Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.Cl.Cl.[CH:27]([CH:40]1[CH2:45][NH:44][CH2:43][CH2:42][N:41]1[CH3:46])([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>CN(C)C=O>[CH:27]([CH:40]1[CH2:45][N:44]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][CH3:15])[CH2:43][CH2:42][N:41]1[CH3:46])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN1CCNCC1C(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1CN1CCN(C)C(C(c2ccccc2)c2ccccc2)C1
Yield: 73.8 %

Procedure:
A 1M solution of sodium triacetoxyborohydride in N,N-dimethylformamide (75 μl) was added portionwise to a mixture of 2-methoxybenzaldehyde (7.5 mg) and a solution of 2-benzhydryl-1-methylpiperazine dihydrochloride (17.0 mg) in N,N-dimethylformamide (50 μl) at 0° C. and the whole was stirred at 0° C. to 5° C. for 1 hour and further at 5° C. to room temperature for 1 hour. The mixture was extracted with aqueous 0.25N sulfuric acid solution and washed with ethyl acetate. The combined solution was applied on solid phase extraction column cartridge (C18, 200 mg) and eluted with water and acetonitrile successively. The eluate was concentrated in vacuo to give 2-benzhydryl-4-(2-methoxybenzyl)-1-methylpiperazine (14.3 mg).
Reaction SMILES: [CH3:1][C@@:2]([S:34]([CH3:37])(=[O:36])=[O:35])([CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[CH:17][C:16]1=[O:33])[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl>CC(O)C>[OH:6][NH:5][C:3](=[O:4])[C@:2]([CH3:1])([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([CH:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:25][CH:26]=2)=[CH:17][C:16]1=[O:33]
Reactant: C[C@@](CCn1ccc(-c2ccc(C3CCOCC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CC(C)O
Product: C[C@@](CCn1ccc(-c2ccc(C3CCOCC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-{2-oxo-4-[4-(tetrahydro-2H-pyran-4-yl)phenyl]pyridin-1(2H)-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (82 mg, 0.15 mmol) in 2-propanol (1.5 mL) was added 1.0 N hydrochloric acid (0.77 mL). The solution was stirred for 1 h. The reaction was concentrated, the residue was triturated with 2-propanol as a white suspension at 50° C. for 30 minutes. A white solid was collected by filtration (75%). LCMS m/z 449.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 1.65-1.74 (m, 4H) 2.11-2.21 (m, 1H) 2.37-2.47 (m, 1H) 2.83 (tt, J=10.40, 5.42 Hz, 1H) 3.11 (s, 3H) 3.39-3.49 (m, 2H) 3.74 (td, J=12.01, 4.69 Hz, 1H) 3.92-3.99 (m, 2H) 4.11 (td, J=11.91, 5.08 Hz, 1H) 6.65 (dd, J=7.03, 2.15 Hz, 1H) 6.69 (d, J=2.15 Hz, 1H) 7.37 (m, 2H) 7.67 (m, 2H) 7.74 (d, J=7.23 Hz, 1H) 9.27 (br. s., 1H) 11.19 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([CH2:26][N:23]4[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]4)=[CH:32][CH:31]=3)=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Product: CN1CCN(Cc2ccc(NC(=O)/C=C/c3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 172 starting from (E)-3-(4′-chloro-biphenyl-4-yl)-acrylic acid and 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine. The crude product was purified by column chromatography (silica gel, dichloromethane/MeOH/conc. aqueous ammonia 90:10:0.1).
Reaction SMILES: [NH2:1][C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:6].CC(C)=O.[C:24](Cl)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>O.[OH-].[Na+]>[C:24]([NH:1][C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:6])(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A suspension of 16 g (0.058 mols) of γ-glutamylglutamic acid in 55 ml of water was dissolved in a 27-% sodium hydroxide aqueous solution until the pH reached 11, and 27 ml of acetone were added thereto. To the solution were added dropwise 12.6 g (0.058 mole) of lauroyl chloride over a period of 1 hour. When adding lauroyl chloride, the temperature was maintained at 10° C., and 27-% sodium hydroxide was added dropwise simultaneously to keep the pH at 11. After the completion of the addition of lauroyl chloride, the reaction solution was warmed at 30° C., and allowed to stand for 30 minutes. Subsequently, the pH was adjusted to 1 with the addition of conc. hydrochloric acid. The solid precipitate was separated by filtration, and dried to obtain 23.6 g of N-(N'-lauroyl-γ-glutamyl)glutamic acid in a yield of 89%. This solid was analyzed by infrared spectrophotometry. A peak diagnostic of an amide group was observed at 1,640 cm-1 and a peak diagnostic of a carboxyl group was observed at 1,730 cm-1, respectively. FAB mass spectrum: 459 (MH+).
Reaction SMILES: [CH2:1]([O:8]C1C(OC)=CC(C(Cl)=O)=CC=1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:24]1CCC[C@H]1CN)C.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(=O)C1C=CC=CC=1.C1(S(O)(=O)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([NH2:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1CCC[C@H]1CN
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NC(=O)c1ccccc1

Procedure:
First, 4-benzyloxy-3,5-dimethoxybenzoic acid chloride represented by Formula 85 and [(2S)-1-ethylpyrrolidin-2-yl]methanamine represented by Formula 103 were prepared in 0.2 M solution, respectively, using a toluene solvent. An amine solution (1.2 mL, 0.240 mmol) entered 10 mL vial and a sodium carbonate solution (0.4 mL, 0.200 mmol) was added thereto. Thereafter, a benzoic acid chloride solution (1.0 mL, 0.200 mmol) entered the vial, vigorously shaken and agitated at room temperature for 18 hours. After terminating the reaction, an organic layer was moved to a cartridge tube (6 mL, benzenesulfonic acid, 904030-WJ, UCT) using ethyl acetate. Impurities were removed using methanol (15 mL) while separation and purification were conducted using an elute solution (ethyl acetate/methanol/triethylamine, 20:2:1, v/v/v), resulting in a benzamide compound represented by Formula 13 as a desired product (VVZ-014; 66 mg, 83% yield).
Reaction SMILES: [C:1]1([NH:7][C:8](N(CC)CC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(O)C>CC1C=CC=CC=1C>[C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)C(=O)Nc1ccccc1
Solvent: CCO
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: O=C=Nc1ccccc1
Temperature: 114 °C

Procedure:
A mixture of 1.95 g (10.1 mmoles) of 1-phenyl-3, 3-diethylurea and 3.24 g, (43.2 mmoles) of pyridine in 100 g of o-xylene was added to a 250 ml round bottom flask fitted with a magnetic stirrer, condenser, and a thermocouple for measuring reaction temperature. A nitrogen atmosphere was maintained over the reaction mixture. The mixture was heated to 114° C. for 60 minutes. A sample was taken from the flask and analyzed by infrared spectroscopy. There was no peak for the NCO band in the spectrum. Another sample was taken and reacted with ethanol. Any phenyl isocyanate that would have been formed would be converted to the carbamate derivative. This sample was then analyzed by high pressure liquid chromatography (HPCL). Only unreacted starting material was observed confirming that no thermal decomposition of the urea to isocyanate occurred.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=O)(C)(C)C.[Br:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[C:34]([F:40])[CH:33]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[NH2:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([Br:31])=[CH:33][C:34]=2[F:40])[CH2:19]1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Br)cc2F)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 4-bromo-2-fluorobenzaldehyde (0.15 mmol), methanol (1.5 mL), and acetic acid (0.016 mL) was added NaBH3CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. The residue was dissolved in methanol (0.25 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature for 5 h and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. The resulting material was dissolved into ethyl acetate (0.5 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5:1 (6 mL), and concentrated to afford (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-bromo-2-fluorobenzyl)pyrrolidine (Compound No. 2120) (16.0 mg, 31%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 517.0 (M++H, C21H21BrF4N4O2).
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:21]([O:25][C:26](=[O:42])[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][S:32][CH:31]([C:35]2[CH:40]=[CH:39][C:38](I)=[CH:37][CH:36]=2)[CH2:30]1)([CH3:24])([CH3:23])[CH3:22].[CH2:43]([OH:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1(C)C=CC=CC=1.[Cu]I.O.CCOC(C)=O>[C:21]([O:25][C:26](=[O:42])[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][S:32][CH:31]([C:35]2[CH:40]=[CH:39][C:38]([O:50][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:37][CH:36]=2)[CH2:30]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCN1CCSC(c2ccc(I)cc2)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)CCN1CCSC(c2ccc(OCc3ccccc3)cc2)C1
Temperature: 100 °C
Yield: 88.1 %

Procedure:
(All solutions were degassed) To a suspension of 1,10-phenanthroline (183.0 mg; 1.02 mmol) in toluene (15 mL) was added CuI (96.7 mg; 0.51 mmol), Cs2CO3 (3.31 g; 10.15 mmol), and a solution of 3-[2-(4-iodo-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butyl ester (2.20 g; 5.08 mmol) and benzyl alcohol (1.05 mL; 10.15 mmol) in toluene (20 mL). The resulting mixture was heated for three days at 100° C. After cooling to RT EtOAc and water were added. The layers were separated and the organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EtOAc/CH2Cl2 1:6) to afford 3-[2-(4-benzyloxy-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butyl ester (1.85 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[OH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:44])=[C:20]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[N:31]=[C:32]4[CH2:43][CH2:42][NH:41][CH2:40][C:33]4=[N:34][C:35]=3[NH:36][CH:37]([CH3:39])[CH3:38])[CH2:26][CH2:25]2)=[O:23])[CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:44])=[C:20]([CH:21]=1)[C:22]([CH:24]1[CH2:25][CH2:26][N:27]([C:30]2[N:31]=[C:32]3[CH2:43][CH2:42][N:41]([C:5](=[O:7])[CH3:6])[CH2:40][C:33]3=[N:34][C:35]=2[NH:36][CH:37]([CH3:39])[CH3:38])[CH2:28][CH2:29]1)=[O:23].[C:9]([OH:10])([C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCNC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2nc(N3CCC(C(=O)c4cc(Cl)ccc4F)CC3)c(NC(C)C)nc2C1
Reaction time: 1 h

Procedure:
Acetic anhydride (3 μL, 0.029 mmol) was added to a solution of (5-chloro-2-fluorophenyl)(1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone TFA salt (8.0 mg, 0.015 mmol) and pyridine (4 μL, 0.044 mmol) in DCM (150 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (3.6 mg, 42%) as a yellow solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.26-1.32 (m, 6H), 1.84-1.96 (m, 2H), 1.97-2.06 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.70-2.76 (m, 0.7H), 2.80-2.86 (m, 1.3H), 2.87-3.00 (m, 2H), 3.34-3.41 (m, 1H), 3.46-3.56 (m, 2H), 3.79-3.84 (m, 1.3H), 3.84-3.89 (m, 0.7H), 4.07-4.18 (m, 1H), 4.57 (s, 1.1H), 4.62 (s, 0.9H), 7.28 (dd, J=10.4, 8.8 Hz, 1H), 7.61 (ddd, J=8.9, 4.2, 2.9 Hz, 1H), 7.76 (dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 474.3.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCC1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 11.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.2 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:34])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: COc1ccccc1N=C=O
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)Nc1ccc(CC(=O)OC(C)(C)C)cc1C
Reaction time: 27 h
Yield: 76.4 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (1.36 g, 6.15 mmol) and triethylamine (170 ml, 1.23 mmol) in THF (30 ml) was added 2-methoxyphenyl isocyanate (820 ml, 6.15 mmol), and the resulting mixture was stirred for 27 h. The mixture was concentrated to a small volume in vacuo, and hexane was added to the residue to give precipitate, which was collected by filtration to give tert-butyl 4-[N′-(2-methoxyphenyl)ureido]-3-methylphenylacetate (1.74 g, 76%) as a white crystallize material. mp 157-158° C.; 1H-NMR (CDCl3) δ1.46 (s, 9 H), 2.30 (s, 3 H), 3.50 (s, 2 H), 3.76 (s, 3 H), 6.43 (s, 1H), 6.83 (br d, J=8.4 Hz, 1 H), 6.95 (br d, J=8.0 Hz, 1 H), 6.98-4.99 (m, 2 H), 7.13 (brs, 1 H), 7.23 (br s, 1 H), 7.48 (d, J=8.8 Hz, 1 H), 8.14 (d, J=8.4 Hz, 1 H); MS (ESI) m/z 371 (M++H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.[CH3:13][N:14]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]1[CH:22]=O.C(OC(=O)C)(=O)C.O>C(O)(=O)C.[Cl-].[Cl-].[Zn+2]>[C:7]1([C:4]2[S:3][C:2]([CH:1]=[CH:22][C:15]3[N:14]([CH3:13])[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=3)=[N:6][N:5]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1nnc(-c2ccccc2)s1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1nnc(-c2ccccc2)s1
Yield: 55.9 %

Procedure:
17.6 g of 2-methyl-5-phenyl-1,3,4-thiadiazole, 15.5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde and 0.5 g of ZnCl2 are heated in 100 ml of acetic acid and 50 ml of acetic anhydride for 7 hours at reflux temperature. After water has been added to the reaction mixture, the precipitated solid is recrystallized from glacial acetic acid. 17.5 g of a product melting at 257° C. is obtained, corresponding to 56% of the theory.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH:17]([CH3:19])[NH:16][C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH:30]=[CH:31][C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@@H:17]([CH3:19])[N:16]([CH2:29][CH:30]=[CH:31][C:32]4[S:33][C:34]([Cl:37])=[CH:35][CH:36]=4)[C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(C=CCBr)s1
Reactant: CC1CN(Cc2ccc3c(Cl)ccnc3c2)C(=O)[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccc3c(Cl)ccnc3c2)C(=O)[C@H](C)N1CC=Cc1ccc(Cl)s1
Reaction time: 8 h
Yield: 27.1 %

Procedure:
The crude (3S,5RS)-1-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (69 mg, 0.20 mmol) obtained from above is dissolved in 1 mL of DMF. Potassium carbonate (76 mg, 0.60 mmol) is added followed by the addition of 2-(3-bromopropenyl)-5-chloro-thiophene (56 mg, 0.24 mmol). The reaction is left to stir overnight. The potassium carbonate is filtered off, and the crude material is purified. The two epimers are separated at this stage by preparative thin layer chromatography (80% EtOAc/hexane) to give a major epimer (3S, 5R)-1-(4-chloro-quinolin-7-ylmethyl)-4-[3-(5-chloro-thiophen-2-yl)-allyl]-3,5-dimethyl-piperazine-2-one (25 mg, 26% yield) and a minor epimer (3S, 5S)-1-(4-chloro-quinolin-7-ylmethyl)-4-[3-(5-chloro-thiophen-2-yl)-allyl]-3,5-dimethyl-piperazine-2-one (7 mg, 7.5% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[N:15][OH:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)CC(=NO)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
A solution of 7-nitrotetralone (4.20 g, 22.0 mmol) in methanol (100 mL) was cooled to 0° C., and hydroxylamine (1.68 g, 23.2 mmol) and sodium acetate (3.69 g, 46.4 mmol) were added. The reaction was then stirred at room temperature for 12 h. The methanol was evaporated at reduced pressure and dichloromethane (100 mL) was added. The mixture was washed with water, dried over NaSO4 and evaporated at reduced presure to yield the title compound (4.37 g, 97%). MS (DCI/NH3) m/e 207 [M+H]+.
Reaction SMILES: CON(C)[C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].[CH2:26]([Mg]Cl)[CH:27]([CH3:29])[CH3:28]>C1COCC1.C(OCC)C>[CH3:26][CH:27]([CH3:29])[CH2:28][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)N(C)OC
Reactant: CC(C)C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)CC(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of N-methoxy-N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyramide (4.80 g, 14.1 mmol) in THF (100 mL) in a dry ice/isopropanol bath was added a solution of isobutylmagnesium chloride (28 mL of a 2 M solution in diethyl ether, 56 mmol) over a period of several minutes. When addition was complete, the reaction flask was removed from the cold bath and the mixture stirred for 4 hours at room temperature. A 10% solution of hydrochloric acid in water (3 mL) was added slowly, followed by a saturated solution of sodium bicarbonate in water (15 mL) and dichloromethane (100 mL). The layers were separated, the aqueous phase extracted with dichloromethane (1×75 mL), and the combined organics dried over potassium carbonate, filtered, and concentrated under reduced pressure. After chromatography on silica gel (elution with 5% methanol in dichloromethane) 6-methyl-1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)heptan-4-one (2.40 g) was obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:20](O)=[O:21])=[CH:4][C:3]=1[F:23].C(Cl)CCl.C1C=CC2N(O)N=[N:34]C=2C=1.[OH-].[NH4+]>C1COCC1.C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([C:20](=[O:21])[NH2:34])=[C:6]2[C:14]=1[C:13]1[CH:12]=[CH:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=1[NH:7]2
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(=O)O)cc(F)c(Br)c12
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(F)c(Br)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
A mixture of 4-bromo-7-(ethoxycarbonyl)-3-fluoro-9H-carbazole-1-carboxylic acid (2.39 g, 6.29 mmol), EDC (1.81 g, 9.43 mmol) and HOBT (1.44 g, 9.43 mmol) in THF (30 mL) and DCM (5 mL) was stirred at room temperature for 20 min Ammonium hydroxide (0.367 mL, 9.43 mmol) was added, and the mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc, washed twice with saturated aqueous NaHCO3, then with brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was triturated with MeOH with sonication to provide ethyl 5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate as a pale yellow solid (2.26 g, 95% yield). Mass spectrum m/z 379, 381 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.70 (d, J=8.3 Hz, 1H), 8.51 (d, J=1.1 Hz, 1H), 8.29 (br. s., 1H), 8.10 (d, J=10.3 Hz, 1H), 7.87 (dd, J=8.5, 1.5 Hz, 1H), 7.74 (br. s., 1H), 4.37 (q, J=6.9 Hz, 2H), and 1.37 (t, J=7.1 Hz, 3H). 1H NMR (500 MHz, MeOH-d4) δ 8.77 (d, J=8.2 Hz, 1H), 8.36 (d, J=0.9 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 4.12 (q, J=7.0 Hz, 2H), 1.58-1.36 (m, 4H), and 1.26 (t, J=7.2 Hz, 3H).