Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:15]([C:19]1([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[O:24][C:23](=[O:25])[CH:22](Cl)[C:21](=[O:27])[CH2:20]1)[CH2:16][C:17]#[CH:18]>CN(C=O)C>[CH2:15]([C:19]1([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[O:24][C:23](=[O:25])[CH:22]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21](=[O:27])[CH2:20]1)[CH2:16][C:17]#[CH:18]
Reactant: Sc1ccccc1
Reactant: C#CCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCCC1(C2CCCC2)CC(=O)C(Sc2ccccc2)C(=O)O1
Yield: 35.8 %

Procedure:
A solution of thiophenol (0.23 mL, 2.2 mmol), triethyl amine (0.156 mL, 1.1 mmol), and 6-but-3-ynyl-3-chloro-6-cyclopentyl-dihydro-pyran-2,4-dione (0.30 g, 1.1 mmol; prepared as described in step 1 above) in DMF (3 mL) was stirred at room temperature for 2 hours. The reaction was then concentrated by rotary evaporation, and then chromatographed (40 g silica gel, gradient elution from 40% EtOAc/Hexanes to 75% EtOAc/Hexanes) to yield the title compound (135 mg, 36%). 1H NMR (CDCl3): δ1.31-1.80 (m, 9H); δ1.96-2.00 (m, 2 H); δ2.03-2.11 (3H, m); δ2.85 (2H, dd, J1=17.94, J2=27.03); δ7.13-7.36 (5H, m). Anal. Calcd. for C20H22O3S.0.1 MeOH.0.15 CH2Cl2: C, 67.86; H, 6.38; S, 8.95. Found C, 68.08; H, 6.48; S, 8.52. ESIMS (M+Na+): 365.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].S([O-])(O)=O.[Na+].[Br:16]([O-])(=O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC#N.O.CCOCC>[Br:16][C:10]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(CO)c1
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: COc1cc(CO)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a solution of 5.00 g of 3-methoxybenzyl alcohol in MeCN-water (180 ml, 1:1) was added 8.60 g sodium hydrogen sulfite and 8.19 g of sodium bromate and the reaction mixture was stirred at room temperature for two hours. After the reaction, an aqueous solution of 10% sodium thiosulfate and Et2O were added, and liquid separation was performed. After the organic layer was sequentially washed with 5% K2CO3, water and saturated brine, and dried over MgSO4, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/4; v/v) to obtain 5.02 g of the title compound (colorless solid).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH:21]([CH3:25])[CH2:22][O:23][CH3:24])=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1>C(OCC)(=O)C.CS(C)=O.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH:21]([CH3:25])[CH2:22][O:23][CH3:24])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COCC(C)Nc1c([N+](=O)[O-])cnc2cc(-c3c(C)noc3C)c(OC)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N-(1-methoxypropan-2-yl)-3-nitroquinolin-4-amine (for a preparation see Intermediate 1)(25.8 g, 66.8 mmol) was dissolved in a mixture of ethyl acetate (1000 ml) and DMSO (50 ml) and the solution was hydrogenated using a flow-hydrogenation apparatus (H-cube™) (settings: 20° C., 1 bar, 1 ml/min flow rate) and a 10% Pd/C CatCart 70 catalyst cartridge. The catalyst cartridge was changed whenever it became blocked. The reaction mixture was evaporated under reduced pressure and partitioned between ethyl acetate (750 ml) and water (3×750 ml). The aqueous layers were combined and extracted with ethyl acetate (750 ml). The organic layers were were combined, dried (hydrophobic frit) and evaporated under reduced pressure. The residue was dissolved in DCM and applied to a silica cartridge (100 g). The cartridge was eluted with a 2M ammonia in methanol/DCM gradient (0-4%). The appropriate fractions were combined and evaporated under reduced pressure to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine and recovered 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N-(1-methoxypropan-2-yl)-3-nitroquinolin-4-amine (6.5 g)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH3:15])[N:10]([CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(-c2ccc(Br)cc2)cc1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(-c2ccc(Br)cc2)nn1C
Yield: 22.4 %

Procedure:
A mixture of 3-(4-bromophenyl)-5-hydroxy-1-methylpyrazole (2.5 g), acetone (200 ml), potassium carbonate (1.6 g) and methyl iodide (1.4 g) was heated at reflux for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by flash column chromatography on silica gel using 10% ethyl acetate/toluene as eluent to give 3-(4-bromophenyl)-5-methoxy-1-methypyrazole (590 mg) as a solid, m.p. 71°-73° C.; NMR: 3.6(3H,s), 3.9(3H,s), 6.2(1H,s), 7.5-7.6(2H,d) and 7.6-7.7(2H,d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[N:17][C:12]3[O:13][CH2:14][CH2:15][NH:16][C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([Br:31])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].C(N(CC)CC)C.O>ClCCl>[Br:19][C:20]1[CH:21]=[C:22]([C:23]([N:16]2[CH2:15][CH2:14][O:13][C:12]3[N:17]=[CH:18][C:9]([C:5]4[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:10][C:11]2=3)=[O:24])[CH:26]=[C:27]([Br:31])[C:28]=1[O:29][CH3:30]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: COc1cncc(-c2cnc3c(c2)NCCO3)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cncc(-c2cnc3c(c2)N(C(=O)c2cc(Br)c(OC)c(Br)c2)CCO3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
In a 10 ml flask, 7-(5-methoxy-pyridin-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (72 mg, 0.30 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (146 mg, 0.45 mmol) were dissolved in dichloromethane. Triethylamine (0.21 ml, 1.50 mmol) was added thereto and then stirred at room temperature for 3 hours. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(5-methoxy-pyridin-3-yl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (116 mg, 73%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[O:20]1[CH2:24][CH2:23][O:22][CH:21]1[CH2:25][CH2:26][NH2:27]>>[O:20]1[CH2:24][CH2:23][O:22][CH:21]1[CH2:25][CH2:26][NH:27][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: NCCC1OCCO1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCC3OCCO3)s2)c(C)[nH]c1=O
Yield: 50.5 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-(1,3-dioxolan-2-yl)ethylamine as described in Step 5, Example 24 to give the title compound as a solid (50.5% yield). LC/MS: RT 2.58 min; m/e 399 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 7.8 (1H, br s); 7.56 (1H, d); 7.35 (1H, s), 7.18 (1H, d), 4.8 (1H, t), 3.8 (2H, m), 3.75 (2H, m), 2.95 (2H, m), 2.4 (2H, q), 2.36 (3H, s), 1.75 (2H, m), 1.08 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Br.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH2:13]([O:12][P:11]([CH2:4][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:14]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1c(Cl)cccc1Cl)OCC
Temperature: 150 °C

Procedure:
2,6-Dichlorobenzyl bromide (1.20 g, 5 mmol) was mixed with triethyl phosphite (1.66 g, 10 mmol) and heated at 150° C. for 2 h. The resulting mixture was then distilled at 160° C. under reduced pressure (10 mm Hg) to remove the excess triethyl phosphite. (2,6-Dichloro-benzyl)-phosphonic acid diethyl ester was obtained as a colorless liquid (1.46g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.33-7.28 (m, 2H), 7.15-7.07 (m, 1H), 4.14-4.02 (m, 4H), 3.60 (d, 2H, J=22.4 Hz), 1.27 (t, 6H, J=7.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[C:16]([CH3:34])=[C:17]([NH:21][CH2:22][C:23]5[CH:31]=CC(OC)=[CH:28][C:24]=5[C:25]([OH:27])=O)[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:12]=[C:11]([C:35](=[O:37])[NH2:36])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[C:72]([O:75][CH2:76][CH3:77])(=O)C.CCCCCC>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[CH2:22][C:23]6[C:24](=[CH:28][C:76]([O:75][CH3:72])=[CH:77][CH:31]=6)[C:25]5=[O:27])[C:16]=4[CH3:34])=[CH:13][N:12]=[C:11]([C:35]([NH2:36])=[O:37])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2cccc(-c3cnc(C(N)=O)c4[nH]c5cc(Br)ccc5c34)c2C)c(C(=O)O)c1
Reactant: CCOC(C)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc2c(c1)C(=O)N(c1cccc(-c3cnc(C(N)=O)c4[nH]c5cc(Br)ccc5c34)c1C)C2
Yield: 78 %

Procedure:
A mixture of 2-((3-(7-bromo-1-carbamoyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-methoxybenzoic acid (0.425 g, the crude product from the previous step), BOP (1.008 g, 2.279 mmol), and N-methylmorpholine (0.752 mL, 6.84 mmol) in DMF (Volume: 5 mL) was stirred at 50° C. for 1 hr. The mixture was diluted with ethyl acetate (100 mL), washed with water (2×25 mL) and brine (25 mL), and dried over anhydrous MgSO4. The desired product (0.198 g, 78% yield over 2 steps), was isolated as a yellow solid by ISCO (40 g silica gel, solid loading, 40-80% ethyl acetate/hexane).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:4]=1.[Br:18]N1C(=O)CCC1=O.CN([CH:29]=[O:30])C>>[Br:18][CH:9]([C:5]1[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=1)[CH:10]([O:30][CH3:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)C=O
Reactant: CCCCCCCCCc1cccc(OC)c1
Product: CCCCCCCC(OC)C(Br)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 1-methoxy-3-nonyl benzene (7.5 g; 32 mmol) in DMF (60 mL) was cooled to −10° C. and N-bromosuccinimide (5.42 g; 30 mmol) was added under stirring over 30 minutes. The MeOH/ice bath was removed after 1 hour and the reaction mixture was left overnight with stirring. The reaction mixture was poured onto H2O (100 mL) and 10 M NaOH (aq) was added. The alkaline slurry was extracted with EtOAc (2×) and the combined organic fractions washed with 1 M NaOH (aq.; 2×), dried (MgSO4), filtered and evaporated to dryness. The crude product was further purified by column chromatography (SiO2; EtOAc/PE80-100° C.=0:1→1:20) to yield 9.8 g (quantitative) of product with satisfactory purity.
Reaction SMILES: [CH:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:12]([Li])[CH2:13][CH2:14]C.C(I)C=C>C1COCC1>[CH2:14]([C:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1)[CH:13]=[CH2:12]
Reactant: CCCCOS(=O)(=O)C1CC1
Reactant: [Li]CCCC
Agent: C=CCI
Solvent: C1CCOC1
Product: C=CCC1(S(=O)(=O)OCCCC)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 1-butyl cyclopropanesulfonate (4.8 g, 24.9 mmol) in THF at −78° C. was added simultaneously butyllithium solution (15.6 ml, 24.9 mmol, 1.6M, THF) and allyl iodide (24.9 mmol) under nitrogen atmosphere. The reaction mixture was stirred 2 hours at −78° C. and 3 hours at room temperature. The volatiles were evaporated under reduced pressure and the residue extracted with CH2Cl2 (100 ml). The extract was washed with water, dried (MgSO4) and evaporated. The residue was purified over silica gel chromatography (eluants: hexane/CH2Cl2) to obtain the titled product (3.75 g, 69.0%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 5.6 (m, 1H), 5.13-5.08 (t, 2H), 4.21 (t, 2H), 2.65 (d, 2H), 1.7 (m, 2H), 1.4 (m, 4H), 0.93 (m, 5H).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[CH3:25])[CH:20]=O>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:20][C:19]3[CH:22]=[CH:23][C:24]([CH3:25])=[C:17]([CH3:16])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1C
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Product: Cc1ccc(CN2CCN(C(=O)Nc3ccccc3)CC2)cc1C

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 3,4-dimethylbenzaldehyde. 1H NMR (400 MHz, CDCl3): 7.35-7.26 (m, 4H), 7.11-7.00 (m, 4H), 6.31 (s, 1H), 3.51-3.48 (m, 6H), 2.49-2.26 (m, 4H), 2.26 (d, J=3.8 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12]([OH:13])=[N:11][N:10]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:31][CH:32]1[CH2:35][O:34][CH2:33]1>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:12]([O:13][CH2:31][CH:32]3[CH2:35][O:34][CH2:33]3)=[N:11][N:10]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:15])=[O:16])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: ICC1COC1
Reactant: Cc1ccc(S(=O)(=O)n2nc(O)c3cc([N+](=O)[O-])cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2nc(OCC3COC3)c3cc([N+](=O)[O-])cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
5-Nitro-1-tosyl-1H-pyrazolo[3,4-b]pyridin-3-ol (0.05 g, 0.150 mmol) was dissolved in DMF (1.5 mL). Cesium carbonate (0.146 g, 0.450 mmole) was added, and then 3-(iodomethyl)oxetane (0.030 g, 0.150 mmol; prepared according to US 2008/0021032) was added to the mixture. The mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water and extracted with EtOAc (2×50 mL), and the extracts were washed with brine (1×), dried over sodium sulfate and concentrated under reduced pressure. Preparative TLC (0.5 mm plate, 1:1 ethyl acetate/hexanes) afforded 5-nitro-3-(oxetan-3-ylmethoxy)-1-tosyl-1H-pyrazolo[3,4-b]pyridine (15 mg, 19%) as a solid. 1H NMR (400 MHz, CDCl3) δ 9.54-9.52 (m, 1H), 8.83-8.81 (m, 1H), 8.05-7.99 (m, 2H), 7.34-7.28 (m, 2H), 4.93-4.86 (m, 2H), 4.78-4.72 (m, 2H), 4.62-4.55 (m, 2H), 3.57-3.48 (m, 1H), 2.40 (s, 3H).
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH2:26][C:27]#[CH:28])[CH3:25]>N1CCCC1.C(Cl)Cl>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:28]#[C:27][CH2:26][N:24]([CH3:25])[CH3:23])=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc(Nc2ccc(I)cc2)nc1Nc1ccccc1
Reactant: C#CCN(C)C
Solvent: C1CCNC1
Solvent: ClCCl
Product: CN(C)CC#Cc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Yield: 17.8 %

Procedure:
A solution of 4-anilino-5-bromo-2-(4-iodoanilino)pyrimidine (Method 12; 200 mg, 0.40 mmol), N,N-dimethylpropargylamine (0.09 ml, 0.85 mmol) and tetrakis (triphenylphosphine)palladium (0) (25 mg, 0.02 mmol) in pyrrolidine (3 ml) was stirred for 60 hours and then heated at 80° C. for 2 hours. The mixture was diluted with DCM (10 ml) and silica (2 g) was added. Volatile material was removed by evaporation and the residue was loaded onto a Varian Mega Bond Elut column. Elution with 0–10% 2.0 M methanolic ammonia solution in DCM gave the product (30 mg, 17%). NMR: 2.2 (s, 6H), 3.4 (s, 2H), 7.2 (m, 3H), 7.4 (m, 2H), 7.6 (m, 4H), 8.2 (s, 1H), 8.6 (s, 1H), 9.5 (s, 1H); MS (MH+): 422.3, 424.3.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].CN(C)C=[O:10].Cl[CH2:13][CH:14]([CH3:30])[C:15]([C:17]1[CH:29]=[CH:28][C:20]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][CH:18]=1)=[O:16].Cl>C(O)CO.O>[OH:4][CH2:2][CH2:5][O:10][CH2:13][CH:14]([CH3:30])[C:15]([C:17]1[CH:29]=[CH:28][C:20]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][CH:18]=1)=[O:16]
Reactant: CC(C)(C)[O-]
Reactant: CC(CCl)C(=O)c1ccc(Cc2cccnc2)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: CC(COCCO)C(=O)c1ccc(Cc2cccnc2)cc1
Yield: 85.8 %

Procedure:
In 50 ml of ethylene glycol was dissolved 5.0 g of potassium tert-butoxide, and a mixed solution of 6 ml of N,N-dimethylformamide and 5.0 g of 3-[p-(3-chloro-2-methylpropionyl)benzyl]pyridine was added in small portions to the above solution with ice-cooling, after which the resulting mixture was subjected to reaction at the same temperature for 2 hours, and then neutralized with 9 ml of 2N hydrochloric acid and diluted with 50 ml of water. The resulting mixture was extracted with two 50-ml portions of methylene chloride. The extracts were combined, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform:ethyl acetate (1:3 by volume)] to obtain 5.63 g (yield 85.8%) of colorless, oily 3-[p-[3-(2-hydroxyethyl)oxy-2-methylpropionyl]benzyl]pyridine.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH2:12][CH2:13][OH:14]>C(O)C>[OH:14][CH2:13][CH2:12][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: OCCCl
Reactant: Oc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCCSc1ccc(O)cc1

Procedure:
4-Mercaptophenol (126 grams) was dissolved in 60 millimeters of ethanol. A solution of KOH (58 grams) dissolved in ethanol (150 millimeters) was added under a nitrogen blanket. 2-Chloroethanol (83 grams) was then added slowly and the combination allowed to react for 11/2 hours. The product was filtered and the volatiles stripped off. The weight of product was 172 grams.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:15])[CH2:4][CH2:3]1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH:31]=O.Cl.[C:38]([C:41]1[O:42][CH:43]=[CH:44][CH:45]=1)(=[NH:40])[NH2:39].N1CCCCC1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(O)(=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]2[C:13]([C:14]([O:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH2:11][O:10][CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[NH:40][C:38]([C:41]3[O:42][CH:43]=[CH:44][CH:45]=3)=[N:39]2)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: N=C(N)c1ccco1
Reactant: CN1CCN(CCOCC(=O)CC(=O)OCCCc2ccccc2)CC1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN1CCN(CCOCC2=C(C(=O)OCCCc3ccccc3)C(c3ccc(Cl)c(Cl)c3)N=C(c3ccco3)N2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 5.7 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(4-methyl-1-piperazinyl)ethoxy)acetoacetate (500 mg, 1.38 mmol), 3,4-dichlorobenzaldehyde (241.5 mg, 1.38 mmol), 2-amidinofuran hydrochloride (202.3 mg, 1.38 mmol) and catalytic amounts of piperidine (1 μL) and acetic acid (10 μL) was stirred in N,N-dimethylformamide (5 mL) for 2 days at room temperature. Sodium hydrogen carbonate was added and the reaction mixture was stirred for an additional 5 days at room temperature before heating to 60° C. for 3 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography to give the title compound (48 mg) as an oil. Electrospray MSm/z 611/613 [M+H]+.
Reaction SMILES: C(N([CH:7]([CH3:9])[CH3:8])CC)(C)C.[CH:10](NCCNC(C)C)([CH3:12])[CH3:11].FC(F)(F)[C:22]([OH:24])=[O:23].O>CS(C)=O>[C:22]([OH:24])(=[O:23])[C:8]1[CH:7]=[CH:9][CH:12]=[CH:10][CH:11]=1
Reactant: CC(C)NCCNC(C)C
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 ml of DMSO, 2 ml of diisopropylethylamine and 5 ml of N,N′-diisopropylethylenediamine were added to the resin obtained in step 1 to conduct the reaction at 60° C. for 3 days. The reaction solution was removed. The resin was washed with DMSO, DMF and dichloromethane 3 times each and then dried under reduced pressure. 5 g of Fmoc-succinimide and 25 ml of NMP were added to the obtained resin, and they were stirred at room temperature for 16 hours. The superfluous solvent was removed. The resin was washed with DMF 3 times, with dichloromethane 3 times, with NMP twice and again with dichloromethane 3 times, and then dried under reduced pressure. The resin thus obtained was treated with 500 μl of trifluoroacetic acid/water (95/5) for 1 hour. The resin was taken by the filtration and then washed with trifluoroacetic acid. The wash solutions were combined together, concentrated and purified by the reversed-phase HPLC (ODS column, developer: water (containing 0.05% of TFA) and acetonitrile (containing 0.05% of TFA) to obtain a benzoic acid derivative having a partial structure in Example 28.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]=O)[CH3:5].[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=C2[C:10]=1[C:11](=[O:31])[C:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=CN2.CI>C(OCC)(=O)C.O>[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:5]2[C:10]=1[C:11](=[O:31])[C:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[CH:6][N:4]2[CH3:3]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
Sodium hydride (60% in oil, 76 mg, 1.9 mmol) was added to a DMF solution (10 ml) of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (400 mg, 1.22 mmol). The mixture was stirred at room temperature for 15 minutes. Methyl iodide (225 mg, 1.6 mmol) was added thereto, and then the resulting mixture was stirred at room temperature for 19 hours. Water and ethyl acetate were added to the reaction mixture to separate the mixture into two layers. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 365 mg of powdery pale yellow 5-fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinolin-4-one (yield: 72%).