Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: CC(C)CCCC(N)c1nc(-c2cccc(Br)c2)c[nH]1
Product: CC(C)CCCC(NC1CCCCC1)c1nc(-c2cccc(Br)c2)c[nH]1
Yield: 38 %

Procedure:
This compound is obtained according to an operating method similar to that of Stage 35.3 of Example 35 using as starting amine, 1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-5-methyl-1-hexanamine (obtained in Stage 7.3; 0.8 g; 0.0019 mol) and as ketone, cyclohexanone (0.32 ml; 0.0023 mol). A white-coloured powder is obtained with a yield of 38%. Melting point: 236-238° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH2:20]([O:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)=[O:5])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1cccc(C(=O)O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1cccc(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 130.3 %

Procedure:
A solution of 2-hydroxy-3-isopropylbenzoic acid (5 g, 27.8 mmol) in acetone (40 ml) was treated with K2CO3 (7.67 g, 55.6 mmol) and benzyl bromide (9.98 g; 58.4 mmol). The reaction was stirred at ambient temperature for 60 hours, then evaporated. The residue was partitioned between ethyl acetate/H2O and the organic phase dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl acetate/hexane) to give benzyl 2-benzyloxy-3-isopropylbenzoate (6.52 g, 18.11 mmol, 65%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: [H][H]
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
10% palladium on carbon (150 mg) was added to a stirred suspension of N-(3-nitro-4-methylphenyl)-3-morpholinobenzamide (1.40 g) in ethanol (100 ml) under argon. The argon atmosphere was replaced with hydrogen and the mixture was stirred at ambient temperature for 4 hours. The catalyst was removed by filtration through diatomaceous earth (Celite®) and the residue washed with methylene chloride. The filtrate was evaporated to give a solid which was triturated with ethyl acetate to yield N-(3-amino-4-methylphenyl)-3-morpholinobenzamide (1.02 g); NMR: 2.0 (s, 3H), 3.19 (t, 4H), 3.78 (t, 4H), 4.8 (s, 2H), 6.8 (m, 2H), 7.08 (s, 1H), 7.11 (d, 1H), 7.34 (m, 2H), 7.4 (s, 1H), 9.8 (s, 1H); m/z 312.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][C:5]=2[CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>O.C([BH3-])#N.[Na+].C(O)(=O)C>[CH2:15]([NH:22][CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc2c(c1)CC(=O)CCC2
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (3.6 g), benzylamine (2.5 ml), and acetic acid (27 ml) in water bath was added portionwise sodium cyanoborohydride (0.49 g), and the mixture was stirred at ambient temperature for 5 hours. Additional benzylamine (2.5 ml) and sodium cyanoborohydride (0.10 g) were added to the mixture, and stirring was continued for an additional 2 hours. The reaction mixture was made alkaline (pH>8) with 10% sodium hydroxide (150 ml), and extracted once with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; n-hexane-ethyl acetate; 3:1 to 2:1 to 1:1) to give N-benzyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (4.8 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:14]3[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[Cl:22])[N:10]=[C:11]([S:12][CH3:13])[C:3]=12.[CH3:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][NH:29][CH2:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:25]=1>C(#N)C>[CH3:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][N:29]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]3[N:9]([C:14]4[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[N:10]=[C:11]([S:12][CH3:13])[C:3]=23)[CH2:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:25]=1
Reactant: Cc1ccc(CNCCCO)cc1
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(Cl)c12
Solvent: CC#N
Product: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(N(CCCO)Cc3ccc(C)cc3)c12
Yield: 88.7 %

Procedure:
A mixture of 4-chloro-3-methylsulfanyl-6-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (788 mg, 2 mmol) and 3-(p-methylbenzyl)amino-1-propanol (716 mg, 4 mmol) in 10 ml of acetonitrile was heated at reflux for 4 hours. The mixture was cooled, quenched with water and dilute hydrogen chloride and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and brine, separated, dried and concentrated to give 953 mg of the title compound as an off-white glass form. The material was purified through silica gel column chromatography using chloroform as eluent to give the title compound as a white glass form. 1H NMR (CDCl3): 1.79 (m, 2H), 2.38 (s, 3H), 2.52 (s, 3H), 2.54 (s, 3H), 3.56 (t, 2H), 3.86 (t, 2H), 5.12 (s, 2H), 7.20 (s, 4H), 7.51 (s,2H) ppm. 13C NMR (CDCl3): 16.20, 21.13, 25.53, 29.64, 43.51, 53.88, 58.24, 127.78, 128.77, 129.33, 133.51, 136.18, 137.41, 142.93, 159.13, 164.89 ppm. IR(KBr): 3350, 2935, 1540 cm−1. Anal. calc. for C24H24N5OSCl3: C, 53.69; H, 4.50; N, 13.04; found: C, 53.33, H, 4.44, N, 12.84.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.F[C:25]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[N:26]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[F:31][C:30]1[C:25]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:26][C:27]([F:32])=[CH:28][CH:29]=1
Reactant: Fc1ccc(F)c(F)n1
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4nc(F)ccc4F)cc3n2C)c1
Yield: 71 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (3.12 g, 10.0 mmol), 2,3,6-trifluoropyridine (1.46 g, 11.0 mmol), copper iodide (0.19 g, 1.00 mmol), 1,10-phenanthroline (0.18 g, 1.00 mmol), cesium carbonate (9.77 g, 30.0 mmol) and DMF (50 mL) to obtain the title compound (3.02 g, 71%) as a white solid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:35][CH2:34][CH2:33][CH:32]([NH:36]C(=O)OC(C)(C)C)[CH2:31][CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:35][CH2:34][CH2:33][CH:32]([NH2:36])[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)NC1CCCNCC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCCC(N)CC5)n4)n[nH]c3cn2)cn1
Yield: 47.1 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl azepan-4-ylcarbamate were reacted. The product was deprotected to give 188 as a white solid (47.1% over two steps). 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.55 (s, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.37 (d, J=7.3 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 4.02-3.86 (m, 4H), 3.85-3.75 (m, 1H), 3.75-3.55 (m, 3H), 2.93-2.85 (s, 1H), 2.10-1.93 (m, 2H), 1.89-1.56 (m, 3H), 1.45-1.31 (m, 1H); 2 protons not seen. LC/MS: m/z 389.2 [M+1]
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>O1CCCC1>[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Product: O=C(CCCCl)Nc1ccccc1
Yield: 97.5 %

Procedure:
A solution of 27.9 g (0.30 mole) of aniline in 100 ml of tetrahydrofuran was added dropwise to a solution of 21.2 g (0.15 mole) of 4-chlorobutyryl chloride in 100 ml of tetrahydrofuran. The reaction mixture was stirred mechanically and the temperature maintained between 5° C. and 15° C. throughout the addition. After the final addition, the solution was filtered to remove solid precipitates and the filtrate was concentrated under reduced pressure to yield 28.9 g (100%) of yellow solid. An analytical sample was prepared by recrystallizing the solid from benzene/petroleum ether (30°-60° C.) to give a white solid, mp 64°-66° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[CH:11]1[CH2:15][CH:7]2[CH2:8][NH:9][CH2:10]1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23]>CC(C)=O>[CH2:22]([N:9]1[CH2:8][CH:7]2[CH2:15][CH:11]([C:12]3[C:6]2=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=3)[CH2:10]1)[CH3:23]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CC2CC(C1)c1cc([N+](=O)[O-])ccc12
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (300 mg, 1.47 mmol) (prepared using the procedure detailed in J. Med Chem, 2005, 48, 3474-3477) in 5 ml acetone was added potassium carbonate (609 mg, 4.41 mmol) and then ethyl iodide (423 μl, 5.29 mmol). The solution was allowed to stir overnight. The reaction was evaporated under reduced pressure and partitioned between water and EtOAc. The water layer was extracted with 2×10 ml portions of EtOAc and the combined organics dried over magnesium sulfate, filtered and evaporated. The resulting brown oil was chromatographed on a 12 g Isco column using a gradient of 0-10% methanol in methylene chloride to yield 10-ethyl-4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (280 mg, 82%) as a brown oil. 1H-NMR (CDCl3) δ 8.07 (d, J=8.1 Hz, 1H), 7.96 (s, 1H), 7.24 (d, J=8.1 Hz, 1H), 3.17 (dd, J=5.5, 4.8 Hz, 2H), 2.87 (dd, J=5.5, 4.8 Hz, 2H); 2.40-2.20 (m, 5H), 1.75 (d, J=10.6 Hz), 0.85 (d, J=10.6 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:26])=[N:6][C:7]2[N:8]([CH:18]=[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:20]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])(=O)[NH2:2].CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([C:4]1[C:5]([CH3:26])=[N:6][C:7]2[N:8]([CH:18]=[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:20]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])#[N:2]
Reactant: COC(=O)Cc1cn2c(-c3ccc(Cl)cc3Cl)c(C(N)=O)c(C)nc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1cn2c(-c3ccc(Cl)cc3Cl)c(C#N)c(C)nc2n1
Yield: 79.7 %

Procedure:
To a suspension of methyl 2-(6-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)acetate (766 mg, 1.95 mmol) in CH2Cl2 (20 mL) was added Et3N (592 mg, 5.85 mmol) and trifluoroacetic anhydride (819 mg, 3.90 mmol). The reaction mixture became a dark brown-green solution within 2 min. Satd aq NH4Cl (20 mL) was added after 30 min. The organic layer was washed with 20 mL each of satd aq NaHCO3 and water, followed by drying with MgSO4, filtration, and concentration under reduced pressure. The residue was purified by silica gel chromatography eluting product through a 40 mm i.d. by 150 mm column with 1.5% MeOH in CH2Cl2. Concentration of the fractions containing product gave methyl 2-(6-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)acetate (583 mg, 80%) as a yellow foam.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][CH2:17][CH2:18][N:19](C)[CH3:20])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30].O>C(Cl)Cl>[C:1]1([C:7]2([CH2:16][CH2:17][CH2:18][N:19]([C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30])[CH3:20])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN(C)CCCC1(c2ccccc2)COc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(CCCC1(c2ccccc2)COc2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Yield: 30.4 %

Procedure:
A mixture of 3-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylpropylamine (7.40 g, 26 mmol), anhydrous K2CO3 (14.3 g, 104 mmol), and CH2Cl2 (125 ml) was stirred at 5°. A solution of 2,2,2-trichloroethyl chloroformate (4.3 ml, 32 mmol) in CH2Cl2 (5 ml) was added dropwise over 15 minutes. The reaction mixture was stirred at room temperature for 4 hours. Water was then added to dissolve the inorganic salts and the phases were separated. The organic phase was washed with saturated NaHCO3 and saturated NaCl, dried over Na2SO4, filtered, and evaporated in vacuo to give 7.6 g of a crude oil. This residue was chromatographed by HPLC using CH2Cl2 /hexane (2:1, by volume) as an eluent to yield 3.5 g (30%) of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.[CH:11](O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[NH:9][CH:11]=[N:8][C:6]=2[CH:7]=1
Reactant: O=CO
Reactant: Cc1cc(Br)cc(N)c1N
Product: Cc1cc(Br)cc2nc[nH]c12
Yield: 97 %

Procedure:
A solution of 5-bromo-3-methyl-benzene-1,2-diamine (Maybridge, 3 g; 14.92 mmol) in formic acid (75 mL) was heated at reflux for 16 hours. Reaction mixture was concentrated under vacuum to give a brown oil. It was extracted by EtOAc from a saturated aqueous solution of NaHCO3, dried over MgSO4 and evaporated under vacuum to give the title compound as a pale yellow solid (3.07 g, 97%). 1H NMR (DMSO-d6) δ 12.92-12.34 (bs, 1H), 8.22 (s, 1H), 7.59 (br s, 1H), 7.17 (s, 1H), 3.33 (s, 3H). LC/MS (Method B): 211.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:21][CH3:22])=[C:6]([CH:8]2[C:16](=[O:17])[CH:15]3[CH:10]([CH:11]4[CH2:19][CH2:18][CH:14]3[CH2:13][CH2:12]4)[C:9]2=[O:20])[CH:7]=1.N1CCC[C@H]1C(O)=[O:26].[OH-].[Na+].Cl>C(OCC)(=O)C.[Cu]I>[CH2:21]([C:5]1[CH:4]=[CH:3][C:2]([OH:26])=[CH:7][C:6]=1[CH:8]1[C:9](=[O:20])[CH:10]2[CH:15]([CH:14]3[CH2:18][CH2:19][CH:11]2[CH2:12][CH2:13]3)[C:16]1=[O:17])[CH3:22]
Reactant: CCc1ccc(Br)cc1C1C(=O)C2C3CCC(CC3)C2C1=O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1ccc(O)cc1C1C(=O)C2C3CCC(CC3)C2C1=O
Temperature: 200 °C

Procedure:
To a solution of 2-(5-bromo-2-ethylphenyl)-3a,4,5,6,7,7a-hexahydro-4,7-ethanoindene-1,3-dione (1.01 g, 2.8 mmol), copper (I) iodide (108 mg, 0.57 mmol) and L-proline (33 mg, 0.28 mmol) is added a solution of 1M aqueous sodium hydroxide (8.8 mL, 8.8 mmol), and the mixture is then heated at 200° C. for 150 minutes under microwave irradiation. After cooling to room temperature the mixture is diluted with ethyl acetate and then acidified with 2M hydrochloric acid and filtered through diatomaceous earth (washing with additional ethyl acetate). The aqueous phase is extracted into ethyl acetate (×3) and the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (ethyl acetate/iso-hexane eluant) to afford 2-(2-ethyl-5-hydroxyphenyl)hexahydro-4,7-ethanoindene-1,3-dione.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[CH2:20]([S:22][CH2:23][C:24]([O:28][CH3:29])([CH3:27])[C:25]#[CH:26])[CH3:21]>>[CH2:20]([S:22][CH2:23][C:24]([C:25]1[N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[C:3]2[C:2]([CH:26]=1)=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=2)([O:28][CH3:29])[CH3:27])[CH3:21]
Reactant: C#CC(C)(CSCC)OC
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1I
Product: CCSCC(C)(OC)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the standard Sonagashira procedure as described in General Procedures Example C. The starting material was N-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide (0.34 g, 0.82 mmol) and 4-ethylsulfanyl-3-methoxy-3-methyl-but-1-yne (0.13 g, 0.82 mmol), reacted to yield the title compound as a yellow film.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)O)O)O)O.[CH3:13][C:14]1C=C(Cl)C=[CH:16][C:15]=1OCC(O)=O.CNC.C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.OCC([C@H]([C@@H]([C@@H](CO)O)O)O)=O.O=C[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>S(=O)(=O)(O)O>[CH:5]1[C:7]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:2][CH:3]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cc1cc(Cl)ccc1OCC(=O)O
Agent: CNC
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: c1ccc2ccccc2c1
Temperature: 160 °C
Reaction time: 20 h

Procedure:
A 50 ml autoclave (Microclave reactor from Autoclave Engineers) was charged with 250 mg glucose, 150 mg of one of the catalysts: HY 2.6, HY 6, HY 30, Hbeta 12.5, Hbeta 19, Hbeta 150, and HZSM-5 (purchased from Zeolyst International, USA) and 10 mL solvent (methanol, ethanol, propanol or butanol) and then pressurized with argon (20 bar). The autoclave was heated to 160° C. and the stirring was started at 300 rpm once the temperature reached 150° C. After 20 hours of stirring, the autoclave was quenched with cold water and 50 mg naphthalene (internal standard) added to the reaction mixture and the content thereafter analyzed. Aliquots of the reaction mixtures were subjected to GC-FID analysis (Agilent 6890N instrument, HP-5 capillary column 30.0 m×320 μm×0.25 μm). The reaction mixtures were also analyzed by HPLC with RI detection (Agilent 1200 series, 30 cm Aminex© HPX-87H column, 0.005 M aqueous sulfuric acid solution as eluent at a flow rate of 0.6 ml/min). An Agilent 6850 GC system coupled with an Agilent 5975C mass detector was used for qualitative analysis. Sugar conversions to levulinic acid esters were determined by HPLC. The amounts of unreacted monosaccharides were calculated from their individual HPLC standards. Sucrose inverts to fructose and glucose on the acidic HPLC-column used, and the conversions were calculated from the monosaccharides fructose, glucose and mannose on a carbon-basis. The yield of levulinate esters were calculated from GC results on series of individual levulinate ester standards with naphthalene as internal standard. The results are shown in Tables 3 and 7.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[C:16]([O:20][C:21](=[O:35])[C@H:22]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:24][CH2:25]I)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[C:16]([O:20][C:21](=[O:35])[C@H:22]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:24][CH2:25][N:6]1[C:7](=[O:14])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH3:3])[C:5]1=[O:15])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCI)C(=O)OC(C)(C)C
Reactant: Cn1c(=O)[nH]c(=O)c2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Sodium hydride (0.408 g, 10.2 mmol) was added to a solution of 1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (2.17 g, 12.4 mmol) and 18-crown-6 (0.045 g) in 25 mL of DMF. After stirring at RT for 30 min, (2R)-(t-butyloxycarbonylamino)-5-iodopentanoic acid t-butyl ester (3.60 g, 9.02 mmol) in 15 mL of DMF was added, and the solution was stirred at RT for 30 min, then at 60° C. for 6 h. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and 0.05M aqueous HCl. The organic phase was washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography (hexane/ethyl acetate 3/1˜2/1) to give the title compound (3.81 g, 95% yield): NMR (400 MHz, CDCl3) 1.42 (s, 9H), 1.45 (s, 9H), 1.60-1.88 (m, 4H), 3.60 (s, 3H), 4.08-4.21 (m, 3H), 5.06 (br d, 1H, J=8.1 Hz), 7.19-7.31 (m, 2H), 7.68 (dt, 1H, J=7.84, 1.56 Hz), 8.22 (dd, 1H, J=7.88, 1.52 Hz).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:17])[NH:6][C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=1.[C:20]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:14]([NH:13][C:10]1[N:9]=[CH:8][C:7]([NH:6][C:5]([N:29]2[CH2:30][CH2:31][N:26]([C:22]3[CH:21]=[C:20]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[O:17])=[CH:12][CH:11]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3cccc(-c4ccccc4)c3)CC2)cn1
Yield: 18 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl[6-(acetylamino)pyridin-3-yl]carbamate (301 mg, 0.923 mmol), 1-biphenyl-3-ylpiperazine (200 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 14 hours. To the reaction solution was added water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound (62.6 mg, 18.0%) as solid product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:22])C>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:22])=[CH:11][C:10]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1
Reactant: CC(=O)O
Product: CC(C)(C)c1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 6.985 g 1-benzyloxy-2-tert-butyl-4-methyl-benzene (27 mmol) and 115 g ammoniumcer (IV)-nitrate in 1000 ml acetic acid (50% v/v) was stirred at 90° C. for one hour. After cooling down to RT, the reaction mixture was extracted with AcOEt/heptane 1:9, dried over magnesium sulfate, filtered off and concentrated under vacuo. The residue was purified by flash column chromatography (heptane/AcOEt 95/5 to 90/10) to give 3.48 g of an orange solid. MS (ISP) 269.3 (M+H)+.