Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[O:14][CH:13]=[C:12]([C:15](=[N:17][OH:18])[NH2:16])[CH:11]=1)(C(C)(C)C)(C)C.[C:19]1([C:25]2[CH:26]=[C:27]([C:34](Cl)=O)[S:28][C:29]=2[C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1.O>[C:19]1([C:25]2[CH:26]=[C:27]([C:34]3[O:18][N:17]=[C:15]([C:12]4[CH:11]=[C:10]([CH2:9][OH:8])[O:14][CH:13]=4)[N:16]=3)[S:28][C:29]=2[C:30]([F:33])([F:31])[F:32])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(N)=NO)co1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: OCc1cc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)co1
Yield: 10 %

Procedure:
To a solution of 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxyfuran-3-carboximidamide (0.14 g, 0.50 mmol) that was obtained in Example 1 (1d) and 4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyl chloride (0.17 g, 0.60 mmol) in dichloromethane (10 ml) was added N,N-diisopropylethylamine (0.17 ml, 1.0 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 1 hour. After stirring, a saturated aqueous solution of sodium hydrogencarbonate (1.0 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in tetrahydrofuran (1.0 ml) was added tetrabutylammonium fluoride (a 1.0 M solution in tetrahydrofuran, 0.75 ml, 0.75 mmol) with stirring, and the resulting mixture was stirred at 60° C. for 3 hours. After stirring, the reaction mixture was poured into water (20 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (0.20 g) in a yield of 10% as a white crystalline solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[C].[Pd].C(O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:11][CH:10]=1
Reactant: c1ccc(COc2ccc(CCCCn3ccnc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(CCCCn2ccnc2)cc1
Yield: 93.5 %

Procedure:
A mixture of 1-[4-(4-benzyloxyphenyl)butyl]imidazole (13.0 g), palladium-carbon (5%, 10.0 g) and ethanol (100 ml) was subjected to catalitic hydrogenation at room temperature under 1 atom. The catalyst was filtered off, and the filtrate was concentrated to give 1-[4-(4-hydroxyphenyl)butyl]imidazole (8.58 g, 94%). Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 124-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[S:19][C:18]([NH2:20])=[N:17][CH:16]=1>>[Br:14][C:15]1[S:19][C:18]([NH:20][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[N:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ncc(Br)s1
Product: O=C(Nc1ncc(Br)s1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 5-Bromo-thiazol-2-ylamine to produce N-(5-Bromo-thiazol-2-yl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 13A, 13B and 13C to provide the title product.
Reaction SMILES: O=P1([O:10][CH:11]([C:25]#[N:26])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)OCC(C)(C)CO1.[Na].[Cl:28][C:29]([Cl:39])=[CH:30][CH:31]1[CH:33]([C:34](O)=[O:35])[C:32]1([CH3:38])[CH3:37]>O>[O:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH:11]([O:10][C:34]([CH:33]1[CH:31]([CH:30]=[C:29]([Cl:28])[Cl:39])[C:32]1([CH3:38])[CH3:37])=[O:35])[C:25]#[N:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1(C)COP(=O)(OC(C#N)c2cccc(Oc3ccccc3)c2)OC1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Agent: [Na]
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Yield: 77 %

Procedure:
A slurry of 38 g of 2-oxo-2-(3-phenoxy-α-cyanobenzyloxy)-5,5-dimethyl-1,3,2-dioxa-phosphorinane, 26 g of the sodium salt of 3-(2,2-dichloro-vinyl)-2,2-dimethylcyclopropane-1-carboxylic acid and 260 g of diglycol dimethyl ether was heated to 150° C. for 20 hours, while stirring. After cooling, the mixture was poured into water and the product was extracted with ligroin. The ligroin phase was washed 3 times with water and dried over sodium sulphate. After filtration, the ligroin was distilled off from the filtrate in vacuo and the residue was subjected to incipient distillation under a high vacuum. 32 g (77% of theory) of 3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid 3-phenoxy-α-cyano-benzyl ester were obtained as the residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1C=CC=CC=1.C(OCC)(=O)C.CCCCCC.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=C(O)c1ccccc1
Solvent: CCCCCC
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=Cc1ccc(OC)cc1OC)C(=O)OCC
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A solution of 10.0 g (60.2 mmol) of 2,4-dimethoxybenzaldehyde, 10.6 g (66.3 mmol) of diethyl malonate, 0.19 g (1.6 mmol) of benzoic acid and 0.20 ml (2.0 mmol) of piperidine in 43 ml of benzene was heated under reflux for 16 hours, whilst removing the water formed. At the end of this time, it was allowed to cool to room temperature, and then the reaction mixture was diluted with a 2:1 by volume mixture of ethyl acetate and hexane, and the diluted solution was washed with a saturated aqueous solution of sodium hydrogencarbonate, with 1 N aqueous hydrochloric acid, with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried. The solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from a mixture of diisbpropyl ether and hexane, to give 17.1 g (yield 92%) of the title compound as crystals, melting at 40-41° C. (from a mixture of diisopropyl ether and hexane).
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br.C([O-])([O-])=O.[K+].[K+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([O:10][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][Br:27])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC/C(=C(\C(=O)OCCCCCCBr)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Yield: 96.5 %

Procedure:
A solution of 2.6 g of (2Z)-4-(acetyloxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid and 17 g of 1,6-dibromohexane in 30 mL of DMF was stirred at rt with 1.0 g K2CO3 for 1 hr. Then saturated ammonium chloride solution was added and extracted with EtOAc. The organic layer was combined and washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography over silica gel (5–50% EtOAc/hexane) to afford 3.6 g of the titled compound as a white solid. 1H NMR (acetone-d6, 500 M Hz): δ 7.80 (d, 2H), 7.47 (d, 2H), 7.22–7.15 (m, 3H), 7.12–7.05 (m, 2H), 5.21 (s, 2H), 4.27 (t, 2 H), 3.48 (t, 2 H), 3.08 (s, 3H), 1.93 (s, 3H), 1.86–1.80 (m, 2H), 1.74–1.68 (m, 2H), 1.50-1.41 (m, 2H), 1.41-1.34(m, 2H).
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.CO.[CH3:15][C:16]1([CH3:23])[CH:21]([OH:22])[C:19](=[O:20])[O:18][CH2:17]1>>[C:19]([OH:1])(=[O:20])[C@@H:21]([C:16]([CH2:17][OH:18])([CH3:23])[CH3:15])[OH:22]
Reactant: CC1(C)COC(=O)C1O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Product: CC(C)(CO)[C@@H](O)C(=O)O
Temperature: 28 °C
Reaction time: 0.33 h

Procedure:
A liquid medium (pH 6.5) consisting of 1% glucose, 0.5% peptone, 0.5% yeast extract and 0.5% corn steep liquor was dispensed in 5 ml portions into test tubes, and then heat-sterilized by autoclaving at 121° C. for 20 minutes. The various strains mentioned in Table 1 were each inoculated from slants into the medium in the test tubes, and subjected to aerobic shake culture at 28° C. for 5 days. After the cultivation, cells were collected by filtration. Into containers each containing different collected cells was dispensed a 2% D,L-pantolactone solution in Tris-HCl buffer (pH 7.5) in 2 ml portions, and the containers were shaken overnight at 28° C. After the reaction, cells were removed by filtration, and each reaction liquid was subjected to HPLC (Nucleosil 5C18 φ 4.6×l 150 mm; eluent 10% methanol; rate of flow 1 ml/min; wavelength for detection 230 nm) to determine the decrease in pantolactone and the amount of pantoic acid formed. Unreacted pantolactone in the reaction liquid is separated by extraction with ethyl acetate, and pantoic acid remaining in the reaction liquid is then heated under acidification with hydrochloric acid for lactonization. The resultant D-pantolactone was extracted with ethyl acetate. The optical purity of the D-pantolactone thus obtained from the pantoic acid was measured by GLC (Analytical Biochemistry 112, 9-19 (1981)). The results are as shown in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.Cl[C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1>>[CH3:23][O:22][C:16]1[N:17]=[C:18]([O:20][CH3:21])[N:19]=[C:14]([CH:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][C:7]2=[O:12])[N:15]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: COc1ccc2c(c1)C(c1nc(OC)nc(OC)n1)C(=O)N2

Procedure:
5-Methoxy-1,3-dihydro-2H-indol-2-one (1.59 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.97 g) are reacted analogously to Example 1 Variant A. This gives the title compound as solid in an HPLC purity of 92% area (1.39 g, 53% of theory).
Reaction SMILES: [B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:18].[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:22][CH2:21]1.FC(F)(F)S(O)(=O)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[I:18][C:29]1[CH:30]=[CH:31][C:26]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)=[C:27]([CH3:32])[CH:28]=1
Reactant: [IH2+]
Reactant: Cc1ccccc1N1CCN(C)CC1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(I)ccc1N1CCN(C)CC1
Yield: 24.1 %

Procedure:
To a mixture of bis(pyridine)iodonium tetrafluoroborate (2.15 g, 5.78 mmol) and DCM (50 mL) at rt was added 1-methyl-4-o-tolylpiperazine (1.00 g, 5.26 mmol). A solution of trifluoromethanesulfonic acid (1 mL, 11 mmol) in DCM (25 mL) was added over about 3 min at rt. The mixture was then treated with saturated aqueous Na2S2O3 (30 mL), extracted with DCM (2×50 mL), washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether: 20%-100%) to give 1-(4-iodo-2-methylphenyl)-4-methylpiperazine, (0.40 g, 24%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:30]=1B(O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:30]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[F:24])[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: OB(O)c1ccncc1F
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccncc4F)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 3-fluoro-pyridine-4-boronic acid following a procedure analogous to that described for Example 3. LC (method 5): tR=1.32 min; Mass spectrum (ESI+): m/z=398 [M+H]+.
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24]C)[C:17]([NH2:19])=[O:18])C>>[CH3:11][O:13][C:14]1[CH:15]=[C:16]([C:17]2[O:18][CH:10]=[C:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:19]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CCOc1ccc(C(N)=O)cc1OCC
Product: CCOC(=O)Cc1coc(-c2ccc(OC)c(OC)c2)n1

Procedure:
Using ethyl 2-chloroacetoacetate and 16 g of 3,4-diethoxybenzamide and following the procedure of Reference Example 5, 3.8 g of ethyl [2-(3,4-dimethoxyphenyl)oxazol-4-yl]acetate was obtained.
Reaction SMILES: B.O1CCCC1.[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1>O1CCCC1>[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][OH:31])=[CH:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1ccc(-c2cccc(CN3Cc4ccccc4C3)c2)cc1
Agent: B
Solvent: C1CCOC1
Product: OCCc1ccc(-c2cccc(CN3Cc4ccccc4C3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
Borane-tetrahydrofuran complex (1M in tetrahydrofuran) (1.0 mL) was added to a solution of [3′-(1,3-dihydro-iso-indol-2-ylmethyl)-biphenyl-4-yl]-acetic acid (0.444 g) in tetrahydrofuran (30 mL) and stirred at room temperature, under nitrogen, for 3 hours, then evaporated The residue was dissolved in methanol and loaded onto a conditioned SCX cartridge (10 g Varian). The cartridge was washed with methanol (3×20 mL) and then eluted with methanolic ammonia solution (2×20 mL). The combined eluents were concentrated to give the subtitle compound as a dark brown oil (165 mg)
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[F:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[F:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2cccc(F)c2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 29.2 %

Procedure:
To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), 3-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(3-fluorophenoxy)ethyl)benzoate (400 mg, 29%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([N:23]=[C:24]=[O:25])=[CH:19][CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[Br:1])[CH:9]=1)=[O:25]
Reactant: O=C=Nc1ccccc1-c1ccccc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccccc2-c2ccccc2)cc1-c1c(Br)cnn1C
Yield: 46.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.036 g, 0.13 mmol) was treated with 2-biphenylyl isocyanate (0.027 g, 24.0 μL, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 22 (0.031 g, 0.06 mmol, 51%) as a white powder. LCMS m/z (%)=477 (M+H79Br, 100), 479 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.41 (s, 1H), 8.17 (d, J=8.3 Hz, 1H), 7.60 (d, J=2.7, 9.0 Hz, 1H), 7.43-7.51 (m, 3H), 7.37-7.43 (m, 3H), 7.29-7.37 (m, 2H), 7.24 (s, 1H), 7.20 (dd, J=1.6, 7.6 Hz, 1H), 7.11 (dd, J=1.0, 7.4 Hz, 1H), 7.08 (d, J=9.0 Hz, 1H), 3.80 (s, 3H), 3.66 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:8].Br[C:29]([CH3:34])([CH3:33])[C:30]([OH:32])=[O:31]>>[CH3:33][C:29]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][NH:9][C:7](=[O:8])[C:6]3[CH:25]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:26][CH3:27])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)([CH3:34])[C:30]([OH:32])=[O:31]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)(Br)C(=O)O
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(-c2ccc(OC(C)(C)C(=O)O)cc2)cc1

Procedure:
2-Methyl-2-{4-[2-(5-chloro-2-methoxy-benzamido)-ethyl]-biphenyl-4'oxy }-propionic acid was prepared from 4-[2-(5-chloro-2-methoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl and 2-bromo-2-methyl-propionic acid analogous to Example 46. M.p. 145° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:5]([O:6][C:7](=[O:9])[CH3:8])[NH:4][C:3]1=[O:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([N:4]1[CH:5]([O:6][C:7](=[O:9])[CH3:8])[C:2]([CH3:11])([CH3:1])[C:3]1=[O:10])(=[O:14])[CH3:13]
Reactant: CC(=O)OC1NC(=O)C1(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1N(C(C)=O)C(=O)C1(C)C
Yield: 82 %

Procedure:
A mixture of 283.3 mg (1.8 mM) 3,3-dimethyl-4-acetoxyazetidin-2-one, 2 ml pyridine and 2 ml acetic anhydride was heated to 100° in a sealed tube for 36 hours. The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel in hexane/ethyl acetate to yield 295 mg (82%) of 1-acetyl-3,3-dimethyl-4-acetoxyazetidin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][NH2:27])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>ClCCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][NH:27][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CN)c3ccccc23)CC1
Reactant: Cc1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CNC(=O)c3ccccc3C)c3ccccc23)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-aminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester (32) (60 mg, 0.153 mmol) in DCE (5 mL), was added pyridine (62 ul, 0.765 mmol), 2-methyl-benzoyl chloride (22ul, 0.168 mmol) and dimethyl-pyridin-4-yl-amine (4 mg, 0.031 mmol). After stirring at 70° C. overnight, the resultant solution was concentrated in vacuo to give the crude product. Purification using reverse phase HPLC provided the title compound (G-1). LC/MS showed m/z: 510 (M+H)+.
Reaction SMILES: C(P(C(C)(C)C)C1C(OC)=CC=C(OC)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(CC)(C)C.FC(F)(S(O[C:65]1[CH:74]=[CH:73][C:72]2[C:67](=[CH:68][CH:69]=[C:70]([C:75]3[CH:80]=[C:79]([N:81]4[CH:86]=[CH:85][C:84](=[O:87])[NH:83][C:82]4=[O:88])[CH:78]=[C:77]([C:89]([CH3:92])([CH3:91])[CH3:90])[C:76]=3[O:93][CH3:94])[CH:71]=2)[CH:66]=1)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[CH3:96][S:97]([NH2:100])(=[O:99])=[O:98]>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]>[C:89]([C:77]1[C:76]([O:93][CH3:94])=[C:75]([C:70]2[CH:71]=[C:72]3[C:67](=[CH:68][CH:69]=2)[CH:66]=[C:65]([NH:100][S:97]([CH3:96])(=[O:99])=[O:98])[CH:74]=[CH:73]3)[CH:80]=[C:79]([N:81]2[CH:86]=[CH:85][C:84](=[O:87])[NH:83][C:82]2=[O:88])[CH:78]=1)([CH3:91])([CH3:90])[CH3:92]
Reactant: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: COc1ccc(OC)c(P(C(C)(C)C)C(C)(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.0066 g, 7.16 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0083 g, 17 μmol) and milled potassium phosphate tribasic (0.334 g, 1.58 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. t-Amyl alcohol (4 mL) was added, the vial was capped, and the contents were heated to 80° C. and stirred at this temperature for 30 minutes. The reaction mixture was cooled down to the room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.0 g, 1.43 mmol), methanesulfonamide (0.163 g, 1.72 mmol) and t-amyl alcohol (8 mL) were added to the 40-mL reaction vial, and the vial was capped. The reaction temperature was raised to 90° C. and the contents were stirred for 5 hours. HPLC analysis of the reaction mixture showed that the product was formed in 94 area % at 210 nm.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[F:6][C:7]1[C:8]([I:22])=[C:9]([CH3:21])[C:10]2[C:15](=O)[O:14]C(=O)[NH:12][C:11]=2[C:18]=1[O:19][CH3:20]>CN(C)C=O>[NH2:12][C:11]1[C:18]([O:19][CH3:20])=[C:7]([F:6])[C:8]([I:22])=[C:9]([CH3:21])[C:10]=1[C:15]([NH2:5])=[O:14]
Reactant: [NH4+]
Reactant: COc1c(F)c(I)c(C)c2c(=O)oc(=O)[nH]c12
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COc1c(N)c(C(N)=O)c(C)c(I)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
Under nitrogen atmosphere, ammonium acetate (4.62 g, 60.0 mmol) was added to an N,N-dimethylformamide (120 ml) solution of 7-fluoro-6-iodo-8-methoxy-5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (I-31) (4.2 g, 12.0 mmol), followed by stirring at room temperature for 16 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed three times with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was suspended in diisopropyl ether, followed by filtration and drying to obtain the entitled compound (3.74 g, 96%) as a white solid.