Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1.[NH3:18]>C(O)C.CCCCCC.C(OCC)(=O)C>[NH2:18][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: O=C1NC(=O)C(c2cccc([N+](=O)[O-])c2)=C1Cl
Reactant: N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: NC1=C(c2cccc([N+](=O)[O-])c2)C(=O)NC1=O

Procedure:
3-chloro-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (1.0 g, 4 mmol) was suspended in a mixture of ethanol (20 mL) and aqueous 880 ammonia (5 mL) and the mixture heated to 80° C. whilst ammonia gas was bubbled through the mixture for 4 hours. The mixture was cooled and concentrated and the residue chromatographed on silica get using hexane-ethyl acetate (gradient from 1:1 v/v) as eluent to afford the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[S:10]1[CH:14]=[C:13](B(O)O)[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]1=2.O.O=[CH:24][C:25]([OH:27])=[O:26]>C(#N)C>[S:10]1[CH:14]=[C:13]([CH:24]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:25]([OH:27])=[O:26])[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]1=2
Reactant: O=CC(=O)O
Reactant: OB(O)c1csc2ccccc12
Reactant: COc1cccc(N)c1
Solvent: CC#N
Solvent: O
Product: COc1cccc(NC(C(=O)O)c2csc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-methoxyaniline (400 mg, 3.25 mmol), benzo[b]thiophen-3-ylboronic acid (578 mg, 3.25 mmol), and 2-oxoacetic acid hydrate (299 mg, 3.25 mmol) in acetonitrile (30 ml) was stirred at room temperature overnight. The solvent was removed under vacuum and the crude was used us such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:30][C:29]=1[F:28]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
The title compound was prepared in analogy to Example 173, step 1 from 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 172) with 3-fluoro-4-methoxycarbonylphenylboronic acid [CAS Reg. No. 505083-04-5]. MS (neg. ion, m/e)=552.5 [(M−H)−].
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[O:28][CH2:29][CH2:30]O>CN(C)C=O.O>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[O:28][CH2:29][CH2:30][S:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(S)cc1
Reactant: OCCOc1ccc2ccccc2c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
A stirred mixture of 1-(4-mercaptophenyl)ethanone (1.2 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.350 g), stirred for 15 minutes and treated with the mesylate of 2-(2-naphthyloxy)ethanol (2.2 g). The mixture was heated at 60° C. for 2 hours and diluted with water and filtered. The solids were dissolve in dichloromethane, washed once with water, dried (Na2SO4), filtered and evaporated. Crystallization from dichloromethane-hexane provided 2.0 g of 1-[4-[[2-(2naphthalenyloxy)ethyl]thio]phenyl]ethanone, mp 151°-152° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:25](Cl)(=[O:27])[CH3:26]>O1CCCC1>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]([C:25](=[O:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)NCc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)C(C)C
Temperature: 0 °C
Yield: 177.5 %

Procedure:
1-Boc-4-[2-(isopropylamino-methyl)-phenyl]-piperazine (0.325 g, 0.975 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to about 0° C. TEA (0.54 mL, 3.9 mmol) was added followed by dropwise addition of acetyl chloride (0.2 mL, 2.93 mmol). The solution was allowed to warm to r.t. The solvents were removed under reduced pressure, and the resulting oil was purified using silica chromatography (ethyl acetate) to afford the title compound (0.650 g, 82%) as an oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([N:23]=[CH:24][C:25]3[N:26]=[C:27]([CH3:30])[S:28][CH:29]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:32]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([NH:23][CH2:24][C:25]3[N:26]=[C:27]([CH3:30])[S:28][CH:29]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: Cc1nc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)cs1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of Example 232A (0.097 g, 0.208 mmol) in tetrahydrofuran (5 mL) and methanol (0.016 mL, 0.40 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.15 mL, 0.3 mmol). The reaction was stirred at 25° C. for 3 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on C-18 reverse phase column eluting with water:acetonitrile 90:10-0:100 to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.68 (s, 3 H) 3.24 (m, 2 H) 6.33 (m, 1 H) 7.10 (m, 1 H) 7.31 (m, 2 H) 7.43 (s, 1 H) 7.61 (m, 4 H) 8.08 (d, J=7.72 Hz, 1 H) 16.24 (s, 1 H). MS (ESI−) (M−H)− m/z 466.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].C(=O)([O-])[O-].[K+].[K+].[CH2:57](Br)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>>[CH2:57]([O:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(C)cc2c(c1OCc1ccccc1)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Yield: 45.7 %

Procedure:
Following General Procedure: Method A using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and benzyl bromide (18 μL, 0.15 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) to afford (6R,6aS,14aR)-methyl 1-(benzyloxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (18 mg, 45%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 14.17 (s, 1H), 7.82 (s, 1H), 7.46-7.44 (m, 2H), 7.40-7.38 (m, 1H), 7.34-7.32 (m, 2H), 6.85 (s, 1H), 6.81 (d, J=8.6 Hz, 1H), 5.86 (s, 1H), 5.07 (br s, 1H), 4.98-4.94 (m, 1H), 4.93 (d, J=11.3 Hz, 1H), 4.82 (d, J=11.3 Hz, 1H), 4.68 (d, J=8.8 Hz, 1H), 4.54 (d, J=10.5 Hz, 1H), 3.82 (s, 3H), 3.74-3.72 (m, 2H), 3.65-3.62 (m, 1H), 3.60 (s, 3H), 3.54 (s, 3H), 3.51-3.38 (m, 1H), 3.39 (s, 3H), 3.36-3.32 (m, 1H), 3.13 (t, J=9.0 Hz, 1H), 2.48 (d, J=4.1 Hz, 1H), 2.19 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 788 (M+H); HPLC 95.4% (AUC), tR 14.56 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:10][N:9]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:7]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:11]([N:9]1[CH2:10][C:6]2[C:4](=[O:3])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[NH:19][C:7]=2[CH2:8]1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1=C(Nc2ccccc2)CN(C(=O)c2ccccc2)C1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(c1ccccc1)N1Cc2[nH]c3ccccc3c(=O)c2C1

Procedure:
50 g of 3-anilino-1-benzoyl-2,5-dihydro-1H-pyrrol-4-carboxylic acid ethyl ester are heated at reflux in 500 ml of diphenyl ether for 1.5 hours, the resulting ethanol being continuously distilled off. Upon cooling, the resulting precipitate is filtered by suction, washed with ether and dried. 2-Benzoyl-1,2,3,4-tetrahydro-9H-pyrrolo[3,4-b]-quinolin-9-one is obtained. M.P. 275°.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37](=[O:43])[NH:38][CH:39]1[CH2:42][NH:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:43])[NH:38][CH:39]1[CH2:42][N:41]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:30])[F:29])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:40]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Product: CC(C)(C)OC(=O)NC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidin-3-yl)-carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and azetidin-3-yl-carbamic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]=1[CH3:12].P([O-])([O-])([O-])=[O:14].[K+].[K+].[K+]>C(O)C>[OH:14][CH:8]1[CH2:9][C:10](=[O:11])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[C:7]1[CH3:12]
Reactant: O=P([O-])([O-])[O-]
Reactant: CCCCCC1=C(C)CCC1=O
Agent: [K+]
Solvent: CCO
Product: CCCCCC1=C(C)C(O)CC1=O
Reaction time: 0.03 h

Procedure:
Experimental description: 270 μL dihydrojasmone was dissolved in 1.2 mL ethanol and added to 150 mL potassium phosphate buffer pH 8.0. Var2 was added to the mixture at a final concentration of 2 μM. The mixture was split in 4.8 mL aliquots into 15 mL scintillation vials equipped with a stir bar. 600 μL 10 mM NADPH in KPi buffer was added to each vial and stirred for 2 minutes. 600 μL cofactor regeneration solution containing 500 mM glucose-6-phosphate and 10 units/mL glucose-6-phosphate dehydrogenase were then added to each vial. The resulting mixtures were stirred at room temperature. After 36 hours, the reaction mixtures were joined together and extracted with chloroform (3×50 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (0-30% ethyl acetate/hexane) afforded the activated product (4-hydroxy-3-methyl-2-pentylcyclopent-2-enone, 222 mg). 210 mg (1.15 mmol) of activated product was dissolved in 2 mL dry dichloromethane (CH2Cl2) and a catalytic amount (4 drops) of ethanol was added to the solution. The solution was cooled to −78° C. (dry ice) and then 215 μL DAST (1.5 mmol) was added. The reaction was stirred in dry ice for 12 hours. The reaction mixture was then added with 5 mL saturated sodium bicarbonate (NaHCO3) and extracted with dichloromethane (3×15 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (0-30% ethyl acetate/hexane) afforded the fluorinated product, 4-fluoro-3-methyl-2-pentylcyclopent-2-enone (193 mg, 92% yield, yellow oil). 1H-NMR (300 MHz, CDCl3): δ 0.88 (t, J=6.6 Hz, 3H, CH3), δ 1.25-1.40 (m, 6H, CH2), δ 2.10 (d, J=2.1 Hz, 2H, CH3), δ 2.20 (t, J=7.1 Hz, 2H), δ 2.44-2.60 (m, 1H), δ 2.70-2.82 (m, 1H), δ 5.47 (dd, J=54.2 Hz, J=5.8, 1H); 13C-NMR (75 MHz, CDCl3): δ 13.7, 14.2, 22.6, 23.1, 27.9, 29.9, 31.9, 41.4 (d, J=19.6 Hz), δ 91.2 (d, J=174 Hz): 19F-NMR (282 MHz, CDCl3): δ −179.08 (ddd, J=51.88 Hz, J=21.43 Hz, J=9.3 Hz). HRMS (EI+): exact mass calculated for C11H17FO requires m/z 184.1263, found 184.1255.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:29])([CH3:28])/[CH:10]=[CH:11]/[CH2:12][C@:13]1([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[CH2:16][C:15](=[O:17])[O:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]([CH3:29])([CH3:28])/[CH:10]=[CH:11]/[CH2:12][C@:13]1([C:18]([OH:20])=[O:19])[CH2:16][C:15](=[O:17])[O:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(/C=C/C[C@]1(C(=O)OCc2ccccc2)CC(=O)O1)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Product: CC(C)(/C=C/C[C@]1(C(=O)O)CC(=O)O1)OCc1ccccc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of benzyl ester 85 (52.8 mg, 0.134 mmol, 1.00 equiv.) were added TEA (3.0 μL, 0.0214 mmol, 0.16 equiv.), triethylsilane (32.1 μL, 0.201 mmol, 1.50 equiv.), and Pd(OAc)2 (1.6 mg, 0.0071 mmol, 0.053 equiv.). The resulting black solution was stirred at 23° C. for 1 h then partitioned between 10 mL sat'd NH4Cl solution and 10 mL CH2Cl2. The phases were separated and the aqueous phase was extracted with 2×10 mL CH2Cl2. The combined aqueous phases were dried over MgSO4 and solvent removal by rotary evaporation left a brown oil that upon purification by silica gel column chromatography (4% HOAc in 1:1 hex:EtOAc) yielded acid 86 (34.4 mg, 85%) as a clear, colorless oil. Rf=0.17 (4% HOAc in 1:1 hex:EtOAc); 1H NMR (500 MHz, CDCl3) δ 10.09 (br s, 1H, CO2H), 7.33-7.23 (m, 5H, aryl H), 5.81 (d, 1H, J=15.9 Hz, (CH3)2CCH), 5.62 (m, 1H, CH2CH), 4.35 (s, 2H, PhCH2), 3.57 (d, 1H, J=16.6 Hz, C(O)CH2), 3.36 (d, 1H, J=16.6, Hz, C(O)CH2), 2.87 (dd, 1H, J=14.6, 7.1 Hz), 2.74 (dd, 1H, J=14.7, 7.3 Hz), 1.35 (s, 6H, (CH3)2); 13C NMR (125 MHz, CDCl3) δ 173.48, 165.44, 143.27, 139.13, 128.48, 127.66, 127.53, 120.34, 75.85, 65.24, 46.06, 37.57, 26.51, 26.29; IR (neat film) 3500-2500 (br m), 3031 (w), 2977 (m), 1843 (s), 1745 (s), 1497 (w), 1453 (w), 1149 (m) cm−1; LRMS (ESI) calc'd for C17H20O5Na 327.1; found 326.9.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:4]1)[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([NH:23][NH:24][CH:25]([CH3:27])[CH3:26])=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](/[CH:12]=[CH:13]/[C:14]([N:24]([CH:25]([CH3:27])[CH3:26])[NH:23][C:21](=[O:22])[C:20]2[CH:28]=[CH:29][CH:30]=[C:18]([F:17])[CH:19]=2)=[O:16])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1cc(/C=C/C(=O)N(NC(=O)c2cccc(F)c2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-ethyl-1H-indol-3-yl)acrylic acid (180.0 mg, 0.83 mmol), 3-fluoro-N′-isopropylbenzohydrazide (245.3 mg, 1.25 mmol) and HATU (475.3 mg, 1.25 mmol) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.22 ml, 1.25 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) and dried so that white (E)-N′-(3-(1-ethyl-1H-indol-3-yl)acryloyl)-3-fluoro-N′-isopropylbenzohydrazide was obtained (203.0 mg, 62.2%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:21][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[I:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:5])=[O:3])=[N:13]2)[CH:19]=1
Reactant: CCOC(=O)c1nn(-c2cc(I)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nn(-c2cc(I)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1aR,5aR)-2-(4-iodo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester in MeOH (10.00 mL) and THF (10.00 mL) was added a 2 M aqueous solution of sodium hydroxide (5.20 mL, 10.40 mmol). The mixture was stirred at room temperature for 2 h then concentrated. The remaining solid was dissolved in water (30 mL). The solution was acidified to pH ˜2 by addition of 6 M aqueous HCl. The resulting precipitate was collected by filtration, rinsed with water, then dried to give the title compound (190 mg) as a white solid. LCMS m/z=368.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1.[OH-].[Na+].O>CO>[CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][CH:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:24][NH2:25])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C=O)cc1
Reactant: N#CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCOc1ccc(CC(CN)c2ccc(F)cc2)cc1
Reaction time: 12 h
Yield: 20 %

Procedure:
A solution of 51.5 g of 4-hexyloxybenzaldehyde and 33.8 g of 4-fluorophenylacetonitrile in methanol was stirred at room temperature and aqueous sodium hydroxide (50 percent) was added dropwise until a precipitate appeared. Water was then added and the solids were collected by filtration to render α-[[4-(hexyloxy)phenyl]methylene]-4-fluorophenylacetonitrile which was reduced as follows. 40.2 g of said nitrile, 10 g of Raney nickel, 150 ml of anhydrous ammonia and 300 ml of tetrahydrofuran were stirred at 110° for 12 hours at a pressure of 2000 psi. The catalyst and solvent were removed and the hydrochloride salt was made in the filtrate by the addition of anhydrous hydrochloric acid. Recrystallization from methanol rendered the title compound (20 percent yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22]>>[F:26][C:14]([F:13])([F:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:22])=[O:23]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2C(F)(F)F)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-trifluoromethylbenzenesulfonyl chloride according to METHOD A, giving 0.13 g (31%) of a red solid after recrystallization from acetone/ether/petroleum ether: mp 171° C.; MS (Ionspray, [M+H]+) m/z 395; Anal. Calcd (found) for C14H13F3N2O4S2: C, 42.6 (43.0)%, H, 3.3 (2.9)%, N, 7.1 (6.9)%.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[CH2:10]1[O:12][CH:11]1[CH2:13][OH:14].[OH-].[Na+]>ClCCl>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([O:14][CH2:13][CH:11]2[O:12][CH2:10]2)[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1nc(Cl)nc(OCC2CO2)n1
Reaction time: 3 h

Procedure:
A solution of 73.76 g (0.4 moles) cyanuric chloride in 360 ml of dichloromethane was chilled in an ice-water bath to about 0–5° C. and 31.85 g (0.43 moles) glycidol was added. A solution of 34.4 g 50% aqueous sodium hydroxide was added over about 30–45 minutes with stirring keeping the temperature between about 0° C. and about 10° C. Stirring was continued for an additional 3 hours after which time the layers were separated and the organic layer washed two times with water, and once with brine and the solution was dried over magnesium sulfate. Filtration and evaporation of the solution afforded a white solid, a sample of which was further purified by trituration withhexane-ethyl acetate. The proton and carbon nuclear magnetic resonance (NMR) spectra were consistent with the desired product, 2,4-dichloro-6-glycidoxy-1,3,5-triazine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:23])[CH:5]=1)([O-])=O.C(OCC)(=O)C.[H][H]>[Ni].CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:23])[CH:5]=1
Reactant: CSc1ccc2c(c1)C(=O)N(c1cc([N+](=O)[O-])ccc1C)C2=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc2c(c1)C(=O)N(c1cc(N)ccc1C)C2=O

Procedure:
The mixture of 6.0 g of N-(4-nitro-o-tolyl)-4methylmercaptophthalimide, 3.0 g of Raney nickel and 200 ml of ethyl acetate is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is diluted with dimethylformamide to solubilize any organic material, filtered and the filtrate evaporated. The residue is recrystallized from chloroform-diethyl ether to yield the N-(4-amino-o-tolyl)-4-methylmercaptophthalimide melting at 173°-177°. The starting material is prepared as follows: The mixture of 8.5 g of potassium methylsulfide, 21.2 g of diethyl 4-chlorophthalate and 100 ml of dimethylformamide is stirred at 100°-120° for one week. After cooling it is diluted with diethyl ether, the precipitate filtered off, the filtrate washed with 5% aqueous sodium hydroxide, water, dried and evaporated, to yield the diethyl 4-methylmercaptophthalate. The mixture of 18.2 g thereof and 100 ml of 30% aqueous ethanolic sodium hydroxide is refluxed for 21/2 hours and evaporated. The residue is acidified with concentrated hydrochloric acid and thoroughly extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue recrystallized from 30% aqueous methanol, to yield the 4-methylmercaptophthalic acid, m.p. 178°-181°. The mixture of 13.0 g thereof and 130 ml of acetic anhydride is refluxed for 3 hours and evaporated, to yield the 4-methylmercaptophthalic anhydride melting at 157°-160°. The mixture of 10.3 g thereof, 7.8 g of 4-nitro-o-toluidine and 100 ml of acetic acid is refluxed for 24 hours and evaporated. The residue is recrystallized from ethanol-ethyl acetate to yield the N-(4-nitro-o-tolyl)-4-methylmercaptophthalimide melting at 155°-157°.