Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:40])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH3:39])[C:36](O)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH4+].O[N:43]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:40])[N:18]([C@H:28]3[CH2:29][CH2:30][C@H:31]([O:34][CH:35]([CH3:39])[C:36]([NH2:43])=[O:37])[CH2:32][CH2:33]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(=O)O)CC2)c2ncnn12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(N)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanoic acid (1.1 g), 1-hydroxybenzotriazole ammonium salt (0.42 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.47 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.8 g, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=3)[O:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([OH:19])=[CH:13][CH:12]=3)[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:44]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([C:20]3[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=3)[O:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([O:19][CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49][O:44]2)=[CH:13][CH:12]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(c2cccc(Br)c2)C(c2ccc(I)cc2)Oc2ccc(O)cc21
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1=C(c2cccc(Br)c2)C(c2ccc(I)cc2)Oc2ccc(OC3CCCCO3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
To a solution of 3-(3-bromophenyl)-2-(4-iodophenyl)-4-methyl-2H-chromen-6-ol (4.95 g, 9.53 mmol) and pyridinium p-toluene sulfonate (480 mg, 1.91 mmol) in DCM (100 mL) was added 3,4-dihydro-2H-pyran (1.3 mL, 14 mmol). The reaction was stirred at room temperature for 4 h, washed (100 mL sat'd aqueous NaHCO3, 50 mL H2O, 50 mL brine), and dried (Na2SO4). The solvent was removed under reduced pressure, and the crude material was purified on a silica gel column to give 3-(3-bromophenyl)-2-(4-iodophenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromene (5.13 g, 89%) as an off-white foam. 1H NMR (DMSO-d6): δ 7.66 (d, 2H), 7.53 (m, 1H), 7.48 (m, 1H), 7.32 (m, 2H), 7.10 (dd, 2H), 7.01 (t, 1H), 6.82 (m, 1H), 6.63 (m, 1H), 6.09 (s, 1H), 5.37 (m, 1H), 3.80 (m, 1H), 3.55 (m, 1H), 2.05 (s, 3H), 1.90-1.66 (m, 3H), 1.66-1.42 (m, 3H).
Reaction SMILES: [O:1]1[C:5](=[O:6])[N:4]=[C:3]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[NH:2]1.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1>N1C=CC=CC=1>[O:1]1[C:5](=[O:6])[N:4]=[C:3]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:9][CH:8]=2)[NH:2]1
Reactant: Nc1ccc(-c2nc(=O)o[nH]2)cc1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)Nc1ccc(-c2nc(=O)o[nH]2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Aniline derivative 16 (0.89 g, 5.0 mmol) was dissolved in pyridine (25 mL). Succinic anhydride (0.75 g, 7.5 mmol) was added together with 4-N,N,-dimethylaminopyridine (63 mg, 0.5 mmol) and the mixture was stirred overnight at 100° C. The solution was concentrated under reduced pressure and the pale brown solid was recrystallized from a mixture of EtOH/MeOH/H2O (60 mL, 5/35/1, v/v/v). After filtration, the mother liquid was concentrated to ˜10 mL to give carboxylic acid 17 as a solid which was dried under vacuum at 50° C. for 16 h. Yield 1.28 g (92%). Rf 0.3 (DCM/MeOH/AcOH, 100/10/1, v/v/v).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[CH:15]=NO)=[C:9]([CH2:19][CH3:20])[CH:8]=1>O>[Br:6][C:7]1[CH:12]=[C:11]2[C:10](=[C:9]([CH2:19][CH3:20])[CH:8]=1)[NH:13][C:14](=[O:18])[C:15]2=[O:2]
Reactant: O=S(=O)(O)O
Reactant: CCc1cc(Br)ccc1NC(=O)C=NO
Solvent: O
Product: CCc1cc(Br)cc2c1NC(=O)C2=O
Temperature: 80 °C
Yield: 74 %

Procedure:
To a solution of sulfuric acid (100 mL) and water (10 mL) at 80° C. (oil bath) was added N-(4-bromo-2-ethyl-phenyl)-2-hydroximino-acetoamide (61.0 g, 225 mmol) in small portions over 20 minutes. The reaction mixture was heated at 80° C. (oil bath) for 15 minutes. After cooling to room temperature, ice-water (500 mL) was added and the mixture was extracted with ethyl acetate. Extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (42.3 g, 74% yield). 1H NMR (DMSO-d6) δ 8.87 (s, 1H), 7.75 (d, 1H), 7.71 (d, 1H), 2.75 (q, 2H), 1.44 (t, 3H).
Reaction SMILES: CCOC(C)=O.[CH3:7][C:8]1[CH:9]=[CH:10][C:11](S(O)(=O)=O)=[CH:12][CH:13]=1.O.[O:19]1C=CC=[N:20]1.[F-].[K+]>O>[O:19]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:7]=[N:20]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1cnoc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc2oncc2c1
Temperature: 40 °C

Procedure:
To a 100 L cylindrical vessel with heating coils were charged EtOAc (20 L) and TsOH/H2O (2.304 kg, 12.11 mol), and the mixture was heated to 35-45° C. to dissolve. The acid solution was fed into the isoxazole batch with further distilling, maintaining a constant volume of 25 L. An additional 20 L of EtOAc was distilled to azeotropically dry the mixture. A slurry began to form, and it continued to thicken on addition and concentration. The final KF was 400 ppm water. The batch was heated to 60° C. and allowed to slowly cool to ambient temperature overnight.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:15][N:16]([CH:20]1[CH2:22][CH2:21]1)[C:17](Cl)=[O:18].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH3:15][N:16]([CH:20]1[CH2:22][CH2:21]1)[C:17](=[O:18])[O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:7][CH:8]=1
Reactant: CN(C(=O)Cl)C1CC1
Reactant: COC(COc1ccc(O)cc1)OC
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: COC(COc1ccc(OC(=O)N(C)C2CC2)cc1)OC
Temperature: 80 °C

Procedure:
4-(2,2-Dimethoxyethoxy)phenol (0.05 mole), N-methyl-N-cyclopropylcarbamoyl chloride (0.08 mole), triethylamine (0.05 mole) and xylene (50 ml) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture is stirred and heated at 80° C. for a period of about 12 hours. After this time the reaction mixture is cooled to room temperature and is filtered. The filtrate is then washed with water and dried over anhydrous magnesium sulfate. The dried solution is then filtered and stripped of solvent and unreacted starting materials to yield the desired product O-[4-(2,2-dimethoxyethoxy)phenyl] N-methyl-N-cyclopropylcarbamate as the residue.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]([F:41])([F:40])[C:6]([NH:8][CH:9]1[CH2:38][C:13]2=[CH:14][N:15]([S:20]([C:23]3[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][C:26]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:24]=3[CH:35]([CH3:37])[CH3:36])(=[O:22])=[O:21])[C:16]3[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=32)[C:10]1=[O:39])=[O:7]>C1COCC1>[OH:39][C:10]1([CH3:1])[C:11]2[C:12]3[C:13](=[CH:14][N:15]([S:20]([C:23]4[C:24]([CH:35]([CH3:37])[CH3:36])=[CH:25][C:26]([CH:32]([CH3:33])[CH3:34])=[CH:27][C:28]=4[CH:29]([CH3:30])[CH3:31])(=[O:21])=[O:22])[C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH2:38][CH:9]1[NH:8][C:6](=[O:7])[C:5]([F:4])([F:40])[F:41]
Reactant: C[Mg]Br
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)n2cc3c4c(cccc42)C(=O)C(NC(=O)C(F)(F)F)C3)c(C(C)C)c1
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)n2cc3c4c(cccc42)C(C)(O)C(NC(=O)C(F)(F)F)C3)c(C(C)C)c1
Yield: 84 %

Procedure:
Methyl magnesium bromide (1M THF solution 8 equivalents) was allowed to react with a solution of 3,4-dihydro-4-trifluoroacetylamino-1-(2,4,6-triisopropylphenylsulfonyl)-5H-benz[cd]indol-5-one (1.5 g, 1.43 mmol) in THF (14.3 ml). The reaction mixture was processed in a conventional manner. The residue was subjected to silica gel column chromatography, eluting with n-hexane-ethyl acetate (4:1) to afford 1.3 g (84%) of the title compound as an amorphous crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].Cl>C(O)C>[CH3:8][CH:7]([CH3:9])[C@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:10]([N:12]1[CH2:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][NH:45]3)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)[nH]2)ccc1-4)C(C)C
Agent: Cl
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3)[nH]2)ccc1-4)C(C)C

Procedure:
Tert-butyl (2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (200 mg, 0.262 mmol) was treated with 2 mL 1.25N HCl in ethanol and heated at 60° C. for 2h, then it was concentrated under reduced pressure and pumped dry under high vacuum and used directly in the next step.
Reaction SMILES: [NH2:1][CH:2]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24].[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]=O)[CH:45]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+].CCOC(C)=O>[Si:27]([O:26][CH2:25][CH:2]([NH:1][CH2:50][C:46]1[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=1)[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24])([C:40]([CH3:43])([CH3:42])[CH3:41])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COc1ccc2c(=O)n(CC(N)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(C#N)c(-c3ccccc3)c2c1
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(=O)n(CC(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)NCc3cccnc3)c(C#N)c(-c3ccccc3)c2c1
Reaction time: 8 h

Procedure:
To a solution of amine 94 (51 mg, 0.075 mmol) in dichloroethane (2 mL) was added pyridine 3-carboxaldehyde (0.017 mL, 180 mmol). After stirring at RT for 15 min NaBH(OAc)3 (48 mg, 0.23 mmol) was added. After stirring overnight, added 1.2 equiv aldehyde and 1.5 equiv NaBH(OAc)3. After stirring for 5 h, the reaction mixture was diluted with NaHCO3/EtOAc and stirred for 10 min. It was then partitioned between EtOAc and NaHCO3. The organic phase was washed once with brine then dried (Na2SO4) and concentrated. The product was purified by automated flash chromatography (70-100% EtOAc/hexane).
Reaction SMILES: C/[C:2](/[OH:27])=[CH:3]\[CH2:4][C:5]1[C:6]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:7][C:8]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[N:9][C:10]=1[CH:11]([CH3:13])[CH3:12].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:6]2[C:5](/[CH:4]=[CH:3]/[CH:2]=[O:27])=[C:10]([CH:11]([CH3:13])[CH3:12])[N:9]=[C:8]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[N:7]=2)=[CH:25][CH:24]=1
Reactant: C/C(O)=C\Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-amino)pyrimidin-5-yl]propen-1-ol (5.1 g) was added to molecular sieves (1 g) in dichloromethane (50 ml) and stirred for 15 min at room temperature. A solution of pyridinium dichromate (6.07 g) in dichloromethane (20 ml) was added to the above reaction mixture and continued stirring for 5 h at room temperature. After completion of the reaction, the reaction mass was filtered through a column of silica gel (230-400 mesh) and the eluate was distilled under reduced pressure to yield a semi-solid compound, which was crystallized from Hexane : Ethyl acetate (95 : 5 v/v) to yield (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-propenal.
Reaction SMILES: [CH2:1]=O.[C:3]([C:6]1([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1)(=[O:5])[NH2:4]>CN(C)C=O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:17]2[C:6]3([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]3)[C:3](=[O:5])[NH:4][CH2:1]2)=[CH:23][CH:22]=1
Reactant: C=O
Reactant: CCOC(=O)N1CCC(Nc2ccc(F)cc2)(C(N)=O)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1
Reaction time: 48 h

Procedure:
To a solution of 6.9 parts of paraformaldehyde in 100 parts of N,N-dimethylformamide are added portionwise 46.3 parts of ethyl 4-carbamoyl-4-(4-fluorophenylamino)-1-piperidinecarboxylate. The whole is stirred and refluxed for 20 hours. Then 50 parts of the solvent are distilled off (t°: 142°-152° C.). A second portion of 1 part of paraformaldehyde in 50 parts of N,N-dimethylformamide is added and stirring and refluxing is continued for 48 hours. The N,N-dimethylformamide is distilled off to a volume of about 50 parts and the distillate is poured onto water. The water is decanted and the residue is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of benzene and 2,2'-oxybispropane, yielding 17.5 parts of ethyl 1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]decane-8-carboxylate; mp. 153° C.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([NH2:15])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][O:13][CH3:14])[CH:6]=1.Cl>[OH-].[Na+]>[NH2:15][CH:4]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][O:13][CH3:14])[CH:6]=1)[C:3]([OH:16])=[O:2]
Reactant: COCc1cc(C(N)C(=O)OC)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COCc1cc(C(N)C(=O)O)ccc1O
Reaction time: 1 h

Procedure:
(-)-α-Amino-4-hydroxy-3-(methoxymethyl)benzeneacetic acid methyl ester is dissolved in aqueous 1 N sodium hydroxide and the solution is stirred at 40°-50° C. for 1 hour. The solution is acidified with 6 N hydrochloric acid to a pH of 7. Evaporation of the solvent gives the title compound in a 90% overall yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[O:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C(N(CC)CC)C.[Br:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[C:26]=1[C:27](Cl)=[O:28]>C1(C)C=CC=CC=1>[Cl:9][C:6]1[CH:5]=[C:4]([N:10]2[C:14](=[O:15])[N:13]([C:27](=[O:28])[C:26]3[C:25]([Br:24])=[CH:33][CH:32]=[CH:31][C:30]=3[Br:34])[C:12](=[O:16])[O:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: O=c1[nH]c(=O)n(-c2cc(Cl)c(Cl)c(Cl)c2)o1
Reactant: O=C(Cl)c1c(Br)cccc1Br
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(Br)cccc1Br)n1c(=O)on(-c2cc(Cl)c(Cl)c(Cl)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3,4,5-Trichlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Dibromobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3,4,5-trichlorophenyl)-4-(2,6-dibromobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:30][CH2:29][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([C:22]([CH3:28])([CH3:27])[CH2:23][NH:24]5)=[CH:20][CH:19]=4)[C:11]=3[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:31]N(C=O)C.C([O-])([O-])=O.[K+].[K+].CI>CCOC(C)=O>[Cl:2][C:3]1[C:4]([N:9]2[CH2:30][CH2:29][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([C:22]([CH3:27])([CH3:28])[CH2:23][N:24]5[CH3:31])=[CH:20][CH:19]=4)[C:11]=3[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)CNc2cc(Nc3ncnc4c3CN(c3ncccc3Cl)CC4)ccc21
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1CC(C)(C)c2ccc(Nc3ncnc4c3CN(c3ncccc3Cl)CC4)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of [6-(3-chloro-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-amine HCl salt (10 mg), DMF (5 mL), and K2CO3 (50 mg) was added MeI (50 μL). The reaction-mixture was stirred at rt for 5 h, and then diluted with EtOAc (50 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column to give an off-white solid (7 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.125 g, 0.49 mmol) and anhydrous pyridine (40 mL) was warmed with a heat gun to dissolve the solid. The resulting solution was allowed to cool to ambient temperature. A solution of 2-phenoxybenzoyl chloride (0.11 g, 0.47 mmol) in pyridine (5 mL) was added. The reaction mixture was maintained at ambient temperature for 18 hours and then concentrated under vacuum. The resulting solid residue was purified by flash chromatography (silica gel eluting with 9:1 dichloromethane:methanol) to provide 0.12 g of N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxybenzamide as a white solid, m.p. 93-94° C. 1H NMR (500 MHz, DMSO-d6) δ 8.23 (t, J=6.0 Hz, 1H), 8.14 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.54 (dd, J=8.0, 1.5 Hz, 1H), 7.43 (dt, J=8.0, 1.5 Hz, 1H), 7.42 (dt, J=8.0, 1.5 Hz, 1H), 7.30 (t, J=8.0 Hz, 2H), 7.22 (t, J=8.0 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 7.07 (t, J=8.0 Hz, 1H), 6.89 (m, 3H), 6.59 (broad s, 2H), 4.55 (t, J=7.0 Hz, 2H), 3.23 (q, J=6.0 Hz, 2H), 1.81 (quintet, J=7.0 Hz, 2H), 1.47 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 451.2004 (451.2008 calcd for C27H25N5O2).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]([C:9]2[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([NH2:15])[CH:14]=2)[CH:6]=[CH:7][CH:8]=1.CC1(C)[O:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:23][C:22](=O)[O:21]1>>[C:29]([C:28]1[CH:27]=[C:26]([C:24](=[O:25])[CH2:23][C:22]([NH:15][C:13]2[CH:14]=[C:9]([N:5]3[CH:6]=[CH:7][CH:8]=[C:4]3[CH2:3][O:2][CH3:1])[CH:10]=[CH:11][C:12]=2[N+:16]([O-:18])=[O:17])=[O:21])[CH:33]=[CH:32][CH:31]=1)#[N:30]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: COCc1cccn1-c1ccc([N+](=O)[O-])c(N)c1
Product: COCc1cccn1-c1ccc([N+](=O)[O-])c(NC(=O)CC(=O)c2cccc(C#N)c2)c1

Procedure:
The title compound was prepared from 5-(2-methoxymethyl-pyrrol-1-yl)-2-nitro-phenylamine (Example F8) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as a light brown solid (620 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C@H:14]1(O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1.O>[C@@H:14]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1
Reactant: O[C@@H]1CCc2ccccc21
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(O[C@H]2CCc3ccccc32)cc1
Temperature: -30 °C
Reaction time: 23 h
Yield: 67.5 %

Procedure:
Methyl 4-hydroxybenzenepropanoate (4.1 g, 22 mmol) was dissolved in tetrahydrofuran (50 mL) and the mixture was stirred at −30° C. (R)-1-Indanol (98% ee) (3.0 g, 22 mmol), 1,1′-(azodicarbonyl)dipiperidine (5.66 g, 22 mmol) and tributylphosphine (5.6 mL, 22 mmol) were added and the mixture was stirred at −30° C. for 23 hrs. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure and the obtained oil was purified by silica gel chromatography (hexane to hexane/ethyl acetate=10:1) to give the title compound (4.4 g, yield 66%) as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][NH2:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:18][CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21]>C(O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:23]([CH3:24])=[C:19]([F:18])[C:20]([CH3:21])=[N:17]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)C(F)C(C)=O
Reactant: NNc1ccccc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: Cc1nn(-c2ccccc2OCc2ccccc2)c(C)c1F
Yield: 70.6 %

Procedure:
500 mg of 2-benzyloxyphenyl hydrazine hydrochloride and 251 mg of 3-fluoropentane-2,4-dione were added to 12 ml of ethanol, and heated at reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure as it is and purified using silica gel column chromatography (hexane:ethyl acetate=6:1 to 5:1) to yield 417 mg of the title compound.