Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[C:15]([F:23])[CH:16]=[CH:17][CH:18]=3)[C:13]([F:25])([F:24])[C:12]([F:27])([F:26])[C:11]=2[C:10]=1[F:28])[CH3:7].B(OC)(OC)[O:30]C.C(O)(=O)C.O.OO>C1COCC1>[CH2:6]([O:8][C:9]1[C:10]([F:28])=[C:11]2[C:20]([C:19]3[CH:18]=[CH:17][C:16]([OH:30])=[C:15]([F:23])[C:14]=3[C:13]([F:24])([F:25])[C:12]2([F:27])[F:26])=[CH:21][CH:22]=1)[CH3:7]
Reactant: COB(OC)OC
Reactant: CCOc1ccc2c(c1F)C(F)(F)C(F)(F)c1c(F)cccc1-2
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOc1ccc2c(c1F)C(F)(F)C(F)(F)c1c-2ccc(O)c1F
Temperature: -60 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Under a nitrogen atmosphere, n-butyllithium (1.63 M, 8.71 mL, 14.20 mmol) was slowly added dropwise, at −60° C. or lower, to a THF (40 mL) solution of compound (87) (4.29 g, 12.91 mmol) prepared in Example 11. The reaction mixture was agitated at −60° C. or lower for 1 hour, and then trimethyl borate (1.61 g, 15.49 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then acetic acid (1.16 g, 19.37 mmol) and hydrogen peroxide water (2.93 g, 25.80 mmol) were added thereto, and the resultant mixture was agitated for 3 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and extracted with 50 mL of toluene three times. Combined organic layers were washed with a sodium thiosulfate aqueous solution, a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 7-ethoxy-1,8,9,9,10,10-hexafluoro-9,10-dihydrophenanthrene-2-ol (91) (3.76 g, yield 84.0%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.FC(F)(F)C(O)=O>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2cc(N)ccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2cc(Nc3ccnc4cc(OC)c(OC)cc34)ccc12
Temperature: 90 °C

Procedure:
To a mixture of methyl-6-amino-1-napthoate (300 mg, 1.5 mmol) and 4-chloro-6,7-dimethoxyquinoline (416 mg, 1.8 mmol) in a 20 mL sealed tube was added isopropyl alcohol (6 mL) and trifluoroacetic acid (287 μL, 3.7 mmol). The reaction vessel was sealed and heated at 90° C. for 1 h before being allowed to cool to ambient temperature. To the resulting thick yellow slurry was added isopropyl alcohol (6 mL). The reaction vessel was sealed and heated at 90° C. for 10 h. The mixture was then cooled to 0° C. and filtered. The resulting solid was washed well with cold CH3OH and dried in vacuo to provide the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 389.3 (M+1). Mass Calc'd for C23H20N2O4: 388.42.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:36][CH2:37][CH2:38]Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:38][CH2:37][O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: ClCCOCc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCOCc2ccccc2)CC1
Yield: 91 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (6 g) as a starting compound, potassium carbonate (10.1 g) and 2-benzyloxyethyl chloride (3 g) were reacted and treated in the same manner as in Example 199 to give 6.36 g of 4-amino-N-((1-(2-benzyloxyethyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide, m.p. 123°-125° C.
Reaction SMILES: [H-].[Na+].[CH3:3]O.[Br:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1.CI>CN(C)C=O>[Br:5][C:6]1[C:11]([O:12][CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CO
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccnc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 60% oil sodium hydride (605 mg, 15.1 mmol) was added in portions to methanol (10 ml) under ice cooling. Twenty minutes later, a dimethylformamide (20 ml) solution of 2-bromo-3-hydroxypyridine (2.5 g, 14.4 mmol) was added to the resulting mixture. The reaction mixture was distilled under reduced pressure to remove methanol and to the residue was added methyl iodide (0.94 ml, 15.1 mmol). The mixture was stirred at room temperature for 3 hours.
Reaction SMILES: N1(C2N=CC(CC(O)=O)=CC=2)C=NN=N1.[N:16]1([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[N:25][CH:26]=2)[CH:20]=[N:19][N:18]=[N:17]1.[Cl:31]C1C(Cl)=CC([N+]([O-])=O)=CN=1>>[Cl:31][C:23]1[C:24]([CH2:27][C:28]([OH:30])=[O:29])=[N:25][CH:26]=[C:21]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH:22]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cn1
Agent: O=C(O)Cc1ccc(-n2cnnn2)nc1
Product: O=C(O)Cc1ncc(-n2cnnn2)cc1Cl

Procedure:
The title compound was prepared in an analagous fashion to that described for the syntheses of [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid (Steps B-F) and [5-(1H-tetrazol-1-yl)pyridin-2-yl]acetic acid (Steps A-E) starting from 2,3-dichloro-5-nitropyridine. LC/MS: [(M+1-28)]+=212.5.
Reaction SMILES: FC(F)(F)C(O)=[O:4].CN([CH:11]=[N:12][C:13]1[S:17][N:16]=[C:15]([C:18](=[N:49][O:50][CH2:51][C:52]([O:54]C(C)(C)C)=[O:53])[C:19]([NH:21][CH:22]2[C:47](=[O:48])[N:24]3[C:25]([C:31]([O:33]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]23)=[O:20])[N:14]=1)C.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[CH:11]([NH:12][C:13]1[S:17][N:16]=[C:15]([C:18](=[N:49][O:50][CH2:51][C:52]([OH:54])=[O:53])[C:19]([NH:21][CH:22]2[C:47](=[O:48])[N:24]3[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]23)=[O:20])[N:14]=1)=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3nsc(N=CN(C)C)n3)[C@H]2SC1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3nsc(NC=O)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trifluoroacetic acid (16.0 ml) was added to a solution of benzhydryl 7-[2-[5-{N-(N,N-dimethylaminomethylene)amino}-1,2,4-thiadiazol-3-yl]-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.0 g) in methylene chloride (8.0 ml) and anisole (4.0 ml) under ice-cooling, and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was added dropwise to diisopropyl ether (200 ml), and the precipitated substance was collected by filtration and then added to a mixture of water and ethyl acetate, followed by adjusting to pH 7.5 with a saturated aqueous sodium bicarbonate. The separated aqueous layer was saturated with sodium chloride and adjusted to pH 2.5 with 10% hydrochloric acid, followed by extraction with a mixed solvent of ethyl acetate and tetrahydrofuran (1:2 by volume). The extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was washed with diethyl ether and collected by filtration to obtain 7-[2-(5-formamido-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.75 g).
Reaction SMILES: [OH-].[K+].O.[C:4]1([CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH2:16][CH2:15]2)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:4]1([CH2:10][O:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:19]2)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (15° C.) mixture of 11.1 parts of potassium hydroxide and 96 parts of water wa added dropwise a solution of 31.8 parts of ethyl 1-[(phenylmethoxy)carbonyl]-4-piperidinepropanoate in 38 parts of ethanol during 20 minutes. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was evaporated at <50° C. The reaction mixture was poured into crushed ice and treated with concentrated hydrochloric acid. The separated aqueous layer was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 29 parts (100%) of 1-[(phenylmethoxy)carbonyl]-4-piperidinepropanoic acid as a residue (int. 33).
Reaction SMILES: [C:1]([C:7]#N)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:9][NH:10][C:11]([NH:13][NH2:14])=[S:12].[OH2:15]>>[NH2:9][N:10]1[C:7](=[O:15])[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[N:14][N:13]=[C:11]1[SH:12]
Reactant: O
Reactant: CC(C)(C)C(=O)C#N
Reactant: NNC(=S)NN
Product: CC(C)(C)c1nnc(S)n(N)c1=O
Yield: 90.1 %

Procedure:
The procedure followed was as described in Example 1 A, but the reaction mixture of concentrated sulphuric acid, acetic anhydride and pivaloyl cyanide was introduced into an aqueous suspension of 26.6 g (0.25 mol) of thiocarbohydrazide and 300 ml of water. 45.1 g (90.1% of theory) of 4-amino-6-tert.-butyl-3-mercapto-1,2,4-triazin-5(4H)-one (V) of melting point 212°-214° C. were obtained; content, according to the gas chromatogram, >99%.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[C:20]([O:22][CH3:23])=[O:21])=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11](=[O:19])[C:10]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c(NCc2ccc(OC)cc2)c2ccccc2[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(N)c2ccccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
Methyl 4-(4-methoxybenzylamino)-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 68a) (0.841 g, 2.49 mmol) was dissolved in TFA (5 mL) and stirred at room temperature for 30 minutes. The TFA was removed under reduced pressure, and the residue was dissolved in dichloromethane, then precipitated out by adding excess diethyl ether. The resultant solid was collected by filtration, suspended in dichloromethane, and washed with concentrated sodium bicarbonate. The solid was collected to give methyl 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylate (0.230 g, 42%) as a white solid. M.p.: 236° C. 1H NMR (400 MHz, DMSO-d6) δ3.73 (s, 3H), 7.12 (t, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.38 (bs, 2H), 10.88 (bs, 1H). MS 219 (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[Na].[CH3:7][Si:8]([CH2:11][C:12]([O-])=O)([CH3:10])[CH3:9].[O:15]1CCCC1>>[CH3:7][Si:8]([CH3:10])([CH3:9])[C:11]([Si:2]([CH3:5])([CH3:4])[CH3:1])([OH:15])[CH3:12]
Reactant: C[Si](C)(C)Cl
Reactant: C[Si](C)(C)CC(=O)[O-]
Reactant: C1CCOC1
Agent: [Na]
Product: CC(O)([Si](C)(C)C)[Si](C)(C)C
Temperature: 80 °C
Yield: 55 %

Procedure:
Trimethylchlorosilane (20.5 g, 190 mmol) is dissolved in 30 mL of tetrahydrofuran. The solution is suspended with sodium (6.50 g, 283 mmol) and then refluxed at 80° C. Under the argon atmosphere, trimethylsilylacetate (3.12 g, 23.6 mmol) in 20 mL of tetrahydrofuran is added via a syringe for an hour and then the solution is refluxed for another 30 minutes. Then, precipitated inorganic residue is filtered and solvent is removed under vacuum. Remained oil is separated by vacuum distillation to give 1,1-bis(trimethylsilyl)ethanol (yield: 55%). b.p. 110° C. (24 mmHg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([N:1]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 500 mg, 2.50 mmol) and potassium carbonate (518 mg, 3.74 mmol) in DMF (5 ml) was added (bromomethyl)benzene (CAS number 100-39-0; 356 μl, 3.00 mmol). The reaction was stirred at room temperature for 24 hours. To this was then added further (bromomethyl)benzene (CAS number 100-39-0; 356 μl, 3.00 mmol) and stirring was continued for 24 hours. The reaction mixture was diluted with ethyl acetate (40 ml) and washed with water (3×30 ml) and brine (30 ml). The organics were filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]([O:4][C:5](=O)[C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[Cl:13])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:22][C:23]1S[CH:25]=[CH:26][C:27]=1[C:28](Cl)=[O:29].[OH2:31]>CCOCC.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([NH:12][C:28]([C:27]2[CH:26]=[CH:25][O:31][C:23]=2[CH3:22])=[O:29])[CH:9]=[CH:8][C:7]=1[Cl:13])(=[O:3])[CH3:2]
Reactant: Cc1sccc1C(=O)Cl
Reactant: O
Reactant: CC(=O)OC(=O)c1cc(N)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc(NC(=O)c2ccoc2C)ccc1Cl

Procedure:
A solution of 22.8 g of the 5-amino-2-chlorobenzoyl acetate from Step 3 above and 17.2 mL of triethylamine in 118 mL ether was prepared and then added dropwise to a second solution of 16.6 g 2-methyl-3-thiophenecarboxylic acid chloride in 118 mL ether at 0° C. to 10° C. and the resultant mixture was stirred at room temperature overnight. 100 mL of water and 100 mL of ethyl acetate were then added to the mixture, the organic phase separated, washed with 2N hydrochloric acid and water, dried over magnesium sulfate, and the solvents removed in vacuo, to produce 29.87 g of N-(3-acetoxymethyl-4-chlorophenyl)-2-methyl-3-furancarboxamide as a beige solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)#[N:2].[CH3:11][O:12][C:13](=[O:18])[CH2:14][C:15](=O)[CH3:16].[CH3:19][O:20][C:21](=[O:24])[C:22]#[CH:23]>CO>[CH3:19][O:20][C:21](=[O:24])[CH:22]=[CH:23][C:14](=[C:15]([NH:2][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[CH3:16])[C:13]([O:12][CH3:11])=[O:18]
Reactant: COC(=O)CC(C)=O
Reactant: C#CC(=O)OC
Reactant: N#Cc1ccc(CN)cc1
Solvent: CO
Product: COC(=O)C=CC(C(=O)OC)=C(C)NCc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A mixture of 4-cyanobenzyl amine (3 g, 22.7 mmol) and 3-oxo-butyric acid methyl ester (2.94 mL, 27.2 mmol) in MeOH (80 mL) was refluxed for 2 h. Propynoic acid methyl ester (3.03 mL, 34 mmol) was added, and the resulting mixture was refluxed for 48 h. After cooling to r.t., the solvent was evaporated, and the crude residue was recrystallized from MeOH to give 3.35 g of the title compound as a light yellow solid. 1H NMR (CDCl3, 200 MHz): δ=10.97 (br s, 1H), 7.72 (d, 1H, J=15.4 Hz), 7.67 (d, 2H, J=8.8 Hz), 7.37 (d, 2H, J=8.4 Hz), 6.11 (d, 1H, J=15.8 Hz), 4.63 (d, 2H, J=6.0 Hz), 3.79 (s, 3H), 3.73 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:19])[CH2:17][CH3:18])=[CH:11][C:7]=1[C:8](Cl)=[O:9])(=[O:4])[CH2:2][CH3:3].[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:19])[CH2:17][CH3:18])=[CH:11][C:7]=1[C:8]([O:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:9])(=[O:4])[CH2:2][CH3:3]
Reactant: OCc1ccccc1
Reactant: CCC(=O)Oc1ccc(OC(=O)CC)c(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(=O)Oc1ccc(OC(=O)CC)c(C(=O)OCc2ccccc2)c1
Temperature: 26 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
To a solution of 2,5-dipropionoxybenzoyl chloride (10.3 gr., 0.036 mole) in 30 ml dry chloroform at 0° C. is added dropwise over a six hour period a solution of benzyl alcohol (3.45 gr., 0.032 mole) and pyridine (5.05 gr., 0.064 mole) in 6 ml of dry chloroform. The temperature is maintained at 0° C.-5° C. during the addition and the entire operation is performed under an argon atmosphere. The reaction is stirred at 26° C. for 16 hours and poured into 50 ml of cold water. The organic portion is extracted with 450 ml of ether and the organic layer is washed with 80 ml of 15% HCL (hydrochloric acid), 3×100 ml water, 100 ml of 1 N sodium hydroxide, 3×100 ml water, and dried over magnesium sulfate. Evaporation of the solvents affords 10.22 grams (90%) of benzyl 2,5-dipropionoxybenzoate as a colorless liquid. Distillation in a Hickman still affords 7.0 grams (60%) of benzyl 2,5-dipropionoxybenzoate as a colorless liquid of b.p. 227° C./0.14 mm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1.C([O-])(O)=O.[Na+].[CH3:15][CH:16]([CH3:21])[CH2:17][C:18](Cl)=[O:19]>O.C1COCC1>[CH3:15][CH:16]([CH3:21])[CH2:17][C:18]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:19]
Reactant: CC(C)CC(=O)Cl
Reactant: O=C(O)[C@@H]1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(=O)N1CCC[C@@H](C(=O)O)C1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of (R)-piperidine-3-carboxylic acid (2.0 g, 15.48 mmol) in water (40 mL) and THF (20 mL) were added NaHCO3 (3.30 g, 38.70 mmol) and 3-methylbutanoyl chloride (2.8 mL, 23.2 mmol) at room temperature. The reaction was stirred overnight, concentrated under reduced pressure, diluted with water (50 mL) and extracted with EtOAc (1×). The aqueous layer was acidified with 1N HCl, extracted with EtOAc (3×) and the combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.53 g, 76%). MS 214 (MH+).
Reaction SMILES: [NH:1]([C:8](=[O:42])[CH:9]([C:19]1[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[B-](F)(F)(F)[F:50].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C1COCC1.C(OCC)(=O)C>[NH:1]([C:8](=[O:42])[C:9]([C:19]1[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:24])=[CH:21][CH:20]=1)([C:10]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11])[F:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(F)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 18 %

Procedure:
tert-Butyl [2-({(4-[2-anilino-1-(anilinocarbonyl)-1-fluoro-2-oxoethyl]benzoyl}amino)phenyl]carbamate. To a solution of tert-butyl [2-({4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoyl}amino)phenyl]carbamate (59 mg, 0.10 mmol) in THF (2 mL) at room temperature was added potassium tert-butoxide (110 μL, 1 M in THF, 0.11 mmol). The solution was stirred for 5 min and Selectfluor™ (40 mg, 0.11 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h, diluted with ethyl acetate, washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by reverse phase HPLC (30% to 100% MeCN in water) gave tert-butyl [2-({-4-[2-anilino-1-(anilinocarbonyl)-1-fluoro-2-oxoethyl]benzoyl}amino)phenyl]carbamate (11 mg, 18%) as a white solid: 1H NMR (600 MHz, CDCl3) δ 9.42 (s br, 1H), 9.11 (s br, 2H), 8.02 (d, J=8.2 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.77 (d, J=7.9 Hz, 1H), 7.58 (d, J=7.6 Hz, 4H), 7.37 (t, J=7.6 Hz, 4H), 7.25-7.16 (m, 5H), 6.78 (s br, 1H); ESIMS calcd 605.2 (M++H), found 605.2 (M++Na).
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([C:7]([NH:9][C:10](=[O:34])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:14]([O:27][CH2:28][O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:43]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:34])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:14]([O:27][CH2:28][O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:13]=2)=[O:8])=[CH:35][CH:36]=1)(=[S:43])[NH2:2]
Reactant: CC(C)(C)OCOc1cc(NC(=O)NC(=O)c2ccc(C#N)cc2)ccc1OCC(=O)OC(C)(C)C
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OCOc1cc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (c) (2.2 g), pyridine (186 ml), triethylamine (26 ml) and H2S gas were reacted to give t-butyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]-2-(t-butoxymethoxy)phenoxyacetate (2.6 g) as a yellow solid: m.p. 198°-199° C.; NMR Spectrum (DMSO-d6) 1.43 (9H, s), 1.44 (9H, s), 4.61 (2H, s), 4.66 (2H, s), 6.89 (1H, d), 7.09 (1H, dd), 7.27 (1H, d), 7.98 (4H, m), 9.68 (1H, s), 10.02 (1H, s), 10.66 (1H, s), 11.07 (1H, s); Mass Spectrum m/Z 582 (M +Na)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C:22](O)=[O:23])[O:13][C:12]1([CH3:35])[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[NH-].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:55]([N:57](CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH3:55][NH:57][C:22](=[O:23])[C:21]([CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)=[CH:20][C@@H:14]1[O:13][C:12]([CH3:35])([CH3:34])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C@H:15]1[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)C[C@H]1[C@H](C=C(CCOC2CCCCO2)C(=O)O)OC(C)(C)N1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: C[NH-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CCOC1CCCCO1
Temperature: -10 °C
Yield: 37.9 %

Procedure:
45 mg of 3-[(4S,5S)-3-benzyloxycarbonyl-4-isobutyl-2,2-dimethyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]-2-propenoic acid was dissolved in 0.3 ml of dry dimethylformamide, and 3.71 mg of methylamide, 32.9 mg of diphenylphosphorylazide and 12.1 mg of triethylamine were added thereto at -10° C. under stirring. Then, the mixture was stirred at -10° C. for one hour and at room temperature overnight. To the reaction solution, 20 ml of ethyl acetate was added. The ethyl acetate layer was washed sequentially with a 10% citric acid aqueous solution, water, a 4% sodium hydrogencarbonate aqueous solution, water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Kieselgel 60) by using a mixture of chloroform/methanol (5/1) to obtain 17.5 mg of 3-[(4S,5S)-3-benzyloxycarbonyl-4-isobutyl- 2,2-dimethyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]-2-propenoic acid methylamide as a colorless oily substance.