Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1.CN(C)[CH:30]=[O:31].Cl>CCCCCC.O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([CH:30]=[O:31])=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CS(=O)(=O)c1ccc(-c2cc(C=O)sc2-c2ccc(F)cc2)cc1
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6M) in hexane (36 ml) was added dropwise to a stirred solution of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (8.0 g) in tetrahydrofuran (80 ml) at -60° C. The mixture was stirred for 30 minutes, and N,N-dimethylformamide (3.7 ml) was added dropwise over ten minutes to the mixture. The mixture was stirred at -70° to -20° C. for 2 hours. 1N Hydrochloric acid (70 ml) was added dropwise, and the solution was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The residual syrup was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (9:1). The obtained crystals (4.5 g) were recrystallized from ethyl acetate to give pale yellow crystals of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbaldehyde (3.7 g).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[O:23])[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(C(=O)O)c3)nc2N1C1CCCC1
Reactant: C1COCCN1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(C(=O)N4CCOCC4)c3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 39, with (R)-1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-imidazole-4-carboxylic acid (Example 37) instead of (R)-1-(8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 44), and with morpholine instead of dimethylamine hydrochloride. 1H NMR (CDCl3) δ: 8.79 (s, 1H), 8.35 (s, 1H), 7.78 (s, 1H), 4.36-4.42 (m, 1H), 4.33-4.35 (m, 1H), 3.76-3.99 (bs, 8H), 3.39 (s, 3H), 1.71-1.93 (m, 10H), and 0.87 ppm (t, J=7.2 Hz, 3H); LCMS: 440.1 m/z (M+H)+; ret. Time: 3.850 min (Analytical Method A).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8](F)[C:5]=1[CH:6]=O.[SH:13][CH2:14][C:15]([OH:17])=[O:16]>CN(C)C=O>[Br:3][C:4]1[C:5]2[CH:6]=[C:14]([C:15]([OH:17])=[O:16])[S:13][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CS
Reactant: O=Cc1c(F)cccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2c(Br)cccc2s1
Temperature: 136 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
Potassium hydroxide (415.1 g, 7.40 mol) is added to a stirred solution of 2-bromo-6-fluorobenzaldehyde (1.00 Kg, 4.93 mol) and mercaptoacetic acid (453.8 g, 4.93 mol) in dimethylformamide (5.0 L). The resultant solution is brought to and maintained at reflux (136° C.) for 90 min. The reaction mixture is allowed to cool to room temperature and is quenched by the slow addition of hydrochloric acid (2.25 M, 5.90 L) over 5 min. The mixture is cooled to 10° C., stirred for 1 h and the observed solid material is collected by filtration. The filter cake is washed with water (1.00 L) and hexanes (2.00 L) and dried in vacuo at 40 to 45° C. to constant weight to yield the title compound (990.0 g, 78.2%). 1H NMR (DMSO, d6): δ 13.8 (bs, 1H), 8.10 (d, 1H, J=8.2 Hz), 7.97 (s, 1H), 7.72 (d, 1H, J=7.6 Hz), 7.45 (t, 1H, J=8.0 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=1.[CH:7](=[O:10])[CH2:8][CH3:9]>>[N:1]1[CH:6]=[C:5]([C:7](=[O:10])[CH2:8][CH3:9])[N:4]=[CH:3][C:2]=1[C:7](=[O:10])[CH2:8][CH3:9]
Reactant: c1cnccn1
Reactant: CCC=O
Product: CCC(=O)c1cnc(C(=O)CC)cn1

Procedure:
The reaction of pyrazine and propionaldehyde is conducted on a 10 mmole scale using the Caronna et al procedure described in J. Chem. Soc., Perkin Trans. 2, 14, 2035-8 (1972). A 50% crude yield of 1,1'-(2,5-pyrazinediyl)bis-1-propanone is obtained.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][Si:9](Cl)([CH3:11])[CH3:10].C(N(CC)CC)C>CCOCC>[CH3:8][Si:9]([CH3:11])([CH3:10])[S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)CS
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)CS[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of ethyl mercaptoacetate (9.0 mL, 83.2 mmol) in 15 mL of anhydrous ether under nitrogen atmosphere was added trimethylsilyl chloride (12.0 mL, 94.6 mmol) followed by triethyl amine (13.0 mL, 93.3 mmol) slowly. White precipitates were formed upon addition of triethyl amine. The suspension was allowed to stir at room temperature overnight. The white precipitate was removed by filtration. The filtrate was concentrated on a rotavap. The residue oil was distilled at 40° C. (0.5 mm Hg) to give 10.9 g (68%) of ethyl (trimethylsilylthio)acetate as a colorless oil. 1HNMR (300 MHz, CDCl3) δ4.18 (2H, q, J=7.19 Hz), 3.20 (2H, s), 1.29 (3H, t, J=7.12 Hz), 0.35 (9H, s).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:20]([NH2:30])[C:21]1[CH:29]=[CH:28][C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=1>>[CH2:25]1[O:26][C:27]2[CH:28]=[CH:29][C:21]([CH2:20][NH:30][C:5]3[N:10]=[C:9]([N:11]4[C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=5[N:13]=[CH:12]4)[CH:8]=[CH:7][N:6]=3)=[CH:22][C:23]=2[O:24]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: c1ccc2c(c1)ncn2-c1ccnc(NCc2ccc3c(c2)OCO3)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with piperonylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 346.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.42 (br s, 1H); 8.11 (br s, 1H); 7.86 (m, 1H); 7.38 (m, 2H); 6.89 (m, 2H); 6.83 (m, 2H); 5.97 (s, 2H); 5.79 (br s, 1H); 4.65 (d, J=5.7 Hz, 2H).
Reaction SMILES: C=O.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]1)[CH2:9]2)([O-])=O.[CH3:21]C(O)=O.C([BH3-])#N.[Na+]>CO.C1COCC1>[CH3:21][NH:3][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]1)[CH2:9]2
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Reaction time: 4 h

Procedure:
To a stirred mixture of formaldehyde (0.026 mL of a 37 wt % aqueous solution, 0.32 mmol), (±)-5′-amino-spiro[imidazolidine-4,2′-indane]-2,5-dione (described in Intermediate 45) (50 mg, 0.23 mmol), and AcOH (0.053 mL, 0.92 mmol) in MeOH (3 mL) at ambient temperature was added sodium cyanoborohydride (0.34 mL of a 1 M solution in THF, 0.34 mmol) and the reaction mixture was stirred for 4 h, then concentrated ill vacuo. The residue was partioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was removed, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as an off-white solid. MS: m/z=232 (M+1).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=[CH:11]2.[CH3:21][NH:22][C:23](=[O:31])[C:24]1[CH:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1>CS(C)=O>[CH3:21][NH:22][C:23]([C:24]1[CH:29]=[C:28]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=[CH:11]3)[CH:27]=[CH:26][N:25]=1)=[O:31]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CNC(=O)c1cc(Oc2ccc3c(C(=O)O)cccc3c2)ccn1
Temperature: 100 °C

Procedure:
Cs2CO3 (52.0 g, 160 mmol) was added to a solution of 6-hydroxy-1-naphthoic acid (10 g, 53.0 mmol) in DMSO (140 mL). After stirring vigorously for 15 min N-methyl-4-chloropicolinamide (10.8 g, 61.0 mmol) was introduced and the mixture was heated at 100° C. for 10 h. After cooling to RT, the mixture was filtered through a plug of silica gel (10:1:0.5; CH2Cl2, CH3OH, AcOH). The filtrate was concentrated and triturated with EtOAc to provide the title compound as a slightly pink solid. MS (ESI, pos. ion) m/z: 323.3 (M+1). Mass Calc'd for C18H12N2O4: 322.31.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=2)[CH:3]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:15]([CH2:16][CH:17]([CH3:19])[CH3:18])=[O:28])=[CH:7][CH:8]=2)[CH:3]=1
Reactant: CC(C)CSc1ccc2cc([N+](=O)[O-])c(N)cc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)CS(=O)c1ccc2cc([N+](=O)[O-])c(N)cc2c1

Procedure:
To 0.1 mol of 2-amino-7-isobutylthio-3-nitronaphthalene, prepared in Example 5, stirring in 200 ml of chloroform at 4°-6° (ice bath), is added 0.1 mol of m-chloroperbenzoic acid in 160 ml of chloroform over 3 hours. Consumption of starting material is confirmed by TLC (silica gel, ether). The reaction mixture is washed 3 times with saturated NaHCO3 solution, dried (Na2SO4), and filtered. The filtrate is evaporated to dryness under vacuum and the residue recrystallized from ethanol (absolute) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[C@@H:14]2[CH2:16][C@@H:15]2[F:17])=[C:4]([N+:24]([O-])=O)[CH:3]=1.C(Cl)(Cl)Cl>C(#N)C.[C].[Pd]>[NH2:24][C:4]1[CH:3]=[C:2]([F:1])[C:11]([O:12][CH3:13])=[C:10]2[C:5]=1[C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[C@@H:14]1[CH2:16][C@@H:15]1[F:17]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)cc([N+](=O)[O-])c2c1=O
Agent: [Pd]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)cc(N)c2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.4 %

Procedure:
Ethyl 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (3.71 g, 10.1 mmol) was dissolved in acetonitrile (50 ml), and after adding a 5% palladium carbon catalyst (water content: 50%, 1.5 g) thereto, it was stirred at room temperature for 20 hours under a hydrogen atmosphere at atmospheric pressure. After removing the catalyst by filtering (methanol washing), the filtrate was concentrated under a reduced pressure, the residue obtained was applied to a silica gel chromatography, and 2.68 g (79%) of the title compound was obtained as a yellow amorphous substance from a chloroform:methanol=30:1 eluate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:75]=[C:74]([O:76][CH3:77])[CH:73]=[C:72]([O:78][CH3:79])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:31]([CH:34](/[CH:58]=[CH:59]/[C:60]1[C:65]([O:66][CH3:67])=[CH:64][C:63]([O:68][CH3:69])=[CH:62][C:61]=1[O:70][CH3:71])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([NH:43][C:44](=[O:57])[C:45]2[CH:50]=[C:49]([N+:51]([O-])=O)[CH:48]=[C:47]([N+:54]([O-])=O)[CH:46]=2)[CH:36]=1)(=[O:33])=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[C:20]([N+:27]([O-])=O)[CH:19]=2)[CH:9]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>O.CC(C)=O>[CH3:79][O:78][C:72]1[CH:73]=[C:74]([O:76][CH3:77])[CH:75]=[C:3]([O:2][CH3:1])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:31]([CH:34](/[CH:58]=[CH:59]/[C:60]1[C:61]([O:70][CH3:71])=[CH:62][C:63]([O:68][CH3:69])=[CH:64][C:65]=1[O:66][CH3:67])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([NH:43][C:44](=[O:57])[C:45]2[CH:50]=[C:49]([NH2:51])[CH:48]=[C:47]([NH2:54])[CH:46]=2)[CH:36]=1)(=[O:32])=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:30])[C:18]2[CH:19]=[C:20]([NH2:27])[CH:21]=[C:22]([NH2:24])[CH:23]=2)[CH:9]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3cc(N)cc(N)c3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3cc(N)cc(N)c3)c2)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4,6-trimethoxystyryl-3-(3,5-dinitrobenzamido)-4-methoxybenzylsulfone (example 5) (1.3 mmol) in acetone water (10:5) was heated to 50° C. After 30 min, sodiumhydrosulfite (Na2S2O4) (26.3 mmol) was added slowly, and the mixture was heated at reflux (50° C., 1 h.), cooled to room temperature and water was added. The product was rinsed with NaHCO3, and then isolated by extraction with ethyl acetate. The organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was recrystallized from 2-propanol to yield pure (E)-2,4,6-trimethoxystyryl-3-(3,5,diaminobenzamido)-4-methoxybenzylsulfone. m.p. 208-210° C. NMR (DMSO-d6) δ 3.76(s, 3H), 3.80(s, 6H), 3.82(s, 3H), 4.4(s, 2H), 5.9(s, 1H), 6.2(s, 2H), 7.05-8.26(m, aromatic), 8.85(s, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[N:17]3[CH:18]=[CH:19][N:20]=[C:16]3[CH:15]=[C:14]([C:21]([O:23]C)=O)[N:13]=2)[CH:9]=[N:8]1.CCO.O.[NH2:31][NH2:32]>>[CH3:26][Si:2]([CH3:1])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[N:17]3[CH:18]=[CH:19][N:20]=[C:16]3[CH:15]=[C:14]([C:21]([NH:31][NH2:32])=[O:23])[N:13]=2)[CH:9]=[N:8]1
Reactant: NN
Reactant: COC(=O)c1cc2nccn2c(-c2cnn(COCC[Si](C)(C)C)c2)n1
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(-c2nc(C(=O)NN)cc3nccn23)cn1
Yield: 92.7 %

Procedure:
In a 20 mL flask, methyl 5-(1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylate (Example 122; Step C) (50 mg, 0.13 mmol) was dissolved in EtOH (540 μL, 0.13 mmol). To this was added a large excess of hydrazine hydrate (104 μL, 3.3 mmol). The reaction mixture was refluxed for 1 hour, and then concentrated down to dryness. The residue was diluted in EtOAc and washed with water and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo to afford 5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carbohydrazide (45 mg, 90% yield) as a yellow oil. MS (apci) m/z=374.4 (M+H).
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[OH:25])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(O)C>[C:14]([C:13]1[CH:22]=[CH:23][C:24]2[O:25][CH2:8][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:10][C:11]=2[CH:12]=1)(=[O:15])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1ccccc1)c1ccc(O)c(O)c1
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)C1COc2ccc(C(=O)c3ccccc3)cc2O1
Reaction time: 8 h

Procedure:
11.63 ml of ethyl 2,3-dibromopropionate was added drop-by-drop over a 15-minute period to a mixture of 15.9 g of 5B, 58.5 g of anhydrous potassium carbonate and 250 ml of acetone. The stirred mixture was refluxed for 7 hours and stored overnight. The mixture was filtered and the solvent was evaporated from the filtrate under reduced pressure (40° C.). The residue was suspended in 600 ml of ether and the mixture was washed with water, then with sodium bicarbonate solution, then dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using chloroform as eluent. Workup with ether and removal of the solvent gave a residue which was suspended in ethanol and placed in a freezer overnight. The solid was collected, washed with ethanol and dried to give 5, mp: 70°-71° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=O)[C:5]([C:6]=23)=[N:4][NH:3]1.ClCCl.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[BH4-].[Na+]>C(O)(=O)C>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:18][C:17]2[CH:16]=[C:15]([CH:14]3[C:5]4=[N:4][NH:3][C:2](=[O:1])[C:11]5[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=54)[NH:12][CH:13]3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:35][CH2:34]1
Reactant: CN1CCNCC1
Reactant: O=Cc1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2cccc(C3c4n[nH]c(=O)c5cccc(c45)NC3c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a stirred solution of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (150 mg, 0.4 mmol) in dryness dichloromethane (10 mL) was added acetic acid followed by 1-methylpiperazine (121 mg, 1.2 mmol). After the addition, the mixture was stirred at room temperature for 1 h, Then the mixture was cooled to 0° C. Sodium borohydride (130 mg, 0.2 mmol) was added. After the addition, the mixture was stirred at this temperature for 3 hr. Dichloromethane was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by pre-HPLC to give 9-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as white solid (22 mg, yield 12%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.31 (s, 3H), 2.36-2.48 (m, 8H), 3.37-3.48 (dd, 2H), 4.30 (dd, 1H), 4.71 (dd, 1H), 7.01 (s, 1H), 7.05 (dd, 1H), 7.17-7.23 (m, 5H), 7.25-7.28 (m, 2H), 7.56 (dd, 1H), 7.61-7.65 (t, 1H); LC-MS (ESI) m/z: 452 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1.C([O-])(O)=O.[Na+]>CO.O>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C:2]2[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=2)[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1ccc[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1[nH]cccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-aminopyridin-2(1H)-one (99 mg, 0.90 mmol), 2,4,5-trichloropyrimidine (165 mg, 0.90 mmol, 1 equiv.) and NaHCO3 (76 mg, 0.90 mmol, 1 equiv.) in a mixture of MeOH (6 mL) and H2O (3 mL) is stirred at room temperature for 24 h. The resulting precipitate is collected by vacuum filtration and washed with small amounts of MeOH and water, providing the product 3-(2,5-dichloropyrimidin-4-ylamino)pyridin-2(1H)-one; ESMS m/z 257.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:27][CH3:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[CH2:31]([O:33][C:34]1[CH:46]=[CH:45][C:37]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:36][CH:35]=1)[CH3:32]>>[CH3:1][N:2]([CH3:30])[C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:19]([CH2:27][CH3:28])[CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:18]=3)([N:38]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH2:31][CH3:32])=[CH:46][CH:45]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[O:9][C:8]2=[O:10])=[CH:5][CH:4]=1
Reactant: CCN(Cc1ccccc1)c1ccc(C(=O)c2ccc(N(C)C)cc2C(=O)O)cc1
Reactant: CCOc1ccc(Nc2ccccc2)cc1
Product: CCOc1ccc(N(c2ccccc2)C2(c3ccc(N(CC)Cc4ccccc4)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Yield: 50.5 %

Procedure:
Following a procedure similar to that described in Example 4 but employing 4.0 g of 5-(dimethylamino)-2-[4-(ethylbenzylamino)benzoyl]benzoic acid and 2.2 g of 4-ethoxy-N-phenyl aniline there was obtained 3.0 g of 6-(dimethylamino)-3-[4-(ethylbenzylamino)phenyl]-3-[(4-ethoxyphenyl)phenylamino]phthalide, m.p. 148°-152° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed an orange-colored image which changed to green on clay after fluorescent light exposure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:12]Br>O1CCOCC1>[Br:12][CH2:10][C:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1cc(F)cc(F)c1
Solvent: C1COCCO1
Product: O=C(CBr)c1cc(F)cc(F)c1
Reaction time: 0.17 h
Yield: 64.3 %

Procedure:
To a solution of 3′,5′-difluoroacetophenone (3 g, 19.2 mmol) (Lancaster Synthesis) in dioxane (30 mL) was added dropwise a solution of bromine (3.67 g, 23 mmol) in dioxane (75 mL). After stirring for 10 minutes, the mixture was concentrated in vacuo and the residue was purified by flash chromatography, with 10:2 hexanes/dichloromethane as an eluant, to provide 2-bromo-1-(3,5-difluorophenyl)ethanone as a colorless oil (2.9 g, 64% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][N:34]3[CH2:33][CH2:32][N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH2:22][CH3:23])[CH2:36][CH2:35]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NOC(CCCC=O)C2)cc1OC
Reactant: CCOc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1N1CCN(CCCCC2CC(c3ccc(OC)c(OC)c3)=NO2)CC1
Yield: 60.2 %

Procedure:
4-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]butanal (25.1 mg, 0.090 mmol), 1-(2-ethoxyphenyl)piperazine hydrochloride (20.0 mg, 0.082 mmol), molecular sieve (5 beads), NaBH(OAc)3 (52.4 mg, 0.247 mmol) and diisopropylethylamine (26.9 L, 0.082 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 23.1 mg (66.7%) of the target compound was obtained.