159877-36-8|1-Boc-octahydropyrrolo[3,4-b]pyridine| Ambeed

CAS No. :	159877-36-8
Formula :	C₁₂H₂₂N₂O₂
M.W :	226.32
SMILES Code :	C(=O)(OC(C)(C)C)N1CCCC2C1CNC2
MDL No. :	MFCD06858490
InChI Key :	LGEWGFOMLJQHLL-UHFFFAOYSA-N
Pubchem ID :	22562202

Safety of [ 159877-36-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Application In Synthesis of [ 159877-36-8 ]

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

Downstream synthetic route of [ 159877-36-8 ]

[ 159877-36-8 ] Synthesis Path-Downstream 1~43

1
[ 159877-36-8 ]
[ 103995-00-2 ]
7-(1-tert-butoxycarbonyl-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-1-(4-hydroxy-phenyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 4693 - 4709.

2
[ 159877-36-8 ]
[ 100491-40-5 ]
7-(1-tert-butoxycarbonyl-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-1-(4-methoxy-phenyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 4693 - 4709.

3
[ 159877-36-8 ]
C₁₉H₁₂BF₄NO₅ [ No CAS ]
7-(1-tert-butoxycarbonyl-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-1-(4-hydroxy-phenyl)-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 4693 - 4709.

4
(7-bromo-4-chloro-benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)-phosphoramidic acid [ No CAS ]
[ 159877-36-8 ]
7-bromo-4-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		To a mixture of (7-bromo-4-chloro-benzo[4,5]thieno[3,2-d]pyrimidin-2-yl)-phosphoramidic acid (100 mg, 0.25 mmol) in EtOH (1.3 mL) was added <strong>[159877-36-8]octahydro-pyrrolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester</strong> (75 mg, 0.33 mmol) and pyridine (41 muL, 0.51 mmol). After 2 h at 75 C., the solution was cooled to rt and treated with 12 N HCl (0.3 mL). The mixture was heated at 75 C. for 1 h, then cooled to 0 C. The mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried and concentrated. The residue was purified by reversed-phase HPLC to yield the title compound (20 mg, 20%). MS: 404.3. 1H NMR (DMSO-d6): 9.35-9.17 (s, 1H), 8.82-8.59 (s, 1H), 8.56-8.40 (s, 1H), 8.33-8.15 (m, 1H), 7.85-7.70 (m, 1H), 4.45-3.78 (m, 6H), 3.06-2.75 (m, 3H), 1.94-1.62 (m, 4H).

References: [1]Patent: US2008/15200,2008,A1 .Location in patent: Page/Page column 22.

5
[ 577775-46-3 ]
[ 159877-36-8 ]
C₃₁H₃₃N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dimethyl sulfoxide; at 80℃; for 20h;	To dimethylsulfoxide (10 ml) suspension of 318 mg (1.00 mmol) of 1-chloro-3-methyl-2-phenylpyrido[1,2-a]benzimidazole-4-carbonitrile (C1-1) were added 2-tertiary butoxycarbonyl-2,8-diazabicyclo[4.3.0]nonane (corresponding to 2.00 mmol) and 500 mul of triethylamine. The system was replaced with nitrogen and sealed up, and heated at 80C for 20 hours. After cooling, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in chloroform, and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography. This was eluted with a mixed solvent of chloroform/methanol (97/3, v/v) to obtain the main product. Concentrated hydrochloric acid was added thereto and stirred at room temperature for 10 minutes, and this was made alkaline with aqueous saturated sodium hydroxide solution and aqueous saturated sodium bicarbonate solution added thereto, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography. This was eluted with a mixed solvent of chloroform/methanol (95/5, v/v) to obtain a crude product of the entitled compound. The crystal was washed with ethanol to obtain 290 mg (71 %) of the entitled compound as a yellow crystal. MS(EI)m/z:407(M+).1H-NMR(CDCl3)delta: 1.20-4.00(12H, m), 2.30(3H, s), 7.15-7.40(3H, m), 7.40-7.60(4H, m) , 7.95-8.03(1.5H, m) , 8.80-9.15(0.5H, m). IR(ATR): 2211, 1622, 1587, 1498, 1475, 1436 cm-1.

References: [1]Patent: EP1479681,2004,A1 .Location in patent: Page 103.

Yield	Reaction Conditions	Operation in experiment
		REFERENCE EXAMPLE 10 1-t-Butoxycarbonyloctahydropyrrolo[3.4-b]pyridine In 50 ml of ethanol was dissolved 2.86 g of 6-benzyl-1-t-butoxycarbonyloctahydropyrrolo[3.4-b]pyridine, and 500 mg of 5% palladium-on-carbon was added thereto. While the reaction vessel was heated by a tungsten lamp, hydrogenation was conducted under a pressurized hydrogen gas atmosphere of 4 kg/cm2 for 1.5 hours. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated to yield 1.98 g of the titled compound as an oily substance. 1 H-NMR (400 MHz, CDCl3) delta ppm: 1.46 (9H, s), 1.40-1.52 (2H, m), 1.66-1.71 (2H, m), 2.07-2.10 (1H, m), 2.71-2.80 (3H, m), 3.09-3.19 (2H, m), 3.91 and 4.50 (each 1H, each br s)

7
5-amino-6,7,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [ No CAS ]
[ 159877-36-8 ]
[ 159877-28-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; triethylamine; In ethanol; chloroform; acetonitrile; trifluoroacetic acid;	EXAMPLE 3 5-Amino-7-[(S,S)-2,8-diazabicyclo[4.3.0]nonan -8-yl]-6,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid STR16 A solution of 158 mg of 5-amino-6,7,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (EP-A-0 341 493), 226 mg of 2-tert -butoxycarbonyl-(S,S)-2,8-diazabicyclo[4.3.0]nonane, 1 ml of triethylamine in 5 ml of acetonitrile was heated under reflux for 22 hours. The solvent was removed under reduced pressure and a residue was dissolved in 50 ml of chloroform. The solution was washed by 10% citric acid aqueous solution (200 ml, once) and saturated sodium chloride aqueous solution (100 ml, once). The solution was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. A residue was dissolved in 10 ml of trifluoroacetic acid, and the solution was stirred at room temperature for 5 hours. Trifluoracetic acid was removed under reduced pressure and to a residue was added 1N NaOH till the pH became pH 12. To the solution was added hydrochloric acid till the pH became 7.4. The solution was extracted with four 50 ml portions of chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and a residue was dissolved in ethanol. The solution was stood in a deep freezer. A resulting crystalline product was collected and dried to yield 118 mg of the titled compound. Melting point: 145-149 C. [alpha]D25: -271.30 (c=0.12, MeOH) 1 H-NMR (400 MHz, 0.1N NaOD) delta ppm: 1.45-1.79 (6H, m), 2.26-2.38 (1H, m), 2.54-2.63 (1H, m), 2.88-2.94 (1H, m), 3.29-3.58 (3H, m), 3.79-4.02 (3H, m), 4.85-5.08 (1H, m), 8.18 (1H, s). Elementary analysis, for C20 H21 F3 N4 O3 *1/4H2 O; Calcd. (%): C 56.27; H 5.08; N 13.12 Found (%): C 56.66; H 5.10; N 12.88

References: [1]Patent: US5654318,1997,A .

8
6,7,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid BF₂-chelate [ No CAS ]
6,7,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [ No CAS ]
[ 159877-36-8 ]
[ 159877-29-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; trifluoroborane diethyl ether; triethylamine; citric acid; In sulfolane; methanol; chloroform; trifluoroacetic acid;	EXAMPLE 4 7-[(S,S)-2,8-diazabicyclo[4.3.0]nonan-8-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid STR17 A solution of 590 mg of 6,7,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid BF2-chelate (obtained by a reaction of 6,7,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (EP-A-0 341 493) and boron trifluoride etherate), 798 mg of 2-tert-butoxycarbonyl-(S,S)-2,8-diazabicyclo[4.3.0]nonan, 0.49 ml of triethylamine in 6 ml of sulfolane was stirred at room temperature for 10 days. To the solution was added 50 ml of 10% citric acid aqueous solution and a resulting crystal was collected by filtration. The crystalline was dissolved in 100 ml of 90% methanol and 2 ml of triethylamine. The mixture was heated under reflux for 3 hours. The solvent was removed under reduced pressure and a residue was dissolved in 6 ml of trifluoroacetic acid. The solution was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. To a residue was added 50 ml of 1N hydrochloric acid, and the mixture was washed by 50 ml of chloroform. To the aqueous layer was added 1N sodium hydroxide aqueous solution till pH became 12. Then to this was added hydrochloric acid and the pH was readjusted to 7.4. The mixture was extracted with four 100 ml portions of chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. A residue was recrystallized from a mixture of chloroform and ethanol twice to yield 133 mg of the titled compound. Melting point: 244-245 C. [alpha]D25: -343.48 (c=0.545, 1N NaOH) 1 H-NMR (400 MHz, 0.1N NaOD) delta ppm: 1.21-1.83 (6H, m), 2.39-2.65 (5H, m), 2.92-3.00 (1H, m), 3.18-3.42 (3H, m), 3.88-4.15 (3H, m), 4.95-5.15 (1H, m), 7.68 (1H, d, J=14.6Hz), 8.44 (1H, s). Elementary analysis, for C21 H23 F2 N3 O3: Calcd. (%): C 62.52; H 5.75; N 10.42 Found (%): C 62.50; H 5.59; N 10.24

References: [1]Patent: US5654318,1997,A .

9
[ 1027332-70-2 ]
[ 159877-36-8 ]
[ 1027332-71-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile; at 160℃; for 1h;Microwave reactor;	Example 59D ferf-butyl 6-(2-amino-617-dihvdro-5H-benzo[6171cyclohepta\|"1,2-d\|pyrimidin-4- yl)octahydro-1 /-/-pyrrolof3,4-fe1pyridine-1 -carboxylate A solution of the product from Example 59C (76 mg, 0.2 mmol), t-butyl octahydro-1 H-pyrrolo[3,4-b]pyridine-1-carboxylate (CAS No. 159877-36-8) (59 mg, 0.22 mmo.) and triethyiamine (0.1 mL) in acetonitrile (1 mL) was heated in a microwave reactor at 160 C for 1 hour. The mixture was concentrated and chromatographed on siiica gel eluting with EtOAc.hexane (1 :1 ) mixture to yield the <n="159"/>title compound.

References: [1]Patent: WO2008/60767,2008,A2 .Location in patent: Page/Page column 157-158.

10
[ 1027332-84-8 ]
[ 159877-36-8 ]
[ 1027332-77-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; at 0 - 20℃;	Example 92A tert-butyl 6-f2-chioro-6J-dihvdro-5H-benzor6J1cvcloheptaf1 ,2-d1py?'midin~4~ yl)octahvdro-1 H-pyrroloF3,4~b]pyridine-1-carboxylateExample 103B (945.8 mg, 3.57 mmol) in EtOH (25 mL) was treated with triethylamine (175 mL), cooled to 0 0C, treated with a solution of tert-butyl octahydro-1 H-pyrrolo[3,4-b]pyridine-1-carboxylate (888 mg, 3,92 mmol) in EtOH (7 mL) and triethylamine (1 ,75 mL), stirred at room temperature overnight, concentrated to near dryness and partitioned between 1 M NaOH (25 mL) and CH2CI2 (50 mL). The layers were separated and the aqueous was extracted with CH2Cl2 (2 x 50 mL). The combined CH2CI2 layers were dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel eiuting with CH2CI2:EtOAc:hexane (9:1 :20, 9:1 :10, 9:1 :5 and 9:1 :0) to provide 2 products, a faster moving isomer and a slower moving isomer. The slower moving isomer is the title compound. 1H NMR (CDCI3) delta 1.34 - 1.45 (m, 1 H), 1.49 (s, 9 H), 1.69 - 1.85 (m, 2 H), 2,11 - 2.33 (m, 5 H), 2.51 - 2 74 (m, 3 H), 2.77 - 2.90 (m, 1 H), 3,45 (d, J=H .2 Hz1 1 H), 3.62 - 3.70 (m, 1 H)1 3.75 (t, J= 10.2 Hz, 1 H), 3.93 (dd, J= 1 1.2, 5.8 Hz, 1 H), 4.00 - 4.08 (m, 1 H), 7-20 - 7,26 (m, 2 H), 7.34 - 7 42 (m, 2 H), 7.79 - 7.86 (m, 1 H); MS (M+H)+ m/z 455.

References: [1]Patent: WO2008/60767,2008,A2 .Location in patent: Page/Page column 176.

11
[ 959983-22-3 ]
[ 159877-36-8 ]
[ 1059609-03-8 ]

Yield	Reaction Conditions	Operation in experiment
94%		To a solution of 8-cyclohexyl-5-(((dimethylamino)sulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid (180 mg, 0.33 mmol) and <strong>[159877-36-8]tert-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate</strong> (90 mg, 0.40 mmol) in DMF (3 mL) and TEA (0.2 mL) was added HATU (162 mg, 0.43 mmol) as solid. The reaction was stirred at rt for 4 h and then diluted with aq HCl (1.0N, 1.4 mL) and H2O (5 mL) while stirring. The off-white precipitate was collected via filtration, washed with H2O and dried to yield a crude intermediate as yellow solid. The crude intermediate (300 mg) was dissolved into CH2Cl2 (3 mL) with TFA (1 mL) and the reaction mixture was stirred at rt for 2 h. The volatile organic solvents was evaporated under vacuum and the yellow residue was purified by prep HPLC (H2O/MeOH with 0.1% TFA buffer) to yield 8-cyclohexyl-N-((dimethylamino)sulfonyl)-11-methoxy-1a-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-ylcarbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide (205 mg, 0.31 mmol, 94%) as a bright yellow solid. Presents as a 1:2 mixture of rotamers or atrope isomers. 1H NMR (300 MHz, MeOD) delta ppm 8.04-8.28 (m, 0.33H), 7.82-8.02 (m, 1.67H), 7.51-7.66 (m, 1H), 7.28-7.40 (m, 1H), 7.20 (s, 1H), 6.95-7.09 (m, 1H), 5.06-5.24 (m, 0.67H), 4.87-5.02 (m, 0.33H), 3.91 (s, 3H), 3.02 (s, 6H), 2.45-4.40 (m, 11H), 1.05-2.40 (m, 16.67H), 0.06-0.32 (m, 0.33H). LCMS: m/e 660 (M+H)+, Column C, Gradient time: 2 min, ret time 1.91 min.

References: [1]Patent: US2008/226590,2008,A1 .Location in patent: Page/Page column 50.

12
cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid, 8-cyclohexyl-5-[[(cyclopropylsulfonyl)amino]carbonyl]-1,12b-dihydro-11-methoxy-, (+/-)- [ No CAS ]
[ 159877-36-8 ]
tert-butyl 5-((8-cyclohexyl-5-((cyclopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ No CAS ]
tert-butyl 5-((8-cyclohexyl-5-((cyclopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ No CAS ]
tert-butyl 5-((8-cyclohexyl-5-((cyclopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ No CAS ]
tert-butyl 5-((8-cyclohexyl-5-((cyclopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;	HATU (180 mg, 0.47 mmol) was added to a stirring solution of 8-cyclohexyl-5-((cyclopropylsulfonyl)carbamoyl)-11-methoxy-1, 12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid (200 mg, 0.36 mmol) and <strong>[159877-36-8]tert-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate</strong> (100 mg, 0.44 mmol) in DMF (4 mL) and TEA (0.2 mL) and the reaction was stirred at rt for 1 h. H2O (10 mL) was added to the mixture and the resulting white precipitate was collected by filtration, rinsed with water and dried to yield a crude yellow solid (285 mg). This crude was then triturated with 1:1 MeOH/H2O and dried to yield tert-butyl 6-((8-cyclohexyl-5-((cyclopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (257 mg, 0.34 mmol, 95%) as a white solid. The compound was isolated as a mixture of four stereoisomers. 1H NMR (300 MHz, CD3OD) delta ppm 8.16-7.84 (m, 2H), 7.70-7.52 (m, 1H), 7.36-7.25 (m, 1H), 7.25-7.14 (m, 1H), 7.06-6.93 (m, 1H), 5.28-5.04 (m, 0.8H), 4.56-4.25 (m, 1H), 4.09-3.94 (m, 0.2H), 3.91 (s, 3H), 3.83-2.70 (m, 7H), 2.43-0.54 (m, 32.8H), -0.17--0.37 (m, 0.2H). LCMS: m/e=757 (M+H)+, retention time=2.28 min (Column=(2)phenomenex 4.6×50 mmC18 10 um, Solvent A=10% MeOH-90% H20-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient Time=2 min, Hold time=1 min, Flow Rate=5 mL/min).

References: [1]Patent: US2008/226590,2008,A1 .Location in patent: Page/Page column 64.

13
[ 1001065-84-4 ]
[ 159877-36-8 ]
C₂₁H₂₈ClN₅O₂ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 7855 - 7865.

14
[ 1195072-11-7 ]
[ 159877-36-8 ]
[ 1195072-29-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile; for 16h;Heating; Reflux;	Example ID 4-octahvdro-6H-pyrrolor3.4-61pyridin-6-yl-6.7-dihvdro-5H-thienor2'.3':6.71cvclohepta?.2-J]pyrimidin-2-amine dihydrochlorideA solution of the product from Example 1C (0.6 g, 1.55 mmol), t-butyl octahydro-leta- pyrrolo[3,4-b]pyridine-l-carboxylate (CAS No. 159877-36-8) (0.38 g, 1.7 mmol) and triethylamine (0.43 mL) in acetonitrile (ImL) was heated to reflux for 16 hours. The mixture was concentrated and chromatographed on silica gel eluting with 5% methanol/dichloromethane mixture to yield the Boc-protected title compound. It was taken in methanol and treated with 4 N hydrochloric acid/dioxane at room temperature for 3 hours. The reaction mixture was concentrated and triturated with ether to yield the title product. 1H <n="55"/>NMR (free base) (300 MHz, DMSO-J6) delta 7.29 (d, J=5.43 Hz, IH), 7.27 (d, J=5.43 Hz, IH), 5.72 (s, 2H), 3.66-3.80 (m, 2H), 3.36 (m, 2H), 3.21 (m, 2H), 2.85 (m, 2H), 2.61-2.73 (m, IH), 2.05-2.28 (m, 5H), 1.68 (m, 3H), 1.37 (m, IH); MS (ESI+) m/z 342 (M+H)+.

References: [1]Patent: WO2009/137492,2009,A1 .Location in patent: Page/Page column 53-54.

15
[ 159877-35-7 ]
[ 159877-36-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 10 wt% Pd(OH)2 on carbon; hydrogen; In methanol; at 20℃; for 2h;	To a solution of ieri-butyl 6-benzyloctahydro- l H-pyrrolo[3,4-b] pyridine- 1 -carboxylate (2.00 g) in MeOH was added a catalytic amount of 20 % Pd(OH)2/C. The suspension was stirred for 2 h at room temperature under H2 and filtered. The filtrate was concentrated in vacuo and the residue was used for the next step without further purification.The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 227.6 (M+1).
	With 20% palladium hydroxide-activated charcoal; hydrogen; In methanol; at 20℃; for 2h;	To a solution of tert-butyl 6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (2.00 g) in MeOH was added a catalytic amount of 20% Pd(OH)2/C. The suspension was stirred for 2 h at room temperature under H2 and filtered. The filtrate was concentrated in vacuo and the residue was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 227.6 (M+1).
	With hydrogen; palladium(II) hydroxide; In methanol; at 20℃; under 1551.49 Torr;	A suspension of compound 6f (2.1 g, 6.6 mmol) and Pd(OH)2 (200 mg) in MeOH (30 ml) was stirred at r.t. under 30 Psi of hydrogen atmosphere overnight. The reaction mixture was filtered and the filtrate was concentrated by rotary evaporation to give compound 6g (1.4 g, yield: 94.0%), which was used to next step directly.

References: [1]Patent: WO2013/71697,2013,A1 .Location in patent: Paragraph 00313.
[2]Patent: US2014/228361,2014,A1 .Location in patent: Paragraph 0485-0486.
[3]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1458 - 1462.

16
[ 184475-71-6 ]
[ 159877-36-8 ]
[ 1438082-56-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 7h;	A mixture of N-(3-chloro-4-fluorophenyl)-6-(3- chloropropoxy)-7-methoxyquinazolin-4-amine (2.00 g), 2C03 (5.00 g) and te -butyl octahydro-l H-pyrrolo[3,4-b]pyridine-l -carboxylate (1.20 g) in 20 mL of DMF was stirred at 80 C for 7 h, then poured into 50 mL of ice-water and extracted with CH2C12 (50 mL*2). The combined organic phases were dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20: 1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (1.10 g, 45.00 %), HPLC: 92.00 %. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 586.2 (?+1);? NMR (400 MHz, CDC13) ?: 1.38 (s, 9H), 1.34-1.82 (m, 6H), 2.09- 2.43 (m, 7H), 3.29 (m, 2H), 3.68 (m, 1 H), 3.83 (s, 3H), 4.06 (m, 2H), 6.93 (s, 1H), 7.06 (s, 1 H), 7.30 (s, 1 H), 7.44 (d, J = 4.0 ??, ? ?), 7.87 (d, J = 4.0 Hz, 1 H), 8.54 (s, 1 H) ppm.

References: [1]Patent: WO2013/71697,2013,A1 .Location in patent: Paragraph 00314.

17
[ 184475-71-6 ]
[ 159877-36-8 ]
[ 1438073-26-7 ]

References: [1]Patent: WO2013/71697,2013,A1 .

18
cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]-nonane [ No CAS ]
[ 159877-36-8 ]

References: [1]Patent: WO2013/71697,2013,A1 .
[2]Patent: US2014/228361,2014,A1 .
[3]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1458 - 1462.

19
[ 18184-75-3 ]
[ 159877-36-8 ]

References: [1]Patent: WO2013/71697,2013,A1 .
[2]Patent: US2014/228361,2014,A1 .
[3]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1458 - 1462.

20
(R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]-nonane [ No CAS ]
[ 159877-36-8 ]

References: [1]Patent: WO2013/71697,2013,A1 .
[2]Patent: US2014/228361,2014,A1 .
[3]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1458 - 1462.

21
[ 1227783-33-6 ]
[ 159877-36-8 ]
[ 1232082-27-7 ]

Yield	Reaction Conditions	Operation in experiment
0.186 g		A mixture of 0.30 g (0.96 mmol) of 6-chloro-3-(pyridin-4-yl)-2-(thien-2-yl)imidazo-[1,2-b]pyridazine, 0.65 g (2.9 mmol) of <strong>[159877-36-8]tert-butyl 1H-octahydropyrrolo[3,4-b]pyridine-1-carboxylate</strong> (CAS 159877-36-8) and 0.16 ml (0.96 mmol) of diisopropylethylamine in 5 ml of pentanol is refluxed for 18 hours at 150 C. The reaction medium is cooled and 5 ml of 3N aqueous hydrochloric acid (15 mmol) are added. The mixture is stirred for one hour and then diluted with water. The aqueous phase is washed with ethyl acetate and then basified using aqueous ammonia, and the product is extracted with dichloromethane. The organic phase is dried over sodium sulphate and the solvent is evaporated off under reduced pressure. The residue is purified by silica gel column chromatography, elution being carried out with a mixture of dichloromethane, methanol and aqueous ammonia (94/6/0.6), to give 0.186 g of 6-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-(pyridin-4-yl)-2-(thien-2-yl)imidazo[1,2-b]pyridazine in the form of a whitish powder after crystallization from 35 ml of diethyl ether, filtration and drying. Mp: 176-179 C. 1H NMR (CDCl3) delta: 8.70 (d, 2H); 7.75 (m, 3H); 7.35 (d, 1H); 7.20 (d, 1H); 7.00 (dd, 1H); 6.65 (d, 1H); 3.5 (m, 5H); 3.05 (m, 1H); 2.70 (m, 1H); 2.40 (s, 1H); 1.9-1.5 (m, 5H) ppm.

References: [1]Patent: US2013/190314,2013,A1 .Location in patent: Paragraph 0195; 0196; 0197; 0198.

22
[ 875877-40-0 ]
[ 159877-36-8 ]
[ 1443216-54-3 ]

References: [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 768 - 772.

23
[ 875877-40-0 ]
[ 159877-36-8 ]
[ 1443216-76-9 ]

References: [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 768 - 772.

24
[ 454709-07-0 ]
[ 159877-36-8 ]
[ 1443216-57-6 ]

References: [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 768 - 772.

25
7-benzyl 3-methyl 9-chloro-1-(2,4-dimethoxybenzyl)-4-hydroxy-2-oxo-5,6-dihydro-1H-benzo[b]pyrido[2,3-d]azepine-3,7(2H)-dicarboxylate [ No CAS ]
[ 159877-36-8 ]
C₄₃H₄₈N₄O₁₀ [ No CAS ]
C₃₅H₄₂N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 98 9-(hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- lH-benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid hydrochloride (Cpd 98) To a vial was added 7-benzyl 3-methyl 9-chloro-l-(2,4-dimethoxybenzyl)-4-hydroxy-2- oxo-5, 6-dihydro-lH-benzo[b]pyrido[2,3-d]azepine-3,7(2H)-dicarboxylate (Example 94, step 3, 189 mg, 0.31 mmol), NaOt-Bu (120 mg, 1.24 mmol), and 2-(2'-Di-tert- butylphosphine)biphenylpalla-dium(II) acetate (4 mg, 8.7 muiotaetaomicron). The vial was purged with Argon for 5 minutes, then toluene (3.0 mL) and tert-butyl octahydro-lH-pyrrolo[3,4- b]pyridine- 1 -carboxylate (140 mg, 0.62 mmol) were each added via syringe. The resultant solution was stirred at 90 C for 60 minutes. The reaction was then cooled, diluted with CH2CI2 (10 mL) and washed with HC1 (15.0 mL, 1.0 M aqueous solution). The organic layer was then concentrated to yield a crude mixture (~1 : 1) of desired product to deprotected product. The crude mixture was used directly in the next step. LC-MS (desired product) 779.5 [M-H]", 781.6 [M+H]+, RT 1.73 min. LC-MS (deprotected product - Cbz removal) 645.4 [M-H]", 647.5 [M+H]+, RT 1.65 min.

References: [1]Patent: WO2013/33228,2013,A1 .Location in patent: Page/Page column 234.

26
[ 912556-91-3 ]
[ 159877-36-8 ]
[ 1438082-56-4 ]

Yield	Reaction Conditions	Operation in experiment
1.1 g	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 7h;	A mixture of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (2.00 g), K2CO3 (5.00 g) and <strong>[159877-36-8]tert-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate</strong> (1.20 g) in 20 mL of DMF was stirred at 80 C. for 7 h, then poured into 50 mL of ice-water and extracted with CH2Cl2 (50 mL×2). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (1.10 g, 45.00%), HPLC: 92.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 586.2 (M+1); 1H NMR (400 MHz, CDCl3) delta: 1.38 (s, 9H), 1.34-1.82 (m, 6H), 2.09-2.43 (m, 7H), 3.29 (m, 2H), 3.68 (m, 1H), 3.83 (s, 3H), 4.06 (m, 2H), 6.93 (s, 1H), 7.06 (s, 1H), 7.30 (s, 1H), 7.44 (d, J=4.0 Hz, 1H), 7.87 (d, J=4.0 Hz, 1H), 8.54 (s, 1H) ppm.

References: [1]Patent: US2014/228361,2014,A1 .Location in patent: Paragraph 0487-0488.

27
[ 912556-91-3 ]
[ 159877-36-8 ]
[ 1438073-26-7 ]

References: [1]Patent: US2014/228361,2014,A1 .

28
[ 25846-90-6 ]
[ 159877-36-8 ]
tert-butyl 6-(2,7-dichloropyrido[2,3-b]pyrazin-3-yl)octahydro-1H-pyrrolo[3,4-b]pyridin-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;	2,3,7-Trichloropyrido[2,3-b]pyrazine (150.0 mg, 0.64 mmol) was dissolved in DCM (6.0 mL). tert-Butyl octahydro-1H-pyrrolo[3,4-b]pyridin-1-carboxylate (151.0 mg, 0.67 mmol) and TEA (288.0 muL, 1.92 mmol) were then added to the mixture at 0 C. The reaction mixture was stirred at room temperature for 2 hours and then diluted in DCM. The organic layer was washed water and brine, dried over anhydrous MgSO4, filtered and then concentrated under reduced pressure. The residue was purified by column chromatography (n-Hex:EtOAc=3:1) on amine silica. The fractions containing the product were collected and concentrated to obtain ivory solid compound of tert-butyl 6-(2,7-dichloropyrido[2,3-b]pyrazin-3-yl)octahydro-1H-pyrrolo[3,4-b]pyridin-1-carboxylate (173.0 mg, 61%). [0993] LCMS ESI(+): 424(M+1), 426(M+3) [0994] 1H-NMR (300 MHz, DMSO-d6); delta: 8.81 (d, 1H, J=2.7 Hz), 8.38 (d, 1H, J=2.7 Hz), 4.69 (m, 1H), 4.00-3.80 (m, 4H), 3.70 (m, 1H), 2.85 (m, 1H), 2.26 (m, 1H), 1.77-1.61 (m, 2H), 1.42 (s, 9H), 1.38-1.26 (m, 2H)

References: [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 2949 - 2961.
[2]Patent: US2014/315888,2014,A1 .Location in patent: Paragraph 0992-0994.

29
ethyl 4-bromo-3-chloro-9H-carbazole-1-carboxylate [ No CAS ]
[ 159877-36-8 ]
ethyl 4-(1-(tert-butoxycarbonyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-3-chloro-9H-carbazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63.1%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 105℃; for 48h;Inert atmosphere;	A mixture of ethyl 4-bromo-3 -chloro-9H-carbazole- 1 -carboxylate (200 mg, 0.567mmol, 1-80), tert-butyl octahydro- 1 H-pyrrolo [3 ,4-b]pyridine- 1 -carboxylate (141 mg,0.624 mmol), cesium carbonate (425 mg, 1.305 mmol), BINAP (17.66 mg, 0.028 mmol)and Pd2(dba)3 (26.0 mg, 0.028 mmol) in degassed 1,4-dioxane (3 mL) was stirred at 105C under nitrogen for 2 days. The mixture was diluted with EtOAc (15 mL) and waswashed with a solution of aqueous saturated sodium bicarbonate (2 x 15 mL) andaqueous 1.0 M HC1 (15 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (silicagel/hexane-EtOAc 100:0 to 50:50 gradient) to yield ethyl 4-(1-(tert-butoxycarbonyl)hexahydro- 1 H-pyrrolo [3 ,4-b]pyridin-6(2H)-yl)-3 -chloro-9H-carbazole- 1 -carboxylate (198 mg, 0.358 mmol, 63.1% yield) as light brown gum. LCMS: 1.36 mi M+H 498.

References: [1]Patent: WO2016/65236,2016,A1 .Location in patent: Page/Page column 187; 188.

30
[ 1346136-07-9 ]
[ 159877-36-8 ]
tert-butyl 6-((3-((3-((4-(4-(methoxycarbonyl)phenethyl)phenyl)carbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)carbamoyl)phenyl)sulfonyl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With triethylamine; In dichloromethane; at -25 - 20℃; for 18h;	The tert-butyl octahydro-1H-pyrrolo [3,4-b] pyridine-1-carboxylate (355mg, 1.57mmol) and triethylamine (0.44mL, 3.2mmol) was dissolved in dichloromethane (20ml), cooled to -25 . Then a solution of 4- (4- (2- (3- (chlorosulfonyl) benzamido) -4,5,6,7-tetrahydro-benzo [b] thiophen-3-carboxamido) acetophenone yl) benzoate (1.00g, 1.57mmol) in dichloromethane (15mL) suspension of 15 minutes the addition was completed. Stirred at -25 5 minutes and brought to room temperature and then stirred for 18 hours. Saturated ammonium chloride solution (20 mL), the aqueous phase with dichloromethane (20mL × 2). The combined organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid 852 mg, yield: 66%.

References: [1]Patent: CN105524053,2016,A .Location in patent: Paragraph 0332; 0333; 0334.

31
[ 699-98-9 ]
[ 159877-36-8 ]