Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:18])(=[O:17])[C:2]1[C:3](=[CH:7][C:8](=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5].[H][H]>O>[CH:8]1([C:9]([OH:11])=[O:10])[CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH:2]([C:1]([OH:18])=[O:17])[CH2:16][CH:12]1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Reactant: [H][H]
Solvent: O
Product: O=C(O)C1CC(C(=O)O)C(C(=O)O)CC1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A 5-L autoclave made of Hastelloy (HC22) was charged with 552 g of pyromellitic acid, 200 g of a catalyst formed by supporting Rh on activated carbon (available from N.E. Chemcat Corporation) and 1656 g of water. The interior of the autoclave was replaced with a hydrogen gas while stirring the contents. Then, the hydrogen pressure was adjusted to 5.0 MPa and the temperature was raised to 60° C. While maintaining the hydrogen pressure at 5.0 MPa, the reaction was allowed to proceed for 2 h. After replacing the hydrogen gas in the autoclave with nitrogen gas, the reaction product solution was discharged from the autoclave. The reaction product solution was filtered while it was hot to separate the catalyst. The filtrate was concentrated by distillation under reduced pressure using a rotary evaporator to evaporate off water, thereby precipitating crystals. The precipitated crystals were collected by a solid-liquid separation at room temperature, and then, dried to obtain 481 g of 1,2,4,5-cyclohexanetetracarboxylic acid (yield: 85.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH2:26]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH3:18])[C:6]1[CH2:11][C@@H:12]3[NH:17][C@H:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Reactant: C=Cc1ccccc1C
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2C)C[C@H]2CCC[C@@H]1N2

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.486 mmol; Example 118A) and 1-methyl-2-vinylbenzene (115 mg, 0.972 mmol; Aldrich) was performed according to the procedure described in Example 114B to provide title compound as a racemic mixture. Individual enantiomers were obtained by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minutes) to afford the title compound as the first-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.13-1.33 (m, 3H), 1.60-1.96 (m, 4H), 2.00 (s, 3H), 2.40 (s, 3H), 2.79 (dd, J=17, 7 Hz, 1H), 2.98-3.08 (m, 1H), 3.16 (ddd, J=14, 9, 6 Hz, 1H), 3.36-3.43 (m, 1H), 4.20 (ddd, J=15, 9, 5 Hz, 1H), 4.32-4.42 (m, 2H), 6.90-6.98 (m, 2H), 6.99-7.11 (m, 3H), 7.14 (s, 1H), 7.27 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 345 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH:8]([CH2:13][C:14]#[C:15][C:16]2[N:17]=[C:18]3[CH:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:19]3=[N:20][CH:21]=2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O.[Cu](I)I>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C@@H:9]([CH3:12])[C@H:8]([C:13]2[N:17]3[C:16]([CH:21]=[N:20][C:19]4[N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[CH:24][C:18]=43)=[CH:15][CH:14]=2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(C)C(CC#Cc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Agent: I[Cu]I
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CCS(=O)(=O)N1CC[C@@H](C)[C@H](c2ccc3cnc4c(ccn4COCC[Si](C)(C)C)n23)C1
Temperature: 130 °C
Reaction time: 5 h
Yield: 5.8 %

Procedure:
To a flask containing (+/−)-2-[3-(1-ethanesulfonyl-4-methyl-piperidin-3-yl)-prop-1-ynyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (395 mg, 0.83 mmol) was added copper iodide (79 mg, 0.41 mmol), and DBU (0.57 mL, 3.8 mmol) in dry dimethyl acetamide (4 mL). The mixture was vacuum degassed and the flask was wrapped with tin foil (protect from light) and heated to 130° C. and stirred for 5 hours. Additional copper iodide (110 mg) was added and the mixture was stirred for another 6 hours and then cooled to ambient with over-night stirring. The material was taken up in water (30 mL) and ethyl acetate (30 mL), transferred to a reparatory funnel and shaken. The organic phase was collected and shaken with an equal volume of brine. The aqueous phases were back extracted with ethyl acetate (2×25 ml), the organics combined, dried (MgSO4), filtered and stripped. The remainder was purified by preparative TLC eluting with 45% ethyl acetate in hexanes (develop plates in the dark). A less polar component was collected providing 23 mg of semi-pure trans-(+/−)-8-(1-ethanesulfonyl-4-methyl-piperidin-3-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-3,4,8a-triaza-as-indacene product. MS (M+H)+=477. Also 17 mg of a more polar cis-(+/−)-8-(1-ethanesulfonyl-4-methyl-piperidin-3-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-3,4,8a-triaza-as-indacene product was collected. MS (M+H)+=477.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[O:9][C:10]2[C:16]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])=[CH:15][CH:14]=[C:13]([Cl:30])[C:11]=2[CH:12]=1)([OH:7])=O.[CH2:31]([NH2:33])[CH3:32]>O>[Cl:30][C:13]1[C:11]2[CH:12]=[C:8]([C:5](=[O:7])[NH:33][CH2:31][CH3:32])[O:9][C:10]=2[C:16]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:15][CH:14]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3cc(C(=O)O)oc23)c1=O
Reactant: CCN
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCNC(=O)c1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Reaction time: 3 h
Yield: 77.7 %

Procedure:
10 ml of thionyl chloride was added to 0.37 g (0.96 mmol) of 3-(2-carboxy-4-chlorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil, followed by stirring for 3 hours under heating and refluxing. After completion of the reaction, thionyl chloride was distilled off under reduced pressure. The obtained residue was dissolved in 20 ml of tetrahydrofuran. To this solution, 0.24 g (3.84 mmol) of ethylamine (70% aqueous solution) was added, followed by stirring for 10 minutes at room temperature. After completion of the reaction, the reaction solution was poured into water, and precipitated crystals were collected by filtration to obtain 0.31 g (yield: 78.3%) of the desired product as white crystals. Melting point: 225-226° C.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[N:9]=[N+:10]([O-:15])[C:11]([Cl:14])=[CH:12][CH:13]=1.O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[OH:26]>O1CCOCC1.CS(C)=O>[Cl:14][C:11]1[N+:10]([O-:15])=[N:9][C:8]([O:26][C:20]2[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=2[O:18][CH3:17])=[CH:13][CH:12]=1
Reactant: [O-][n+]1nc(Cl)ccc1Cl
Reactant: COc1ccc(C)cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C)cc1Oc1ccc(Cl)[n+]([O-])n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
In a mixed solvent of 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL) was dissolved 167.5 mg (1.21 mmol) of commercially available 2-methoxy-5-methylphenol, and 142.8 mg (1.27 mmol) of potassium tert-butoxide was added to the solution, then 202.9 mg (1.23 mmol) of 3,6-dichloropyridazine 1-oxide was added to the mixture and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=2:1) to obtain 226.5 mg (0.849 mmol, Yield: 70.2%) of 6-chloro-3-(2-methoxy-5-methylphenoxy)pyridazine 1-oxide.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[CH:11]=[CH:12][C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[O:1]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][C:13]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[O:14])[CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1cccc(Oc2ccccc2)c1)c1ccc[nH]1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCc1cccc(Oc2ccccc2)c1)c1ccc[nH]1
Yield: 99.3 %

Procedure:
A mixture of 9 g (31.1 mmol) of 2-(3-phenoxycinnamoyl)pyrrole, 3, and 2 g of 10% Pd/C in 200 ml of ethanol was stirred and hydrogen gas was passed over the reaction mixture for 2 hours and 15 minutes. The mixture was dried and concentrated on a rotary evaporator to give 9 g of solid product. The crude reaction product was chromatographed on silica gel (for dry column chromatography), eluting with ethyl acetate/hexane (1:4). The chromatographed material was recrystallized twice from isopropanol yielding analytically pure light yellow solid material, m.p. 75°-76° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O1CCCC1>[CH2:10]([O:17][C:18]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(N)CC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-aminobutyric acid (0.52 g), 2 mol/L aqueous sodium hydroxide solution (10 mL) and tetrahydrofuran (10 mL) was added benzyloxycarbonyl chloride (1.07 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue (solid) was treated with n-hexane. The crystals were collected by filtration, washed with n-hexane and dried under reduced pressure to give 3-benzyloxycarbonylaminobutyric acid (0.59 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added 1,1′-carbonylbis-1H-imidazole (0.59 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia solution (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with diethylether. The insoluble material was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 3-benzyloxycarbonylaminobutyramide (0.54 g). The obtained 3-benzyloxycarbonylaminobutyramide (76 mg) was dissolved in methanol (3 mL). To the solution was added 10% palladium-carbon powder (20 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (32 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:19])[CH:13]([CH3:18])[CH2:14][C:15]([OH:17])=O)=[CH:8][CH:7]=1.C(OC(C)=C)(=O)C>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C@H:12]2[O:19][C:15](=[O:17])[CH2:14][C@H:13]2[CH3:18])=[CH:10][CH:11]=1
Reactant: CC(CC(=O)O)C(=O)c1ccc(OCCCBr)cc1
Agent: C=C(C)OC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H]1CC(=O)O[C@@H]1c1ccc(OCCCBr)cc1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-(3-bromopropyloxy)-γ-oxo-β-methylbenzenebutanoic acid (50 g), anhydrous cupric sulfate (50 g), isopropenyl acetate (200 ml) and toluene (200 ml) was refluxed in an atmosphere of nitrogen for 30 minutes during which about 150 ml of the distillate was collected. The mixture was cooled, diluted with ethyl acetate (150 ml) and filtered through a bed of Celite. The solid was washed with ethyl acetate (150 ml) and the combined filtrates were washed with saturated NaHCO3 (100 ml×4), brine (100 ml×2) and dried over Na2SO4. The organic layer was concentrated and the residue was dissolved in ethyl acetate (about 300 ml). Platinum oxide (PtO2) (3.0 g) was added and the cooled (about 10° C.) mixture was hydrogenated at 20 p.s.i. H2 pressure for 90 minutes. The mixture was filtered, concentrated and the residue was purified by (suction) chromatography on silica gel to provide the title compound as an oil, uncontaminated with the (5S, 4S) and (5R, 4R) diastereomers as determined by NMR.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][O:6][C:7]1[CH:25]=[CH:24][C:10]([CH2:11][N:12]2[C:16]([CH2:17][OH:18])=[C:15]([Cl:19])[N:14]=[C:13]2[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=1)#[N:2].[CH3:30]C(C)([O-])C.[K+].CI.O>CS(C)=O>[C:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][N:12]2[C:16]([CH2:17][O:18][CH3:30])=[C:15]([Cl:19])[N:14]=[C:13]2[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:24][CH:25]=1)#[N:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(OCc2ccccc2C#N)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(OCc2ccccc2C#N)cc1
Reaction time: 2.5 h
Yield: 56.7 %

Procedure:
To a solution of 0.29 g of 1-[4-(2-cyanobenzyloxy)benzyl]-2-butyl-4-chloro-5-hydroxymethylimidazole in 8.0 mL of dimethyl sulfoxide at 25° was added 0.93 g of potassium t-butoxide followed by 0.060 mL of methyl iodide. The reaction mixture was stirred at 25° for 2.5 hours and then was poured into water. The aqueous emulsion was extracted with ethyl acetate; the organic phases were combined and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 5-25% ethyl acetate/benzene) furnished 0.17 g of 1-[4-(2-cyanobenzyloxy)benzyl]-2-butyl-4-chloro-5-methoxymethylimidazole; NMR (200 MHz, CDCl3):δ7.72-7.57 (m, 3H); 7.43 (m, 1H); 6.94 (s, 4H); 5.22 (s, 2H); 5.04 (s, 2H); 4.27 (s, 2H); 3.26 (s, 3H); 2.56 (t, 2H); 1.65 (quint., 2H); 1.33 (sext., 2H); 0.88 (t, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36])[CH2:4][NH:5][C:6](=[O:28])[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:9]1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:10]2[N:11]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:12](=[O:13])[N:8]([CH2:7][C:6]([NH:5][CH2:4][CH:3]([NH:2][S:40]([CH3:39])(=[O:42])=[O:41])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:37])[F:36])=[O:28])[N:9]=2)=[CH:22][CH:23]=1
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1ccccc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CS(=O)(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1ccccc1C(F)(F)F

Procedure:
Analogously to Example 16, treatment of 67 mg (0.114 mmol) of the compound of Example 57A with methanesulphonyl chloride gave 40 mg (56% of theory) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH2:5][NH:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:17]1[CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][C@H:4]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:29])=[O:30])[C:3]([OH:37])=[O:2])=[O:26])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(OCCc2cc3ccccc3[nH]2)cc1)NS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc(OCCc2cc3ccccc3[nH]2)cc1

Procedure:
A methanol solution (50 mL) of 4-5 (1.3 g, 4.0 mmol) and 1N NaOH (20 mL, 20 mmol) was stirred at 50° C. for 4 h. The reaction was concentrated and the residue acidified with 1M NaHSO4 solution to provide 4-6 as a beige colored solid.
Reaction SMILES: [C:1]1([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16](Cl)=[O:17])[CH2:12][CH2:11]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1.C(Cl)(=O)C(Cl)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[C:1]1([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:17])[C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=3[F:32])[CH2:12][CH2:11]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1
Reactant: O=C(Cl)C1CCN(CC2=Cc3ccccc32)CC1
Reactant: Fc1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1F)C1CCN(CC2=Cc3ccccc32)CC1
Yield: 35 %

Procedure:
0.025 mole of 1-(benzocyclobuten-1-ylmethyl)-4-piperidinecarbonyl chloride (prepared by the action of oxalyl chloride on the acid described above), dissolved in 50 ml of dichloromethane, is introduced into a suspension of 0.025 mole of 1,3-difluorobenzene and 0.026 mole of aluminum trichloride in 10 ml of dichloromethane. When the gaseous evolution has ceased, the mixture is hydrolyzed with ice, settling is allowed to take place and the product is extracted with 1 N hydrochloric acid. The aqueous phase is then alkalinized and extracted with dichloromethane. After evaporation of the solvent, the expected product is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:13]([N+:26]([O-:28])=[O:27])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].CO.O.[OH-].[Li+].Cl>C1COCC1.[Cl-].[Na+].O.O>[CH3:25][C@H:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)=[CH:12][C:13]=1[N+:26]([O-:28])=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC[C@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1[N+](=O)[O-]
Yield: 91.8 %

Procedure:
Ester 41a (1.679 g, 4.36 mmol) was dissolved in 10 ml of THF, and with vigorous stirring methanol (40 ml) was added, followed by water (approximately 10 ml) until the solution remained milky white. To this suspension was added lithium hydroxide monohydrate (1.83 g, 43.6 mmol). The reaction mixture was refluxed overnight and was then acidified with concentrated HCl. Brine was added, the reaction mixture was extracted with ether and the organic layer was washed with brine and dried over MgSO4. Evaporation of the solvent yielded 1.486 g (92%) of a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44])[CH2:31][CH:32]=[CH2:33].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:33]=[CH:32]/[CH2:31][CH2:30][N:34]2[C:42](=[O:43])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]2=[O:44])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]1(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=CCCN1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/CCN3C(=O)c4ccccc4C3=O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 100 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (100 mg, 0.184 mmol) in MeCN (5 mL) in a pressure tube is added 2-but-3-enylisoindole-1,3-dione (41 mg, 0.202 mmol), Pd(OAc)2 (3 mg) and triethylamine (186 mg, 1.84 mmol) then the mixture is heated at 100° C. for 10 h. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 20-40% EtOAc/hexane as eluent to give the title compound: (M+NH4)+=635.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:5].C1C[O:36][CH2:35]C1>>[C:22]([N:19]1[CH2:18][CH2:17][N:16]([C:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:30][CH:29]=[C:28]([O:31][CH3:32])[CH:27]=4)[NH:1][C:35]3=[O:36])[CH2:9][CH2:10]2)=[O:15])[CH2:21][CH2:20]1)(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: COc1ccc(N)c(C(=O)NC[C@H]2CC[C@H](C(=O)N3CCN(C(=O)C(C)C)CC3)CC2)c1
Reactant: C1CCOC1
Product: COc1ccc2[nH]c(=O)n(C[C@H]3CC[C@H](C(=O)N4CCN(C(=O)C(C)C)CC4)CC3)c(=O)c2c1

Procedure:
A solution of 2-amino-N-[trans-4-(4-isobutyryl-piperazine-1-carbonyl)-cyclohexylmethyl]-5-methoxy-benzamide (156 mg, 0.35 mmol) and 1,1-carbonyldiimidazole (130 mg, 0.8 mmol) in THF (4 mL) was irradiated with microwave at 150° C. (250 W) for 20 minutes. The desired product precipitated from the reaction mixture and was filtered. 85 mg of the titled compound were obtained (yield 52%).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[CH3:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH3:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC2=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (0.5 g) and triethylamine (1.0 ml), and 4-methylbenzoyl chloride (0.3 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.