Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Br[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[N:6]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=c1[nH]cc(Br)cc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCn1cc(Br)cc(N2CCOCC2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 0.3 M solution of 5-bromo-3-morpholinopyridin-2(1H)-one (1.00 equiv.) in DMF was treated with sodium hydride (1.20 equiv.). The mixture was stirred for 15 min at ambient temperature. Tert-butyl (2-bromoethyl)carbamate (1.20 equiv.) was added. The mixture was stirred at 60° C. for 3 hr. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined organics were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated to give tert-butyl (2-(5-bromo-3-morpholino-2-oxopyridin-1(2H)-yl)ethyl)carbamate. LCMS (m/z) (M+H)=402.1/404.1, Rt=0.78 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](=O)[CH3:8])[CH2:3][CH2:2]1.[CH3:10][C:11]([S@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>O1CCCC1.C(O[Ti](OCC)(OCC)OCC)C>[CH3:10][C:11]([S@:14](/[N:16]=[C:7](/[CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)\[CH3:8])=[O:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)C1CCOCC1
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: C/C(=N\[S@](=O)C(C)(C)C)C1CCOCC1
Yield: 43.8 %

Procedure:
To a solution of 1-(tetrahydro-2H-pyran-4-yl)ethanone (1.9 g, 14.8 mmol) in tetrahydrofuran (30 mL) was added (R)-2-methylpropane-2-sulfinamide (2.15 g, 17.8 mmol) and tetraethoxytitanium (5.06 g, 22.2 mmol) at 25° C. under N2. The reaction was refluxed for 7 hrs. Then the mixture was quenched by water, extracted with ethyl acetate and filtered. The crude product was purified by column chromatography on silica gel eluted with dichloromethane: methanol=200:1 to give (R,E)-2-methyl-N-(1-(tetrahydro-2H-pyran-4-yl)ethylidene)propane-2-sulfinamide (1.5 g, 44.1%) as a yellow oil.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH:12]4[CH2:18][CH2:17][N:15]([CH2:16][C:6]=3[C:5]=2[CH:4]=1)[CH2:14][CH2:13]4.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=1.C1(C=CC(O)=CC=1)O>CS(C)=O>[Br:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=3)[C:7]3[CH:12]4[CH2:13][CH2:14][N:15]([CH2:16][C:6]=3[C:5]=2[CH:4]=1)[CH2:17][CH2:18]4
Reactant: Brc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C=Cc1ccc(Cl)cc1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: CS(C)=O
Product: Clc1ccc(CCn2c3c(c4cc(Br)ccc42)CN2CCC3CC2)cc1
Temperature: 105 °C
Yield: 32.7 %

Procedure:
Sodium dispersion in paraffin (30%; 162 mg, 2.11 mmol; Aldrich) was combined with 9-bromo-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (290 mg, 0.996 mmol; Example 174A) in a 20 mL vial with stir bar and septum cap. Dimethyl sulfoxide (4.0 mL) was added, and the vial was evacuated and purged with nitrogen (10 cycles). The mixture was stirred at room temperature for 30 minutes, and a solution of 4-chlorostyrene (213 mg, 1.54 mmol; Aldrich) and hydroquinone (53 mg, 0.48 mmol; Aldrich) in dimethyl sulfoxide (2 mL) was added. The vial was evacuated and purged with nitrogen (5 cycles) and the mixture was stirred with heating at 105° C. for 110 hours. The mixture was cooled to room temperature, diluted with water (100 mL) and 25% NaOH (2 mL) and extracted with chloroform (3×50 mL). The combined organic phase was concentrated and the residue was purified by flash chromatography (silica, eluted with CHCl3—CH3OH-14.8 M aqueous NH4OH (90:10:1). The product-containing fractions were combined and concentrated under vacuum to provide a residue (140 mg), which was further purified by reverse-phase HPLC [Waters XBridge RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to provide the title compound: 1H NMR (300 MHz, CDCl3) δ 1.60-1.74 (m, 2H), 1.81-1.97 (m, 2H), 2.80-2.88 (m, 1H), 2.97 (t, J=6.8 Hz, 2H), 3.00-3.08 (m, 2H), 3.25 (ddd, J=14.1, 9.0, 5.4 Hz, 2H), 4.20-4.31 (m, 2H), 4.24 (s, 2H), 6.88-6.94 (m, 2H), 7.09 (d, J=7.8 Hz, 1H), 7.21 (d, J=7.1 Hz, 1H), 7.20-7.25 (m, 2H), 7.50 ppm (d, J=1.7 Hz, 1H); MS (DCI) m/z 429/431/433 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[C:7]([CH3:22])[C:8]([C:12]([CH:14]3[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]3=[O:21])=[O:13])=[CH:9][CH:10]=2)[S:5](=[O:24])(=[O:23])[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>C(Cl)Cl>[C:33]1([C:32]([O:20][C:19]2[CH2:18][CH2:17][CH2:16][C:15](=[O:21])[C:14]=2[C:12]([C:8]2[C:7]([CH3:22])=[C:6]3[C:11]([C:2]([CH3:25])([CH3:1])[CH2:3][CH2:4][S:5]3(=[O:24])=[O:23])=[CH:10][CH:9]=2)=[O:13])=[O:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1c(C(=O)C2C(=O)CCCC2=O)ccc2c1S(=O)(=O)CCC2(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(C(=O)C2=C(OC(=O)c3ccccc3)CCCC2=O)ccc2c1S(=O)(=O)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.8 g (2.2 mmol) of 2-(4,4,8-trimethyl-1,1-dioxothiochroman-7-yl)carbonyl-1,3-cyclohexanedione was dissolved in 10 ml of methylene chloride, and 0.17 g (2.2 mmol) of pyridine and 0.31 g (2.2 mmol) of benzoyl chloride was added. The mixture was stirred at room temperature for 2 hours, water was added, and the organic phase was separated off, extracted with 2 N hydrochloric acid and dried. The solvent was subsequently distilled off and the residue was chromatographed over silica gel.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7](C(OC(C)(C)C)=O)[N:6]=1.O.[OH-].[Li+].O1CCCC1.CO>O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][NH:7][N:6]=1
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)nc1OCOC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]nc1OCOC
Temperature: 25 °C
Yield: 76.7 %

Procedure:
A mixture of 4-ethyl 1-tert-butyl 3-(methoxymethoxy)-1H-pyrazole-1,4-dicarboxylate (3.52 g), lithium hydroxide monohydrate (1.47 g), tetrahydrofuran (60 mL), methanol (30 mL) and water (30 mL) was stirred at room temperature for hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-4:1, v/v) to give ethyl 3-(methoxymethoxy)-1H-pyrazole-4-carboxylate as a colorless solid (1.80 g, yield 77%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[CH2:7][N:8]([C:18](=[O:41])[C@@H:19]([NH:23][C:24](OCC1C2CC3C(=CC=CC=3)C=2C=CC=1)=[O:25])[CH:20]([CH3:22])[CH3:21])[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(NCC)C.C(O)(=O)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(Cl)CCl>CC#N.C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[C:1]([O:5][C:6](=[O:42])[CH2:7][N:8]([C:18](=[O:41])[C@@H:19]([NH:23][C:24](=[O:25])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH:20]([CH3:21])[CH3:22])[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1cccc2c1Cc1ccccc1-2)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a solution of compound 722 (500 mg, 0.88 mmol) in CH3CN (6.0 mL) was added diethylamine (455μ, 4.4 mmol) and the reaction allowed to stir for 2 hr. The reaction was concentrated and the residue co-concentrated with toluene (2×) to provide a viscous oil. The residue was dissolved in CH2Cl2 (5 mL) containing DMF (2 mL), treated with benzoic acid (161 mg, 1.32 mmol) followed by EDC (252 mg, 1.32 mmol) and the reaction allowed to stir overnight. The reaction was diluted with EtOAc and washed with H2O. The aqueous layer was re-extracted with EtOAc. The extracts were combined washed with 5% KHSO4, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 10% EtOAc:hexane) provided 240 mg of compound 723. ##STR102##
Reaction SMILES: ClC1C=C(C=CC=1)C(O)=[O:6].[F:11][C:12]1[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[CH2:31][N:32]2[C@@H:36]([CH3:37])[C@@H:35]([C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[O:34][C:33]2=[O:44])=[C:14]([O:45][CH3:46])[CH:13]=1>C(Cl)Cl>[F:11][C:12]1[C:17]([CH:18]([CH3:19])[CH3:20])=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:22]=2[CH2:31][N:32]2[C@@H:36]([CH3:37])[C@@H:35]([C:38]3[CH:43]=[CH:42][N+:41]([O-:6])=[CH:40][CH:39]=3)[O:34][C:33]2=[O:44])=[C:14]([O:45][CH3:46])[CH:13]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccncc2)[C@@H]1C
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc[n+]([O-])cc2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
m-Chlorobenzoic acid (77%, 47.9 mg, 0.214 mmol) was added to a solution of (4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-pyridin-4-yl-1,3-oxazolidin-2-one (53.7, 0.107 mmol) in dry CH2Cl2 (10.8 mL) at 0° C. After 15 min at 0° C., the reaction was stirred at room temperature for 3 h. The reaction was diluted with CH2Cl2 (40 mL) and washed with saturated Na2SO3 (20 mL) and saturated K2CO3 (2×20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford (4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(1-oxidopyridin-4-yl)-1,3-oxazolidin-2-one as an oil. LCMS calc.=519.2; found=519.3 (M+1)+.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11](Cl)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN(C=O)C>O>[CH2:1]([C:8]1[S:12][C:11]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(Cl)sc2Cc2ccccc2)cc1
Reactant: C1COCCN1
Agent: [Li]O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(N3CCOCC3)sc2Cc2ccccc2)cc1
Temperature: 100 °C
Yield: 62.8 %

Procedure:
To 25 ml eggplant-shaped bottle were added 1.00 g (3.17 mmol) 5-benzyl-2-chloro-4-(4-methoxy-phenyl)-thiazole prepared in the step 1, 0.27 g (6.34 mmol) LiOH.H2O, 20 mg KI, 0.55 g (6.34 mmol) morpholine, 5 ml DMF and 0.5 ml water. The mixture was stirred until homogeneous, heated to 100° C., stirred for 20 hours, added 20 ml water, and extracted with ethyl acetate 3×10 ml. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a thick crude product, which was purified under a reduced pressure by silica gel column chromatography eluted with petroleum ether and ethyl acetate at a ratio 4:1-3:1 (V:V) to give a 0.73 g product as a white solid in a yield of 62.9%, mp: 88-89 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.47 (4H, m, 2×CH2), 3.80 (4H, t, J=5.2 Hz, 2×CH2), 3.82 (3H, s, OCH3), 4.12 (2H, s, CH2), 6.92 (2H, d, J=8.40 Hz, ArH), 7.18˜7.32 (5H, m, ArH), 7.53 (2H, d, J=8.40 Hz, ArH); EI-MS m/e (%): 366.1 (M+, 100), 309.1 (23); HREI-MS Calcd. for C21H22N2O2S: 366.1402. found: 366.1404. Anal. Calcd. for C21H22N2O2S: C, 68.83; H, 6.05; N, 7.64. found: C, 68.73; H, 6.26; N, 7.83.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:15])[C@@H:13]([OH:14])[C:11](=[O:12])[O:10][CH2:9]1>C1COCC1>[CH3:7][C:8]([CH3:15])([CH2:9][OH:10])[C@@H:13]([OH:14])[CH2:11][OH:12]
Reactant: CC1(C)COC(=O)[C@@H]1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of lithium aluminium hydride (3.00 g, 79.1 mmol) in dry THF (100 mL) at 0° C. was added a solution of (R)-pantolactone (10.30 g, 79.14 mmol) in THF (100 mL). The mixture was stirred overnight at room temperature and was then heated to reflux for a further 2 h. The mixture was cooled to 0° C. and the reaction was quenched with saturated aqueous Na2SO4 until a white solid precipitated. The solid was filtered off, the filter cake was washed with THF (2×60 mL) and the filtrate was concentrated under reduced pressure to give the title compound as a pure colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([CH2:8][S:9][C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:7])[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:27])C=1.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([O:5][C:6]([CH2:8][S:9]([C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:27])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CSc1nc2cccnc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOC(=O)CS(=O)c1nc2cccnc2s1
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 68.5 %

Procedure:
Dissolved in 50 ml of methylene chloride was 18.5 g of the compound obtained in Example 1, and the solution was cooled down to -10° C. 16.2 g of m-chloroperbenzoic acid (with a 70% purity) was added to the solution, which was in turn stirred at that temperature for 40 minutes. Ethyl acetate (600 ml) was added to the solution, which was then washed once with an aqueous solution of sodium thiosulfate, three times with sodium hydrogencarbonate and once with water, dried over magnesium sulfate, and distilled to remove the solvent. The residue was purified by silica gel column chromatography, and eluting with n-hexane-ethyl acetate (5:3 to 3:1) to obtain the title compound (13.4 g).
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:20])[NH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:21]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:21][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12]([NH:11][C:1]12[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2)=[O:20]
Reactant: O=C(O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.4 %

Procedure:
A mixture of 4-(3-adamantan-1-yl-ureido)butyric acid 822 (0.15 g, 0.54 mmol), K2CO3 (0.09 g, 0.64 mmol), and iodomethane (0.04 mL, 0.59 mmol) in DMF (20 mL) was stirred at room temperature for 20 h. Then the product was extracted with ether (20 mL), and the ether was washed with 1 N NaOH aqueous solution (20 mL) and brine (20 mL), dried over Na2SO4, and evaporated to afford 0.15 g (95%) of 883: 1H NMR (CDCl3) 1.66-1.68 (6H, m), 1.81 (2H, quint, J=6.9 Hz), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.37 (2H, t, J=6.9 Hz), 3.16 (2H, q, J=6.9 Hz), 3.68 (3H, s), 4.09 (1H, s), 4.25 (1H, s); LC-MS (ESI) m/z calcd for C16H26N2O3 [M+H]+ 295.19, found [M+H]+ 295.24; mp 114 C. Anal. (C16H26N2O3) C, H, N.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.Cl.CN(C)CCCN=C=NCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH2:46])[CH:26]=[CH:27][C:28]=1[C:29]1[O:30][C:31]([C:34]2[C:35]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[N:36][O:37][C:38]=2[CH3:39])=[N:32][N:33]=1>ClCCl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:46][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[O:8])[CH:26]=[CH:27][C:28]=1[C:29]1[O:30][C:31]([C:34]2[C:35]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[N:36][O:37][C:38]=2[CH3:39])=[N:32][N:33]=1
Reactant: O=C(O)c1ccsc1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccsc2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reaction time: 72 h
Yield: 50.8 %

Procedure:
To a solution of 3-thiophenecarboxylic acid (162 mg, 1.26 mmol) in dichloromethane (4 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (242 mg, 1.26 mmol). After stirring for 2 min 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (400 mg, 1.15 mmol) was added and stirring was continued for 3 d at ambient temperature. The reaction mixture was extracted with aqueous HCl (1 M, 15 mL) and ethyl acetate (20 mL) and the aqueous layer was extracted with ethyl acetate (20 mL. Drying over sodium sulfate, concentration and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20) afforded the title compound (268 mg, 51%) as a white solid. MS: m/e=459.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8]([NH:14][C:15]([CH3:17])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].[C:18]([N:25]1[C:37]2[CH:36]=[CH:35][C:34]([CH2:38]Br)=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[CH2:12]([O:11][C:9](=[O:10])[C:8]([NH:14][C:15](=[O:16])[CH3:17])([CH2:38][C:34]1[CH:35]=[CH:36][C:37]2[N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH3:13]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)n1c2ccccc2c2cc(CBr)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc2c(c1)c1ccccc1n2C(=O)OC(C)(C)C)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 27.5 %

Procedure:
To a stirred suspension of sodium hydride (100 mg of a 60% dispersion in oil, 2.5 mmol) in THF (10 mL) at about 0° C. under an atmosphere of argon, was added dropwise a solution of acetamido diethyl malonate (241 mg, 1.1 mmol) in THF (1 mL). The stirred reaction mixture was allowed to warm to room temperature over about 30 minutes, cooled to about 0° C. and a solution of N-Boc 3-bromomethylcarbazole (400 mg, 1.1 mmol) in THF (2 mL) was added. The stirred reaction mixture was heated at about 60° C. for about 6 h. The cooled reaction mixture was quenched with brine (10 mL), and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with water (10 mL), dried (MgSO4) and solvent was removed in vacuo. The crude product was purified using column chromatography on silica gel with 1:1 hexane/ethyl acetate as eluant to afford the product (150 mg, 27% yield). ES-MS (M+H)+ 497.3 (calc. 497.2).
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].[O:12]1[CH2:22][CH:13]1[CH2:14][C:15]([O:17]CC(C)C)=O>CO>[CH2:14]1[C:15](=[O:17])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:22][CH:13]1[OH:12]
Reactant: O=C1CNC2(CCCCC2)N1
Reactant: CC(C)COC(=O)CC1CO1
Solvent: CO
Product: NC(=O)CN1CC(O)CC1=O

Procedure:
0.5 g 2,2-dimethyl-4-imidazolidinone ((5); R4 =R5 =CH3) (4.38 mmoles) are heated at 115° C. (external temperature) for 12 h with stirring by a magnetic stirrer, with 0.57 g ethyl 3,4-epoxybutanoate ((4); X=C2H5) (4.38 mmoles). The mixture is cooled, taken up with methanol and filtered. Oxiracetam is obtained, m.p. 167°-70° C.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[N:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22][NH2:23].Cl.CN(C)CCCN=C=NCC>ClCCl>[F:17][C:18]([F:31])([F:32])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH2:22][NH:23][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][N:14]=[CH:15][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:16]
Reactant: Cc1ccccc1-c1cnccc1C(=O)O
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1-c1cnccc1C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 12 h
Yield: 42.4 %

Procedure:
To a solution of 0.28 g (1.17 mol) 3-o-tolyl-isonicotinic acid and 0.34 g (1.40 mmol) 3,5-bis(trifluoromethyl)benzylamine in 10 ml dichloromethane 0.38 ml N-methylmorpholine and 0.27 g (1.40 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added and the mixture stirred for 12 h. The phases were separated, the water phase extracted with three portions of dichloromethane. The combined organic phases were dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 0.26 g (51%) of the title compound as a colorless oil.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[C:9]([Br:16])=[CH:8][C:6]=1[NH2:7])(=[O:4])(=[O:3])[NH2:2].[Cl:17][CH2:18][C:19](Cl)=O>O1CCOCC1>[Cl:17][CH2:18][C:19]1[NH:2][S:1](=[O:3])(=[O:4])[C:5]2[CH:11]=[C:10]([S:12](=[O:14])(=[O:15])[NH2:13])[C:9]([Br:16])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Br)c(S(N)(=O)=O)cc1S(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc2c(cc1Br)N=C(CCl)NS2(=O)=O
Reaction time: 2 h

Procedure:
A mixture of 2,4-disulfamoyl-5-bromoaniline (0.02 mole) and chloroacetyl chloride (0.022 mole) in 75 ml. of dioxane is heated under reflux for about 24 hours and then concentrated to dryness. The residue is dissolved in ethanol and then heated on the steam bath in a mixture of 2.0 g. of potassium or sodium acetate and 50 ml. of water for two hours. The solution is cooled and the product separated by acidification with hydrochloric acid and purified by recrystallization from a mixture of ethanol and water.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C@@H:7]2[CH2:12][C@@H:11]([NH:13]C(=O)C)[CH2:10][CH2:9][N:8]2[C:17](=[O:26])[C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl.CO.N>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][C@@H:11]([NH2:13])[CH2:10][CH2:9][N:8]2[C:17](=[O:26])[C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)=[CH:27][CH:28]=1
Reactant: CC(=O)N[C@H]1CCN(C(=O)c2cc(C)cc(C)c2)[C@H](Cc2ccc(Cl)cc2)C1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C)cc(C(=O)N2CC[C@H](N)C[C@H]2Cc2ccc(Cl)cc2)c1

Procedure:
A suspension of 730 mg (1.83 mmol) of (2R*,4S*)-2-(4-chlorobenzyl)-1-(3,5-dimethylbenzoyl)-N-acetyl-4-piperidinamine in 6N hydrochloric acid is heated at 100°for 16 hours, during which the starting material dissolves. The reaction mixture is basified with 10% strength aqueous sodium carbonate solution and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude title compound is purified by chromatography on silica gel with dichloromethane/methanol/25% strength ammonia solution (90:10:0.1) as mobile phase and is obtained as almost colourless resin. TLC (dichloromethane/methanol/25% strength ammonia solution; 90:10:0.1): Rf =0.26;FD-MS: (M+1)+=357