Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].[CH:12]([C:14]1[O:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C(=O)(O)[O-].[Na+].O>CN1C(=O)CCC1.[Pd](Cl)Cl>[CH:12]([C:14]1[O:18][C:17]([C:2]2[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=2[CH3:11])=[CH:16][CH:15]=1)=[O:13]
Reactant: CC(=O)Nc1nc(C)c(Br)s1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(C=O)o2)s1
Yield: 37.6 %

Procedure:
To a solution of 3.0 g of N-(5-bromo-4-methylthiazol-2-yl)acetamide in 50 mL of NMP was added 3.0 g of 5-formylfuran-2-ylboronic acid. To the stirred solution was then added 300 mg of 1,1 bis-(diphenylphosphino)-ferrocene) palladium dichloride followed by 10 mL of saturated sodium bicarbonate. The resulting biphasic mixture was irradiated at 150° C. in a microwave for 20 min. The resulting mixture was poured into 200 mL of water and filtered. The filtrate was extracted with ether and the ether layers were combined, dried over sodium sulfate and concentrated. The resulting oil was precipitated with methylene chloride and filtered, yielding 1.2 g of N-(5-(5-formylfuran-2-yl)-4-methylthiazol-2-yl)acetamide as an orange solid which was used without further purification. LC/MS: 251.07 (M+H)/2.18 min.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].N1C=CC=CC=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O1CCCC1>[C:11]([N:3]([CH3:2])[OH:4])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNO
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
10.0 g of N-methylhydroxylamine hydrochloride was added to 100 ml of tetrahydrofuran. 19.8 g of pyridine was added to the mixture. A solution of 16.8 g of benzoyl chloride in 100 ml of tetrahydrofuran was dropwise added to the mixture under stirring at room temperature over 1 hr. The stirring was continued at room temperature for additional 8 hr. to conduct the reaction. 50 ml of dilute hydrochloric acid was added thereto and then tetrahydrofuran was removed under reduced pressure. After extraction with ethyl acetate, the extract was dehydrated over anhydrous magnesium sulfate. Ethyl acetate was removed under reduced pressure. The resultant crude product was purified according to column chromatography (packing: silica gel, developer: ethyl acetate/hexane) to obtain 8.5 g of N-benzoyl-N-methylhydroxylamine as an oil having a melting point of 20° C. or below. 130 ml of tetrahydrofuran was added to 7.6 g of N-benzoyl-N-methylhydroxylamine and 12.6 g of 4-vinyl-1-naphthalenesulfonyl chloride. A solution of 5.1 g of triethylamine in 20 ml of tetrahydrofuran was dropwise added thereto under stirring over 2 hr. while the mixture was cooled so that the temperature of the solution was below 25° C. After conducting the reaction at 15° to 25° C. for additional 2 hr., the reaction solution was poured into 700 ml of water and the precipitate thus formed was collected by filtration. After recrystallization from acetonitrile, 12.8 g of o-(4-vinyl-1-naphthalenesulfonyl)-N-benzoyl-N-methylhydroxylamine was obtained.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH2:9]([NH:11][C:12]1[C:17]([CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=2)=[CH:16][N:15]=[C:14]([N:30]([O:32][CH3:33])[CH3:31])[CH:13]=1)[CH3:10].CCN(CC)CC>>[CH2:9]([N:11]1[C:12]2[CH:13]=[C:14]([N:30]([O:32][CH3:33])[CH3:31])[N:15]=[CH:16][C:17]=2[CH2:18][N:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=2)[C:4]1=[O:3])[CH3:10]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCNc1cc(N(C)OC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Product: CCN1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(N(C)OC)cc21
Yield: 79.9 %

Procedure:
Diphosgene (2.4 mL, 20 mmol), N4-ethyl-5-((4-fluoro-3-nitrophenylamino)methyl)-N2-methoxy-N2-methylpyridine-2,4-diamine (5.6 g, 16 mmol) and Et3N (4.3 g, 40 mmol) were combined by the procedure of Example A4 to provide 1-ethyl-3-(4-fluoro-3-nitrophenyl)-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (4.8 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.14 (m, 1 H), 7.96 (s, 1 H), 7.79 (m, 1 H), 7.61 (m, 1 H), 6.57 (s, 1 H), 4.78 (s, 2 H), 3.88 (d, J=7.2 Hz, 2 H), 3.71 (s, 3 H), 3.15 (s, 3 H), 1.20 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 376.2 [M+H]+.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]2[N:14]3[CH2:15][CH2:16][C@@H:11]([C@@H:12]([C:17](O)=[O:18])[CH2:13]3)[C:10]2=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([N:29](CC)[CH2:30]C)C.ClC(OCC)=O.N>C1COCC1.O>[CH3:27][N:29]([CH3:30])[C:17]([C@@H:12]1[C@@H:11]2[CH2:16][CH2:15][N:14]([CH:9]([CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]2=[O:20])[CH2:13]1)=[O:18]
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A suspension of 46 (1.1 g, 3.3 mmol) in THF (10 ml) was treated with triethylamine (0.66 g, 6.6 mmol) at room temperature. To this suspension was added ethyl chloroformate (0.36 g, 3.3 mmol) at 0° C. After 30 minutes, NH3 aq (0.67 g, 6.7 mmol) was added at 0° C. The mixture was stirred at room temperature for 1 hour, poured into H2O and extracted with EtOAc three times. The combined extracts were dried over Na2SO4 and concentrated to give 48 (1.2 g, 3.0 mmol, 90%; 4:1 mixture of isomers at 3-position). This was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C@@H:19]([NH:21][C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][N:26]3C1CCCCO1)[CH3:20])=[CH:7]2.Cl>C(O)C>[N:30]1[C:22]([NH:21][C@H:19]([C:8]2[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[CH3:20])=[C:23]2[C:27]([NH:26][CH:25]=[N:24]2)=[N:28][CH:29]=1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: Cl
Solvent: CCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1

Procedure:
3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) are combined in the presence of triethylamine and isopropyl alcohol. The reaction solution is heated at 82° C. for 24 hours to afford Compound 10. The intermediate compound 10 is treated with concentrated HCl and ethanol under aqueous conditions at 35° C. to remove the tetrahydropyranyl group to yield (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one. Isolation/purification under aqueous conditions affords polymorph Form C.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39].O1CCOCC1>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: CCNCC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCN(CC)CCS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.6 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol) and N,N-diethylamine (0.14 mL, 1.35 mmol) in THF (20 mL) was stirred at room temperature for 17 hrs, refluxed for 1 hr, and then stirred at room temperature for 4 hrs. 1,4-Dioxane (20 mL) was added and the mixture was refluxed for 21 hrs. Additional N,N-diethylamine (0.14 mL, 1.35 mmol) was then added and the mixture was refluxed for another 4.5 hrs. The reaction mixture was cooled to room temperature and the solvents were removed under vacuum. The residue was diluted with water and extracted with CH2Cl2 (2×). The organic layers were combined, dried (Na2SO4), and concentrated under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98:2), gave N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-diethylamine (54 mg, 53%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].C(OCC)(OCC)[O:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(Cl)Cl.C(O)CO>[CH3:1][C:2]1([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[O:14][CH2:15][CH2:16][O:3]1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: ClCCl
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Temperature: 25 °C

Procedure:
P-Nitroacetophenone (1.65 g, 10 m mol), ethylene glycol (5 ml, 89 m mol), triethyl orthoformate (2.96 g, 20 m mol), and p-toluenesulfonic acid (0.086 g, 0.5 m mol) were combined in methylene chloride (4 ml). The solution was heated with an oil bath (50°-70° C., 6 hrs), cooled to room temperature, and poured into excess 10% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted twice with methylene chloride. The combined organic phase was washed three times with water and dried with anhydrous sodium sulphate. Evaporation of the solvent left a light yellow product (1.78 g) with mp. 69°-71° C., [lit. 73°-75° C., see J. Pharm. Sci. 57, 784 (1968)].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[O:19][CH3:20].[H][H]>C(O)C.[C].[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: [H][H]
Reactant: CCCCCCCC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCC(=O)CCc1ccc(O)c(OC)c1
Yield: 55.9 %

Procedure:
Moreover, 10 g (36 mmol) of the resulting (E)-1-(4′-hydroxy-3′-methoxyphenyl)dec-1-en-3-one was dissolved in 100 mL of ethanol followed by the addition of 1 g of palladium carbon (5% palladium) to this solution and stirring overnight at normal temperature in a hydrogen atmosphere (normal pressure). After filtering the insoluble matter, the filtrate was concentrated under reduced pressure to obtain 9.8 g of crude product. This crude product was purified by column chromatography (SiO2/CHCl3) to obtain 1-(4′-hydroxy-3′-methoxyphenyl)-3-decanone (5.6 g, yield: 58%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCC)cc2)CCCN3CCC)cc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCC)cc2)CCCN3CCC)cc1
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-2-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (430 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-per-benzoic acid (238 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, the dry ice-acetone bath was removed, and an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (hexane:ethyl acetate=1:4→ethyl acetate) and re-crystallized from diisopropyl ether-ethyl acetate to give 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-2-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (288 mg) as yellow crystals (Compound 20).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.Cl[C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>C1COCC1.CCOC(C)=O>[C:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:2]=1
Reactant: COC(=O)CCCCCCC(=O)Cl
Reactant: Nc1cccc(-c2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCC(=O)Nc1cccc(-c2ccccc2)c1
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of biphenyl-3-amine (180) (0.171 g, 1.01 mmol) in THF (3 mL) was cooled to 0° C. then treated with methyl 8-chloro-8-oxooctanoate (181) and stirred for 2 h. The reaction mixture was then diluted with AcOEt, washed with saturated NH4Cl, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (eluent: 30 to 40% AcOEt in hexane), to provide title compound 182 (0.212 g, 69% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][CH2:15][CH2:14][S:13]1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19].CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:15][CH2:14][S:13]1
Reactant: CCC(=O)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NCCS1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCSC1=Nc1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (prepared in a manner analogous to that described in Method C1a; 0.084 g, 0.35 mmol) in CH2Cl2 (5 mL) was added propionyl chloride (0.033 g, 0.35 mmol) and Et3N (0.049 mL, 0.35 mmol). The mixture was allowed to stir at room temp for 1 h, then was diluted with CH2Cl2 (40 mL). The resulting solution was sequentially washed with H2O (10 mL) and a saturated NaCl solution (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by preparative TLC (40% EtOAc/hex) to give 2-(2-methyl-4-nitrophenylimino)-3-propanoyl-1,3-thiazolidine (0.036 g, 35%): FAB-MS m/z 294 ((M+H)+).
Reaction SMILES: [C:1]1([CH:7]2[NH:10][C:9](=[O:11])[CH:8]2[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].[K+].[Br-]>CO>[CH:1]1([CH:7]2[NH:10][C:9](=[O:11])[CH:8]2[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1NC(c2ccccc2)C1O
Reactant: [H][H]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: O=C1NC(C2CCCCC2)C1O
Temperature: 90 °C
Reaction time: 120 h

Procedure:
A suspension of 500 mg (3.06 mmol) of 4-phenyl-3-hydroxy-2-azetidinone VIa and 15 mg of Rh--C in 10 mL of methanol was heated at 90° C. under 800 psi in an autoclave. After 5 days, the hydrogen pressure was released and the catalyst filtered on celite. Evaporation of the solvent afforded a solid which was recrystallized in ethyl acetate to give 440 mg (85%) of VIIe as a white solid: White solid; mp 140°-140.5° C.; [α]D20 +65.1° (c 0.66, CH3OH); 1H NMR (250 MHz, MeOH-d4) δ 0.75-1.10 (m, 2H), 1.12-1.35 (m, 3H), 1.40-2.00 (m, 6H), 3.28 (dd, J=9.7, 4.6 Hz, 1H), 4.81 (d, J=4.6 Hz, 1H); 1H NMR (250 MHz, DMSO-d6) δ 0.75-1.00 (m, 2H), 1.10-1.35 (m, 3H), 1.37-1.55 (m, 1H), 1.58-1.85 (m, 5H), 3.10 (dd, J=9.6, 4.7 Hz, 1H), 4.67 (m, 1H), 5.87 (d, J=7.8 Hz, 1H), 8.21 (bs, 1H); 13C NMR (63 MHz, DMSO-d6) δ 25.08, 25.36, 26.07, 28.83, 29.17, 37.51, 59.04, 76.41, 170.21; IR (KBr) 3312, 3219, 2928, 1726 cm-1. Anal. Calcd for C9H15NO2 : C, 63.88, H, 8.93, N, 8.28. Found: C, 63.70, H, 9.00, N, 8.06.
Reaction SMILES: [CH3:1][C@:2]1([NH:36]C(=O)OC(C)(C)C)[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.C(Cl)[Cl:45].[ClH:47]>O1CCOCC1>[ClH:45].[ClH:47].[CH3:1][C@:2]1([NH2:36])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:10])([F:11])[F:9])[CH2:3]1
Reactant: COCCOc1ccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: COCCOc1ccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(N)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (72 mg, 0.12 mmol), DCM (1 mL) and 4N HCl in dioxane (0.3 mL) was stirred at ambient temperature overnight. Removal of the solvents under reduced pressure gave (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine dihydrochloride (65 mg, 95%) as a yellow solid. LCMS APCI (+) m/z 501 (M+H). Specific rotation: [α]25D=−0.89° (c=0.97, MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[NH2:13][CH2:14][CH2:15][CH2:16]N>C(O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[NH:13][CH2:14][CH2:15][CH2:16][N:9]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: NCCCN
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C2=NCCCN2)cc1
Reaction time: 6 h

Procedure:
4-Nitrobenzonitrile (17.76 g) was added to a solution of sodium metal (0.138 g) in dry ethanol (150 ml) at room temperature, and the mixture was stirred for 6 h. To the suspension was added 1,3-diaminopropane (8.88 g) and the mixture was heated under reflux for 4 days. Evaporation of the solvent under reduced pressure gave a solid which was dissolved in hot ethyl acetate (450 ml). The solution was extracted with 2N hydrochloric acid (90 ml, 20 ml). The combined acidic extracts were washed with ethyl acetate (100 ml) and then basified with 5N sodium hydroxide (60 ml). The emulsion was extracted into hot ethyl acetate (250 ml, 2×100 ml), the organic extracts were combined, reduced to about 250 ml by evaporation and hot cyclohexane (125 ml) was added. On cooling the title compound deposited as needles (17.7 g), m.p. 168°-172°.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[N:23]([CH:27]6[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]6)[N:24]=[CH:25][CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:42]([CH3:49])([CH3:48])[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C)C=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[N:23]([CH:27]6[CH2:32][CH2:31][CH2:30][N:29]([C:42]([CH3:49])([CH3:48])[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:28]6)[N:24]=[CH:25][CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4ccnn4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCCC(n2nccc2-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)C1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a solution of 2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-9-[2-(3-piperidyl)pyrazol-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine; I; 100 mass % in N,N-Dimethylformamide; 100 mass % was added Cesium Carbonate; 2.00 equiv.; 1.090 mmol; 100 mass % followed by ethyl 2-bromo-2-methyl-propanoate; G; 3.00 equiv.; 1.635 mmol; 100 mass %. The reaction mixture was heated to 90° C. and was stirred for 12 hours. LC-MS analysis of the reaction mixture showed almost complete conversion to the desired product. The solvent was removed and the residue was purified on silica gel (0→10% MeOH/DCM) to yield ethyl 2-(3-(5-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methylpropanoate as a light yellow foam.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](Cl)=[O:12]>ClCCl>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:11]([C:7]1[O:6][CH:10]=[CH:9][CH:8]=1)=[O:12]
Reactant: O=C(Cl)c1ccco1
Reactant: CNCCO
Solvent: ClCCl
Product: CN(CCO)C(=O)c1ccco1
Yield: 59.1 %

Procedure:
A one liter, three necked flask was equipped with overhead stirrer, nitrogen atmosphere and an addition funnel. The flask was charged with 115 g of 2-(methylamino)ethanol (1.53 mol.) and 500 ml of dichloromethane. The reaction flask was cooled with an ice bath. Next, 100 g of furoyl chloride (0.77 mol.) was slowly added via the addition funnel over 2.5 hours. The dichloromethane was washed with NaCl(aq.). Next, the NaCl(aq.) layer was extracted with dichloromethane and the two dichloromethane layers were combined and dried over MgSO4. The dichloromethane was removed with a rotoevaporator to yield 77 g (44%) of N-(2-hydroxyethyl)-N-methylfuranamide.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.[CH3:18]O>>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:18])=[O:10])=[CH:12][CH:13]=1)(=[O:3])=[O:4]
Reactant: CO
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a suspension of 4-(aminosulfonyl)benzoic acid (500 mg, 2.5 mmol) in MeOH (2 ml) at 0° C. is added thionylchloride (0.2 ml, 7.4 mmol). The reaction mixture is stirred at rt overnight. When TLC confirms the total consumption of the starting acid, the solvent and excess thionyl chloride are removed under reduced pressure to afford 400 mg (75%) of the title compound, which was used in the next step without any further purification. LC/MS: (ES+):215.9, (ES−):214.1.