Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][O:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:9][N:10]([CH3:13])[CH:11]=O>>[CH3:9][N:10]([CH3:13])[CH:11]=[CH:2][C:1]([C:4]1[CH:8]=[CH:7][O:6][CH:5]=1)=[O:3]
Reactant: CN(C)C=O
Reactant: CC(=O)c1ccoc1
Product: CN(C)C=CC(=O)c1ccoc1

Procedure:
A mixture of 50.0 g. of 3-acetylfuran and 60 ml. of N,N-dimethylformamide is heated at reflux temperature for 16 hours. The solvent is removed in vacuo and hexane is added to the residue to give 3-dimethylamino-1-(3-furyl)-2-propen-1-one. A mixture of 0.01 mole of the preceding compound and 0.01 mole of 3-aminopyrazole in glacial acetic acid is refluxed for 8 hours and the solvent removed in vacuo. The residue is purified as described in Example 1 to give the product of the example.
Reaction SMILES: C([C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:10](=[N:26][N:27]([CH2:30][CH3:31])[C:28]=3[CH3:29])[C:11]([N:19](C([O-])=O)C([O-])=O)=[N:12][C:13]=2[C:14]=1C(C)(C)C)(C)(C)C.C([C:36]1[CH:37]=[CH:38][C:39]2[C:40]3[C:41](=[N:57][N:58]([CH2:61][CH2:62]C)[C:59]=3C)[C:42]([N:50](C([O-])=O)C([O-])=O)=[N:43][C:44]=2[C:45]=1C(C)(C)C)(C)(C)C.[O:64]=[C:65]1[CH2:70][CH2:69][N:68]([C:71](OC(C)(C)C)=O)[CH2:67][CH2:66]1.C1(=O)CCC1>>[NH2:19][C:11]1[C:10]2=[N:26][N:27]([CH2:30][CH3:31])[C:28]([CH2:29][C:65]3([OH:64])[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]3)=[C:9]2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:14][C:13]=2[N:12]=1.[NH2:50][C:42]1[C:41]2=[N:57][N:58]([CH2:61][CH3:62])[C:59]([CH2:71][N:68]3[CH2:67][CH2:66][CH:65]([OH:64])[CH2:70][CH2:69]3)=[C:40]2[C:39]2[CH:38]=[CH:37][CH:36]=[CH:45][C:44]=2[N:43]=1
Reactant: CCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Agent: O=C1CCC1
Product: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCNCC1
Product: CCn1nc2c(N)nc3ccccc3c2c1CN1CCC(O)CC1

Procedure:
4-[(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]piperidin-4-ol was prepared according to the method of Example 1 Part F using di(tert-butyl)2-ethyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate in lieu of di(tert-butyl)1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate and tert-butyl 4-oxopiperidine-1-carboxylate in lieu of cyclobutanone. The crude product was recrystallized from acetonitrile to provide 1.09 g of 1-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]piperidin-4-ol as an off-white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][NH2:10])=[O:8].[CH2:11]([O:18][CH2:19][C:20](Cl)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][CH2:19][C:20]([NH:10][NH:9][C:7](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNC(=O)c1ccccn1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COCc1ccccc1)NNC(=O)c1ccccn1

Procedure:
Picolinohydrazide (4.55 g) was dissolved in dichloromethane (40 mL) and 2-(benzyloxy)acetyl chloride (6.06 mL) was added slowly with cooling. Triethylamine (5.98 mL) was added slowly with a strong exotherm. Additional dichloromethane (45 mL) was added to aid stirring. The reaction was allowed to stir overnight. The reaction was partitioned between ethyl acetate and sodium hydrogen carbonate aqueous solution. The organic phase was washed with brine, dried and purified by column chromatography using an eluant of 10% ethyl acetate/dichloromethane to provide the title compound (4.1 g) having the following physical data.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:39])[CH3:38])[C:28]([CH:40]=[O:41])=[C:27]([I:42])[C:26]1=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].CO>O1CCCC1>[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:35])([CH3:36])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:38])[CH3:39])[C:28]([C@H:40]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[OH:41])=[C:27]([I:42])[C:26]1=2)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: CC(C)[Mg]Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: -20 °C
Reaction time: 5 h

Procedure:
1.1 ml 4-iodobenzotrifluoride are dissolved in 60 ml tetrahydrofurane and cooled to −20° C. 3.7 ml of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane are added dropwise and the solution is stirred for further 5 hours. Then the solution is cooled to −40° C. and 1.17 g (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde in 5 ml tetrahydrofurane are added dropwise. The mixture is stirred for 12 hours while warming to room temperature. Then it is cooled to 0° C., 10 ml methanol are added and it is stirred for 30 minutes. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 95:5 to 80:20).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.CCN(CC)CC.Cl>CN(C=O)C.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.[Cu]I.CCOCC>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(SCC#Cc2ccc(C(F)(F)F)cc2)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
A degassed (argon) solution of 96.0 mg (0.33 mmol) (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester, 0.053 ml (0.36 mmol) 1-iodo-4-trifluoromethyl-benzene and 0.086 (0.621 mmol) Et3N in 1 ml DMF was treated with 37.9 mg (0.03 mmol) Pd(PPh3)4 and 12.5 mg (0.07 mmol) of CuI. After stirring for 2 h at room temperature, the reaction was distributed between 1N HCl and ether (three times). Washing of the organic layer with saturated aqueous NH4Cl solution and brine, drying (Na2SO4) and evaporation of the solvents, followed by flash chromatography (SiO2, n-heptane/EtOAc 1 to 5%), yielded 76 mg of the title compound as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH:13]=[CH:14][C:15]=1Br)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[C:24]2[CH:36]=[CH:37][N:38]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:23]=2[C:22]1=[O:49]>>[NH2:12][C:11]1[CH:13]=[CH:14][C:15]([C:25]2[C:24]3[CH:36]=[CH:37][N:38]([S:39]([C:42]4[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=4)(=[O:41])=[O:40])[C:23]=3[C:22](=[O:49])[N:21]([CH3:20])[CH:26]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: Nc1ccc(Br)c(OCc2ccccc2)c1[N+](=O)[O-]
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c([N+](=O)[O-])c4OCc4ccccc4)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 3-(benzyloxy)-4-bromo-2-nitroaniline and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C28H25N4O6S (M+H)+: m/z=545.1. found: 545.2.
Reaction SMILES: [NH2:1][C:2]1[C:12](I)=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C.O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:12](/[CH:17]=[CH:16]/[C:15]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: C=CC(=O)OC
Reactant: Nc1c(I)cc(Br)c2c1C(=O)NC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)/C=C/c1cc(Br)c2c(c1N)C(=O)NC2=O
Yield: 70.8 %

Procedure:
3-Amino-4-iodo-6-bromophthalimide (500 mg, 1.36 mmol) was dissolved in acetonitrile (25 mL), and the solution was added with methyl acrylate (0.245 mL, 2.72 mmol), palladium acetate (24 mg, 0.11 mmol) and triethylamine (1.90 mL, 13.6 mmol), followed by stirring under reflux for 5 hours under argon atmosphere. The mixture was added with methyl acrylate (0.122 mL, 1.36 mmol), palladium acetate (24 mg, 0.11 mmol) and triethylamine (1.90 mL, 13.6 mmol) and further stirred for 142 hours. The mixture was added with methyl acrylate (0.245 mL, 2.72 mmol), palladium acetate (24 mg, 0.11 mmol) and triethylamine (0.95 mL, 6.8 mmol) and further stirred for 20 hours. The reaction mixture was added with water, extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using chloroform to obtain (E)-3-amino-4-(2-methoxycarbonylvinyl)-6-bromophthalimide (313 mg, yield 71%).
Reaction SMILES: [N+:1]([CH:4]([C:8]([OH:10])=O)[C:5]([OH:7])=O)([O-:3])=[O:2].[NH2:11][C:12]([NH2:14])=[O:13]>>[CH:4]1([N+:1]([O-:3])=[O:2])[C:5](=[O:7])[NH:14][C:12](=[O:13])[NH:11][C:8]1=[O:10]
Reactant: NC(N)=O
Reactant: O=C(O)C(C(=O)O)[N+](=O)[O-]
Product: O=C1NC(=O)C([N+](=O)[O-])C(=O)N1

Procedure:
Nitration of malonic acid with acetyl nitrate in acetic acid/acetic anhydride was conducted to obtain nitromalonic acid. To the nitromalonic acid is added urea to obtain a condensation reaction mixture which is refluxed to form dilituric acid in situ. Various salts are separately prepared from the dilituric acid in situ using as cation sources potassium chloride, ammonia, and guanidinium chloride. The potassium diliturate salt, ammonium diliturate, guanidinium diliturate salts are each recovered and isolated by filtration.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16]C(C)(C)C(C)(C)[O:9]2)=[CH:4][C:3]=1[O:17][CH3:18].[CH3:19][O:20][CH3:21].[C:22]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(OC)(C)C.CCCCCCC>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([B:8]([OH:9])[OH:16])[CH:6]=[CH:7][C:2]=1[O:1][CH2:22][CH2:19][O:20][CH3:21]
Reactant: COC
Reactant: O=C([O-])[O-]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: CCCCCCC
Product: COCCOc1ccc(B(O)O)cc1OC

Procedure:
4-Hydroxy-3-methoxyphenylboronic acid pinacol ester (Aldrich, 518786) (1 g; 4 mmol), 2-bromomethyl)-methylether (0.83 g; 6 mmol) and Cs2CO3 (2.6 g; 8 mmol) in DMF (10 ml) are heated to 130° C. for 45 minutes. The reaction mixture is diluted with TBME/heptane (5 ml/5 ml), filtered and evaporated to deliver the title compound as yellow oil used without further purification in Example 79.
Reaction SMILES: C([O:9][C:10]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([I:20])[CH:18]=2)[N:13]([CH3:21])[C:12](=[O:22])[CH:11]=1)(=O)CCC(OC)=O.Cl[C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29]C)=[O:28].OC1C2C(=NC=C(I)C=2)N(C)C(=O)C=1>ClCCCl>[OH:9][C:10]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([I:20])[CH:18]=2)[N:13]([CH3:21])[C:12](=[O:22])[C:11]=1[C:24](=[O:31])[CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: COC(=O)CCC(=O)Oc1cc(=O)n(C)c2ncc(I)cc12
Reactant: COC(=O)CCC(=O)Cl
Agent: Cn1c(=O)cc(O)c2cc(I)cnc21
Solvent: ClCCCl
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2cc(I)cnc21
Reaction time: 0.25 h
Yield: 60 %

Procedure:
6-Iodo-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl methyl succinate. Methyl 4-chloro-4-oxobutyrate (0.08 mL, 0.662 mmol) was added to a suspension of 4-hydroxy-6-iodo-1-methyl-1,8-naphthyridin-2(1H)-one (0.20 g, 0.66 mmol), TEA (0.092 mL, 0.66 mmol) in 1,2-dichloroethane (3 mL). The mixture was stirred for 15 minutes and evaporated. The remaining solids were purified by flash chromatography using EtOAc/hexane to afford the title compound in 60% yield. 1H-NMR (300 MHz, CDCl3) δ ppm 8.78 (1H, d, J=2.2 Hz), 8.34 (1H, d, J=2.2 Hz), 6.68 (1H, s), 3.78 (3H, s), 3.77 (3H, s), 3.02-2.98 (2H, m), 2.84-2.79 (2H, m). MS m/z: 417 (M+).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:13])([F:12])[S-:11].CN([S+](N(C)C)N(C)C)C.O>C(#N)C>[F:9][C:10]([S:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([F:13])[F:12]
Reactant: FC(F)(F)[S-]
Reactant: BrCc1ccccc1
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CC#N
Solvent: O
Product: FC(F)(F)SCc1ccccc1
Yield: 82 %

Procedure:
Benzyl bromide, 16.2 g (0.095 mol), was added dropwise at 25° to 0.11 mol of tris(dimethylamino)sulfonium trifluoromethanethiolate (prepared as in Example 11) in 75 mL of acetonitrile. The reaction mixture was stirred one h and then poured into water. The aqueous mixture was extracted with ether, and the ether extracts were washed with water, dried (MgSO4), and distilled to give 15.1 g (82%) of benzyl trifluoromethyl sulfide as a colorless liquid: bp 55° (12 mm); 1H NMR (CDCl3) δ4.08 ppm (s, 2H), 7.33 ppm (s, 5H); 19F NMR (CDCl3) δ-42.5 ppm (s).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:10]2[S:11][C:12]([CH3:15])=[C:13]([CH3:14])[C:9]=2[CH:8]=1)C.[OH-].[Na+].Cl>C(O)C>[Cl:18][C:17]1[C:7]([O:6][CH2:5][C:4]([OH:20])=[O:3])=[CH:8][C:9]2[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]=2[C:16]=1[Cl:19]
Reactant: CCOC(=O)COc1cc2c(C)c(C)sc2c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc2c(Cl)c(Cl)c(OCC(=O)O)cc2c1C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a mixture of 22.0 g of ethyl[ (6,7-dichloro-2,3-dimethylbenzo[b]thien-5-yl)oxy]acetate and 600 ml of 95% ethanol is added 600 ml of 20% sodium hydroxide solution and the mixture is refluxed for 2 hrs. Most of the solvent is removed in vacuo to give a white slurry to which is added 600 ml of a 6 N hydrochloric acid. After stirring for about 3 hrs, the mixture is filtered. The solid is taken up in 1:1-ethyl acetate-ethyl ether. The organic layers are washed, dried and filtered and the solvent is removed to give a solid. Recrystallization from acetone-hexane gives 17.1 g of [(6,7-dichloro-2,3-dimethylbenzo[b]thien-5-yl)oxy]acetic acid, mp 218°-219°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17]C(C(F)(F)F)=CC=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24]([O:26]CC)=[O:25].C1(CN2CCN(C3SC(C(OCC)=O)=C(C)C=3)C2=O)CC1>>[CH:13]1([CH2:12][N:9]2[CH2:10][CH2:11][N:7]([C:5]3[S:4][C:3]([C:24]([OH:26])=[O:25])=[C:2]([CH3:1])[CH:6]=3)[C:8]2=[O:23])[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Agent: CCOC(=O)c1sc(N2CCN(CC3CC3)C2=O)cc1C
Product: Cc1cc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Yield: 80 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 5-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylate, the title compound was obtained as a colorless solid in 80% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.32 (br s, 1H), 6.27 (s, 1H), 3.89-3.78 (m, 2H), 3.69-3.58 (m, 2H), 3.06 (d, J=6.9 Hz, 2H), 2.39 (s, 3H), 1.00-0.86 (m, 1H), 0.53-0.44 (m, 2H), 0.25-0.18 (m, 2H); MS (ES+) m/z 281.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:22]=[N:23][C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:25][CH:26]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(N2CCOCC2)nc1
Temperature: 25 °C

Procedure:
A solution of 5-chloro-2-(6-chloropyridin-3-ylcarbonyl-amino)-N-(5-chloropyridin-2-yl)benzamide (0.2 g) and morpholine (2 mL) in DMSO (2 mL) was heated at 80° C. in a sealed tube overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water, sodium bicarbonate, and dried over sodium sulfate. After evaporation of the solvent, the product was purified by RPHPLC [ethyl acetate/hexane (3:7)]. Yield=0.054 g.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH:7]1([CH2:13][C@H:14]([CH2:33][C:34](=[O:41])[N:35]2[CH2:40][CH2:39]S[CH2:37][CH2:36]2)[C:15]([NH:17][C@@H:18]([CH3:32])[CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH:7]1([CH2:13][C@H:14]([CH2:33][C:34]([N:35]2[CH2:40][CH2:39][S:3](=[O:5])(=[O:2])[CH2:37][CH2:36]2)=[O:41])[C:15]([NH:17][C@@H:18]([CH3:32])[CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:29])[F:30])=[CH:23][CH:22]=2)=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@@H](CC(=O)N1CCSCC1)CC1CCCCC1
Reactant: O=S([O-])OO
Agent: [K+]
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@@H](CC(=O)N1CCS(=O)(=O)CC1)CC1CCCCC1

Procedure:
The compound was synthesized in a similar fashion to Example 6. An OXONE oxidation was employed title compound of Example 51 to furnish the sulfone. A procedure was used as described in McCarthy, J. R. et al. Org. Synth., CV9, 446. 1H NMR (CD3OD, 400 MHz) δ 0.73-0.79 (m, 2H), 1.00-1.19 (m, 7H), 1.10 (d, J=6.8 Hz), 1.34-1.75 (m, 6H), 2.34-2.37 (m, 1H), 2.64-2.71 (m, 2H), 2.94-3.08 (m, 7H), 3.79-4.01 (m, 5H), 6.53-6.56 (m, 2H), 6.87-6.89 (m, 2H). HPLC-MS calcd. for C25H36F3N3O5S (M+H+) 548.2, found 548.2.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:17][C:18]1[N:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.CO.C(Cl)Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:17][C:18]1[N:23]=[CH:22][C:21]([S:24]([N:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
To a stirred ice-cooled solution of 4-(dimethylamino)piperidine (1.2 mL, 9.4 mmol), triethylamine (2.6 mL, 19 mmol), and 4-dimethylaminopyridine (0.012 g, 0.094 mmol) in DCM (18 mL) was added 6-chloropyridine-3-sulfonyl chloride (2.0 g, 9.4 mmol) in one portion. The resulting mixture was stirred at 0° C. for 1.5 h. Upon workup, the mixture was directly subjected to combi-flash column chromatography (methanol/DCM) to give compound 363 (2.7 g, 94% yield) as a white solid. LCMS-ESI (POS), M/Z, M+1: Found 304.0.
Reaction SMILES: [CH:1]([C:4]([CH3:6])=O)(C)C.C([CH:10]([C:23]([CH:25]([O:29][C:30]1[C:35]([F:36])=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40])CCC)=[O:24])[O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[F:22])CC.[CH3:41][C:42](=O)[CH2:43]CC>>[CH:4]([CH:25]([C:23]([CH:10]([O:11][C:12]1[C:13]([F:22])=[C:14]([F:21])[C:15]([F:20])=[C:16]([F:19])[C:17]=1[F:18])[CH:42]([CH3:43])[CH3:41])=[O:24])[O:29][C:30]1[C:35]([F:36])=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40])([CH3:6])[CH3:1]
Reactant: CCCC(Oc1c(F)c(F)c(F)c(F)c1F)C(=O)C(CCC)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCC(C)=O
Reactant: CC(=O)C(C)C
Product: CC(C)C(Oc1c(F)c(F)c(F)c(F)c1F)C(=O)C(Oc1c(F)c(F)c(F)c(F)c1F)C(C)C

Procedure:
This compound is prepared from isopropylmethylketone by the same procedure used to prepare compound 60 from 2-pentanone.
Reaction SMILES: [C:1]([NH2:5])(=O)[CH:2]=[CH2:3].[CH3:6][C:7]([CH3:9])=[O:8].[CH3:10][C:11]([CH3:13])=[O:12].Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>O>[C:1](=[N:15][OH:16])([NH2:5])[CH:2]=[CH2:3].[CH3:6][C:7]([CH3:9])=[O:8].[CH3:10][C:11]([CH3:13])=[O:12]
Reactant: C=CC(N)=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CC(N)=NO
Yield: 82 %

Procedure:
To a solution of 408 g. (2.4 moles) of diacetone acrylamide ##STR12## and 200 g. (2.88 moles; 20% molar excess) of hydroxylamine hydrochloride in 1.5 l. of distilled water was added a solution of 200 g. (1.44 moles) of potassium carbonate in 250 ml. of water at room temperature of about 25° C. over a period of 15 min. A precipitate formed after about 15 minutes. Stirring was continued until a thick paste formed and the mixture was then allowed to stand for another hour. The solid product was isolated by filtration, washed with small portions of water (amounting to a total of 500 ml.) and dried at 40° C. in a vacuum oven. Yield of 365 g. of a white crystalline powder (82% yield), m.p. 103° C. The material was of sufficient purity to be directly employed in polymerization and was employed in the polymerization described in Example 2 hereinafter. If desired, further purification can be attained through recrystallization from benzene or toluene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH2:15])[CH:9]=2)=[CH:4][CH:3]=1.[C:16](=[O:19])([O-])[O-:17].[K+].[K+].[C:22](OCC)(=[O:24])C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH:15][C:22](=[O:24])[C:16]([OH:17])=[O:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(-c2ccc(F)cc2)cc1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(F)cc2)cc1NC(=O)C(=O)O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2.0 g (9.9 mmol) of 4′-fluoro-4-methylbiphenyl-3-amine and 1.64 g (11.9 mmol) of potassium carbonate were suspended in THF, and 1.49 g (10.9 mmol) of chloroglyoxylic acid ethyl were added thereto at 0° C., and stirred at room temperature for 4 hours. After completion of the reaction, ethyl acetate was added to the mixture, and the mixture was washed with an aqueous sodium bicarbonate solution and a sodium chloride solution in this order. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2.76 g of [(4′-fluoro-4-methylbiphenyl-3-yl)amino] (oxo)acetic acid.ethyl ester (yield: 93%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:10]1[C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]2[C:14]1=[O:15])[C:7]([O:9][CH2:11][C:12]1[CH:13]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:8]
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: O=C(OCc1ccccc1)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Yield: 198.6 %

Procedure:
6-Hydroxy-2(S)-phthalimidohexanoic acid (5.0 g) was dissolved in a mixture of 90 ml of methanol and 9 ml of water. To this solution, an aqueous 0.5 M cesium carbonate solution (18 ml) was added and the mixture stirred for a few minutes. Most of the methanol was removed in vacuo and the resulting aqueous residue was freeze-dried. The lyophilized material was dissolved in DMF (70 ml) and treated with 3.08 g of benzyl bromide. After stirring under nitrogen for 6 hours, the reaction mixture was diluted with 450 ml of water and repeatedly extracted with ethyl acetate. Organic layers were then back-washed with water, dried (Na2SO4), and concentrated to give 6.58 g of benzyl 6-hydroxy-2(S)-phthalimidohexanoate. Recrystallization from ether gave a white solid, m.p. 106.5°-108°; [α]D25° =-27.6° (MeOH, c=1.77).