Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17][C:18](=[O:28])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1C(=O)CCC1.O>[CH2:1]([O:17][C:18](=[O:28])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC(=O)C=Cc1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCCCCCOC(=O)C=Cc1ccc(OCCCCCCO)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
3-(4-Hydroxy-phenyl)-acrylic acid hexadecyl ester (4.8 g, 12.4 mmol) was dissolved in 100 ml of NMP. To this was added 6-chlorohexanol (2.19 g, 16 mmol), anhydrous potassium carbonate (1.7 g, 12 mmol) and a catalytic amount of potassium iodide. The reaction was stirred at 90° C. for 18 hours. Water was added to the cooled solution, which was subsequently extracted with 3×100 mls of ethyl acetate. The combined organics were washed with water (2×100 mls), water/brine (100 ml, 50:50) and brine solution and then dried over magnesium sulfate. The concentrated product was purified by silica gel chromatography eluting with 25% ethyl acetate in hexane to give 2.6 g white solid.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[C:17]3[CH:18]=[CH:19][C:20]([CH:22]=C)=[CH:21][C:16]=3[O:15][N:14]=2)[CH2:8]1.CSC>ClCCl>[CH3:4][O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[C:17]3[CH:18]=[CH:19][C:20]([CH:22]=[O:1])=[CH:21][C:16]=3[O:15][N:14]=2)[CH2:8]1
Reactant: C=Cc1ccc2c(N3C[C@H](COC)OC3=O)noc2c1
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: COC[C@H]1CN(c2noc3cc(C=O)ccc23)C(=O)O1
Reaction time: 3 h

Procedure:
A stream of ozone at -40° C. is passed for 2 hours into a solution of 8.0 g (0.029 mol) of (R)-5-(methoxymethyl)-3-(6-ethenyl-1,2-benzisoxazol-3-yl)oxazolidin-2-one in 210 ml of dichloromethane, then the ozone is driven off with a stream of argon, and 10.7 ml (0.15 mol) of dimethyl sulphide are added. The mixture is stirred for 3 hours while allowing the temperature to return to ambient temperature, and then the solvent is evaporated off under reduced pressure. By chromatography of the residue on a silica column with a mixture of 30% ethyl acetate in cyclohexane, 5.0 g of product are obtained.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:12]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([NH2:22])[CH:13]=1>>[F:1][C:2]1[C:7]([C:12]2[N:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[N:15]=[C:14]([NH2:22])[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)nc(C(F)(F)F)n1
Reactant: OB(O)c1cccnc1F
Product: Nc1cc(-c2cccnc2F)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in an analogous manner to that described above in Example 4 using 2-fluoropyridin-3-ylboronic acid and 6-chloro-2-(trifluoromethyl)pyrimidin-4-amine (SynChem Inc., Elk Grove Village, Ill.), and the desired product 6-(2-fluoropyridin-3-yl)-2-(trifluoromethyl)pyrimidin-4-amine was isolated as a white solid (34%). LCMS (API-ES) m/z 259 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 8.57 (t, J=8.80 Hz, 1H) 8.38 (d, J=3.91 Hz, 1H) 7.83 (br. s., 2H) 7.46-7.63 (m, 1H) 7.15 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=3)[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:41])([F:40])[F:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42]=O>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([N:25]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[CH3:42])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:39])([F:40])[F:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: COC(=O)Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Product: COC(=O)Cc1ccc(CN(C)c2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from methyl {4-[({3-[3-benzoyl-8-(trifluoromethyl) quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate and formaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 569; HRMS: calcd for C34H27F3N2O3, 568.1974; found (ESI, [M+H]+), 569.2039; Anal. Calcd for C34H27F3N2O3: C, 71.82; H, 4.79; N, 4.93. Found: C, 71.57; H, 4.64; N, 4.87.
Reaction SMILES: [C:1]([CH:4]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)[C:5]([OH:7])=[O:6])([OH:3])=O.S(Cl)(Cl)=O.[C:21]([O:24][CH2:25][C:26]1[CH2:33][S:32][CH:31]2[N:28]([C:29](=[O:35])[CH:30]2[NH2:34])[C:27]=1[C:36]([OH:38])=[O:37])(=[O:23])[CH3:22].C(N(CC)CC)C.Cl>CN(C)C=O.C(OCC)(=O)C.CCOCC.O>[C:21]([O:24][CH2:25][C:26]1[CH2:33][S:32][CH:31]2[N:28]([C:29](=[O:35])[CH:30]2[NH:34][C:1](=[O:3])[CH:4]([C:5]([OH:7])=[O:6])[C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH2:14][CH2:13][C:12]=3[CH:16]=2)[C:27]=1[C:36]([OH:38])=[O:37])(=[O:23])[CH3:22]
Reactant: O=C(O)C(C(=O)O)c1ccc2c(c1)CCO2
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)O)c3ccc4c(c3)CCO4)C2SC1
Temperature: 0 °C

Procedure:
α-Carboxy-(2,3-dihydro-5-benzofuranyl)acetic acid (14 mmole) is added to 50 ml of ether. Thionyl chloride (14.5 mmole) is added along with 1 drop of dimethylformamide. This mixture is refluxed about 3 hours and then evaporated under reduced pressure at room temperature. The residue is added to 50 ml of ether which is added to an ice-cold mixture of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (14 mmole), 30 ml of water 15 ml of ether, 14 mmole of triethylamine. After 30 minutes the pH is adjusted to 1.5 with dilute hydrochloric acid and the layers separated. The ether is extracted with water. Evaporation of the ether gives a residue which is taken up in ethyl acetate, dried, filtered and evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)[CH2:22][C:23]1[CH:32]=C2C(C=CC=C2)=C[CH:24]=1.CC(C)=O>CCCCCC>[CH:22]([O:13][C:3]1[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[Br:1])=[C:23]([CH3:32])[CH3:24]
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1O
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(C)=COc1c(Br)cc(Br)cc1C(C)(C)C
Temperature: 23 °C
Reaction time: 56 h

Procedure:
In a 3000 mL 3-neck flask, equipped with Ar inlet and magnetic stirrer, is placed 2,4-dibromo-6-tert-butylphenol (70.0 g, 226 mmol), K2CO3 (37.6 g, 276 mmol, 1.2 eq), Nal (3.38 g, 22.6 mmol, 0.1 eq), p-methallyl chloride (33.9 mL, 339 mmol, 1.5 eq), and acetone (1500 mL). The reaction mixture is vigorously stirred at 23° C. for 56 hrs, and monitored by TLC analysis (pet. ether). The solids are removed by filtration, washed with acetone, and the filtrates rotoevaporated (bath temperature kept below 35° C.) to give an oil. The oil is dissolved in hexane (100 mL), and stirred with silica gel (80 g). The slurry is filtered through a pad of Celite, and eluted with additional hexane (6×100 mL). The filtrate is evaporated to give 2,4-dibromo-6-tert-butylphenyl isobutenyl ether as a yellow oil. The material is stored in the freezer and is used as soon as possible.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]([O:24]CC)=O)=[O:19])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1.CO>[C:3]1([C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:19])[O:20][CH2:21][C:22]([NH:2][CH3:1])=[O:24])=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)NCCc1ccc(-c2ccccc2)nc1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COC(=O)NCCc1ccc(-c2ccccc2)nc1
Reaction time: 4 h

Procedure:
4.6 ml (9.17 mmol) of a solution of methylamine (2M) in tetrahydrofuran are added to a solution of 1.0 g (3.06 mmol) of ethyl ({[2-(6-phenylpyrid-3-yl)ethyl]amino}carbonyl)-oxyacetate, obtained in stage 1.3., in 6 ml of methanol. Stirring is continued at ambient temperature for 4 hours.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:18]([O:17][C:15]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCCN[C@H]1c1ccccc1)OCc1ccccc1
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a solution of (2S,3S)-(−)-3-amino-2-phenylpiperidine (152 mg, 0.86 mmole) (L-tartaric acid salt, [a]D=−57.1 (EtOH, c=0.1138)) in methylene chloride (10 mL) at room temperature was added benzyl chloroformate (0.123 mL, 0.86 mmole) and diisopropylethylamine (0.45 mL, 2.58 mmole). The reaction was stirred for 16 hours and was then diluted with methylene chloride and quenched by addition of water. The mixture was separated and the aqueous was reextracted with 2 additional aliquots of methylene chloride. The organic layers were successively washed with a portion of brine, dried over sodium sulfate, combined and evaporated. The residue was purified by flash chromatography (5% methanol in methylene chloride) to afford 214 mg (80%) of the title compound. NMR (CDCl3): δ 1.55 (br, d, J=9 Hz, 1 H), 1.6-1.9 (m, 2 H), 2.02 (br. d, J=9 Hz, 1 H), 2.79 (dd, J=9 and 10 Hz, 1 H), 3.22 (dd, J=1 and 10 Hz, 1 H), 3.91 (br. s, 1 H), 4.01 (dd, J=1 and 8 Hz, 1 H), 4.89 (s, 2 H), 5.65 and 5.88 (2 br. s, 1 H), 7.1-7.4 (m, 10 H).
Reaction SMILES: CO.[CH3:3][C:4]1[C:12]([C:13]([O:15]CC)=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1>[OH-].[Na+]>[CH3:3][C:4]1[C:12]([C:13]([OH:15])=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: CCOC(=O)c1c(C)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn2ccccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.1 %

Procedure:
A small amount of methanol was added to a solution of 0.356 g of ethyl 2-methyl-3-pyrazolo[1,5-a]-pyridinecarboxylate in 10 ml of 5N aq. NaOH solution, followed by stirring at room temperature for 24 hours. The reaction mixture was washed with benzene and then made acidic with concentrated hydrochloric acid. Crystals precipitated were collected by suction filtration. The crystals so obtained were dried and then recrystallized from benzene, whereby 0.16 g of the title compound was obtained (yield: 52.4%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([CH3:3])=[CH2:2]>O1CCCC1.[OH-].[OH-].[Pd+2]>[CH:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cnc2[nH]ccc2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1cnc2[nH]ccc2c1
Reaction time: 0.5 h

Procedure:
To 5-isopropenyl-1H-pyrrolo[2,3-b]pyridine (98, 0.080 g, 0.501 mmol) in tetrahydrofuran (5.0 mL) was added 20% palladium hydroxide on carbon (5.0 mg). The reaction was stirred under hydrogen at 40 psi for 30 minutes. The reaction mixture was filtered and concentrated to give the compound (99, 0.078 g, 96%). MS (ESI) [M+H+]+=161.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:7][CH2:6][N:5]1C(OC(C)(C)C)=O)[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:3][CH:2]([C@@H:4]1[NH:5][CH2:6][CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:9]1)[CH3:1]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)[C@@H](C(C)C)C2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCN[C@@H](C(C)C)C2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 100 %

Procedure:
1,1-Dimethylethyl (2S)-2-(1-methylethyl)-4-[3-(methyloxy)-4-nitrophenyl]-1-piperazinecarboxylate (0.482 g, 1.27 mmol) was dissolved in 20 mL of DCM with stirring. TFA (4.0 mL, 52 mmol) was added, and the reaction was stirred for 4 h. The reaction was cooled to 0° C. and slowly quenched with 40 mL of 3N NaOH (aq.). The mixture was poured into H2O and DCM, and the layers were separated. The aqueous layer was washed with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound of step E (0.356 g, 1.27 mmol, 100%). 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J=9.5 Hz, 1H), 6.57 (dd, J=9.5, 2.6 Hz, 1H), 6.46 (d, J=2.6 Hz, 1H), 3.88 (s, 3H), 3.77-3.86 (m, 2H), 2.93-3.02 (m, 1H), 2.82 (td, J=11.9, 3.3 Hz, 1H), 2.54-2.71 (m, 2H), 2.29-2.39 (m, 1H), 2.22 (br. s., 1H), 1.55-1.67 (m, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC.O.[Br:24][CH2:25][CH2:26]Br>>[Br:24][CH2:25][CH2:26][O:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9]
Reactant: BrCCBr
Reactant: CC(=O)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)c1cc(F)ccc1OCCBr
Reaction time: 8 h
Yield: 21.9 %

Procedure:
Dissolved 1-(5-fluoro-2-hydroxyphenyl)ethanone (10.0 g, 64.9 mmol) in 18 mL 1,2-Dibromoethane and added Potassium carbonate (18.8 g, 136 mmol) and 100 mL 2-Butanone. Heated the reaction mixture to reflux and allowed to stir overnight under nitrogen. Reaction was complete by LCMS. Diluted reaction mixture with water and extracted the product with ethyl acetate. Concentrated in vacuo and purified by flash chromatography (0 to 30% ethyl acetate/heptanes) to give 3.71 g (21.9% yield) of 1-(2-(2-bromoethoxy)-5-fluorophenyl)ethanone.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:25])[C@H:14]([CH2:15][S:16]2)[C@:13]2([CH3:22])[C@H:8]([C:9]([CH3:24])([CH3:23])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.B(Br)(Br)Br>C(Cl)Cl>[CH3:25][C@@:5]12[CH2:6][CH2:7][C@@H:8]3[C@:13]([CH3:22])([CH2:12][CH2:11][CH2:10][C:9]3([CH3:23])[CH3:24])[C@H:14]1[CH2:15][S:16][C:17]1[C:4]2=[C:3]([OH:2])[CH:20]=[C:19]([CH3:21])[CH:18]=1
Reactant: COc1cc(C)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,10R,11S,16S)-3-methoxy-1,5,11,15,15-pentamethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 14) (1.16 g, 3.23 mmol) in CH2Cl2 (100 mL) was added BBr3 (1.0 M in CH2Cl2, 9.70 mL, 9.70 mmol) dropwise at 0° C., and the resulting mixture stirred at room temperature overnight, then concentrated to dryness. Water (20 mL) was added at 0° C., followed by EtOAc (100 mL). The organic layer was separated, washed with brine (2×20 mL), dried (Na2SO4), and concentrated. Purification by chromatography on silica gel (Hexanes/EtOAc, 9:1) gave (1R,10R,11S,16S)-1,5,11,15,15-pentamethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-ol (Compound No. 15) (0.88 g, 79%) as a white solid. 1H NMR (CDCl3): δ 6.50 (s, 1H), 6.15 (s, 1H), 4.60 (s, 1H), 3.38 (m, 1H), 2.90 (m, 1H), 2.78 (m, 1H), 2.18 (s, 3H), 1.84-1.42 (m, 9H), 1.40 (s, 3H), 1.20-1.00 (m, 2H), 0.98 (s, 3H), 0.89 (s, 3H), 0.89 (s, 3H). MS m/z 343 (C22H32OS−H+).
Reaction SMILES: ClC1C(O[C:9](=[O:29])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:28])[CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=C(Cl)C(Cl)=C(Cl)C=1Cl.[CH3:34][O:35][C:36](=[O:40])[C@H:37]([CH3:39])[NH2:38].Cl.C(N1CCCCC1)C>CN(C)C=O>[CH3:34][O:35][C:36](=[O:40])[C@H:37]([CH3:39])[NH:38][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19]
Reactant: O=C(NCC(=O)N1CCC[C@H]1C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)OCc1ccccc1
Reactant: COC(=O)[C@H](C)N
Agent: CCN1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 50 %

Procedure:
To a solution of benzyloxycarbonylglycyl-proline pentachlorophenyl ester (5.55 g, 10 mmoles) in dimethylformamide (30 ml) was added alanine methyl ester liberated from its hydrochloride (1.4 g, 10 mmoles) with N-ethylpiperidine (1.4 ml). After 5 hours of a stirring and 12 hours of standing at room temperature the solution was evaporated, the residue was taken into ethyl acetate and the organic phase was washed successively with 1M hydrochloric acid, water, 5% sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from ethyl acetate-petroleum ether to give 1.95 g (50%) of the title product, m.p. 103° to 106° C. An analytical sample was recrystallized similarly, m.p. 105° to 108° C. [α]D20 -100.1° (c 0.2, MeOH).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][C:23]=1[C:24]([NH2:26])=[O:25]>>[C:1]([O:5][C:6](=[O:17])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:18][C:19]2[S:20][C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][C:23]=2[C:24]([NH2:26])=[O:25])[N:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cccc(Br)n1)C(=O)OC(C)(C)C
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)sc1N
Product: CN(Cc1cccc(Nc2sc(-c3ccc(F)cc3)cc2C(N)=O)n1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the general procedure in Example 1 using tert-butyl[(6-bromopyridin-2-yl)methyl]methylcarbamate (90.0 mg, 0.299 mmol) and 2-amino-5-(4-fluorophenyl)thiophene-3-carboxamide (78.0 mg, 0.329 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7])[CH3:2].[CH3:16][O:17][C:18](=[O:21])[C:19]#[CH:20]>CO>[CH3:16][O:17][C:18](=[O:21])[CH:19]=[CH:20][C:5](=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: CCOC(=O)C=C(C)Nc1ccccc1
Reactant: C#CC(=O)OC
Solvent: CO
Product: CCOC(=O)C(C=CC(=O)OC)=C(C)Nc1ccccc1
Yield: 59.6 %

Procedure:
A mixture of 3-phenylamino-but-2-enoic acid ethyl ester (7 g, 34.1 mmol) and propynoic acid methyl ester (4.6 mL, 51.2 mmol) in MeOH (114 mL) was refluxed for 48 h. The solvent was evaporated, and the crude oil was purified by silica gel chromatography (0-20% EtOAc/hexanes) to give 5.88 g of the title compound as an orange oil. MS: (+) m/z 290.27 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH2:6][O:7][N:8]=[C:9]2[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:25])[CH:21]([CH3:24])[CH2:22][CH3:23])[CH:15]3[C:10]2=[CH:11][C:12](=[O:38])[CH:13]([CH3:37])[CH:14]3[CH2:26][CH2:27][C:28](=[O:36])[CH2:29][CH:30]([OH:35])[CH2:31][C:32]([OH:34])=[O:33])[CH:3]=[N:2]1.O1CCOCC1.[OH-].[Na+:46]>O>[O:1]1[CH:5]=[C:4]([CH2:6][O:7][N:8]=[C:9]2[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:25])[CH:21]([CH3:24])[CH2:22][CH3:23])[CH:15]3[C:10]2=[CH:11][C:12](=[O:38])[CH:13]([CH3:37])[CH:14]3[CH2:26][CH2:27][C:28](=[O:36])[CH2:29][CH:30]([OH:35])[CH2:31][C:32]([O-:34])=[O:33])[CH:3]=[N:2]1.[Na+:46]
Reactant: CCC(C)C(=O)OC1CCC(=NOCc2cnoc2)C2=CC(=O)C(C)C(CCC(=O)CC(O)CC(=O)O)C21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C)C(=O)OC1CCC(=NOCc2cnoc2)C2=CC(=O)C(C)C(CCC(=O)CC(O)CC(=O)[O-])C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
151 mg of 7-[5-(isoxazol-4-yl)methoxyimino-2-methyl-8-(2-methylbutyryloxy)-3-oxo-1,2,3,5,6,7,8,8a -octahydro-1-naphthyl]-3-hydroxy-5-oxoheptanoic acid (prepared as described in Example 9b) were dissolved in 2.5 ml of a 1:1 by volume. mixture of dioxane and water. 2.7 ml of a 0.1N aqueous solution of sodium hydroxide were then added dropwise over a period of 5 minutes at 0° C. to the solution, and the resulting mixture was stirred for 1 hour at room temperature. At the end of this time, the solution was freeze-dried, to obtain 153 mg of the title compound as a colorless moisture sensitive powder.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:30][O:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:35]4[CH2:36][CH2:37][CH:32]([O:31][CH3:30])[CH2:33][CH2:34]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: COC1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: COC1CCN(c2ccc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cn2)CC1

Procedure:
4-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and 4-methoxypiperidine. MS calcd. for C28H27ClN4O3 [(M+H)+] 503.2, obsd. 503.0.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][CH2:7][O:8][C:9](=O)[CH3:10])(=O)[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17]C(O)=C[CH:14]=1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>ClC1C=CC=CC=1Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:1]([O:4][CH2:5][O:6][CH2:7][O:8][C:9]2[CH:10]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=2)=[CH:2][CH:14]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(=O)OCOCOC(C)=O
Agent: [Al+3]
Agent: [O-2]
Solvent: Clc1ccccc1Cl
Product: Clc1ccc(OCOCOc2ccc(Cl)cc2)cc1
Yield: 63.5 %

Procedure:
A solution of 16.2 g (0.1 mole) of bis(acetoxymethyl) ether and 39 g (0.30 mole) of p-chlorophenol in 80 ml of o-dichlorobenzene were treated with 1.0 g of neutral aluminum oxide (80-240 mesh) and heated to reflux (pot temp. 180°-185° C.). Distillate was removed at about 10 ml/hr over a 4 hour period. The reaction mixture was filtered hot, stripped in vacuo, and triturated with light petroleum ether to furnish 19.0 g (61% yield) of product, mp 53.5°-4° C.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([N+:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[S:16][C:15]=1[CH3:23])[CH3:13].[Cl:24][C:25]([Cl:36])([Cl:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:24][C:25]([Cl:35])([Cl:36])[C:26]1[CH:34]=[CH:33][C:29]([C:30]([CH:23]=[C:15]2[N:14]([CH2:12][CH3:13])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16]2)=[O:31])=[CH:28][CH:27]=1
Reactant: CC[n+]1c(C)sc2ccccc21
Reactant: O=C(Cl)c1ccc(C(Cl)(Cl)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN1C(=CC(=O)c2ccc(C(Cl)(Cl)Cl)cc2)Sc2ccccc21

Procedure:
35 g (0.1 mol) of 3-ethyl-2-methyl-benzothiazolium p-toluenesulfonate are suspended in 300 ml of toluene, 28 g (0.11 mol) of p-trichloromethyl-benzoyl chloride are added, and 23 g (0.23 mol; 31.5 ml) of triethylamine are added dropwise at 15° C.