Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(O)(=O)C.O>[C:1]1([S:7]([CH2:10][C:11]([NH:13][NH:14][C:15](=[O:17])[CH3:16])=[O:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)CS(=O)(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)NNC(=O)CS(=O)(=O)c1ccccc1
Yield: 78 %

Procedure:
To a stirred solution of 1.50 g (7.0 mmol) of benzenesulfonyl-acetic acid hydrazide in 5 mL of acetic acid, 1.44 g (14.0 mmol, 2 eq) of acetic anhydride were added, and the solution was heated at reflux for 1 hour. The reaction mixture was diluted with water, extracted with EtOAc, the organic phase dried over Na2SO4, filtered and evaporated, to afford 1.40 g (78%) of acetic acid N′-(2-benzenesulfonyl-acetyl)-hydrazide as a white solid, MS: 274 (MNH4+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([N:23](C(OC(C)(C)C)=O)[CH3:24])=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:24][NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:16])=[CH:18][N:19]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(C(=O)NC2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above prepared 4-{[6-(tert-butoxycarbonyl-methyl-amino)-pyridine-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (0.495 g, 1.14 mmol) was dissolved in 14 ml of CH2Cl2 and treated with 2.8 ml of trifluoroacetic acid. After stirring for 3 h at ambient temperature, TLC indicated the absence of starting material. Evaporation of all volatiles left 0.704 g of the title compound as trifluoroacetate as light brown amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:25][CH2:26][Cl:27]>O1CCCC1>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:25][CH2:26][Cl:27])[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCN(CCCl)CC1)c1ccc(F)cc1

Procedure:
A mixture of 4-(4-fluorobenzamido)piperidine (2 g; preparation 2), triethylamine (3.75 ml) and 1-bromo-2-chloroethane (1.11 ml) in 150 ml of dry tetrahydrofuran was refluxed overnight, then further triethylamine (3.75 ml) and 1-bromo-2-chloroethane (1.11 ml) were added. The mixture was refluxed for an additional 5 hours, treated again with 3.75 ml of triethylamine and 1.11 ml of 1-bromo-2-chloroethane and refluxed overnight. The reaction mixture was concentrated to a small volume, treated with ethyl acetate (200 ml) and the mixture washed with an aqueous saturated potassium carbonate solution. The organic phase was dried over sodium sulfate and concentrated to dryness. The residue (1.3 g) was crystallized from 10 ml of diethyl ether and dried under vacuum at 50° C., to give 1.06 g of the product, m.p. 220-225° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:14][CH:13]3[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.Cl.[C:23]([OH:29])(=[O:28])[CH2:24][C:25]([OH:27])=[O:26]>C(O)(C)C>[C:23]([OH:29])(=[O:28])[CH2:24][C:25]([OH:27])=[O:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH:10]3[N:15]([CH3:16])[CH:13]([CH2:12][CH2:11]3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CN1C2CCC1CC(O)(c1ccc(F)cc1)C2
Agent: Cl
Agent: O=C(O)CC(=O)O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CN1C2C=C(c3ccc(F)cc3)CC1CC2

Procedure:
The title compound was prepared from 3-(4-fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (4.7 g, 20 mmol), glacial acetic acid (20 mL) and concentrated hydrochloric acid (20 mL). The free base of the title compound was dissolved in isopropanol and malonic acid (1.7 g, 16.3 mmol) was added, after a while the title compound precipitated as powder and was isolated by filtration. Yield 4.6 g (72%), m.p. 122.2-123° C.
Reaction SMILES: [N+](C1C=CC([N:10]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]3[CH2:26][C@@H:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C@H:24]([N:34]([C:36](=[O:53])[N:37]([C:39]4[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:40]=4)[CH3:38])[CH3:35])[CH2:23]3)=[O:21])[CH2:16][CH2:15]2)[C:11](=O)[O-:12])=CC=1)([O-])=O.[CH3:54][NH:55][CH2:56][CH3:57]>C(#N)C.C(OCC)(=O)C>[F:48][C:45]([F:46])([F:47])[C:43]1[CH:44]=[C:39]([N:37]([CH3:38])[C:36]([N:34]([C@H:24]2[C@H:25]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:26][N:22]([C:20]([C@H:17]3[CH2:16][CH2:15][C@H:14]([NH:10][C:11](=[O:12])[N:55]([CH2:56][CH3:57])[CH3:54])[CH2:19][CH2:18]3)=[O:21])[CH2:23]2)[CH3:35])=[O:53])[CH:40]=[C:41]([C:49]([F:50])([F:51])[F:52])[CH:42]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](N(C(=O)[O-])c3ccc([N+](=O)[O-])cc3)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCNC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(C)C(=O)N[C@H]1CC[C@H](C(=O)N2C[C@@H](N(C)C(=O)N(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccc(F)cc3)C2)CC1

Procedure:
A solution of the compound (0.20 g) obtained in Example 261 and N-methylethanamine (0.11 mL) in acetonitrile (2.7 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 80→100% ethyl acetate/hexane) to give the title compound (0.15 g, 83%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1.O>[NH:20]([C:21]([NH:1][C:2]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC1(CC(=O)O)CCCCC1
Reactant: O=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC1(NC(=O)Nc2ccccc2)CCCCC1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 55.7 %

Procedure:
To a solution of (1-aminocyclohexyl)acetic acid (0.232 mg, 1.48 mmol) in a mixture of 1,4-dioxane (9 ml) and water (3 ml) was added 30% aqueous sodium hydroxide solution to pH 9. Phenylisocyanate (0.24 ml, 2.22 mmol) was added dropwise at 35° C. and 30% aqueous sodium hydroxide solution was added to adjust the solution to pH9. The reaction mixture was stirred at 40° C. for 1.5 hrs and concentrated under reduced pressure. 5N Hydrochloric acid was added to acidify the solution (pH3) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried (over anhydrous MgSO4). After concentration under reduced pressure, the precipitated solid was collected by filtration and washed with diisopropyl ether to give the title compound (0.228 g) as a colorless powder with contamination.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]#[N:22]>>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:20]([CH2:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH3:11])[C:21]([NH2:22])=[N:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(F)ccc1C=O
Reactant: COc1ccccc1CCC#N
Product: COc1ccccc1Cc1cc2ccc(F)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4-fluorobenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:3]#[C:2][C:1]([NH2:5])=[O:4])=[CH:23][CH:22]=1)=[O:19]
Reactant: C#CC(N)=O
Reactant: O=C(Nc1ccc(I)cc1)Nc1cc(C(F)(F)F)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C#Cc1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.1 %

Procedure:
To a mixture of propynoic acid amide (41.4 mg, 0.60 mmol), 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(4-iodophenyl)urea (169.7 mg, 0.40 mmol), triethylamine (0.167 mL, 1.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (22.5 mg, 0.032 mmol), and triphenylphosphine (5.2 mg, 0.020 mmol) in 3.0 mL DMF (degassed) was added copper(I)iodide (7.6 mg, 0.04 mmol) and the reaction stirred at rt for 17 hours. The reaction was combined with a prior test reaction (36.5 mg theoretical yield) and partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed 3 times with H2O/brine mixture, then brine, dried with anhydrous Na2SO4 and rotary evaporated to a solid. The solid was chromatographed eluting with EtOAc/CHCl3 and then triturated with EtOAc/hexane to give the title compound as a light tan solid (118.5 mg, 65%). 1H NMR (DSMO-d6) δ: 9.45 (s, 1H), 8.98 (d, J=2.9 Hz, 1H), 8.59 (dd, J=7.3, 2.1 Hz, 1H), 8.07 (br. s, 1H), 7.59 (br. s., 1H), 7.47-7.58 (m, 5H), 7.38-7.45 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2OC2C=CC=CC=2)=[CH:4][CH:3]=1.[NH2:19]C1C2C(=CC(Br)=CC=2)C=CN=1>>[NH2:19][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Nc1nccc2cc(Br)ccc12
Reactant: Brc1ccc2ccnc(Oc3ccccc3)c2c1
Product: Nc1nccc2ccc(Br)cc12

Procedure:
Compound 37d was prepared from 37c using the procedure described for 1d. 1H-NMR 200 MHz (CDCl3) δ: 5.1 (2H, br. s), 7.03 (1H, dd, J=6 Hz and J=1 Hz), 7.59 (1H, d, J=9 Hz), 7.70 (1H, dd, J=9 Hz and J=2 Hz), 7.95-8.00 (2H, m).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][C:19]2[N:20]=[C:21]([OH:30])[C:22]3[N:27]=[C:26]([S:28][CH3:29])[O:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1.[CH2:33](O)[CH2:34][CH3:35].C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][C:19]2[N:20]=[C:21]([O:30][CH2:33][CH2:34][CH3:35])[C:22]3[N:27]=[C:26]([S:28][CH3:29])[O:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1
Reactant: CSc1nc2c(O)nc(Cc3ccc(Cl)cc3)nc2o1
Reactant: CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(SC)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 8.7 mmol of polystyrene-bound triphenylphosphine (Argonaut) and 1.5 g of diethyl azodicarboxylate (DEAD) in 55 ml of tetrahydrofuran was stirred for 15 min at 0° C. Then 2.2 g of 5-(4-chloro-benzyl)-2-methylsulfanyl-oxazolo[5,4-d]pyrimidin-7-ol, 0.65 ml of propan-1-ol and 1 ml of triethylamine were added. The reaction mixture was stirred at room temperature for 3 h. The polymer was filtered off and washed thoroughly with tetrahydrofuran. The solvent was removed in vacuo and the title compound isolated by silica gel chromatography (method SC1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].S(=O)(=O)(O)O.[CH:36](=O)[CH2:37][CH2:38][CH2:39][CH:40]=O>>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:10]2[NH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:1]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:3][CH:4]=3)=[N:12][C:11]=2[C:13]([NH:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[O:14])=[CH:22][CH:23]=1
Reactant: O=CCCCC=O
Reactant: COc1ccc(-c2[nH]c(-c3ccc(N)cc3)nc2C(=O)Nc2nccs2)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(-c2[nH]c(-c3ccc(N4CCCCC4)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
2-(4-Aminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (2.0 g) obtained in Example 48, sodium borohydride (0.8 g), 3N sulfuric acid (4 ml) and 25% glutaraldehyde (4 ml) were treated in the same manner as in Example 62 to give 5-(4-methoxyphenyl)-2-(4-piperidinophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (1.53 g). This was converted to hydrochloride to give 5-(4-methoxyphenyl)-2-(4-piperidinophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide hydrochloride (0.25 g), melting point 250° C. or above.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8]([CH2:11][C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O>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.O1CCOCC1>[CH3:13][C:12]([N+:14]([O-:16])=[O:15])([CH3:17])[CH2:11][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)[C:3]2=[N:10][CH:9]=1
Reactant: OB(O)c1cccs1
Reactant: CC(C)(Cc1cnc2c(Br)cccn12)[N+](=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: [Na+]
Solvent: C1COCCO1
Product: CC(C)(Cc1cnc2c(-c3cccs3)cccn12)[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
A mixture of 8-bromo-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (1.5 g, 5.0 mmol), Pd(PPh3)4 (0.68 g), 2M aqueous sodium carbonate solution (8 ml), and dioxane (68 ml) is stirred for 30 minutes under an atmosphere of argon. After addition of thiophene-2-boronic acid (0.96 g, 7.5 mmol), the mixture is stirred overnight at 80° C. The solids are removed by filtration, and the residue is chromatographed (silica gel, dichloromethane/ethanol 95:5) to give 1.52 g of 3-(2-methyl-2-nitropropyl)-8-(2-thienyl) imidazo[1,2-a]pyridine (100%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]([CH3:17])=[O:16])[CH:11]=[CH:10][C:9]=1Br.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CO.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>[CH3:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]([CH3:17])=[O:16])[CH:11]=[CH:10][C:9]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)Nc1ccc(Br)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(-c2ccccc2)c(C)c1

Procedure:
225 g of sodium carbonate and 0.15 g of PdCl2(PPh3)2 in 450 ml of methanol are heated to reflux temperature. A solution of 342 g of 4-bromo-3-methylacetanilide and 270 g of the ethylene glycol ester of phenylboronic acid in 225 ml of methanol, which has been heated to 50° C., is added dropwise over a period of 60 minutes. During the addition, methanol is distilled off in such an amount that the internal temperature can be kept at at least 85° C. After addition is complete, a further 0.1 g of the Pd catalyst is added and the reaction mixture is refluxed for another 6 hours. After this time, the monitoring of the reaction by HPLC indicates a conversion of 99.9%. The remaining methanol is distilled off as completely as possible (620 ml), with the reaction mixture having to remain stirrable. 1250 ml of chlorobenzene are subsequently added. Hydrolysis is carried out by addition of 85 ml of water. At 70-80° C., the phases are separated and the aqueous phase is discarded. The organic phase is washed once with 50 ml of water and is subsequently filtered through a 0.5 cm thick layer of aluminum oxide. The chlorobenzene is distilled off at 300-500 mbar. The residue of crude 2-methyl-4-acetaminobiphenyl which remains is used further without further purification. The yield is quantitative.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:18]([CH3:22])=[CH:17][CH2:16][C:15]([CH3:24])([CH3:23])[C:14]=3[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:26](=O)[CH3:27]>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:26][CH3:27])[C:12]2[CH:21]=[CH:20][C:19]3[C:18]([CH3:22])=[CH:17][CH2:16][C:15]([CH3:24])([CH3:23])[C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)CC=C3C)cc1
Reactant: CC=O
Product: CCOC(=O)c1ccc(N(CC)c2ccc3c(c2)C(C)(C)CC=C3C)cc1

Procedure:
Following General Procedure M, 4-(5,8,8-trimethyl-7,8-dihydro-naphthalen-2-ylamino)-benzoic acid ethyl ester (Compound 65, 38 mg, 0.11 mmol), was reacted to with acetaldehyde to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:23]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>ClCCl>[O:21]=[C:19]1[NH:18][C:17](=[O:22])[CH:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[C:37]([NH:36][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:35][CH:34]=4)=[O:38])[CH:4]=3)=[CH:14][CH:13]=2)[S:20]1
Reactant: CCCCCCOc1ccc(N=C=O)cc1
Reactant: CNc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCOc1ccc(NC(=O)N(C)c2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1
Yield: 68.6 %

Procedure:
0.67 g (2.14 mmol) of 5-(3′-methylaminobiphenyl-4-ylmethyl)thiazolidine-2,4-dione in 20 ml of dichloromethane is introduced into a 50 ml round-bottomed flask. 1 g (4.3 mmol) of 1-hexyloxy-4-isocyanatobenzene is added and the mixture is heated under reflux for 16 hours. The reaction medium is poured at room temperature over a 1 N HCl solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate. After evaporation of the solvents, the product obtained is purified by chromatography on silica gel (eluent: heptane/ethyl acetate=3/2). 0.78 g (68%) of 1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]-3-(4-hexyloxyphenyl)-1-methylurea is obtained in the form of a white powder having a melting point of 146–148° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH2:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:31])=[N:13][N:12]=1>CN(C=O)C>[Cl:31][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:30])[C:24]=1[CH2:23][C:14]1[C:15]2[C:20](=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][N:13]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Oc3ccccc3)c2c1
Temperature: 25 °C
Yield: 43 %

Procedure:
A suspension of DMF (15 ml), phenol (0.53 g, 5.64 mmoles) and NaH (4.23 mmoles) was stirred under dry N2 at room temperature. After 15 minutes 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.5 g, 1.41 mmoles), prepared as described in example 45, was dropped and the temperature brought to 100° C. After 20 hours the mixture was partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give a residue which was triturated in ethyl ether. The insoluble was flash chromatographed (eluent: hexane/ethyl acetate 7:3) to give a solid which was crystallised from isopropyl ether (15 ml) and yielded 0.25 g of the title compound (yield: 49%). m.p.: 130-132° C.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:9]([OH:11])=O)[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:47]([C:49]1[CH:50]=[C:51]([CH:56]=[C:57]([CH2:60]C)[C:58]=1[OH:59])[C:52]([NH:54]O)=[NH:53])[CH3:48]>C(Cl)Cl>[CH2:47]([C:49]1[CH:50]=[C:51]([C:52]2[N:54]=[C:9]([C:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:6]([CH2:2][CH:3]([CH3:4])[CH3:5])[CH:7]=3)[O:11][N:53]=2)[CH:56]=[C:57]([CH3:60])[C:58]=1[OH:59])[CH3:48]
Reactant: CCc1cc(C(=N)NO)cc(CC)c1O
Reactant: Cc1cc(C(=O)O)cc(CC(C)C)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of 2-isobutyl-6-methyl-isonicotinic acid hydrochloride (2.18 g, 9.53 mmol) and DIPEA (3.69 g, 28.6 mmol) in DCM (10 mL), TBTU (3.67 g, 11.44 mmol) is added. The mixture is stirred for 5 min before 3,5-diethyl-4,N-dihydroxy-benzamidine (1.85 g, 9.53 mmol) is added. The mixture is stirred at rt for 1 h. The mixture is diluted with DCM, washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude 2-isobutyl-6-methyl-isonicotinic acid (3-ethyl-4,N-dihydroxy-5-methyl-benzamidine) ester (LC-MS: tR=0.79 min, [M+1]+=370.06) is dissolved in dioxane (50 mL) and heated to 100° C. for 4 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (1.97 g) as a colourless oil; LC-MS: tR=0.93 min; [M+1]+=352.16; 1H NMR (CDCl3): δ 7.85 (s, 2 H), 7.75 (s, 1 H), 7.70 (s, 1 H), 5.05 (s br, 1H), 2.78 (d, J=7.5 Hz, 2H), 2.74 (q, J=7.5 Hz, 2H), 2.69 (s, 3H), 2.37 8 s, 3H), 2.19 (hept, J=7.5 Hz, 1H), 1.34 (t, J=7.5 Hz, 3H), 1.00 (d, J=6.5 Hz, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])[CH2:5][CH2:4][O:3]1.F[C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[C:24]3[CH:45]=[CH:44][C:43]([O:46]CC4C=CC=CC=4)=[CH:42][C:25]=3[S:26][C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=2)=[O:22])=[CH:17][CH:16]=1>>[O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:23]3[C:24]4[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][C:25]=4[S:26][C:27]=3[C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:32][CH:33]=3)=[O:22])=[CH:17][CH:16]=2)[CH2:5][CH2:4][O:3]1
Reactant: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2cc(OCc3ccccc3)ccc12
Reactant: O=C1OCCN1[C@@H]1CCCC[C@H]1O
Product: O=C(c1ccc(O[C@@H]2CCCC[C@H]2N2CCOC2=O)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2cc(O)ccc12
Yield: 49 %

Procedure:
Using a procedure similar to that described below in Example 19, the title compound was prepared in 49% yield from (±)-trans-2-(2-oxooxazolidin-3-yl)cylohexanol (Part A) and 6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo[b]thiophen-3-yl 4-fluorophenyl ketone (Part B).