Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH:16]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH:16]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 60 °C

Procedure:
A mixture of 2.6 g of methyl 3-methoxy-4-[3-(2-quinolinylmethyloxy)benzyloxy]benzoate and 0.6 g of NaOH in 15 ml of THF and 2 ml of H2O are heated at 60° C. overnight. The reaction mixture is diluted with 20 ml of HO and acidified to pH 4. The product is collected on a filter and dried to give 3-methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid. (M.P. 188°-190° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10](Cl)(Cl)=[S:11]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:10]=[S:11])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: S=C(Cl)Cl
Solvent: O
Product: S=C=Nc1ccc(Cl)c(Cl)c1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
3,4-Dichloroaniline (19.44 g., 120 mM.) is added with vigorous stirring to a solution of thiophosgene in H2O (100 ml.) while maintaining the temperature at 15° C during the addition. The reaction is allowed to warm slowly to room temperature and is stirred for 1 hr. The aqueous layer is separated and extracted with 3 × 50 ml. CHCl3 ; the combined organic layers are dried over CaCl2 and filtered. The filtrate is evaporated in vacuo to give 3,4-dichlorophenylisothiocyanate (20.5 g.) which is used without purification in the next step.
Reaction SMILES: C1CCC([N:7]=[C:8]=[N:9]C2CCCCC2)CC1.ON1C(=O)CCC1=O.[CH2:24]([O:26][CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][CH:42]=2)=[CH:34][CH:33]=1)[C:28](O)=[O:29])[CH3:25].C(N(C(C)C)CC)(C)C.N#CN>C(#N)C.C(O)(=O)C>[C:8]([NH:9][C:28](=[O:29])[CH:27]([O:26][CH2:24][CH3:25])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][CH:42]=2)=[CH:34][CH:33]=1)#[N:7]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Agent: N#CN
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)NC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
DCC (0.444 g; 2.15 mmole) and N-hydroxy-succinimide (0.247 g; 2.15 mmole) were added to a solution of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid (described in Example 2) (0.8 g; 1.96 mmole) in acetonitrile (20 ml) at 0° C. After stirring at room temperature overnight a precipitate was filtered off and diisopropylethylamine (1 ml; 5.88 mmole) and cyanamide (0.165 g; 3.92 mmole) were added. After stirring overnight the reaction mixture was poured onto potassium hydrogen sulfate (1M, 20 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried (sodium sulfate) and the solvent was evaporated. Chromatography of the crude product on silica gel using ethyl acetate:heptane; acetic acid (10:10:1) as eluant gave 0.755 g (yield 89%) of N-cyano-2-ethoxy-3-[4-(2-{4-methanesulfonyloxy-phenyl}ethoxy)phenyl]propanoic amide.
Reaction SMILES: [F:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](O)=[O:4].S(Cl)([Cl:15])=O>>[F:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([Cl:15])=[O:4]
Reactant: O=C(O)C(F)=Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C(F)=Cc1ccccc1
Temperature: 80 °C

Procedure:
To α-fluorocinnamic acid (5.48 g, 33 mM), thionyl chloride (40 ml) was added, and the thus obtained mixture was stirred at 80° C. under refluxing for 2 hours. After cooling it to a room temperature, the unreacted thionyl chloride was distilled off under reduced pressure to give a syrup-like α-fluorocinnamoyl chloride.
Reaction SMILES: [OH:1][CH:2]([CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH:8]=[CH:9][CH:10]=1.CCOCC>CO.C(Cl)(Cl)Cl>[O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH:8]=[CH:9][CH:10]=1.[C:24]1([N:21]2[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CC(c2cccc(OCC(O)CN3CCN(c4ccccc4)CC3)c2)CN1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CO
Product: O=C1CC(c2cccc(OCC3CO3)c2)CN1
Product: c1ccc(N2CCNCC2)cc1
Yield: 95 %

Procedure:
From 8.6 mmol of 4-[3-(2,3 -epoxypropoxy)phenyl]-2-pyrrolidone and 8.6 mmol of 1-phenylpiperazine (95% strength), 4-{3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propoxy]phenyl}-2-pyrrolidone, m.p. 82°-84°, is obtained analogously to Example 1 in a 77% yield (ether; after chromatography in methanol/chloroform 2:8).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][N:25]([CH3:37])[C:26](=[O:36])[CH2:27][CH2:28][NH:29][C:30]1[CH2:34][S:33][C:32](=[O:35])[N:31]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:34]2/[C:30]([NH:29][CH2:28][CH2:27][C:26]([N:25]([CH3:24])[CH3:37])=[O:36])=[N:31][C:32](=[O:35])[S:33]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN(C)C(=O)CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (520 mg) and N,N-dimethyl-N3-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-β-alaninamide (330 mg) in 2-propanol (60 mL) was added piperidinium acetate (223 mg). The reaction mixture was stirred at 80° C. for 4 hr and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol). The obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (356 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH3:19])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1
Reactant: Nc1nc2ccccc2c2ccc(Cl)nc12
Reactant: CNC
Product: CN(C)c1ccc2c(n1)c(N)nc1ccccc12
Temperature: 100 °C

Procedure:
A solution of 3-chlorobenzo[f][1,7]naphthyridin-5-amine (Example 20) (1.0 eq.) was dissolved in 40% aqueous dimethylamine (0.26 M) and heated in a microwave reactor at 100° C. for 30 minutes. The reaction mixture was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-90% ethyl acetate in hexane to give N3,N3-dimethylbenzo[f][1,7]naphthyridine-3,5-diamine. 1H NMR (methanol d-4): δ 8.63 (d, 1H), 8.20 (d, 1H), 7.55 (d, 1H), 7.41-7.45 (dd, 1H), 7.29-7.33 (dd, 1H), 7.27 (d, 1H), 3.26 (s, 6H). LRMS [M+H]=239.1
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH2:44][CH3:45])[CH:36]=2)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23].O>C1COCC1>[CH2:44]([O:43][C:37]1[CH:36]=[C:35]([C:33]([C:27]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=2)=[CH:9][C:10]#[N:11])[CH:40]=[CH:39][C:38]=1[O:41][CH3:42])[CH3:45]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(OCC)c2)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(OCC)c2)ccc1OC
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (7.0 mL, 44.4 mmol) in anhydrous THF (20 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 44.4 mL, 44.4 mmol) at 0° C. and stirred for 30 min followed by addition of bis-(3-ethoxy-4-methoxy-phenyl)-methanone (7.34 g, 22.2 mmol) and refluxed for 3 h. The reaction mixture was poured into water (100 mL), extracted with CH2Cl2 (2×100 mL). The combined organic phases were washed with brine (100 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc/Hexane) to give 3,3-bis-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile as a white solid (3.92 g, 50% yield): 1H NMR (DMSO-d6) δ 1.31 (t, J=7 Hz, 6H, 2CH2CH3), 3.79 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.94-4.04 (two q, J=7 Hz, 4H, 2CH2CH3), 6.11 (s, 1H, CH), 6.77-7.09 (m, 6H, Ar); 13C NMR (DMSO-d6) δ 14.6, 14.6, 55.5, 55.5, 63.8, 92.6, 111.3, 111.5, 112.3, 113.8, 118.9, 122.3, 122.4, 129.3, 130.6, 147.3, 147.8, 150.1, 151.0, 161.4; Anal. Calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.42; H, 6.42; N, 3.97.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.Cl.[NH2:26][CH:27]1[C:48](=[O:49])[N:29]2[C:30]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])=[C:31]([Cl:34])[CH2:32][S:33][C@H:28]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:10]([NH:26][CH:27]2[C:48](=[O:49])[N:29]3[C:30]([C:35]([O:37][CH2:38][C:39]4[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=4)=[O:36])=[C:31]([Cl:34])[CH2:32][S:33][C@H:28]23)=[O:12])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)O)cs1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=C(Cl)CS[C@H]23)cs1
Yield: 96.7 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetic acid (syn isomer, 0.9 g.), N,N-dimethylformamide (0.24 g.) and phosphoryl chloride (0.5 g.) in ethyl acetate (10 ml.) and a solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (1.23 g.) and trimethylsilylacetamide (2.8 g.) in ethyl acetate (20 ml.) were treated in a similar manner to that of Example 21-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 1.9 g.).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9](Br)[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:16])=[O:4].[CH2:17]([O:19][C:20](=[O:35])[CH2:21][Sn](CCCC)(CCCC)CCCC)[CH3:18]>CN(C=O)C.[Br-].[Zn+2].[Br-].CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:35])[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:16])=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)CC(=O)OCC
Reactant: COC(=O)n1c(C)cc2c(Br)c(Cl)ccc21
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: [Br-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(Cl)ccc2c1cc(C)n2C(=O)OC
Temperature: 80 °C

Procedure:
4-Bromo-5-chloro-2-methyl-indole-1-carboxylic acid methyl ester (1.99 g, 6.57 mmol) and tributylstannanyl-acetic acid ethyl ester (3.22 g, 8.55 mmol) are dissolved in dry DMF (55 ml) under an atmosphere of argon. Zinc(II) bromide (1.92 g, 8.55 mmol) and dichlorobis(tri-o-tolylphosphin)palladium (0) (1.03 g, 1.31 mmol) are added. The reaction mixture is heated to 80° C. for 18 hours. TLC analysis indicates complete consumption of the starting material. The reaction mixture is cooled to RT and poured on a saturated aqueous solution of NH4Cl. After addition of EtOAc (30 ml), the mixture is filtered through a pad of Celite. The organic layer is washed with saturated aq. NaCl solution, dried over Na2SO4 and concentrated. The residue is purified by FCC (hexane/EtOAc 4:1) to yield the desired compound, still contaminated with tin residues. The mixture is dissolved in a 1:1 mixture of 1 M NaOH/EtOAc (200 ml in total) and stirred at RT for 18 hours. The organic layer is separated, washed once with concentrated aqueous NaCl solution, and then dried over Na2SO4. Concentration yields a solid residue which is purified by FCC (hexane/EtOac 4:1) to afford the desired compound, still slightly contaminated. A further round of purification with an automated preparative HPLC system (Gilson HPLC, Xterra 5 mikron, gradient 10% to 100% MeCN in H2O, 30 min) affords the pure title compound. 1H NMR (DMSO, 400 MHz) δ 1.20 (t, J=6.6 Hz, 3H), 2.59 (s, 3H), 4.01 (s, 2H), 4.03 (s, 3H), 4.11 (q, J=6.6 Hz, 2H), 6.68 (s, 1H), 7.32 (d, J=9 Hz, 1H), 7.96 (d, J=9 Hz, 1H); ES-MS: 332.1 [M+Na]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][C:39]3=[N:40][O:41][N:42]=[C:38]3[CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[N:40]1[O:41][N:42]=[C:38]2[CH:37]=[C:36]([C:2]3[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:5]4[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=4[N:7]=3)[CH:44]=[CH:43][C:39]=12
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4nonc4c3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.180 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,1,3-benzoxadiazole (57.7 mg, 0.235 mmol), DMSO(2 mL), sodium carbonate (0.271 mL, 0.541 mmol), and bis(triphenylphosphine)palladium(II) chloride (12.67 mg, 0.018 mmol) wherein the reaction time was 8 h. The final product was collected as 17 mg (20%). LCMS LCMS E-S (M+H)=472.4 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (d, J=6.8 Hz, 6 H), 2.12 (s, 3 H), 2.27 (s, 3 H) 4.42 (d, J=4.8 Hz, 2 H) 5.32 (quin, J=6.6 Hz, 1 H), 5.90 (s, 1 H), 8.00 (s, 1 H), 8.23 (d, J=9.4 Hz, 1 H), 8.54-8.64 (m, 1 H), 8.79 (t, J=4.7 Hz, 1 H), 8.91 (s, 1 H), 11.54 (br. s., 1 H).
Reaction SMILES: O[NH:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11].S(Cl)(Cl)=O.C(N(CCCC)CCCC)CCC.[OH-].[Na+]>C(OC)(C)(C)C>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3]([OH:12])=[N:2][O:11][C:5]=2[CH:6]=1
Reactant: Cc1ccc(C(=O)NO)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: COC(C)(C)C
Solvent: O=S(Cl)Cl
Product: Cc1ccc2c(O)noc2c1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
50.0 g of N,2-dihydroxy-4-methylbenzamide was added to 350 mL of tert-butylmethylether, and 38.1 g of thionyl chloride was added dropwise at −1-0° C. This was stirred for 30 minutes at the same temperature. Then, 164 mL of tributylamine was added dropwise at −5-−3° C., and this was stirred for 1.5 hours at −5-5° C. To the reaction mixture, 200 mL of 20% sodium hydroxide aqueous solution was added, an organic layer was separated, and 100 mL of water, 42 mL of 20% sodium hydroxide aqueous solution and 5.0 g of celite were added. After insoluble matter was filtered off, the cake was washed with 100 mL of water. The filtrate and the washing solution were combined and an aqueous layer was separated. To the aqueous layer, 10 mL of acetone and 50 mL of acetic acid were added at 40-50° C. After stirring at the same temperature for 30 minutes, solids were filtered to obtain 40.1 g of 6-methyl-1,2-benzisoxazol-3-ol in the form of a pale yellow solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[N:19]([CH3:28])[N:18]=2)=[CH:12][C:11]=1[CH3:29])=[O:7]>O1CCCC1>[C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:29])=[CH:12][C:13]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[N:19]([CH3:28])[N:18]=2)=[CH:14][C:15]=1[CH3:16])([OH:7])=[O:5]
Reactant: COC(=O)COc1c(C)cc(-c2nn(C)c(=O)c3ccccc23)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2nn(C)c(=O)c3ccccc23)cc(C)c1OCC(=O)O
Reaction time: 18 h
Yield: 93.2 %

Procedure:
Lithium hydroxide monohydrate (0.22 g) was added to a solution of example 107 (1.52 g) in aqueous tetrahydrofuran (1:1 50 ml) and the reaction stirred 18 h, the mixture was the concentrated in vacuo and the residual slurry acidified with 10% hydrochloric acid. The resulting precipitate was collected to give the title compound as a white solid (1.36 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].[Cl-].[NH4+].O>CO.[Zn]>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7]
Reactant: COCCC1(C(=S)N[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COCCC1(C(=S)N[C@@H](Cc2ccc(N)cc2)C(=O)OC)CCCC1
Reaction time: 0.33 h
Yield: 106.4 %

Procedure:
To a suspension of N-[[1-(2-methoxyethyl)cyclopentyl]thioxomethyl]-4-nitro-L-phenylalanine methyl ester (4.58 g, 11.6 mmol), zinc dust (7.50 g, 116 mmol) and ammonium chloride (9.20 g, 174 mmol) in methanol (200 mL) was added H2O (100 mL) slowly over 5 min. After stirring for 20 min, the reaction mixture was partitioned between ethyl acetate (400 mL) and sat. ammonium chloride solution (150 mL). The separated aqueous layer was back-extracted with ethyl acetate (3×100 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residual oil was dried under high vacuum for 2 h to give crude 4-amino-N-[[1-(2-methoxyethyl)cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (4.5 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:9]=[C:10]1[CH2:19][C:12]2([CH2:15][CH:14]([C:16]([OH:18])=[O:17])[CH2:13]2)[CH2:11]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl.C(#N)C>[O:9]=[C:10]1[CH2:11][C:12]2([CH2:15][CH:14]([C:16]([O:18][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:17])[CH2:13]2)[CH2:19]1
Reactant: O=C1CC2(C1)CC(C(=O)O)C2
Reactant: BrCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CC2(C1)CC(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (bromomethyl)benzene (564 mg) in CHCl3 (1 mL) was added to a stirred solution of 6-oxospiro[3.3]heptane-2-carboxylic acid (462 mg) and DIPEA (0.576 mL) in acetonitrile (2 mL) and CHCl3 (2 mL) and the mixture was stirred at rt overnight. The reaction mixture was evaporated to dryness and then purified by silica gel FCC (1:1 DCM:hexanes) to afford benzyl 6-oxospiro[3.3]heptane-2-carboxylate as a clear oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(S(O)(=O)=[O:15])=CC=CC=1>[Cu].CO>[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:4]1(=[O:15])[CH:5]=[CH:6][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: [Cu]
Solvent: Oc1ccccc1
Solvent: CO
Product: O=C1C=CC(=O)C=C1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Twenty milligrams of the inactive copper salt complex obtained from Example 1, 100 milligrams of phenol and 1 gram of methanol were dissolved in a 1/2 ounce bottle. Twenty micrograms of toluene sulfonic acid were added and solution was effected under steam heat at 100° C. One-half of the insoluble complex appeared to go into solution. One hundred microliters of the solution were charged into a micro reactor and reacted under the same conditions as described in Example 2. Samples were taken at 30 and 60 minutes. After 30 minutes of oxidation, a conversion of less than 1 percent phenol to benzoquinone was obtained. After 60 minutes reaction time, 4.74 percent conversion of phenol to benzoquinone was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][NH:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1.C(N(CC)CC)C.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][N:13]([C:30]([N:29]([CH3:33])[CH3:28])=[O:31])[CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)CNC2)c1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC(c2ccccc2)C1

Procedure:
5-(2,5-difluorophenyl)-3-phenyl-1,2,3,6-tetrahydropyridine (1-7, 1.0 mg, 4 μmol) was dissolved in anhydrous CH2Cl2 (1.0 mL) and treated with excess triethylamine (10 μL) and dimethylcarbamoyl chloride (1.1 mg, 12 μmol). Upon completion the reaction was directly subjected to flash column chromatography (SiO2, 0-80% EtOAc-hexanes gradient) to yield 5-(2,5-difluorophenyl)-N,N-dimethyl-3-phenyl-3,6-dihydropyridine-1(2H)-carboxamide (1-8). MS 343.4 found 343.4 (M+H+) required.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[O:16])[CH3:15])=[CH:4]1)[CH3:2].[CH2:17]([N:19]1C2C(=CC=C(OC)C=2)C=C1)C.COC(OC)N(C)C.N1CCCC1.Cl.ON>O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[O:16][N:19]=[CH:17][CH:15]=2)=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(C)=O)c2ccc(OC)cc21
Reactant: CCn1ccc2ccc(OC)cc21
Agent: COC(OC)N(C)C
Agent: Cl
Agent: NO
Solvent: O
Solvent: C1CCNC1
Product: CCn1cc(-c2ccno2)c2ccc(OC)cc21
Temperature: 80 °C
Yield: 66 %

Procedure:
1-(1-Ethyl-6-methoxy-1H-indol-3-yl)ethanone (100 mg, 0.46 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, is heated with 1.5 mL of dimethylformamide dimethylacetal and 100 μL of pyrrolidine at 110° C. overnight. The dimethylformamide dimethylacetal is then concentrated in vacuo. The residue is redissolved in 1.25 mL of EtOH and 250 μL of H2O, and is treated with hydroxyamine hydrochloride (66 mg, 0.95 mmol) and heated at 80° C. for 2 h. Partitioning between H2O and EtOAc and drying and concentration of the organic phase followed by purification by silica gel chromatography (EtOAc/CH2Cl2, 5/95) gives 1-ethyl-3-isoxazol-5-yl-6-methoxy-1H-indole as a white solid (72 mg, 66%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[C:11]([CH2:19][C:20](=O)[CH3:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C.CCCCCC>[NH2:4][C:3]1[C:19]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:20]([CH3:21])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: N#CC(N)c1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1[nH]c(-c2ccccc2)c(N)c1C(=O)c1ccccc1

Procedure:
Starting from 2-amino-2-phenylacetonitrile and benzoylacetone, the open-chain intermediate compound is obtained, melting at 134°-135° C. (from diethyl ether/hexane). The title compound is obtained in a 60% overall yield. M.P. 285°-290° C. (from methanol/diethyl ether). The free base melts at 203°-5° C. (from methanol).