Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:32]=[CH:31][C:12]([O:13][CH2:14][C:15]3([CH3:30])[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:21]=4)[O:16]3)=[CH:11][CH:10]=2)[S:3]1>C(O)(=O)C.[Pd]>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:32]=[CH:31][C:12]([O:13][CH2:14][C:15]3([CH3:30])[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:21]=4)[O:16]3)=[CH:11][CH:10]=2)[S:3]1
Reactant: CCOC(=O)c1ccc2c(c1)C=CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(c1)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Yield: 55.5 %

Procedure:
2.1 g of ethyl 2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2-methyl-2H-chromene-6-carboxylate (prepared as described in Example 16) were dissolved in 20 ml of acetic acid and hydrogenated for 20 hours under atmospheric pressure at 80° C. in the presence of 2 g of 10% w/w palladium-on-carbon. The catalyst was then removed by filtration, and the filtrate was freed from the solvent by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to afford 1.17 g of the title compound as a white powder.
Reaction SMILES: [Mg].II.C(I)C.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19]C)=O.[Cl-].[NH4+]>C(OCC)C>[NH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:19]
Reactant: COC(=O)c1ccccc1N
Reactant: Nc1ccccc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCI
Solvent: CCOCC
Product: Nc1ccccc1C(=O)Nc1ccccc1
Reaction time: 0.5 h

Procedure:
9.6 g (0.4 mol) Magnesium, 0.1 g iodine and 180 ml anhydrous (sodium dried) diethyl ether were placed in a 2 liter flask equipped with magnetic stirrer, condenser, dropping funnel containing 62.4 g (0.4 mol) ethyl iodide and drying (CaCl2) tubes. The ethyl iodide was added dropwise slowly until the reaction started. The magnetic stirrer was then started and the remaining ethyl iodide added over a period of about 3/4 hr. It was not found necessary to apply external cooling. Stirring was continued for a further 1/2 hr at ambient temperature to ensure completion of reaction. To the resulting solution 18.6 g (0.2 mol) of aniline were added dropwise over a period of about 1/2 hr. and stirring was again continued at ambient temperature for a further 1/2 hr. To this mixture 15.1 g (0.1 mol) methyl 2-aminobenzoate were added dropwise over a period of about 1/2 hr. The reaction mixture became relatively viscous (a quantity e.g. 80 ml anhydrous diethyl ether can be added to this mixture and the stirring can be supplemented by manual agitation). Stirring, or manual agitation, was continued for about one hour. A saturated aqueous solution of ammonium chloride was then added to quench the reaction, about 300 to 350 ml is usually adequate. This mixture was thoroughly stirred and the aqueous and organic phases were separated. The aqueous phase was washed with fresh diethyl ether (ca 100 ml.) and the ethereal solutions were combined, washed with water and dried over anhydrous magnesium sulphate. The intermediate, 2-amino-N-phenylbenzamide was isolated by evaporating off the ether solvent. This crude 2-amino-N-phenylbenzamide (21 g; 0.1 mol; 99% theory based on methyl 2-aminobenzoate) had a melting point of 95° C. 10.6 g (0.05 mol) of the 2-amino-N-phenylbenzamide and 7.46 g (0.05 mol) of 4-dimethylaminobenzaldehyde were heated under reflux in 100 ml ethanol for 5 hrs. The reaction mixture was allowed to cool and the product slowly crystallised out. The crystals were filtered off to give 13 g (0.038 mol; 76% theory) of a pale yellow solid. The title compound, recrystyallised from methanol, had a melting point of 195° C. The IR and NMR spectra of this purified product were taken, as described above. The compound was also imaged onto CF paper to give an intense yellow-gold colour. The UV-visible reflectance spectrum of this colouration was measured. The results of spectral analysis were as follows:
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N+:10](C1C=C(C=N[C@H](C)C(C2C=C(C(C)(C)C)C=CC=2OCCCC)(C2C=C(C(C)(C)C)C=CC=2OCCCC)O)C(O)=CC=1)([O-])=[O:11].[OH-].[Na+]>O.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1](=[N:10][OH:11])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=Cc1ccccc1O
Reactant: CCCCOc1ccc(C(C)(C)C)cc1C(O)(c1cc(C(C)(C)C)ccc1OCCCC)[C@@H](C)N=Cc1cc([N+](=O)[O-])ccc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: ON=Cc1ccccc1O
Temperature: 80 °C

Procedure:
Optically active Salicylideneaminoalcohol compound were synthesized from optically active aminoalcohols and salicylaldehyde derivatives as in Reference Example 1 To a 100 ml Schlenk, 0.2 mmol of (R)-N-(5-nitrosalicylidene)-2-amino-1,1-di(2-butoxy-5-t-butylphenyl)-1-propanol were added 35.9 mg(0.18 mmol) of copper acetate monohydrate and 50 ml of toluene, and the resulting mixture was reacted for 1 hour under stirring at 80° C. The reaction mixture was cooled to a room temperature, and an aqueous solution of 40 mg of sodium hydroxide dissolved in 30 ml of water was added thereto. The mixture was transferred to a separatory funnel, and was thoroughly stirred, settled and the separated aqueous layer was removed. 10 ml of water was added thereto, stirred again and settled. The oily layer was transferred to a Schlenk tube and azeotropically dehydrated under heating to give the product. The product was diluted with toluene to make a 50 ml toluene solution of the optically active copper complex catalyst mixture.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[C:35]([CH2:36][NH2:37])=[CH:34][C:33]([CH:38]3[CH2:40][CH2:39]3)=[N:32]2)[CH:28]=[CH:29][CH:30]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[C:35]([CH2:36][NH:37][C:15]([NH:14][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][S:10]([CH3:13])(=[O:11])=[O:12])=[C:2]([F:1])[CH:3]=3)=[O:23])=[CH:34][C:33]([CH:38]3[CH2:39][CH2:40]3)=[N:32]2)[CH:28]=[CH:29][CH:30]=1
Reactant: NCc1cc(C2CC2)nn1-c1cccc(Cl)c1
Reactant: CS(=O)(=O)CCc1ccc(NC(=O)Oc2ccccc2)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)CCc1ccc(NC(=O)NCc2cc(C3CC3)nn2-c2cccc(Cl)c2)cc1F
Temperature: 150 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a stirred solution of phenyl 3-fluoro-4-(2-(methylsulfonyl)ethyl)phenylcarbamate (90 mg, 0.267 mmol) and (1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methanamine (70 mg, 0.286 mmol) in THF (4 mL) was added N-ethyldiisopropylamine (0.087 mL, 0.507 mmol) and stirred for 1 h in a microwave (150° C., 7 bar). The reaction mixture was concentrated in vacuo and purified by CC (eluent: ethyl acetate/cyclohexane (2:1)) to give 1-[[2-(3-chlorophenyl)-5-cyclopropyl-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-methylsulfonyl-ethyl)-phenyl]-urea (30 mg, 23%).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][C:7]2[Te:11][C:10]([CH3:12])=[NH+:9][C:8]=2[CH:13]=1.C(=O)(O)[O-].[Na+].C(=O)=O>O>[CH3:2][O:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][C:7]2[Te:11][C:10]([CH3:12])=[N:9][C:8]=2[CH:13]=1
Reactant: COc1cc2[nH+]c(C)[te]c2cc1OC
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Cl-]
Solvent: O
Product: COc1cc2nc(C)[te]c2cc1OC
Yield: 95.2 %

Procedure:
5,6-Dimethoxy-2-methylbenzotellurazolium chloride (Example 12) (10 g) was ground with an equal quantity of sodium bicarbonate and a little water in a mortar until evolution of carbon dioxide ceased. The product was collected by filtration, washed with water and dried in a vacuum to yield ≃8.5 g of colorless powder, m.p. 78°-80° C. Slow crystallization from cyclohexane yielded well defined prisms, m.p. 80°-83° C. The mass spectra and nuclear magnetic resonance spectra were in agreement with that expected for the structural formula.
Reaction SMILES: [N:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][N:12]=3)[C:7](=O)[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C(O)C>[CH:4]1[C:5]2[C:6]3[C:7]([C:8]4[CH:9]=[CH:10][CH:11]=[N:12][C:13]=4[C:14]=2[N:1]=[CH:2][CH:3]=1)=[N:24][C:17]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:23]=3
Reactant: Nc1ccccc1N
Reactant: O=C1C(=O)c2cccnc2-c2ncccc21
Solvent: CCO
Product: c1ccc2nc3c4cccnc4c4ncccc4c3nc2c1
Reaction time: 8 h
Yield: 55.1 %

Procedure:
Into a 200 mL recovery flask were placed 1,10-phenanthroline-5,6-dione (1.09 g, 5.19 mmol) and ethanol (10 mL), and the mixture was stirred to provide a suspension. And then, 1,2-phenylenediamine (0.592 g, 5.20 mmol) and ethanol (40 mL) were added to the suspension, and the mixture was refluxed for 2 hours. After allowing the reaction liquid to stand overnight, an insoluble substance was collected by filtration, and washed with cold ethanol. And then, the product was recrystallized with ethanol, and dipyrido[3,2-a:2′,3′-c]phenazine (Qxphen) (0.808 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.[NH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:11]1[CH2:12][CH:13]=[C:8]([C:5]2[C:4]([NH:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=4[F:25])[N:18]=[C:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:16]=3[CH3:33])=[CH:3][C:2]([N:68]3[CH2:73][CH2:72][O:71][CH2:70][CH2:69]3)=[CH:7][N:6]=2)[CH2:9][CH2:10]1
Reactant: C1COCCN1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1C1=CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1C1=CCOCC1
Temperature: 100 °C
Reaction time: 21.5 h

Procedure:
A mixture of N-(5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine (35.5 mg, 0.07 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (7.1 mg, 0.015 mmol), tris(dibenzylideneacetone)dipalladium (0) (6.9 mg, 7.54 μmol), morpholine (0.05 mL, 0.57 mmol), and sodium tert-butoxide (20.7 mg, 0.215 mmol) in dry toluene (2.0 mL) was degassed by nitrogen. The mixture was heated to 100° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organic layers were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the light orange film was purified by HPLC 10-60% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution. The desired fractions were concentrated then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a white solid as N-(2-(3,6-dihydro-2H-pyran-4-yl)-5-(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. Mass Spectrum (pos.) m/e: 516.3 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:7][CH:6]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][C@@H:32]2[CH2:34][C@H:29]1[CH2:30][NH:31]2)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(C(C)C)CC)(C)C>CC#N>[C:21]([O:25][C:26]([N:28]1[CH2:33][C@@H:32]2[CH2:34][C@H:29]1[CH2:30][N:31]2[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:7][CH:6]=1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: BrCCOc1ccc(Oc2nc3ccccc3s2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2CCOc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a stirred solution of 2-[4-(2-bromo-ethoxy)-phenoxy]-benzothiazole (1.5 g, 4.3 mmol) and (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.0 g, 5.1 mmol) in CH3CN (20 mL) at rt was added diisopropylethylamine ((i-Pr)2NEt) (900 μL, 5.1 mmol). The resulting suspension was stirred at rt for 4 h and then heated for 65 h at 60° C. The solution was cooled to rt and then partitioned between CH2Cl2 (200 mL) and satd. aq. NaHCO3 (80 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 5% CH3OH in CH2Cl2) afforded the title compound as a yellow oil (1.8 g, 92%). MS (ESI): mass calcd. for C25H29N3O4S, 467.19; m/z found, 468.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.75 (d, J=8.0 Hz, 1H), 7.68-7.66 (m, 1H), 7.42-7.38 (m, 1H), 7.31-7.25 (m, 3H), 6.99-6.95 (m, 2H), 4.40 (br s, 0.5H), 4.27 (br s, 0.5H), 4.13-4.03 (m, 2H), 3.66-3.51 (m, 2H), 3.26-2.97 (m, 4H), 2.78 (d, J=9.5 Hz, 0.5H), 2.63 (d, J=9.7 Hz, 0.5H), 1.92-1.85 (m, 1H), 1.79-1.70 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4](=O)[CH2:5][S:6][C:7](=[NH:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1>S(=O)(=O)(O)O>[Cl:2][CH2:3][C:4]1[N:15]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[S:6][CH:5]=1
Reactant: N=C(SCC(=O)CCl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Product: ClCc1csc(-c2ccc(Cl)cc2)n1
Reaction time: 0.5 h

Procedure:
11.95 g (40 mmol) of the 4-chlorothiobenzimidic acid-3-chloroacetonyl ester hydrochloride obtained in (b) were introduced into 40 ml concentrated sulphuric acid at room temperature, with stirring, left to stand at room temperature for 30 minutes and then poured onto ice. The crystallate was drawn off, washed free of acid with water, and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21]CC)=[O:20])[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1ccc2ccnc(NCc3ccc(OC)cc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CNc2nccc3ccc(C(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of ethyl 1-(4-methoxybenzylamino)isoquinoline-7-carboxylate (430 mg, 1.28 mmol) in methanol (8.5 mL) was added 6 N aqueous sodium hydroxide (1.1 mL, 6.4 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated. The residue was taken up in water and acidified with 1 N aqueous hydrochloric acid until a precipitate formed. The solid was collected by filtration and dried under vacuum to give the title compound (328 mg, 83%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ): 8.92 (s, 1H), 8.30 (t, J=5.8 Hz, 1H), 8.06 (dd, J=8.4, 1.4 Hz, 1H), 7.88 (d, J=5.7 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.24-7.31 (m, 2H), 6.88 (d, J=5.7 Hz, 1H), 6.79-6.85 (m, 2H), 4.62 (d, J=5.9 Hz, 2H), 3.67 (s, 3H).
Reaction SMILES: Br[C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.BrC1C=CC(N)=CC=1Cl.FC(F)(F)C1C=CC(B(O)O)=CC=1>>[Cl:10][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[C:8]([Cl:9])[C:2]=1[C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1cc(Cl)c(Br)c(Cl)c1
Agent: Nc1ccc(Br)c(Cl)c1
Agent: OB(O)c1ccc(C(F)(F)F)cc1
Product: Nc1cc(Cl)c(-c2ccc(Cl)cc2)c(Cl)c1

Procedure:
The title compound was prepared as described in Example 159 substituting 4-bromo-3,5-dichloroaniline and (4-chlorophenyl)boronic acid for 4-bromo-3-chloroaniline and (4-(trifluoromethyl)phenyl)boronic acid, respectively.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[C:8]([O:11][C:12](=O)C)(=O)[CH3:9].C(O)(=O)C>C(O)C>[CH2:8]([O:11][CH:12]=[CH:2][C:1]([CH2:4][C:5](=[O:7])[CH3:6])=[O:3])[CH3:9]
Reactant: CC(=O)CC(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC=CC(=O)CC(C)=O
Reaction time: 2.5 h

Procedure:
253 g (2.5 moles) of acetylacetone, 1,110 g (7.5 moles) of orthformic acid triethyl ester and 8 g of acetic anhydride are heated to ebullition in a flask with vigorous stirring. During the reaction, about 23 g of acetic acid is added and the ethanol formed is distilled off. After 2 to 3 hours the reaction is completed. The unreacted orthoformic acid triethyl ester is distilled out at reduced pressure (5 to 1 Torr) through the top of the column and fed back to the next batch. Following this, 355 g of ethoxymethylene acetylacetone is evaporated, separated from the residue through a simple distillation bridge at 0.1 to 0.3 Torr. The yield, referred to acetylacetone, was 91% of theory.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:8]([CH3:12])=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.[Cl:14][C:15]1[CH:21]=[C:20]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH:19]=[CH:18][C:16]=1[NH2:17]>>[Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:8]([CH3:12])=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH:17][C:16]1[CH:18]=[CH:19][C:20]([S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])=[CH:21][C:15]=1[Cl:14])=[O:7]
Reactant: Cc1c(Cl)cc(Br)c(O)c1C(=O)O
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1Cl
Product: Cc1c(Cl)cc(Br)c(O)c1C(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1Cl

Procedure:
3-Bromo-5-chloro-N-(2-chloro-4-trifluoromethanesulfonylphenyl)-2-hydroxy-6-methylbenzamide is synthesized from 3-bromo-5-chloro-2-hydroxy-6-methylbenzoic acid and 2-chloro-4-(trifluoromethanesulfonyl)aniline by General Procedure F.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[I-].[K+].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[N:31]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:21]=[CH:20][C:19]3[O:18][C:17]4[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:15][CH:16]=4)[CH2:11][C:10]=3[CH:9]=2)=[O:7])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1O2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCCN3CCCCC3)ccc1O2
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 30 g. (0.07 mole) of 2,7-bis(5-chlorovaleryl)-xanthene, 2 g of potassium iodide, 100 ml. of piperidine, and 200 ml. of tetrahydrofuran was heated and stirred at 100°C. for 24 hours. After cooling, the tetrahydrofuran was evaporated off and the resulting mixture was poured into water. The resulting solid was filtered off and recrystallized twice from heptane to give the desired product after drying at 80°C. under vacuum. M.P. 129°-130°C.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([CH:9]1[CH2:14][CH2:13][C:12](=O)[C:11](=[CH:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=2)[CH2:10]1)[CH2:7][CH3:8].C(C1CCC(=O)CC1)CC.FC1C=C(C=C(F)C=1F)C=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[CH2:6]([CH:9]1[CH2:14][CH2:13][C:12]2[C:11](=[CH:16][C:17]3[C:22]([CH:1]=2)=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=3)[CH2:10]1)[CH2:7][CH3:8]
Reactant: [Li]CCCC
Reactant: CCCC1CCC(=O)C(=Cc2cc(F)c(F)c(F)c2)C1
Agent: CCCC1CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=Cc1cc(F)c(F)c(F)c1
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCc2cc3c(F)c(F)c(F)cc3cc2C1
Reaction time: 4 h

Procedure:
A mixture of 5 mmol of methyltriphenylphosphonium bromide and 5 mmol of butyllithium in 25 ml of tetrahydrofuran which has been reacted to completion at 0° C. was treated over the course of 10 minutes with a solution of 4.5 mmol of 4-propyl-2-(3,4,5-trifluorobenzylidene)cyclohexanone [prepared from 4-propyl-cyclohexanone and 3,4,5-trifluorobenzaldehyde analogously to Walton, J. Org. Chem. 22, 1161 (1957)] in 5 ml of tetrahydrofuran. After 4 hours at room temperature, 50 ml of water were added, the mixture was extracted twice with 25 ml of tert-butyl methyl ether each time, the extract was washed with water and evaporated in a rotary evaporator, and the residue was chromatographed over silica gel with heptane. The resultant crude product [(Z2) from Scheme 1 with R1=propyl, L2=L3=F, X═F) was dissolved in 1 l of benzene and irradiated with a 450 W UV lamp with cooling in a circulation apparatus. After 8 hours, the reaction solution was evaporated in a rotary evaporator, and the residue was chromatographed over silica gel with heptane/ethyl acetate 9:1. Recrystallization from acetonitrile gave colorless crystals.
Reaction SMILES: [C:1]1([C@@H:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:13][C@H:11]([C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)[CH3:12])=[CH:40][CH:41]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cccc2ccccc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc4ccccc34)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(naphthalen-1-yl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 553 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][C@H:10]1[N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][C:23]([N:44]1[CH2:48][CH2:47][C@@H:46]([NH:49][C:50]([N:52]3CCN(C)CC3)=[O:51])[CH2:45]1)=[N:24][C:25]=2[NH:29][CH2:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:38]1([CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:30][NH:29][C:25]2[N:24]=[C:23]([N:44]3[CH2:48][CH2:47][C@@H:46]([NH:49][C:50]([NH:52][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=4)=[O:51])[CH2:45]3)[N:22]=[C:21]3[C:26]=2[N:27]=[CH:28][N:20]3[C@@H:10]2[CH2:11][C@H:12]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[C@@H:13]([OH:14])[C@H:9]2[OH:8])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Nc1ccccn1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N5CCN(C)CC5)C4)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5ccccn5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to 4-methyl-piperazine-1-carboxylic acid {(R)-1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-amide trifluoro acetate (Example 77) by replacing 1-methyl piperazine with 2-amino pyridine.