Azzindani/Open_Reaction_Data huggingface dataset:
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:33]=[N:32][C:18]3[N:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:20][CH2:21][C:22]([C:24]([O:26]C)=[O:25])=[CH:23][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:33]=[N:32][C:18]3[N:19]([CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:20][CH2:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:17]=3[CH:16]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)OC)CCN3CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Temperature: 90 °C
Yield: 93.7 %

Procedure:
To a solution of methyl 3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylate (720 mg) in THF (25 ml) and methanol (25 ml) was added a 1 N aqueous sodium hydroxide solution (6.4 ml), and the mixture was heated at 90° C. for 3 hours. After cooling to 0° C., water was added thereto, and the mixture was neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was washed with hexane to give 3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylic acid (654 mg) as yellow crystals.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[C:10]([F:22])[CH:9]=[CH:8][CH:7]=2)[CH3:3].CS(O[C@@H](C1OC2C(C(=O)C=1C1C=CC=C(F)C=1)=C(F)C=CC=2)C)(=O)=O.[N-:49]=[N+:50]=[N-].[Na+]>CN(C=O)C>[N:1]([C@@H:2]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[C:10]([F:22])[CH:9]=[CH:8][CH:7]=2)[CH3:3])=[N+:49]=[N-:50]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](N)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Agent: C[C@@H](OS(C)(=O)=O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](N=[N+]=[N-])c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (S)/(R)-1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl methane sulfonate (0.900 g, 2.36 mmol) in DMF (18 ml), sodium azide (0.306 g, 4.72 mmol) is added and heated to 60° C. After 2 h, the reaction mass is quenched with water, extracted with dichloromethane, dried over sodium sulphate and concentrated. The crude product is column chromatographed with ethyl acetate:petroleum ether to afford the title compound as a brown liquid which is used as such in next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[CH:6]=[CH:5]2.[CH3:14]B(O)O.C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:14])[CH:3]=2)[C:8]1=[O:12]
Reactant: Cn1ccc2cc(Br)ccc2c1=O
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2c(=O)n(C)ccc2c1
Yield: 82.5 %

Procedure:
A mixture of 6-bromo-2-methylisoquinolin-1-one (200.0 mg, 0.84 mmol), methylboronic acid (251.0 mg, 4.2 mmol), Pd(PPh3)4 (93.0 mg, 0.08 mmol), K2CO3 (232.0 mg, 1.68 mmol) and H2O (2 drops) in dioxane (10.0 mL) was microwaved at 120° C. for 1 h. Purification by silica gel chromatography (PE:EA=5:1) gave the title compound (120.0 mg, 82.8%) as a light yellow solid. LCMS: 174.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[C:18]1([N:24]2[C:28]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[CH:27][C:26]([CH:34]=O)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH2:34][C:26]2[CH:27]=[C:28]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:25]=2)[CH2:11][CH2:10]1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Product: Cc1ccc(N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)c(C)c1
Yield: 92.2 %

Procedure:
Compound 30 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F-].[K+].[CH:12]1(B(O)O)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C2CC2)cc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a solution of 4-bromobenzaldehyde (94 g) in toluene (470 mL) were added potassium fluoride (95 g), cyclo-propylboronic acid (48 g) and bis(triphenylphosphine)-palladium (II) dichloride (3.6 g) under nitrogen atmosphere. The reaction mixture was stirred at 110° C. for 24 hr under nitrogen atmosphere. The reaction mixture was filtered using Celite. The filtrate was concentrated in vacuo to give the crude title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[NH:31][C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[C:36](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([CH3:36])[C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a mixture of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (100 mg, 0.2 mmol), Cesium carbonate (131 mg, 0.4 mmol) in N,N-dimethylformamide (5 mL) was added CH3I (0.025 mL, 0.4 mmol) at −15° C. The mixture was slowly warmed to room temperature and stirred for about 30 min. The reaction mixture was added 30 mL of water. The solid was collected to give 70 mg of 313. Yield=60%. 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1 H), 7.51-7.46 (m, 1H), 7.11-6.97 (m, 4 H), 6.46 (d, J=8.8 Hz, 1 H), 4.18 (t, J=4.8 Hz, 2 H), 3.85 (d, J=13.6 Hz, 2 H), 3.08 (t, J=4.8 Hz, 2 H), 2.59 (t, J=7.2 Hz, 2 H), 2.26-2.19 (m, 4 H), 1.14 (d, J=6.8 Hz, 6 H). ESI-MS: m/z=509 [M+H+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH:36]([NH2:40])([CH2:38][CH3:39])[CH3:37]>C(Cl)(Cl)Cl.C(N(CC)CC)C.ClCCl>[CH:36]([NH:40][C:28]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[F:23])=[O:34])([CH2:38][CH3:39])[CH3:37]
Reactant: CCC(C)N
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)NC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1F
Yield: 89 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a solution of triphosgene (104 mg) in dichloromethane was then added to the solution. The mixture was heated under reflux for 5 min. Next, sec-butylamine (48 μl) was added to the reaction solution. The mixture was heated under reflux for 10 min. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (8/2) to give 117 mg (yield 89%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]5([CH2:39][CH2:38]5)[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:40]=[CH:41][N:42]=[C:10]12.C(O)(C(F)(F)F)=O>ClCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]5([CH2:38][CH2:39]5)[CH2:26][NH:27][CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:40]=[CH:41][N:42]=[C:10]12
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Nc3ncc4c(=O)n(-c5c(Cl)cccc5Cl)c5nccn5c4n3)ccc2C2(CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2cnc(Nc3ccc4c(c3)CNCC43CC3)nc2n2ccnc2n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 109A (0.12 g, 0.2 mmol) in 3 ml dichloromethane was added excess TFA. The reaction mixture was stirred at room temperature for one hour. The mixture was concentrated and the crude material was dried over high vacuum to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.87-1.27 (m, 4H) 3.18-3.38 (m, 2H) 4.34-4.58 (m, 2H) 6.94 (d, J=8.48 Hz, 1H) 7.13 (d, J=1.70 Hz, 1H) 7.39-8.01 (m, 6H) 8.91-9.45 (m, 3H) 10.88 (s, 1H). MS (ESI+) m/z 504.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23](ON)=[CH:22][CH:21]=1)([O-:19])=[O:18].O>C(O)(=O)C>[CH2:11]([C:10]1[O:15][C:23]2[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][C:22]=2[C:9]=1[C:8](=[O:16])[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=O)CC(=O)c1ccc(O)cc1
Reactant: NOc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Temperature: 115 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
1-(4-hydroxyphenyl)-1,3-heptandione, 697 g, is dissolved in 2532 g acetic acid. O-(4-Nitrophenyl)hydroxylamine, 488 g, is added in portions at ca 20° C. The formed slurry is diluted with 739 g acetic acid and the mixture heated to 115° C. and stirred for 3 h. The dark solution is cooled and 1635 g water is added keeping the temperature at 70-80° C. The temperature is adjusted to 60° C. and seeding crystals are added. When crystallisation has started, the slurry is cooled to 4° C., filtered and washed with 870 g of 67% aqueous acetic acid followed by 580 g water. Drying at reduced pressure at 70° C. gives 736 g 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran. Yield 69%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7]1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:22])=O.N>C(Cl)(Cl)Cl>[Cl:22][C:15]1[C:14]2[C:9](=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C1C=Nc2c(cccc2[N+](=O)[O-])C1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Yield: 75 %

Procedure:
A mixture of 3-ethoxycarbonyl-8-nitro-4-oxo-3,4-dihydro-quinoline (10.2 g) and phosphorous oxychloride (10 ml) was stirred at reflux for 2 hours. The warm reaction mixture was added cautiously to a vigorously stirred mixture of ice, concentrated aqueous ammonia and chloroform. The organic layer was separated, washed with water, dried and evaporated to dryness. The residue was purified by flash chromatography on silica using chloroform as eluant to give 4-chloro-3-ethoxycarbonyl-8-nitro-quinoline in 75% yield, mp 253-254° C.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[C:13]([CH:29]=2)[O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=2)[C:19]([O:21]C(C)(C)C)=[O:20])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[C:13]([CH:29]=2)[O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=2)[C:19]([OH:21])=[O:20])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCCCCOc1ccc(C(=O)N2CCOCC2)cc1OCc1cccc(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCOc1ccc(C(=O)N2CCOCC2)cc1OCc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of the compound obtained in Example 5 (0.17 g; 0.35 mmol) in dichloromethane (17 ml) is added trifluoroacetic acid (3.4 ml) and the medium is stirred at room temperature for 2 hours. After evaporating to dryness, the residue is crystallized from pentane. The powder is filtered off by suction and dried (0.14 g; 93% yield).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C@H:18]([NH2:22])[C:19]([OH:21])=O)[CH2:13][CH2:12]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH2:32][NH2:33])=[CH:26][CH:25]=1>>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:22][C@@H:18]([CH2:17][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]1)[C:19]([NH:33][CH2:32][CH2:31][NH:30][C:27]1[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=1)=[O:21]
Reactant: NCCNc1ccc(F)cc1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: Clc1nc2ccccc2o1
Product: O=C(NCCNc1ccc(F)cc1)[C@H](CC1CCCCC1)Nc1nc2ccccc2o1

Procedure:
The title compound was prepared from 2-chlorobenzoxazole, L-cyclohexylalanine and N1-(4-fluoro-phenyl)-ethane-1,2-diamine.2HCl using the procedure analogous to that described in example 2. 1H NMR (DMSO-d6, 400 MHz) δ 8.16(m, 2H), 7.30(m, 1H) 7.16(m, 1H), 7.04(m,1H), 6.92(m, 1H), 6.84(m, 2H), 6.50(m, 2H), 4.24 (m, 1H), 3.15(m, 2H), 2.97(m, 2H), 1.55(m, 7H), 1.30(m, 1H), 1.05(m, 3H), 0.83(m, 2H). HPLC-MS calcd. for C24H29FN4O2 (M+H+)424.23, found 425.5.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]5[NH:39][C:38](=[O:40])[O:37][N:36]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=[C:16]3[CH3:44])=[CH:11][CH:10]=2)[CH2:4][C:3]1([CH3:46])[CH3:45].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:45][C:3]1([CH3:46])[C:2](=[O:1])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]5[NH:39][C:38](=[O:40])[O:37][N:36]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=[C:16]3[CH3:44])=[CH:11][CH:10]=2)[CH2:4]1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCC(O)C(C)(C)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC(=O)C(C)(C)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of 3-{4-[(4-hydroxy-3,3-dimethylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.33 g) in methylene chloride (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.34 g), and the mixture was stirred for 1 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.20 g, 61%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24].Cl>O1CCCC1.C(OCC)(=O)C>[C:23]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COC(=O)CCCc1ccccc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCc1ccccc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Methyl 4-(2-aminophenyl)butanoate hydrochloride (7.20 g, 0.037 mol) synthesized by a known method by documents (Synthetic communications, 26(18), 3443 (1996)) and triethylamine (5.06 g, 0.05 mol) were dissolved in tetrahydrofuran (60 ml). Acetyl chloride (3.51 g, 0.045 mol) was added dropwise to the mixture, which was stirred at room temperature for 30 minutes. Ethyl acetate and 1N hydrochloric acid were added to the reaction mixture, and extraction was conducted. The organic layer was washed with water, concentrated and dried. A mixed solution of ethyl acetate-n-hexane (1:1) was added to the residue. The crystallized product was collected by filtration, to give methyl 4-(2-acetylaminophenyl)butanoate (6.40 g) as a white powder.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:38][C:39]([F:47])([F:46])[CH2:40][CH2:41][S:42](Cl)(=[O:44])=[O:43].O>ClCCl>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][S:42]([CH2:41][CH2:40][C:39]([F:47])([F:46])[F:38])(=[O:44])=[O:43])=[CH:20][CH:21]=2)[C:14]([CH3:15])=[C:10]([C:8](=[O:9])[NH:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxylic piperidin-1-ylamide, from Ex 2, Step 1, (0.89 g, 2.00 mmol) was dissolved in dichloromethane (20 ml), cooled to 0° C. and triethylamine (0.35 ml, 2.4 mmol) added followed by 3,3,3-trifluoropropanesulfonyl chloride (prepared by an analogous method to that described in WO00/010968 for the butyl homologue) (0.35 ml, 2.40 mmol). The reaction mixture was stirred at room temperature overnight. TLC showed remaining starting material and so another portion of triethylamine and 3,3,3-trifluoropropanesulfonyl chloride was added and the reaction mixture stirred for additional 2 hrs. Water was added and the product was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. Flash chromatography (hexane:EtOAc 1:3-EtOAc) followed by recrystallization (hexane:EtOAc) afforded 700 mg (59%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:16])C)[CH:5]=[CH:4][C:3]1=2.Cl[O-].[Na+].[OH-:21].[Na+]>O1CCOCC1>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([OH:16])=[O:21])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: [OH-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21

Procedure:
A mixture of 3.8 g (16.5 mmol) of 5,5,8,8-tetramethyl-2-acetyl-5,6,7,8-tetrahydronaphthalene from the preceding Example 3, 70 ml of 5.25% aqueous sodium hypochlorite (49 mmol), 25 ml of aqueous 2N NaOH and 30 ml of dioxane was heated at 60°-70° C. for 2 hours. The mixture was allowed to cool and the oily organic layer removed. Then the aqueous layer was washed with two portions of ether. The aqueous layer was then treated with sodium metabisulfite solution until the solution was negative to the potassium iodide/starch test. The aqueous layer was then cooled and acidified with H2SO4. The resultant white precipitate was collected by filtration and washed with water. This crude product was further purified by recrystallization from an ethanol/water mixture to give the title compound as a white, crystalline solid.
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13]1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH2:1]([NH:11][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCCO1
Reactant: CCCCCCCCCCN
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCNC(=O)CCCO
Yield: 44.6 %

Procedure:
A mixture of 15 g of decylamine, 5.48 g of gamma butyrolactone, 100 ml of toluene, and 20 mg of zinc chloride was refluxed under nitrogen for 4 days. Upon cooling the reaction mixture formed a precipitate which was recrystallized from toluene to yield 6.91 g (44.6%) of N-decyl-4-hydroxybutyramide, m.p. 74°-75° C.
Reaction SMILES: S(=O)(=O)(O)O.Cl[C:7]1[NH:8][CH2:9][CH2:10][N:11]=1.[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].[OH-].[Na+]>CO.O>[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[N:15]=[C:7]1[NH:8][CH2:9][CH2:10][NH:11]1
Reactant: Nc1ccccc1Cl
Reactant: ClC1=NCCN1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccccc1N=C1NCCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To 2-chloroimidazoline bisulfate (60.0 g, 300 mmoles) in methanol (600 ml) and water (150 ml) is added with stirring 2-chloroaniline (81.1 g, 67 ml, 636 mmoles). The heterogeneous mixture is stirred at ambient temperature overnight. After 20 hours the mixture is poured into ice water, made strongly alkaline with sodium hydroxide and extracted with dichloromethane twice. The organic extracts are washed once with water and once with saturated sodium chloride solution and then extracted with 2 N acetic acid (2×1 liter). The combined acid extracts are backwashed with dichloromethane, made strongly alkaline with sodium hydroxide, and once again extracted with dichloromethane twice. The dichloromethane extracts are combined, washed with water and then sodium chloride solution and finally dried and evaporated in vacuo. The solid residue (31 g) is dissolved in hot toluene, filtered, and diluted with hexane (total volume 3 liters). Colorless crystals separate which are filtered, washed with hexane and air-dried, to give 28.2 g of 2-(2-chlorophenylimino)imidazolidine, m.p. 133°-134° C.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([C:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].C(O)C.[OH-].[K+]>CCOCC>[C:5]([C:9]1[CH:13]=[CH:12][C:11](=[C:2]([CH3:4])[CH3:1])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)=O
Reactant: CC(C)(C)C1=CC=CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)=C1C=CC(C(C)(C)C)=C1

Procedure:
Dry acetone (99.3 mmol, 5.77 g, 7.3 mL) and t-butylcyclopentadiene (50.6 mmol, 6.17 g) were mixed in a dropping funnel and added at room temperature to an ethanol solution (10 mL) of KOH (10.3 mmol, 0.58 g) stirring under nitrogen. After stirring overnight, the golden solution was diluted with ether, washed with 2 N HCl, water, and dried over sodium sulfate. A sample of the crude organic fraction (7.4 g) was taken for analysis (GCMS) showing 90% conversion to the title compound. The product was submitted to distillation. 1H-NMR (CDCl3): δ 1.38 (s, 9H), 2.28 (s, 6H), 6.24 (m, 1H), 6.63 (m, 2H).