Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7][C:8]([CH2:12][CH:13]=[CH2:14])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([C:5]1[C:6]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7][C:8]2[CH2:12][CH:13]([CH3:14])[O:11][C:9]=2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCc1cc(OC(=O)C(C)(C)C)c(C(C)(C)C)cc1O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC1Cc2cc(OC(=O)C(C)(C)C)c(C(C)(C)C)cc2O1
Temperature: 25 °C
Yield: 30 %

Procedure:
0.50 g of 5-t-butyl-4-trimethylacetoxy-2-(2-propenyl)phenol was dissolved in 30 ml of dichloromethane, 30 ml of boron trifluoride etherate was added, and the solution was stirred at room temperature under a nitrogen stream. The solution was further refluxed for 30 minutes, and the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with n-hexane. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 0.5%-1% ethyl acetate) to give 0.15 g of 6-t-butyl-2-mehtyl-5-trimethylacetoxy-2,3-dihydrobenzofuran as a colorless solid (yield 30%).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH:9]1[C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]O.B(F)(F)F>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH3:25])=[O:15])[CH:9]1[C:17]1[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1c1c(Cl)cccc1Cl
Reactant: CO
Agent: FB(F)F
Product: COC(=O)C1CC(=O)N(Cc2ccccc2)C1c1c(Cl)cccc1Cl

Procedure:
A solution of 25 g of 1-benzyl-2-(2,6-dichlorophenyl)-5-oxopyrrolidin-3-carboxylic acid in 247 ml of boron trifluoride methanol was refluxed for 7 hours and then concentrated in vacuo to a solid. The solid was dissolved in chloroform and the chloroform washed with a saturated sodium carbonate solution and then with a saturated sodium bicarbonate solution. Drying (Na2SO4), filtration, and concentration in vacuo provided 18 g of off-white crystals, m.p. 97°-102°.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH:20]O.Cl>[OH-].[Na+].O>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH:8]2[O:20][CH:9]2[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(C2OC2C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 18.9 g of 4-carboxybenzalacetophenone in 7.5 ml of 1 N sodium hydroxide solution and 225 ml of water was added 15 ml of 30% hydrogen peroxide. After cooling in an ice-water bath, 50 ml of 0.5 N sodium hydroxide was added dropwise over 5 min. The reaction mixture was stirred at room temperature for 31/4 hrs. and acidified to pH of 6.5 with 1 N hydrochloric acid. After stirring at room temperature for 1 hr., the solid was collected on a filter, washed with water and air-dried. Recrystallization from ethanol gave 11 g of 3-(4-carboxyphenyl)-1-phenyl-2,3-epoxy-1-propanone as colorless crystals, m.p. 170°-172° C. after drying at 80° C. under vacuum for 3 hrs.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:24][OH:25]>N1C=CC=CC=1.C(O)C>[CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[N:24][OH:25])[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NO
Reactant: CCCCCCN1CCC(C)(c2cccc(C=O)c2)C(C)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCCCN1CCC(C)(c2cccc(C=NO)c2)C(C)C1
Yield: 21.1 %

Procedure:
A solution of 1-hexyl-3,4-dimethyl-4-(3-formylphenyl)piperidine (Example 28, 80 mg, 0.27 mmol) in a mixture of pyridine (1 mL) and ethanol (1 mL) was treated with hydroxylamine hydrochloride (22 mg, 0.32 mmol) and the resulting mixture was heated at reflux for 18 hours. The solvent was evaporated in vacuo and the residual orange oil was purified by column chromatography on silica gel (10 g) eluted with a gradient of dichloromethane:methanol:0.880 ammonia (98:1:1 to 94:5:1). This gave the title compound as an oil (18 mg).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4]P(=O)(OC)OC.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[Br:1])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COP(=O)(Cc1ccccc1Br)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccccc2Br)CC1
Reaction time: 1 h

Procedure:
A solution of dimethyl 2-bromobenzylphosphonate (45.66 g, 148.9 mmol) in THF was added slowly to a mixture of NaH (7.14 g of a 60% mineral oil dispersion, 178.5 mmol) in THF (200 ml) and the mixture was stirred for 1 hr. A solution of 1-(tert-butoxycarbonyl)-4-piperidinone (29.67 g, 148.9 mmol) in THF was added dropwise and the mixture was heated to reflux for 1.5 hr. The mixture was cooled and quenched with brine. The mixture was diluted with ethyl acetate, washed with water, and dried with brine. The organic layer was concentrated in vacuo to an oil. The oil was dissolved in acetonitrile and extracted with hexane. The acetonitrile layer was concentrated in vacuo to give 1-(tert-butoxycarbonyl)-4-[(2-bromophenyl)methylene]piperidine as an oil that solidified upon standing (48.3 g, 97%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH2:18]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]2[CH:3]=[C:2]([Br:1])[S:6][C:5]=2[CH3:7])=[CH:10][CH:11]=1)[CH:17]=[CH2:16]
Reactant: Cc1sc(Br)cc1Cc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(Cc2cc(Br)sc2C)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of phenol 12 (860 mg, 3.04 mmol) in acetone (20 mL) were added allyl bromide (0.5 mL, 4.56 mmol) and Cs2CO3 (2.0 g, 6.08 mmol) at room temperature. The mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered off through celite. The filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 13 (906 mg, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24](O)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]1([CH3:36])[O:33][C:32](=[O:34])[CH2:31][C:30](=[O:35])[O:29]1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24]([CH:31]1[C:32](=[O:34])[O:33][C:28]([CH3:36])([CH3:27])[O:29][C:30]1=[O:35])=[O:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)COC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4-methanesulfonyloxypyrrolidine (79.4 g), 2,2-dimethyl-1,3-dioxane-4,6-dione (29.55 g) and 4-(dimethylamino)pyridine (25.05 g) in dichloromethane (635 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (39.3 g) at 5°-10° C. The solution was stirred at the same temperature for one hour and at ambient temperature for 18 hours. The mixture was washed with water (650 ml), 1N hydrochloric acid (650 ml), saturated aqueous sodium hydrogen carbonate (650 ml), and brine (650 ml) successively, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (800 g) and eluted with a mixture of methanol and dichloromethane (2:98 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-[2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxoethyl]oxymethyl-4-methanesulfonyloxypyrrolidine (80.98 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.Cl.[Cl:11][CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[Cl:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: NCCCCl
Reactant: ClCc1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: ClCCCNCc1ccc(Cl)nc1
Yield: 86.9 %

Procedure:
16.20 g (100 mmol) of 2-chloro-5-(chloromethyl)pyridine, 16.90 g (130 mmol) of 3-chloropropan-1-amine hydrochloride and 36.24 ml (260 mmol) of triethylamine in 200 ml acetonitrile stirred at 60° C. for 20 hours. After addition of 30.67 g (230 mmol) of 30 percent strength aqueous sodium hydroxide solution, the reaction mixture is concentrated under reduced pressure and the residue is extracted with chloroform. Concentration of the extract under reduced pressure gives 19.03 g (87% of theory) of 3-chloro-N-[(6-chloropyridin-3-yl)methyl]propan-1-amine which can be used without further purification for the next reaction (cf. Ex. II-2).
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:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[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:44]6[C:45]([CH3:49])=[CH:46][CH:47]=[CH:48][C:43]6=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[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:44]6[C:45]([CH3:49])=[CH:46][CH:47]=[CH:48][C:43]6=[N:42][CH:41]=5)=[O:59])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cnc5cccc(C)n45)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cnc5cccc(C)n45)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]thio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.157 g) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.50 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 3:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 407) (1.05 g) as yellow amorphous.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:31])[CH2:18][CH:19]1[CH2:25][CH2:24][CH2:23][C:22]2[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:21]=2[CH2:20]1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:31])[CH2:18][CH:19]1[CH2:25][CH2:24][CH2:23][C:22]2[CH:26]=[C:27]([O:30][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH:28]=[CH:29][C:21]=2[CH2:20]1)[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: CCOC(=O)CC1CCCc2cc(O)ccc2C1
Product: CCOC(=O)CC1CCCc2cc(OCCCCNC(=O)OC(C)(C)C)ccc2C1

Procedure:
The title compound was prepared according to the procedure of Example 19 except that (4-bromo-butyl)-carbamic acid tert-butyl ester was used in place of (3-bromo-propyl)-carbamic acid tert-butyl ester and (2-hydroxy-6,7,8,9-tetrahydro-5H-benzo-cyclohepten-6-yl)-acetic acid ethyl ester was used in place of (7-hydroxy-1,2,3,4-tetrahydro-napthalen-2-yl)-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[N+:28]([O-])=O)[S:13][C:12]=1[C:31]([O:33][CH3:34])=[O:32])[CH3:9]>CCOC(C)=O.[Pt]>[NH2:28][C:18]1[CH:19]=[C:20]([O:23][C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][C:17]=1[NH:16][C:14]1[S:13][C:12]([C:31]([O:33][CH3:34])=[O:32])=[C:11]([O:10][C@@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH3:9])[CH:15]=1
Reactant: COC(=O)c1sc(Nc2ccc(OC(F)(F)F)cc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1Cl
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(Nc2ccc(OC(F)(F)F)cc2N)cc1O[C@H](C)c1ccccc1Cl
Yield: 99.7 %

Procedure:
Methyl 3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-({2-nitro-4-[(trifluoromethyl)oxy]phenyl}amino)-2-thiophenecarboxylate (3.5 g, 6.8 mmol) was dissolved in EtOAc (100 mL) with stirring. Sulfided platinum (5% weight on carbon, 1.32 g) was added, and the reaction was placed under 50 atm of H2. After 36 h the reaction was filtered through a Celite pad washing with EtOAc. The filtrate was concentrated to afford 3.3 g of methyl 5-({2-amino-4-[(trifluoromethyl)oxy]phenyl}amino)-3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxylate which was immediately dissolved in trimethyl orthoformate (50 mL) with stirring. Pyridinium p-toluenesulfonate (0.26 g, 1.0 mmol) was added in a single portion. The reaction was stirred for 24 h. The volatiles were evaporated under reduced pressure and the residue was dissolved in CHCl3 (30 mL) and TFA (30 mL). The mixture was heated to 60° C. for 2 h. The volatiles were evaporated under reduced pressure and the residue was quenched by the addition of 7 N ammonia in MeOH (40 mL). The volatiles were evaporated under reduced pressure and the residue was partitioned between DCM (200 mL) and water (100 mL). The layers were separated, and the organics were washed with water (3×50 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting solid was taken up as a suspension in ether/hexanes(1/9), filtered and washed with ether/hexanes(1/9) to afford 1.5 g (62%) of the title compound as a solid. MS (ESI): 359 [M+H]+.
Reaction SMILES: [C@H:1]12[CH2:25][C@H:4]([N:5]([C:7]([C:9]3[N:13]4[CH:14]=[C:15]([C:19](N(OC)C)=[O:20])[CH:16]=[C:17]([Br:18])[C:12]4=[N:11][CH:10]=3)=[O:8])[CH2:6]1)[CH2:3][O:2]2.Cl.[CH2:27]1COCC1>>[C@H:1]12[CH2:25][C@H:4]([N:5]([C:7]([C:9]3[N:13]4[CH:14]=[C:15]([C:19](=[O:20])[CH3:27])[CH:16]=[C:17]([Br:18])[C:12]4=[N:11][CH:10]=3)=[O:8])[CH2:6]1)[CH2:3][O:2]2
Reactant: CON(C)C(=O)c1cc(Br)c2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)n2c1
Reactant: C1CCOC1
Agent: Cl
Product: CC(=O)c1cc(Br)c2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)n2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-8-bromo-N-methoxy-N-methylimidazo[1,2-a]pyridine-6-carboxamide (286 mg) in THF (10 mL) was added dropwise 1M methylmagnesium bromide THF solution (2.1 mL) under ice-cooling. The reaction mixture was stirred at 0° C. for 20 min, 1N hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a crude product.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH2:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])[CH:36]([CH3:38])[CH3:37]>C(Cl)Cl>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[O:15][C:47](=[O:48])[C:46]([S:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[CH2:35][CH:36]([CH3:37])[CH3:38])=[C:50]([OH:51])[CH:14]=2)[CH:8]=1
Reactant: CC(C)Cc1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1cccc(-c2ccccc2)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccccc1Sc1c(O)cc(-c2cccc(-c3ccccc3)c2)oc1=O

Procedure:
The title compound was prepared by Method A using 3'-phenylacetophenone (2 g, 10.20 mmol), trimethylsilyl triflate (2.27 g, 10.20 mmol), triethylamine (2.06 g, 20.40 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isobutylphenyl)thio]propanedioic acid (1.14 g, 5.1 mmol). m.p. 187-188° C. 1H NMR (400 MHz, DMSO-d6) δ 0.83 (d, 6H), 1.78 (m, 1H), 2.4 (d, 2H), 7.03 (s, 1H), 7.08 (s, 4H), 7.44 (t, 1H), 7.53 (t, 2H), 7.67 (t, 1H), 7.75 (s, 1H), 7.78 (s, 1H), 7.86 (m, 2H), 8.08 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([C:19]3([OH:27])[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[N:16][CH:15]=2)=[CH:10][C:9]=1[F:28])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([C:19]3([OH:27])[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[N:16][CH:15]=2)=[CH:10][C:9]=1[F:28]
Reactant: CCN1CCC(O)(c2ncc(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1CCC(O)(c2ncc(-c3ccc(N)c(F)c3)s2)CC1
Reaction time: 2 h

Procedure:
To an ambient solution of Example 8A (0.20 g, 0.48 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 2 h, and was then concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×5 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound, which was used without further purification. MS (ESI) m/z 322 [M+H]+.
Reaction SMILES: CO[C:3](=[O:11])[CH2:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH2:16].CO>C1(C)C=CC=CC=1>[CH3:9][C:6]([CH3:7])([CH3:8])[C:5](=[O:10])[CH2:4][C:3]([NH:16][C:15]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:14]=1[O:13][CH3:12])=[O:11]
Reactant: COC(=O)CC(=O)C(C)(C)C
Reactant: COc1ccc([N+](=O)[O-])cc1N
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)CC(=O)C(C)(C)C
Reaction time: 4 h

Procedure:
Methyl-4,4-dimethyl-3-oxovalerate (15.8 g, 0.1 mol) and 2-methoxy-5-nitroaniline (16.8 g, 0.01 mol) were taken up in toluene (150 mL) in a round bottomed flask fitted with a Dean-Stark trap. The mixture was heated to a vigorous reflux while the MeOH side-product was distilled off and removed. After 4 hours, the mixture was cooled and the toluene removed in vacuo. The residue was recrystallized from acetonitrile to yield 27 g of the desired condensation product.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].[OH:16][C@@H:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18](=[CH2:22])[C:19](O)=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:19](=[O:20])[C:18](=[CH2:22])[C@@H:17]([OH:16])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:10]
Reactant: C=C(C(=O)O)[C@@H](O)c1ccccc1
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)NCC(=O)OCC)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (3.75 mL, 0.027 mol, 1.2 eq) was added to a suspension of glycine ethyl ester hydrochloride (3.44 g, 0.024 mol, 1.1 eq) in anhydrous dichloromethane (60 mL) (see FIG. 4). The mixture was stirred for 15 min at room temperature and then cooled to 0° C. (ice bath). Compound 9a (4 g, 0.022 mol, 1 eq) and dicyclohexylcarbodiimide (5.09 g, 0.02469 mol, 1.1 eq) were added successively to the reaction mixture which was stirred at room temperature for 17 h. The precipitate (dicyclohexylurea and triethylamine hydrochloride) was collected by filtration. The filtrate was washed with a 1N aqueous solution of HCl (50 mL), brine (50 mL) and dried over sodium sulfate. Evaporation of the solvent afforded an oil which was purified by column chromatography (eluent: hexane/EtOAc=6:4). The desired product 10a was obtained as a yellow oil (3.51 g, 60%). Rf0.25 (hexane/EtOAc=4:6). 1H NMR δ (CDCl3) 1.25 (t, 3H), 3.63 (s, 1H), 4.02 (m, 2H), 4.17 (q, 2H), 5.49 (s, 1H), 5.58 (d, 1H), 5.96 (s, 1H), 6.86 (s, 1H), 7.65 (m, 5H).[M+H]+ 264.1,: tR=2.55 min; purity: 96%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH2:11]([O:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH2:21][CH2:20]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(COC2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: Nc1ccc(N2CCC(OCc3ccccc3)CC2)nc1

Procedure:
Intermediate B-23 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 4-benzyloxypiperidine as starting materials. MS (M+1): 284.
Reaction SMILES: [CH3:1][C:2]1[N:25]([CH3:26])[C:5]2[CH:6]=[C:7]([C:20](OCC)=[O:21])[C:8]3[CH2:9][CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:12][C:13]=3[C:4]=2[N:3]=1.[NH2:27][CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][NH:27][C:20]([C:7]1[C:8]2[CH2:9][CH2:10][CH:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:12][C:13]=2[C:4]2[N:3]=[C:2]([CH3:1])[N:25]([CH3:26])[C:5]=2[CH:6]=1)=[O:21]
Reactant: NCCO
Reactant: CCOC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)N2
Product: Cc1nc2c3c(c(C(=O)NCCO)cc2n1C)CCC(c1ccccc1)N3
Temperature: 145 °C
Yield: 52 %

Procedure:
A suspension of 1.0 g (2.9 mmol) ethyl 2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5h]-quinoline-5-carboxylate in 10 ml 2-aminoethanol was heated to 140-150° C. until no starting material was left. The mixture was partitioned between saturated aqueous ammonium chloride and dichloro-methane/methanol 9:1. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel (toluene/dioxane/methanol=6:3:1). Crystallization from diisopropyl ether yielded 0.55 g (52%) of the title compound as a colourless solid. m.p. 248-251° C.