Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]([O:25][CH3:26])=[O:24]>>[CH3:26][O:25][C:23]([CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[NH:16][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:12]=1)=[O:15])=[O:24]
Reactant: COC(=O)C1CCCCC1N
Reactant: O=C(O)c1cccc(C2CCCCC2)n1
Product: COC(=O)C1CCCCC1NC(=O)c1cccc(C2CCCCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclohexyl-pyridine-2-carboxylic acid (Example 7 b) and methyl 2-aminocyclohexane-1-carboxylate (CAN 40015-88-1) as starting materials, MS (EI): m/e=345.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8]C(=O)[O:10][C:11](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:14][C:15]1[C:16]([CH3:22])=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([Br:14])[C:16]=1[CH3:22])=[O:10]
Reactant: Cc1c(N)cccc1Br
Reactant: O=c1[nH]c2c(F)cccc2c(=O)o1
Product: Cc1c(Br)cccc1NC(=O)c1cccc(F)c1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.9 %

Procedure:
A suspension of 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (3.00 g, 16.6 mmol) in xylenes (50 mL) was treated with 3-bromo-2-methylaniline (3.08 g, 16.6 mmol) and heated to reflux. After 6 h the mixture was allowed to cool to room temperature overnight. The resulting suspension was diluted with hexanes and the precipitate was collected by filtration, rinsed with hexanes and air-dried to provide 2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide as a white solid (4.50 g, 84% yield). 1H NMR (400 MHz, chloroform-d) δ 7.69 (d, J=7.9 Hz, 1H), 7.65 (br. s., 1H), 7.50-7.46 (m, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.19-7.11 (m, 2H), 6.73-6.64 (m, 1H), 5.69 (br. s., 2H), 2.44 (s, 3H).
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[F:25])=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[F:25][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)=[CH:16][C:11]=1[NH:10][C:9]([NH2:26])=[NH:8]
Reactant: COc1ccnc(-c2ccc(F)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccnc(-c2ccc(F)c(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(2-fluoro-5-(4-methoxypyridin-2-yl)phenyl)guanidine (0.2 g) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the resultant precipitate was collected by filtration and dried under reduced pressure to give (2-fluoro-5-(4-methoxypyridin-2-yl)phenyl)guanidine dihydrochloride (143 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH:7]1([Mg]Cl)[CH:11]=[CH:10][CH:9]=[CH:8]1>>[CH2:2]([C:11]1[CH2:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCBr
Reactant: Cl[Mg]C1C=CC=C1
Product: C=CCCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-1-pentene (100 g of 95 wt %, 0.637 mol) was added cyclopentadienyl magnesium chloride (700 mL of 1 M solution in THF, 0.7 mol) at 0° C. in an hour. After stirring for an additional 30 minutes at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a yellow-brown liquid (98 g, crude pent-4-enylcyclopentadiene). To the crude pent-4-enylcyclopentadiene (89 g) dissolved in THF (500 mL) was added n-BuLi (60 mL of 10 M in hexanes, 0.6 mol) at −78° C. The mixture was warmed up to room temperature and stirred overnight. The anion solution was added to benzophenone (110 g, 0.604 mol) dissolved in THF (500 mL) at 0° C. in 25 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 40° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (145 g, 84% yield based on 5-bromo-1-pentene) as a dark red viscous oil. 1H NMR (300 MHz, CDCl3) δ 7.41-7.48 (m, 10H), 6.59-6.62 (dd, J=5.1 Hz, 1.4 Hz, 1H), 6.40-6.42 (dd, J=5.1 Hz, 1.4 Hz, 1H), 6.12-6.15 (m, 1H), 5.86-6.02 (m, 1H), 5.08-5.20 (m, 2H), 2.55-2.60 (t, J=7.2 Hz, 2H), 2.22-2.30 (m, 2H), 1.76-1.88 (quin, J=7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 148.28, 148.13, 143.28, 140.85, 140.76, 138.01, 133.51, 131.34, 131.29, 127.76, 127.74, 127.13, 127.08, 124.74, 118.24, 114.24, 33.95, 30.13, 28.46.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:11][N:10]2[C:12]3[CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[CH:16][C:17]=3[C:18]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:9]2[C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][CH2:5]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]1[CH2:11][N:10]2[C:12]3[CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[CH:16][C:17]=3[C:18]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:9]2[C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N=[N+]=[N-])COc1ccccc1-3
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N)COc1ccccc1-3
Reaction time: 4 h
Yield: 92 %

Procedure:
A solution of the foregoing product from Step 2 in MeOH (0.1 M) containing palladium on charcoal (10%, w/w) was stirred under hydrogen at atmospheric pressure for 4 h. The catalyst was filtered off and the solution was concentrated to dryness under reduced pressure to afford the title compound (92%) MS (ES+) m/z 405 (M+H)+. MS (ES+) m/z 405 (M+H)+; %; [α]D20=+46.4 (c=1, CHCl3).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH:12]=[C:13]([CH3:17])[C:14](=[O:16])[CH3:15])=[O:6])[CH:2]=[CH2:3].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@H:34]1[NH:37][C:36](=[O:38])[C@@H:35]1[C@H:39]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH3:40])(=O)C.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C.[Br-].[Zn+2].[Br-].O.C(N(CC)CC)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](\[CH3:17])/[C:14](=[O:16])[CH2:15][C@H:34]1[NH:37][C:36](=[O:38])[C@@H:35]1[C@H:39]([O:41][Si:42]([C:45]([CH3:46])([CH3:48])[CH3:47])([CH3:44])[CH3:43])[CH3:40])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)N1CCC[C@H]1C=C(C)C(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1CCC[C@H]1/C=C(\C)C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a solution of (2S)-1-allyloxycarbonyl-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (9.00 g) and triethylamine (6.3 ml) in dichloromethane (200 ml) was added trimethylsilyl trifluoromethanesulfonate (11.7 ml) at -20° C. After stirring at 0° C. for 1 hour, a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-azetidinone (10.9 g) and zinc bromide (11.9 g) in ethyl acetate (70 ml) was added to the mixture and the resultant mixture was stirred at 0° C. for 45 minutes. The reaction mixture was taken up into a mixture of ethyl acetate (600 ml) and water (600 ml). After adjusting pH to 4 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (400 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-5:5 V/V) to give (3S, 4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (9.96 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[N:12]=[C:13]([CH2:16]O)[S:14][CH:15]=2)[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClCCl>[Br:24][CH2:16][C:13]1[S:14][CH:15]=[C:11]([C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:22])=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)[N:12]=1
Reactant: CC(C)(C)c1cc(-c2csc(CO)n2)cc(C(C)(C)C)c1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2csc(CBr)n2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Yield: 92 %

Procedure:
1.5 g (4.70 mmol) of intermediate 353.2, (2,6-ditert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol are dissolved in dichloromethane (30 ml). After adding CBr4 (2.02 g; 6.10 mmol), the reaction medium is cooled down to 0° C. PPh3 (1.48 g; 5.63 mmol) is added by fractions then the mixture is allowed to return to ambient temperature. The reaction medium is then poured into ice-cold water before being extracted with dichloromethane. The organic phase is washed with salt water before being dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is obtained after chromatography on a silica column (eluent: 30% of ethyl acetate in heptane), in order to produce a brown oil with a yield of 92%. This product is sufficiently pure to be able to be used directly in the following stage.
Reaction SMILES: [ClH:1].Cl.[OH:3][CH:4]([CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34]CC2C=CC=CC=2)=[CH:30][CH:29]=1)[CH2:5][NH:6][C:7]([CH3:25])([CH3:24])[CH2:8][N:9]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10].Cl>C(O)C>[ClH:1].[ClH:1].[OH:3][CH:4]([CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([CH3:25])([CH3:24])[CH2:8][N:9]([CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:10]
Reactant: CN(CC(C)(C)NCC(O)COc1ccc(OCc2ccccc2)cc1)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CN(CC(C)(C)NCC(O)COc1ccc(O)cc1)C(c1ccccc1)c1ccccc1

Procedure:
A solution of b 2-[2-hydroxy-3-(4-phenylmethoxyphenoxy)-propylamino]-2-methyl-N-diphenylmethyl-N-methyl-propylamine dihydrochloride (5 g; 0.0084 mol), prepared as described in Example 10, in ethyl alcohol saturated with hydrochloric acid (50 ml) is refluxed for 6 hours.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.C(N(CC)CC)C.[OH:45][C:46]([C:48]([F:51])([F:50])[F:49])=[O:47].OC(C(F)(F)F)=O.[NH:59]1[CH2:64][CH2:63][CH:62]([N:65]2[CH2:70][C:69]3[CH:71]=[CH:72][CH:73]=[N:74][C:68]=3[NH:67][C:66]2=[O:75])[CH2:61][CH2:60]1>O1CCCC1.CS(C)=O>[C:46]([OH:47])([C:48]([F:51])([F:50])[F:49])=[O:45].[O:75]=[C:66]1[NH:67][C:68]2[N:74]=[CH:73][CH:72]=[CH:71][C:69]=2[CH2:70][N:65]1[CH:62]1[CH2:61][CH2:60][N:59]([C:35]([NH:1][C@@H:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]2=[O:24])=[O:36])[CH2:64][CH2:63]1
Reactant: O=C1Nc2ncccc2CN1C1CCNCC1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(N2Cc3cccnc3NC2=O)CC1
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A solution of (3R) 3-amino-2-oxo-5-phenyl-1-(2,2,2-trifluorethyl)-2,3-dihydro-1H-1,4-benzodiazepine (0.037 g, 0.112 mmol) and 4-nitrophenylchloroformate (0.0238 g, 0.112 mmol) in dry tetrahydrofuran (2 mL) was cooled to 0° C. under argon. Triethylamine (0.011 g, 0.112 mmol) was added and the reaction stirred for 1 h. 3-Piperidin-4-yl-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one bisTFA salt (0.112 mmol) in DMSO (1 mL) followed by triethylamine (0.055 g) in were added. The reaction was allowed to come to room temperature and stirred for 4 h. The reaction was concentrated and purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution) to give TFA salt of the title compound (0.023 g, 29% yield). MS 592.2261 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[CH2:25]([O:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31])[CH3:26].CCCCCC.C(OCC)(=O)C>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH:31][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13])[CH3:26]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: CCOc1ccccc1CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CCOc1ccccc1CNC(=O)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (6.3 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-ethoxybenzyl amine (64.9 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was re-dissolved in CH2Cl2 (50 mL). The organic layer was washed with aqueous NaHCO3, dried over anhydrous Na2SO4, and concentrated to give the crude mixture. Flash column chromatography of the crude (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (85.0 mg, 96%): m.p. 79-80° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([C:9]1[N:10]=[CH:11][N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:13]=1)O.Cl.[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>CCO.[OH-].[OH-].[Pd+2]>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:9]1[N:10]=[CH:11][NH:12][CH:13]=1
Reactant: Cc1sccc1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd+2]
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: Cc1sccc1Cc1c[nH]cn1

Procedure:
A solution of (2-methylthien-3-yl)-1-trityl-imidazol-4-yl-methanol (1.5 g, 3.5 mmol) was combined with HCl (3.4 mmol) and Pd(OH)2 (1.5 g) in EtOH and hydrogenated (55 psi) at 55° C. for 48 hrs. The catalyst was removed by filtration through Dicalite and the solvent was evaporated in vacuo. The residue was dissolved in water, washed twice with Et2 O, and then basified with Na2CO3 and extracted twice with EtOAc. The combined extracts were dried (K2CO3), filtered and solvent evaporated. The residue was chromatographed on flash silica gel (99:0.75:0.25 EtOAc/MeOH/NH4OH) to give a thick syrup which was dissolved in 2-PrOH and combined with fumaric acid (116 mg). The solvent was evaporated and the residue recrystallized from acetone to give the target compound, m.p. 140°-141° C. 1H NMR (DMSO-d6) supported the assigned structure: δ6 2.3 (s, 3H), 3.75 (s, 2H), 6.6 (s, 2H), 6.75 (s, 1H), 6.85 (d, J=5.3 Hz, 1H), 7.15 (d, 1H), 7.65 (s, 1H). Elemental Analysis: Calc. for C9H10N2 S.C4H4O4C, 53.05; H, 4.79; N, 9.52. Found C, 53.22; H, 4.87; N, 9.50.
Reaction SMILES: N.[N+:2]([C:5]1[CH:19]=[CH:18][C:8]([NH:9]C(=O)C2C=CC=CC=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N)(=O)C1C=CC=CC=1>CO>[N+:2]([C:5]1[CH:19]=[CH:18][C:8]([NH2:9])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: N
Agent: NC(=O)c1ccccc1
Solvent: CO
Product: Nc1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
Approximately 10 ml of liquid ammonia was added rapidly to a solution of 100 mg of 4'-nitrobenzanilide and 50 ml of methanol in a Parr bomb at -50° C. The Parr reactor was stirred at 120° C./300 psi (21.1 kg/cm2) for 3 days. After the reactor was cooled to -50°C., the pressure was released and the reactor was opened. An aliquot was taken out for HPLC analysis which revealed a 50% yield of 4-nitroaniline and benzamide. The remainder of the material was unreacted.
Reaction SMILES: O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH2:15]([N:17]([CH2:56][CH3:57])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][C:27]1[C@H:28]([CH3:55])[C@@H:29]2[C@@H:46]([C@H:47]([O:49][Si](C)(C)C)[CH3:48])[C:45](=[O:54])[N:30]2[C:31]=1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])=[O:19])[CH3:16].CO>C(Cl)Cl>[CH2:56]([N:17]([CH2:15][CH3:16])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][C:27]1[C@H:28]([CH3:55])[C@@H:29]2[C@@H:46]([C@H:47]([OH:49])[CH3:48])[C:45](=[O:54])[N:30]2[C:31]=1[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)=[O:33])=[O:19])[CH3:57]
Reactant: CCN(CC)C(=O)c1ccccc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]2[C@H]1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 102.5 %

Procedure:
41 mg (0.195 mmol) of citric acid hydrate were added to 30 ml of a solution of 1.072 g (1.71 mmol) of 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 34) in a 2:1 by volume mixture of methanol and methylene chloride, and the mixture was stirred for 20 minutes at room temperature. At the end of this time, the reaction solution was condensed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 25 g of silica gel. Elution with ethyl acetate afforded 970 mg (quantitative yield) of the title compound as a colorless foam-like solid.
Reaction SMILES: N1CC(=O)NC1=O.N1C(=O)[C:11]2([C:24]3[C:17]([CH:18]=[C:19]4[S:23][CH:22]=[CH:21][C:20]4=3)=[CH:16][CH:15]=[CH:14]2)NC1=O>>[S:23]1[CH:22]=[CH:21][C:20]2[CH2:24][C:17]3[C:18]([C:19]1=2)=[CH:11][CH:14]=[CH:15][CH:16]=3
Reactant: O=C1NC(=O)C2(C=CC=C3C=c4sccc4=C32)N1
Agent: O=C1CNC(=O)N1
Product: c1ccc2c(c1)Cc1ccsc1-2

Procedure:
Synthesis substrates 4H-indeno[1,2-b]thiophen-4-one and 4H-indeno [1,2-b]thiophene can be prepared according to a general process of MacDowell and Jefferies, J. Org. Chem., 35, 871 (1970). In this process the 4-one substrate is prepared by the Ullmann coupling of ortho-iodo or ortho-bromo, di, tri and tetrasubstituted benzoic acid lower alkyl esters, such as 3-fluoro-2-iodo-benzoic acid ethyl or methyl ester (Chem. Abst.; 27:1339/G) or 2-bromo-4-fluoro-benzoic acid methyl ester (Chem. Abst. 99(1):5630j) or 2-bromo-5-chlorobenzoic acid methyl ester (J. Med. Chem., 13, 567-8 (1970)) with 2-iodo or 2-bromothiophene (Aldrich Chemical, Inc.). Saponification of the coupled product will yield the corresponding substituted 2-(2'-thienyl) benzoic acid (e.g., 5-chloro-2-(2'-thienyl)benzoic acid from 2-bromo-5-chloro-benzoic acid methyl ester. Cyclization of the acid is performed via the aroyl halide using stannic chloride or aluminum chloride to yield to substituted 4H-indeno[ 1,2-b]thiophen-4-one (B-1) (e.g., 6-chloro-4H-indeno[1,2-b]thiophen-4-one). This 4-one derivative is converted (in accordance with Method I) into a hydantoin derivative such as spiro-(6-chloro-4H-indeno[1,2-b]thiophen-4,4'-imidazolidine)-2',5'-dione. See Example XIII for the preparation of spiro-(4H-indeno[1,2]thiophen-4,4'-imidazolidine)-2',5'-dione. The Wolff-Kishner reduction (Method VIII) of B-1) yields the corresponding 4H-indeno[1,2-b]thiophene. Product isolation is best accomplished by fractional distillation, but may involve other separation methods as are known in the art. The resulting substituted or unsubstituted 4H-indeno[1,2-b]thiophene (which may be further derivatized according to Method V) is metalated by n-butyllithium and carbonated in the methylene bridge to yield the corresponding 4-carboxylic acid which after esterification at reflux with a lower alkyl alcohol such as methanol under acid catalyzed conditions such as concentrated hydrochloride acid yields the corresponding substituted or unsubstituted 4H-indeno[1,2-b]thiophen-4-carboxylic acid lower alkyl ester, e.g., 6-chloro-4H-indeno[1,2-b]thiophen-4-carboxylic acid methyl ester. The ester is utilized according to Methods II, III and IV to yield the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide such as spiro-(6-chloro-4H-indeno[1,2-b]thiophen-4,5'-thiazolidine]-2',4'-dione, spiro-(6-chloro-4H-indeno[1,2-b]thiophen-4,5'-oxazolidine)-2',4'-dione and spiro-(6-chloro-4H-indeno[1,2-b]thiophen-4,3'-succinimide) respectively. The resulting spiro-derivatives may be further derivatized according to Method VI.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[H-].[Na+].[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:35])=[O:34])[CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)CC1
Reaction time: 0.5 h

Procedure:
A stirred solution of tert-butyl 4-[(5-fluoro-1H-indol-3-yl)methyl]-1-piperidinecarboxylate (665 mg, 2.0 mmol) in tetrahydrofuran is treated with NaH (60% in mineral oil, 120 mg, 3.0 mmol) portion-wise, under nitrogen, at room temperature, stirred for 0.5 hr, treated with benzenesulfonyl chloride (0.38 ml, 3.0 mmol), stirred for 18 hr under nitrogen at room temperature, quenched with water and diluted with ethyl acetate. The resultant phases are separated and the organic phase is washed with water and saturated NaCl, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane, 2/8) to afford the title compound as a white solid, 740 mg, mp 155-157° C., identified by NMR and mass spectral analyses.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:5][CH2:4]1.C(O)(=O)C.C(N(C(C)C)C(C)C)C.[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[CH3:42])[CH:37]=O)[CH3:32].C([BH3-])#N.[Na+]>C(O)C>[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[CH3:42])[CH2:37][N:3]1[CH2:4][CH2:5][CH:6]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:7][CH2:8]1)[CH3:32]
Reactant: N#Cc1ccc(NC2CCNCC2)nc1
Reactant: CCOc1cc(C=O)ccc1C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(Nc3ccc(C#N)cn3)CC2)ccc1C
Temperature: 55 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a solution of 6-(piperidin-4-ylamino)-nicotinonitrile dihydrochloride (41.3 mg, 0.15 mmol, 1.0 equiv; intermediate B2) in ethanol (2 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) was added 3-ethoxy-4-methyl-benzaldehyde (29.6 mg, 0.18 mmol, 1.2 equiv; intermediate E10, vide infra) and the mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 20.5 mg (39%) of the title compound. MS (ISP): 350.7 [M+H]+.