Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[CH2:5][CH2:6][C:7](NCC)=[C:8]2[C:17]=1C(=O)C1C(=CC=CC=1)C2=O)C.N[C:24]1([CH:46]=[CH:45][C:44](OC)=[CH:43][CH2:42]1)[NH:25][C:26]1[CH2:27][CH2:28][CH:29]=[C:30]2[C:39]=1[C:38](=[O:40])[C:37]1[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:31]2=[O:41]>>[NH:3]([C:29]1[CH2:28][CH2:27][C:26]([NH:25][C:24]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:39]2[C:30]=1[C:31](=[O:41])[C:32]1[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]2=[O:40])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:17]=1
Reactant: CCNC1=C2C(=O)c3ccccc3C(=O)C2=C(NCC)CC1
Reactant: COC1=CCC(N)(NC2=C3C(=O)c4ccccc4C(=O)C3=CCC2)C=C1
Product: O=C1C2=C(Nc3ccccc3)CCC(Nc3ccccc3)=C2C(=O)c2ccccc21

Procedure:
1,4-bis(ethylamino)-2,3-dihydroanthraquinone and leuco dyes bearing CI numbers 61100, 61105, 61107, 61116, 61120, 61140, 61500, 61505, 61510, 61515, 61520, 61525, 61530, 61535, 61540, 61545, 61565 and 61650 [for instance, 1-amino-4-methoxyanilino-2,3-dihydroanthraquinone and 1-p-(2-hydroxyethylamino)anilino-4-methylamino-2,3-dihydroanthraquinone].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([N+:22]([O-:24])=[O:23])=[CH:17][CH:18]=2)[NH:13][C:12]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:27]>O=P(Cl)(Cl)Cl>[Cl:27][C:12]1[N:11]([CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([N+:22]([O-:24])=[O:23])=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)n1CCc1ccc(Cl)cc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2ccc([N+](=O)[O-])cc2nc(Cl)n1CCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.8 %

Procedure:
3-[2-(2,4-Dichlorophenyl)ethyl]-7-nitro-2,4(1H, 3H)-quinazolinedione (2.0 g, 5.26 mmol) and PCl5 (1.2 g, 5.79 mmol) were added to a flask containing POCl3 (20 mL) and the resulting solution was refluxed with stirring for 6 hours. The reaction was allowed to cool to RT and stirred overnight at this temp. The POCl3 was removed under reduced pressure and CH2Cl2 was added to the residue. The unreacted starting material was removed via vacuum filtration and the product was purified by silica gel flash chromatography (100% CH2Cl2 eluent) to give the product (0.96 g, 46% yield) as a white solid. 1H NMR (DMSO-D6) 400 MHz δ ppm 8.35-8.25 (m, 3H), 7.58 (d, J=2.2 Hz, 1H), 7.41-7.34 (m, 2H), 4.41 (t, J=7.5 Hz, 2H), 3.15 (t, J=7.5 Hz, 2H) ppm.
Reaction SMILES: [Na].[CH2:2](O)[CH3:3].[C:5]([CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:7][CH2:8][CH3:9])=[O:6].C(I)C>[Cl-].[Na+].O.O>[CH2:2]([C:10]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])[CH3:3]
Reactant: CCO
Reactant: CCOC(=O)C1CCCC1=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCI
Solvent: O
Product: CCOC(=O)C1(CC)CCCC1=O
Yield: 99 %

Procedure:
In a three-necked flask 5.0 g. of sodium metal was dissolved in 250 ml. of dry ethanol and 31.24 g. (0.20 mole) 2-carboethoxycyclopentanone added. To the resulting yellow solution 18.4 ml. (0.23 mole) ethyl iodide was added dropwise and the mixture heated at reflux for two hours. After cooling, 250 ml. of brine and 50 ml. of water were added and the mixture extracted with ethyl ether (2×100 ml.). After drying (MgSO4) and evaporation of solvent 36.5 g. (99%) of 2-ethyl-2-carboethoxycyclopentanone was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][NH:3]1.F[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:36][O:35][C:33]([C:32]1[CH:37]=[CH:38][C:29]([N:3]2[C:2](=[O:1])[C:6]3([CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:13])[CH2:10][CH2:11]3)[N:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:4]2)=[CH:30][CH:31]=1)=[O:34]
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Yield: 99.4 %

Procedure:
Benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.50 g, 1.37 mmol), methyl 4-fluorobenzoate (0.21 g, 1.37 mmol), and potassium carbonate (0.38 g, 2.74 mmol) in dimethyl sulfoxide were stirred at 100° C. for 3 days. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by Biotage flash chromatography (gradient from 0 to 30% ethyl acetate/hexanes) to give product as an oil (0.68 g, 21%); 1H NMR (DMSO-d6); δ1.90 (d, 15.6 hz, 2H); 2.25-2.34 (m, 2H); 3.56 (m, 2H); 3.98-4.02 (m, 2H); 5.13 (m, 2H); 5.24 (s, 2H); 6.92 (t, J=8.4 hz, 1H); 6.98 (d, J=8.8 hz, 2H); 7.26-7.39 (m, 7H); 8.02 (dd, J=10 Hz and 17.6 Hz, 4H); MS for C29H29N3O5 m/z 500 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH3:21])[N:5]=[C:4]([C:22]2[C:27]([CH2:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:30][CH3:31])[N:3]=1.CC(N(C)C)=O.[O:38]1[C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:28]([C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:30][CH3:31])[C:22]=1[C:4]1[N:3]=[C:2]([N:45]2[CH2:46][CH2:47][C:42]3([O:41][CH2:40][CH2:39][O:38]3)[CH2:43][CH2:44]2)[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH3:21])[N:5]=1)[CH3:29]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(Cl)n1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(N2CCC3(CC2)OCCO3)n1
Temperature: 85 °C

Procedure:
To a vial containing [4-chloro-2-(2,6-diethyl-phenyl)-6-methyl-pyrimidin-5-ylmethyl]-methyl-(1S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (1.0 mL of a 0.2M DMA solution, 0.2 mmol) is added 1,4-dioxa-8-azaspiro(4,5)decane (1.0 ml of a 1.0M DMA solution, 5.0 eq.) and the resulting solution is vortex heated at 85° C. for 12 h. Once the reaction has cooled to room temperature, EtOAc (1.0 mL) and sat NaHCO3 (1.0 mL) is added and the organic layer is plated directly onto a SiO2 preparatory chromatography plate and the product is eluted using hexanes:Et2O 1:1, which affords the title compound as a colorless oil. [mass expected (540.74); mass found (540.43)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:18]=3[N:14]2[CH2:13][CH2:12]1)[C:5]([OH:7])=O.[NH4+].O[N:31]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([CH:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[C:18]=3[N:14]2[CH2:13][CH2:12]1)[C:5]([NH2:31])=[O:7]
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(C(=O)O)cc1Cl
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 3-chloro-4-[8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl]benzoic acid (45.4 mg, 0.109 mmol) in N,N-dimethylformamide (1.0 mL) were added 1-hydroxy-1H-benzotriazole ammonium salt (21.4 mg, 0.141 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (22.9 mg, 0.119 mmol). The reaction mixture was stirred at room temperature for 8 hr. The reaction mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2), aqueous saturated sodium hydrogen carbonate (×1) and brine (×1), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless solid (36.4 mg, 0.0872 mmol, 80%).
Reaction SMILES: [C:1]([CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:3])[CH3:2].[BH4-].[Na+].Cl>CO>[OH:3][CH:1]([CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: COC(=O)C(Cc1ccccc1)C(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Cc1ccccc1)C(C)O
Yield: 99.7 %

Procedure:
Methyl 2-acetyl-3-phenylpropionate (60 g) is dissolved in methanol (300 ml), and thereto is added portionwise sodium boro hydride (2.9 g) with stirring under ice cooling, and the mixture is stirred under ice cooling from 2 hours. The reaction mixture is adjusted to pH 1 with 10% hydrochloric acid, and methanol is distilled off under reduced pressure. The residue is extracted with ethyl acetate. The extract is washed with diluted aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and ethyl acetate is distilled off under reduced pressure to give methyl 2-(1-hydroxyethyl)-3-phenylpropionate (60.4 g). IR (film; cm-1): 3400 (broad), 1730
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][S:6][C:7]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].NO[C:25]1CCCCCC=1>C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][S:6][C:7]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:8]=1[C:9]([O:11][CH3:25])=[O:10]
Reactant: NOC1=CCCCCC1
Reactant: Cc1cccc(CSc2ccc(C(F)(F)F)cc2C(=O)O)c1
Solvent: CCOCC
Product: COC(=O)c1cc(C(F)(F)F)ccc1SCc1cccc(C)c1

Procedure:
A mixture of 2-(m-methylbenzylthio)-5-trifluoromethylbenzoic acid (1.65 g, 5.06 mmol) and 1-aza-2-methoxy-1-cycloheptene (643 mg, 5.06 mmol) was heated at 80°-85° C. for 18 hours, cooled, diluted with diethyl ether, washed with 1N aqueous sodium hydroxide solution, water, dried (sodium sulfate), and evaporated. The product was crystallized from methanol; yield 885 mg (51%). The 60 MHz NMR spectrum in chloroform-d was in accord with the desired structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH2:30]([O:29][CH2:28][CH2:27][NH:26][C:24]([C:7]1[C:6](=[O:32])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:39]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:40])[C:14]2[C:9]([C:8]=1[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH:13]=2)=[O:25])[CH3:31]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Step 2 of Example 373 and was obtained as a white solid: ES+ MS: 556 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([NH2:12])=[N:9][CH:8]=2)=[CH:5][C:4]([C:13]([F:16])([F:15])[F:14])=[N:3]1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([NH:12][C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:13]([F:16])([F:14])[F:15])[CH:5]=2)=[CH:8][N:9]=1)=[O:21]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cn1nc(C(F)(F)F)cc1-c1cnc(N)s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(F)(F)F)cc1-c1cnc(NC(=O)c2c(F)cccc2F)s1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a mixture of 5-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-1,3-thiazole-2-ylamine (63, 4.6 mg, 0.019 mmol) in 0.5 ml DCM were added 2,6-difluorobenzoyl chloride (5 μl, 2 eq), DIEA (17 μl, 3 eq) and DMAP (2 mg). After stirred at r.t for overnight, the reaction mixture was worked up with DCM/aq. NaCO3, the DCM phase was concentrated to dryness. The solid residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1). 0.1 ml of 1N NaOH were added and mixture was stirred at r.t for 1 h before worked up DCM//aq. NaCO3. DCM phase was concentrated and subjected to silica gel flash column to give 5.6 mg of (2,6-difluorophenyl)-N-{5-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl] (1,3-thiazol-2-yl)}carboxamide (64) as white solid (yield: 75.9%; purity>95%). LC-MS: calcd. for C15H9F5N4OS: 389 (M+1).
Reaction SMILES: BrN[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>C1(C)C=CC=CC=1>[CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: BrNc1cccc2ccccc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc2ccccc2c1
Temperature: 70 °C

Procedure:
A mixture of 4-bromoaminonaphthalene (5.0 g) and di-tert-butyldicarbonate (5.9 g) in 100 mL toluene was heated at 70° C. for 15 hours, cooled to room temperature and the volatiles removed in vacuo. The residue was dissolved in ethyl acetate, washed with 0.1M HCl and brine, dried (MgSO4) and the volatiles removed in vacuo. Recrystallization of the residue from hot petroleum ether provided LXXXIV. 4-Vinylpyridine (0.86 mL) was added to a suspension of LXXXIV (2.0 g) in 5 mL of triethylamine, followed by palladium (II) acetate (0.014 g) and tri-ortho-tolylphosphine (0.038 g). The mixture was heated at 110° C. for four hours, cooled to room temperature, diluted with water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the volatiles removed in vacuo. Purification of the residue by flash chromatography using 50% ethyl acetate in hexanes as the eluent and concentration of the product-rich fractions in vacuo provided naphthalene LXXXV. A solution of LXXXV (0.34 g) in 10 mL TFA was stirred one hour and the volatiles removed in vacuo to provided LXXXVI. LXXXVI and LXVII (Example 1) were reacted according to Method B to provide 6, m.p. 203° C. (dec).
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:16]=[CH:15]1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:3]1([C:16]2[C:17]3[C:22](=[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:20]=[CH:19][CH:18]=3)[NH:14][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CS(=O)(=O)Nc1cccc2cc[nH]c12
Reactant: CCC1(O)CCc2cc(F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1(c2c[nH]c3c(NS(C)(=O)=O)cccc23)CCc2cc(F)ccc21
Yield: 84.3 %

Procedure:
Combine 1-ethyl-5-fluoro-indan-1-ol (502 mg, 2.79 mmol, 1.30 equivalents), N-(1H-Indol-7-yl)-methanesulfonamide (450 mg, 2.14 mmol, 1.00 equivalents), and trifluoroacetic acid (0.25 ml, 3.21 mmol, 1.50 equivalents) in dichloromethane (5 ml) and stir at room temperature under nitrogen overnight. Load the solution on silica and purify eluting with 0 to 100% ethyl acetate/hexanes over 25 minutes to obtain the title compound (672 mg, 84%). LC-MS m/z 373.0 (M++1). The racemic mixture is separated on a Chiralcel OJ 8×33 cm column eluting with methanol with 0.2% dimethylethylamine (flow: 375 ml/min, UV detection at 230 nm) to provide the individual enantiomers, Examples 1A and 1B, in 96.3% ee and 97.4% ee, respectively.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]OC1C=CC(Cl)=CC=1Br)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([I:26])=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=1[I:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: Oc1cccc(Cl)c1I
Product: CC(C)(C)OC(=O)COc1cccc(Cl)c1I
Yield: 86 %

Procedure:
Following the general method as outlined in Intermediate 1, starting from 3-chloro-2-iodophenol (prepared as described in J. Org. Chem., 2005, 70, 6548-6551), the title compound was obtained as a white solid in 86% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]1[N:16]([CH2:17][C@H:18]([OH:20])[CH3:19])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: O=CCC1Cc2cc(F)ccc2C1=O
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)Cn1ccc2c1-c1ccc(F)cc1C2
Reaction time: 0.75 h
Yield: 79.4 %

Procedure:
A solution of 2.88 g of (RS)-2-(2-oxoethyl)-5-fluoro-1-indanone and 100 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 4.51 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 2.75 g (79%) of (R)-1-(6-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]([NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH:17][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: COC(=O)NC(CN)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC(CNC(=O)c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
0.22 g of benzoyl chloride was added to 10 ml of a solution of 0.25 g of N-(methoxycarbonyl)-1-phenylethylenediamine and 0.2 g of triethylamine in dichloromethane under ice cooling, and the mixture was stirred for 30 minutes at 5° C. and at room temperature for 3 hours. The reaction mixture was rinsed with water, the organic layer was dried over magnesium sulfate anhydrous, and the residual oily material obtained under a reduced pressure was purified by column chromatography on silica gel (2:1 hexane/ethyl acetate) to obtain 0.28 g of the title compound as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[K+].[Br-]>>[CH2:19]([O:18][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOc1cc(-c2ccccc2)c(OCC(=O)OC)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [K+]
Product: CCCCOc1cc(-c2ccccc2)c(OCC(=O)O)c(-c2ccccc2)c1

Procedure:
The title compound was prepared as an off white solid (0.167 g, 85%) from (5′-butoxy-[1,1′;3′1″]terphenyl-2′-yloxy)acetic acid methyl ester using a procedure similar to step 2 of Example 36, mp 92-94° C.; 1H NMR (DMSO-d6) δ0.92 (t, J=7.5 Hz, 3H), 1.38-1.49 (m, 2H), 1.65-1.74 (m, 2H), 3.64 (s, 2H), 4.02 (t, J=6.6 Hz, 2H), 6.87 (s, 2H), 7.33-7.39 (m, 2H), 7.39-7.44 (m, 4H), 7.57-7.61 (m, 4H), 12.30-12.55 (bs, 1H); IR (KBr) 3420, 3060, 2930, 2860, 2770, 2590, 1725, 1590, 1570, 1460, 1420, 1360, 1260, 1235, 1215, 1195, 1075, 1050, 1010, 925, 760, 750, 700, and 620 cm−1; mass spectrum [(+) ESI], m/z 394 (M+NH4)+; Anal. Calcd. for C24H24O4: C, 76.57; H, 6.43; N, 0.00, Found: C, 76.33; H, 6.55; N, −0.04.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[CH:32]=[CH:31][O:30][N:29]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO.O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[CH:32]=[CH:31][O:30][N:29]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCc2ccon2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCc2ccon2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 73.5 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-(3-isoxazolylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.20 g.) and conc. hydrochloric acid (1.09 g.) in methanol (18 ml.) and tetrahydrofuran (9 ml.) was stirred at room temperature for 2 hours. The solution was treated in a similar manner to that of Example 5-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(3-isoxazolylmethoxyimino)-acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.83 g.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](/[O-:7])\[CH3:6].[Na+].[I-].[K+].Br[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1CCCN(C)C1=O>[CH3:1][O:2][C:3](=[O:8])[CH:4]([C:5](=[O:7])[CH3:6])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)/C=C(\C)[O-]
Reactant: BrCCCc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CCCc1ccccc1)C(C)=O
Temperature: 80 °C

Procedure:
85 g (616 mmol) of sodium (2E)-4-methoxy-4-oxo-2-buten-2-olate suspended in 1,3-dimethyltetrahydro-2(1H)-pyrimidone and 3.50 g (21.1 mmol) of potassium iodide are treated dropwise with 129 g (646 mmol) of 1-bromo-3-phenylpropane and the mixture is stirred under reflux at 80° C. for 1 h. The cooled mixture is then added to ice water and extracted with diethyl ether. The ether phase is washed with sodium thiosulphate solution, dried, concentrated and chromatographed. The eluent used is cyclohexane containing an increasing proportion of ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]O)#[N:2].P(Br)(Br)[Br:14]>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][Br:14])#[N:2]
Reactant: COc1ccc(CO)cc1C#N
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1ccc(CBr)cc1C#N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-cyano-4-methoxybenzyl alcohol (500 mg) in dichloromethane (5 mL) was added phosphorus tribromide (0.146 mL) under ice-water cooling. The mixture was stirred at 0° C. for 3 hours and partitioned between chloroform and water. The separated organic layer was washed successively with water, an aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residual solid was triturated with diisopropyl ether to give 3-cyano-4-methoxybenzyl bromide as an off-white solid (456.3 mg).