Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][N:48]([CH3:64])[C:49]([C:51]1[N:52]=[C:53]([C:60]([F:63])([F:62])[F:61])[N:54]2[CH2:59][CH2:58][NH:57][CH2:56][C:55]=12)=[O:50].C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:57]1[CH2:58][CH2:59][N:54]2[C:53]([C:60]([F:63])([F:61])[F:62])=[N:52][C:51]([C:49]([N:48]([CH3:64])[CH3:47])=[O:50])=[C:55]2[CH2:56]1)=[O:6]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 10.4 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), N,N-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 22c (200 mg, 0.80 mmol) and N,N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-N,N-dimethyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 22 (45 mg, yield 11.0%) as a light yellow solid.
Reaction SMILES: [CH:1]1[CH:2]=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]1[CH:11]3[CH2:16][NH:15][CH2:14][CH:13]([C:6]=1[CH:5]=2)[CH2:12]3.[C:17]([OH:25])(=[O:24])[CH:18]([CH2:20][C:21]([OH:23])=[O:22])[OH:19]>CC(O)C>[CH:2]1[CH:1]=[N:10][C:9]2[C:4]([N:3]=1)=[CH:5][C:6]1[CH:13]3[CH2:14][NH:15][CH2:16][CH:11]([C:7]=1[CH:8]=2)[CH2:12]3.[C:17]([O-:25])(=[O:24])[CH:18]([CH2:20][C:21]([O-:23])=[O:22])[OH:19]
Reactant: O=C(O)CC(O)C(=O)O
Agent: c1cnc2cc3c(cc2n1)C1CNCC3C1
Solvent: CC(C)O
Product: O=C([O-])CC(O)C(=O)[O-]
Temperature: 40 °C

Procedure:
To a solution of Varenicline base (1 g) in 2-propanol (15 mL) at 40° C., malic acid (1.55 g) was added. The resulting suspension was heated at 40° C. for 1 h and allowed to cool to ambient temperature for 5 h. Finally, the solid was filtered and dried at 40° C. under vacuum. HPLC purity: 99.70%; XRD Analysis: Form III.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C:5]([F:23])=[C:6]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[CH2:7][O:8][CH2:9][CH2:10][O:11]C1CCCCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O>[F:23][C:5]1[C:6]([CH2:7][O:8][CH2:9][CH2:10][OH:11])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:4]=1[CH:3]=[O:2]
Reactant: COc1cc(COCCOC2CCCCO2)c(F)c(C(OC)OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c(COCCO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
2-[2-(3-Dimethoxymethyl-2-fluoro-5-methoxybenzyloxy]ethoxy]tetrahydropyran (1.035 g) was dissolved in 10 ml of THF and 3 ml of water, and 1 g of p-toluenesulfonic acid was added thereto. The resulting mixture was stirred at room temperature overnight, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give the title compound (305 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH:28]2[CH2:32][O:31]C(C)(C)[O:29]2)[CH:23]=[CH:22][C:21]=1[F:35])=[O:19]>C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH:28]([OH:29])[CH2:32][OH:31])[CH:23]=[CH:22][C:21]=1[F:35])=[O:19]
Reactant: CC1(C)OCC(COc2ccc(F)c(C(=O)c3ccc(Nc4ccccc4[N+](=O)[O-])cc3Cl)c2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(c1cc(OCC(O)CO)ccc1F)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 519 (46 mg, 0.092 mmol) was dissolved in TFA:H2O (3:1, 10 mL) and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography using DCM/MeOH (v:v=4:1 to 1:4) as the eluent, affording the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]([OH:12])[C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]2[O:11][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:12][C:9]=2[C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)c(O)c(O)c1Cl
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Yield: 28.2 %

Procedure:
2,5-Dichloro-3,4-dihydroxybenzoic acid (1 g, 4.48 mmol) and dichlorodiphenylmethane (2.12 g, 9.96 mmol) are dissolved in toluene (40 ml) and heated to reflux for 24 hours. After cooling the solvent is evaporated and the residue is purified by column chromatography on silic agel (100 g, dichloromethane then 5% methanol in dichloromethane eluant) to yield the acid as white crystals (490 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]([C:19]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20]2)=[O:18])[C@H:14]([C:29]([O:31][CH3:32])=[O:30])[CH2:13]1)(=[O:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[F:39][C:40]([F:45])([F:44])[C@H:41]([OH:43])[CH3:42]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:43][C@@H:41]([CH3:42])[C:40]([F:45])([F:44])[F:39])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]([C:19]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:20][CH2:21]2)=[O:18])[C@H:14]([C:29]([O:31][CH3:32])=[O:30])[CH2:13]1)(=[O:10])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: C[C@@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(O[C@@H](C)C(F)(F)F)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
Under an atmosphere of argon, (2S,4R)-methyl 4-(2-chloro-4-fluorophenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)pyrrolidine-2-carboxylate (200 mg, 331 μmol, Eq: 1.00, [prepared in analogy to General Procedure C, steps C1-C5, using 2-chloro-4-fluorothiophenol in step C2]) and cesium carbonate (194 mg, 595 μmol, Eq: 1.8) were combined with N,N-dimethylacetamide (2 ml) to give a colorless solution. (R)-1,1,1-trifluoropropan-2-ol (90.5 mg, 793 μmol, Eq: 2.4) was added. The reaction mixture was stirred over night at rt. The crude reaction mixture was concentrated in vacuo. The residue was poured into HCl (0.5 M, 5 ml) and extracted with ethyl acetate (5×20 ml). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 40% EtOAc in heptane) to yield the title compound as a white foam (178 mg, 67.1%, MS (m/e)=594.07 [M+H+])
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:14].C(=O)([O-])[O-].[NH4+].[NH4+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:14])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Product: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Nitro-benzenesulfonyl chloride (2.0 g, 9.0 mmol) was dissolved in acetonitrile (20 mL). To this solution was added concentrated aqueous ammonia (20 mL) saturated with ammonium carbonate and the reaction mixture was vigorously stirred for 1 h at room temperature. Then acetonitrile was removed under reduced pressure and the residue diluted with cold water (30 mL) leading to a precipitate formation. The precipitate was filtered out and washed with water (2×15 mL), ether and dried. Yield of 3-nitro-benzenesulfonamide 1.46 g (80%). Beige powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[C:19]3[N:20]([N:24]=[C:25]([NH2:27])[N:26]=3)[CH:21]=[CH:22][N:23]=2)[CH:15]=[N:14]1>>[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[C:19]3[N:20]([N:24]=[C:25]([NH:27][C:2]4[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=4)[N:26]=3)[CH:21]=[CH:22][N:23]=2)[CH:15]=[N:14]1
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Reactant: CC(C)(O)c1ccc(Br)cc1
Product: Cn1cc(-c2nccn3nc(Nc4ccc(C(C)(C)O)cc4)nc23)cn1

Procedure:
2-(4-Bromophenyl)propan-2-ol and 8-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine are reacted under Buchwald Hartwig conditions as described in general procedure 2.
Reaction SMILES: [C@@H:1]1([N:10](C)[C:11](=O)OC(C)(C)C)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[ClH:19]>CO>[ClH:19].[CH3:11][NH:10][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCc2ccccc21
Agent: Cl
Solvent: CO
Product: CN[C@H]1CCc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of tert-butyl(1S)-2,3-dihydro-1H-inden-1-yl(methyl)carbamate (1.84 g, 7.44 mmol) in MeOH (50.0 mL) under an atmosphere of nitrogen was added hydrochloric acid (6.00 mL, 72.4 mmol) and the mixture was stirred overnight. The reaction was concentrated in vacuo to afford the title compound as a white solid without further purification (1.35 g, 99%). LC/MS: Rt=0.85 min, ES+ 148 (AA standard).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:15])[CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[OH:16].[H][H].S(=O)(=O)(O)O>[C].[Pd].[O-2].[O-2].[O-2].[Cr+6].O>[CH2:10]1[C:11]2[C:6](=[C:5]3[C:14](=[CH:13][CH:12]=2)[CH2:1][C:2](=[O:16])[CH2:3][CH2:4]3)[CH2:7][CH2:8][C:9]1=[O:15]
Reactant: [H][H]
Reactant: Oc1ccc2c(ccc3cc(O)ccc32)c1
Agent: [Cr+6]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCc2c(ccc3c2CCC(=O)C3)C1

Procedure:
Phenanthren-2,7-diol was reduced with hydrogen in the presence of a 5% palladium-carbon (wet) catalyst, and then oxidized using a mixture of chromium trioxide, sulfuric acid and water to yield 1,3,4,5,6,8-hexahydrophenanthren-2,7-dione. One of the carbonyl groups of this compound was protected with an ethylene glycol, and the compound was then reacted with propylmagnesium bromide, dehydrated in the presence of an acid catalyst, and the partially deprotected group reformed to yield 7-propyl-3, 4,5,6-tetrahydro-1H-phenanthren-2-one ethylene acetal. This compound was then reduced with hydrogen in the presence of a 5% palladium-carbon (wet) catalyst, and then isomerized using potassium-t-butoxide in DMF to yield trans-7-propyl-3,4,5,6,7,8-tetrahydro-1H-phenanthren-2-one. This compound was reacted in the same manner as that described in Example 17 to Example 22, and yielded the compounds listed below.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.N1CCCC1.ClC1C=C2C(/C(=C/C3C=CC=C(Cl)C=3)/C(=O)N2)=CC=1>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: O=Cc1cccc(Cl)c1
Agent: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Temperature: 65 °C

Procedure:
To the mixture of 6-bromooxindole (16.2 g, 92 mmol) (Combi-block) and 3-chloro-benzaldehyde (12.9 g, 92 mmol) in methanol (109 mL) was added pyrrolidine (6.55 g, 92 mmol) dropwise. The mixture was then heated at 65° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 16.2 g, 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:6]([C:21]([F:24])([F:23])[F:22])[CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl.C(Cl)Cl.CCOC(C)=O>CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:6]([C:21]([F:23])([F:24])[F:22])[CH:5]=1
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3C(F)(F)F)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(-c3ccc(N)cc3C(F)(F)F)sc2c1
Yield: 93 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-(4-nitro-2-trifluoromethylphenyl)-6-methoxybenzothiazole (0.6 g, 1.69 mmol) and tin (II) dichloride dihydrate (3.06 g, 13.56 mmol) in EtOH (35 ml) to give the title compound (0.51 g, 93%) as a colourless solid after work-up and flash chromatography (30:1 DCM/EtOAc).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[N:23]OCC)[CH:20]=4)[NH:15][N:14]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:27][NH:28][C:29](=O)[CH2:30][N:31]([CH3:33])[CH3:32].C[O-].[Na+]>CO>[CH3:32][N:31]([CH2:30][C:29]1[N:23]=[C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:8]=[C:7]([C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:6])[CH:12]=[CH:11][CH:10]=2)[NH:27][N:28]=1)[CH3:33]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NC4CC4)c3)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NC5CC5)c4)c3c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 367 C using N-cyclopropyl(3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)carboxamide.2HCl (377 mg, 0.89 mmol), N-amino-2-(dimethylamino) acetamide (315 mg, 2.69 mmol) and sodium methoxide (515 μL of a 25% w/w in methanol) in anhydrous methanol (5.0 mL) with a reaction time of 24 h. Purification of the residue by flash chromatography on silica gel with 50% methanol in ethyl acetate gave the desired product as a light orange solid. Further purification by preparatory TLC using 50% methanol in ethyl acetate afforded the title compound (145 mg, 40% yield) as an off-white powder. 1H NMR (DMSO-d6) δ 8.8 (br d, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 8.14–8.05 (m, 2H), 7.84 (d, 1H), 7.7–7.6 (m, 2H), 3.55 (s, 2H), 2.92–2.85 (m, 1H), 2.2 (s, 6H); ES-MS (m/z) 402 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Br[C:22]1[C:23]2[C:28]([CH:29]=[C:30]3[C:35]=1[CH:34]=[CH:33][CH:32]=[CH:31]3)=[CH:27][CH:26]=[CH:25][CH:24]=2.C(Cl)Cl>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:24]1([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[C:23]2[C:28](=[CH:29][C:30]3[C:35]([CH:22]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:26][CH:25]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc2c(c1)Cc1ccccc1N2c1cccc2cc3ccccc3cc12
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A mixture of 10.00 g of acridan (55.2 mmol), 247.7 mg of Pd(OAc)2 (1.10 mmol), 178.6 mg of tri-t-butylphosphine (0.88 mmol), 7.95 g of sodium t-butoxide (82.7 mmol), and 15.61 g of 9-bromoanthracene (60.7 mmol) in 100 mL of dry toluene was allowed to stir under inert atmosphere for 1 h. An additional 200 mL of toluene was added to the mixture and stirring was continued at room temperature for 30 min. The reaction mixture was poured into a mixture of 600 mL of CH2Cl2 and 100 g of silica gel. After stirring 15 min, the mixture was filtered, and the solid material was washed with an acditional 600 mL of CH2Cl2. The filtrate was concentrated in vacuo to afford a thick liquid, which was treated with 500 mL of hexanes. After stirring 15 min, the precipitate was collected by filtration, washed with 500 mL of hexanes, and dried. The solid was then triturated in 500 mL of hexanes for 1 h, filtered and dried to afford 14.39 g of N-anthracenylacridan by 1H-NMR analysis. The mother liquor was concentrated to a yellow solid which was trituratec in 300 mL of hexanes for 15 min. The precipitate was collected by filtration, washed with 200 mL of hexanes and dried to afford 5.40 g of solid. 1H-NMR analysis showed the second crop of product was slightly less pure than the first. The two lots were combined to afford 19.79 g of the N-anthracenylacridan (100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12](=O)N(C)C)=[C:7]([Cl:17])[CH:6]=1.C[O-].[Na+].[Br:22][C:23](Br)(C)[CH3:24]>CO>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:24][CH2:23][Br:22])=[C:7]([Cl:17])[CH:6]=1
Reactant: COC(=O)Cc1ccc(SC(=O)N(C)C)c(Cl)c1
Reactant: CC(C)(Br)Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(SCCCBr)c(Cl)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloro-4-dimethylcarbamoylthiophenyl acetic acid methyl ester (10.028 grams; 34.848 mmol) in dry MeOH (90 mL) was treated with a solution of sodium methoxide (4.37 M; 11.16 mL; 48.788 mmol). The reaction was refluxed for 2 hours. The reaction mixture was cooled to 20 ° C. and transferred to a dropping funnel. The dropping funnel was placed atop a flask containing a solution of dibromopropane (14.15 mL; 139.392 mmol) in dry MeOH (50 mL). The contents of the dropping funnel were added to the flask dropwise, and the solution stirred for 2 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The layers were separated and the organic washed once with water. The organic was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography afforded 3-chloro-4-(3-bromopropyl)thiophenyl acetic acid methyl ester.
Reaction SMILES: [Br-].COC(C)([O:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C([Li])CCC.[C:35]1([CH2:41][O:42][C:43]2[CH:44]=[C:45]([CH:48]=[C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH:50]=2)[CH:46]=O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>C1COCC1.O.Cl>[C:53]1([CH2:52][O:51][C:49]2[CH:48]=[C:45]([CH:46]=[CH:9][CH2:8][CH2:7][OH:6])[CH:44]=[C:43]([O:42][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:50]=2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: COC(C)(C)OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: OCCC=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
A stirred suspension of [3-(1-methoxy-1-methylethoxy)propyl](triphenylphosphonium)bromide (4 g) in dry THF (25 ml) at 0° C. was heated with butyl lithium (5.28 ml) and the mixture stirred at 0° C. for 10 min. 3,5-Bis(phenylmethoxy)benzaldehyde (2.24 g) in dry THF (15 ml) was added and the mixture stirred for a further 45 min at room temperature under nitrogen, diluted with ER (100 ml) and filtered through silica (20 g) twice. The filtrate was evaporated in vacuo to give a yellow oil which was dissolved in a mixture of THF (50 ml), water (5 ml) and 2M hydrochloric acid (1 ml) and left at room temperature for 30 min. The mixture was basified with sodium bicarbonate solution and extracted with ER (200 ml). The organic phase was washed with water (150 ml), brine (100 ml), dried and evaporated in vacuo to give a yellow oil. Purification by FCC eluting with ER-CX (3:2) gave a colourless oil (1.48 g). T.l.c. (ER-CX 3:1) Rf 0.26
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[C:8]3[CH:11]=[N:12][CH:13]=[C:7]3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N[CH2:15][C:16]([O-])=[O:17].[K+].C(OC(=O)C)(=O)C>>[C:16]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3=[CH:13][N:12]=[CH:11][C:8]3=[CH:9][C:10]=2[N:1]=1)(=[O:17])[CH3:15]
Reactant: NCC(=O)[O-]
Reactant: C1=NC=C2Cc3cccnc3C=C12
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1ccc2c(n1)C=C1C=NC=C1C2

Procedure:
The pyrrolo[3,4-g]quinoline derivatives of formula (1) and (2) are prepared by reacting a 7-dimethylaminomethylene-6-oxo-trans-quinoline derivative of formula (7a) or (7b) with potassium glycinate, followed by treatment of the thus formed intermediate product with acetic anhydride. This yields a 2-acetylpyrrolo[3,4-g]quinoline compound. The acetyl group is removed by basic hydrolysis, for example using sodium ethoxide in ethanol. Preparation of the pyrrolo[3,4-g]quinolines of formula (1) is illustrated in Reaction Scheme III: ##STR18## The pyrrolo[3,4-g]quinolines of formula (2) are prepared using the same procedures and starting materials of formula (7b).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][O:8][C:9]=1[C:10](O)=[O:11])=[O:4].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:27]>C(Cl)Cl>[F:27][C:10]([C:9]1[O:8][N:7]=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:11]
Reactant: COC(=O)c1c(-c2ccccc2)noc1C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccccc2)noc1C(=O)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4-(methoxycarbonyl)-3-phenylisoxazole-5-carboxylic acid (100 mg, 0.405 mmol) and pyridine (0.039 mL, 0.485 mmol) in DCM (4 mL) at rt was added cyanuric fluoride (0.041 mL, 0.485 mmol) and the reaction mixture was stirred at rt for 2 hr. The reaction mixture was diluted with dichloromethane (20 ml) and washed with ice-cold 0.5N HCl (20 mL). The aqueous layer was extracted with DCM (10 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated to afford methyl 5-(fluorocarbonyl)-3-phenylisoxazole-4-carboxylate (100 mg, 0.401 mmol, 99% yield) as a colorless oil. The compound was found to react readily with methanol and was characterized as the methyl ester. HPLC retention time=1.59 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+H)=262.15 (methyl ester).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=O)[N:6]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH:33][C:10]([C:7]1[N:6]=[C:5]([CH2:4][C:3]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: CCOC(=O)c1noc(Cc2ccc(F)cc2F)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccc(F)cc2F)n1
Yield: 46.5 %

Procedure:
This compound was prepared according to method F with ethyl 5-(2,4-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.116 g; 0.433 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.084 g (47%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,4-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.