Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.Br[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[NH:10][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>O.CCOC(C)=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[NH:10][CH:11]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(Br)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
To a stirred DMF solution (40 mL) containing methyl 4-bromo-1H-pyrrole-2-carboxylate (1.0 g, 4.9 mmol), commercially available from Bionet, and Pd(Ph3)4 (195 mg, 0.17 mmol) was added Na2CO3 (1.3 g, 12.52 mmol) (dissolved in minimum amount water) and 4-chlorophenyl boronic acid (0.85 g, 5.43 mmol) under Ar. The mixture was degassed, with Ar prior to stirring overnight at 110° C. After cooling the reaction to RT, it was diluted with 10 mL of water and 200 mL of EtOAc. The aqueous layer was extracted, with EtOAc (3×20 mL). The organic layers were combined, dried over Na2SO4, and cone, in vacuo to yield a brown oil. The oil was purified by column chromatography (silica gel, 0%-15% gradient elution with EtOAc/hexanes) to yield 288 mg (25%) of product as white solid. MS (ESI) 236 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](O)([CH2:32][CH3:33])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[CH:24]=3)[CH2:19]2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:42][C:39]2[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=2)([CH2:32][CH3:33])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[CH:24]=3)[CH2:19]2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1ccc(S)cc1
Reactant: CCC(O)(CCCCC(=O)N1CCc2cc(OC)c(OC)cc2C1)c1ccc(OC)c(OC)c1
Product: CCC(CCCCC(=O)N1CCc2cc(OC)c(OC)cc2C1)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1
Yield: 58 %

Procedure:
The procedure of Example 60 is repeated using of 2.7 g of 2-[6-(3,4-dimethoxyphenyl)-6-hydroxy-1-oxooctyl]-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline and 1.06 g of p-thiocresol. This affords 1.92 g of the desired product as a white foam.
Reaction SMILES: C(S[C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[N:13][N:14]([CH3:16])[CH:15]=2)[N:5]=1)C.[CH:24]1C=C(Cl)C=C(C(OO)=O)[CH:25]=1.[S:35]([O-:39])([O-])(=[O:37])=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.C(Cl)Cl>[CH2:24]([S:35]([C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[N:13][N:14]([CH3:16])[CH:15]=2)[N:5]=1)(=[O:39])=[O:37])[CH3:25]
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1nc(-c2cn(C)nc2-c2ccccc2F)ccc1N
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCS(=O)(=O)c1nc(-c2cn(C)nc2-c2ccccc2F)ccc1N
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a solution of 2-(ethylthio)-6-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine-3-amine(1.00 g, 3.04 mmol, 1.0 eq.) in THF (100 mL) under nitrogen at 0° C. was added MCPBA (77%, 1.60 g, 9.27 mmol, 3.05 eq.). After 3 h 15 min, 5% aqueous sodium thiosulfate and saturated aqueous NaHCO3 were added, and the solution was stirred for 10 min. CH2Cl2 was then added, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×), and the organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Trituration with EtOAc afforded 2-(ethylsulfonyl)-6-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine-3amine as a light tan solid (0.94 g, 85% yield).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:28]4[C:19](=[CH:20][C:21]5[O:26][CH2:25][CH2:24][O:23][C:22]=5[CH:27]=4)[O:18][CH2:17]3)[C:9]2=[O:29])[CH2:4][O:3]1>C(O)(=O)C.O>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([C:28]3[C:19](=[CH:20][C:21]4[O:26][CH2:25][CH2:24][O:23][C:22]=4[CH:27]=3)[O:18][CH2:17]2)[C:9]1=[O:29]
Reactant: CC1(C)OC[C@H](CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)O1
Solvent: CC(=O)O
Solvent: O
Product: O=C1N(C[C@H](O)CO)c2ccccc2C12COc1cc3c(cc12)OCCO3
Yield: 99.2 %

Procedure:
A solution of 1′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.66 g, 1.61 mmol) in glacial acetic acid (10 mL) and water (5 mL) was stirred at ambient temperature for 18 h and concentrated in vacuo. The residue was recrystallized from ethyl acetate to afford 1′-[(2S)-2,3-dihydroxypropyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.59 g, 99%): mp 179-181° C. (ethyl acetate/hexane); 1H NMR (300 MHz, DMSO-d6) δ 7.30-7.25 (m, 1H), 7.13-7.07 (m, 2H), 7.01-6.95 (m, 1H), 6.46 (s, 1H), 6.21-6.19 (m, 1H), 5.02-4.94 (m, 1H), 4.71-4.57 (m, 3H), 4.14-4.06 (m, 4H), 3.81-3.54 (m, 3H), 3.39-3.32 (m, 2H); MS (ES+) m/z 369.9 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:8][CH:9]=2)[C:4](=[O:19])[N:3]1[CH2:20][C:21]([OH:23])=[O:22].OS(O)(=O)=O.[CH3:29]O>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:8][CH:9]=2)[C:4](=[O:19])[N:3]1[CH2:20][C:21]([O:23][CH3:29])=[O:22]
Reactant: Cc1ccccc1Oc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CN1C(=O)c2ccc(Oc3ccccc3C)cc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(1,3-dioxo-5-(o-tolyloxy)isoindolin-2-yl)acetic acid (10.1 g, 32.5 mmol) and concentrated H2SO4 (2.0 mL) in MeOH (41 mL) was heated to reflux with stirring for 18 hours. After cooling to room temperature, the solvent was removed in vacuo. To the residue was added sat'd NaHCO3 solution (100 mL) and EtOAc (100 mL). The layers were separated and the organic layer was dried over Mg SO4 and then concentrated in vacuo to give the title compound as white solid in 10.0 g. 1H NMR (CDCl3, 200 MHz): δ=7.78 (d, 1H, J=9.0 Hz), 7.31-7.13 (m, 5H), 6.98 (d, 1H, J=7.4 Hz), 4.40 (s, 2H), 3.75 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=O)=O)=CC=1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(OC2CCCC2)c(Cl)cc1F
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A solution of 2-fluoro-4-chloro-5-hydroxynitrobenzene (7.1 g, 37.1 mmol) and potassium carbonate (5.1 g, 37.1 mmol) in acetonitrile (300 ml) was stirred for 2 hours at a refluxing temperature. Cyclopentyl p-toluenesulfonate (10.3 g, 40.8 mmol) was added thereto, followed by stirring further for 2 hours under refluxing. After completion of the reaction, the solvent was distilled off under reduced pressure from the reaction mixture, in hydrochloric acid (300 ml) was added thereto, and the mixture was extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with an aqueous solution of sodium bicarbonate and water, dried, and the solvent was distilled off under reduced pressure to obtain 2-fluoro-4-chloro-5-cyclopentyloxynitrobenzene as a yellow solid (8.93 g, 34.3 mmol, 92.6% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: CC(C)=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(OCC=C(C)C)c(C=O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (7.6 g, 50 mmol) in dry N,N-dimethylformamide (100 mL) was added potassium carbonate (10.4 g), followed by 1-bromo-3-methylbut-2-ene (10.0 g, 67 mmol). The mixture was stirred at room temperature for 48 hours and ethyl acetate added. Sufficient 1M hydrochloric acid was cautiously added to neutralize the base, and the organic layer was washed with water three times, followed by brine, and dried over magnesium sulfate. The mixture was filtered, and solvent removed from the filtrate under reduced pressure, to provide 5-methoxy-2-(3 -methylbut-2-enyloxy)benzaldehyde.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10](C)[C:11](=[O:13])[CH3:12].[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([NH:10][C:11](=[O:13])[CH3:12])[CH2:3]2)=[O:21]
Reactant: CC(=O)N(C)C1Cc2ccccc2C1
Reactant: O=C(Cl)CCCCCl
Product: CC(=O)NC1Cc2ccc(C(=O)CCCCCl)cc2C1

Procedure:
Using N-(2,3-dihydro-1H-inden-2-yl)-N-methylacetamide and 5-chlorovaleryl chloride according to the same method as that of Example 1, the title compound was obtained as colorless crystals.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([Cl:21])(=O)[C:17](Cl)=[O:18].C1C([Cl:28])=CC=C(Cl)C=1>>[Cl:21][C:16]1[C:17](=[O:18])[N:12]([C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[CH:9][CH:10]=2)[CH:13]=[C:14]([Cl:28])[N:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Clc1ccc(Cl)cc1
Reactant: N#CCNc1ccnn1-c1ccccc1
Product: O=c1c(Cl)nc(Cl)cn1-c1ccnn1-c1ccccc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of [(1-phenyl-1H-pyrazol-5-yl)amino]acetonitrile (1.20 g) in dichlorobenzene (15.0 mL) was added oxalyl chloride (0.922 g) at room temperature, and the mixture was stirred at 100° C. for 12 hr. The reaction mixture was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (0.850 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[CH:11][C:2]=1[O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1cnc2ccccc2n1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1cnc2ccccc2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.6 %

Procedure:
A mixture of 2-hydroxyquinoxaline (0.44 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours followed by heating at 40° C. for 24 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.65 g, 77% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[SH:10][CH2:11][CH2:12][OH:13].C(=O)(O)[O-].[Na+].ClCCl>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][OH:13]
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: OCCS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCSc1cc(Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3,4,6-trichioropyridazine (25 g) in tetrahydrofuran (200 ml) and triethylamine (19 ml) was treated at 0° C. (ice bath cooling) with 2-mercaptoethanol (8.33 ml) over 5 minutes. After the addition was complete, the mixture was stirred at room temperature for 72 hours. The mixture was stirred with aqueous sodium bicarbonate solution and dichloromethane and the solid was collected, washed with water, ether and pentane and dried in vacuo, giving (22.9 g). The combined aqueous and organic fraction was evaporated to half volume giving further solid, which was washed and dried as above (5.0 g). The total yield of solid (27.9 g; 91%) contained some bromo-analogue (5-10%) by NMR.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][C@@H:42]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[C@@H:41]([C:52]([OH:54])=[O:53])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[CH3:1][O:53][C:52]([C@@H:41]1[C@H:42]([C:45]2[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=2)[CH2:43][CH2:44][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:38])[CH2:40]1)=[O:54]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@@H](C(=O)O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.9 %

Procedure:
To a solution of triphenylphosphine (3.82 g, 14.6 mmol) in 70 ml tetrahydrofuran was added diethyl azodicarboxylate (2.53 g, 14.6 mmol) at 0° C. After 30′ methanol (4.55 ml, 112.0 mmol) and a solution of (+)-(3R,4R)-4-(4-fluoro-phenyl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (3.62 g, 11.2 mmol, 93.6% ee) in 30 ml tetrahydrofuran were added subsequently at 0-5° C. The reaction mixture was stirred for 20 h at room temperature. Quenching with water was followed by extraction with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (3.55 g, 94%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[O:19][N:20]=[CH:21][C:11]=3[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(N(CC)CC)C>O1CCCC1.O1CCOCC1.O1CCOCC1>[O:19]1[C:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[CH3:24])=[CH:3][CH:4]=3)=[O:7])[CH2:9][CH2:10][C:11]=2[CH:21]=[N:20]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCc3cnoc3-c3ccccc32)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3cnoc3-c3ccccc32)cc1
Reaction time: 4.5 h

Procedure:
A partial solution of 0.250 g of 5,6-dihydro-6-(4-aminobenzoyl)-4H-isoxazolo[4,5-d][1]benzazepine in 4 ml of tetrahydrofuran-dioxane (1:3) under argon is treated with 160 μl of 2-methylbenzoyl chloride in 1.5 ml of dioxane followed by 114 μl of triethylamine and stirring continued for 4.5 hours at room temperature. The volatiles are evaporated in vacuo to a residue which is dissolved in methylene chloride containing methanol, washed with 10% NaHCO3 and brine, then treated with activated carbon. The mixture is filtered through MgSO4 and the filtrate filtered through silica gel with 15% ethylacetate in methylene chloride. The filtrate is evaporated in vacuo to a residue which is dissolved in methylene chloride, filtered through glass wool, evaporated to a residue which is dissolved in ethyl acetate by warming to give 0.25 g of the desired product as tan crystals, m.p. 257°-260° C. HR FABMS: (M+H)=424.1657.
Reaction SMILES: [OH-:1].[Na+:2].[Br:3]Br.O.[Cl:6][C:7]1[CH:26]=[CH:25][C:10]2[C:11](=[O:24])[C:12]3[N:13]([CH3:23])[C:14]([CH2:19][C:20](=[O:22])C)=[CH:15][C:16]=3[CH2:17][O:18][C:9]=2[CH:8]=1>CCOCC>[Br:3][O-:1].[Na+:2].[Cl:6][C:7]1[CH:26]=[CH:25][C:10]2[C:11](=[O:24])[C:12]3[N:13]([CH3:23])[C:14]([CH2:19][C:20]([OH:22])=[O:1])=[CH:15][C:16]=3[CH2:17][O:18][C:9]=2[CH:8]=1
Reactant: CC(=O)Cc1cc2c(n1C)C(=O)c1ccc(Cl)cc1OC2
Reactant: BrBr
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cn1c(CC(=O)O)cc2c1C(=O)c1ccc(Cl)cc1OC2
Product: [O-]Br
Temperature: 0 °C

Procedure:
A cold solution of sodium hypobromite is prepared from 1.6 g. of sodium hydroxide, 3.2 g of bromine, and 10 g of ice and water. To this solution is added with stirring 1-[7-chloro-4,10-dihydro-1-methyl-10-oxo-1H[1]benzoxepino[4,3-b]pyrrole-2-yl]propan-2-one (Q) (1.5 g, 0.005 m), while keeping the temperature below 10° C. The resulting mixture is stirred at low temperature for an additional 4 hours before water and ether are added. The layers are separated and the aqueous layer is treated with a sufficient amount of sodium bisulfite. The treated aqueous layer is filtered and the filtrate acidified with 2 N hydrochloric acid to give crude 7-chloro-4,10-dihydro-1-methyl-10-oxo-1H[1]benzoxepino[4,3-b]pyrrol-2-acetic acid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[OH-:10].[Cu+2:11].[OH-]>O>[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[C:1]([O:9][OH:10])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Cu+2:11].[Cu+2:11].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3]
Reactant: [OH-]
Agent: [Cu+2]
Agent: O=C(O)CC(O)C(=O)O
Solvent: O
Product: O=C([O-])CC(O)C(=O)OO

Procedure:
An aqueous solution of malic acid was prepared by mixing 134.09 g of malic acid with 50 mL of water. An aqueous solution of copper(II)hydroxide was also prepared in a separate container by thoroughly mixing 195.12 g of copper(II)hydroxide in 50 mL of water. The copper(II)hydroxide solution was then slowly added to the malic acid solution. The resulting solution was spray dried to produce a powdered dicopper(II)hydroxy malate.
Reaction SMILES: [S:1]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([O:4][IH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)(=[O:3])=[O:2].[C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[S:1]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([O-:4])(=[O:3])=[O:2].[C:20]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[I+:5][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O[IH](=O)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: c1ccc([I+]c2ccccc2-c2ccccc2)cc1
Temperature: 135 °C
Yield: 63 %

Procedure:
A mixture of 9.3 grams (0.023 mole) phenyliodoso tosylate and 9.25 grams (0.06 mole) biphenyl was heated to 135° C. for 1 hour and the mixture poured into 50 ml diethyl ether. After filtering off the insoluble salt and washing with ether, the product was dried. A 63% yield of biphenylyl phenyl iodonium tosylate was obtained.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:12]N(C)C=O.[CH2:17]([O:21][CH2:22][CH2:23]Br)[CH2:18][CH2:19]C>C1(C)C=CC=CC=1.O>[CH3:12][CH:17]([O:21][CH2:22][CH2:23][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH2:18][CH3:19]
Reactant: CCCCOCCBr
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CN(C)C=O
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)OCCOc1ccc(C(=O)O)cc1

Procedure:
To a 1 l three-neck flask were added 70 g of sodium salt of p-hydroxybenzoic acid ##STR4## and 200 ml of N,N-dimethylformamide, and the contents were heated under reflux. To the heated contents, 50 g of β-n-butoxyethyl bromide was dropped over a period of 30 minutes and heating was continued under reflux for further 8 hours. After cooling with water, 300 ml of water and 200 ml of toluene were added to the contents and after shaking, the resulting organic layer was separated, washed with 4 N hydrochloric acid and then with a 20% aqueous solution of sodium hydroxide. After distilling off toluene and heating the remaing material together with 200 ml of a 20% aqueous solution of sodium hydroxide for 3 hours, the resulting material was neutralized with hydrochloric acid to precipitate the objective material. After washing with water, the objective material was recrystallized from ethanol to obtain 55 g of p-(β-n-butoxy)ethoxybenzoic acid. The melting point of this material was 114.5°-115° C. and the values of the elemental analysis thereof showed a good agreement with the calculated values as seen below.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[C:40]([NH:42][CH3:43])=[O:41]>C(#N)CC.CS(C)=O>[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1[N:47]1[CH2:48][CH2:49][N:50]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:51][CH2:52]1)[C:40]([NH:42][CH3:43])=[O:41]
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(Cl)c1
Temperature: 90 °C
Yield: 28.7 %

Procedure:
To a suspension of (S)-3-((S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (111 mg, 0.476 mmol) in propiononitrile (1.2 mL) was added (cyanomethyl)trimethylphosphonium iodide (139 mg, 0.571 mmol) and DIEA (249 μl, 1.428 mmol) and finally 3-chloro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (138 mg, 0.476 mmol). The vial was heated to 90° C. for 16 hours. The crude r×n was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic). The fractions were collected, concentrated until a precipitate was visible and filtered. The solids were washed with water and collected to retrieve the product as a white solid (64 mg, 29% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (br. s., 1H), 8.43 (d, J=4.3 Hz, 1H), 7.87 (s, 1H), 7.76 (dd, J=8.3, 1.5 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.54-7.74 (m, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.99 (br. s., 1H), 4.52 (d, J=12.6 Hz, 1H), 3.85 (br. s., 1H), 3.44 (br. s., 2H), 2.92 (d, J=4.5 Hz, 4H), 2.75 (d, J=4.5 Hz, 4H), 2.52-2.69 (m, 3H), 1.99-2.09 (m, 1H), 1.85 (d, J=12.4 Hz, 1H), 1.64 (d, J=12.4 Hz, 1H), 1.32-1.58 (m, 3H). [M+H] calc'd for C24H29ClN6O2, 469; found, 469.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:13])[N:7]([CH3:15])[C:6]=2[CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC(=O)c2ccc(Cl)cc2N1
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CCC(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
8-Chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-j) (0.2 g, 1 mmol) was dissolved in a mixture of THF (10 mL) and DMF (2 mL). Cesium carbonate (0.98 g, 3 mmol) and methyl iodide (0.069 mL, 1.1 mmol) were added and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure and dichloromethane (10 mL) was added. The inorganic precipitate was filtered and the filtrate was concentrated under reduced pressure to give a viscous residue. This residue was purified utilizing column chromatography, eluting with 50% ethyl acetate/hexane to afford the title compound as a white solid (0.1 g, 45%): MS m/z=224 (M+H).