Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:47]2[CH2:52][CH2:51][C:50]([C:58]([O:60][CH2:61][CH3:62])=[O:59])([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:49][CH:48]=2)O1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:32][C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:47]2[CH2:52][CH2:51][C:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:49][CH:48]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCOC(=O)C1(C(=O)OCC)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 11.3 %

Procedure:
To a sealable vial containing (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (0.25 g, 0.448 mmol) was added diethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1,1-dicarboxylate (0.374 g, 0.531 mmol), sodium carbonate hydrate (0.167 g, 1.345 mmol), and palladium tetrakis (0.016 g, 0.013 mmol). The mixture was diluted with 1,4-dioxane (4 mL) and water (1 mL) then was flushed with nitrogen and was sealed and heated to 85° C. in an oil bath. After 5 h of heating, the mixture was cooled to rt, was diluted with water (20 mL), and was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10-50% ethyl acetate in hexanes gradient. diethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1,1-dicarboxylate, a white solid, was recovered as the minor isolate (0.032 g, 0.05 mmol, 11.3% yield). LCMS: m/e 634.6 (M+H)+, 2.10 min (method 1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:13]=1[CH:14]=[O:15].O>O1CCCC1.CCOC(C)=O>[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:13]=1[CH:14]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[OH:15]
Reactant: c1ccoc1
Reactant: COc1cccc(Cl)c1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(Cl)c1C(O)c1ccco1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 96.6 %

Procedure:
To a solution of furan (10.7 mL, 147 mmol) in anhydrous tetrahydrofuran (100 mL) under an N2 atmosphere at −10°C. was added n-butyl lithium (65 mL of a 2.5M solution in hexanes, 162 mmol) dropwise over 35 minutes (the internal temperature was maintained at less than −7°C.). The mixture was stirred at this temperature for 1 hour 35 minutes before adding a solution of 2-chloro-6-methoxy-benzaldehyde (27.6 g, 162 mmol) in anhydrous tetrahydrofuran (100 mL) dropwise over 1 h 30 (internal temperature approx −5°C.). On completion of addition, the reaction mixture was warmed to room temperature and stirred at this temperature for 18 hours. Water (100 mL) was added then the mixture was diluted with EtOAc (100 ml). The phases were separated and aqueous phase was extracted into EtOAc (2×100 ml). The combined organics extracts were washed with brine (50 ml), dried over MgSO4 and concentrated to a yellow oil. The crude product was adsorbed onto silica and purified by flash chromatography over silica using an EtOAc/isohexane gradient to give the desired product (33.9 g, 97%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.37 (d, 1H), 7.25-7.21 (m, 1H), 7.05 (dd, 1H), 6.89 (d, 1H), 6.34-6.29 (m, 2H), 6.06 (dt, 1H), 4.38 (d, 1H), 3.87 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][OH:16])[NH:13][C@@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]1[C:23]([O:25][CH3:26])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O>COCCOC.CCOC(C)=O>[CH2:33]([O:32][C:30]([N:13]1[C@H:14]([CH2:15][OH:16])[C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:11]([C:23]([O:25][CH3:26])=[O:24])[C@@H:12]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@H]1[C@H](COCc2ccccc2)[C@@H](CO)N[C@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H]1[C@H](COCc2ccccc2)[C@@H](CO)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Reaction time: 8 h
Yield: 112 %

Procedure:
To a stirred and ice-cooled suspension of (2R*,3S*,4S*,5S*)-4-benzyloxymethyl-5-hydroxymethyl-3-methoxycarbonyl-2-phenylpyrrolidine semifumarate (12.0 g, 29.0 mmol) in 1M NaOH aqueous solution (70.0 ml, 70.0 mmol) and DME (40 ml) was added benzyl chloroformate (Cbz-Cl, 4.97 ml, d1.195, 34.8 mmol) rapidly. After the heterogeneous white reaction mixture was stirred with ice-cooling for an hour, H2O (40 ml) and AcOEt(40 ml) was added to dissolve the white solids, and then a further amount of Cbz-Cl (1.0 ml, d1.195, 7.0 mmol) was added to the mixture at room temperature; on the addition, the reaction mixture became neutral. After stirring at room temperature for 30 minutes, the reaction went to almost completion. The stirring was continued at room temperature overnight, and then the layers were separated. The aqueous layer was extracted with AcOEt (50 ml×4). The combined organic layer and AcOEt extracts were washed with 0.5M NaOH aq. solution (×2), half sat. NaCl aq. solution (×1), 0.5M HCl aq. solution (×1), sat. NaCl aq. solution (×1), sat. NaHCO3 aq. solution (×1) and sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give crude title compound (15.9 g, quant.) as an almost colorless viscous oil: IRmax (film): 3420(s), 1738(vs), 1698(vs), 1680(vs), 1605(w), 1595(w), 1492(s), 1280(s), 1210(s), 1075(s), 758(s), 699(vs) cm-1 ; 1H-NMR δ: 7.53-7.10(m, 14H), 6.94(br.s, 1H), 5.30(d, J=9.5 Hz, 1H), 5.02(br.s, 2H), 4.53(d, J=12.1 Hz, 1H), 4.47(d, J=12.1 Hz, 1H), 4.13-3.90(m, 3H), 3.62(dd, J=9.7, 3.5 Hz, 1H), 3.58-3.41(m, 1H), 3.53(dd, J=9.7, 4.6 Hz, 1H), 3.29(s, 3H), 2.73(br.s, 1H), 1.61(br.s, OH, 1H) ppm. This was employed in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH2:12][OH:13])[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[Cl:14][C:15]1[C:16](F)=[CH:17][C:18]([F:28])=[C:19]([CH:27]=1)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:14][C:15]1[C:16]([O:13][CH2:12][C:2]2([CH3:1])[CH2:11][CH2:10][C:5]3([O:6][CH2:7][CH2:8][O:9]3)[CH2:4][CH2:3]2)=[CH:17][C:18]([F:28])=[C:19]([CH:27]=1)[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: CC1(CO)CCC2(CC1)OCCO2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCC2(CC1)OCCO2
Temperature: 70 °C
Reaction time: 96 h
Yield: 53.8 %

Procedure:
To a solution of (8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methanol (4.30 g, 23 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (10.66 g, 30 mmol) in anhydrous dimethylsulfoxide (37 mL) was added cesium carbonate (14.99 g, 46 mmol). The reaction mixture was heated to 70° C. and stirred for 4 days. At this point, HPLC and TLC analysis indicated remaining starting material, but the reaction was not progressing any further. The reaction mixture was cooled to ambient temperature, filtered through a pad of diatomaceous earth and rinsed with ethyl acetate (100 mL). The filtrate was washed with 1N aqueous hydrochloric acid solution (100 mL). The organic layer was separated, washed with brine (40 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 20% ethyl acetate in hexanes) afforded the title compound (5.13 g, 54%) as a colorless oil: MS (ES+) m/z 359.1 (M−55).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[CH:19]=[N:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[Sn](CCCC)(CCCC)CCCC)[CH3:31]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[CH:19]=[N:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH3:31]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1ncc1occc12
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ncc3occc32)c1C(=O)OC
Temperature: 100 °C
Yield: 15.9 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-furo[2,3-c]quinoline-6-carboxylate (Intermediate 9, 0.165 g), N,N-diethyl-N-((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.3 g), tri-tert-butylphosphinium tetrafluoroborate (0.01 g), tris-(dibenzylideneacetone)dipalladium (0.019 g) in dioxane (6 mL) was degassed then heated at 100° C. for 75 minutes. After cooling, the mixture was evaporated to approximately half volume then partitioned between ethyl acetate and water. The organic layer was washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-14% to give methyl 7-[2((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-furo[2,3-c]quinoline-6-carboxylate (0.028 g) as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[F:18])C1C=CC=CC=1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].CCN(CC)CC>C(Cl)Cl>[C:20]([Si:23]([CH3:25])([CH3:24])[O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:18])[CH:11]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: OCCc1ccc(OCc2ccccc2)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 2-(4-benzyloxy-3-fluoro-phenyl)-ethanol (9.2 g, 37.4 mmol) in CH2Cl2 (150 mL) and TBDMS-Cl (5.6 g, 37.4 mmol), was added Et3N (5.2 mmol, 37.4 mmol) portionwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours at the same temperature. The reaction was washed with H2O (150 mL). The CH2Cl2 was dried over MgSO4 and concentrated under vacuum. To a solution of the residue in MeOH (100 mL), was Pd/C (150 mg) added. The reaction was stirred under H2 (1 atm) for 5 hours. The solid material was filtrated off and the filtrate was concentrated under vacuum to afford the desired compound (8.9 g, 88.3%) as a grayish solid. The crude compound was used for the next step without further purification. 1H NMR (400 Mz, DMSO-d6) δ 9.53 (s, 1H), 6.99˜6.96 (m, 1H), 6.83˜6.81 (m, 2H), 3.70 (t, 2H), 2.63 (t, 2H), 0.83 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCO
Product: CCCCCCCCOC(C)=O
Temperature: 16 °C
Reaction time: 2 h

Procedure:
A mixture of 1-octanol (40 mL, 252 mmol), acetic anhydride (26 mL, 278 mmol) and compound from Example 1 (0.6 g, 1 wt %) was stirred at 16° C. for 2 h. The solution was filtered and excess acetic anhydride removed by distillation to give 1-octyl acetate as the only product.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[NH:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>ClCCl>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]([N:12]=[C:5]([O:4][CH2:2][CH3:3])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=NC(=O)C(C)(C)C)OCC
Temperature: -15 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
Ethyl 3-Ethoxy-3-iminopropanoate Hydrochloride (Preparation 118, 50 g, 0.256 mol) was suspended in dichloromethane (600 mL). The suspension was cooled to −15° C. and triethylamine (7.8 mL, 0.56 mol) followed by pivaloyl chloride (31.5 mL, 0.256 mol) were added. The reaction mixture was left for 18 hours at room temperature, then washed with water, dried over MgSO4, and evaporated. The residue was triturated with hexane. The resulting precipitate was filtered and dried to afford the title compound (44 g, 70%). Taken directly on to the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].O1CCCC1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[O:23])=[CH:18][CH:17]=1>C(O)(=O)C.CC1C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[OH:23])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=C(c1ccncc1)c1ccc(F)cc1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC(c1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A Grignard-complex was previously prepared starting from 22.75 parts of 1-bromo-4-fluorobenzene, 3.2 parts of magnesium and 45 parts of anhydrous tetrahydrofuran. The whole was cooled in 2-propane/CO2 to a temperature of -20° to -25° C. A solution of 20.1 parts of (4-fluorophenyl)(4-pyridinyl)methanone in 45 parts of anhydrous methylbenzene was added dropwise, during a 30 minutes-period, at -20° C. Upon completion, the whole was stirred overnight at room temperature. After cooling to 0° C., the reaction mixture was decomposed by the dropwise addition of 50 parts of acetic acid. After stirring for 1 hour at room temperature, the precipitated product was filtered off and set aside. From the filtrate, the organic layer was separated, washed with 50 parts of water, dried, filtered and evaporated. The solid residue and the precipitated product, which was set aside (see above), were washed with water and distilled azeotropically with 180 parts of methylbenzene. The solid distillate was suspended in 80 parts of acetonitrile. The product was filtered off and dried, yielding 28 parts (94%) of α,α-bis(4-fluorophenyl)-4-pyridinemethanol (intermediate 26).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1ccc(C(F)(F)F)cc1Cl)c1cc(Br)ccc1O
Yield: 34.9 %

Procedure:
Using 5-bromosalicylic acid and 2-chloro-4-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=1[O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42].C(N(CC)CC)C.C(OC(C)(C)C)=O>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([CH3:27])=[C:29]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=2)[CH:15]([CH3:16])[CH3:17])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCOc1cc(C(=O)O)ccc1C
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Agent: CC(C)(C)OC=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)ccc1C

Procedure:
From (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 12.9 mmol), 4-methyl-3-(3-methoxy-propoxy)-benzoic acid (4.06 g, 18.1 mmol), BOPCI (4.6 g, 18.1 mmol) and triethylamine (7.2 mL, 51.7 mmol). TLC, Rf (AcOEt)=0.7. MS (LC-MS): 493 [M+H-Boc]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](O)([CH3:12])[CH3:11].[CH:14]1[CH:19]=[C:18]2[CH:20]=[CH:21][O:22][C:17]2=[CH:16][CH:15]=1>O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:21]1[O:22][C:17]2[CH:16]=[CH:15][CH:14]=[CH:19][C:18]=2[CH:20]=1)([CH3:12])[CH3:11]
Reactant: c1ccc2occc2c1
Reactant: COc1ccc(C(C)(C)O)c(Br)c1
Solvent: O
Product: COc1ccc(C(C)(C)c2cc3ccccc3o2)c(Br)c1
Temperature: 90 °C
Yield: 51 %

Procedure:
Mixture comprising 2-(2-bromo-4-methoxyphenyl)-propan-2-ol (100 mg), 2,3-benzofuran (0.19 ml) and polyphosphoric acid (1 g) was stirred and heated at 90° C. for 30 min. The reaction mixture was added with water and extracted with DCM. The residues obtained after concentration under reduced pressure were purified by silica gel column (DCM/hexane) to obtain the title compound (143 mg, 51%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].CCN(CC)CC.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (750 mg, 2.28 mmol) was dissolved in 35 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. To the stirred solution were added Et3N (0.35 mL, 2.50 mmol) and benzoyl chloride (260 μL, 2.28 mmol) and the reaction was allowed to warm to room temperature over 2.5 h. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL) and CH2Cl2 (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a tan foam. Mass spectral analysis showed the presence of some bis-amide in addition to the desired product. The tan foam was treated with 1N aqueous HCl solution (50 mL) at 100° C. for 5 h. HPLC analysis showed that all of the bis-amide had been converted to the desired product. The reaction was cooled to room temperature and treated with 10% NaOH until the pH˜11. The mixture was extracted with CHCl3 (3×30 mL). The combined organic extracts were washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. Purification by column chromatography (SiO2, 5–10% MeOH/CHCl3) gave 100 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)benzamide as a white powder. m.p. 184–187° C.;
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][C:28]([C:31]([O:33]C)=[O:32])=[CH:27][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[ClH:37]>O1CCCC1.CO>[ClH:37].[CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(-c2cccnc2)cccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(-c2cccnc2)cccc1-3
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
To a solution of methyl 12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (130 mg, 0.203 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 4N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was adjusted to pH 6.5 with 2N hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. To a solution of the residue in chloroform was added 4N HCl-ethyl acetate solution (0.5 ml), and the solvent was evaporated under reduced pressure. A mixed solvent (hexane:ethyl acetate=4:1) was added to the residue. The precipitated solid was collected by filtration to give 12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid hydrochloride (88 mg, yield 91%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[CH:14]=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CO.O.C(O)C>[CH3:1][O:4][CH2:5][C:6]1[C:7]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[CH:14]=1
Reactant: CC(=O)OCc1cc2c(cc1CCC(=O)O)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: COCc1cc2c(cc1CCC(=O)O)OCO2
Yield: 87.3 %

Procedure:
1.6 g of 3-(6-acetoxymethyl-1,3-benzodioxole-5-yl)propionic acid was dissolved in 100 ml of methanol. A catalytic amount of p-toluenesulfonic acid was added to the solution and the mixture was heated under reflux for 4 h and 15 min. The solvent was distillef off from the reaction mixture. A solution of 1 g of sodium hydroxide in a mixture of 5 ml of water and 45 ml of ethanol was added to the residue and the mixture was heated under reflux for 20 min. The reaction mixture was concentrated. 200 ml of ethyl acetate and 200 ml of water were added to the concentrate. The mixture was acidified with concentrated hydrochloric acid. The layers thus formed were separated. The product was washed with water three times and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 1.25 g of the intended compound in the form of a white powder.