Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:9]([NH2:13])=[C:10]([NH2:12])[CH:11]=1.O=[C:19]([C:25](OCC)=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[C:10]2[C:9]([NH:13][C:25](=[O:26])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12]2)=[CH:8][C:7]=1[C:14]([F:15])([F:16])[F:17]
Reactant: Nc1cc(-c2ncc[nH]2)c(C(F)(F)F)cc1N
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1nc2cc(-c3ncc[nH]3)c(C(F)(F)F)cc2[nH]c1=O
Yield: 33.6 %

Procedure:
To a solution of 5-imidazolyl-4-trifluoromethyl-1,2-phenylenediamine (303 mg, 1.25 mmol) in ethanol (50 ml) was added diethyl ketomalonate (210 μl, 1.38 mmol) at room temperature, and the mixture was refluxed for 6 hours. The reaction mixture. was concentrated to around half volume under reduced pressure, then the precipitate was collected by filtration and washed with cold ethanol. The filtrate was distilled off under reduced pressure, small quantity of mixed solution of ethyl acetate-diisopropyl ether was added to the residue obtained and the precipitate was collected by filtration to obtain 148 mg of the title compound as pale yellowish brown powder. Yield 34%.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:27]3[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cc1
Yield: 43 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (46 mg) was reacted with 4-(methanesulfonyl)phenyl boronic acid as in General Procedure 4B to give the title compound as a yellow solid (43% yield). LCMS: m/z=394.22 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.08 (3H, s), 4.54 (2H, s), 5.28 (2H, s), 7.30 (3H, m), 7.39 (3H, m), 7.45 (2H, d, J=8.3 Hz), 7.78 (1H, d, J=1.5 Hz), 7.94 (2H, d, J=8.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]([NH2:28])[CH3:27])=[C:16]([F:29])[CH:15]=1.C(N(CC)CC)C>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]([NH:28][S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH3:27])=[C:16]([F:29])[CH:15]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(N)c1ccccc1-c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)cc1

Procedure:
The title compound was prepared from 4-methoxybenzenesulfonyl chloride (331 mg, 1.6 mmol), 1-(4′chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethylamine (400 mg, 1.6 mmol), and triethylamine (246 μL, 1.7 mmol) according to the procedure and in the same manner as described in Example 105, step c resulting in the isolation of 644 mg (96%) of a white solid;
Reaction SMILES: [OH:1][C:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]2[CH:17]=[C:18]([OH:23])[CH:19]=[C:20]([OH:22])[CH:21]=2)[CH:11]=[CH:12][CH:13]=1>[Pd]>[OH:1][C:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([OH:23])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(O)CCCCCc1cccc(C=Cc2cc(O)cc(O)c2)c1
Agent: [Pd]
Product: CC(C)(O)CCCCCc1cccc(CCc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 9(a), by reacting 600 mg (1.76 mmol) of 5-{2-[3-(6-hydroxy-6-methylheptyl)phenyl]vinyl}benzene-1,3-diol with 60 mg of 10% palladium/carbon, pinkish crystals (m=368 mg; Y=61%) are obtained. m.p.=102-3° C.
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[OH-].[K+].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.O>C(O)C>[I-:1].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH:9][CH:4]2[N:5]([CH3:8])[CH:6]=[CH:7][NH+:3]2[CH3:2])=[CH:15][CH:14]=1
Reactant: CC1N(C)C=C[NH+]1C
Reactant: O=Cc1ccc(Cl)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1C=C[NH+](C)C1C=Cc1ccc(Cl)cc1
Yield: 59.6 %

Procedure:
A mixture of 6.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 1g of potassium hydroxide, and 6 g of p-chlorobenzaldehyde is refluxed in 25 ml of absolute ethanol for 15 minutes during which time a precipitate is formed. The reaction mixture is cooled, 5 ml of water is added, and the solid is filtered off and dried. Crystallization from absolute ethanol yields 5.4 g of the title compound, melting point 266°-268° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].C(OC1C=C(C=C(OCC2C=CC=CC=2)C=1)CN)C1C=CC=CC=1>>[OH:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH2:1][NH2:2]
Reactant: N#Cc1cccc(C=O)c1
Agent: NCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: NCc1cccc(CO)c1
Yield: 66 %

Procedure:
This compound was prepared by reduction of 3-cyanobenzaldehyde according to the procedure described in preparation of 3,5-dibenzyloxybenzylamine. Yield was 66%: 1H NMR (Acetone-d6, 500 MHz) δ 7.32 (s, 1H), 7.23 (dd, 1H, J=7.6 and 7.0), 7.19, complex, 2H), 4.59 (s, 2H), 4.40 (s, 2H), 4.10 (br, 1H), 1.96 (br, 1H), 1.88 (br, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][C:11](=[O:13])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:14]1([O-])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C(OC(=O)C)(=O)C>[CH2:1]([C:8]1=[N:9][NH:10][C:11](=[O:13])/[C:12]/1=[C:15]1\[NH:14][C:23]2[C:18]([CH:17]=[CH:16]\1)=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(Cc2ccccc2)=NN1
Reactant: [O-][n+]1cccc2ccccc21
Solvent: CC(=O)OC(C)=O
Product: O=C1NN=C(Cc2ccccc2)/C1=C1\C=Cc2ccccc2N1

Procedure:
A mixture of 3-benzyl-1H-pyrazol-5(4H)-one (0.234 g, 1.34 mmol) and quinoline N-oxide (0.24 g, 1.34 mmol) were stirred in acetic anhydride (1.5 mL) at ambient temperature for 20-30 minutes. The reaction mixture was concentrated and the resulting solid filtered off and washed with a minimum amount of ether to yield the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (s, 2H) 3.98 (bs, 1H) 7.23-7.29 (m, 6H) 7.61 (t, J=7.58 Hz, 1H) 7.76-7.82 (m, 1H) 7.93 (d, J=8.34 Hz, 1H) 8.08-8.18 (m, 2H); ESI-MS: m/z calc'd for C19H15N3O 301.12. found 302.2 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]3[C:11]=2[CH2:12][N:13]([CH3:23])[C:14]3=[O:22])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[OH-].[Na+]>C(O)C.[Fe]>[NH2:19][C:16]1[CH:17]=[CH:18][C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]2)=[C:11]2[C:15]=1[C:14](=[O:22])[N:13]([CH3:23])[CH2:12]2
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)N1CCN(c2ccc(N)c3c2CN(C)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of 4-(4-Isopropyl-piperazin-1-yl)-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (4.56 g, 14 mmol) in ethanol (130 mL), iron powder (4.0 g, 70 mmol) and 1N hydrochloric acid (28 mL) are the mixture is added stirred at 60° C. for 3 hours. The mixture is cooled and then, 1N sodium hydroxide (28 mL) is added. After removing insoluble materials by filtration, the mixture is evaporated. The resulting pale yellow solids are collected by filtration and dried in vacuo at 50° C. to afford 7-Amino-4-(4-isopropyl-piperazin-1-yl)-2-methyl-2,3-dihydro-isoindol-1-one (3.43 g) as brown solids in 83% yield. Rf=0.18 (Hexane/AcOEt=111). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.09 (s, 3H), 1.10 (s, 3H), 2.65 (t, 4H), 2.75-2.69 (m, 1H), 2.96 (t, 4H), 3.13 (s, 3H), 4.28 (s, 2H), 4.99 (s, 2H), 6.56 (d, 1H), 6.99 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:21](=[CH:22][CH:23]=1)[O:20][C:11]1([CH2:14][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12]1)[CH2:10][C:9]2=[O:24].[OH-].[Na+]>>[CH2:18]([O:17][C:15]([N:13]1[CH2:14][C:11]2([CH2:10][C:9](=[O:24])[C:8]3[C:21](=[CH:22][CH:23]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:25])=[O:2])[CH:7]=3)[O:20]2)[CH2:12]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)OC)ccc3O2)C1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Yield: 70.2 %

Procedure:
(E)-3-[1′-Ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester (300 mg, 0.86 mmol) was hydrolyzed with 1 M NaOH following the procedure described in Example 30, Step A, giving (E)-3-[1′-ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (200 mg, hydrochloride salt) as a yellow solid.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:20])[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:26]N1C(C)(C)C(=O)N(Cl)C1=O>ClCCl.S(=O)(O)[O-].[Na+]>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([Cl:26])=[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:20])[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)ccc2c1=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)c(Cl)cc2c1=O

Procedure:
A solution of Example 74A (448 mg) and 1,3-dichloro-5,5-dimethylhydantoin (282 mg) in dichloromethane (15 mL) was stirred for 8 hours, diluted with 10% sodium bisulfite (30 mL), and extracted with dichloromethane. The extract was washed with water and brine (30 mL), and dried (MgSO4), filtered, and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[O:9][CH3:10].[S:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:13]2[CH:14]=[CH:15][S:11][CH:12]=2)[C:3]=1[O:9][CH3:10]
Reactant: COc1c(F)cccc1I
Reactant: OB(O)c1ccsc1
Product: COc1c(F)cccc1-c1ccsc1

Procedure:
2-Fluoro-6-(thien-3-yl)anisole is prepared from 2-fluoro-6-iodoanisole (1.35 g, 5.36 mmol) by Suzuki coupling with thiophene-3-boronic acid according to the general procedure described in Representative Procedure 4(b) below; yield: 1.05 g (94%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:22][C:23]([O:25]C)=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH:2]=[CH2:3].[OH-].[Na+]>>[CH2:1]([C:4]1[CH:5]=[C:6]([CH2:22][C:23]([OH:25])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(CC(=O)O)ccc1OCc1ccc2ccccc2n1

Procedure:
In analogy to the procedure of Example XV, the title compound is prepared from 2.0 g (5.8 mmol) of the compound from Example XXXVII and 10 ml (10 mmol) of 1N sodium hydroxide solution.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.Cl.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([NH:28][C:29]2[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=2)[C:25]([OH:27])=[O:26])[CH:21]=[CH:22][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>O1CCCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:24]([NH:28][C:29]2[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=2)[C:25]([O:27][C@@H:50]2[CH:51]3[CH2:54][CH2:55][N:48]([CH2:53][CH2:52]3)[CH2:49]2)=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1cc(F)c(F)c(F)c1)c1cccc(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cc(F)c(F)c(F)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
Polymer-Supported DiCyclohexylCarbodiimide (PS-DCC) (972 mg, 1.29 mmol, loading: 1.33 mmol/g) was suspended in dry tetrahydrofuran (10 ml). 2-(3-fluorophenyl)-2-(3,4,5-trifluorophenylamino)acetic acid hydrochloride (I42) (217 mg, 0.65 mmol), HOBT (198 mg, 1.29 mmol), and (R)-quinuclidin-3-ol (247 mg, 1.94 mmol) were added, and the mixture was shaken at r.t. for 16 hours. PS-DCC was filtered off, the filtrate was evaporated and the residue was dissolved in EtOAc and washed with NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The resulting crude compound was purified by filtration through a pad of silica-gel eluting with DCM/MeOH=93/7. The resulting white foam was dissolved in DCM and passed through an Isolute PE-AX cartridge (5 g, 0.6 mmol/g, DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(3-fluorophenyl)-2-(3,4,5-trifluorophenylamino)acetate (264 mg, 32% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]=[CH2:8])(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:14]>ClCCl>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[O:14][CH2:8]1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OCCC1CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-buten-1-yl acetate (5.7 g, 50 mmol) in dichloromethane (200 mL) was added m-chloroperoxybenzoic acid (12.9 g, 75 mmol). The reaction was then stirred at room temperature for 3 hours. The reaction mixture was then filtered through celite and concentrated in vacuo. The residue was purified by silica gel flash chromatography (4:1 hexanes:ethyl acetate) to yield 3,4-epoxybutan-1-yl acetate as a colourless oil in a yield of 3.8 g (58%). 1H NMR (CDCl3) δ 1.78-1.88 (m, 2H), 2.03 (s, 3H), 2.47 (m, 1H), 2.75 (m, 1H), 2.99 (m, 1H), 4.18 (t, 1H, J=6.6 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:16](I)[O:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([OH:27])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].CC#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CCOC(C)=O>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:16]([C:32]3[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:25]([OH:27])=[O:26])[O:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccn(Cc2ccccc2)c2oc(I)c(-c3ccccc3)c12
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)c1cccc(-c2oc3c(c2-c2ccccc2)c(=O)ccn3Cc2ccccc2)c1
Temperature: 85 °C

Procedure:
To a mixture of iodide 4f (2.94 g, 6.89 mmol, 1.0 equiv), 3-carboxyphenylboronic acid (1.26 g, 7.57 mmol, 1.1 equiv), tetrakis(triphenylphosphine)palladium (0.796 g, 0.689 mmol, 0.1 equiv), and sodium carbonate (2.92 g, 27.6 mmol, 4.0 equiv), was added MeCN (30 mL) and H2O (30 mL). The slurry was heated at 85° C. for 8 h. After cooling to rt, EtOAc (ca. 100 mL) and H2O (ca. 50 mL) were added. The aqueous layer was separated, filtered, and acidified with 1N HCl. The resulting white precipitate was filtered to provide acid 4k. MS (MH+) 422; Calculated 421.1 for C27H19NO4.
Reaction SMILES: [OH:1]O.[OH-].[Na+].[C:5]([C:8]1[N:12]([CH3:13])[N:11]=[C:10]([CH2:14][CH2:15][CH3:16])[C:9]=1[NH:17][C:18](=O)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1)(=[O:7])[NH2:6]>O.O1CCOCC1>[OH:1][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:18]2[NH:6][C:5](=[O:7])[C:8]3[N:12]([CH3:13])[N:11]=[C:10]([CH2:14][CH2:15][CH3:16])[C:9]=3[N:17]=2)=[CH:21][CH:22]=1
Reactant: CCCc1nn(C)c(C(N)=O)c1NC(=O)Cc1ccc(CBr)cc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(CO)cc3)nc12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Aqueous hydrogen peroxide (0.24 ml, 30% w/w, 0.0021 mol) was added to a solution of sodium hydroxide (180 mg, 0.0045 mol) in water (10 ml). A solution of N-(5-carbamoyl-1-methyl-3-propyl-1H-pyrazolyl)-2-(4-bromomethylphenyl)acetamide (400 mg, 0.001 mol) in dioxan (5 ml) was then added and the mixture stirred at 90° C. for 4 hours. On cooling, the reaction mixture was concentrated under reduced pressure, the residue dissolved in water (10 ml) and acidified to pH 5 with 1N aqueous hydrochloric acid. This solution was then extracted with dichloromethane (2×20 ml), the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:36]=[CH:37][C:38]=2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[CH2:12][N:13]2[C:18]([CH2:19][OH:20])=[CH:17][C:16](=[O:21])[C:15]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14]2)=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4].ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:36]=[CH:37][C:38]=2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[CH2:12][N:13]2[C:18]([CH:19]=[O:20])=[CH:17][C:16](=[O:21])[C:15]([O:22][CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14]2)=[CH:49][CH:50]=1
Reactant: COc1ccc(COc2ccc(Cn3cc(OC(c4ccccc4)c4ccccc4)c(=O)cc3CO)cc2OCc2ccc(OC)cc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(COc2ccc(Cn3cc(OC(c4ccccc4)c4ccccc4)c(=O)cc3C=O)cc2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
To a dichloromethane solution (210 ml) of 1-[3,4-bis(p-methoxybenzyloxy)benzyl]-3-diphenylmethoxy-6-hydroxymethyl-4-pyridone (0.462 g) is added active manganese dioxide (2.40 g), and the mixture is stirred at room temperature for 20 minutes. Insolubles are removed by filtration, the filtrate is subjected to flash column chromatography on 50 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroform-methanol (20:1) to perform separation and purification. The title compound (0.264 g) is thus obtained as colorless crystal.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[O:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccccc1Oc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
A 1.0 M solution of lithium aluminum hydride in THF (25 ml, 25 mmol) was added to a solution of crude 2-phenoxybenzoic acid methyl ester (5.23 g, 22.9 mmol) in THF. The reaction mixture was stirred for 2.5 hours at room temperature. Methanol (10 ml) was added carefully. THF (50 ml) was added. Magnesium sulphate was added. The solids were filtered off. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane (1:1) as eluent, to give 4.08 g of 2-phenoxybenzylalcohol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]2[CH3:21])=[CH:4][CH:3]=1.Br[C:23]1[C:24](=[O:31])[N:25]([CH3:30])[N:26]=[C:27]([Cl:29])[CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[Cl:29][C:27]1[CH:28]=[C:23]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]3[CH3:21])=[CH:4][CH:3]=2)[C:24](=[O:31])[N:25]([CH3:30])[N:26]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 100 °C
Yield: 86.6 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (S)-tert-butyl 4-(6-aminopyridin-3-yl)-3-methylpiperazine-1-carboxylate 191f (2.5 g, 8.5 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (2.2 g, 10.0 mmol), XantPhos (240 mg, 0.40 mmol), tris(dibenzylideneacetone)dipalladium(0) (360 mg, 0.40 mmol), Cs2CO3 (5.5 g, 17 mmol), and 1,4-dioxane (100 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2.5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1 to 30:1) to afford 224a as a pale yellow solid (3.2 g, 86%). MS-ESI: [M+H]+ 435.1.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](O)=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1>>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][C:7]([Cl:6])=[CH:8][CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: Oc1ccnc2cc(Cl)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(Cl)ccnc2c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Phosphorus oxychloride (4 mL, 429 mmol) was added to 7-chloro-4-hydroxyquinoline 2.86 g, 15.9 mmol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 2 h, then allowed to cool to room temperature. The solution was concentrated in vacuo to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NaHCO3 (aq). The slurry was filtered and washed with water. The solids were dried under vacuum, afforded 4,7-dichloroquinoline as a white solid (2.79 g, 88.5% yield).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([OH:10])=O)(=O)C.[C:17]1([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[C:17]1([S:23]([NH:26][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:5]([NH2:4])[CH:6]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CC(=O)Nc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)NS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N'-carbonyldiimidazole (28.9 g) was added to a solution of 20.0 g of 3-acetylamino-4-nitrobenzoic acid in 300 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Further, 28.00 g of benzenesulfonamide and 27.16 g of diazabicycloundecene were added thereto, and the mixture was stirred at 100° C. for 4 days. The solvent was distilled off under reduced pressure. Chloroform and a 10% sodium hydroxide aqueous solution were added to the residue, and the mixture was vigorously stirred. The aqueous layer was neutralized with 10% hydrochloric acid, and the mixture was vigorously stirred with the addition of chloroform. The crystals precipitated were separated through filtration, and were dried to 14.4 g of N-benzenesulfonyl-3-amino-4-nitrobenzamide.