Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([O:17][C@@H:18]([CH2:29][O:30][CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:19]([NH:21][C:22]3[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=3)=[O:20])=[C:11]2[CH:10]=[N:9]1>[Pd].C(O)C>[CH:31]1([O:30][CH2:29][C@H:18]([O:17][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=4)[N:9]=[CH:10][C:11]=23)[C:19]([NH:21][C:22]2[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=2)=[O:20])[CH2:34][CH2:33][CH2:32]1
Reactant: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2ccccc2Cl)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2ccccc2)cn1
Reaction time: 24 h
Yield: 17.1 %

Procedure:
(2S)-2-(1-(2-Chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-cyclobutoxy-N-(5-methylpyrazin-2-yl)propanamide (Example 156) (102 mg, 0.21 mmol) and 10% palladium on carbon (25 mg, 0.02 mmol) in ethanol (20 mL) were stirred under an atmosphere of hydrogen for 16 hours. The suspension was filtered through celite. 10% Palladium on carbon (25 mg, 0.02 mmol) was added and the resulting suspension was stirred under an atmosphere of hydrogen for 24 hours. The reaction mixture was filtered through celite and evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 50% ethyl acetate in isohexane to afford the product (16.0 mg, 16.9%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=1>O1CCCC1>[Br:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([S:15][CH3:14])=[CH:17][CH:18]=2)=[CH2:23])[CH:8]=1
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(SC)cc1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 4.50 mL, 7.20 mmol, 1.2 eq) was added over 20 min to a solution of 1,3-dibromobenzene (0.80 mL, 6.61 mmol, 1.1 eq) in 15 mL of dry tetrahydrofuran at −78° C. and under an inert atmosphere. The white suspension formed and was stirred at −78° C. for 30 min. A solution of 1-(4-methylsulfanyl-phenyl)-ethanone (1 g, 6.01 mmol, 1.0 eq.) in 10 mL of tetrahydrofuran was then added dropwise and the reaction stirred for 1 h. The reaction mixture was examined by LC-MS which showed the complete formation of tertiary alcohol. The solution was quenched with a saturated aqueous solution of ammonium chloride and then water was added. 2N hydrochloric acid was added to adjust the pH=5. The two phases were separated; the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude was dissolved in a mixture of acetic acid/sulfuric acid (10 mL of acetic acid, 0.3 mL of sulfuric acid) and the reaction mixture was stirred for 1 h at room temperature; then it was examined by LC-MS which showed the complete formation of desired product. The solution was quenched with ice and dichloromethane (20 mL) was added. The two phases formed and were separated. The organic layer was washed with a saturated solution of sodium bicarbonate and then brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography eluting with cyclohexane. The desired product was obtained as an orange liquid (1.61 g, Yield: 88% over two steps).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[CH2:18]([N:36]1[C:40](=[O:41])[CH:39]=[CH:38][C:37]1=[O:42])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(O)(C)(C)C>[C:13]([C:9]1[CH:10]=[C:11]([CH:39]2[CH2:38][C:37](=[O:42])[N:36]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:40]2=[O:41])[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]=1[OH:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCCCCCCCCCCCCCCCCN1C(=O)C=CC1=O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCCCCCN1C(=O)CC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 36.9 %

Procedure:
This compound is prepared by the procedure of Example 1 from 2.40 g (0.1 mol) of sodium hydride, 20.63 g (0.1 mol) of 2,6-di-tert-butylphenol, and 34.96 g (0.1 mole) of N-n-octadecylmaleimide in tert-butyl alcohol. The residue is purified by dry-column chromatography (3:1 heptane:ethyl acetate eluent) followed by recrystallization from petroleum ether to give 20.5 g (37%) of a white solid: mp 70°-73° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:6]([C:8]([O:10]CC)=O)[N:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][CH3:27].Cl.O>C(O)CO>[CH3:1][NH:2][C:3]1[S:4][C:5]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:6]([C:8](=[O:10])[NH:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH2:26][CH3:27])[N:7]=1
Reactant: CCN1CCCC1CN
Reactant: CCOC(=O)c1nc(NC)sc1-c1ccncc1
Agent: Cl
Solvent: OCCO
Solvent: O
Product: CCN1CCCC1CNC(=O)c1nc(NC)sc1-c1ccncc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 43.5 %

Procedure:
A mixture of ethyl 2-methylamino-5-(4-pyridyl)-4-thiazolecarboxylate (2.63 g), 2-aminomethyl-1-ethylpyrrolidine (2.6 g) in a mixture of ethyleneglycol (10 ml) and conc. HCl (0.5 ml) was stirred at 80° C. for 6 hours. The reaction mixture was poured into water and the resultant solution was extracted with ethyl acetate. The organic extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on alumina eluting with a mixture of diisopropylether and ethylacetate (1:1) and the fractions containing the desired compound were combined and evaporated in vacuo to give 2-methylamino-5-(4-pyridyl)-4-[(1-ethyl-2-pyrrolidinyl)methylcarbamoyl]thiazole (1.5 g). mp 76°-8° C.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3=[N:18][NH:19][C:20](=[O:21])[C:10]3=[CH:9]2)=[CH:3][CH:2]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3=[N:18][N:19]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:20](=[O:21])[C:10]3=[CH:9]2)=[CH:5][CH:6]=1
Reactant: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-c4ccccc4)cc3)cc1-2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cn(Cc3ccc(-c4ccccc4)cc3)c3ccccc3c-2nn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-Biphenyl-4-ylmethyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one [(Example 8, Step 3), 110 mg, 0.313 mmol] was dissolved in N,N-dimethylformamide (5 mL), cooled to 0° C. and treated with sodium hydride (37.6 mg, 0.939 mmol, 3 equiv). After stirring for 15 minutes, the mixture was warmed to ambient temperature and stirred for an additional 15 minutes. The mixture was cooled to 0° C., treated with benzyl bromide (0.112 mL, 0.939 mmol, 3 equiv) and after 5 minutes, was warmed to ambient temperature over 2 hours and stirred for an additional 14 hours at ambient temperature. The mixture was poured into water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol), providing the titled compound: high resolution mass spectrometry (ES+) m/z 442.1922 [(M+H)+; calculated for C30H24N3O: 442.1914].
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[CH:12][C:13]([C:15]([NH2:17])=[O:16])=[CH:14][C:5]=3[C:4](=O)[O:3]1)[CH:8]=[CH:9][CH:10]=2.[NH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>C(O)C>[C:15]([C:13]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]2=[C:5]([CH:14]=1)[C:4](=[O:3])[N:19]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:2]3=[O:1])(=[O:16])[NH2:17]
Reactant: NC(=O)c1cc2c3c(cccc3c1)C(=O)OC2=O
Reactant: NCCCC(=O)O
Solvent: CCO
Product: NC(=O)c1cc2c3c(cccc3c1)C(=O)N(CCCC(=O)O)C2=O
Temperature: 150 °C

Procedure:
A mixture of 1,3-dioxo-1H,3H-benzo[de]isochromene-5-carboxamide (0.5 mmol), 4-Aminobutyric acid (1.5 mmol) and 4 mL ethanol was heated to 150° C. for 30 minutes in microwave reactor (Biotage, Initiator). The reaction mixture was cooled to room temperature and the cream color precipitate was collected by filtration and washed with ethanol. The final product was dried in vacuum for 24 hours to give desired compound.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][PH3+].CC(C)([O-])C.[K+].[CH:12]([CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=O>C1COCC1>[CH3:2][O:3][CH:4]=[CH:12][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:15]1
Reactant: COC[PH3+]
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=CC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a suspension of methoxymethylphosphonium chloride (5.14 g, 15 mmol) in THF (18 mL) was added potassium tert-butoxide (1.98 g, 15 mmol) at 0° C., and the mixture was stirred at 0° C. for 0.5 hr. A solution of tert-butyl 3-formyl-1-piperidinecarboxylate (2.13 g, 10 mmol) in THF (8 mL) was added dropwise at −20° C., and the resulting mixture was stirred at 0° C. to room temperature overnight. The mixture was partitioned between toluene and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by column chromatography on silica gel (hexane/ethyl acetate=5/1) gave tert-butyl 3-(2-methoxyethenyl)-1-piperidinecarboxylate as a colorless oil (1.16 g, yield; 48%).
Reaction SMILES: N.CO.[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:14](O)=[O:15])[CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][S:20](=[O:25])(=[O:24])[CH2:19]1.C[N:27](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:14]([NH2:27])=[O:15])[CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][S:20](=[O:25])(=[O:24])[CH2:19]1
Reactant: O=C(O)c1cc(Br)cc2c(CC3CCCS(=O)(=O)C3)c[nH]c12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cc(Br)cc2c(CC3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A solution of NH3/MeOH (40 mL) was added to a mixture of 5-bromo-3-((1,1-dioxo-tetrahydro-2H-thiopyran-3-yl)methyl)-1H-indole-7-carboxylic acid (1.30 g, 0.0034 mol), TEA (0.68 g, 0.0067 mol), and TBTU (2.16 g, 0.067 mol) in DCM (30 mL). The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was washed with water and extracted with DCM (2×100 mL). The organic layers were dried, filtered, concentrated under reduced pressure, and purified by chromatography eluting with a mixture of DCM:MeOH (60:1), giving 0.94 g (72.5%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][N:3]=1.[C:11]([NH:14][NH2:15])(=[O:13])[CH3:12].C(O)C>CCCCCC>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=[N:15][NH:14][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(=O)NN
Reactant: CC(=O)c1ccc(C)nc1
Solvent: CCCCCC
Solvent: CCO
Product: CC(=O)NN=C(C)c1ccc(C)nc1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
A mixture of 6.76 gm (0.05 mole) of 2-methyl-5-acetylpyridine, 3.7 gm (0.05 mole) of acetic acid hydrazide and 100 ml of ethanol was refluxed 5 hr. The solution was diluted with Skellysolve B until cloudy. The mixture was cooled to room temperature and then chilled in the freezer. The product was collected, washed ith Skellysolve B and dried to afford 7.93 gm (83%) of the title compound having a melting point of 178.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.C(C1C=C(C=C(C)C=1O)C#[N:18])C>>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:18])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: CCc1cc(C#N)cc(C)c1O
Product: COc1cc(O)ccc1C#N

Procedure:
The title compound is prepared from commercially available 4-hydroxy-2-methoxy-benzaldehyde in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile). LC-MS: tR=0.74 min. 1H NMR (D6-DMSO): δ 3.84 (s, 3H), 6.47 (d, J=8.5 Hz, 1H), 6.54 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 10.60 (s, 1H).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].[F:12][C:13](F)([F:21])S(OC(F)F)(=O)=O>C(#N)C.O>[F:12][CH:13]([O:11][C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Br:3])[F:21]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=S(=O)(OC(F)F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: FC(F)Oc1ccc(Cl)cc1Br
Reaction time: 0.08 h

Procedure:
36 ml of aqueous potassium hydroxide solution (6M) were added to a solution of 3.5 g (16.9 mmol) of 2-bromo-4-chlorophenol in 36 ml of acetonitrile, the mixture was cooled in an ice bath and 6.5 ml (26.9 mmol, 1.6 eq.) of difluoromethyl trifluormethanesulphonate [Angew. Chem. Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670] were added dropwise with vigorous stirring. The reaction mixture was stirred for 5 min and diluted with 200 ml of water. The aqueous phase was extracted twice with in each case 150 ml of diethyl ether. The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The aqueous phase was once more extracted with diethyl ether. The organic phase was dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield of the two combined residues: 3.4 g (80% of theory)
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.[Al]>C1COCC1>[CH:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@@H:2]2[NH:1][C:14](=[O:16])[O:12][C:10]2=[O:11])=[CH:5][CH:6]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Al]
Solvent: C1CCOC1
Product: O=C1N[C@@H](Cc2ccccc2)C(=O)O1
Temperature: 50 °C

Procedure:
A 1 L round bottom was dried in an oven prior to use (oven temp=120 ° C.). The glassware was cooled under an inert nitrogen atmosphere. Phenylalanine (50.0 g, 303 mmol) was added to the flask. Anhydrous THF (600 mL, 0.5 M) was charged to give a suspension of white solid. The mixture was heated to 50° C. and triphosgene (35.9 g, 121 mmol) was added as a solid. The suspension was stirred until the reaction was clear (−30 min). The reaction mixture was concentrated to an oil and then was slowly poured into 3 L of hexanes with rapid stirring to yield a white precipitate. The resulting suspension was capped using aluminum foil and placed in the freezer for a minimum of 3 h. The white precipitate was then filtered via vacuum filtration while maintaining an inert environment. The white solid was rinsed with hexanes (3×20 mL) to give the product. The white solid was collected and dried overnight under vacuum. 1H NMR (500 MHz, CHCl3-d): δ 7.37-7.30 (3 H, m); 7.18 (2 H, d, J=7.21 Hz); 6.23 (1 H, s); 4.53 (1 H, dd, J=8.18, 4.21 Hz); 3.27 (1 H, dd, J=14.14, 4.20 Hz); 3.00 (1 H, dd, J=14.13, 8.17 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30].C(=O)([O-])[O-:32].[K+].[K+].O>CN(C)C=O>[OH:32][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30]
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCO
Temperature: 60 °C
Reaction time: 120 h
Yield: 5.7 %

Procedure:
1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone (37 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare a solution. Potassium carbonate (363 mg) and water (0.1 ml) were added to the solution, and the mixture was stirred at 60° C. for 5 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (2 mg, yield 6%).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[CH3:15][CH:16]([CH3:22])[CH2:17][CH2:18][C:19](Cl)=[O:20].C(N(CC)CC)C>O1CCCC1>[CH3:15][CH:16]([CH3:22])[CH2:17][CH2:18][C:19]([NH:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:20]
Reactant: CC(C)CCC(=O)Cl
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CCC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 37.8 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), 4-methylvaleryl chloride (1.5 g, 5.3 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (23 mL) provided 4-methyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-pentanamide (0.54 g). Mp 145.5-146.0° C.; Anal. Calcd. for C18H23NO2: C, 75.76; H, 8.12; N, 4.91; Found: C, 75.46; H, 8.14; N, 4.92.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[C:22]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[N+:27]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[H][H]>O.[Pt]=O>[NH2:27][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([S:23](=[O:26])(=[O:25])[NH2:24])[C:14]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:31][CH:30]=1)[C:18]([OH:20])=[O:19]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccc(OCc2ccccc2)cc1

Procedure:
A suspension of 4-(4-benzyloxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid (10 g) in water (250 ml) was adjusted to pH 11 by addition of 1N sodium hydroxide. The resulting solution was hydrogenated at room temperature and at 1.1 atmospheres hydrogen pressure after addition of a platinum oxide catalyst (0.4 g). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the 3-amino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid was precipitated by adjusting the filtrate to pH 2.5 by addition of 4N hydrochloric acid. After recrystallization from aqueous ethanol and drying, the compound was obtained with a melting point of 264°-265° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:5](COCC[Si](C)(C)C)[CH:6]=1.Cl.O>CCO>[Br:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[NH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)nc1-c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2nc(Br)c[nH]2)cc1

Procedure:
4-Bromo-2-(4-fluorophenyl)-1-(2-trimethylsilanyl-ethoxymethyl)imidazole (3.4 g; 9 mmol) is dissolved in EtOH (34 ml) and HCl conc. (37%; 34 ml) and heated to 55 C for 1 h. Water is added to the reaction mixture and the aqueous phase extracted three times with ethyl acetate. The combined organic phases are washed with 2N Na2CO3 and saturated NaCl-solution, dried over Na2SO4, filtered and evaporated to dryness to yiled the title compound as colorless crystals (2.1 g, 92%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:29])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22]>C(Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:29])[C:26]=1[O:27][CH3:28])[C:21]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:22]
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1Cl
Reactant: c1ccc2c(c1)NCS2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole was dissolved in chloroform (50 mL), and triethylamine (17.4 mL) and 3,5-dichloro-4-methoxybenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (d).
Reaction SMILES: [CH2:1]1SSO[C:4]([C:8]2[CH:12]=[C:11]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[NH:10][CH:9]=2)([O:5]CC)[O:3][CH2:2]1>C(O)C.[Ni]>[CH2:13]([C:11]1[NH:10][CH:9]=[C:8]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:12]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCC(=O)c1cc(C2(OCC)OCCSSO2)c[nH]1
Agent: [Ni]
Solvent: CCO
Product: CCCCCCCCCCCCCc1cc(C(=O)OCC)c[nH]1
Yield: 88.9 %

Procedure:
A mixture of 3.74 g (9.1 mmol) of ethyl 5-tridecanoyl-pyrrole-3-carboxylate dithioethylene ketal prepared in Sythetic Example 5 and 30 ml of Raney-nickel in 200 ml of ethanol was heated under reflux for 2 hours. After filteration through celite, the separated Raney-nickel was washed well with ethanol. The solvent was removed under reduced pressure, the residue was purified by subjecting it to silica gel column chromatography (eluent: ethyl acetate/hexane=1/7) to obtain 2.60 g (89% yield) of ethyl 5-tridecylpyrrole-3-carboxylate, m.p. 59.5°-60.5° C.
Reaction SMILES: [Br:1][CH:2]1[C:6](=[O:7])[N:5]([C:8]([CH3:17])([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:4]=[C:3]1[CH:18]([CH3:20])[CH3:19].C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:28]([O:7][C:6]1[N:5]([C:8]([CH3:16])([CH3:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:4]=[C:3]([CH:18]([CH3:20])[CH3:19])[C:2]=1[Br:1])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)C1=NN(C(C)(C)Cc2ccccc2)C(=O)C1Br
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1nn(C(C)(C)Cc2ccccc2)c(OC(=O)c2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
4-Bromo-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-5(4H)-one (3.00 g, 8.90 mmol) was dissolved in 39 mL of tetrahydrofuran and cooled with ice to 0° C., and after dropwise addition of 1.80 g (17.8 mmol) of triethylamine and 1.38 g (9.82 mmol) of benzoyl chloride, stirred at room temperature for 3 hours under a nitrogen atmosphere. The reaction was quenched with distilled water, and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel 12 g, ethyl acetate:hexane=1:20) to give 3.34 g of the desired product as a yellow oil.