Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[S:10][C:9]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH:15]([C:23]2[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][N:24]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:8][CH:7]=1)[CH2:3][O:4][CH3:5].C([O-])(=O)C.[NH4+:37].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:5][O:4][CH2:3][CH:2]([C:6]1[S:10][C:9]([C:11]2[NH:37][C:14]([CH:15]([C:23]3[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][N:24]=3)[CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:8][CH:7]=1)[OH:1]
Reactant: [NH4+]
Reactant: COCC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(SC)cn2)s1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(SC)cn3)[nH]2)s1
Temperature: 110 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of 1-[5-(1-hydroxy-2-methoxyethyl)-1,3-thiazol-2-yl]-5-[5-(methylsulfanyl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (103 mg) in acetic acid (1.7 mL) was added ammonium acetate (265 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (62.8 mg, yield 64%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH:9]1([C:15]#[CH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CCCCCC>COCCOC.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:9]1([C:15]#[C:16][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cccc(Br)n1
Reactant: C#CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1cccc(C#CC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
2-Bromo-6-methyl pyridine (2.0 g, 11.6 mmol) and Cui (440 mg, 2.3 mmol) were combined in DME (30 mL), and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamne (8.0 mL, 58 mmol) and PdCl2(PPh3)2 (814 mg, 1.16 mmol) were added, followed by the dropwise addition of cyclohexylethyne (1.25 g, 11.6 mmol). The reaction was stirred at ambient temperature overnight. GC/MS showed no starting 2-bromo-6-methylpyridine remaining. The mixture was diluted with ethyl acetate (100 mL), and filtered through Celite.™, The pad was then thoroughly washed with ethyl acetate and the combined filtrates were washed with water (200 mL), brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography eluting with hexane then 98:2, 96:4 hexane:ethyl acetate to afford 2-(cyclohexylethynyl)-6-me-thylpyridine (1.78 g, 77% yield) as a pale brown liquid that partially solidified on standing in the freezer. 1H NMR (CDCl3, 300 MHz) Δ7.52-7.46 (m, 1H), 7.20 (d, J=9 Hz, 1H), 7.03 (d, J=9 Hz, 1H), 2.6 (m, 1H), 2.54 (s, 3H), 2.93-2.89 (m, 2H), 1.78-1.73 (m, 2H), 1.57-1.54 (m, 3H), 1.36-1.32 (m, 3H). MS (ESI) 200.1 (M++H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH2:24]1COCC1.CN1CCCC1=O.C[Mg]Br>CCOC(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH3:23][C:22]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([CH3:24])=[N:3][N:4]=[CH:5]2
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(C)c(-c2ccc3c(C)nncc3c2)c1
Reaction time: 0.17 h

Procedure:
A 150-ml round-bottom flask under argon was charged with ethyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate (358 mg, 1096 μmol), iron(III) acetylacetonate (38.7 mg, 109.6 □mol), THF (4200 μl), and 1-methyl-2-pyrrolidinone (420 μl). Methylmagnesium bromide (1.4M solution in toluene/tetrahydrofuran (75:25); 1174 μl, 1643 μmol) was then added via a syringe to the resulting orange red suspension, causing an immediate color change to brown, and finally to violet. The resulting mixture was stirred for 10 min, and the reaction (which remained a suspension) was diluted with EtOAc and carefully quenched with a few drops of 10% aqueous HCl solution. The mixture was washed with saturated aqueous NaHCO3 solution and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. CombiFlash purification (20% to 90% EtOAc in Hexanes) afforded ethyl 4-methyl-3-(1-methylphthalazin-6-yl)benzoate as a light golden brown oil. MS (ES+): 307.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=2)[CH:12]=[CH:13][C:14]([NH:16][C:17]2[CH:29]=[CH:28][C:20]([CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][CH:18]=2)=[O:15])=[CH:5][CH:4]=1.[CH3:33][I:34]>CN(C)C=O>[I-:34].[CH3:33][N+:22]1([CH2:21][C:20]2[CH:28]=[CH:29][C:17]([NH:16][C:14](=[O:15])[CH:13]=[CH:12][C:11]3[CH:30]=[CH:31][CH:32]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH:10]=3)=[CH:18][CH:19]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1ccc(-c2cccc(C=CC(=O)Nc3ccc(CN4CCCCC4)cc3)c2)cc1
Reactant: CI
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(C=CC(=O)Nc3ccc(C[N+]4(C)CCCCC4)cc3)c2)cc1
Product: [I-]

Procedure:
A solution of 1-(4-(3-(4-methoxyphenyl)cinnamoyl-amino)benzyl)piperidine (0.32g) and methyl iodide (0.2ml) in dimethylformamide (5ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which were recrystallized from ethanol-hexane to give 1-methyl-1-(4-(3-(4-methoxyphenyl)cinnamoylamino)-benzyl)piperidinium iodide (Compound 88) (0.33g) as pale brown crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.B1([C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+].[Cl:43]CCl>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.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>[ClH:43].[ClH:43].[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[O:10][N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:3]=2)[N:12]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Ic1cccc(-c2noc(-c3ccccn3)n2)c1
Reactant: ClCCl
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: COCCOC
Product: Cl
Product: c1ccc(-c2nc(-c3cccc(-c4cccnc4)c3)no2)nc1
Temperature: 100 °C
Yield: 55.45 %

Procedure:
A mixture of 3-(3-iodophenyl)-5-(2-pyridyl)-1,2,4-oxadiazole (55 mg, 0.158 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (51.4 mg, 0.3152 mmol), and tetrakis(triphenylphosphine)palladium(0) Pd(PPh3)4, 25 mg, 0.0216 mmol), in a solution of ethylene glycol dimethyl ether (1.5 mL) and 2M sodium carbonate (1.5 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using 40% and 60% ethyl acetate in hexane and then the treatment of 1M HCl (0.2 mL) afforded 29.4 mg (55.45%) 5-(2-pyridyl)-3-[3-(3-pyridyl)-phenyl]-1,2,4-oxadiazole hydrochloride. 1H-NMR (CDCl3), δ (ppm): 9.34 (s, 1H), 8.88 (m, 3H), 8.54 (s, 1H), 8.40 (d, 1H), 8.28 (d, 1H), 8.16 (d, 1H), 8.00 (m, 3H), 7.82 (m, 2H).
Reaction SMILES: [P:1]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2]C1C=CC=CC=1.[CH:23]1[C:28]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[C:25]([Cl:33])[CH:24]=1.[CH:34](=O)[CH2:35][CH3:36]>ClC1C=CC=CC=1>[Cl:33][C:25]1[CH:24]=[CH:23][C:28]([S:29]([NH:32][CH:34]([P:1](=[O:2])([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:35][CH3:36])(=[O:31])=[O:30])=[CH:27][CH:26]=1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCC=O
Solvent: Clc1ccccc1
Product: CCC(NS(=O)(=O)c1ccc(Cl)cc1)P(=O)(Oc1ccccc1)Oc1ccccc1
Reaction time: 1 h

Procedure:
When a mixture of 0.25 mole each of triphenyl phosphite and p-chlorobenzenesulfonamide and 0.275 mole of redistilled propionaldehyde in 150 g of chlorobenzene is warmed, heat of reaction is observed at 85°-90°. The temperature is kept at 95°-100° for 1 hr, and then the solvent is removed at reduced pressure. Acetonitrile (150 ml) is added to the residue, and the solution is cooled and filtered, giving 50 g of solid product. Recrystallization of a portion from acetonitrile gives a white solid: mp 136°-138°; 31P nmr(DMSO-d6)- 17.3 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=O)[CH3:9])=[CH:4][CH:3]=1.[CH3:22][C:23]([S@:26]([NH2:28])=[O:27])([CH3:25])[CH3:24]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13](=[N:28][S@@:26]([C:23]([CH3:25])([CH3:24])[CH3:22])=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: C[C@H](NCCC(=O)c1ccc(F)cc1)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NCCC(=N[S@](=O)C(C)(C)C)c1ccc(F)cc1)c1ccc(Br)cc1
Yield: 73.3 %

Procedure:
A mixture of (S)-3-(1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)propan-1-one (14.5 g, 0.04 mol), (R)-2-methylpropane-2-sulfinamide (5.5 g, 0.046 mol), and Ti(OEt)4 (18 g, 0.08 mmol) in THF (150 mL) was heated to reflux overnight. The mixture was treated with brine, and the precipitate was filtered. The filtrate was concentrated to give (R)—N-(3-((1S)-1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)propylidene)-2-methylpropane-2-sulfinamide (13.3 g, 59%), which was used for the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[CH:8]=[C:9](I)[CH:10]=1)=[O:4].C[C:21]1[N:22]=[CH:23][S:24][CH:25]=1.CC(O[K])=O>CC(N(C)C)=O.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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[CH:8]=[C:9]([C:25]2[S:24][CH:23]=[N:22][CH:21]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cc2F)c1
Reactant: Cc1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[K]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(-c2cncs2)cc(-c2ccc(C)cc2F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a stirred solution of 2′-fluoro-5-iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester (50 mg, 0.135 mmol) and 4-methylthiazole (57.4 mg, 0.675 mmol) in 10 ml of dimethylacetamide was added Pd(PPh3)4 (8 mg, 0.00675 mmol) and CH3COOK (20 mg, 0.2 mmol). The reaction mixture was heated to 100° C. and stirred overnight. After cooling down to room temperature, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexanes/EtOAc=1:5) to afford 30 mg (68%) of 2′-fluoro-4′-methyl-5-thiazol-5-yl-biphenyl-3-carboxylic acid methyl ester, MS (M+H)=328.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CO[C:17]1[C:21](OC)=[N:20][S:19](=[O:25])(=[O:24])[N:18]=1.[CH2:26]([NH2:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CO>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[C:21]([NH:38][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[N:20][S:19](=[O:25])(=[O:24])[N:18]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CCCCCCCCCCCCN
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CO
Product: CCCCCCCCCCCCNC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Reaction time: 0.25 h
Yield: 37 %

Procedure:
A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2.41 g; 11.2 mmoles) in 25 ml of methanol was added dropwise to a well stirred cold suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in 200 ml of methanol. After stirring at 2°-5° for 15 minutes, a solution of dodecylamine (4.15 g; 22.4 mmoles) in 25 ml of methanol was added all at once, and stirring was continued at ambient temperature for 18 hours. The reaction mixture was filtered and evaporated under reduced pressure, and the residue placed on 60 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined, evaporated and the residue was rechromatographed on 60 g of silica gel using a gradient elution of acetonitrile-methanol. The appropriate fractions from the second chromatography were combined, concentrated under reduced pressure and the crystallized product was collected by filtration and dried to give 2.13 g of the title compound, mp 136°-139°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:20]C)=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[B].O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2[nH]nc(-c3cccc(F)c3)c2cc1C(=O)O
Agent: [B]
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cc2c(-c3cccc(F)c3)n[nH]c2cc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
A total of 96.2 mg of 3-(3-fluoro-phenyl)-6-methoxy-1H-indazole-5-carboxylic acid obtained in Production Example II-1-e was dissolved in 3.36 ml of dichloromethane, 4.0 ml of a 1.0 M solution of boron tribormide in dichloromethane was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The resulting organic layer was washed brine, dried over magnesium sulfate and the solvent was evaporated, to give 84.1 mg of the crude product of the title compound.
Reaction SMILES: [O:1]1C=CC=[C:2]1[C@@H:6]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:7]([CH3:15])[CH2:8][O:9][CH2:10][C:11]([OH:14])([CH3:13])[CH3:12].I([O-])(=O)(=O)=[O:26].[Na+]>O.C(Cl)(Cl)(Cl)Cl.CC#N.[Ru](Cl)(Cl)Cl>[C:19]([O:18][C:17]([N:16]([CH3:24])[C@@H:6]([C@H:7]([CH3:15])[CH2:8][O:9][CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])[C:2]([OH:1])=[O:26])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@H](COCC(C)(C)O)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@H](COCC(C)(C)O)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.75 h
Yield: 89.5 %

Procedure:
To a solution of compound 2.7b (120.0 mg, 0.35 mmol) in water:CCl4:MeCN (3:2:3, 9.6 ml) at room temperature was added sodium periodate (451.0 mg, 2.1 mmol, 6.0 equiv) followed by ruthenium chloride (25.0 mg, 0.12 mmol, 0.34 equiv). After stirring for 45 minutes, the aqueous layer was extracted with ethyl acetate (3×5 ml). Combined organic layer was washed with saturated aqueous NaHSO3 (25 ml), brine, dried with anhydrous sodium sulfate, and concentrated in vacuo to give compound 2.7c (100.0 mg) which was used for the next step without further purification. MS m/z (M+Na) 342.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: COC(=O)COCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)COCCOc1ccc(N)cc1
Yield: 71.1 %

Procedure:
[2-(4-Nitrophenoxy)ethoxy]acetic acid methyl ester 42 (1 g, 3.9 mmol) was dissolved in anhydrous ethyl acetate (20 ml). Palladium on carbon (10%, 0.1 g) was added and the mixture stirred under a hydrogen atmosphere using a balloon for 30 mins. The catalyst was filtered, the filtrate concentrated, hexane (3 ml) added, and the solid filtered to give 43(625 mg, 70.9%) as a light brown powder with a m.p. between 51-52.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:26][C:27]1[N:28]=[C:29]2[N:33]([C:34]=1[S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:31][S:30]2>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:35]([C:34]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[Cl:26])(=[O:36])=[O:37])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1c(Cl)nc2sccn12
Yield: 64.1 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (92) (150 mg, 0.53 mmol), pyridine (Aldrich, 0.21 mL, 2.63 mmol) and 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride (Maybridge, 149 mg, 0.58 mmol) in THF. 172 mg (65%) of 98 was obtained as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[O:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:4]=1)#N.[OH-:24].[K+].C(O)C.[OH2:29]>>[C:12]1([C:8]2[C:7]3[CH:6]=[C:5]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:4]=[C:3]([C:1]([OH:29])=[O:24])[C:11]=3[O:10][CH:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O
Reactant: N#Cc1cc(-c2ccccc2)cc2c(-c3ccccc3)coc12
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)coc12

Procedure:
A mixture containing 30 g. (0.10 mole) of the product of step C, 14.5 g. (0.22 mole) of 85 percent potassium hydroxide, 400 ml. of ethanol and 50 ml. of water is heated at its reflux temperature for 16 hours, cooled and filtered. The product is washed with ethanol, suspended in water and acidified with 6 N hydrochloric acid. The mixture is heated on a steam bath for one hour, cooled and filtered. Recrystallization from ethanol provides 3,5-diphenylbenzofuran-7-carboxylic acid as a white solid.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:26][CH:25]=1.[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH2:52])=[CH:49][CH:48]=1>>[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH:52][C:40]([C:36]2[S:35][C:34]([N:31]3[CH2:32][CH2:33][N:29]([CH2:28][C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:45][CH:44]=4)[C:30]3=[O:43])=[N:38][C:37]=2[CH3:39])=[O:41])=[CH:49][CH:48]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 38 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 4-fluorobenzylamine in place of benzylamine, the title compound was obtained as a white powder in 38% yield: mp 177-178° C.; NMR (300 MHz, CDCl3) δ 729-721 (m, 4H), 7.04-6.96 (m, 4H), 5.98 (s, 1H), 4.50 (d, J=5.7 Hz, 2H), 4.41 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.42 (t, J=8.1 Hz, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.1, 162.4, 160.8, 155.3, 153.2, 133.8, 131.3, 129.9, 129.5, 117.2, 115.7, 115.4, 47.2, 43.2, 42.0, 41.6, 17.2; MS (ES+) m/z 443.2 (M+1).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)(Cl)=O.Cl.[CH3:16][NH:17][CH3:18].C(N(CC)CC)C>ClCCl>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([N:17]([CH3:18])[CH3:16])=[O:10]
Reactant: CNC
Reactant: O=C(O)c1ccccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A mixture of 156 g (1.13 mol) of salicylic acid and 471 g (3.96 mol) of thionyl chloride was stirred for 4 hr at 50° C.-60° C. Excess thionyl chloride was distilled off under vacuum, and the residue was additionally dried in vacuum. A solution of this product in 300 mL of dichloromethane was added dropwise with vigorous stirring to a mixture of 270 g (3.31 mol) of dimethylamine hydrochloride and 702 g (6.95 mol) of triethylamine in 1200 mL of dichloromethane for 1 hr at 0° C. The resulting mixture was slowly warmed to room temperature, stirred for 1 hr, and then filtered through glass frit. The precipitate was additionally washed with 300 mL of dichloromethane. The combined filtrate was washed by 5% hydrochloric acid, water, dried over K2CO3, and then evaporated to dryness. The residue was washed with 200 mL of diethyl ether to yield 112 g (60%) of white solid.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=2)[CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Product: CN1CC=C(c2cn(C(=O)c3ccc(F)cc3)c3ccc(OC4CCCCC4)cc23)CC1

Procedure:
(24.0 mg, 68%); from 5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4c, 25.6 mg, 0.082 mmol) and 4-fluorobenzoyl chloride (25 uL, 0.21 mmol); HRMS-FAB+ for C27H29N2O2F: calculated MH+ : 433.22913; found: 433.22733.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Reactant: CCS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
To a solution of 1.0 g (4.4 mmol) of 1-Boc-4-(2-amino-phenyl)-piperazine and 1.1 mL (6.6 mmol) of triethylamine in 12 mL of DCM was added 0.63 mL (6.6 mmol) of ethanesulfonyl chloride, and the mixture was stirred at r.t. for about 16 hours. The mixture was diluted with ethyl acetate and washed once with 10% aqueous sodium bisulfate and then once with saturated aqueous sodium bicarbonate. The organic portion was dried (Na2SO4), filtered and concentrated in vacuo. Silica gel chromatography (3iotage, 40% ethyl acetate/hexanes) of the residue afforded about 0.73 g (45%) of the title compound. LRMS (ESI−): 368 (M−1)