Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:18][C:19]([C:21]1[N:22]=[CH:23][C:24]2[C:29]([C:30]=1[OH:31])=[CH:28][CH:27]=[C:26]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]=2)=O.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:16])[CH:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][NH:9][C:19]([C:21]1[N:22]=[CH:23][C:24]2[C:29]([C:30]=1[OH:31])=[CH:28][CH:27]=[C:26]([O:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:25]=2)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(CN)c1ccccc1
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)c1ccccc1
Temperature: 150 °C
Yield: 76.2 %

Procedure:
A mixture of 3-amino-2-phenyl-propionic acid tert-butyl ester (90 mg), 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (40 mg) and DBU (0.030 mL) in DMA (1 mL) was heated in an oil bath (150° C.) for 1.5 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (50 mg). LC-MS ESI+: 485 (M+1)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:34](Cl)=[O:35]>>[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([C:34]([N:8]2[CH2:13][CH2:12][C@H:11]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C@H:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:9]2)=[O:35])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCOCC2)[C@H](c2ccc(Cl)c(Cl)c2)C1

Procedure:
The title compound, MS: m/e=555.1 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-(3,4-dichloro-phenyl)-piperidin-4-one, morpholine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].C(N(CC)CC)C.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>ClCCl.C(OCC)(=O)C>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH:12][C:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[O:26])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(=O)N1CCN(N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(NC(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-acetyl-4-aminopiperazine dihydrochloride (250 mg) and triethylamine (0.65 ml) in dichloromethane (9 ml) was added 2-thiophenecarbonyl chloride (0.19 ml) at 0° C. The mixture was stirred at ambient temperature for 1 hour, diluted with ethyl acetate and washed with water (×2). The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with a mixture of methanol and ethyl acetate (1:10) to give crystals. Recrystallization from ethanol gave N-(4-acetyl-1-piperazinyl)thiophene-2-carboxamide (256 mg).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:20])[NH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:21]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N+:17]([C:13]1[CH:12]=[C:11]([C:8]2[NH:7][C:6](=[O:20])[C:5]([CH:2]([NH:1][C:26]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:27])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH:16]=[CH:15][CH:14]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCC(N)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Product: CCC(NC(=O)C1CCCC1)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 16A, 3.0 g (10.9 mmol) 6-(1-aminopropyl)-3-(3-nitrophenyl)-1,2,4-triazin-5(4H)-one (Example 15A), 2.2 g (16.3 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: CCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In DMF (195 ml) was dissolved 2-(4-bromophenoxy)-1-ethanol (19. 5 g). To the mixture was added under ice-cooling 65% sodium hydride (5.3 g), and the mixture was stirred at room temperature for 2 hours. To the mixture was added dropwise iodohexane (19.9 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-4-(2-hexyloxyethoxy)benzene (16.2 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([O-])(O)=O.[Na+].[C:19](=[O:26])([O:23][CH2:24]I)[S:20][CH2:21][CH3:22]>O.C(Cl)Cl>[C:19](=[O:26])([O:23][CH2:24][O:12][C:11](=[O:13])[CH2:10][CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[S:20][CH2:21][CH3:22]
Reactant: CCOP(=O)(CCC(=O)O)OCC
Reactant: CCSC(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(CCC(=O)OCOC(=O)SCC)OCC
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
To a mixture of 3-(diethylphosphono)propanoic acid (79, 1.0 g, 4.76 mmol) in H2O (12 mL) and CH2Cl2 (12 mL) was added NaHCO3 (1.0 g, 11.9 mmol) and TBAHSO4 (1.62 g, 4.76 mmol). After stirring for 20 min, S-ethyl O-iodomethyl carbonothioate (1.17 g, 4.76 mmol) in CH2Cl2 (2 mL) was added. The biphasic reaction was stirred vigorously for 4 h 20 min and was diluted with water and CH2Cl2. The layers were separated, the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on a Biotage™ flash chromatography system, using EtOAc as the eluent, to yield compound 80 (1.29 g, 83%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.30-1.65 (m, 9H), 2.03-2.12 (m, 2H), 2.64-2.71 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 4.06-4.14 (m, 4H), 5.82 (s, 2H). 31P NMR (162 MHz, CDCl3) δ 30.45 (s).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][C:3]1=[CH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C1(S(NN)(=O)=O)C=CC=CC=1>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH:3]1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(C=C2COc3ccccc3C2=O)cc1
Agent: NNS(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC2COc3ccccc3C2=O)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 42.2 %

Procedure:
A suspension of 260 (400 mg, 1.36 mmol) and benzenesulfonyl hydrazine (702 mg, 4.08 mmol) in DMF (7 ml) was stirred at 100° C. during 48 h. The solvent was evaporated and the residue was diluted in AcOEt, washed with NH4Cl sat., brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (5% AcOEt/HEx) to afford the title compound 264 (170 mg, 42%) as a white solid. LRMS: 296.1 (Calc.); 297.0 (found).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:17][CH2:18]O>>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH2:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1F
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1cccc(Cl)c1F
Yield: 79.3 %

Procedure:
A solution of 2-(3-chloro-2-fluorophenyl)acetic acid (2.56 g, 13.6 mmol) and thionyl chloride (100 mL, 1371 mmol) was stirred at 95° C. for 2 hours in a 250 mL round bottom flask. The solution was concentrated, azeotroped in toluene, and dried in vacuo to give the crude acid chloride, which was then stirred in EtOH (150 mL, 2576 mmol) at 25° C. for 16 hours. The solution was concentrated in vacuo, diluted with saturated NaHCO3 (aq) (100 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with saturated NaHCO3 (aq) (100 mL), with water (100 mL), and then with brine (75 mL). The organic layer was dried over MgSO4, concentrated, and purified by silica flash column chromatography (0-10% EtOAc in hexane) to give ethyl 2-(3-chloro-2-fluorophenyl)acetate (2.335 g, 79.4% yield). MS m/e=217 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[CH:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>C1COCC1>[C:28]1([C:25]2[CH:24]=[CH:23][CH:22]=[CH:27][CH:26]=2)[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH:13]=[CH:14][CH:15]=3)[CH2:6][CH2:5]2)=[O:36])=[CH:32][CH:33]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCN)CC2)c1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCNC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(2-aminoethyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-biphenyl isocyanate: ESMS m/e: 485.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[C:12]([O:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=2)[CH:21]=[N:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([N:28]=[C:1]=[O:2])=[CH:25][CH:26]=2)[CH:21]=[N:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc2cc(N=C=O)ccc21
Reaction time: 1.5 h

Procedure:
A 0° C. mixture of 1.93M solution of phosgene in toluene (8.9 mL, 17 mmol) and CH2Cl2 (80 mL) was added dropwise a solution of 5-amino-indazole-1-carboxylic acid tert-butyl ester (2 g, 8.5 mmol) and pyridine (3.5 mL, 43 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred for 1.5 h, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL) and was used without further purification.
Reaction SMILES: O=[C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@@H:6]2[C:9]([CH3:25])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH3:10])[C@H:3]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[N+:66]([C:69]1[CH:82]=[CH:81][C:72]([CH2:73][O:74][C:75]([NH:77][CH2:78][CH2:79][SH:80])=[O:76])=[CH:71][CH:70]=1)([O-:68])=[O:67]>C(#N)C.C(OCC)(=O)C>[CH3:25][C:9]([C@H:6]1[C:5](=[O:26])[N:4]2[C@@H:7]1[CH2:8][C:2]([S:80][CH2:79][CH2:78][NH:77][C:75]([O:74][CH2:73][C:72]1[CH:81]=[CH:82][C:69]([N+:66]([O-:68])=[O:67])=[CH:70][CH:71]=1)=[O:76])=[C:3]2[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])([O:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])[CH3:10]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 4-nitrobenzyl(2R,5R,6S)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (148.5 mg) and 4-N,N-dimethylaminopyridine (3.35 mg) in acetonitrile (7.4 ml) was added dropwise a solution of di-isopropylethylamine (57.3 μl) in acetonitrile (0.516 ml). To the mixture was further added a solution of diphenyl chlorophosphate (59.6 μl) in acetonitrile (0.536 ml) at 0° C. After stirring for an hour at 0° C., a solution of diisopropylethylamine (190.9 μl) in acetonitrile (1.72 ml) was added to the mixture. To the mixture was further added a solution of N-(4-nitrobenzyloxycarbonyl)cysteamine (73.8 mg) in acetonitrile (0.664 ml) at -15° C. The mixture was allowed to stand overnight at -15° C. The resulting solution was diluted with ethyl acetate (15 ml) and washed in turn with water and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residue was chromatographed on silica gel (3 g) eluting with a mixture of methylene chloride and ethyl acetate (50:1 to 5:1) to give 4-nitrobenzyl(5R,6S)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-[2-(4-nitrobenzyloxycarbonylamino)-ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (167.8 mg) as an amorphous solid.
Reaction SMILES: [S:1]([CH:5]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:8])=O)([OH:4])(=[O:3])=[O:2].[OH-].[Na+:14].C(OC(=O)C)(=O)C>C(OCC)(=O)C>[Na+:14].[O:8]=[C:6]1[CH:5]([S:1]([O-:4])(=[O:3])=[O:2])[CH2:9][C:10](=[O:11])[O:12]1
Reactant: O=C(O)CC(C(=O)O)S(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: O=C1CC(S(=O)(=O)[O-])C(=O)O1

Procedure:
Tetrahydro-2,5-dioxo-3-furansulfonic acid sodium salt was prepared by stirring 1.71 moles of sulfosuccinic acid with 1.87 moles of sodium hydroxide at 50° C. until a milky suspension formed and then adding 1 kg acetic anhydride over 6 hours. After cooling, 1 L of ethyl acetate was added and the mixture was filtered. The filter cake was washed with 500 mL ethyl acetate. On drying 344.32 g of white crystalline product was obtained. 13C-NMR (d6-DMSO) 171.3, 167.2, 60.4, 34.0 ppm.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:15]=[CH:14][C:7]2[N:8]([CH2:12][CH3:13])[C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=1)=[O:3].[CH:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>O1CCCC1.O>[CH2:12]([N:8]1[C:7]2[CH:14]=[CH:15][C:4]([C:2](=[O:3])[CH:1]=[CH:16][CH:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22][CH2:23]3)=[CH:5][C:6]=2[N:10]=[C:9]1[CH3:11])[CH3:13]
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: CCn1c(C)nc2cc(C(C)=O)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(C)nc2cc(C(=O)C=CC3CCN(Cc4ccccc4)CC3)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A mixture of 0.1 g (0.5 mM) of 1-ethyl-2-methylbenzimidazole-5-yl methyl ketone and 0.1 g (0.5 mM) 4-formyl-N-benzylpiperidine in 10 mL of tetrahydrofuran (THF) was cooled to -78° C. under a nitrogen atmosphere. To this mixture were added dropwise 0.5 mL (0.5 mM) of a IM solution of lithium bis(trimethylsilyl)amide in THF. The reaction was stirred at -78° C. for 1 hour, then warmed to room temperature. To the reaction was added 10 mL of water and the pH was adjusted to 2.0 with 1N hydrochloric acid (HCl). The mixture was extracted with 15 mL of ethyl acetate. The pH of the water layer was then sequentially adjusted to 3.0, 4.0, 5.0, 6.5, and 8.5 with IN NaOH, each time extracting with 15 mL of ethyl acetate. The ethyl acetate extracts at pH=5.0 and 6.5 were combined, dried with sodium sulfate (Na2SO4) and evaporated to yield 50 mg (26%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12](F)[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1)([CH3:4])[CH3:3].Cl.[F:22][C:23]([F:33])([F:32])[C:24]([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)=[O:25].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[F:33][C:23]([F:22])([F:32])[C:24]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([C:12]2[CH:13]=[C:14]3[C:9]([C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6][N:5]3[C:2]([CH3:4])([CH3:1])[CH3:3])=[CH:10][C:11]=2[F:16])[CH2:28]1)=[O:25]
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: O=C(NC1CCNC1)C(F)(F)F
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NC(=O)C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A mixture of 600 mg (2.13 mmoles) 1-(1,1-dimethylethyl)-1,4-dihydro-6,7-difluoro-4-oxo-3-quinolinecarboxylic acid, 700 mg (3.2 mmoles) of 3-trifluoroacetylamino pyrrolidine hydrochloride and 1.3 mL (8.5 mmoles) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 3 mL pyridine was stirred 30 minutes at room temperature, evaporated to dryness and poured into water. The pH was adjusted to 7.5 with 1N hydrochloric acid. The precipitate was filtered to give 430 mg of 7-(3-trifluoroacetylamino-1-pyrrolidinyl)-1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid. mp 200° C. dec. 409 mg (0.92 mmole) of that compound was suspended in 2 mL 1N NaOH and refluxed 2 hours. The solution was cooled and diluted with water, the pH was adjusted to 7.5 with 10% acetic acid. The precipitate was filtered, washed with water, dried and recrystallized as an hydrochloride in ethanol to give 180 mg of titled compound. MP>270° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.7 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (71.0 mg, 62%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[O:32]=[C:33]1[NH:37][CH:36]([CH2:38][C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:35][O:34]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:43][C:42]3[CH:41]=[CH:40][C:39]([CH2:38][CH:36]4[CH2:35][O:34][C:33](=[O:32])[NH:37]4)=[CH:45][CH:44]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(CC2COC(=O)N2)cc1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CC3COC(=O)N3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-[(2-oxo-1,3-oxazolidin-4-yl)methyl]aniline (Specs, 130 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH2:16][CH:17]([CH2:21][CH3:22])[C:18](O)=[O:19].[CH2:23]([NH:30][CH2:31][C:32](OCC)=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:21]([C@@H:17]1[NH:16][C:32](=[O:33])[CH2:31][N:30]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:19])[CH3:22]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CCC(N)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of DCC (5.07 g) in DCM (140 mL) at 0° C. was added N—BOC-L-□-aminobutyric acid (5 g) followed by ethyl JV-benzylglycinate (4.6 mL) dropwise. The resulting solution was stirred at 0° C. for 2 h and RT 1 h, filtered and the concentrated to give an oil. This was dissolved in DCM (100 mL) and TFA (100 ml) and stirred for 1 h. The solution was concentrated under reduced pressure. The residue was stirred in saturated aq NaHCO3 (125 ml) and EtOAc (125 ml) for 6 h. The organics were separated, dried (Na2SO4), and concentrated to give the sub title compound as a white solid. (5.68 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]([NH:17][CH2:18][CH2:19][CH2:20][N:21]1[C:30]([S:31][C:32]2[CH:37]=[C:36]3[O:38][CH2:39][O:40][C:35]3=[CH:34][C:33]=2I)=[N:29][C:23]2[C:24]([NH2:28])=[N:25][CH:26]=[N:27][C:22]1=2)[CH3:16].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:33]2[C:32]([S:31][C:30]3[N:21]([CH2:20][CH2:19][CH2:18][NH:17][CH:15]([CH3:16])[CH3:14])[C:22]4[C:23]([N:29]=3)=[C:24]([NH2:28])[N:25]=[CH:26][N:27]=4)=[CH:37][C:36]3[O:38][CH2:39][O:40][C:35]=3[CH:34]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccc(C(C)(C)C)cc2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 82.4 %

Procedure:
4-tert-Butylphenylboronic acid (15.6 mg, 0.0876 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (0.5 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 3 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 4:5:2:1) to give 25.0 mg (83%) of DZ2-390. 1H NMR (500 MHz, MeOH-d4) δ 8.11 (s, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.14 (s, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.86 (s, 1H), 6.06 (s, 2H), 3.93 (t, J=6.9 Hz, 2H), 2.92 (septet, J=6.5 Hz, 1H), 2.61 (t, J=7.3 Hz, 2H), 1.86 (m, 2H), 1.28 (s, 9H), 1.12 (d, J=6.5 Hz, 6H); 13C NMR (125 MHz, MeOH-d4) δ 155.9, 153.3, 151.9, 151.8, 150.9, 150.2, 149.2, 141.9, 138.8, 130.0, 125.9, 120.4, 120.3, 115.4, 112.3, 103.6, 50.6, 44.0, 41.8, 35.4, 31.8, 29.3, 21.1; HRMS (ESI) m/z [M+H]+ calcd. for C28H35N6O2S, 519.2542; found. 519.2545; HPLC: method A Rt=7.43, method B Rt=9.45.