Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br.Br[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.O>CO>[N:1]([CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCCCC1CCNCC1
Agent: Br
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCCCC1CCNCC1

Procedure:
Sodium azide (1 g) was added to a mixture of 4-(3'-bromopropyl)-piperidine hydrobromide (2 g), water (7 ml) and methanol (7 ml). The pH of the mixture was adjusted to 6.3, and the resulting solution was refluxed for 2 hours. After cooling, methanol was evaporated, 30 percent aqueous sodium hydroxide was added and the mixture was extracted several times with ether. The ether extracts were dried and evaporated to leave the desired compound as an oil. The IR-spectrum (CHCl3) showed strong bands at 2925, 2100 and 1450 cm-1.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OOC(C)(C)C)(C)(C)C.[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1>>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][CH:36]2[CH2:35][CH2:34][CH2:33][CH:32]=[CH:31]2)[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: C1=CCCCC1
Agent: CC(C)(C)OOC(C)(C)C
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1C=CCCC1
Yield: 81 %

Procedure:
A solution of 33.6 grams (122 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 23.0 grams (157 mmol) of di-tert-butyl peroxide, and 70 ml of cyclohexene is heated in a Fischer-Porter pressure bottle at 138° C. for 6.5 hours. The reaction mixture is purified by flash chromatography on silica gel (200:1 heptane:ethyl acetate) to afford 35.1 grams (81% yield) of the title compound as a colorless oil.
Reaction SMILES: [O:1]=[C:2]([CH2:25][OH:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[C@@H:13](/[CH:14]=[CH:15]/[CH2:16][C:17]([OH:23])([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]1=[O:24].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[O:1]=[C:2]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[C@@H:13](/[CH:14]=[CH:15]/[CH2:16][C:17]([OH:23])([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]1=[O:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(C)(O)C/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)CO
Solvent: c1ccncc1
Product: CCCCC(C)(O)C/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)COC(C)=O
Reaction time: 18 h

Procedure:
To a solution of 0.1 g of 1,9-dioxo-16-hydroxy-1-hydroxymethyl-16-methyl-10,13-trans-prostadiene in 0.75 ml of pyridine is added 0.026 g of acetic anhydride. After 18 hours at room temperature, the solvent is removed at reduced pressure and the residue is chromatographed on silica gel to give the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=O.[CH3:17][NH2:18]>C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][C:14]([NH:18][CH3:17])=[O:16]
Reactant: O=C(O)Cc1cc(F)ccc1Br
Reactant: CN
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CNC(=O)Cc1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (9.4 mL, 129 mmol) is added to a solution of (2-bromo-5-fluoro-phenyl)-acetic acid (20.0 g, 85.8 mmol) in dry toluene (400 mL). The mixture is heated at reflux for 4 hours and the solvent is removed in vacuo. The remanence is redissolved in dry toluene (400 mL) and cooled to 0° C. 40% methylamine (aq.) (17.7 mL, 515 mmol) is added dropwise at 0-5° C. The mixture is then stirred at ambient temperature for 16 hours, poured onto water (250 mL) and extracted with ethyl acetate (3×200 mL). The combined organic fractions are washed successively with saturated sodium bicarbonate solution (150 mL) and brine (150 mL), dried (MgSO4) and concentrated in vacuo. This gives 16.2 g (77%) of crystalline 2-(2-bromo-5-fluoro-phenyl)-N-methyl-acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)[CH3:2].[C:13]([O:17][C:18](=[O:22])[CH:19](Br)[CH3:20])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:22])[CH:19]([S:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:12])[N:7]=1)[CH3:20])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1csc(S)n1
Product: CCOC(=O)Cc1csc(SC(C)C(=O)OC(C)(C)C)n1

Procedure:
The title compound was obtained by an operation similar to that of Example 2 and using (2-mercapto-1,3-thiazol-4-yl)acetic acid ethyl ester synthesized in Example 1 and 2-bromopropionic acid tert-butyl ester to give 2-{[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester, followed by sequential operations similar to those of Examples 3, 4 and 34.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[F:26][C:27]([F:40])([F:39])[S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[F:39][C:27]([F:26])([F:40])[S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)=[CH:33][CH:32]=1)(=[O:29])=[O:30]
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: Cl
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCc3ccc(S(=O)(=O)C(F)(F)F)cc3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 4-[(trifluoromethyl)sulfonyl]benzylamine hydrochloride gave the title compound as an oil. M+(LC/MS(ESI)): 552.7. HPLC (Condition A), Rt: 4.85 min (HPLC purity: 36%).
Reaction SMILES: [K].[CH2:2]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(N(C)C)=O>O>[CH2:2]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Reactant: Brc1ccccc1
Agent: [K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCc1cccc(Oc2ccccc2)c1
Temperature: 150 °C

Procedure:
Into the round bottom flask containing potassium salt of 3-pentadecyl phenol is added bromobenzene followed by Cu powder and in a solvent, DMAc (dimethyl acetamide). The reaction mixture is heated at 150° C. for 6 h. After completion of the reaction, the obtained dark colored reaction mixture is poured into water and the Cu salts are removed by filtration. The filtrate is extracted in a solvent, washed with water and dried, purified to obtain arylated product, 1-pentadecyl-3-phenoxybenzene.
Reaction SMILES: CN=C=O.[CH3:5][CH:6]([N:8]=[C:9]=[O:10])[CH3:7].CP1CC=CC1.CN1[C:22](=O)[N:21](C)[C:20](=[O:25])[P:19]1[CH3:26]>>[CH3:26][P:19]1[C:20](=[O:25])[N:21]([CH3:22])[C:9](=[O:10])[N:8]1[CH:6]([CH3:7])[CH3:5]
Reactant: Cn1c(=O)n(C)p(C)c1=O
Reactant: CC(C)N=C=O
Agent: CN=C=O
Agent: CP1CC=CC1
Product: CC(C)n1c(=O)n(C)c(=O)p1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 0.41 g (7.2 mmol) of methyl isocyanate and 6.13 g (72 mmol) of 2-propyl isocyanate was added, at room temperature, over the course of 1 h, 0.7 g (7 mmol) of 1-methyl-2,5-dihydro-1H-phosphole. No exothermicity was observed. The initially colourless liquid mixture gradually changed colour to pale yellow. Stirring at room temperature for 48 hours was followed by analysis by means of 1H and 31P NMR and GC-MS. As well as unconverted 1-methyl-2,5-dihydro-1H-phosphole and small amounts of the P-oxide thereof, essentially 2 singlets in the 31P NMR spectrum at 30.8 ppm (1,2,4-trimethyl-1,4,2-diazaphospholidine-3,5-dione; cf. Ex. 1) and 15.6 ppm (compound 3) were found. The integration ratio was 1:2.2. This ratio was determined by gas chromatography to be 1:3.5. The arrangement of the N-bonded exocyclic substituents was confirmed by means of 2D NMR.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: CNC(=O)c1cccc(C)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Yield: 18.8 %

Procedure:
A solution of 2-amino-N,3-dimethylbenzamide (562 mg) and 2,4,5-trichloropyrimidine (1.3 g) in N-methylpyrrolidinone (20 mL) were heated with potassium carbonate (2 g) at 80° C. for 16 hours. The mixture was diluted with ethyl acetate, washed three times with brine, dried with sodium sulfate, filtered, and concentrated. Column chromatography (20-30% ethyl acetate in methylene chloride) followed by trituration with ethyl ether provided 200 mg of 2-(2,5-dichloropyrimidin-4-ylamino)-N,3-dimethylbenzamide: 1H NMR (300 MHz, CDCl3) δ 9.3 (s, 1H), 8.15 (s, 1H), 7.4 (d, 1H), 7.3 (d, 1H), 7.2 (t, 1H), 6.05 (m, 1H), 3.0, (d, 3H), 2.2 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.[NH2:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1.[OH-].[Na+]>ClCCl.O>[NH2:7][C:8]1[C:12]([S:3][C:2]([F:6])([F:5])[F:1])=[CH:11][N:10]([CH3:13])[N:9]=1
Reactant: FC(F)(F)SCl
Reactant: Cn1ccc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1cc(SC(F)(F)F)c(N)n1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfenyl chloride (11.6 g, 85.0 mmol) was added to a solution of 3-amino-1-methylpyrazole (8.0 g, 82.4 mmol) in 150 mL of dichloromethane with stirring at a rate such that the temperature did not rise above 5° C. when the addition was complete the mixture was allowed to warm to ambient temperature and stir for 18 hours and was then purged with nitrogen gas for 1 hour to remove any unreacted trifluoromethanesulfenyl chloride. The solid that formed during the reaction was collected by filtration and the filtrate was concentrated by evaporation under reduced pressure to obtain additional solids. The combined solids were dissolved in water and the solution as basified with 1N aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2×100 mL) and the extracts were combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain a solid residue that appeared to be a mixture of two compounds. This solid was recrystalized from methylcyclohexane to obtain 16.2 g (40 percent of theory) of the title compound as a yellow solid melting at 138°-140° C. The impurity was identified as 1-methyl-3-((trifluoromethanesulfenyl)amino)-4-(trifluoromethylthio)pyrazole.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([CH2:37][CH2:38][C:39]([N:22]2[CH2:23][CH2:24][N:19]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=4)[N:9]=[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[OH:18])[N:7]=3)[CH2:20][CH2:21]2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)CCC4CCCC4)CC3)nc(-c3ccccc3O)nc2c1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (200 mg, 0.62 mmol) in CH2Cl2 (6.0 mL) was stirred under an N2 atmosphere. Then triethylamine (170 μL, 1.24 mmol) was added, and the reaction was cooled to −10 to −20° C. After adding 3-cyclopentylpropanoyl chloride (96 μL in 600 μL THF, 0.62 mmol), the reaction mixture was stirred for 30 minutes. CH2Cl2 was added, and the organic phase was washed 2× with H2O, dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2: hexanes gave 3-cyclopentyl-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one (240 mg, 86%). LC/MS: m/z 445.50 (M+H)+ at 3.07 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.45 (dd, J=8.2, 1.8 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.69 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 3.95 (dd, J=19.9, 5.6 Hz, 4H), 3.74 (m, 4H), 2.52 (s, 3H), 2.38 (t, J=7.8 Hz, 2H), 1.76 (m, 3H), 1.55 (m, 6H), 1.16 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2,6-dibromo-pyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][CH:10]=2)[CH:7]=1.[NH2:11][C:12]1[C:21]2[C:16](=[C:17](Br)[C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[N:14][C:13]=1[C:24]([NH2:26])=[O:25]>>[NH2:11][C:12]1[C:21]2[C:16](=[C:17]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[N:9][CH:10]=4)[CH:7]=3)[C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[N:14][C:13]=1[C:24]([NH2:26])=[O:25]
Reactant: Brc1ccc2cncn2c1
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2cncn2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 96 using 6-bromoimidazo[1,5-a]pyridine and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 2.45 (s, 3 H), 6.77 (dd, J=9.22, 1.39 Hz, 1 H), 7.47 (s, 1 H), 7.72 (d, J=9.09 Hz, 1 H), 7.67 (d, J=9.35 Hz, 1 H), 8.10-8.32 (m, 2 H), 8.37 (s, 1 H); ESI-MS m/z [M+H]+ 319.2.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C@@H:11]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:7][CH:8]=1.[CH3:30][S-:31].[Na+]>CC(C)=O.C(OCC)(=O)C>[Cl:28][C:20]1[CH:19]=[C:18]([CH:11]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:10]([NH:9][C:6]2[CH:5]=[N:4][C:3]([CH2:2][S:31][CH3:30])=[CH:8][N:7]=2)=[O:29])[CH:23]=[CH:22][C:21]=1[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: C[S-]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CBr)cn2)cc1Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CSCc1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.6 %

Procedure:
A solution of N-(5-bromomethyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (95.1 mg, 0.19 mmol) in acetone (1 mL) was cooled to 0° C. and then treated with sodium thiomethoxide (12.9 mg, 0.18 mmol). The reaction stirred at 0° C. for 1.5 h and then was treated with a second aliquot of sodium thiomethoxide (3.6 mg, 0.051 mmol). The reaction was stirred at 0° C. and then slowly warmed to 25° C. over 1.5 h. A third aliquot of sodium thiomethoxide (3–4 mg, 0.042–0.057 mmol) was added, and the reaction mixture was stirred at 25° C. for 1.5 h, at which point, APCI-LRMS indicated the reaction had gone to completion. The reaction was then diluted with ethyl acetate (50 mL), washed with water (2×25 mL) and a saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/2 ethyl acetate/hexanes) afforded racemized 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanylmethyl-pyrazin-2-yl)-propionamide (51.9 mg, 58%) as a white foam: mp 70–75° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H26ClN3O3S2 (M+H)+ 468.1177, found 468.1179.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:18]/[C:14]1[NH:13][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)c1cc2c(s1)NC(=O)C2
Reactant: O=Cc1ccc[nH]1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: NC(=O)c1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Temperature: 75 °C
Yield: 34 %

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide (30 mg, 0.17 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (2 ml). Pyrrole-2-carboxaldehyde (16 mg, 0.18 mmol) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (10 ml) and the precipitated solid was collected by filtration and washed with water to give 15 mg of (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxamide as a yellow/brown solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].IC.[CH3:39]COC(C)=O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH3:39])[CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(C)=O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)c[nH]c34)no2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)cn(C)c34)no2)cc1Cl
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 3.98 mg) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D7) (80 mg) in dry DMF (2 mL) at RT. After stirring for 5 min, iodomethane (0.016 mL) was added. The resulting solution was stirred at RT for 45 min. EtOAc (50 mL) was added and the resulting solution was washed with aqueous HCl (20 mL), followed by water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 1,1-dimethylethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoate (D8) (85 mg) as a pale yellow oil. MS (ES): C27H30ClN3O4 requires 495; found 496.0 (M+H+).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]1([O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCCC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred mixture of 5,6,7,8-tetrahydronaphthalen-1-ol (200 mg, 1.35 mmol) in MeCN (5 mL) was added ethyl bromoacetate (269 mg, 1.62 mmol) and K2CO3 (372 mg, 2.70 mmol). The mixture was stirred at 80° C. for 4 hours. The mixture was filtered, the filtrate concentrated to yield the desired product which used directly for the next step without further purification (300 mg, Yield 95%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19](=[O:32])[CH2:20][C:21](=[O:31])/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(NC1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=CC=2)=CC=1)=O)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:30][C:27]1[CH:28]=[CH:29][C:24](/[CH:23]=[CH:22]/[C:21](=[O:31])[CH2:20][C:19](=[O:32])/[CH:18]=[CH:17]/[C:14]2[CH:15]=[C:16]3[C:11]([CH2:10][CH2:9][NH:8]3)=[CH:12][CH:13]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(/C=C/C(=O)CC(=O)/C=C/c3ccc(O)cc3)cc21
Agent: CC(C)(C)OC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(/C=C/c1ccc(O)cc1)CC(=O)/C=C/c1ccc2c(c1)NCC2

Procedure:
The title compound was synthesized using the same procedure employed for Example 281, but with (1E,6E)-1-[1-(tert-butoxycarbony)-indolin-6-yl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (14 mg, 32 μmol, synthesized in Example 292) as the starting material instead of (1E,6E)-1-[4-(tert-butoxycarbonylamino)phenyl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel chromatography (chloroform/methanol=100/0 to 95/5). The product was obtained as a solid (1.4 mg, 13%) having the following characteristic.
Reaction SMILES: [C:1]1([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[CH:2]=1.N1C(C)=CC=CC=1C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>O1CCCC1>[OH:12][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([O:11][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Cl:21])(=[O:30])=[O:29])[CH:2]=1
Reactant: Oc1cc(O)c2ccccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: O=S(=O)(Oc1cc(O)c2ccccc2c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
At 0° C. to 1.0 g (6.24 mmol) of 1,3-naphthalenediol in tetrahydrofuran (20 mL) containing 1.5 mL of 2,6-lutidine was added 1.35 g (6.40 mmol) of 2-chlorobenzenesulfonyl chloride. The reaction mixture was stirred to ambient temperature overnight, quenched with 3 N hydrochloric acid, extracted into methylene chloride, and dried (MgSO4). Purification by flash chromatography (2% ethyl acetate/methylene chloride) gave 277 mg (13% yield) of the title compound as a colorless solid. 1H-NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1 H), 8.06 (d, 1 H, J=1.7 Hz), 7.78-7.95 (m, 4 H), 7.43-7.57 (m, 3 H), 7.11 (d, 1 H, J=2 Hz), and 6.63 (d, 1 H, J=2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([OH:11])[CH:3]=1.S(Cl)([Cl:14])=O.CN(C)C=O>CCCCCCC>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)cc1O
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: O=C(Cl)c1ccc(F)cc1O
Temperature: 60 °C
Yield: 84.7 %

Procedure:
A suspension of 4-fluoro-2-hydroxy-benzoic acid (15 g, 96.1 mmol) in heptane (190 mL) was treated with thionyl chloride (21 mL, 288 mmol) in a dropwise manner over 30 min. A drop of N,N-dimethylformamide was added and the solution was heated for 4 h at 60° C. The excess thionyl chloride was distilled off under reduced pressure. The remaining solution was cooled to room temperature, filtered, and concentrated to give 4-fluoro-2-hydroxy-benzoyl chloride as a pale yellow crystalline solid (14.2 g, 85%).