Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([NH:35]C(=O)C)=[CH:33][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][C:31]2[CH:40]=[CH:39][C:34]([NH2:35])=[CH:33][CH:32]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNc3ccc(N)cc3)ccc21
Yield: 95.9 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4′-aminoacetanilide (44 mg, 0.29 mmol), acetic acid (0.084 mL, 1.5 mmol) and sodium triacetoxyborohydride (46 mg, 0.22 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(4-aminophenylaminomethyl)indol-2-yl]isoindolinone (35.2 mg, yield 88%).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27])=O>CC(C)=O>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[C:16]1[N:1]=[C:2]([C:3]2[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=2[CH3:8])[S:13][CH:15]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc(OC)cc3OC)cs2)c(C)s1
Yield: 54.8 %

Procedure:
99 mg (0.424 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-2′,4′-dimethoxyacetophenone (0.440 mmol; 114 mg) was added and the solution was allowed to reflux for 2.5 h. The solution was allowed to cool and the crude product was collected as a solid and washed with methanol and dried yielding 91 mg (56% yield) of methyl 4-[4-(2,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCI
Product: CCCCCCCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21

Procedure:
3-(3,5-Di-tertiary butyl-4-hydroxyphenyl)-1-octyl-1H-pyrazolo[3,4-b]pyridine is prepared by reacting the compound of Example 1 with octyl iodide as yellowish brown oil in a similar manner as Example 9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C)C=O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:22]1[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]1
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)c(F)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 4.77 g (30.0 mmol) of 3,4-difluoronitrobenzene in 100 mL of N,N-dimethylformamide were added 5.33 g (40.0 mmol) of potassium carbonate and 3.03 g (30.0 mmol) of 4-hydroxypiperidine and the mixture was stirred for 1 hour at 120° C. After the reaction mixture was cooled to room temperature, the reaction mixture was diluted with chloroform and insoluble substances were removed off by filtration. The filtrate was condensed and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1.5/1) to give 3.1 g (43%) of the title compound.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=S.Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:18][CH:17]2[NH2:19])=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>[Hg](Cl)Cl.C(#N)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:18][CH:17]2[NH:19][C:2]2[S:1][CH2:7][C:5](=[O:6])[N:4]=2)=[CH:14][CH:15]=1
Reactant: O=C1CSC(=S)N1
Reactant: NC1CC1c1ccc(F)cc1
Agent: Cl
Agent: Cl[Hg]Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NC2CC2c2ccc(F)cc2)=N1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.4 %

Procedure:
In a three-neck flask equipped with argon inlet was charged with rhodanine (200 mg, 1.5 mmol, 1.4 eq), anhydrous Acetonitrile (5 mL), 2-(4-fluoro-phenyl)-cyclopropylamine HCl salt (200 mg, 1.1 mmol, 1 eq) and diisopropylehtylamine (0.58 mL, 3 eq). The mixture was cooled to 0° C. and mercury (II) chloride (376 mg, 1.3 eq) was added. The reaction mixture was stirred at 0° C. for 30 minutes and room temperature for another 1.5 hours. The reaction mixture was filtered through a celite cake and washed with dichloromethane (3×20 mL), methanol (3×20 mL) and diethyl ether (3×20 mL). The filtrate and washing solutions were combined and concentrated by rotavaping to afford crude product. The crude was purified by flash chromatography (40 gram prepacked column by Isco, Inc., 230400 mesh, eluant: 0-10% methanol in dichloromethane) to obtain 136 mg of pure product. The structure was confirmed with
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]>CC(O)=O.CCOC(C)=O.[Fe]>[NH2:15][C:14]1[CH:13]=[CH:12][C:4]([C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=C(O)CNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)NCC(=O)O)cc1F
Temperature: 87.5 °C
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
To a suspension of iron powder (231 mg, 4.13 mmol) in AcOH (2 mL) was added 2-(3-fluoro-4-nitrobenzamido)acetic acid (100 mg, 0.413 mmol) at rt and stirred at 85-90° C. for 15 min. The reaction mixture was attained to rt and diluted with EtOAc (20 mL). The solution was stirred for 5 min and filtered through celite. The celite bed was washed with EtOAc (10 mL) and the combined organic layer was evaporated under reduced pressure. The residue was chromatographed over silica gel column using chloroform:methanol (70:30) as eluents to give the product as an off-white color solid (62 mg, 71%), 198-200° C.
Reaction SMILES: [CH3:1][C@@H:2]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][CH2:4][CH3:5].FC1N=C2C(N=CN2C2CCCCO2)=C(N)N=1.C[C@H](N)CCC>>[CH3:1][C@H:2]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1
Agent: CCC[C@H](C)N
Agent: Nc1nc(F)nc2c1ncn2C1CCCCO1
Product: CCC[C@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 70 from 2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine and (2S)-2-pentanamine.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11](=[S:13])[NH2:12].Cl[CH2:15][C:16](=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[Br:1][C:2]1[N:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[N:5]=[CH:4][C:3]=1[C:11]1[S:13][CH:15]=[C:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:12]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(C)(C)n1ncc(C(N)=S)c1Br
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2Br)n1
Yield: 64.1 %

Procedure:
A solution of the compound (2.80 g, 10.68 mmol) obtained in step 5 and ethyl 4-chloroacetoacetate (1.588 mL, 11.75 mmol) in ethanol (30 mL) was stirred at 80° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give ethyl 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)acetate (2.55 g, 6.85 mmol, 64%) as a colorless oil
Reaction SMILES: [CH3:1][Mg]Br.[Cl-].[Li+].[CH3:6][C:7]1[N:8]([C:13]2[N:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:30]4[N:35]=[CH:34][C:33]([C:36]5[N:41]=[N:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=5)=[CH:32][CH:31]=4)([CH3:29])[CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[CH:15][N:14]=2)[C:9]([CH3:12])=[CH:10][CH:11]=1>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[CH3:6][C:7]1[N:8]([C:13]2[N:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([C:30]4[N:35]=[CH:34][C:33]([C:36]5[N:41]=[N:40][C:39]([C:42]([OH:44])([CH3:1])[CH3:43])=[CH:38][CH:37]=5)=[CH:32][CH:31]=4)([CH3:29])[CH:26]([CH3:27])[CH3:28])=[CH:23][CH:24]=3)=[CH:15][N:14]=2)[C:9]([CH3:12])=[CH:10][CH:11]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(-c2ccc(C(C)(c3ccc(-c4cnc(-n5c(C)ccc5C)nc4)cc3)C(C)C)nc2)nn1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ncc(-c2ccc(C(C)(c3ccc(-c4ccc(C(C)(C)O)nn4)cn3)C(C)C)cc2)cn1
Reaction time: 1 h

Procedure:
Methyl magnesium bromide (32.4 mL of a 1.4 M solution in THF:toluene (25:75)) was added to a stirred solution of lithium chloride (1.93 g, 45.4 mmol) and 4z (11.7 g, 22.7 mmol) in THF (70 mL) at 0° C. After approximately 1 h at 0° C., the reaction was quenched by the dropwise addition of 1.0 M hydrochloric acid, and the resulting mixture stirred for 15 min. The resulting mixture was poured slowly into saturated aqueous sodium bicarbonate and extracted with EtOAc. The combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 35%-75% EtOAc/hexanes as eluent) to furnish the title compound 4e. m/z (ES) 533 (MH)+. 1HNMR (500 MHz, CDCl3): δ 9.23 (d, 1H, J=2.1 Hz), 8.95 (s, 2H), 8.39 (dd, 1H, J=2.3, 8.5 Hz), 7.89 (d, 1H, J=9.0 Hz), 7.79 (d, 1H, J=8.9 Hz), 7.57 (m, 4H), 7.46 (d, 1H, J=8.5 Hz), 5.92 (s, 2H), 4.20 (s, 1H), 3.22 (m, 1H), 2.38 (s, 6H), 1.81 (s, 3H), 1.70 (s, 6H), 0.93 (d, 3H, J=6.4 Hz), 0.88 (d, 3H, J=6.6 Hz).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].N[C:13]1([O:22]O)[CH2:18][CH:17]([CH3:19])[CH2:16][C:15]([CH3:21])([CH3:20])[CH2:14]1>C(O)C>[C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][CH:17]1[CH2:16][C:15]([CH3:21])([CH3:20])[CH2:14][C:13](=[O:22])[CH2:18]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O=C1CCCC1
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 8 h

Procedure:
To a stirred mixture of cyclopentanone (33.8 g.) and ethanol (100 c.c.) containing ammonium acetate (3.2 g.) and kept at or below 0°C, was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (44.6 g., 68% pure). After storing at 0°C overnight the reaction mixture was worked up as in the previous Examples to give unreacted cyclopentanone and dihydroisophorone together with a fraction (20.0 g.) b.p. 82° - 86°/0.5 mm.Hg. This last fraction was redistilled to give: material b.p. 74° - 76°C/0.3 mm.Hg., peroxide equivalent 202, shown by mass spectroscopy to be a mixture of the peroxide ##SPC61##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[CH2:13]([NH:16][CH:17]1[CH2:25][CH2:24][C:20]2[N:21]=[CH:22][S:23][C:19]=2[CH2:18]1)[CH2:14][CH3:15]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:16]([CH2:13][CH2:14][CH3:15])[CH:17]2[CH2:25][CH2:24][C:20]3[N:21]=[CH:22][S:23][C:19]=3[CH2:18]2)=[CH:6][CH:5]=1
Reactant: CCCNC1CCc2ncsc2C1
Reactant: COC(=O)c1ccc(C=O)cc1
Product: CCCN(Cc1ccc(C(=O)OC)cc1)C1CCc2ncsc2C1
Yield: 74 %

Procedure:
42A is prepared from 4-formyl-benzoic acid methyl ester and 1C as described for 1.
Reaction SMILES: CI.O1CCC[CH2:4]1.[CH3:8][CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[O:11][CH2:10]1.[K]>O>[CH3:8][C:9]1([CH3:4])[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[O:11][CH2:10]1
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1)OCC(C)C2=O
Agent: [K]
Solvent: O
Solvent: CI
Product: COc1ccc2c(c1)OCC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under nitrogen atmosphere, 0.4 ml of methyl iodide was added to 10 ml solution tetrahydrofuran with 240 mg of 3-methyl-7-methoxychroman-4-one, 100 mg of potassium hydrogenate was added and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified by silicagel chromatography (hexane/ethyl acetate=5/1) to obtain 145 mg of the above compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])[C:5]1=[O:14].C(O[Cl:20])(C)(C)C>CO>[Cl:20][N:7]1[C:8]([CH3:10])([CH3:11])[CH2:9][N:4]([CH2:3][CH2:2][OH:1])[C:5](=[O:14])[C:6]1([CH3:13])[CH3:12]
Reactant: CC1(C)CN(CCO)C(=O)C(C)(C)N1
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CC1(C)CN(CCO)C(=O)C(C)(C)N1Cl
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of 1-(2-hydroxyethyl)-3,3,5,5-tetramethylpiperazin-2-one (125 mg, 0.63 mmol) in methanol (1 ml) was cooled to 0° C. tert-Butylhypochlorite (106 ul, 0.94 mmol) was added. The resulting solution was stirred for 60 minutes, and then concentrated under reduced pressure. The crude material was purified by column chromatography eluting from silica gel with a gradient of 0-8% methanol in dichloromethane to give 111 mg of a white solid. 1H NMR (D2O, 400 MHz) δ 1.21 (s, 3H), 1.43 (s, 3H), 3.36 (s, 2H), 3.43-3.345 (t, J=5.6 Hz, 2H), 3.64-3.66 (t, J=5.6 Hz, 2H). 13C NMR (D2O, 100 MHz) δ 172.9, 68.1, 60.0, 58.4, 57.4, 49.6, 25.5, 22.7. LRMS (ESI/APCI) m/z 235 [M+H]+.
Reaction SMILES: [CH2:1]([CH:11]([CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]([OH:22])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[CH3:34][N:35]([CH3:42])[CH2:36][CH2:37][CH2:38][C:39](O)=[O:40].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:34][N:35]([CH3:42])[CH2:36][CH2:37][CH2:38][C:39]([O:22][CH:12]([CH:11]([CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:40]
Reactant: CN(C)CCCC(=O)O
Reactant: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(O)CC/C=C\CCCCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CC/C=C\CCCCC)OC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of (6Z,15Z)-11-((Z)-dec-4-enyl)henicosa-6,15-dien-10-ol 17 (0.5 g, 1.1 mmol), 4-(dimethylamino)butanoic acid hydrochloride (0.3 g, 1.7 mmol), EDCI hydrochloride (0.3 g, 1.7 mmol), DIPEA (0.4 g, 3.4 mmol) in anhydrous dichloromethane (10 mL) was added DMAP (5 mg). The solution was stirred at room temperature overnight under a nitrogen atmosphere. The mixture is concentrated in vacuo to dryness then taken up in DCM (150 mL) and extracted with saturated sodium bicarbonate. The reaction mixture was purified by column chromatography on silica gel 60 (1:1 ethyl acetate/hexanes) to afford (6Z,15Z)-11-((Z)-dec-4-enyl)henicosa-6,15-dien-10-yl 4-(dimethylamino)butanoate 22 as a colorless oil (0.4 g, 67%). 1H NMR (400 MHz, CDCl3) δ 5.40-5.28 (m, 6H), 4.97-4.90 (m, 1H), 2.36-2.25 (m, 4H), 2.25-2.19 (m, 6H), 2.07-1.95 (m, 12H), 1.85-1.73 (m, 2H), 1.58-1.45 (m, 3H), 1.45-1.10 (m, 24H), 0.93-0.85 (m, 9H). Rf 0.4 (10% MeOH—CH2Cl2).
Reaction SMILES: C([Li])CCC.[CH3:6][S:7]([O:10][CH3:11])(=[O:9])=[O:8].[CH:12]([C:14]1[CH:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[NH:16][C:15]=1[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=O.[O:29]1CCC[CH2:30]1>>[CH3:6][S:7]([O:10][CH3:11])(=[O:9])=[O:8].[OH:29][CH2:30][CH:12]([C:14]1[CH:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[NH:16][C:15]=1[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[S:7]([CH3:6])(=[O:9])=[O:10]
Reactant: O=Cc1cc(-c2cccs2)[nH]c1-c1cccs1
Reactant: C1CCOC1
Agent: COS(C)(=O)=O
Agent: [Li]CCCC
Product: CS(=O)(=O)C(CO)c1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 43 %

Procedure:
The lithio derivative of methyl methanesulfonate was prepared at -78° C. under argon by the dropwise addition of 0.56 mL of a 1.60M n-butyllithium (0.891 mmol) to a solution of 72 μL (0.85 mmol) of methyl methanesulfonate in 2 mL of anhydrous tetrahydrofuran. After 45 minutes at -78° C., 3-formyl-2,5-dithienylpyrrole (105 mg, 0.41 mmol) in 1 mL of tetrahydrofuran was added dropwise over a 5 minute period to the lithio methyl methanesulfonate solution. The reaction mixture was allowed to stir for 30 minutes at -78° C. After the completion of reaction, it was then quenched with a saturated aqueous ammonium chloride solution. The aqueous layer was extracted three times with 50 mL portions of ethyl acetate and the combined organic layers were washed with water (10 mL×1) and brine (10 mL×1). The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified on 50 g of silica gel. Elution with hexane-ethyl acetate (5:1), gave 64 mg (43%) of title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:14]([O:16][CH3:17])=[O:15])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:1][C@H:2]([C:14]([O:16][CH3:17])=[O:15])[CH2:3][C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)=[O:36])=[CH:38][CH:39]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(C[C@H](N)C(=O)OC)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C[C@H](NC(=O)c2ccc(C(C)(C)C)cc2)C(=O)OC)cc1
Reaction time: 2 h
Yield: 44.6 %

Procedure:
Prepared using General Procedure 3: To the solution of (S)-methyl 4-(2-amino-3-methoxy-3-oxopropyl)benzoate (425.0 mg, 1.79 mmol) in DCM (10 mL) and DIEA (463.0 mg, 3.58 mmol) was added 4-(tert-butyl)benzoyl chloride (556.6 mg, 2.83 mmol) at RT. The reaction was stirred for 2 h and the reaction was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 317 mg (45%) of (S)-methyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate. LCMS-ESI (m/z) calculated for C23H27NO5: 397.2; found 398.1 [M+H]+, tR=2.31 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 7.97-7.75 (m, 2H), 7.67-7.51 (m, 2H), 7.46-7.26 (m, 2H), 7.14 (d, J=8.3 Hz, 2H), 6.60 (d, J=7.4 Hz, 1H), 5.03 (dt, J=7.4, 5.7 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 3.28 (dd, J=13.7, 5.8 Hz, 1H), 3.18 (dd, J=13.7, 5.5 Hz, 1H), 1.24 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:11]
Reactant: BrBr
Reactant: COc1cccc(C(C)=O)c1
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of 1-(3-methoxyphenyl)ethanone (5.5 mL, 40 mmol) in chloroform (100 mL) was added dropwise a solution of bromine (2.05 mL, 40 mmol) in chloroform (20 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was diluted in methylene chloride (50 mL) and washed with water (2×25 mL). The organic layer was dried (Na2SO4) and the solvent removed under reduced pressure. Purification by column cromatography using methylene chloride as eluent gave the title compound (8.44 g. 84%) as oil.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:44][CH3:45])[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN1C(=O)N(C)CC1>[CH3:45][O:44][C:37]1[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:36]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCC2
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN1CCN(C)C1=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCC2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
After adding 27 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 128 mg of [2-(7-methoxy-2,3-dihydrobenzofuran-5-yl) -2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMI, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.