydride Reductions • Lawesson's Reagent • Preparation of Amines • Reactions of Amines • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Ketenes

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

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

{[proInfo.proName]}

CAS No.: 1237535-78-2

{[proInfo.proName]}

CAS No.: 1237535-78-2

Alternative Products

Product Details of [ 1237535-78-2 ]

Safety of [ 1237535-78-2 ]

Application In Synthesis of [ 1237535-78-2 ]

[ 1237535-78-2 ] Synthesis Path-Downstream 1~55

Related Products

Historical Records

Technical Information

Categories

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Molarity Calculator

Total Compounds Calculator

Dissolution Calculator