Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH:25]=[CH2:26]>>[CH2:26]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[CH2:25][CH:24]=[CH2:23]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: C=CCCBr
Product: C=CCCN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 143 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4-bromobut-1-ene and conditions outlined in procedure V. LCMS: 356 [M+H]; Rt=0.88 min.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:33])[C@@H:8]([O:30][CH2:31][CH3:32])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)C>O.O1CCCC1>[CH2:31]([O:30][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)[C:7]([OH:33])=[O:6])[CH3:32]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 20 °C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
Lithium hydroxide hydrate (0.229 g; 5.45 mmole) dissolved in water (6 ml) was slowly added to a mixture of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl} ethoxy)phenyl]-propanoic acid ethyl ester (2.29 g; 5.24 mmole) in tetrahydrofuran (50 ml) and water (10 ml) at 5° C. The reaction mixture was stirred at 5° C. for 2.5 hours, at 20° C. for 3 hours, at 0° C. for 15 hours and at 20° C. for 3,5 hours. More lithium hydroxide hydrate (44 mg, 1.05 mmole) dissolved in water (1 ml) was added at 10° C. After another 21.5 hours of stirring at 10° C., more lithium hydroxide hydrate (44 mg; 1.05 mmole) dissolved in water (1 ml) was added. The reaction mixture was stirred at 25° C. for 3 hours and then kept at 2° C. for 67 hours. Tetrahydrofuran was evaporated in vacuo and then water and ethyl acetate were added. Insoluble material was filtered off and the phases of the filtrate were separated. The water phase was washed twice with ethyl acetate, acidified with hydrochloric acid (2 M; 3.2 ml) and extracted with ethyl acetate (30 ml). The organic phase was washed twice with water, dried (magnesium sulfate), filtered and the solvent was evaporated in vacuo to give 1.9 g (yield 72% in 2 steps) of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic acid.
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][CH:24]=1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=4)=[CH:25][CH:24]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Reactant: NCCc1ccc(C2=NNC(=O)CC2)cc1
Product: O=C1CCC(c2ccc(CCNCC(O)COc3ccc(CCOCC4CCC4)cc3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Cl[C:2]1[N:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:15][NH2:16].CO>>[CH3:15][NH:16][C:2]1[N:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CN
Reactant: CC(C)(C)OC(=O)c1cccnc1Cl
Solvent: CO
Product: CNc1ncccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 30 h
Yield: 92 %

Procedure:
t-Butyl 2-chloronicotinate (k) (50.0 g, 0.234 mol) was dissolved in a 40% methylamine-methanol solution (300 mL) and the mixture was stirred at room temperature for 30 h. The mixture was evaporated under reduced pressure and the resulting residue was dissolved in EtOAc (750 mL). The EtOAc solution was washed with water, dried over MgSO4 and evaporated under reduced pressure. The obtaining oily crude product was purified by a short silica gel column chromatography (ca. 300 g of silica gel, eluent: EtOAc/hexane=1/3) to give t-butyl 2-(N-methylamino)nicotinate (1) (45.0 g, ca. 92%) contaminated by starting meterial; 1H NMR (CDCl3): δ 1.57 (s, 9H), 3.05 (d, J=5.0 Hz, 3H), 6.49 (dd, J=4.6 and 7.6 Hz, 1H), 7.96 (bs, 1H), 8.04 (dd, J=2.0 and 7.6 Hz, 1H), 8.28 (dd, J=2.0 and 4.6 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 37.1 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.92 g, 6.36 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride (1.07 g, 6.36 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (1.2 g, 37%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1C2=CC=C3C(OC(C4C=CC=CC=4)=C(I)C3=O)=[C:41]2[N:40](C)[N:39]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]3[N:40]([CH3:41])[N:39]=[C:38]([Cl:37])[C:23]3=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(Cl)c2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: Cn1nc(Cl)c2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-chloro-7-iodo-1-methyl-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a pale yellow gum (34 mg). LCMS (Method H): RT=4.76 min, [M+H]+=556/558.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Br[C:25]([CH3:30])([CH3:29])[C:26](Br)=[O:27]>O>[CH3:29][C:25]1([CH3:30])[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=2[O:12]1
Reactant: CC(C)(Br)C(=O)Br
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)NC(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
To solution of 2-amino-4-methoxycarbonylphenol [Acta Chimica Academiae Scientiarum Hungaricae, 99 (1), 49-50 (1979)] (4.78 g) in a mixed solvent of ethyl acetate (50 ml) and water (50 ml) were added sodium hydrogen carbonate (3.6 g) and 2-bromoisobutyryl bromide (6.90 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (70 ml), to the solution was added potassium carbonate (4.35 g) and the mixture was stirred at room temperature for a day. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 2,2-dimethyl-6-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (5.4 g).
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[C:10]([C:13]1[CH:38]=[CH:37][C:16]([CH2:17][NH:18][C:19]2[C:29]3[CH2:28][CH2:27][N:26]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][C:20]=2[Cl:36])=[CH:15][CH:14]=1)(=O)[CH3:11]>C(O)C>[Cl:36][C:20]1[CH:21]=[CH:22][C:23]2[CH2:24][CH2:25][N:26]([C:30](=[O:35])[C:31]([F:34])([F:32])[F:33])[CH2:27][CH2:28][C:29]=2[C:19]=1[NH:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:10](=[N:2][OH:3])[CH3:11])=[CH:38][CH:37]=1
Reactant: NO
Reactant: CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 10.1 %

Procedure:
Add hydroxylamine hydrochloride (19 mg, 0.27 mmol) and pyridine (0.04 mL, 0.54 mmol) to a solution of 6-(4-acetylbenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (115 mg, 0.27 mmol) in ethanol (10 mL). Heat the mixture to reflux for 2 h. Remove the solvent in vacuo and partition the residue between DCM and 0.1N aqueous HCl. Dry the organic phase over Na2SO4, filter and concentrate. Dissolve the oil into the minimum amount of ether and add hexane to precipitate the solid. Filter to obtain 7-chloro-6-[4-(1-hydroxyiminoethyl)-benzylamino]3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a solid (12 mg, 94%) that was used without further purification. MS (ES+) m/z: 440 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.CC([O-])(C)C.[Na+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)[N:3]=2)[CH:19]=1
Reactant: Cc1ccnc(N)c1
Reactant: Brc1cccc(-c2cnco2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccnc(Nc2cccc(-c3cnco3)n2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
A sealed tube with a teflon screw cap was charged with 2-bromo-6-oxazol-5-ylpyridine (4.00 g, 17.8 mmol), 2-amino-4-methylpyridine (2.30 g, 21.3 mmol), Pd2(dba)3 (320 mg, 0.349 mmol), (±)-BINAP (440 mg, 0.707 mmol), NaOtBu (2.40 g, 25.0 mmol) and anhydrous toluene (80 ml) and heated to 90° C. with stirring for 1 h. The cooled reaction mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2, eluting with 30% EtOAc in cyclohexane to afford the title compound as a yellow-orange solid (1.89 g, 42%). 1H NMR (300 MHz, DMSO-d6): δ=9.78 (s, 1H), 8.53 (s, 1H), 8.11 (d, J=5.0 Hz, 1H), 7.84-7.59 (m, 4H), 7.25 (d, J=7.3 Hz, 1H), 6.76 (d, J=5.0 Hz, 1H), 2.32 (s, 3H). (ESI+) m/z 253 (M+H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cccnc3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 92.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(2-methylpyridin-3-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.05 g, 0.08 mmol) prepared in Example 70c, triethylsilane (0.06 mL), trifluoroacetic acid (0.08 mL) and dichloromethane (0.75 mL), to yield the title compound (34 mg, 98%) as a colorless solid.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)C.O.[NH2:23][NH2:24]>O>[C:2]1([C:1]2[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:24][N:23]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: O
Product: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Temperature: 85 °C

Procedure:
22.4 Grams (0.10 moles) of dibenzoylmethane in 200 ml. of isopropyl alcohol are heated to reflux (approximately 85° C.), and to this is added hydrazine hydrate at a rate sufficient to maintain reflux. Thirty minutes after addition, the reaction is complete. The reaction mixture is permitted to cool and is then poured into water. The desired product as a fine white solid precipitates and is filtered, washed with cold water and dried, yielding 22.1 grams of product, melting point 198.5° C. to 200.5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([O:14]C(OCC)C)[CH2:11][C@H:10]([C:20]([O:22][CH3:23])=[O:21])[C@H:9]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]([C:20]([O:22][CH3:23])=[O:21])[C@H:9]1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)O[C@@H]1C[C@H](C(=O)OC)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C[C@@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 2-benzyl 3-methyl(2S,3S,5R)-1-benzyl-5-(1-ethoxyethoxy)piperidine-2,3-dicarboxylate (5.70 g, 0.0125 mol) in 100 mL of THF was added 20 mL of water followed by 20 mL of 1N HCl. The mixture was stirred at rt fro 1 h. After diluted with EtOAc, the mixture was neutralized with 1N NaOH, washed with brine, dried. The residue obtained after concentration was applied on silical, eluting with 0 to 50% EtOAc in hexane, to provide the alcohol compound (4.80 g, 89.6%). MS (ESI): (M+H)+=384.2.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:32])[CH:24]([NH:25][C:26](=[S:31])[CH2:27][CH2:28][C:29]#[N:30])[C@H:21]2[S:20][CH2:19][C:18]=1O)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:35]>>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:32])[CH:24]([NH:25][C:26](=[S:31])[CH2:27][CH2:28][C:29]#[N:30])[C@H:21]2[S:20][CH2:19][C:18]=1[Br:35])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: N#CCCC(=S)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Product: N#CCCC(=S)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Br)CS[C@H]12

Procedure:
The desired product is prepared from 7-cyanomethylthioacetamido-3-cephem-3-ol-4-carboxylic acid benzhydryl ester using the procedure described in Example 5, but replacing phosphorus trichloride with phosphorus tribromide.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][NH2:52])[CH:46]=1.NC(C)(C)CO>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:52][CH2:51][C:47]4[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=4)=[CH:35][CH:36]=3)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NCc1cccnc1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)CO
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCCNCc2cccnc2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 57 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-phenyl]methyl}-5-isopropyl-1H-pyrazole and 3-picolylamine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=1[I:21].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[C:15]=1[I:21])=[CH:7]2
Reactant: Oc1cnc2c(F)cccc2c1
Reactant: Fc1cccc(F)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Fc1cccc(Oc2cnc3c(F)cccc3c2)c1I
Temperature: 130 °C
Reaction time: 24 h
Yield: 22.1 %

Procedure:
16 ml of N-methylpyrrolidone was added to 1.06 g of 8-fluoro-3-hydroxyquinoline, 1.94 g of 2,6-difluoroiodobenzene, and 1.7 g of potassium carbonate, and the mixture was stirred for 24 hours at 130° C. The reaction solution was purified by silica gel column chromatography, and 0.55 g of 8-fluoro-3-(3-fluoro-2-iodophenoxy)-quinoline was obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C[O:25][C:26](=[O:63])[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([CH2:60][CH3:61])([C:43]3[CH:48]=[CH:47][C:46]([C:49]#[C:50][C:51]4([OH:58])[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]4)=[C:45]([CH3:59])[CH:44]=3)[CH2:41][CH3:42])=[CH:36][C:35]=2[CH3:62])[CH:33]=1.C(=O)(O)[O-].[Na+]>>[CH2:41]([C:40]([C:37]1[CH:38]=[CH:39][C:34]([C:32]2[CH:33]=[C:28]([CH2:27][C:26]([OH:63])=[O:25])[CH:29]=[N:30][CH:31]=2)=[C:35]([CH3:62])[CH:36]=1)([C:43]1[CH:48]=[CH:47][C:46]([C:49]#[C:50][C:51]2([OH:58])[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)=[C:45]([CH3:59])[CH:44]=1)[CH2:60][CH3:61])[CH3:42]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.4 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 mL, 1.0 mmol) was added to the mixture containing [5-(4-{1-ethyl-1-[4-(1-hydroxy-cycloheptylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (32.0 mg), and the mixture was stirred at room temperature for 15 minutes. The mixture was further stirred with microwave heating at 100° C. for five minutes. A sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Shiseido CAPCELL PAK C18 MGII, 20 mm I.D.×50 mm, methanol:20 mM ammonium acetate solution=55:45 to 100:0, mL/min). A sodium bicarbonate solution was added to the eluate, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to give the target compound as a colorless oil (10.1 mg, 22% in two steps).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[NH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>>[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[N:18][C:28]([NH:27][C:22]1[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=1)=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: N=C1CCCN1Cc1ccccc1
Agent: F[B-](F)(F)F
Product: O=C(N=C1CCCN1Cc1ccccc1)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The fluoroborate salt of 1-benzyl-2-iminopyrrolidine (6.55 g; 0.025 mole) is converted to the free base (4.36 g.; 0.025 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 4.29 g.; (0.025 mole) of 3-chloro-4-fluorophenylisocyanate is added. The reaction mixture is stirred at room temperature for 1 hour and then evaporated to dryness in vacuo to give a soild residue. Recrystallizations from acetone-ether yields the pure product, 1-(1-benzyl-2-pyrrolidylidene)-3-(3-chloro-4-fluorophenyl)urea, m.p. - 131°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].O.[C:39]([O:42][CH2:43][CH3:44])(=O)C>>[C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH2:44][C@H:43]1[CH2:39][O:42]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[C:2]([Cl:1])[CH:7]=1)#[N:20]
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(C#N)cc23)cc1Cl
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)cc1Cl
Temperature: 50 °C

Procedure:
N-[2-Chloro-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl]-N′-methylurea (600 mg) was added to dimethylformamide (4 ml), and then p-toluenesulfonic acid (2R)-glycidyl ester (484 mg) and potassium carbonate (450 mg) were added thereto and the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized with ethyl acetate to obtain the title compound (650 mg) as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1cc(I)c(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Clc1ccc(-c2cc(Cl)ncc2Br)cc1
Temperature: 20 °C
Yield: 70.7 %

Procedure:
To a degassed solution of 5-bromo-2-chloro-4-iodopyridine (Ref. Cottet, F. and Schlosser, M. Tetrahedron 60, 11896-11874 (2004)) (2.0 g, 6.3 mmol), 4-chlorophenylboronic acid (1.1 g, 6.9 mmol) and K2CO3 (1.7 g, 12.6 mmol) in 1,2-dimethoxyethane (24 mL) and H20 (8.0 mL) was added Pd(PPh3)4 (0.727 g, 0.63 mmol) under argon at 20° C. The reaction mixture was refluxed for 15 h under argon, then allowed to cool to 20° C. The reaction was quenched by addition of H2O (30 mL) and extracted with EtOAc (50 mL×3). The combined organic was washed with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was crystallized in EtOH to afford 1.35 g of the title compound as a light beige solid as the first crop. The second crop of the title product (0.44 g) was also isolated by concentrating the mother liquid followed by recrystallization in EtOH. LC/MS (method B): retention time=2.03 min, [M+H]+=301.9.