Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([CH2:12][O:13]CC3C=CC=CC=3)[S:11][C:7]=2[CH:6]=1)=[O:4].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([CH2:12][OH:13])[S:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2nc(COCc3ccccc3)sc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(CO)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112 %

Procedure:
A solution of 2-Benzyloxymethyl-benzothiazole-6-carboxylic acid methyl ester (0.10 g, 0.32 mmol) in 2 ml of DCM was cooled to −78° C. followed by addition of BBr3 (0.06 ml, 0.64 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO3 (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.08 g, Crude yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][N:10]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]ncn1-c1cccc(Br)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1n(-c2cccc(Br)c2)cnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(3-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (250 mg, 1.04 mmol) and NaH (50 mg of a 60% dispersion in mineral oil, 1.25 mmol) in DMF (3 mL) was stirred at room temperature for 30 min. To the solution was added 1,1′,1″-(chloromethanetriyl)tribenzene (305 mg, 1.09 mmol) and the mixture stirred at room temperature for 4 hr. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4 then concentrated in vacu. The residue was purified by silica gel chromatography (EtOAc/Hexanes) to give 4-(3-bromophenyl)-2-(triphenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as a pale yellow foam. 1H NMR (400 MHz, DMSO-d6) δ 7.22-7.31 (m, 15H), 7.40-7.42 (m, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.90 (s, 1H), 8.60 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[S:8][C:7]=2[CH:27]=1.CS(C)=[O:30]>>[F:24][C:23]([F:26])([F:25])[C:13]1[CH:12]=[C:11]([C:9]2[S:8][C:7]3[CH:27]=[C:3]([CH:2]=[O:30])[CH:4]=[CH:5][C:6]=3[CH:10]=2)[CH:16]=[CH:15][C:14]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1cc(-c2cc3ccc(CBr)cc3s2)ccc1-c1ccccc1
Reactant: CS(C)=O
Product: O=Cc1ccc2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1

Procedure:
To a solution of 6-bromomethyl-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene (180mg, 0.4 mmol) in 5 mL DMSO, Ag2CO3(330mg, 1.2 mmol) is added. The suspension is heated to 100IC for 3 hours. After work up, the organic layer is dried and concentrated. The residue is applied in column (hexane:EtOAc 9:1) to afford 100mg of 2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene-6-carbaldehyde as a off white solid. MS m/z 383[M+1]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.CCN=C=NCCCN(C)C.[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[O:44][C:45]([C:51]([F:54])([F:53])[F:52])=[C:46]([C:48](O)=[O:49])[N:47]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>ClCCl.C([O-])(O)=O.[Na+]>[CH3:2][O:3][C:4](=[O:24])[CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:23])[CH2:20][CH2:21][NH:22][C:48]([C:46]3[N:47]=[C:43]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[F:36])[O:44][C:45]=3[C:51]([F:54])([F:53])[F:52])=[O:49])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: O=C(O)c1nc(-c2ccccc2F)oc1C(F)(F)F
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCN)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4F)oc3C(F)(F)F)cc2)CC1
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-aminopropionylamino)phenyl]cyclohexyl}acetic acid methyl ester HCl salt (50 mg, 0.14 mmol), EDCI (67.5 mg, 0.35 mmol), 2-(2-fluorophenyl)-5-trifluoromethyloxazole-4-carboxylic acid (46.5 mg, 0.17 mmol), HOBt (28.6 mg, 0.2 mmol) and ethyldiisopropylamine (63.9 mg, 0.5 mmol) dissolved in dichloromethane solvent (10 mL) were stirred for 24 hours. The reaction mixture was diluted with aqueous NaHCO3 and extracted with dichloromethane. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography to obtain trans-{4-[4-(3-{[2-(2-fluorophenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (73 mg, 90%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:10])[CH:9]=1)=[O:4]>CO.O1CCCC1.[OH-].[Na+]>[CH3:10][C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[S:6][CH:7]=1
Reactant: COC(=O)c1cc(C)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1csc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
5-Bromo-4-methyl-2-thiophenecarboxylic acid (3.33 g) was dissolved in dimethylformamide (50 ml), and potassium carbonate (4.0 g) and iodomethane (4.0 ml) were added. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (3.47 g). A mixture of 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (2.36 g), zinc powder (1.65 g), acetic acid (10 ml) and water (10 ml) was stirred under reflux for 3 hours. Zinc powder (1 g) and acetic acid (10 ml) were further added. The mixture was stirred under reflux for 1 day, cooled, poured into concentrated aqueous ammonia and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid methyl ester (1.42 g). 4-Methyl-2-thiophenecarboxylic acid methyl ester (1.42 g) was dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (30 ml), and 1N aqueous sodium hydroxide (15 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid (1.16 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5]C)=[O:4].Cl[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:16]=[C:17]([C:22]3[S:26][C:25]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[N:24][CH:23]=3)[CH:18]=[C:19]([CH3:21])[CH:20]=2)[N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>>[CH3:21][C:19]1[CH:20]=[C:15]([NH:14][C:10]2[N:9]=[C:8]([O:1][CH2:2][C:3]([OH:5])=[O:4])[CH:13]=[CH:12][N:11]=2)[CH:16]=[C:17]([C:22]2[S:26][C:25]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[N:24][CH:23]=2)[CH:18]=1
Reactant: Cc1cc(Nc2nccc(Cl)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Reactant: COC(=O)CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(OCC(=O)O)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
Methyl hydroxyacetate (22 mg, 0.24 mmol) and 2-(5-{3-[(4-chloropyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-1,1,1-trifluoropropan-2-ol (Example 98, 50 mg, 0.12 mmol) were taken up in N,N′-dimethylacetamide (1.2 mL). Cesium carbonate (118 mg, 0.36 mmol) was added and the mixture was stirred for 24 h at 70° C. The reaction was cooled to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate (2×). The combined organics were concentrated under reduced pressure and purified by reverse phase HPLC (10-80% acetonitrile/water+0.05% TEA modifier). Desired fractions were combined and lyophilized to afford {[2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}acetic acid (10 mg, 0.018 mmol, 15%) as the trifluoroacetic acid salt as a white solid. MS ESI: [M+H]+ m/z 455.1.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CN(C=O)C.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:19])=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CCC(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of trans-4-methyl-1-cyclohexane carboxylic acid (8.2 g, 56.5 mmol) in CH2Cl2 (350 mL) at 0° C. was added DMF (44 μl, 0.6 mmol) and oxalyl chloride (11.5 g, 90.0 mmol) dropwise. The reaction mixture was stirred at rt for 18 h. The reaction mixture was concentrated. The product was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[N:2]1.CN(C)C=O.[NH2:13][C:14]1[C:19]([NH2:20])=[CH:18][C:17]([CH:21]2[CH2:25][CH2:24][CH2:23][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:16]([O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH:15]=1>C(OCC)(=O)C>[CH3:43][S:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][C:16]2[C:17]([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:18][C:19]3[NH:20][C:6]([C:3]4[CH:4]=[CH:5][NH:1][N:2]=4)=[N:13][C:14]=3[CH:15]=2)=[CH:35][CH:36]=1)(=[O:42])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc(N)c(N)cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: O=Cc1cc[nH]n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1c1cc2[nH]c(-c3cc[nH]n3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
10.0 mg of 1H-pyrazole-3-carboxaldehyde was added to an N,N-dimethylformamide (1 ml) solution of 49.0 mg of t-butyl 2-(4,5-diamino-2-(4-methanesulfonyl-phenoxy)-phenyl)-pyrrolidine-1-carboxylate obtained in Example 306 (step 3), and the reaction liquid was stirred overnight at 90° C. After cooled, the reaction liquid was diluted with ethyl acetate, washed with saturated saline, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as a brown solid.
Reaction SMILES: C[C@]12CC[C@H]3[C@@H](CCC4[C@]3(C)CCC(=O)C=4)[C@@H]1CCC2=O.[C:22]([C:24]1([O:44][C:45](=[O:47])[CH3:46])[CH2:29][CH2:28][C@H:27]2[C@H:30]3[C@H:40]([CH2:41][CH2:42][C@:25]12[CH3:26])[C@:38]1([CH3:39])[C:33](=[CH:34][C:35](=[O:43])[CH2:36][CH2:37]1)[CH2:32][CH2:31]3)#[N:23]>CC(C)(O)C#N>[C:22]([C@@:24]1([O:44][C:45](=[O:47])[CH3:46])[CH2:29][CH2:28][C@H:27]2[C@H:30]3[C@H:40]([CH2:41][CH2:42][C@:25]12[CH3:26])[C@:38]1([CH3:39])[C:33](=[CH:34][C:35](=[O:43])[CH2:36][CH2:37]1)[CH2:32][CH2:31]3)#[N:23]
Reactant: CC(=O)OC1(C#N)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC(C)(O)C#N
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CC(=O)O[C@]1(C#N)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
4-Androsten-3,17-dione (20 g) is dissolved by gentle warming in acetone cyanohydrin (30 ml). The crystals which form after several minutes are filtered, washed with pentane, and then dissolved in a mixture of pyridine (50 ml) and acetic anhydride (50 ml). After 48 hours the volatiles are removed under reduced pressure. The residue is then dissolved in ether and washed successively with 5% hydrochloric acid and aqueous sodium bicarbonate. The organic solution is dried and concentrated to afford a mixture of C-17 epimers of 17-cyano-17-acetoxyandrost-4-ene-3-one. Chromatography affords 17β-Cyano-17α-acetoxyandrost-4-ene-3-one.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[C:7](Cl)(=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11]>>[C:7]([N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6])(=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCC(=O)Cl
Reactant: O=C1NCCO1
Product: C=CCCC(=O)N1CCOC1=O
Yield: 53 %

Procedure:
Using the method of preparation 20 and reagents oxazolidin-2-one (10.22 g, 117.3 mmol) and pent-4-enoyl chloride affords 10.62 g (53%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[N:10]([CH2:17][CH:18]=C)[CH:11](C)[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl>[CH2:1]([O:8][C:9]([N:10]1[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH:17]1[CH3:18])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(C)N(CC=C)C(=O)OCc1ccccc1
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CC1CCC=CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
Allyl-(1-methyl-pent-4-enyl)-carbamic acid benzyl ester (1.036 g, 3.8 mmol) was dissolved in CH2Cl2 (10 ml) and a stream of argon gas was bubbled into the reaction mixture for 10 minutes. Then bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (Strem Chemicals, Grubbs' catalyst, 22 mg, 0.027 mmol) was added and the reaction mixture was refluxed for 2 h. Additional bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (11 mg, 0.014 mmol) was added and the reaction mixture was refluxed for an additional 1.5 hours. The reaction was cooled to RT under argon overnight, then was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 5% EtOAc/hexanes) to give the title compound (0.83 g, 89%): 1H NMR: 7.35–7.20 (m, 5H), 5.65 (1H, m), 5.13 (2H, AB), 4.45–4.05 (m, 2H), 3.56 (1H, d), 2.25–2.10 (m, 2H), 1.90–1.60 (m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=246.2.
Reaction SMILES: COC1C=C2C(=CC=1)CC(=O)CC2.C1([PH2](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41]([CH:45]([CH3:51])[C:46]([O:48]CC)=[O:47])=[CH:40][CH:39]=[CH:38]2>>[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41]([CH:45]([CH3:51])[C:46]([OH:48])=[O:47])=[CH:40][CH:39]=[CH:38]2
Reactant: CCOC(=O)C(C)c1cccc2cc(OC)ccc12
Agent: COc1ccc2c(c1)CCC(=O)C2
Agent: c1ccc([PH2](c2ccccc2)c2ccccc2)cc1
Product: COc1ccc2c(C(C)C(=O)O)cccc2c1

Procedure:
Thus, for example, by reacting 6-methoxy-2-tetralone with the triphenylphosphorane derived from ethyl 2-halopropionate, 2,2-(1'-carbethoxyeth-1', 1'-ylidene)-6-methoxytetralin is prepared. Dehydrogenation thereof provides ethyl 6-methoxynaphthyl-α-methylacetate which upon hydrolysis affords 6-methoxynaphthyl-α-methylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].C(=O)([O-])[O-].[K+].[K+].Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>O1CCCC1>[CH3:1][O:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:27](=[O:28])[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:9][C:8]=1[C:14]([F:16])([F:15])[F:17]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(C)(C)CCOc1ccc(N)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(C)(C)CCOc1ccc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
According to the procedure described in Example 113B, 4-(3-methoxy-3-methylbutoxy)-3-(trifluoromethyl)aniline (490 mg, 1.77 mmoles) was dissolved in 20 mL of dry tetrahydrofuran. To this solution was added potassium carbonate (318 mg, 2.30 mmoles) followed by phenyl chloroformate (360 mg, 2.30 mmoles). The mixture was stirred overnight at room temperature, then purified with silica gel chromatography (using a gradient of 0-30% ethyl acetate/hexanes) to afford phenyl 4-(3-methoxy-3-methylbutoxy)-3-(trifluoromethyl)-phenylcarbamate as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.58 (m, 2H), 7.40 (m, 2H), 7.35-7.1 (m, 4H), 6.9 (m, 1H), 4.10 (m, 2H), 3.22 (s, 3H), 2.1 (m, 2H), 2.1 (m, 2H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH:30]([CH3:34])[CH2:31][C:32]#[N:33])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([CH:30]([CH3:34])[CH2:31][C:32]#[N:33])[CH2:26][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CC#N)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(CC#N)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C
Yield: 53.1 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.33 g, 45.4 mmol), 3-(4-amino-piperidin-1-yl)-butyronitrile (hydrochloride salt) (50.0 mmol), diisopropylethylamine (24.5 ml, 141 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 18 h. The mixture was cooled to 25° C. and was concentrated to approximately 25 ml volume. This material was partitioned between water (200 ml) and CH2Cl2 (2×200 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 6% CH3OH in CH2Cl2) afforded 3-[4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-butyronitrile (11.3 g, 53% over 3 steps) as a yellow-orange foam. LCMS (Method G, ESI): RT=0.70 min, m+H=469.3. This material was used in the next step below without additional characterization.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27]Br)[CH2:9][CH3:10]>CCOCC>[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27][N:3]1[C:4](=[O:6])[CH2:5][NH:1][C:2]1=[O:7])[CH2:9][CH3:10]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: O=C1CNC(=O)N1
Solvent: CCOCC
Product: CCCc1c(OCCCN2C(=O)CNC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
3-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione was prepared as for Example 10 from imidazolidine-2,4-dione and the bromide from Example 7. After aqueous ether work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[C:9]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(Cl)c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=O)c(Cl)c1OCc1ccccc1

Procedure:
A mixture of 78 g of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, 60.7 g of benzyl chloride, 3.9 g of sodium jodide, 74.6 g of potassium carbonate in 0.5 l of 95% ethanol was refluxed for 2 hours. After cooling the mixture was poured in water, the separated product was filtered and then recrystallized from absolute ethanol. 2-chloro-3-benzyloxy-4-methoxybenzaldehyde was obtained, m.p. 86°-88° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:33][C:34]([O:36][CH2:37][C:38]1[CH2:47][S:46][C@@H:41]2[C@H:42]([NH2:45])[C:43](=[O:44])[N:40]2[C:39]=1[C:48]([OH:50])=[O:49])=[O:35].C(N(CC)CC)C>O1CCCC1.CN(C)C(=O)C.O.C(O)(=O)C>[CH3:33][C:34]([O:36][CH2:37][C:38]1[CH2:47][S:46][C@@H:41]2[C@H:42]([NH:45][C:8](/[C:7](/[C:5]3[N:6]=[C:2]([NH2:1])[S:3][CH:4]=3)=[N:11]\[O:12][CH3:13])=[O:10])[C:43](=[O:44])[N:40]2[C:39]=1[C:48]([OH:50])=[O:49])=[O:35]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reaction time: 3.5 h

Procedure:
2,2'-Dithio-bis-5-methyl-1,3,4-thiadiazole (48.09 g) and (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (23.38 g) were suspended in tetrahydrofuran (297 ml) and triphenylphosphine (48.09) was added at 20°-25° C. This mixture was stirred for half an hour to generate 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate in solution. Thereafter, the reaction mixture was cooled to 3°-5° C., diluted with N,N-dimethylacetamide (46.8 ml), water (297 ml) and 7-aminocephalosporanic acid (27.2 g) was added, followed by triethylamine addition in 20 min. The reaction was continued for 3-4 hours at 3°-5° C. Thereafter, acetic acid (18 g) and water (100 ml) were added and the aqueous layer was thoroughly extracted with methylene chloride to remove tetrahydrofuran and other by-products. The aqueous phase containing triethylamine salt of cefotaxime acid was mixed with excess isopropyl alcohol (250 ml) and acidified to pH 2.80 at 0°-5°° C. with hydrochloric acid to precipitate cefotaxime acid. The mixture was then filtered, the solids washed with water, isopropyl alcohol and dried to obtain cefotaxime acid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:29])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.O1CCCC1.[OH-].[Li+].Cl>CO>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:9]2[C:10]([O:17][CH:18]([F:19])[F:20])=[N:11][C:12]3[C:7]([C:8]=2[CH3:29])=[C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])[CH:15]=[CH:14][C:13]=3[F:16])=[CH:27][CH:26]=1
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(Cl)cc2)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12

Procedure:
A solution of [3-(4-chlorobenzyl)-2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.45 g), tetrahydrofuran (5.0 mL), methanol (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (1.3 mL) was stirred at room temperature for 18 hours. The solution was acidified by the addition of 1.0 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Crystallisation of the residue from a mixture of water and propan-2-ol gave title compound as a white solid, 0.33 g.