Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[N+:7]([CH2:10][S:11]([C:13]1[C:18]2[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:12])([O-:9])=[O:8].S(S([O-])=O)([O-])(=O)=[O:27].[Na+].[Na+]>C(O)(=O)C.O>[N+:7]([CH2:10][S:11]([C:13]1[C:18]2[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:17]=2[CH:16]=[CH:15][CH:14]=1)(=[O:27])=[O:12])([O-:9])=[O:8]
Reactant: O=[N+]([O-])CS(=O)c1cccc2c1oc1ccccc12
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])CS(=O)(=O)c1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3% aqueous solution of potassium permanganate (83 ml, 16.2 mmol) was added to a stirred solution of 4-(nitromethylsulphinyl)dibenzofuran (3.72 g, 13.5 mmol) at 50° C. in acetic acid (100 ml). The reaction mixture was stirred for 1 hour at ambient temperature and then treated with a saturated aqueous solution of sodium metabisulphite until colourless. The reaction mixture was then diluted with water (200 ml). The solid material was removed by filtration, air dried and recrystallised from toluene/cyclohexane to give 4-(nitromethylsulphonyl)dibenzofuran as a white crystalline solid (2.95 g), m.p. 162°-165° C.; NMR (DMSOd6): 6.80 (s,2H) 7.48-8.79 (m,7H); m/e (electron impact): 291 (M+); microanalysis, found: C,53.6; H,3.0; N,4.7%; C13H9NO5S requires: C,53.6; H,3.1; N,4.8%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Br-].[CH2:10]([Zn+])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1.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>[CH2:10]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cccc(Br)n1
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Brc1cccc(Cc2ccccc2)n1
Temperature: 60 °C

Procedure:
2,6-Dibromopyridine (2.36 g, 1 mmol), benzylzinc bromide (0.9 M in THF, 1.05 mL, 0.95 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.01 mmol) were placed in THF (75 mL) and heated to 60° C. for 20 hours. The reaction mixture was cooled, submitted to standard aqueous workup and purified on silica gel to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.S(O[CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C.[K]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)ccc1OCC1CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 117.1 %

Procedure:
5-Chlorosalicylaldehyde (7.7 g, 49.4 mmol) was dissolved in DMF (20 ml) with potassium carbonte (7.5 g, 54.1 mmol) and the cyclobutanemethanol tosylate (1 3 g, 54.1 mmol). The mixture was stirred at 50° C. under argon for 16 hours. Poured into water (500 ml). extracted with ethyl acetate (4×100 ml)and the combined organic fractions washed with 1M sodium hydroxide solution (100 ml), water (100 ml), saturated brine (100 ml) dried (MgSO4) and concentrated in vacuo to give 5-chloro-2-(cyclobutylmethoxy)benzaldehyde as a brown oil (13 g) which was used without further purification.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:40])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:39])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:39][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:40])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
Lithium hydroxide monohydrate (0.021 g, 0.50 mmol) was added to a stirred solution of {6-chloro-3-methyl-4-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.07 g, 0.13 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-3-methyl-4-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.048 g, 70%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s., 1 H) 8.23 (d, J=8.80 Hz, 2 H) 8.17 (d, J=7.82 Hz, 2 H) 7.97 (d, J=8.80 Hz, 1 H) 7.91 (s, 1 H) 7.68 (d, J=7.82 Hz, 2 H) 7.55 (d, J=8.80 Hz, 2 H) 7.48 (d, J=7.82 Hz, 1 H) 6.94 (s, 1 H) 3.85 (s, 2 H) 2.02 (s, 3 H). MS calcd. for C26H17ClF3O5S [(M−H)−] 533, obsd. 533.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].C(N(C(C)C)C(C)C)C.Cl.[CH3:34][O:35][C:36](=[O:41])[C@H:37]([CH2:39][OH:40])[NH2:38]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:17])[C:6]([C:18]([NH:38][C@H:37]([C:36]([O:35][CH3:34])=[O:41])[CH2:39][OH:40])=[O:19])=[C:5]2[OH:23]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CO)NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
Ethyl 6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (287 mg, 852 μmol, Example 1 A-C) was dissolved in 1,4-dioxane (852 μL) and N-ethyl-N-isopropylpropan-2-amine (445 μL, 2557 μmol). L-Serine methyl ester hydrochloride (199 mg, 1278 μmol) was added, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the 180 mg of the title compound as a white solid after flash chromatography. MS m/e=410 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@H:12]([O:21][Si](C(C)(C)C)(C)C)[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=O)=O)=CC=1.[H-].[Na+].[OH:32][CH2:33][C:34]1[CH:35]=[C:36]([C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)[CH:37]=[CH:38][CH:39]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[OH:32][CH2:33][C:34]1[CH:35]=[C:36]([C:40]2[CH:45]=[CH:44][C:43]([O:10][CH2:11][C@H:12]([OH:21])[CH2:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:42][CH:41]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)O[Si](C)(C)C(C)(C)C)cc1
Reactant: OCc1cccc(-c2ccc(O)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
Prepared according to the method described in Example 26e) from (2R)-2-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-1-butyl para-toluenesulfonate (0.68 g), sodium hydride (60%, 0.073 g) and 3'-hydroxymethylbiphenyl-4-ol (0.39 g) in N,N-dimethylformamide (10 ml). The adduct was deprotected by dissolving in tetrahydrofuran (10 ml) to which tetrabutylammonium fluoride (0.93 g) was added. The reaction was stirred at ambient temperature for 1 hour, poured into brine and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give the title compound (0.2 g) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[N:4]=1)[CH3:2]
Reactant: CCc1cc(CC)n(-c2ccc(OC)cc2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc(CC)n(-c2ccc(O)cc2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-diethyl-1-(4-methoxyphenyl)-1H-pyrazole (893 mg, 3.88 mmol) in methylene chloride (50 mL) at −78° C. was added boron tribromide (1.10 mL, 11.63 mmol). The reaction was stirred at −78° C. for 1 hour and at room temperature for an additional 1 hour. The reaction was quenched with saturated sodium bicarbonate. After the aqueous layer was extracted with methylene chloride, the combined organic layers were dried (MgSO4) and concentrated to give the desired product. The reaction was assumed to be quantitative. LC-MS (C13H16N2O calculated 216) m/z 217 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[O:17][CH3:18])[C:3]=1[C:4]#[N:5].O=[C:20]([CH3:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[O:17][CH3:18])[N:1]=[C:20]([CH3:27])[C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COC1CCCCC1Oc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3OC)c2c1N

Procedure:
Prepared as in Example 2a from 2-Amino-6-(2-methoxycyclohexyloxy)benzonitrile (Example 109b) and ethyl 3-oxobutanoate as a pale yellow oil (16%). MS 359 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH3:22])[CH2:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([O:20][CH3:21])=[C:14]([N+:17]([O-])=O)[CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:2]>[Pd].CO>[CH2:1]([N:3]([CH2:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([O:20][CH3:21])=[C:14]([NH2:17])[CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:22])[CH3:2]
Reactant: CCN(C)CC(=O)N1CCCc2cc(OC)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CCN(C)CC(=O)N1CCCc2cc(OC)c(N)cc21
Yield: 63.7 %

Procedure:
A solution of N-ethyl-N-methyl-2-[6-(methyloxy)-7-nitro-3,4-dihydro-1(2 H)-quinolinyl]-2-oxoethanamine (2.02 g, 6.57 mmol) and 10% palladium on carbon (1.05 g) in methanol (55 mL) was maintained under 40 psi of H2 gas in a pressure flask for 24 hours. The solution was purged with nitrogen, filtered through celite, taken to a residue under reduced pressure, and purified by column chromatography to afford 1-{[ethyl(methyl)amino]acetyl}-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (1.16 g, 64% yield) as a dark orange oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.82 (s, 1H), 6.56 (s, 1 H), 4.54 (s, 2 H), 3.72 (s, 3 H), 3.61 (t, J=5.82 Hz, 2 H), 3.25 (s, 2 H), 2.57 (t, J=6.22 Hz, 2 H), 2.43 (q, J=7.02 Hz, 2 H), 2.20 (s, 3 H), 1.70-1.89 (m, 2 H), 0.84-1.03 (m, 3 H).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:27][CH:28]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH:31][C:16]([C:13]([CH3:14])([O:12][C:8]2[CH:7]=[C:6]([CH2:5][C@H:4]([O:19][CH3:20])[C:3]([OH:2])=[O:21])[CH:11]=[CH:10][CH:9]=2)[CH3:15])=[O:18])[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)O)c1)OC
Reactant: NCCc1cccc(Cl)c1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1cccc(OC(C)(C)C(=O)NCCc2cccc(Cl)c2)c1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (EXAMPLE 56, step 2) and 2-(3-chloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H29ClNO5 [M−H]−: 418.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH:10]3[CH2:12][C:6]([C:13]([O:15][CH3:16])=[O:14])([CH2:7][CH:8]1[CH2:9]3)[CH2:5]2)(=[O:3])[CH3:2].[CH2:17](O)[CH2:18][OH:19].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH3:2][C:1]1([C:4]23[CH2:11][CH:10]4[CH2:12][C:6]([C:13]([O:15][CH3:16])=[O:14])([CH2:7][CH:8]2[CH2:9]4)[CH2:5]3)[O:19][CH2:18][CH2:17][O:3]1
Reactant: OCCO
Reactant: COC(=O)C12CC3CC(C1)C(C(C)=O)(C3)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C12CC3CC(C1)C(C1(C)OCCO1)(C3)C2
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture of methyl 3-acetyltricyclo[3.3.1.03,7]nonane-1-carboxylate (2.0 g, 8.9 mmol) obtained in step II, 1,2-ethanediol (8.9 mL), p-TSA (47 mg, 5 mol %) and benzene (36 mL) was refluxed using a Dean-Stark apparatus for 1 h. The reaction mixture was cooled to room temperature, 10% aq. NaHCO3 (36 mL) was added, and the two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure to obtain methyl 3-(2-methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]nonane-1-carboxylate (2.2 g) in 93% yield as viscous liquid. m/z (M+1) 267. IR cm−1 2954, 1731, 1698, 1460, 1236, 1046, 752. 1H NMR (CDCl3) 300 MHz δ 4.07-3.94 (m, 4H), 3.66 (s 3-H), 2.44-2.36 (m 2-H), 2.27-2.18 (m, 1H), 2.12-2.02 (m, 1H), 1.94-1.81 (m, 8-H), 1.30 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([Cl:28])[C:19]=1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1.Cl>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([Cl:28])[C:19]=1[S:29]([NH:14][CH:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[C:2]([F:1])([F:15])[F:16])(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(NC(Cc1c[nH]c2ccccc12)C(F)(F)F)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A mixture of 100 mg (0.44 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 137 mg (0.44 mmol) of 2,6-dichloro-4-(trifluoromethyl)benzenesulfonyl chloride in 8 mL of pyridine was stirred at room temperature for 2 hours, and warmed at 70° C. for 18 hours. The mixture was cooled to room temperature and diluted with 1 M HCl until acidic and extracted with ethyl acetate. The combined organic layers were washed with 1 N aqueous HCl, saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, decanted, and concentrated in vacuo. The crude material was crystallized from ether-hexanes to afford 40 mg (18%) of the title compound as a colorless powder. MS: m/z 505 (M), 507 (M+2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH2:29])[CH3:28].C(N(CC)CC)C>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH:29][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:28]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(N)c1ccccc1-c1cc(F)ccc1F
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)NC(C)c2ccccc2-c2cc(F)ccc2F)c1
Yield: 94.2 %

Procedure:
The title compound was prepared from 3-methoxybenzenesulfonyl chloride (326 mg, 1.6 mmol), 1-(-2′,5′-difluoro-biphenyl-2-yl)ethylamine (350 mg, 1.5 mmol), and triethylamine (418 μL, 3 mmol) according to the procedure and in the same manner as described in Example 112, step c. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (570 mg, 94%) as a clear glass;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([NH:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:11])[CH3:10].C([O-])(=O)C.[Na+].O>C(OC(=O)C)(=O)C.CC(C)=O>[C:9]([NH:12][C:13](=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:14]([OH:16])=[O:15])(=[O:11])[CH3:10]
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1cccnc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)NC(=Cc1cccnc1)C(=O)O
Reaction time: 0.17 h
Yield: 23.1 %

Procedure:
Pyridine-3-carboxaldehyde (92.6 g), N-acetylglycine (86.0 g) and sodium acetate (35.3 g) were heated together under reflux in acetic anhydride (150 ml) for 1 hour. After cooling, water (250 ml) was added and the mixture was filtered to give the crude azlactone (50.9 g) m.p. 155°-60°. Partial hydrolysis of the azlactone (50 g) was achieved by heating under reflux in acetone (450 ml) and water (175 ml) for four hours. After this time the bulk of the acetone was distilled off and more water (300 ml) added. The resulting deep red solution was boiled with charcoal for 10 minutes and filtered through celite. The filtrate was evaporated to dryness and the residue was triturated and washed with acetone to give 2-acetamido-3-(3-pyridyl)acrylic acid (35 g) m.p. 191°-92° which was not further purified.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[C:22](=[O:40])[NH:23][C:24](=[O:39])[C:25]=2[C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH:35](OC)[CH3:36])[CH:27]=2)=[CH:13]1)[CH3:11]>Cl.ClCCl>[C:1]1([S:7][CH:35]([N:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]([C:25]3[C:24](=[O:39])[NH:23][C:22](=[O:40])[C:21]=3[C:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]([CH:10]([S:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:11])[CH:13]=3)=[CH:27]2)[CH3:36])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(C)n1cc(C2=C(c3cn(C(C)OC)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: Sc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC(Sc1ccccc1)n1cc(C2=C(c3cn(C(C)Sc4ccccc4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 2 h
Yield: 93.7 %

Procedure:
220 mg of thiophenol and 1 drop of concentrated hydrochloric acid were added to a solution of 150 mg of the product of Example 10 in 40 ml of dichloromethane. The solution was stirred nitrogen for 2 hours. The solvent was evaporated and the residue was recrystallized from diethyl ether/hexane to give 190 mg of 3,4-bis[1-(1-phenylthioethyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 102°-105° C.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1.[Cl-].[NH4+]>C1COCC1>[O:12]=[C:9]1[N:8]([CH2:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[CH:19][CH:18]=2)[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CN2C(=O)OC[C@@H]2c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(4S)-4-phenyl-1,3-oxazolidin-2-one (0.158 g, 0.968 mmol) was added to a stirred, 0° C. cooled mixture of sodium hydride (0.041 g, 1.014 mmol) in THF (2 ml) and the mixture was stirred at 0° C. for 15 min. 1,1-dimethylethyl 4-(bromomethyl)benzoate (0.25 g, 0.922 mmol) was then added and the reaction mixture was allowed to stirred at 0° C. for 30 min. Saturated ammonium chloride was added and the mixture was extracted with ethyl acetate (10 mL×2×). The combined organic fractions were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to obtain 1,1-dimethylethyl 4-{[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]methyl}benzoate. The ester was taken to the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].Cl[C:14]1[C:15]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][NH:20][C:16]=2[N:17]=[CH:18][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Pd]>[CH2:26]([O:25][C:23]([C:22]1[C:15]2[C:14]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:1]([OH:3])=[O:2])=[N:19][CH:18]=[N:17][C:16]=2[NH:20][CH:21]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)c1c[nH]c2ncnc(Cl)c12
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(C(=O)O)c3)c12
Temperature: 100 °C

Procedure:
To a mixture of 3-carboxyphenyboronic acid (215 mg, 1.30 mmol) and ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (195 mg, 0.864 mmol) in 2 M aqueous sodium carbonate (2.0 mL, 2.1 mmol) and dioxane (8.0 mL) was added SiliaCat® heterogeneous catalysts DPP-Pd (loading=0.28 mmol/g, 617 mg, 0.173 mmol). The reaction mixture was purged with argon and heated to 100° C. overnight. The reaction mixture was filtered and rinsed with ethyl acetate and methanol. The reaction solution was concentrated under reduced pressure to give 3-(5-(ethoxycarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzoic acid which was used for next step without further purification. LRMS (ESI) calc'd for C16H14N3O4 [M+H]+: 312, found 312.
Reaction SMILES: O=[C:2]([CH3:15])[CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6]CC)=O.Cl.[C:17](=[NH:22])([NH2:21])[CH2:18][CH2:19][CH3:20].N12CCCN=C1CCCCC2.C(OCC)(=O)C>CN(C)C=O.O>[CH3:15][C:2]1[N:21]=[C:17]([CH2:18][CH2:19][CH3:20])[NH:22][C:4](=[O:6])[C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1
Reactant: CCCC(=N)N
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccccc2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-oxo-2-phenylbutanoate (2.28 g) and butanimidamide hydrochloride (2.04 g) in N,N-dimethylformamide (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 mL), and the mixture was stirred at 100° C. for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.26 g, 10%).