Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.Cl>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:11]2[CH2:13][CH2:12]2)=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: COc1cc(Br)ccc1Cl
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(C2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-1-chloro-2-methoxy-benzene (1.45 g, 6.55 mmol) in dry tetrahydrofuran (10 ml), was added {1,3-bis(diphenylphosphino)-propane}dichloronickel (II) and cyclopropylmagnesium bromide (46 ml, 0.5 M in tetrahydrofuran, 23 mmols) at room temperature. The solution was stirred at room temperature for 2 hours, and then heated at 65° C. for 48 hours. Aqueous hydrochloric acid solution (1 N, 20 mL) was added, and the mixture was then cooled to room temperature and stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (2% ethyl acetate in hexane) to yield 1-chloro-4-cyclopropyl-2-methoxy-benzene as yellow oily residue (0.81 g, 67%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([F:35])[CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([F:35])[CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cc(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3cc(F)cc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
Sodium hydroxide (40 mg) was added to a solution of ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D139) (330 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by MDAP to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoic acid (E101) (150 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.62 (2H, t), 2.96 (2H, t), 5.43-5.49 (1H, m), 7.35 (1H, d), 7.65-7.69 (2H, m), 8.77 (1H, s), 9.07 (1H, s), 10.99 (1H, s), 12.13 (1H, br s). δF (DMSO-d6, 376 MHz): −124.9. MS (ES): C21H18ClFN4O4 requires 444. found 445.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH2:50]([SH:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:50]([S:57][C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:13][CH:14]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)cc(SCc2ccccc2)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Yield: 67 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g), benzylmercaptan (0.11 ml) and potassium carbonate (0.13 g) in acetonitrile (10 ml) was heated under reflux for 4 hours with stirring. The reaction mixture was allowed to cool and the precipitate was removed by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and then 1N hydrochloric acid (1.5 ml) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.26 g, 67%).
Reaction SMILES: C([N:8]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]([F:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(O)C.[OH-].[OH-].[Pd+2]>[CH:18]1([NH:8][CH2:9][C:10]([F:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)C(C)(F)CN(Cc1ccccc1)C1CCCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)C(C)(F)CNC1CCCCC1
Yield: 95.1 %

Procedure:
A solution of ethyl 3-(benzyl(cyclohexyl)amino)-2-fluoro-2-methylpropanoate (1.6 g, 5 mmol) in ethanol (20 mL) was hydrogenated with Pd(OH)2 (20%, 176 mg, 0.25 mmol) in presence of TFA (5 mmol) at atmospheric pressure for 20 h. The reaction mixture was filtered through celite. The filtrate was concentrated and diluted to EtOAc/H2O, aqueous layer was basified to pH=11-12 by 1N NaOH. The organic layer was then dried and concentrated to give the product (1.1 g, 95%) as light yellow liquid. [M+H] calc'd for C12H22FNO2, 232. found 232.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].[Na+]>CO>[C:1]([NH:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)c1ccc(COCCNC(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCCOCc1ccc(C(=O)O)cc1)OCc1ccccc1

Procedure:
Ester 15-2 (500 mg, 1.46 mmol) and 1N NaOH (3.6 mL, 3.6 mmol) were combined in 14 mL MeOH. After 3 h the mixture was concentrated, diluted with EtOAc, and extracted with H2O. The aqueous layer was acidified with 10% KHSO4 and extracted with EtOAc, and this organic layer was washed with brine, dried (MgSO4), and concentrated, providing 15-3 as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([S:19][CH3:20])[C:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.ClC1C=CC=C(C(OO)=[O:30])C=1.O>C(Cl)Cl>[F:21][C:2]([F:1])([S:19]([CH3:20])=[O:30])[C:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: CSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CS(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a 10 ml solution of 150 mg (0.47 mmol) of 3,3-difluoro-2-(2',4'-difluorophenyl)-3-methylthio-1-(1H-1,2,4-triazol-1-yl)propan-2-ol [Compound (1a-1)] in methylene chloride, 114 mg (0.56 mmol) of m-chloroperbenzoic acid were added at room temperature, followed by stirring for 30 minutes. To the reaction mixture, water was added, followed by extraction with chloroform. The extract was then washed successively with a 10% aqueous solution of sodium thiosulfate and a 10% aqueous solution of sodium carbonate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The oil so obtained was purified by chromatography on a silica gel column using chloroform:methanol (10:1), whereby 64 mg of the title Compound (1b-1) [diastereomers (1b-1A):(1b-1B)=2.5:1] were obtained in the form of colorless crystals (yield: 403).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[C:27]([C:31]1[CH:36]=[C:35]([O:37][CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)[C:34]([CH3:48])=[CH:33][C:32]=1[S:49]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CO.Cl>[C:27]([C:31]1[CH:36]=[C:35]([O:37][CH2:38][CH2:39][OH:40])[C:34]([CH3:48])=[CH:33][C:32]=1[S:49][C:3]1[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH2:7][C:2]=1[OH:1])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCCO[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(CCc3ccc(O)cc3)OC2=O)c(C(C)(C)C)cc1OCCO

Procedure:
The title compound was synthesized using General Method 9 using 0.07 g (2 mmol) of 4-hydroxy-6,6-bis-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example PP), 1.00 g (2 mmol) of toluene-4-thiosulfonic acid S-{2-tert-butyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-phenyl} ester (prepared in Example PPP), 1.06 g (8 mmol) K2CO3, and DMF (5 mL). The solid which was obtained was then dissolved in 20 mL MeOH and 2 mL of IN HCl. After 15 minutes the reaction was concentrated and the residue partitioned between EtOAc and H2 0; the organic layer was separated, dried (Na2SO4) and concentrated. Trituration with Et2O yielded the title compound, m.p. 106-107° C. 1H NMR (DMSO-d6) δ 1.49 (s, 9 H), 1.75 (s, 3 H), 2.0 (t, 4 H), 2.5 (t, 4 H), 3.4 (dd, 2 H), 3.7 (bs, 2 H), 3.95 (t, 2 H), 4.8 (br s, 1 H), 6.66 (d, 4 H), 6.7 (s, 1 H), 6.8 (s, 1 H), 6.98 (d, 4 H), 9.17 (s, 2 H).
Reaction SMILES: [O:1]=[S:2]1(=[O:45])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25]OP(OC5C=CC=CC=5)(OC5C=CC=CC=5)=O)[N:22]=[N:21]4)[O:16][C:15]3=[O:43])=[CH:10][C:9]=2[F:44])[CH2:4][CH2:3]1.[SH:46][C:47]1[NH:48][CH:49]=[CH:50][N:51]=1.[H-].[Na+]>CN(C=O)C>[O:45]=[S:2]1(=[O:1])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25][S:46][C:47]5[NH:48][CH:49]=[CH:50][N:51]=5)[N:22]=[N:21]4)[O:16][C:15]3=[O:43])=[CH:10][C:9]=2[F:44])[CH2:4][CH2:3]1
Reactant: O=C1O[C@@H](Cn2cc(COP(=O)(Oc3ccccc3)Oc3ccccc3)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Reactant: Sc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1O[C@@H](Cn2cc(CSc3ncc[nH]3)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-[(diphenoxyphosphinyl)oxymethyl]-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 15) (0.125 g, 0.19 mmol) was added to a solution of 2-mercaptoimidazole (38 mg, 0.38 mmol) in DMF (2 ml) and the resulting solution was added to a suspension of sodium hydride (15 mg, 0.38 mmol) in DMF (2 ml). The reaction mixture was stirred for 30 minutes and then quenched with excess of aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, was washed with sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated in vacuo to give 40 mg (42%) of the title compound as a colourless solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:14]=[CH:15][C:16](O)=[O:17].OS(O)(=O)=O>C1COCC1>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:16](=[O:17])[CH2:15][CH:14]([C:13]3[CH:19]=[CH:20][C:21]([OH:22])=[C:11]([O:10][CH3:9])[CH:12]=3)[O:5]2)=[CH:7][CH:8]=1
Reactant: COc1cc(C=CC(=O)O)ccc1O
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COc1cc(C2CC(=O)c3ccc(O)cc3O2)ccc1O
Yield: 90 %

Procedure:
Resorcinol (15), 3-methoxy-4-hydroxy-cinnamic acid (16) and H2SO4 (5%) were refluxed in THF for 4 hours to provide 7,4′-dihydroxy-3′-methoxy flavanone (17) (90% yield). The product, 7,4′-dihydroxy-3′-methoxy flavanone (17) was then treated with 10% sodium hydroxide at 80° C. for 1 hour, followed by reduction with sodium borohydride in propanol to provide, as confirmed LC-MS/PDA detection, 1-(2,4-dihydroxyphenyl)-3-(3′-methoxy-4′-hydroxyphenyl)-1-propanol (19). The crude product exhibits quite strong tyrosinase inhibitory activity. The mixture was further purified by HTP.
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]1[CH:22]=[C:21]([CH2:23]Br)[O:20][N:19]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:25]([O:27][C:28](=[O:42])[CH:29]([NH:35][C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)C>[CH2:33]([O:32][C:30](=[O:31])[C:29]([NH:35][C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])([CH2:23][C:21]1[O:20][N:19]=[C:18]([CH:14]2[CH2:15][CH2:16][CH2:17][N:13]2[C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH:22]=1)[C:28]([O:27][CH2:25][CH3:26])=[O:42])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc(CBr)on1
Reactant: C=CCOC(=O)NC(C(=O)OCC)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A dimethyl formamide (260 mL) solution of 2-(5-Bromomethyl-isoxazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (7.29 g, 56 mmol) and 2-allyloxycarbonylamino-malonic acid diethyl ester (8.25 g, 32 mmol) was cooled to 0° C. and cesium carbonate (25.41 g, 78 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was then poured into diethyl ether (2 L) and washed with water (5×200 mL) and brine. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with ethyl acetate:hexane (3:7) to afford the title compound as a clear colorless oil (10.95 g; 83%). MS (Cl) m/z 260.1 (M−99). G. 2-Allyloxycarbonylamino-malonic acid diethyl ester
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:29])=[C:7]([C:21]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:22])[C:8]([I:20])=[C:9]([C:18]=1[I:19])[C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])(=[O:3])[CH3:2].C[O-].[Na+].Cl[CH2:34][CH:35]([OH:38])[CH2:36][OH:37].NC1C(I)=C(C(NCC(O)CO)=O)C(I)=C(C=1I)C(NCC(O)CO)=O>C(O)C(O)C>[OH:38][CH:35]([CH2:36][OH:37])[CH2:34][N:4]([C:5]1[C:18]([I:19])=[C:9]([C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])[C:8]([I:20])=[C:7]([C:6]=1[I:29])[C:21]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:22])[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: OCC(O)CCl
Agent: C[O-]
Agent: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: [Na+]
Solvent: CC(O)CO
Product: CC(=O)N(CC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 50 °C
Reaction time: 48 h

Procedure:
5-Acetamido-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide (37.4 g; 50 mmole) was dissolved in propylene glycol (110 ml) by adding 5.3 M sodium methoxide (14.2 ml; 75 mmole) and heating in an oil bath at 50° C. When all or nearly all of the starting material was dissolved, the excess of methanol was evaporated in vacuo. After cooling to room temperature 3-chloropropane-1,2-diol (6.3 ml; 75 mmole) was added. When the reaction mixture was applied to TLC in system (B) after stirring for two days, two new spots with Rf values 0.26 and 0.33 in a ratio of about 1:9 and less than 0.5% of the starting material with Rf 0.42 were observed. The new spots were assumed to represent endo/exo isomers. The reaction mixture was evaporated in vacuo and the residue dissolved in methanol (125 ml). A small amount of undissolved material was filtered off and water (30 ml) added. This solution was treated with a mixture of Amberlite cation exchange resin IR 120H (27.5 g) and Dowex anion exchange resin 1×4 (50 g) for two hours. After filtration, the pH of the solution was adjusted to 4.9, and then evaporated in vacuo. The oily residue was triturated in butanol (125 ml). The product crystallized out following this treatment. After storing at -20° C., the product was filtered off. Then the product was dissolved in water, and the solution evaporated in vacuo. Yield 38 g.
Reaction SMILES: C([Li])CCC.CC1(C)CC=CC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)C>[Cl:16][C:17]1[C:22]([CH:29]([C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[OH:30])=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Clc1cnccn1
Agent: CC1(C)C=CCC(C)(C)N1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(O)c2nccnc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of n-butyllithium (1.57 mol/L solution in tetrahydrofuran, 2.0 mL) in tetrahydrofuran (23 mL) was added 2,2,6,6-tetramethylpyridine (0.57 mL) at −78° C. The temperature was raised to 0° C., and the mixture was stirred for 30 minutes. After the reaction mixture was cooled to −78° C., 2-chloropyrazine (0.22 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added 4-methoxybezaldehyde (0.35 mL), and the mixture was stirred for additionally 1.5 hours. To the reaction-mixture were added concentrated hydrochloric acid (1.2 mL), ethanol (1.2 mL) and tetrahydrofuran (4.8 mL), and the temperature was raised to room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. After the residue was extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2) to give 2-chloropyrazin-3-yl 4-methoxyphenyl methanol (0.31 g). To a suspension of the obtained 2-chloropyrazin-3-yl 4-methoxyphenyl methanol(0.13 g), sodium hydroxide (0.12 g) and potassium carbonate (0.072 g) in toluene (1 mL) were added benzyl alcohol (0.080 mL) and tris-[2-(2-methoxyethoxy)ethyl]amine (0.017 mL), and the mixture was stirred for 2,hours at 120° C. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/1) to give 2-benzyloxy-3-(4-methoxybenzyl)pyrazine (0.026 g). To a solution of the obtained 2-benzyloxy-3-(4-methoxybenzyl)-pyrazine (0.025 g) in ethanol (1 mL) was added 10% palladium carbon powder (0.0099 g), and the mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/3) to give 3-(4-methoxybenzyl)-1H-pyridin-2-one (0.0055 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=CNc1cc(N)nc(SC)n1)C(=O)OCC
Product: CCOC(=O)C(=CNc1cc(NC(C)=O)nc(SC)n1)C(=O)OCC
Reaction time: 16 h

Procedure:
A mixture of EXAMPLE 16A (9.91 g) and acetic anhydride (150 mL) at reflux was stirred for 16 hours, treated with additional acetic anhydride (60 mL), refluxed for 5 hours, cooled and concentrated. The concentrate was dissolved in 9:1 ethanol/ethyl acetate (100 mL), stored at 0° C. for 18 hours, and filtered. 1H NMR (300 MHz, DMSO-d6) δ 10.65 (d, 1H), 8.90 (d, 1H), 7.66 (s, 1H), 4.23 (q, 2H), 4.14 (q, 2H), 2.52 (s, 3H), 2.26 (s, 1H), 2.11 (s, 3H), 1.27 (t, 3H), 1.23 (t, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[C:11]([OH:16])([CH2:14][F:15])[CH2:12][F:13].[CH2:17](Cl)[O:18][CH2:19][CH2:20]OC.CC(=O)OCC>C1COCC1.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[C:11]([O:16][CH2:17][O:18][CH2:19][CH3:20])([CH2:12][F:13])[CH2:14][F:15]
Reactant: Cc1ccc(Br)c(C(O)(CF)CF)c1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOCOC(CF)(CF)c1cc(C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
NaH (362 mg, 9.05 mmol) was added to a solution of 2-(2-bromo-5-methylphenyl)-1,3-difluoropropan-2-ol (2.0 g, 7.54 mmol) in THF (10 mL) slowly at 0° C. MEMCl (1.41 g, 11.32 mmol) was added dropwise. The mixture was stirred at rt overnight. The mixture was diluted with H2O and extracted with EA (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:1 to 6:1) to give the product (1.8 g, yield 68%) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([CH:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11]Br)[CH3:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:8]([CH:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: CCCCC(CC)CBr
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)CNc1ccccc1
Temperature: 75 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A mixture of aniline (18.6 parts), 2-ethylhexyl bromide (42.4 parts), anhydrous potassium carbonate (30.3 parts) and dry N,N-dimethylformamide (100 parts) was stirred at 75° C. for 24 hours. The cooled mixture was filtered, diluted with dichloromethane and washed with 2N-hydrochloric acid (100 parts). The organic phase was evaported to leave oil which was triturated with petroleum ether and water to give N-(2-ethylhexyl)aniline (18 parts, 43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([N+:18]([O-])=O)[CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc([N+](=O)[O-])c2c1N(C(=O)OC(C)(C)C)CC2
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)c2c1N(C(=O)OC(C)(C)C)CC2
Reaction time: 8 h
Yield: 81.9 %

Procedure:
1-t-Butoxycarbonyl-2,3-dihydro-7-methyl-4-nitroindole (2.169 g; 8.7 mmol) is dissolved in methanol (35 mL), treated with a catalytic amount of 10% palladium-on-carbon (210 mg) and placed under an atmosphere of hydrogen. The solution is allowed to stir overnight. The black suspension is filtered through Celite and the solvent is removed by rotary evaporation. The crude product is purified by silica gel flash column chromatography using 15% ethyl acetate/hexanes as eluent to afford 1.769 g of 1-t-butoxycarbonyl-4-amino-2,3-dihydro-7-methylindole as a white solid (94% yield).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].BrCC#CC>>[CH3:10][O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:11][C:12]#[C:13][CH3:14]
Reactant: [Li]CCCC
Reactant: COC(=O)CC(C)=O
Agent: CC#CCBr
Agent: [H-]
Agent: [Na+]
Product: CC#CCCC(=O)CC(=O)OC

Procedure:
In accordance with the process of Reference 1, sodium hydride (550 mg; 23 m mol), methyl acetoacetate; (2.56 g; 22 m mol), n-butyl lithium (23 m mol) and 4-bromo-2-butyne were used to obtain 2.53 g of 3-oxo-6-octynoic acid methyl ester.