Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Br:15][Si](C)(C)C.O.BrN1C(=O)CCC1=O>ClCCl.C(N(CC)CC)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[N:8][CH:9]=1)=[O:3]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)c1ccc(-n2ccnc2)nc1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)c1ccc(-n2ccnc2)nc1
Temperature: 25 °C
Yield: 19.7 %

Procedure:
87 mg (corresponding to 0.462 mmol) of 5-acetyl-2-(1H-imidazole-1-yl)pyridine was dissolved in 3.0 mL of dichloromethane and 193 μL of triethylamine, and then 120 μL (corresponding to 0.924 mmol) of bromotrimethylsilane was dropped under ice cooling. The resulting solution was stirred over night at room temperature under argon gas atmosphere, and then the reaction solution was supplemented with water and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, the resulting residue was dissolved in 3.0 mL of tetrahydrofuran, and 82.2 mg (corresponding to 0.462 mmol) of N-bromosuccinimide was added thereto under ice cooling. The resulting solution was stirred at room temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=2/1), to obtain 24.3 mg (corresponding to 0.091 mmol) of 5-(2-bromoacetyl)-2-(1H-imidazole-1-yl)pyridine (FIG. 3, step 2).
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].C([Li])CCC.[N:10]1([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[O:17])[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)(O)[O-].[Na+]>O1CCCC1.CCCCCC.C(O)(=O)C>[C:1]([CH:2]([CH3:3])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])([OH:17])[CH2:15][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)#[N:4]
Reactant: CCC#N
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C#N)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Propionitrile (1.21 g) in dry tetrahydrofuran (50 ml) was cooled to -72° C. A solution of n-butyllithium in n-hexane (14.2 ml, 1.55 molar) was then slowly added while maintaining the temperature of the reaction mixture at -45° C. or below. After stirring for about 30 minutes, 2-(1H-1,2,4-triazol-1-yl)-2',4'-dichloroacetophenone (2.56 g) in dry tetrahydrofuran (THF) (50 ml) was added slowly with stirring over a 20 minute period, the temperature of the mixing being maintained at -70° C. Stirring was continued at this temperature for one hour and then at -10° for a half hour, then glacial acetic acid (10 ml) in dry THF (15 ml) was added. The reaction mixture was allowed to warm to room temperature (20° C.), adjusted to pH 8 with solid sodium bicarbonate, and extracted with ethyl acetate (3×75 ml). The combined organic extracts were washed three times with water, dried (MgSO4), evaporated and ethyl ether (30 ml) was added to the residue, yielding a white crystalline solid and a yellow solution. The solid was filtered off, dissolved in a small volume of methylene chloride, and loaded onto an 18 g. flash chromatography column of Merck's "Kieselgel 60" (Trade Mark) 230-400 mesh silica in ether (11×2 cm. diameter). Elution was carried out using 5% (by volume) acetone in ether at one p.s.i. (4.88 kg/m2). "Diastereoisomer 1" of the title compound was eluted first, 0.79 g, m.p. 178°-180° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:8]([O:10][CH3:11])=[O:9].C(N(CC)C(C)C)(C)C.ClCCl.[CH2:31]=[C:32]1[O:36][C:34](=[O:35])[CH2:33]1>C(OCC)(=O)C>[CH3:11][O:10][C:8](=[O:9])[C@@H:7]([NH:12][C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2][C:34](=[O:35])[CH2:33][C:32](=[O:36])[CH3:31]
Reactant: COC(=O)[C@H](CCCCN)NC(=O)C(F)(F)F
Reactant: C=C1CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCCCNC(=O)CC(C)=O)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To (S)-methyl 6-amino-2-(2,2,2-trifluoroacetamido)hexanoate hydrochloride (0.943 g, 3.22 mmol), N,N-diisopropyl ethylamine (DIEA, 1.39 mL) and dichloromethane (DCM, 10 mL) in a 40 mL glass vial was added diketene (0.37 mL) under N2 atmosphere, and the reaction was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (EtOA), washed successively with H2O, 1 N HCl, H2O, sat aq Na2CO3, and sat aq NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by a SiO2 flash chromatography, affording (S)-methyl-6-(3-oxobutanamido)-2-(2,2,2-trifluoroacetamido)hexanoate (TU3000-012) as a yellow oil. MS (ESI+): calcd. 341.12. found 341.10 (MH+). H-NMR (400 MHz, CDCl3):1.33 (2H, m), 1.55 (2H, m), 1.89 (2H, m), 2.259(3H, s), 3.31 (2H, m), 3.410 (2H, s), 3.783 (3H, s), 4.543 (1H, dt, J=4.4, 8.0 Hz). 7.091 (1H, br.s), 7.279 (1H, br.d, J=7.6 Hz). F-NMR (376 MHz, CDCl3): −75.609.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][P:18]([O:26][CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])=[CH:14][CH:15]=2)[C:10]([C:28]2[N:29](C(OC(C)(C)C)=O)[CH:30]=[CH:31][CH:32]=2)=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][P:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])[O:26][CH3:27])[CH:12]=2)[NH:8][N:9]=1
Reactant: COP(=O)(Oc1ccc2c(c1)c(-c1cccn1C(=O)OC(C)(C)C)nn2C(=O)OC(C)(C)C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COP(=O)(Oc1ccc2[nH]nc(-c3ccc[nH]3)c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
39 mg of 3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-5-(methoxyphenyl-phosphinoyloxy)indazole-1-carboxylic acid tert-butyl ester are dissolved in 0.5 ml of dichloromethane and then 0.5 ml of trifluoroacetic acid is added. The solution is stirred at ambient temperature for approximately two hours. The solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by preparative LC/MS to obtain 19 mg of phenylphosphonic acid methyl ester 3-(1H-pyrrol-2-yl)-1H-indazol-5-yl ester as a trifluoroacetate salt.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[C:23]([F:30])=[CH:24][C:25]([F:29])=[C:26]([OH:28])[CH:27]=1.C(=O)([O-])O.[Na+]>C(Cl)(=O)C(Cl)=O.O1CCCC1.O>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])=[O:6]
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Reactant: Nc1cc(O)c(F)cc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cc(O)c(F)cc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (4.42 g, 20 mmol) produced in Example C62(ii) in oxalyl chloride (10 mL) was added N,N-dimethylformamide (100 μL)), and the mixture was stirred at room temperature for 1 hr, and concentrated to dryness under reduced pressure. This was dissolved in tetrahydrofuran (10 mL), and the solution was added dropwise with vigorous stirring to a two-layer mixture of a solution of 5-amino-2,4-difluorophenol (2.90 g, 20 mmol) in tetrahydrofuran (5 mL) and a solution (10 mL) of sodium hydrogen carbonate (2.70 g, 30 mmol) in water under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50) to give the title compound (4.90 g, 70%) as white crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([O:27][C:28](=[O:31])[CH2:29][N:16]([C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[N:15]=1)[CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)c1ccc(-c2nccc(NCc3cccs3)n2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(-c2nccc(N(CC(=O)OC(C)(C)C)Cc3cccs3)n2)cc1

Procedure:
{[2-(4-Isopropyl-phenyl)-pyrimidin-4-yl]-thiophen-2-ylmethyl-amino}-acetic acid tert-butyl ester was prepared (149 mg) from [2-(4-isopropyl-phenyl)-pyrimidin-4-yl]-thiophen-2-ylmethyl-amine (135 mg, 0.44 mmol) and bromoacetic acid tert-butyl ester in THF by following the general procedure F. LCMS m/z: 425 (M+1)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH2:4]([CH:9]1[C:13](O)([CH3:14])[CH:12]=[CH:11][C:10]1=[O:16])[CH2:5][CH2:6][CH2:7][CH3:8]>O1CCCC1>[CH2:4]([C:9]1[C:10](=[O:16])[CH2:11][CH:12]([NH:3][CH2:1][CH3:2])[C:13]=1[CH3:14])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC1C(=O)C=CC1(C)O
Reactant: CCN
Solvent: C1CCOC1
Product: CCCCCC1=C(C)C(NCC)CC1=O
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
Into a four-necked flask equipped with a stirrer and a thermometer, a 30% aqueous solution of monoethylamine (70 g) and tetrahydrofuran (18 g) were charged, and then 2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone (18.2 g) was dropwise added thereto at a temperature of 10° to 20° C. for 30 minutes. At the same temperature, the reaction mixture was kept for 2 hours. After completion of the reaction, the mixture was extracted with toluene, and the organic layer was washed with water. From the organic layer, toluene was evaporated off to give 2-n-pentyl-3-methyl-4-ethylamino-2-cyclopentenone (20.3 g). Yeild, 97%. The product was purified by alumina chromatography using toluene-ethyl acetate (10:1 by volume). nD20 1.4864.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.CC(O)=O>[CH3:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:19]3[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=3)[CH2:25][CH2:26]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Reactant: Cc1cc(CC=O)ccc1C#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-methyl-4-(2-oxoethyl)benzonitrile (130 mg, 0.8 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (190 mg, 0.8 mmol) in 25 mL of dry methanol were added 2 drop of HOAc and then stirred at room temperature for 1 hr. Then NaBH(OAc)3 (380 mg, 1.8 mmol) was added an the then the mixture was stirred overnight. Concentrated and the residue was purified via prep-TLC to give 2-Methyl-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.15 (d, J=8.6 Hz, 2H), 7.36˜7.53 (m, 3H), 7.12 (t, J=9.4 Hz, 2H), 2.65˜2.97 (m, 16H), 2.52 (s, 3H). MS m/e: 379 (M+1)+. (0.19 μM)
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][C:7]([C:12]([OH:14])=O)=[N:6][C:5]=2[N:4]([CH3:15])[C:3]1=[O:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH:52]([N:55]1[CH2:60][CH2:59][CH:58]([NH2:61])[CH2:57][CH2:56]1)([CH3:54])[CH3:53]>CN(C=O)C>[CH:52]([N:55]1[CH2:60][CH2:59][CH:58]([NH:61][C:12]([C:7]2[NH:8][C:9]3[C:10](=[O:11])[N:2]([CH3:1])[C:3](=[O:16])[N:4]([CH3:15])[C:5]=3[N:6]=2)=[O:14])[CH2:57][CH2:56]1)([CH3:54])[CH3:53]
Reactant: CC(C)N1CCC(N)CC1
Reactant: Cn1c(=O)c2[nH]c(C(=O)O)nc2n(C)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(NC(=O)c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.45 mmol) 1,3-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid were dissolved in 5 mL DMF. Subsequently 227 μl (1.35 mmol) DIPEA and 186.5 mg (0.495 mmol) HATU were added. After 1 h 105.6 mg (0.495 mmol) 1-isopropyl-piperidine-4-ylamine-dihydrochloride and 227 μl (1.35 mmol) DIPEA were added and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and purified by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) to give 1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as its formiate.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.C1[O:19]C1>[OH-].[Na+].C(O)(=O)C>[CH2:13]1[O:16][CH2:14]1.[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[OH:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CO1
Product: CCCCCCCCCc1ccccc1O
Temperature: 120 °C
Yield: 333.5 %

Procedure:
To a 1,000 ml autoclave equipped with an ethylene oxide inlet tube, 220 g (0.998 mole) of nonylphenol having a branched nonyl group and an ortho/para ratio of 1/9, and 0.55 g of 40% aqueous sodium hydroxide solution (5.5 mmoles of sodium hydroxide) were charged. The reaction system was substituted with nitrogen and thereafter heated to 120° C. Successively the reaction system was evacuated to 50 mmHg and dehydrated for an hour. After dehydration, the system was returned to atmospheric pressure with nitrogen and heated to 150° C. While maintaining the same temperature, 220 g (4.99 moles) of ethylene oxide were charged to the reaction system over 5 hours under the pressure of 0.2 to 0.4 MPa (gauge). After finishing ethylene oxide charge, the reaction mixture was kept at the same temperature for an hour. After cooling, the reaction mixture was neutralized with 0.0.35 g (5.8 mmoles) of acetic acid to obtain 440 g of nonylphenol ethylene oxide adduct. The adduct obtained had an ethylene oxide addition mole numbers of 5.0 for one mole of nonylphenol.
Reaction SMILES: [NH:1]([CH2:3][C:4](OC)=O)[CH3:2].Cl[C:9](=[CH2:14])[C:10]([O:12][CH3:13])=[O:11].[Na].[OH:16]P(O)(O)=O>CO.O>[OH:16][C:14]1[CH:4]=[CH:3][N:1]([CH3:2])[C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CNCC(=O)OC
Reactant: O=P(O)(O)O
Reactant: C=C(Cl)C(=O)OC
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(O)ccn1C
Reaction time: 18 h

Procedure:
Methyl sarcosinate (14.5 g, 0.14 moles) is added dropwise to methyl α-chloroacrylate (16.9 g, 0.14 moles), stirred and cooled in an ice bath. After 15 minutes the mixture is dissolved in methanol (30 mL) and added dropwise to a solution of sodium (9.7 g, 0.42 moles) in methanol (125 mL) under argon. After 18 hours at room temperature, the mixture is striped of methanol under reduced pressure. The residue is taken up in water (300 mL), acidified with H3PO4, and extracted with ethyl acetate (5×100 mL). The combined extracts are dried over MgSO4, concentrated under reduced pressure and filtered through a short column of silica gel. The filtrate is stripped of solvent under reduced pressure, leaving the product (16.5 g) as an oil sufficiently pure for further use. An analytically pure sample was obtained by vacuum distillation; bp 61°-64° C. (0.5 mm) followed by recrystallization of the distillate from n-pentane to afford the product as shiny white crystals; mp 44°-46° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH2:6])[CH:3]=[N:2]1.ClCCl.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18].[C:24](OCC)(=[O:26])[CH3:25]>>[C:17]([N:1]1[CH:5]=[C:4]([NH:6][C:24](=[O:26])[CH3:25])[CH:3]=[N:2]1)(=[O:19])[CH3:18]
Reactant: Nc1cn[nH]c1
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnn(C(C)=O)c1
Temperature: 5 °C

Procedure:
A 250-mL 3-neck flask was charged with 1H-pyrazol-4-amine (5 g, 60.2 mmol) and dichloromethane (50 mL). The resulting suspension was cooled to 5° C. and triethylamine (9.13 g, 90.0 mmol) was added, followed by acetic anhydride (7.37 g, 72.2 mmol) at <20° C. The reaction was stirred at room temperature for 18 hours, at which point thin layer chromatography [Eluent: ethyl acetate] analysis indicated that the reaction was incomplete. Additional triethylamine (4.57 g, 45.0 mmol) and acetic anhydride (3.70 g, 36.0 mmol) were added and the reaction was heated at 30° C. for an additional 3 hours to give a dark solution, at which point thin layer chromatography analysis indicated that only a trace of starting material remained. The reaction mixture was purified by flash column chromatography using ethyl acetate as eluent. The fractions containing pure product were combined and concentrated to dryness to afford an off-white solid. The solid was dried under vacuum at room temperature for 18 hours (5.55 g, 55%): 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1 H), 8.39 (d, J=0.7 Hz, 1 H), 7.83 (d, J=0.7 Hz, 1H), 2.60 (s, 3 H), 2.03 (s, 3 H); EIMS m/z 167 ([M]+).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O.N[C@H:31]1[CH2:36][C:35]2[C:37]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)=[CH:38][CH:39]=[CH:40][C:34]=2[O:33][CH2:32]1>CN(C)C=O>[CH3:47][N:44]1[CH2:45][CH2:46][N:41]([C:37]2[C:35]3[CH2:36][C@@H:31]([C:23]4[C:15]([O:14][CH3:13])=[C:16]([CH:20]=[CH:21][C:22]=4[N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:17]([NH2:3])=[O:19])[CH2:32][O:33][C:34]=3[CH:40]=[CH:39][CH:38]=2)[CH2:42][CH2:43]1
Reactant: COc1cc(N2CCOCC2)ccc1C(=O)O
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1c(C(N)=O)ccc(N2CCOCC2)c1[C@H]1COc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 120 h
Yield: 32.7 %

Procedure:
A stirred solution of 1,1′-carbonyldiimidazole (222 mg, 1.37 mmol) and 2-methoxy-4-morpholinobenzoic acid (176 mg, 0.740 mmol) in anhydrous N,N-dimethylformamide (5 mL) was heated at 75° C. for 2 h, and was then allowed to cool. A solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (183 mg, 0.740 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added. The reaction mixture was stirred at room temperature for 5 days. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and a 2 M NH3 solution (15 mL). The organic layer was dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol, 93:7+0.5% conc. NH3) affording 113 mg (30% yield) of the title compound as an uncolored foam: [α]21D−141° (c 0.5, chloroform); EIMS (70 eV) m/z (relative intensity) 466 (20, M30 ).
Reaction SMILES: [ClH:1].[N:2]1([C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.[CH2:31](Br)[CH:32]([CH3:34])[CH3:33].C(=O)([O-])O.[Na+]>C(#N)C.C(N(CC)CC)C>[ClH:1].[CH2:31]([N:5]1[CH2:6][CH2:7][N:2]([C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[O:9])[CH2:3][CH2:4]1)[CH:32]([CH3:34])[CH3:33]
Reactant: O=C1Cc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: CC(C)CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CN1CCN(C(=O)c2ccc3c(c2)CC(=O)N3)CC1
Reaction time: 6 h
Yield: 32.5 %

Procedure:
5-(1-Piperazinylcarbonyl)oxindol hydrochloride (1.0 g), 1.2 g of DBU, and 0.73 g of isobutyl bromide were suspended in 15 ml of acetonitrile and the suspension was reflexed for 6 hours. To the mixture were then added 0.6 ml of triethylamine and 0.73 g of isobutyl bromide and the mixture was further reflexed for 8 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The chloroform layer was washed with a saturated saline solution and dried over sodium sulfate. The residue obtained after the solvent was distilled off was purified by silica-gel column chromatography (eluent: dichloromethane:methanol=20:1). The product was converted into the hydrochloride with acetone and hydrochloricacid, and recrystallized from a mixture of ethanol and methanol to give 0.39 g of 5-(4-isobutyl-1-piperazinylcarbonyl)oxindol hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6](=[C:12]1[CH:17]=[CH:16][NH:15][CH:14]=[CH:13]1)[C:5]2=O.O.[NH2:20][NH2:21]>>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH2:6][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:21][NH:20]1
Reactant: NN
Reactant: O=C1C(=C2C=CNC=C2)C(=O)c2cc(Br)ccc21
Solvent: O
Product: O=c1[nH]nc(Cc2ccncc2)c2cc(Br)ccc12

Procedure:
Under exclusion of air, 4.75 g (15.7 mmol) 5-bromo-2-(1H-pyridin-4-ylidene)indan-1,3-dione and 14 ml hydrazine hydrate are heated for 4 h to 130° C. Cooling, filtering, and washing with ethanol yields title compound A in the mixture with a little 1-oxo-4-[(pyridin-4-yl)-methyl]-6-bromo-1,2-dihydrophthalazine (B). A: HPLC: tRet(Grad5-40)=1.5; 1H-NMR (DMSO-d6) 12.76 (HN), 8.46 (d, J=6, 2H), 8.34 (d, J=2, 1H), 8.07 (dd, J=8, 2, 1H), 7.85 (d, J=8, 1H), 7.30 (d, J=6, 2H), 4.33 (s, 2H); B: HPLC: tRet(Grad5-40)=11.3; 1H-NMR (DMSO-d6) 12.76 (HN), 8.46 (d, J=6, 2H), 8.16 (d, J=8, 1H), 8.14 (d, J=2, 1H), 8.00 (dd, J=8, 2, 1H), 7.3 (d, J=6, 2H), 4.35 (s, 2H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:26]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: Nc1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 42.3 %

Procedure:
200 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 99 mg of 5-aminoisoindoline, 200 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 117 mg of the target compound.