Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].CS(C)=O.Br.Br.[NH2:9][CH2:10][CH2:11][CH2:12][S:13][C:14](=[NH:16])N.ClC1[N:23]2[CH:24]=[CH:25]N=[C:22]2[CH:21]=[CH:20][CH:19]=1>O>[NH2:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[N:16]2[CH:25]=[CH:24][N:23]=[C:22]2[CH:21]=[CH:20][CH:19]=1
Reactant: Clc1cccc2nccn12
Reactant: N=C(N)SCCCN
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: NCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
To a mixed solution of 10% (w/w) potassium hydroxide (69.3 g, 105 mmoles) and dimethylsulfoxide (50 ml) was added S-(3-aminopropyl)isothiourea dihydrobromide (8.85 g, 39 mmoles) and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added 5-chloroimidazo[1,2-a]pyridine (3.05 g, 20 mmoles), followed by stirring at room temperature and additionally at 65° C. for 20 hours. Water was added to the reaction mixture, which was extracted with chloroform, washed with 1N sodium hydroxide several times and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to obtain 2.66 g of the desired product (64.3%, pale yellow oily product).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH2:27])[CH:21]=1>>[ClH:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][S:16]([C:14]2[O:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH:21]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)o2)c(C)[nH]c1=O
Reactant: NCc1cccnc1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3cccnc3)o2)c(C)[nH]c1=O
Product: Cl
Yield: 10 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-sulfonyl chloride is reacted with (pyridin-3-yl)methylamine as described in Steps 5 and 6, Example 24 to give the title compound as a solid (10% yield). LC/MS: RT 2.05 min; m/e 374 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[N:17]=[N:18][C:19]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][CH:23]=3)[CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:40]>O1CCOCC1>[ClH:40].[ClH:40].[CH2:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[CH:21]=[C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:17]=[N:18][C:19]=2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:27][CH:26]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCCCc1nnc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nnc(OCC2CCNCC2)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-[5-(4-Benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (0.47 mmol, 250 mg) was dissolved in 4.0 M HCl in dioxane and stirred for 45 min at room temperature. The solvent was evaporated and the resultant solid was washed with ether and dried to provide 4-(4-benzyloxy-phenyl)-3-butyl-6-(piperidin-4-ylmethoxy)-pyridazine dihydrochloride.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17])/[CH2:3][OH:4].[C:18]([O:21][C@@H:22]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:26]([O:32][C:33](=[O:35])[CH3:34])[C@@H:25]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[O:24][C@@H:23]1Br)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([O:21][C@@H:22]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:26]([O:32][C:33](=[O:35])[CH3:34])[C@@H:25]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[O:24][C@H:23]1[O:4][CH2:3]/[C:2](/[CH3:1])=[CH:5]/[CH2:6][N:7]1[C:8](=[O:17])[C:9]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:10]2[C:11]1=[O:12])(=[O:20])[CH3:19]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C/C(=C\CN1C(=O)c2ccccc2C1=O)CO
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](OC/C(C)=C/CN2C(=O)c3ccccc3C2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The general procedure of glucuronide formation of R. B. Conrow and S. Bernstein, 1971, supra, was followed. A mixture of 11 g (0.048 mol) of E-2-methyl-4-phthalimidobut-2-enol (mp 104°-105°, J. Corse and J. Kuhnle, Synthesis 618-619 (1972) and 17.2 g of CdCO3 (Johnson and Matthey, Seabrook, N. H.) in 1200 mL of toluene was dried by distilling about 200 mL of toluene from the flask (stirring). A solution of 39.7 g (0.1 mol) of 2,3,4,6-tetra-O-acetyl-α-glucopyranosyl bromide (acetobromoglucose) in 200 mL of dry toluene was added to the stirred, refluxing mixture over 1 h. The hot mixture was filtered through a Celite pad and the toluene was removed in vacuo from the filtrate. The resulting tan gum (46 g) contained the desired product, starting alcohol and its acetate. Purification was simplified by acetylating the entire mixture with 50 mL of acetic anhydride, 135 mL of pyridine and 1 g of 4-dimethylaminopyridine (steam bath, 1/2 h). The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate and the solution washed with H2O, dilute HCl, KHCO3 solution and H2O. After drying and removal of the solvent, 29.8 g remained, which was divided into 4 portions and chromatographed on silica (J. T. Baker, flash chromatography grade, 40 μm, 50 cm×4 cm column, hexane:ethyl acetate (65:35); yield 14.36 g (53.3%); mp 118°-120°; 1H NMR identical to that reported by C. C. Duke et al., Australian Journal of Chemistry 31: 1291-1301 (1978).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13]O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I.N1C=CN=C1>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13][I:34])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: II
Reactant: COc1cccc2c(CCO)coc12
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc2c(CCI)coc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(7-methoxy-1-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. The reaction mixture was extracted with chloroform, washed well with 5% Na2S2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide, was obtained as brown liquid. Yield: 1.3 g (86%); 302 (M+H).
Reaction SMILES: C(O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:12]([CH2:24][CH3:25])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:14]=1)[CH3:11].[C:26]([O:29][C:30](=[O:32])[CH3:31])(=O)[CH3:27]>CO>[CH2:20]([N:19]([CH2:22][CH3:23])[C:15]1[CH:14]=[C:13]([N:12]([CH2:10][CH3:11])[CH2:24][CH3:25])[CH:18]=[CH:17][C:16]=1[C:26]1([C:5]2[CH:4]=[CH:3][C:2]([N:12]([CH3:13])[CH3:10])=[CH:7][CH:6]=2)[C:27]2[C:31](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:30](=[O:32])[O:29]1)[CH3:21]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccccc1
Solvent: CO
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3ccccc32)c(N(CC)CC)c1
Temperature: 52 °C

Procedure:
A mixture of 2-(4-dimethylamino)benzoyl)benzoic acid (8.07 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (7.26 g.) and acetic anhydride (5 ml.) was heated (at 52° C.) during one and one-half hours. Addition of methanol (10 ml., then 15 ml.) afforded 3-(2,4-bis(diethylamino)phenyl)-3-(4-(dimethylamino)phenyl)phthalide (I: X=(CH3CH2)2N, Y2 =Z4 =Z5 =Z6 =Z7 =H, Y4 =CH3)2N) (10.92 g., m.p. 117°-119° C.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[C:14]([N+]([O-])=O)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.O>CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:8][C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1Oc1cc(Br)cnc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 2-methylpyridin-3-ol (11.8 g, 108 mmol) in DMF at 0° C. was added sodium hydride (60% dispersion in oil, 4.32 g, 108 mmol) in small portions and the reaction was warmed to ambient temperature. 5-Bromo-3-nitropicolinonitrile (24.6 g, 108 mmol) was added and the reaction was stirred overnight at ambient temperature. The reaction was poured into water (1000 mL) and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated in vacuo to yield 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g, 48%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9](I)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([C:16]1[CH:17]=[C:18]([CH:26]([OH:29])[C:27]#[CH:28])[CH:19]=[C:20]([Cl:25])[C:21]=1[N:22]([CH3:24])[CH3:23])([CH3:15])([CH3:14])[CH3:13]>[Cu](I)I.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>[C:12]([C:16]1[CH:17]=[C:18]([CH:26]([OH:29])[C:27]#[C:28][C:9]2[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([OH:1])[CH:10]=2)[CH:19]=[C:20]([Cl:25])[C:21]=1[N:22]([CH3:23])[CH3:24])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(O)c1ccc(I)cc1O
Reactant: C#CC(O)c1cc(Cl)c(N(C)C)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CN(C)c1c(Cl)cc(C(O)C#Cc2ccc(C(=O)O)c(O)c2)cc1C(C)(C)C
Yield: 42 %

Procedure:
In a manner analogous to example 1 f, the process is carried out by a reaction of 220 mg (0.83 mmol) of 2-hydroxy-4-iodobenzoic acid with 320 mg (1.2 mmol) of 1-(3-tert-butyl-5-chloro-4-dimethylaminophenyl)prop-2-yn-1-ol in the presence of 9 mg (0.05 mmol) of copper iodide and 17 mg (0.025 mmol) of bis(triphenyl-phosphine)palladium chloride. 140 mg of 4-[3-(3-tert-butyl-5-chloro-4-dimethylaminophenyl)-3-hydroxyprop-1-ynyl]-2-hydroxybenzoic acid are obtained in the form of a yellowish oil (Mp=175° C., yield=42%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A151) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(=O)(=O)(O)O.[C:19](=O)(O)[O-].[Na+].[CH3:24][OH:25]>>[CH3:24][O:25][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH3:19])=[O:12])[C:2]=1[F:1]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccc(C(=O)O)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1cccc(C(=O)OC)c1F
Yield: 95 %

Procedure:
430 g (2.34 mol) of 2-fluoroisophthalic acid was dissolved in 4.3 l of methanol; sulfuric acid with catalytic amount was dropped; and then the resultant solution was refluxed and stirred. 860 ml of a saturated sodium bicarbonate aqueous solution was added to the finished reaction mixture, and then distilled under reduced pressure with methanol. 860 ml of distilled water was added and then stirred for 1 hour at a room temperature. A resulting solid was filtered, washed with water, and then dried to obtain 471 g of dimethyl-2-fluoroisophthalate in a white solid phase.
Reaction SMILES: C1(N2C3C(=CC=CC=3)C(CCCN3CCC(C4C=C(NC(=O)C(C)C)C=CC=4)CC3)=C2C2C=CC=CC=2)C=CC=CC=1.[CH3:43][CH:44]([CH3:71])[C:45]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH:54]2[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][CH2:62][C:63](=O)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:56][CH2:55]2)[CH:49]=1)=[O:46].[NH:72]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][N:75]=1)[NH2:73]>>[CH3:43][CH:44]([CH3:71])[C:45]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH:54]2[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][CH2:62]/[C:63](/[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[N:73]\[NH:72][C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][N:75]=3)[CH2:56][CH2:55]2)[CH:49]=1)=[O:46]
Reactant: NNc1ccccn1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Agent: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC/C(=N\Nc3ccccn3)c3ccccc3)CC2)c1
Yield: 23.2 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide (8.70 mg, 0.0223 mmol) and 2-hydrazinopyridine (2.92 mg, 0.0268 mmol) provided 2-methyl-N-(3-{1-[(4E)-4-phenyl-4-(2-pyridinylhydrazono)butyl]-4-piperidinyl}phenyl)propanamide (2.5 mg, 24%). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 1H, J=8.6 Hz), 7.85 (d, 1H, J=7.3 Hz), 7.64-7.27 (m, 9H), 7.09 (d, 1H, J=8.0 Hz), 6.97 (d, 1H, J=8.4 Hz), 6.73 (q, 1H, J=6.6 Hz), 3.52-3.48 (m, 2H), 3.20-3.10 (m, 2H), 2.85-1.75 (m, 13H), 1.26 (d, 6H, J=6.8 Hz); ESMS m/e: 484.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]S([O-])(=O)=O)=[C:7]([CH3:14])[N:6]=[C:5]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[CH:17][C:16]=2[CH3:24])[N:4]=1.COC1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1B(O)O.[C:37](=[O:40])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[F:33][C:31]1[CH:30]=[CH:29][C:28]([O:40][CH3:37])=[C:9]([C:8]2[C:3]([O:2][CH3:1])=[N:4][C:5]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[CH:17][C:16]=3[CH3:24])=[N:6][C:7]=2[CH3:14])[CH:32]=1
Reactant: COc1cc(C)cc(C)c1-c1nc(C)c(CS(=O)(=O)[O-])c(OC)n1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1-c1c(C)nc(-c2c(C)cc(C)cc2OC)nc1OC
Temperature: 95 °C

Procedure:
A mixture of 4-methoxy-2-(6-methoxy-2,4-dimethylphenyl)-6-methylpyrimidin-5-ylmethylsulfonate (203 mg, 0.5 mmol), 2-methoxy-4-fluorophenylboronic acid (169 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg, 5 mol %) in toluene (5 mL) and sodium carbonate (1M in water, 2 mL) is heated at 95° C. (oil bath temperature) in a pressure tube for 14 hours. The reaction is cooled to room temperature, diluted with ethyl acetate, washed with NaOH (2M) and then brine (2×50 mL). The solvents are dried (sodium sulfate) and removed under reduced pressure. Flash chromatography of the crude product (50% ethyl acetate in hexanes) yields 4-fluoro-1-methoxy-2-[4-methoxy-2-(6-methoxy-2,4-dimethylphenyl)-6-methylpyrimidin-5-yl]benzene (Compound 7) as an oil. MS: 383. NMR (400 MHz, CDCl3): 2.14 (s, 3H), 2.28 (s, 3H), 2.35 (s, 3H), 3.76 (s, 3H), 3.77 (s, 3H), 3.88 (s, 3H), 6.66 (s, 1H), 6.70 (s, 1H), 6.91-6.98 (m, 2H), 7.04-7.09 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[C:6]([CH3:9])[C:7]=1[F:8].[H][H]>CO.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:9])[C:7]=1[F:8])[NH2:10]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cc(C)c1F
Yield: 99.7 %

Procedure:
In 3 liters of methanol was dissolved 15 g of this 3,5-dimethyl-4-fluoro-1-nitrobenzene, and the resulting solution was treated with nitrogen to replace the air, after which 10 g of palladium carbon was added and catalytic reduction with hydrogen gas was carried out. After completion of the reaction, the insoluble materials were filtered off and the filtrate was concentrated to obtain 12.3 g of 3,5-dimethyl-4-fluoroaniline.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:15][CH:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution prepared by adding 30 g (0.2 mol.) of phthalic anhydride to 122 ml of dried chlorobenzene, was added 64 g (0.48 mol.) of well-ground anhydrous aluminium chloride with stirring. The reaction temperature rose gradually, and the reaction system reached a refluxing condition. The refluxing was continued for 1 hour as the reaction temperature was controlled so that the reaction system refluxed moderately using the ice bath. Then, the reaction product solidified spontaneously. 300 ml of water was added dropwise to the reaction system while cooling by means of an ice bath. The thus produced white precipitate was thoroughly washed with water and cooled ethanol to obtain 45 g of crude crystals. These crude crystals were recrystallized from benzene to obtain the intended compound. Yield 38 g, Melting Point 146° to 148° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[ClH:26].[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:11]=[CH:10][C:9]3[O:8][C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:30][CH2:29]1
Reactant: OC1CCNCC1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: ClCCCCCCBr
Product: Cl
Product: O=c1cc(-c2ccccc2)oc2ccc(OCCCCCCN3CCC(O)CC3)cc12

Procedure:
The compound was prepared by a method similar to Example 1 from 6-hydroxyflavone, 1-bromo-6-chlorohexane and 4-hydroxypiperidine: mp 219°-221° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3(O)[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][C:3]=2[O:2]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a solution of ethyl(1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate (0.29 g, 0.65 mmol) in CH2Cl2 (3 ml) at 0° C. under an argon atmosphere was added triethylsilane (91 mg, 0.78 mmol), followed by boron trifluoride etherate (0.3 ml, 2.4 mmol). The reaction mixture was stirred for 10 min, at which time was added ice-cold 1M HCl, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was placed on a small pad of silica gel, eluting with CH2Cl2 to provide the title compound (257 mg, 92%).
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH3:5].[CH2:6]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH:21]=[CH:22][NH:23]3)[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>C(O)(=O)C.O>[CH3:3][N:4]([CH3:1])[CH2:5][C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[CH:27][C:19]=2[CH:15]2[CH2:16][CH2:17][CH2:18][N:13]([CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:14]2)[NH:23][CH:22]=1
Reactant: c1ccc(CN2CCCC(c3cccc4[nH]ccc34)C2)cc1
Reactant: CNC
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)Cc1c[nH]c2cccc(C3CCCN(Cc4ccccc4)C3)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.5 ml of acetic acid and then 1.4 ml of an aqueous 40% formaldehyde solution were slowly added with stirring at 0° to 5° C. under an inert atmosphere to 2.5 ml of an aqueous 35% dimethylamine solution and then a solution of 5.5 g of 4-(1-benzyl-piperidin-3-yl)-1H-indole in 25 ml of acetic acid was added to the mixture. The mixture was stirred at room temperature for 90 minutes and was then diluted with water. Sodium hydroxide was added to the mixture to make it basic and the mixture was filtered. The recovered product was washed with water, dried under reduced pressure and crystallized from benzene to obtain 3 g of N,N-dimethyl-4-(1-benzyl-piperidin-3-yl)-1H-indole-3-methanamine melting at ≃150° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:35])[C@H:30]([C@@H:32]([CH3:34])[OH:33])[NH2:31])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:35])[CH:30]([NH:31][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=1)[CH:32]([OH:33])[CH3:34])[CH3:27]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1)C(C)O

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.736 g (10 mmol) of L-threonine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38]=[O:39])[CH:34]=[CH:35][CH:36]=1>O1CCCC1>[F:30][C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:39])[NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)Nc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (220 mg, 0.74 mmol) in tetrahydrofuran (5 mL) and triethyl-amine (0.2 mL, 1.48 mmol) was added 3-fluorophenyl isocyanate (0.1 mL, 0.89 mmol) dropwise. The reaction mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-{3-[3-(3-fluoro-phenyl)-ureido]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (67 mg, 20%) as a white solid: LC/MS m/e calcd for C25H24FN3O3 (M+H)+: 434.49, observed: 434.1.