Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[O:16]1CCOCC1>O>[NH2:1][C:2]1[C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH2:9])=[O:16]
Reactant: C1COCCO1
Reactant: N#Cc1ccnc(-c2ccccc2)c1N
Solvent: O
Product: NC(=O)c1ccnc(-c2ccccc2)c1N

Procedure:
1 g of 3-amino-2-phenyl-4-pyridinecarbonitrile was heated to reflux for 3.5 hours in 20 ml of water and 10 ml of dioxan in the presence of 4 g of Amberlite lRA-400-OH (basic form). The resin was removed by filtration and the filtrate was evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate (1:19) for the elution and the product was recrystallized from ethyl acetate/petroleum ether to yield 900 mg of 3-amino-2-phenyl-4-pyridinecarboxamide of melting point 163°-164° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([O:13][C:14](=[O:16])[CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Se](=O)=[O:18].O>O1CCOCC1>[CH:1]([C:2]1[C:11]([CH3:12])=[C:10]([O:13][C:14](=[O:16])[CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:18]
Reactant: CC(=O)Oc1c(C)c(C)nc2ccccc12
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Oc1c(C)c(C=O)nc2ccccc12
Yield: 52.3 %

Procedure:
A solution of 4.30 g (20.0 mmols) of 2,3-dimethyl-4-acetoxyquinoline, 2.44 g (22.0 mmols) of selenium dioxide, 8 ml of water and 80 ml 1,4-dioxane was refluxed for 3 hours. The solvent was distilled off under reduced pressure, after which 100 ml of chloroform was added, followed by washing with a saturated sodium hydrogencarbonate aqueous solution and then with water, and drying with sodium sulfate. The solvent was distilled off under reduced pressure and the resultant crude product was purified by silica gel column chromatography (Wako Gel C-200) (solvent: n-hexane : ethyl acetate=10:1) to obtain 2.40 g (yield 52%) of 2-formyl-3-methyl-4-acetoxyquinoline.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=1.[Cl:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:2]2[CH:3]=[CH:4][C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=2)=[CH:14][CH:13]=1
Reactant: CCn1cc(Br)ccc1=O
Reactant: OB(O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1cc(-c2ccc(Cl)nc2)ccc1=O
Temperature: 140 °C
Yield: 54.1 %

Procedure:
A mixture of 5-bromo-1-ethylpyridin-2(1 H)-one (1.9 g, 9.45 mmol), 6-chloropyridin-3-ylboronic acid (1.8 g, 11.46 mmol), Cs2CO3 (9.9 g, 30.37 mmol) and tetrakis(triphenylphosphine)palladium (0) (543 mg, 0.55 mmol) were suspended in dioxane:water (15:1, 20 ml). After degassing, the mixture was heated in a microwave at 140° C. for 30 min. The reaction was then diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness via rotary evaporation. The resulting residue was purified by LCMS to provide the title compound, 5-(6-chloropyridin-3-yl)-1-ethylpyridin-2(1 H)-one (1.2 g, 51% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[S:14][C:13]([NH2:15])=[N:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:9])[CH2:4][CH2:3]1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:11]1[N:12]=[C:13]([NH:15][C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:28])[S:14][C:10]=1[C:8]([CH:5]1[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:9]
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCC(=O)CC2)s1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 56.3 %

Procedure:
Compound 447 (150 mg, 0.517 mmol) was dissolved in DMF (2.5 mL), and isonicotinic acid (191 mg, 1.55 mmol), EDC hydrochloride (298 mg, 1.55 mmol) and 1-hydroxybenzotriazole monohydrate (237 mg, 1.55 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 448 (115 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=O)[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1>CO.CN(C1C=CN=CC=1)C>[CH3:7][O:8][C:9](=[O:10])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:13]=[CH:12][C:5]=1[NH2:6]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: CN(C)c1ccncc1
Solvent: CO
Product: COC(=O)c1cc(Cl)ccc1N
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a suspension of 6-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (10 g, 50.61 mmol) in methanol (200 ml) was added DMAP (615 mg, 5.03 mmol) and the reaction mixture was heated to reflux for 3 h. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was dissolved in EtOAc and washed with 0.1M HCl solution (3×), brine, dried over MgSO4, filtered and concentrated in vacuo to give the desired product (9.25 g, 97%) as a white solid which did not require further purification. 1H NMR (DMSO-d6, 300 MHz): δ 7.64 (d, J=2.5 Hz, 1H), 7.30 (dd, J=2.5 and 9.0 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 6.78 (br s, 2H), 3.79 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[CH3:18]O>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:18])=[O:11]
Reactant: O=C(O)Cc1cc(O)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(O)ccc1O

Procedure:
2,5-Dihydroxyphenylacetic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(2,5-dihydroxyphenyl)acetate.
Reaction SMILES: CON(C)[C:4]([C:6]1([CH3:14])[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8][CH2:7]1)=[O:5].[CH3:16][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH3:13][C:9]1([CH3:12])[O:8][CH2:7][C:6]([C:4](=[O:5])[CH3:16])([CH3:14])[CH2:11][O:10]1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1(C)COC(C)(C)OC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C1(C)COC(C)(C)OC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a mixture of N-methoxy-N,2,2,5-tetramethyl-1,3-dioxane5-carboxylic acid amid (1.07 g, 4.92 mmol) and THF (10 mL) was gradually added 3 mol/L methylmagnesium bromide in THF (2.46 mL, 7.4 mmol) at 0° C. under nitrogen atmosphere, and the resulting mixture was stirred at 0° C. for 4 hours. After the reaction was completed, saturated ammonium chloride aqueous solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulphate, and concentrated in vacuo to give 1-(2,2,5-trimethyl-1,3-dioxane5-yl)ethanone (0.76 g, yield: 90%) as colorless oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[C:7]12([CH2:17][NH:18][C:19]([C:21]3[C:22]4[N:23]([N:27]=[C:28]([CH2:30][CH2:31][C:32]#[N:33])[CH:29]=4)[CH:24]=[CH:25][CH:26]=3)=[O:20])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.O>CS(C)=O>[C:7]12([CH2:17][NH:18][C:19]([C:21]3[C:22]4[N:23]([N:27]=[C:28]([CH2:30][CH2:31][C:32]5[NH:33][N:3]=[N:2][N:1]=5)[CH:29]=4)[CH:24]=[CH:25][CH:26]=3)=[O:20])[CH2:14][CH:13]3[CH2:15][CH:9]([CH2:10][CH:11]([CH2:12]3)[CH2:16]1)[CH2:8]2
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccn2nc(CCc3nnn[nH]3)cc12
Temperature: 130 °C

Procedure:
NaN3 (65 mg, 0.48 mmol) and NH4Cl (26 mg, 0.48 mmol) are added to a solution of 2-(2-cyano-ethyl)-pyrazolo[1,5-a]pyridine-4-carboxylic acid (adamantan-1-ylmethyl)-amide (58 mg, 0.16 mmol) in DMSO at rt. The mixture is heated to 130° C. for 6 h. Additional NaN3 (65 mg, 0.48 mmol) is added, and the mixture is heated for 14 h. The mixture is cooled to rt. H2O is added and pH is adjusted to about 7. The aqueous layer is extracted with EtOAc (3×15 mL), dried over Na2SO4 and the solvent is removed to dryness. The crude product is purified by PTLC (eluted with 2% MeOH in DCM) to give the title compound. 1H NMR (CDCl3): 8.49-8.47 (d, 1H), 7.52-7.50 (d, 1H), 6.79-6.69 (t, 1H), 6.69 (s, 1H), 6.40 (b, 1H), 3.44-3.41 (m, 2H), 3.31-3.29 (m, 2H), 3.20-3.19 (m, 2H), 2.00 (b, 3H), 1.74-1.60 (m, 12H). LC-MS m/z (M+H+): 406.07.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH:11]=[CH:10]2)(=O)C>Cl>[OH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH:11]=[CH:10]2
Reactant: CC(=O)Oc1cccc2ccc(=O)[nH]c12
Agent: Cl
Product: O=c1ccc2cccc(O)c2[nH]1
Temperature: 0 °C
Yield: 70 %

Procedure:
Quinolin-8-ol 1-oxide (20 g, 124 mmol) in acetic anhydride (200 ml) was stirred at 90° C. for 5 hours. Then the reaction mixture was poured into water/ice mixture (1.5 L), and made neutral by addition of conc. aq. NH3. The precipitate formed was collected by filtration and washed with water. The crude product was purified by suspending in propan-2-ol and addition of petroleum ether to give 2-oxo-1,2-dihydroquinolin-8-yl acetate. 2-Oxo-1,2-dihydroquinolin-8-yl acetate was heated in conc. aq. HCl (200 ml) at 90° C. for 4 hours. The reaction mixture was poured into ice-cold water (400 ml), and the precipitate formed was collected by filtration and washed with water. Recrystallization from propan-2-ol/petroleum ether afforded the subtitle compound (14.1 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]2[C:12](=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:19][CH3:20])[C:5](=[O:21])[C:4]=2[CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>N1C=CC=CC=1>[CH3:17][O:16][C:14]1[C:13]2[C:12](=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:19][CH3:20])[C:5](=[O:21])[C:4]=2[CH:3]=[C:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:15]=1
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(N)cc1C2=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1cccc2c1C(=O)c1c(OC)cc(NS(C)(=O)=O)cc1C2=O
Temperature: 90 °C

Procedure:
2-Amino-9,10-dihydro-4,5-dimethoxy-9,10-dioxoanthracene (1.5 g) was dissolved in dry pyridine (30 ml) and freshly distilled methanesulphonyl chloride (0.61 g) slowly added. The mixture was heated to 90° C. for 3 hours under an atmosphere of nitrogen before being allowed to cool to room temperature. The mixture was then poured into water (150 ml), generating a brown precipitate. The solid was collected by filtration and dried in vacuo over silica gel to yield N-(4,5-dimethoxy-9,10-dihydro-9,10-dioxoanthracen-2-yl)methanesulphonamide at 94% purity (HPLC) as brown lustrous crystals. To improve purity, the crystals were dissolved in 2N sodium hydroxide solution, washed with CHCl3, and filtered to remove any remaining solid residue.
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([O:20]CC4C=CC([N+]([O-])=O)=CC=4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1.CO.O.C(O)(=O)C>O1CCCC1.[C].[Pd]>[O:1]1[C:6]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)C1=CSCCO1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C1=CSCCO1
Reaction time: 0.75 h
Yield: 63.4 %

Procedure:
Thus obtained 4-nitrobenzyl 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 3.30 g.) was suspended in a mixture of tetrahydrofuran (150 ml.), methanol (70 ml.), water (10 ml.) and acetic acid (1 ml.). 10% Palladium carbon (2.3 g.) was added to the solution, and subjected to catalytic reduction at room temperature for 45 minutes. After removing the catalyst from the resultant solution by filtration, the filtrate was concentrated in vacuo. Water and a saturated aqueous solution of sodium bicarbonate were added to the residue and adjusted to pH 7.0. After filtration, the filtrate was washed with ethyl acetate (60 ml.) and methylene chloride (20 ml.), and then the organic solvent was removed by introducing nitrogen gas. The solution was adjusted to pH 2.0 with 10% hydrochloric acid under ice cooling. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer, 1.55 g.).
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6][N:5]([C:8](OC(C)(C)C)=O)[CH2:4][CH2:3]1.Cl.ClC1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>Cl.O1CCOCC1>[CH3:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3][CH2:4][N:5]([C:8]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-tert-Butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate (500 mg, 1.84 mmol) obtained in Step 1 was dissolved in 4N hydrochloric acid/1,4-dioxane (4 ml), and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethanol (18.4 ml). 4-Chloropyridine hydrochloride (276 mg, 1.84 mmol) and triethylamine (2.57 ml, 18.4 mmol) were added thereto, and the reaction mixture was stirred at 170° C. overnight in a sealed tube. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate 95:5-10:90) to give the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].ClCCl.[F:10][C:11]1[CH:12]=[C:13]([C@H:19]2[NH:24][C@H:23]([CH:25]([OH:27])[CH3:26])[CH2:22][O:21][CH2:20]2)[CH:14]=[C:15]([F:18])[C:16]=1[F:17].N1C=CC=CC=1>O>[CH3:26][CH:25]1[C@H:23]2[CH2:22][O:21][CH2:20][C@@H:19]([C:13]3[CH:12]=[C:11]([F:10])[C:16]([F:17])=[C:15]([F:18])[CH:14]=3)[N:24]2[C:2](=[O:3])[C:1](=[O:5])[O:27]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(O)[C@@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC1OC(=O)C(=O)N2[C@@H]1COC[C@H]2c1cc(F)c(F)c(F)c1
Reaction time: 1 h

Procedure:
Under ice-cooling, oxalyl chloride (0.27 mL) was added dropwise into a dichloromethane (5 mL) solution containing 1-[(3S,5R)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]ethanol (269 mg) and pyridine (5 mL). Stirring was continued for 30 minutes at the same temperature and for 1 hour at room temperature. Water was added, and the organic layer was partitioned, and the resultant was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the resultant was purified by silica gel column chromatography (heptane/ethyl acetate→ethyl acetate), and the title compound (136 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[S:13])[CH2:6][CH2:5]2.Cl[C:15]1[S:16][C:17]([C@@:20]2([OH:27])[CH2:25][CH2:24][O:23][C@@H:22]([CH3:26])[CH2:21]2)=[CH:18][N:19]=1>>[OH:27][C@:20]1([C:17]2[S:16][C:15]([S:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[S:13])[CH2:6][CH2:5]4)=[N:19][CH:18]=2)[CH2:25][CH2:24][O:23][C@@H:22]([CH3:26])[CH2:21]1
Reactant: CN1C(=S)CCc2cc(S)ccc21
Reactant: C[C@H]1C[C@@](O)(c2cnc(Cl)s2)CCO1
Product: C[C@H]1C[C@@](O)(c2cnc(Sc3ccc4c(c3)CCC(=S)N4C)s2)CCO1
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 3, 6-mercapto-1-methyl-2-thioxo-1,2,3,4-tetrahydroquinoline was reacted with (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran to give (2S,4R)-4-hydroxy-2-methyl-4-[2-(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thiazol-5-yl]tetrahydropyran as a foam (0.365 g, 45%);
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]2[O:6][C:7]3[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=3[C:9]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:32][N:33](C=O)C>>[C:32]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:9]2[C:8]3[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=3[O:6][C:5]3[CH:28]=[CH:29][CH:2]=[CH:3][C:4]=3[N:10]=2)[CH2:16][CH2:15]1)#[N:33]
Reactant: CN(C)C=O
Reactant: Clc1ccc2c(c1)N=C(N1CCN(Cc3ccccc3)CC1)c1ccccc1O2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1ccccc1CN1CCN(C2=Nc3ccccc3Oc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine (2.79 g, 10.0 mmol) (prepared from 10,11-dihydrodebenz[b,f][1,4]oxazepine-11-one, Aldrich and piperazine, as in example 1) in DMF (25 mL) was added sodium hydride (0.56 g, 60% in oil, 14 mmol) at 0° C. under argon. The mixture was stirred at 0° C. for 10 minutes at room temperature for 20 minutes, and then treated with β-bromo-ο-tolunitrile (2.35 g, 12.0 mmol, Aldrich). The resulting mixture was stirred at room temperature overnight and quenched with saturated ammonium chloride solution (25 mL). The mixture was separated and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography using ethyl acetate:hexane (1:2) as the eluent. The title compound was obtained as a white solid (2.34 g, 59%), m.p. 136°-138° C.; MS 395 (M+ +1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:14](=[O:23])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: COC(=O)CNc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)CN(C(=O)/C=C/c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
(4-Bromophenylamino)acetic acid, methyl ester (8.74 g, 0.036 mol) was treated with cinnamoyl chloride (11.99 g, 0.072 mol) in pyridine (50 mL) in the presence of 4-dimethylaminopyridine (0.489 g, 0.004 mol). The reaction mixture was stirred at room temperature for 2 h. The crude product was purified by flash column chromatography on silica gel, eluting with ethyl acetate/dichloromethane (1:20), to give the title compound as a white crystalline solid (13.13 g, 98%). 1HNMR (300 MHz) (CDCl3) δ 3.67 (3H, s), 4.42 (2H, s), 6.28 (1H, d, J=16 Hz), 7.19 (2H, d), 7.2-7.3 (5H, m), 7.51 (2H, d) and 7.66 (1H, d, J=16Hz).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].O>C1COCC1>[C:29]([O:28][C:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH:34]1[S:14]([C:13]1[C:7]2[O:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:8]=2[CH:10]=[CH:11][C:12]=1[Cl:18])(=[O:16])=[O:15])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCNCC1S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.6 %

Procedure:
The solution of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (10.75 g, 34.9 mmol) in 100 mL of THF was cooled to 0° C., Et3N (3.47 mL, 24.9 mmol) and then Boc-piperazine (5.0 g, 26.8 mmol) were added. The resulting mixture was stirred for 20 h, warming to room temperature. The mixture was poured into water, extracted with EtOAc and washed with another portion of water; organic layers were dried and concentrated. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v), yielded 11.12 g (91%) desired product 1c. LC-MS (m/z) 458.2 (M+H).
Reaction SMILES: [ClH:1].CN1CCCC(C(O)=O)C1.[N:12]1([CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>>[ClH:1].[N:12]1([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)CCCN1CCCCC1
Agent: CN1CCCC(C(=O)O)C1
Agent: Cl
Product: O=C(O)CCCN1CCCCC1

Procedure:
4-Piperidinobutyric acid hydrochloride may be obtained by working according to the method described in Example 4 for the preparation of 1-methyl-3-piperidinecarboxylic acid hydrochloride, but starting with ethyl 4-piperidinobutyrate (19.9 g) and 6N aqueous hydrochloric acid solution (66.5 cc), and by heating for 24 hours under reflux. 4-Piperidinobutyric acid hydrochloride (16.3 g), m.p. 190° C., is thereby obtained.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.[CH:10](=[O:13])[CH2:11][CH3:12].C(O)(=O)C(O)=O>O>[OH:13][CH:10]([C:4]1([CH3:9])[C:5](=[O:8])[C:6]([OH:7])=[C:2]([CH3:1])[O:3]1)[CH2:11][CH3:12]
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: CCC=O
Agent: O=C(O)C(=O)O
Solvent: O
Product: CCC(O)C1(C)OC(C)=C(O)C1=O
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a mixture of 1.0 g of 2,5-dimethyl-4-hydroxy-3-(2H)-furanone, 5 g of propanal and 20 ml of water were added 0.2 g of oxalic acid and the mixture was stirred at room temperature for 25 hours and then extracted three times with chloroform. The chloroform extract was evaporated and the residue purified by column chromatography on polyamide using ether-pentane 10/90 as the eluent. Pure 2-(1-hydroxypropyl)-2,5-dimethyl-4-hydroxy-3-(2H)-furanone was obtained, which was recrystallized from ether-pentane 50/50; solid mass at room temperature.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[NH2:3].[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>CO>[NH2:17][C:16]1[N:2]([C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)[N:3]=[C:14]([C:13]([CH3:20])([CH3:19])[CH3:12])[CH:15]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(N)n(-c2ccc(C#N)cc2)n1
Yield: 82.1 %

Procedure:
A flask was charged with 4-hydrazinylbenzonitrile hydrochloride (0.70 g, 3.8 mmol.), 4,4-dimethyl-3-oxopentanenitrile (0.48 g, 3.8 mmol) and MeOH and the reaction was heated at refluxed overnight. The reaction was cooled, and the solids which formed upon cooling were filtered off and discarded. Additional solids formed upon further standing (product) along with product material in solution. The solution containing, the solids was concentrated to yield 0.75 g of solid product (92%). MS M+1 (241).