Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([CH:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)([CH3:12])[CH3:11].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:14]2[CH:13]([C:10]([F:9])([CH3:12])[CH3:11])[CH2:17][O:16][C:15]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(F)C1COC(=O)N1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(F)C1COC(=O)N1c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To the solution of 2,4-dichloropyrimidine (150 mg, 1.006 mmol) and 4-(2-fluoropropan-2-yl)oxazolidin-2-one (148 mg, 1.01 mmol) in DMF (4.5 mL), sodium hydride (60% wt. 89 mg, 2.21 mmol) was added to give a pale yellow mixture. The mixture was stirred at room temperature for 2 hr, diluted with EtOAc and stirred for additional 30 min. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane=0/100 to 80/20] providing 3-(2-chloropyrimidin-4-yl)-4-(2-fluoropropan-2-yl)oxazolidin-2-one (150 mg) as a brown solid. MS m/z 260.1 (M+H)+; Rt-0.72 min. 1H NMR (400 Mhz, CDCl3) δ ppm 8.51 (d, J=5.9 Hz, 1H), 8.17 (d, J=5.9 Hz, 1H), 5.14 (dd, J=17.4, 8.0 Hz, 1H), 4.66 (d, J=9.4 Hz, 1H), 4.43-4.52 (m, 1H), 1.42-1.52 (m, 3H), 1.30-1.40 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[O:8]1[C:9]2[C:4](=[CH:3][C:2]([N:1]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: Nc1ccc2c(c1)CCCO2
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: c1cc2c(cc1N1CCNCC1)CCCO2

Procedure:
A solution of 6-aminochroman from part 2 of this example (0.300 g, 2.013 mmol), bis-(2-choroethyl)amine hydrochloride (0.539 g, 3.020 mmol) and potassium carbonate (0.278 g, 2.013 mmol) in 10 mL chlorobenzene is heated at reflux for 24 h . The dark brown reaction mixture is then partitioned between 3N NaOH and methylene chloride. The organic layer is separated, dried over Mg2SO4, filtered and concentrated. Purification by flash column chromatography (5% methanol-methylene chloride) affords 0.157 g (36%) of 1-(chroman-6-yl)piperazine as a white solid, TLC Rf 0.35 (elution with 10% hanol-methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([CH3:28])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:13][C:12]=3[OH:27])[C:9](=[O:10])[C:4]=2[CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH2:35][CH2:36][F:37])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([CH3:28])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:13][C:12]=3[O:27][CH2:35][CH2:36][F:37])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Cc1nc2cnc(Cl)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cnc(Cl)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1OCCF
Temperature: 80 °C
Reaction time: 10 h
Yield: 76.8 %

Procedure:
6-chloro-3-[2-hydroxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]-pyrimidin -4(3H)-one (10 mg), 2-fluoroethyl tosylate (7.6 mg) and potassium carbonate (16 mg) were mixed in dimethylformamide (2 mL) and stirred at 80° C. for 10 hours. Distilled water was added, the mixture extracted with ethyl acetate, and dried with anhydrous sodium sulfate. The product was purified by silica gel thin layer chromatography (chloroform/methanol=10/1), and the title compound (8.5 mg, 77%) was obtained as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](F)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]([CH:22]1[CH:31]([OH:32])[C:30]2[C:25](=[CH:26][C:27]([C:33](=[N:35]O)[NH2:34])=[CH:28][CH:29]=2)[O:24][CH2:23]1)=[N+:20]=[N-:21].CCN(C(C)C)C(C)C>C(#N)C>[N:19]([CH:22]1[CH:31]([OH:32])[C:30]2[C:25](=[CH:26][C:27]([C:33]3[N:35]=[C:16]([C:10]4[O:9][N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[C:11]=4[C:12]([F:15])([F:14])[F:13])[O:17][N:34]=3)=[CH:28][CH:29]=2)[O:24][CH2:23]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=NC1COc2cc(C(N)=NO)ccc2C1O
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NC1COc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2C1O
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride Int-1-G (273 mg, 1.05 mmol) in ACN (6.7 mL) was added racemic (3R*,4S*,E/Z)-3-azido-N′,4-dihydroxychroman-7-carboximidamide (250 mg, 1.0 mmol) and Hunig's Base (210 μL, 1.2 mmol). The resulting solution was stirred overnight. Next, the solvent was evaporated. The resulting residue was purified by column chromatography (ISCO Combiflash Companion, 12 g silica gel, 10% ethyl acetate-hexane for 5 min then ramp to 50% ethyl acetate-hexane over 7 min then 50% ethyl acetate-hexane for 3 more min, product came out 8-10 min) to give racemic (3R*,4S*)-3-azido-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-4-ol (280 mg, 0.59 mmol, 59.3% yield): LCMS=470.98 [M+H]+, 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (1H, dd, J=8.03, 1.65 Hz), 7.66-7.72 (3H, m), 7.52-7.62 (4H, m), 4.96-5.02 (1H, m), 4.43-4.51 (1H, m), 4.32-4.38 (1H, m), 4.08-4.17 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.Cl[CH2:10][CH:11]=O.Cl.C(OCC)(=O)C>O>[F:8][C:4]1[N:3]2[CH:10]=[CH:11][N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=1
Reactant: O=CCCl
Reactant: Nc1cccc(F)n1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cccc2nccn12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-Amino-6-fluoropyridine (12 g) was completely dissolved in 120 mL of distilled water at 60° C. To the solution was added 35 mL (2 equivalents) of 40% chloroacetaldehyde. The mixture was stirred for 3 hours at 60° C. The reaction mixture was gradually cooled to room temperature, to which were added a 1N—HCl aqueous solution (50 mL) and ethyl acetate (150 mL). The ethyl acetate solution was subjected to extraction with a 1N—HCl aqueous solution (100 mL). The extract was mixed with the aqueous solution. To this aqueous solution was added NaHCO3 for neutralization (pH 0.35-7.30). To the neutralized aqueous solution was added a mixture of ethyl acetate and THF (4:1) (150 mL×3) to extract the product. The extract solutions were combined and dried over anhydrous magnesium sulfate, which was concentrated under reduced pressure to afford 5-fluoroimidazo[1,2-a]pyridine as a black liquid product (9.5 g, yield 65%).
Reaction SMILES: [O:1]=[C:2]([C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[NH2:5])[OH:3].CO.[F:17][C:18]([F:24])([F:23])[C:19](OC)=[O:20]>O>[F:17][C:18]([F:24])([F:23])[C:19]([NH:5][C@@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[C:2]([OH:3])=[O:1])=[O:20]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: COC(=O)C(F)(F)F
Solvent: O
Solvent: CO
Product: O=C(O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)C(F)(F)F
Reaction time: 0.17 h

Procedure:
1.97 g L-DOPA (10 mmol) and 5 ml of dry methanol was added into an oven-dried 25 ml round-bottomed flask equipped with a Teflon stirring bar and rubber septum and purged with dry argon. Then, 1.3 ml of TMG (10 mmol) and 1.4 ml of methyl trifluoroacetate (12.5 mmol) was added. The mixture was stirred vigorously at room temperature until DOPA had completely dissolved (after about 24 hr). At this point, the flask was immersed in cold water (0° C.) and 5 ml of methanol and 4 g Dowex 50 resin (H+ form) were added. The mixture was filtered after stirring for 10 min. The filtrate was evaporated under reduced pressure. The crude product was re-crystallized from ethyl acetate and the yield of N-trifluoroacetyl-L-DOPA was 78%. See Curphey, T. J. Trifluoroacetylation of amino acids and peptides by ethyl trifluoroacetate. J. Org. Chem. 1979, 44, 2805-2807; Lapidot, Y.; Rappoport, S.; Wolman, Y. Use of ester of N-hydroxysuccinimide in the synthesis of N-acrylamino acids. J. Lipid Research 1967, 8, 142-145.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:1]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:14])[CH:7]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a mixture of 2-Amino-4-methylpyridine (21.6 g, 0.2 mol) and phthalic anhydride (29.6 g, 0.2 mol) in toluene (160 ml), was added triethylamine (2.8 ml, 0.02 mol). The mixture was refluxed for 5 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was suspended in acetic anhydride (250 ml). The mixture was then heated to reflux for 4 hr until the solid dissolves completely. After cooling to room temperature, white precipitate was collected by filtration and washed with acetic anhydride and hexane, and dried in high vacuo to give 26.6 g (56%) of 2-(4-methyl-pyridin-2-yl)-isoindole-1,3-dione as a white solid. 1H NMR (200 MHz, CDCl3) δ 2.45 (3H, s), 7.18 (1H, d, J=5.0 Hz), 7.25 (1H, s), 7.76-7.99 (4H, m), 8.53 (1H, d, J=5.0 Hz). m/z (EI) 238 (M+).
Reaction SMILES: [CH:1]1([CH2:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:25])=[O:24])=[CH:19][CH:18]=2)([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])[CH2:4][CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:27].[K+]>CO.O>[CH:1]1([CH2:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:25])(=[O:27])=[O:24])=[CH:19][CH:18]=2)([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])[CH2:4][CH2:3][CH2:2]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CS(=O)c1ccc(C(O)(CC2CCC2)c2cc3cccnc3[nH]2)cc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(O)(CC2CCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To a solution of 2-cyclobutyl-1-(4-methanesulfinyl-phenyl)-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanol (94.2 mg, 0.266 mmol) in methanol (10 mL) at 0° C. was added a solution of potassium permanganate (42.0 mg, 0.266 mmol) in water (5 mL) dropwise. The mixture was stirred for 2 h at 0° C., extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered through a short silical gel pad (QingDao silica gel, 200-300 mesh), and concentrated in vacuo. The residue was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-cyclobutyl-1-(4-methanesulfonyl-phenyl)-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanol (32.2 mg, 33%): LC/MS m/e calcd for C20H22N2O3S [M+H]+ 371.47, observed 371.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.49 (m, 1H), 1.57-1.83 (m, 4H), 1.95 (m, 1H), 2.52 (m, 3H), 3.10 (s, 3H), 6.53 (s, 1H), 7.07 (dd, J=4.9, 7.8 Hz, 1H), 7.79 (d, J=8.7 Hz, 2H), 7.90 (d, J=8.7 Hz, 2H), 7.95 (dd, J=1.5 Hz, J=7.8 Hz, 1H), 7.95 (dd, J=1.5 Hz, J=4.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](Cl)=[O:9])=[CH:4][CH:3]=1.ClCCl.[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)C=Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc(Cl)cc2)cc1
Reaction time: 0.5 h

Procedure:
The 21.8 g. of p-chlorocinnamoyl chloride is dissolved in 250 ml. of dichloromethane. To this is added, with stirring, a solution of 35.7 g. of ethyl 4-aminobenzoate in 250 ml. of dichlormethane. The mixture is stirred overnight, then 300 ml. of water are added, stirring is continued for 30 minutes, and the solid is collected by filtration and dried. This solid is boiled in 600 ml. of ethanol and 100 ml. of chloroform, filtered, and the volume reduced to 450 ml., giving a solid, 15.0 g. of which is recrystallized from a mixture of 800 ml. of ethanol and 250 ml. of chloroform by boiling to a volume of 250 ml., giving 13.57 g. of the desired product as off-white crystals, m.p. 203°-204° C.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH:10]1[CH2:11][CH:12]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:13]2)(C(C)(C)C)(C)C.Cl>CO.O>[OH:8][CH:9]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH:10]1[CH2:11][CH:12]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:13]2
Reactant: COC(=O)CC1CC2CC(O[Si](C)(C)C(C)(C)C)C(C1)N2C(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)CC1CC2CC(O)C(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
crude 109e was dissolved in MeOH (400 mL), 12 N HCl (40 mL, 3.0 eq) was added and then stirred at room temperature for 30 min. The mixture was diluted with water (800 mL), and extracted two times with EA (500 mL). The organic layers were combined, dried over Na2SO4 and concentrated, the residue was purified by silica gel (EA/PE=1:3) to give benzyl 6-hydroxy-3-(2-methoxy-2-oxo-ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 109f as a colorless oil, 30 g, yield for two steps, 70%. 1H NMR (400 MHz, DMSO-d6) δ: 7.43-7.26 (m, 5H), 5.09 (s, 2H), 4.90 (dd, J=3.6, 6.8 Hz, 1H), 4.23 (d, J=6.4 Hz, 1H), 4.16-4.09 (m, 1H), 4.12-3.92 (m, 1H), 3.59 (s, 3H), 2.38 (d, J=7.2 Hz, 2H), 2.14-1.93 (m, 5H), 1.72 (br, 1H); MS: calc'd (MH+) 334, measured (MH+) 334.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[OH:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[OH:25])=[C:11]([C:40]3[CH2:41][CH2:42][O:37][CH2:38][CH:39]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)c1nc2c(c(I)c1[C@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (R)—((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(4-tert-butylphenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[CH3:23].O>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH3:23])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
1-Acetyl-4-hydroxypiperidine (9.2 g) was dissolved in dimethylformamide (20 ml) and to the solution was added sodium hydride (oily, 60%, 2.6 g). The mixture was stirred at room temperature for 30 minutes, followed by adding dropwise 2-fluoro-5-nitrotoluene (10 g). The mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added water (50 ml) which was extracted with methylene chloride (50 ml×3). The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (developing solvent: methylene chloride/methanol=20/1 (v/v)) to obtain 1-acetyl-4-(4-nitro-2-methylphenyloxy)piperidine (12.6 g) as yellow crystals, m.p. 139°-141° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:19])=[C:6]([CH:15]=[CH:16][C:17]=1[F:18])[O:7][CH2:8][CH:9]=[CH:10][C:11]([O:13]C)=[O:12])=[O:3].[OH-].[Na+].Cl>C(O)(C)C.O>[NH2:1][C:2]([C:4]1[C:5]([F:19])=[C:6]([CH:15]=[CH:16][C:17]=1[F:18])[O:7][CH2:8][CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[O:3]
Reactant: COC(=O)C=CCOc1ccc(F)c(C(N)=O)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: NC(=O)c1c(F)ccc(OCC=CC(=O)O)c1F
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of methyl 4-[3-(aminocarbonyl)-2,4-difluorophenoxy]-2-butenoate (1.25 g, 4.61 mmol, 1 equiv.) and NaOH (0.75 g, 18.44 mmol, 4 equiv.) in isopropanol (10 ml) and H2O (20 ml) was heated under reflux for 1 h. After cooling to r.t., the mixture was acidified with conc. HCl to pH 1. The white precipitant solid was filtered and washed with Et2O (50 ml), to give 568 mg, 48% yield, mp 187-188° C., HPLC-MS (method 1): m/z 258 [M+H]+, Rt=0.98 min. By 1H-NMR analysis it was determined to be a mixture of isomeres in a ratio (3:2) E:Z.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6](Cl)[N:5]=[C:4]([CH3:14])[N:3]=1.C(C1C=C(O)C=CC=1)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH3:31][NH:32][CH3:33]>CN(C)C=O.O>[CH3:31][N:32]([CH3:33])[N:5]1[CH:6]=[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:2]=[N:3][CH:4]1[CH3:14]
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1Cl
Reactant: CNC
Agent: CC(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC1=CN(N(C)C)C(C)N=C1
Reaction time: 16 h

Procedure:
Methyl 4,6-dichloro-2-methyl-pyrimidin-5-yl-acetate (23.5 g, 0.1 mol), 3-isopropylphenol (13.6 g, 0.1 mol) and potassium carbonate (20.7 g, 0.15 mol) are heated in dimethylformamide (30 ml) at 100° C. for 45 minutes. The mixture is cooled and an aqueous solution of dimethylamine (50 ml of a 40% solution) is added. Stirring is continued for 16 hours at room temperature. Addition of water, filtering and drying gives the methyl 1-dimethylamino-2-methyl-pyrimidin-5-yl-acetate as a brownish solid (28 g).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C(N(CC)CC)C>[CH3:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH2:27][C:28]([O:22][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:29]
Reactant: Cc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CC(C)CCCC(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)CCCC(C)C)nc2n1
Yield: 74.2 %

Procedure:
The procedure is as in example 7, but starting with 2-(7-methyl-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (3.7 g), 5-methylhexanoyl chloride (7.8 g), triethylamine (12 cc) and 4-diemthylaminopyridine (50 mg). After the solid obtained after treatment has been recrystallized in methylcyclohexane, 2-(7-methyl-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (3.8 g), m.p. 144° C., is obtained.
Reaction SMILES: O(C([N:10]1[CH2:15][CH2:14][C:13]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:16]2)[CH2:12][CH2:11]1)=O)C1C=CC=CC=1.[OH-].[K+]>C(O)CO.O>[C:24]1([CH:17]2[S:16][C:13]3([CH2:12][CH2:11][NH:10][CH2:15][CH2:14]3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=3)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1ccccc1)c1ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: c1ccc(C2SC3(CCNCC3)c3ccccc32)cc1
Temperature: 155 °C

Procedure:
A mixture of 3.0 g of 1,3-dihydro-1'-phenoxycarbonyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine], Example 3, 8.0 g of potassium hydroxide pellets in 50 ml of ethylene glycol is stirred at 155° C. until a clear solution results. The solution is permitted to cool, diluted with water and the biphasic mixture extracted thrice with chloroform. The combined chloroform extracts are washed carefully with water and dried and the chloroform removed leaving a solid residue. The residue is recrystallized from an acetone-hexane to give prisms, mp 142°-144° C. of 1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: [CH2:1]([F:12])[O:2][CH:3]([C:8](F)([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].C(OCC)OCC>>[F:5][C:4]([F:6])([F:7])[C:3]([O:2][CH2:1][F:12])=[C:8]([F:9])[F:10]
Reactant: FCOC(C(F)(F)F)C(F)(F)F
Solvent: CCOCOCC
Product: FCOC(=C(F)F)C(F)(F)F

Procedure:
In a reaction similar to Example 1a, about 30.0 grams of sevoflurane (0.15 mols) was placed in a 250-mL 3-neck flask under nitrogen, and cooled in a dry ice-acetone bath to about −0.1° C. Approximately 50 mL of a 3.0 M solution of CH3Li/CH2(OC2H5)2 (0.15 mols of the base) was added to the sevoflurane over about 2 hours and 38 minutes while maintaining a reaction temperature between about −8° C. and about +9° C. A violent, exothermic reaction was observed. The reaction mixture was then stirred at about −2° C. to about +6° C. for an additional 30 minutes. A vacuum (3.3 mm Hg) applied to the reaction mixture for approximately 2 hours, 17 minutes while the reaction mixture was held at a temperature between about −30° C. and about −17° C. yielded about 17.9 grams of a crude liquid product. The crude liquid contained 17.9% sevoflurane compound A, 70.6% CH2(OC2H5)2, and other side products.
Reaction SMILES: [CH2:1]([S:9](Cl)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:13][C:14]1[C:19]2[CH:20]=[C:21]([CH2:23][CH:24]([NH:34]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]3)=[O:26])[S:22][C:18]=2[CH:17]=[CH:16][N:15]=1>>[NH2:13][C:14]1[C:19]2[CH:20]=[C:21]([CH2:23][CH:24]([NH:34][S:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:11])=[O:10])[C:25]([N:27]3[CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH2:32]3)=[O:26])[S:22][C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: CCCCCCCCS(=O)(=O)Cl
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Product: CCCCCCCCS(=O)(=O)NC(Cc1cc2c(N)nccc2s1)C(=O)N1CCC(C)CC1

Procedure:
This compound was prepared from 0.15 mL of octane sulfonyl chloride and 210 mg of 30a using the procedure described for 58c. Yield: 150 mg; m.p. 101-112° C., (+)-FAB-MS: 495 (MH+).
Reaction SMILES: [NH2:1][OH:2].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]=[C:12]=[O:13]>O.C1(C)C=CC=CC=1>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[C:5]=1[NH:11][C:12]([NH:1][OH:2])=[O:13]
Reactant: NO
Reactant: Cc1cccc(C)c1N=C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1NC(=O)NO
Reaction time: 18 h
Yield: 97.1 %

Procedure:
A 500 mL side arm flask equipped with a thermometer and an addition funnel with a nitrogen inlet was charged with 100 mL of toluene and 2.00 g (0.10 mol) of 50% hydroxylamine in water. A solution of 4.41 g of 2,6-dimethylphenyl isocyanate (0.03 mol) dissolved in 50 mL of toluene was added dropwise over 15 min. External cooling was used to maintain the, internal reaction temperature below 25° C. Stirring was continued at room temp for 18 h. The solvent was removed under reduced pressure to give a white solid. The residual solvent was further co-evaporated twice with toluene, then oven dried overnight to give the desired product (5.25 g) as a white solid melting at 192-193° C.