Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[S:17][C:16]([S:18]([NH:21][C@H:22]([CH2:27][OH:28])[C@H:23]([CH2:25][CH3:26])[CH3:24])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[S:17][C:16]([S:18]([NH:21][C@H:22]([CH:27]=[O:28])[C@@H:23]([CH3:24])[CH2:25][CH3:26])(=[O:20])=[O:19])=[CH:15][CH:14]=1
Reactant: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
Molecular sieves (15 g, 4 Å) were stirred in dry CH2Cl2 (175 mL) for 10 min. Then a mixture of pyridinium chlorochromate (8.6 g, 39.9 mmol) and silica gel (9 g) was added and the mixture was stirred an additional 10 min. To the suspension was added 5-chlorothiophene-2-sulfonyl isoleucinol (4 g, 13.4 mmol) dissolved in CH2Cl2 (15 mL) and the resulting slurry was stirred for 2 h. The reaction mixture was filtered and the solvent was removed. The residue was subjected to a Biotage™ eluting with 20% EtOAc/hexane to give 3.22 g (81%) of the aldehyde (LCMS=294.21 (M−H), rt=1.10 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:12]([Cl:11])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 95 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (3.0 g, 21.3 mmol) in chlorosulfonic acid (5.5 mL, 84 mmol) was stirred at 90-100° C. for 8 hours before being cooled to room temperature and slowly poured into ice water and extracted with EtOAc. The organic extract was washed with saturated aq. NaHCO3 and water, dried (sodium sulfate), and concentrated to give 2-fluoro-5-nitrobenzenesulfonyl chloride (3.2 g, 63%) as a colorless oil, which was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH:10]([CH3:12])[CH3:11]
Reactant: [H][H]
Reactant: CC(C)Cn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)Cn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.5 %

Procedure:
3-Nitro-1-iso-butyl-1H-pyrazole (83 mg, 0.49 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the reaction. The vial was charged with hydrogen gas (via balloon) and the reaction stirred for 16 h at 25° C. The reaction was passed through a plug of celite and concentrated in vacuo to afford 1-iso-butyl-1H-pyrazol-3-ylamine (59 mg, 86%) as a golden oil: ESI-LRMS m/e calcd for C7H13N3 [M+] 139.1, found 140.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:18].O>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:11])([CH3:12])[C:8](=[O:10])[N:9]([CH3:18])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: CC1(C)Oc2ccc(Br)cc2NC1=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C(C)(C)Oc2ccc(Br)cc21
Reaction time: 0.08 h
Yield: 67.7 %

Procedure:
To a solution of 6-bromo-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (185 mg, 0.722 mmol) in DMF (3 mL) at 0° C. was added NaH (43.3 mg, 1.08 mmol, 60%), and the reaction was stirred for 5 minutes. Iodomethane (205 mg, 1.45 mmol) was added the reaction was stirred at room temperature for 60 minutes. Water, EtOAc, and brine were added, the layers were separated and the organic layer was washed with brine. The organics were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (10-35% EtOAc in hexanes) to afford 6-bromo-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one 7.31 (132 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C11H13BrNO2: 270.0; found: 270.0.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10](=[O:13])[C:9]([C:14]3[N:15]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][Si](C)(C)C)[CH:20]=4)[N:16]=[CH:17][CH:18]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-]>C1COCC1>[C:25]([C:21]1[CH:20]=[C:19]([N:15]2[C:14]([C:9]3[C:10](=[O:13])[CH:11]=[CH:12][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)=[CH:18][CH:17]=[N:16]2)[CH:24]=[CH:23][CH:22]=1)#[CH:26]
Reactant: C[Si](C)(C)C#Cc1cccc(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccc(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of 1-phenyl-3-[2-(3-trimethylsilanylethynyl-phenyl)-2H-pyrazol-3-yl]-1H-pyridazin-4-one (example 31, 50 mg, 0.12 mmol) is dissolved in THF (2 ml). Tetrabutylammoniumfluoride trihydrate (77 mg, 0.24 mmol) is added at 0° C. and the reaction mixture is allowed to warm up to ambient temperature within 15 minutes. Stirring is continued for another 2 hours. The reaction mixture is quenched with water and extracted with ethyl acetate. The solvent is removed and the obtained crude product is triturated with diethyl ether. The solid material is filtrated and dried to obtain 39 mg (94% yield) of the product.
Reaction SMILES: [CH2:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:26])[C:21]2[S:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(C(OCC)=O)[C:4]([O:6]CC)=[O:5])[CH3:2].[OH-].[Na+]>O>[C:21]1([C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:3]([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])=[CH:15][CH:16]=2)=[O:26])[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(CC)(C(=O)OCC)c1ccc(C(=O)c2cccs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 16.8 parts of diethyl 2-ethyl-2-[p-(2-thenoyl)phenyl]malonate, 4 parts of sodium hydroxide and 80 parts of water is stirred and refluxed for 6 hours. The reaction mixture is poured onto water and the whole is extracted with ether. The aqueous phase is separated and acidified with hydrochloric acid solution: the product is separated as an oil which solidifies. It is extracted with ether. The extract is washed three times with water, dried, filtered and evaporated. The solid residue is crystallized from 24 parts of acetonitrile at room temperature, yielding 2-[p-(2-thenoyl)phenyl]butyric acid, also named p-(2-thenoyl)-α-ethyl-phenylacetic acid; m.p. 122.8° C.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[ClH:35].C(OCC)(=O)C>C(O)(=O)C>[ClH:35].[NH2:21][CH2:20][CH2:19][NH:18][C:16](=[O:17])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:6][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NCCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 2-(((4-([1,1′-biphenyl]-4-ylmethoxy)phenyl)acetyl)amino)ethylcarbamate (1.5 g) in acetic acid (100 ml) was added 4N hydrochloric acid/ethyl acetate (4 ml) at room temperature. After stirring at room temperature for 2 hr, the precipitate was collected by filtration, which was washed with ethyl ether and dried to obtain the titled compound (0.9 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[CH:13]1([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[NH:9][C:10](=[O:12])[CH3:11])[CH2:15][CH2:14]1
Reactant: OB(O)C1CC1
Reactant: CC(=O)Nc1ccc(F)cc1Br
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)Nc1ccc(F)cc1C1CC1
Reaction time: 6 h

Procedure:
A mixture comprising N-(2-bromo-4-fluorophenyl)acetamide (1 g, 4.31 mmol), cyclopropylboronic acid (0.481 g, 5.60 mmol), tricyclohexylphosphine (0.121 g, 0.431 mmol), potassium phosphate (tribasic) (3.20 g, 15.08 mmol), toluene (10 ml) and water (10 ml) was equally divided between two 10-20 ml microwave tubes. Each reaction tube was sealed, evacuated and filled with nitrogen (3×) and placed in the microwave at 100° C. for 6 hrs. The contents of the vials were combined, diluted with EtOAc and the layers separated. The organic extracts were washed with water (2×), dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a brown solid. The product was used crude in the next step.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C:5]([O:14][CH3:15])=[N:6][CH:7]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:9]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:13][S:10]([C:8]1[CH:9]=[C:4]([CH:3]=[O:2])[C:5]([O:14][CH3:15])=[N:6][CH:7]=1)(=[O:12])=[O:11]
Reactant: COc1ncc(S(C)(=O)=O)cc1C(OC)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ncc(S(C)(=O)=O)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
0.81 g of 5-(methylsulfonyl)-2-methoxy-3-pyridinecarboxaldehyde dimethyl acetal was dissolved in 8 ml of acetone, 2 ml of 5N-hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 30 minutes. An aqueous sodium carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, n-hexane was added to the residue and the resulting product was collected by filtration, to give 0.62 g of the title compound as a white powder.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH2:8][C:7](=O)[N:6]([C:12]3[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=3[F:19])[C:5]2=[O:20])[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:23])=O.CN(C)C1C=CC=CC=1>O>[Cl:23][C:7]1[N:6]([C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:5](=[O:20])[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:9](=[O:10])[CH:8]=1
Reactant: O=C1CC(=O)N(C2CC2)C(=O)N1c1ccc(I)cc1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: O
Product: O=c1cc(Cl)n(-c2ccc(I)cc2F)c(=O)n1C1CC1
Temperature: 110 °C

Procedure:
To 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-pyrimidine-2,4,6-trione 49 (59.0 g) obtained in Step 2 were added phosphorus oxychloride (85.0 ml) and dimethylaniline (29.0 ml), and water (8.3 ml) was added dropwise to the mixture at room temperature with stirring. After the completion of the dropwise addition, the mixture was stirred with heating at 110° C. for 1 hr. After allowing to cool to room temperature, the reaction mixture was added dropwise to ice water-toluene [2:1 (volume ratio), 900 ml] with stirring. The mixture was stirred at room temperature for 1 hr. The organic layer was separated, and washed successively with water (300 ml) and brine (300 ml). Anhydrous magnesium sulfate and activated carbon were added and the mixture was stirred. Anhydrous magnesium sulfate and activated carbon were filtered off, and the filtrate was concentrated under reduced pressure to give a 1:2 mixture (62.9 g) of 6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 50 and 6-chloro-1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 51 as a yellow foamy oil, which was used for the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH3:13])=[C:6]([CH:9]=1)[CH:7]=O.Cl.[NH2:15]O>C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH3:13])=[C:6]([CH:9]=1)[C:7]#[N:15]
Reactant: CCCOc1ccc(Br)cc1C=O
Reactant: NO
Agent: Cl
Solvent: O=CO
Product: CCCOc1ccc(Br)cc1C#N
Temperature: 25 °C
Yield: 73.4 %

Procedure:
In formic acid (110 ml) was dissolved 5-bromo-2-propoxybenzaldehyde (21.8 g). To the mixture was added hydroxylamine hydrochloride (9.4 g), and the mixture was refluxed for 7 hours and cooled to room temperature. Under reduced pressure, the solvent was evaporated, and the residue was added to 1N potassium hydroxide. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 5-bromo-2-propoxybenzonitrile (15.8 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:34])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5([C:32]#[N:33])[CH2:31][CH2:30]5)[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:35]=1)=[O:4].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(#N)C>[C:32]([C:29]1([C:25]2[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=2)[C:22]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:11]3[CH:12]=[CH:13][C:8]4[N:9]([CH:35]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)[N:7]=4)[N:10]=3)[CH:16]=2)=[O:34])[CH2:31][CH2:30]1)#[N:33]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)CCl)cn5n4)c3)c2)CC1
Reactant: C1COCCN1
Solvent: CC#N
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)CN6CCOCC6)cn5n4)c3)c2)CC1
Yield: 79 %

Procedure:
Using N-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(1-cyanocyclopropyl)benzamide (140 mg, 0.287 mmol), morpholine (1 mL) and acetonitrile (2 mL) as starting materials and in the same manner as in Example 408, the title compound (123 mg, 79%) was obtained as a white powder.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH2:22]([NH2:25])[CH:23]=[CH2:24].C(N(CC)CC)C>C(O)C>[CH2:22]([NH:25][S:18]([C:4]1[CH:5]=[C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])[CH:7]=[CH:8][C:3]=1[Cl:2])(=[O:20])=[O:19])[CH:23]=[CH2:24]
Reactant: C=CCN
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CCNS(=O)(=O)c1cc(C2(O)CSC(=NC)N2C)ccc1Cl

Procedure:
8.7 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 1.5 g of allyl amine and 4 g of triethyl amine in 50 ml of ethanol and worked up. The water was decanted and the amorphous end product was crystallized under diethyl ether. Colorless solid body, melting point: 146° C (decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:20])[C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:27]1(C)C=CC=C[CH:28]=1>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>[Cl:20][C:4]1[C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][CH:7]=[C:2]([CH:27]=[CH2:28])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncc(Br)cc1Cl
Reactant: Cc1ccccc1
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: [K+]
Product: C=Cc1cnc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Yield: 65 %

Procedure:
To a stirred solution of 2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (0.23 g, 0.65 mmol) in toluene (10 mL) were added Pd(PPh3)4 (3.7 mg, 0.003 mmol), K2CO3 (0.269 g, 1.95 mmol) and vinyl boronic anhydride pyridine complex (0.78 g, 3.28 mmol), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as an off-white solid (0.2 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.72 (m, 1H), 6.63 (m, 1H), 5.79 (d, J=16.0 Hz, 1H), 5.39 (d, J=16.0 Hz, 1H), 5.12 (s, 2H); ESIMS m/z 299.20 ([M+H]+).
Reaction SMILES: C([O:3][C:4]1[C:5](=[O:17])[C:6](=O)[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[O:18]([C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O>[O:18]([C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH:27][C:6]1[C:5](=[O:17])[C:4](=[O:3])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Solvent: CS(C)=O
Product: O=c1c(Nc2ccccc2O)c(Nc2ccccc2Oc2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-penoxyaniline (49 mg, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 373 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:14](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:13])[C:11]=1[O:12][CH3:14])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)c(O)c(I)c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OC)c(I)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
Methyl 3-chloro-4-hydroxy-5-iodobenzoate (3.00 g) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (3.98 g) and dimethylsulfuric acid (1.82 mL) were added to the solution, and then the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered and water was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.96 g) as a pale yellow crystal.
Reaction SMILES: O.O.O.C([O-])(=O)C.[Na+].[Na].[C:10]1([S:16]([OH:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:19][C:20]1[CH:21]=[C:22]([OH:27])[C:23]([OH:26])=[CH:24][CH:25]=1>O.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[Fe+3]>[CH3:19][C:20]1[CH:21]=[C:22]([OH:27])[C:23]([OH:26])=[CH:24][C:25]=1[S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: O=S(O)c1ccccc1
Reactant: Cc1ccc(O)c(O)c1
Agent: [Fe+3]
Agent: CC(=O)[O-]
Agent: [C-]#N
Solvent: O
Product: Cc1cc(O)c(O)cc1S(=O)(=O)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 50 g (152 mmol) of potassium hexacyanoferrate (III) and 95 g of sodium acetate trihydrate in 200 ml of water is added dropwise in the course of 30 minutes, at room temperature under nitrogen, to a solution of 16.4 g (100 mmol) of the sodium salt of benzenesulphinic acid and 13.6 g (110 mmol) of 4-methyl-1,2-benzenediol in 150 ml of water. After stirring for 11/2 hours, the reaction mixture is acidified and repeatedly extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The residue is recrystallised from ether/hexane, yielding 4-methyl-5-phenylsulphonyl-1,2-benzenediol having a melting point of 145°-149°.
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].[C:12]1(=[O:19])[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]1.C1(C)C=CC=CC=1>C(O)C>[Cl:7][C:6]12[C:2]([Cl:11])([Cl:1])[C:3]([Cl:10])([C:17]3[C:12]([OH:19])=[CH:13][CH:14]=[C:15]([OH:18])[C:16]=31)[C:4]([Cl:9])=[C:5]2[Cl:8]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Reactant: O=C1C=CC(=O)C=C1
Solvent: CCO
Solvent: Cc1ccccc1
Product: Oc1ccc(O)c2c1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
A mixture of 54.6 g. (0.2 mole) of hexachlorocyclopentadiene, 21.6 g. (0.2 mole) of p-benzoquinone, and 10 ml. of toluene were placed in a 125 ml. round bottom flask and heated for 3 hours so that the toluene refluxed gently. At the end of this period the reaction mixture suddenly solidified completely, indicating completion of the reaction. The crude product was bright yellow. The damp material was transferred to a Buchner funnel, raised with absolute ethanol, dried on the funnel, and crystallized from ethanol. 49 g. of bright yellow dense crystals were obtained, m.p. 189° -193° C. (reported 188° C.). The yield was 64%.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.ClC(Cl)C.[CH3:14][C@H:15]1[CH2:20][O:19][CH2:18][CH2:17][NH:16]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:16]2[CH2:17][CH2:18][O:19][CH2:20][C@@H:15]2[CH3:14])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C[C@H]1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Reductive Amination Method B: 6-Bromopyridine-2-carbaldehyde (1.3 g, 7.0 mmol) was added to a 200 ml, round bottom under argon. Dichloroethane (28.0 ml) was added followed by (3S)-3-methylmorpholine (HCl salt) (1 g, 7.3 mmol) and triethylamine (1.0 ml, 7.3 mmol). The mixture was stirred for 0.5 hours at room temperature followed by the addition of sodium triacetoxyborohydride (2.07 g, 9.8 mmol) and the resulting slurry was maintained at room temperature overnight. The reaction was quenched by the careful addition of saturated aqueous sodium bicarbonate and was extracted once with DCM and once with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oily residue was purified via flash chromatography (silica, 0-10% methanol/ethyl acetate) to afford the title compound as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>C1COCC1>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:17][CH:16]=1
Reactant: COC(=O)CBr
Reactant: NCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CNCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl bromoacetate (24.0 mL, 253.5 mmol) in anhydrous THF (264 mL) was added triethylamine (35.34 mL, 253.5 mmol). The cloudy mixture was treated rapidly with 4-fluorobenzylamine (30.3 mL, 263.7 mmol), and the resulting viscous mixture was stirred at ambient temperature under inert atmosphere for 18 h. TH was removed in vacuo, and the residue was suspended in diethyl ether. The mixture was filtered and the solids washed with excess diethyl ether. Concentration of the filtrate in vacuo afforded the product as a light yellow oil.
Reaction SMILES: C[C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].FC(F)(F)C1C=CC(OC2C=CC(OC(C)C(OCCCC)=O)=CC=2)=NC=1.[Cl:41]C1C=C2C(=CC=1)N=C(OC1C=CC(OC(C)C(OCC)=O)=CC=1)C=N2>>[Cl:41][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: Cc1cc(Cl)ccc1OCC(=O)O
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Agent: CCCCOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: O=C(O)COc1ccc(Cl)cc1Cl

Procedure:
2-methyl-4-chlorophenoxyacetic acid; butyl 2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionate (including esters and salts thereof); ethyl 2-[4-(6-chloro-2-quinoxalinyloxy)phenoxy]propionate; etc.