Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:23](OC(=O)C)(=[O:25])[CH3:24].CCOC(C)=O>N1C=CC=CC=1.O>[C:23]([O:1][C@:2]([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C[C@](O)(CC=C(C)C)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C[C@@](CC=C(C)C)(OC(C)=O)C(=O)OCc1ccccc1

Procedure:
To a solution of tertiary alcohol 77 (33.0 mg, 0.109 mmol, 1.00 equiv) in dry pyridine (500 μL) at 0° C. was added acetic anhydride (114 μL, 1.09 mmol, 10.0 equiv) and N,N-dimethylaminopyridine (DMAP) (3.0 mg, 0.0246 mmol, 0.23 equiv). The solution was then stirred at 23° C. for 17 h at which time further DMAP (13.0 mg, 1.09 mmol, 1.00 equiv) and acetic anhydride (22 μL, 0.21 mmol, 1.9 equiv) were added. After 1 h the solution was diluted with H2O (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with 0.1M aqueous CuSO4 soln, dried over MgSO4, and concentrated by rotary evaporation to yield a dark red oil. Purification by silica gel column chromatography (5:1 hexanes:EtOAc) provided S11 (28.1 mg, 74%) as a colorless oil. Rf=0.32 (5:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.35 (m, 5H, ArH), 5.14 (m, 2H, ArCH2), 5.00 (tt, 1H, J=7.5, 1.3 Hz, vinyl H), 3.64 (s, 3H, CO2CH3), 3.27 (d, 1H, J=14.7 Hz, C(O)CH2), 2.96 (d, 1H, J=14.7 Hz, C(O)CH2), 2.80 (dd, 1H, J=14.6, 7.6 Hz, CHCH2), 2.69 (dd, 1H, J=14.6, 7.6 Hz, CHCH2), 2.06 (s, 3H, C(O)CH3), 1.67 (s, 3H, CCH3), 1.56 (s, 3H, CCH3); 13C NMR (125 MHz, CDCl3) δ 170.34, 170.10, 169.79, 137.21, 135.45, 128.64, 128.50, 128.46, 115.89, 80.51, 67.48, 51.85, 37.41, 34.35, 26.11, 21.09, 18.00; IR (neat film) 3067 (w), 2955 (w), 1746 (s), 1441 (m), 1371 (m), 1227 (m); LRMS (ESI) calcd for C19H24O6Na (M++Na) 371.16 observed 371.00.
Reaction SMILES: Cl.C([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:22])[NH:10][C:11]3([CH2:20][CH:19]4[NH:21][CH:16](CC4)[CH2:15]3)[CH2:12]2)=[N:7]1)(C)(C)C.[CH3:23][C:24]1[C:32]2[C:27](=[C:28]([CH3:36])[CH:29]=[C:30]([C:33]([OH:35])=O)[CH:31]=2)[NH:26][N:25]=1.C(N(CC)CC)C.[CH3:44][CH2:45][CH2:46]P1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:23][C:24]1[C:32]2[C:27](=[C:28]([CH3:36])[CH:29]=[C:30]([C:33]([N:21]3[CH2:16][CH2:15][C:11]4([NH:10][C:9](=[O:22])[C:8]5[N:7]([CH:45]([CH3:46])[CH3:44])[N:6]=[CH:14][C:13]=5[CH2:12]4)[CH2:20][CH2:19]3)=[O:35])[CH:31]=2)[NH:26][N:25]=1
Reactant: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Reactant: Cc1n[nH]c2c(C)cc(C(=O)O)cc12
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(C2)CC2CCC(C1)N2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2c(C)cc(C(=O)N3CCC4(CC3)Cc3cnn(C(C)C)c3C(=O)N4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a solution of 1′-isopropyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(1H)-one hydrochloride salt (Intermediate 2, 430 mg, 1.3 mmol) and 3,7-dimethyl-1H-indazole-5-carboxylic acid (306 mg, 1.6 mmol) in dimethylformamide (2 mL) was added triethylamine (0.75 mL, 5.4 mmol), 4-dimethylaminopyridine (33 mg, 0.37 mmol), and 1-propanephosphonic acid cyclic anhydride (0.52 mL, 1.74 mmol, 50% solution in ethyl acetate), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to a solid. The solid was purified via flash column chromatography (0-15% methanol/dichloromethane) to afford a glassy solid. The glassy solid was stirred in ethyl acetate for 16 hours and the resulting solid collected by vacuum filtration to afford the desired product as a white solid (138 mg). +ESI (M+H) 421.0; 1H NMR (400 MHz, CD3OD, δ): 7.65 (s, 1H) 7.42 (s, 1H) 7.21 (s, 1H) 5.50 (m, 1H) 3.95 (br. s., 1H) 3.50-3.62 (br. s., 3H) 2.97 (s, 2H) 2.56 (m, 6H) 1.83 (br. s., 4H) 1.44 (d, 6H).
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[C:10]([C:11](O)=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(N)([NH2:18])=O>CCOC(C)=O>[CH2:1]([C:6]1[CH:14]=[C:10]([C:11]([NH2:18])=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(O)c(C(=O)O)c1
Reactant: NC(N)=O
Solvent: CCOC(C)=O
Product: CCCCCc1ccc(O)c(C(N)=O)c1
Yield: 51.4 %

Procedure:
18 g compound 19 (86 mmole), 20.8 g ureum (346 mmole) and 5 drops polyphosphoric acid were heated at 150° C. during 18 h. After cooling, 500 ml EtOAc was added and the resulting solution was washed twice with brine. After evaporation of the organic phase, the resulting residue was purified by flash chromatography (Acros Silicagel 0.060-0.200 mm) using cyclohexane/isopropanol 95:5, affording compound 20 as a white powder (9.17 g, 51% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[N:18](C)[C:19](=O)C.Cl>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[NH:18][CH3:19]
Reactant: CCOC(=O)c1cc(N(C)C(C)=O)c(C)nc1C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(NC)c(C)nc1C(=O)OCC

Procedure:
A solution of 90.6 g of 6-methyl-5-(N-methylacetamido)-pyridine-2,3-dicarboxylic acid, diethyl ester in 700 mL absolute ethanol is treated with 60 mL of concentrated hydrochloric acid, and the solution is heated at reflux for 17 hours. The reaction is cooled, 75 mL of concentrated hydrochloric acid is added, and the reaction is heated at reflux for another 8 hours. The solution is concentrated in vacuo; the residue is stirred in water and basified to pH 8 using a saturated bicarbonate solution. The mixture is then extracted with methylene chloride, and the extracts are dried and concentrated in vacuo to afford the desired product as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([N:14]([CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)[CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:35]1[CH:40]=[C:39]([C:41]2[C:50]3[C:45](=[CH:46][C:47]([O:53][CH3:54])=[C:48]([O:51][CH3:52])[CH:49]=3)[CH:44]=[C:43]([CH2:55][OH:56])[C:42]=2[CH2:57][OH:58])[CH:38]=[CH:37][N:36]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[O:1]=[C:2]1[CH:11]=[C:10]([C:12]([N:14]([CH2:25][CH2:26][OH:27])[CH2:15][CH2:16][OH:17])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:35]1[CH:40]=[C:39]([C:41]2[C:50]3[C:45](=[CH:46][C:47]([O:53][CH3:54])=[C:48]([O:51][CH3:52])[CH:49]=3)[CH:44]=[C:43]([CH2:55][OH:56])[C:42]=2[CH2:57][OH:58])[CH:38]=[CH:37][N:36]=1
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)cc(C(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c5ccccc54)c3)c2cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)cc(C(=O)N(CCO)CCO)c5ccccc54)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 1-{2-(2-oxo-4-bis(2-tert-butyldimethylsilyloxyethyl)aminocarbonyl-1,2-dihydroquinolin-1-yl]-4-pyridyl}-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (1.9 g) in tetrahydrofuran (20 ml) is added a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2.8 ml) under ice-cooling, and the mixture is stirred at room temperature for one hour. After the reaction is complete, the mixture is concentrated under reduced pressure to remove the solvent, and to the resultant are added methylene chloride and an aqueous sodium hydrogen carbonate solution. The methylene chloride layer is separated, washed, dried, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=10:1˜5:1), and triturated with ether to give 1-{2-(2-oxo-4-bis(2-hydroxyethyl)aminocarbonyl-1,2-dihydroquinolin-1-yl)-4-pyridyl}-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (0.68 g) which is listed in Table 7.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[F:14][CH:15]([F:25])[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:21][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH:15]([F:14])[F:25])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: FC(F)Oc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2ccn(Cc3ccc(OC(F)F)cc3)c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 21.1 %

Procedure:
To a solution of commercially available 1H-indole-6-carboxylic acid methyl ester (0.35 g, 2.0 mmol) and 4-difluoromethoxy-benzyl bromide (0.52 g, 2.2 mmol) in DMF (2 mL) was added sodium hydride (92 mg, 2.3 mmol). After stirring at room temperature for 3.5 hr, the solution was diluted with water (25 mL) and ethyl acetate (75 mL), the organic layer was washed again with dilute NaHCO3 (25 mL) and then brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane. 1:5) to provide 1-(4-difluoromethoxy-phenylmethyl)-1H-indole-6-carboxylic acid methyl ester as a colorless oil (0.14 g, 21% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:13]([O:15][C:16](=[O:23])[CH2:17][C:18]([CH2:20][O:21][CH3:22])=O)[CH3:14].[CH2:24]([O:26][C:27](=[O:32])/[CH:28]=[C:29](\[NH2:31])/[CH3:30])[CH3:25]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:9]([C:8]2[CH:11]=[CH:12][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[C:28]([C:27]([O:26][CH2:24][CH3:25])=[O:32])=[C:29]([CH3:30])[NH:31][C:18]=1[CH2:20][O:21][CH3:22])=[O:23])[CH3:14]
Reactant: CCOC(=O)CC(=O)COC
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(COC)=C(C(=O)OCC)C1c1ccc(S(C)(=O)=O)cc1
Yield: 65 %

Procedure:
A solution of 9.2 g of 4-methylsulphonylbenzaldehyde, 8 g of γ-methoxyacetoacetic acid ethyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 40 ml of ethanol is heated to the boil and, after cooling, 2-methoxymethyl-6-methyl-4-(4'-methylsulphonylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained in the form of yellow crystals of melting point 156°-158° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=O)=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:4][N:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[C:6]2[N:7]=[C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:5]=2[NH:4][N:3]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1cccs1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1n[nH]c2c1nc(-c1cccs1)c1ccccc12
Temperature: 120 °C

Procedure:
To a suspension of 682.4 mg of thiophene-2-carboxylic acid (3-methyl-5-phenyl-1H-pyrazol-4-yl)-amide in 11.0 mL of phosphorous oxychloride was added 5.00 g of phosphorous pentoxide and the resulting suspension was heated at 120° C. for 5 h. The reaction mixture was cooled to rt and quenched with the addition of ice and water and then neutralized with solid sodium carbonate. The aqueous mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by means of MPLC (4 g SiO2, 30% ethyl acetate:dichloromethane) to give the title compound as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[C:5]2[C:14]([F:17])([F:16])[F:15].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:27]=[C:28]=[S:29])=[CH:21][CH:20]=1>CN1C(=O)CCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][NH:27][C:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[C:5]3[C:14]([F:17])([F:15])[F:16])=[S:29])=[CH:23][CH:24]=1
Reactant: S=C=NCCc1ccc(Cl)cc1
Reactant: Cn1c(=O)cc(C(F)(F)F)c2cc(N)ccc21
Solvent: CN1CCCC1=O
Product: Cn1c(=O)cc(C(F)(F)F)c2cc(NC(=S)NCCc3ccc(Cl)cc3)ccc21
Yield: 40 %

Procedure:
Reaction of 6-amino-1-methyl-4-trifluoromethyl-1H-quinolin-2-one (Preparation 1, 200 μL of a 0.2 M solution in NMP, 40 μmol) with 2-(4-chlorophenyl)ethyl isothiocyanate (240 μL of a 0.2 M solution in NMP, 48 μmol), by the procedure outlined for Example 492, furnished the title compound (7.1 mg, 40%): RT=1.95 min; m/z (ES+)=440.1 [M+H]+.
Reaction SMILES: [BH4-].[Na+].O.C(=O)(O)[O-].[Na+].[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[N:15][CH2:14][CH2:13]2>C(OCC)(=O)C>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][CH:21]=1)[NH:15][CH2:14][CH2:13]2
Reactant: Fc1ccc2c(c1)CCN=C2c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)CCNC2c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6-fluoro-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline (2.6 g, 8.9 mmol) in methanol (50 mL) from step 2 was cooled to 0° C. and sodium borohydride (1.0 g, 2.7 mmol) was added in small portions over 5 min and the reaction mixture was stirred at RT for 16 h. The reaction was quenched with ethyl acetate (20 mL) and concentrated to yield a reddish-yellow residue which was taken up in ethyl acetate (100 mL), water (30 mL), and saturated sodium bicarbonate (30 mL). After stirring for 15 min, it was transferred to a separatory funnel, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel chromatography (20-30% EtOAc in hexanes) to give 6-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as a pale-yellow solid. MS (ESI pos. ion) m/z: 296 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH2:15][C:16]3[N:20]4[C:21](=[O:33])[C:22]5[NH:23][CH:24]=[N:25][C:26]=5[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:19]4=[N:18][N:17]=3)[N:10]=2)=[CH:5][CH:4]=1.[Br:34]N1C(=O)CCC1=O>CN(C=O)C>[Br:34][C:24]1[NH:23][C:22]2[C:21](=[O:33])[N:20]3[C:16]([CH2:15][CH2:14][C:11]4[N:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[O:13][N:12]=4)=[N:17][N:18]=[C:19]3[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:26]=2[N:25]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCc3noc(-c4ccc(OC)cc4)n3)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCc3noc(-c4ccc(OC)cc4)n3)nnc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 3-2-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (160 mg, 0.36 mmol) in DMF (15 mL) at room temperature was added N-bromosuccinimide (110 mg, 0.61 mmol). After stirring at 70° C. for 1 hour, the reaction mixture was concentrated and purified by preparative LCMS to provide the desired product. LCMS calculated for C22H24BrN8O3 (M+H): 527.1, 529.0. found: 527.0, 529.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[C:5]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:4]([F:15])[CH:3]=1.C([O-])(=O)C.[Na+].[OH-].[Na+]>C(OC(=O)C)(=O)C.C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([F:15])[C:5]2[O:10][C:11]([C:12]([OH:14])=[O:13])=[CH:8][C:6]=2[CH:7]=1
Reactant: O=Cc1cc(Br)cc(F)c1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)c1cc2cc(Br)cc(F)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A solution of [(4-bromo-2-fluoro-6-formylphenyl)oxy]acetic acid (3.79 mmol) in acetic anhydride (10 mL) was treated with sodium acetate (11.37 mmol). The resulting solution was heated to reflux and stirred overnight. The brown reaction solution was allowed to cool to room temperature, and was diluted with toluene (10 mL). The solution was then treated with 1N aq NaOH (20 mL) and was stirred at room temperature for 30 min. The solution was then further diluted with water (50 mL) and was extracted using hexanes. The aqueous phase was then acidifed to pH˜1 using 1N aq HCl, and was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the title compound (0.47 g, 48% yield) which was used without further purification. MS(ES)+ m/e 258.5, 260.7 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88 (d, J=1.77 Hz, 1H) 7.75 (dd, J=10.36, 1.77 Hz, 1H) 7.69 (d, J=2.53 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH2:2].[ClH:25].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])[C:12]3[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3c(Cl)cccc3NC(=O)[C@@H]2OC(C)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3c(Cl)cccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Product: O
Yield: 169.6 %

Procedure:
A mixture of 200 mg of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 84 mg of 2-(dimethylamino)ethyl chloride hydrochloride, 220 mg of powdered potassium carbonate and 10 ml of acetone is refluxed for 20 hours. After the reaction is completed, insoluble materials are removed by filtration. The filtrate is evaporated to remove solvent. The residue is converted to its hydrochloride and then recrystallized from methanol. 226 mg of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride hydrate are obtained. Yield: 85%
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[F:13])[CH3:2].[CH3:15][C:16]1[CH:17]=[C:18]([NH:25][C:26]([C:28]2([CH3:31])[CH2:30][O:29]2)=[O:27])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]>>[CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:31][C:28]([OH:29])([C:26](=[O:27])[NH:25][C:18]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([CH3:15])[CH:17]=2)[CH3:30])=[CH:8][C:7]=1[F:13])[CH3:2]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)Nc1ccc(O)cc1F
Product: CCOC(=O)Nc1ccc(OCC(C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1F

Procedure:
{2-Fluoro-4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl)propoxy]-phenyl}carbamic acid ethyl ester was prepared as described in Example 1 starting from (2-fluoro-4-hydroxyphenyl)carbamic acid ethyl ester and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1.8% methanol). 1H NMR (400 MHz, DMSO-d6): 1.20 (3H, t, J=7.0 Hz), 1.43 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J=9.7 Hz), 4.07 (2H, q, J=7.0 Hz), 4.22 (1H, d, J=9.7 Hz), 6.21 (1H, s), 6.71-6.73 (1H, m), 6.83-6.87 (1H, m), 7.31-7.35 (1H, m), 7.86-8.05 (3H, m), 8.95 (1H, s), 10.12 (1H, s).
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12.CN(C)C=O.[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38](O)=[O:39])=[O:36]>C(N(CC)CC)C>[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:18][N:19]=[N:20][N:21]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12)=[O:39])=[O:36]
Reactant: O=C(O)CS(=O)CC(F)(F)F
Reactant: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1

Procedure:
A suspension of 4.0 g. (0.01 mol.) of 7-amino-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 50 ml. of dry dimethylformamide is treated with 2 ml. of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol. of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C(NC(C)C)(C)C.[CH3:13][CH:14]([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([O-:17])=[O:16].[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCC.O1CCCC1>[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][C:14]([CH3:13])([CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]([O:17][CH2:1][CH3:2])=[O:16])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(CCCc1ccccc1)C(=O)[O-]
Reactant: [Li]CCCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium in hexane (1.65M, 19.4 ml) was added dropwise over a period of 20 minutes at −60° C. to a solution of diisopropylamine (3.23 g) in anhydrous tetrahydrofuran (60 ml). The mixture was stirred at 0° C. for 30 minutes. To this mixture a solution of 2-methyl-5-phenylvalerate (7.05 g) in anhydrous tetrahydrofuran (30 ml) was added dropwise over a period of 20 minutes at −70° C. and the mixture was stirred at −70° C. for 40 minutes. To this reaction mixture a solution of 4-benzyloxybenzyl chloride (9.68 g) in anhydrous tetrahydrofuran (80 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 3 hours. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=15/1 as the eluant to afford the desired compound (1.88 g) as a syrup.