Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=O)=[CH:4][CH:3]=1.[F:21][C:22]([F:34])([F:33])[S:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:30]([C:29]3[CH:31]=[CH:32][C:26]([S:23]([C:22]([F:34])([F:21])[F:33])(=[O:25])=[O:24])=[CH:27][CH:28]=3)[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(-n2c(-c3ccc(Br)cc3)ccc2-c2ccc(Br)cc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a slurry of the product from Example 26E (0.60 g, 1.52 mmol) and 4-(trifluoromethylsulfonyl)aniline (0.51 g, 2.27 mmol) in toluene (12 mL) was added a 1N solution of titanium(IV) chloride (1.6 mL, 1.6 mmol) in toluene. The mixture was stirred overnight at room temperature and then heated to reflux for 3 hours. The cooled mixture was filtered and the solid residue was suspended in a mixture of water and diethyl ether. The solid was diluted with water and ether and stirred vigorously for 15 minutes. The mixture was filtered and then washed thoroughly with diethyl ether to give the title compound as a crude mixture that was used in subsequent reactions without further purification (0.60 g, 68% yield crude).
Reaction SMILES: [C:1]([C:5]1([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:12][C:8]2=[CH:9][S:10][CH:11]=[C:7]2[CH2:6]1)([O:3]C)=[O:2].[OH-].[K+]>C(O)C.O.O1CCCC1>[C:1]([C:5]1([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:12][C:8]2=[CH:9][S:10][CH:11]=[C:7]2[CH2:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1(SCc2ccc(OC)cc2)Cc2cscc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CSC2(C(=O)O)Cc3cscc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 5-(carbomethoxy)-5-(4-methoxybenzylthio)-2,4,5,6-tetrahydro-cyclopenta[c]thiophene (1.14 g, 3.55 mmol) in 95% ethanol (25 mL), water (12 mL) and tetrahydrofuran (15 mL). Treat with potassium hydroxide (1.3 g, 23 mmol) and stir at room temperature for 1 hour. Filter and evaporate the solvent in vacuo. Partition between water (125 mL) and ether (75 mL). Separate the aqueous phase and acidify with cold concentrated hydrochloric acid. Extract with methylene chloride (75 mL), dry (Na2SO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give 5-(carboxy)-5-(4-methoxybenzylthio)-2,4,5,6-tetrahydrocyclopenta[c]thiophene.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([OH:13])([C:9]([F:12])([F:11])[F:10])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([I+:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.[C:44](Cl)(=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:46][C:45]([CH3:48])([CH3:47])[C:44]([O:13][C:3]([C:2]([F:1])([F:14])[F:15])([C:9]([F:12])([F:10])[F:11])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6])=[O:49].[C:33]([C:30]1[CH:31]=[CH:32][C:27]([I+:26][C:23]2[CH:22]=[CH:21][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:25][CH:24]=2)=[CH:28][CH:29]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=S(=O)([O-])CC(O)(C(F)(F)F)C(F)(F)F
Agent: CC(C)(C)c1ccc([I+]c2ccc(C(C)(C)C)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC(CS(=O)(=O)[O-])(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
Into a mixture solution of 6.5 g (0.010 mole) of bis(4-tert-butylphenyl)iodonium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate prepared in Synthesis Example 1-13, 2.2 g (0.022 mole) of triethylamine, 0.2 g (0.002 mole) of 4-dimethylaminopyridine, and 25 g of methylene chloride was added 2.4 g (0.020 mole) of pivaloyl chloride, and they were stirred at room temperature for 8 hours. Thereafter, the reaction was terminated by adding 22 g of 5% hydrochloric acid, and then the organic layer was separated, washed by water, and concentrated under reduced pressure. Into the concentrated solution was added methyl isobutyl ketone, and the resulted mixture was concentrated again under reduced pressure to distil the remaining water out. The obtained residue was recrystallized by adding diisopropyl ether, and then the crystals were recovered and dried to obtain the intended bis(4-tert-butylphenyl)iodonium 2-(2,2-Dimethylpropionyloxy)-3,3,3-trifluoro-2-trifluoromethylpropane-1-sulfonate (1.8 g of white crystals (yield 23%)). The structure of the intended product is shown below.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:35]([CH:37]1[O:39][CH2:38]1)Br.O>CN(C)C=O>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH2:35][CH:37]1[CH2:38][O:39]1)[N:19]=[CH:18][CH:17]=[C:16]2[O:15][C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 345) (146 mg) was dissolved in N,N-dimethylformamide (4 ml) to prepare a solution, potassium carbonate (162 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (98 mg, yield 59%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N+:10]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CCN)cc1F
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 2-fluoro-1-methoxy-4-(2-nitro-vinyl)benzene (1.5 g, Intermediate (2)] in THF (50 mL) is treated dropwise with a solution of lithium aluminum hydride in ether (23 mL, 1M). The mixture is heated at 40° C. for 3 hours, cooled to room temperature, diluted with ether and quenched with Na2SO4.10 H2O (104 g). After standing at room temperature overnight the reaction mixture is filtered and the filtrate is evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc to give 2-(3-fluoro-4-methoxy-phenyl)-ethylamine [0.81 g, Intermediate (3)] as an oil. MS: 170 (M+H); 1H NMR (CDCl3): δ 6.9-7 (3H, m); 3.85 (3H, s); 2.95 (2H, t); 2.7 (2H, t).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.Cl.N>C(OC(=O)C)(=O)C>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccncc1
Agent: Cl
Agent: N
Solvent: CC(=O)OC(C)=O
Product: Oc1ccc(C=Cc2ccncc2)cc1
Reaction time: 1 h
Yield: 82.7 %

Procedure:
In 65.8 g of acetic anhydride, 20.0 g of γ-picolin and 26.2 g of p-hydroxybenzaldehyde were refluxed for 24 hours. The resultant reaction mixture and 100 ml of 6 N hydrochloric acid added thereto were further refluxed for 60 minutes and then cooled. The reaction product was neutralized by addition of aqueous ammonia and stirred for 1 hour. The yellow crystals which consequently deposited therein were separated by filtration. The crystals were recrystallized from a mixed solvent of ethanol and ether, to afford 35 g of 4-[2-(4-hydroxyphenyl)-ethenyl]-pyridine having a melting point of 272° to 275° C.
Reaction SMILES: C1(N=C=[O:9])C=CC=CC=1.[Si:10]([N:17]1[C@H:20]([C:21]#[CH:22])[CH2:19][C:18]1=[O:23])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[CH2:24]([N:26](CC)CC)[CH3:25]>C1C=CC=CC=1.[N+](CC)([O-])=O>[Si:10]([N:17]1[C@H:20]([C:21]2[O:9][N:26]=[C:24]([CH3:25])[CH:22]=2)[CH2:19][C:18]1=[O:23])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: O=C=Nc1ccccc1
Reactant: CCN(CC)CC
Reactant: C#C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C
Solvent: c1ccccc1
Solvent: CC[N+](=O)[O-]
Product: Cc1cc([C@@H]2CC(=O)N2[Si](C)(C)C(C)(C)C)on1

Procedure:
A solution of phenylisocyanate (0.93 ml) in benzene (5 ml) was added to a mixture of 1-tert-butyldimethylsilyl-4(S)-ethynyl-2-azetidinone (1.0 g) in benzene (10 ml), nitroethane (0.35 ml), and triethylamine (0.1 ml) in benzene (5 ml) at room temperature. The reaction mixture was refluxed for 8 hours, then evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with n-hexane-ethyl acetate (9:1) to give 1-tert-butyldimethylsilyl-4(S)-(3-methyl-5-isoxazolyl)-2-azetidinone (0.96 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.N1([S:22]([C:25]2[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=2)[C:28]([OH:30])=O)(=[O:24])=[O:23])CCOCC1.[CH3:38]CCCCCC.C(OCC)(=O)C>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:9])[C:28](=[O:30])[C:27]2[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:25]([S:22]([CH3:38])(=[O:23])=[O:24])[CH:26]=2)=[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Reactant: CCCCCCC
Reactant: CNc1nnc(Cl)cc1-c1ccccc1
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1nnc(Cl)cc1-c1ccccc1
Yield: 14 %

Procedure:
The title compound was prepared in analogy to example 1, from (6-chloro-4-phenyl-pyridazin-3-yl)-methyl-amine (example 5, intermediate a) and 3-(morpholine-4-sulfonyl)-5-trifluoromethyl-benzoic acid and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Another purification step using preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2) furnished the title compound as a colorless solid (14%). MS (ESI+): m/z=541.090 ([M+H]+).
Reaction SMILES: [C:1]1(=O)[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:14]=1[NH2:15].[Fe:22](Cl)Cl>C(OCC)(=O)C>[C:13]1([CH3:12])[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:14]=1[N:15]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[N:15][C:14]2[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:13]=2[CH3:12])[NH:5]1.[Fe+2:22]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cl[Fe]Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(N=C2NC(=Nc3c(C)cc(C)cc3C)c3ccccc32)c(C)c1
Product: [Fe+2]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 100-mL round-bottom flask equipped with a nitrogen inlet and an internal fritted-glass filter is charged with phthalimide (2.94 g, 20.0 mmol) and ethyl acetate (60 mL). (The fritted-glass filter is attached to the end of a glass tube, which is inserted into the reactor through a rubber septum. The filter is easily raised above or lowered below the surface of liquids in the reactor.) 2,4,6-Trimethylaniline (5.41 g, 40.0 mmol, 2.0 eq.) and iron(II) chloride (2.54 g, 20.0 mmol) are added to the flask, and the mixture is stirred under nitrogen at room temperature for 1 h. The yellow mixture is heated to reflux (77° C.) for 10 h, and is then stirred at room temperature for 32 h. A brown precipitate forms. The reaction mixture is concentrated by stripping out the ethyl acetate under a stream of nitrogen. Cold diethyl ether (30 mL) is added to the residue, and the mixture is stirred to wash the residue. The glass filter is immersed in the liquid phase, which is then removed at reduced pressure through the internal filter. The solids are dried under vacuum for 2 h to give a brown powder. Yield: 10.11 g (99.4%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][Mg]Cl.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH3:9][CH:7]1[CH2:8][C:3](=[O:2])[CH:4]=[CH:5][N:6]1[C:20]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: C[Mg]Cl
Reactant: COc1ccncc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: CC1CC(=O)C=CN1C(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
The methodology of D. L. Comins and J. D. Brown, Tetrahedron Letters, 1986, pp 4549-4552 was used: To a stirred solution of 2.5 g of 4-methoxypyridine in 75 mL of anhydrous tetrahydrofuran cooled to -23° C. under a nitrogen atmosphere was added 8 mL of 3M methylmagnesium chloride in tetrahydrofuran followed by 4 g of benzylchloroformate, keeping the internal temperature below -20° C. After stirring for 4 h at -25°±5° C., the reaction was quenched with 100 mL of 1N HCl and extracted with 5×100 mL portions of ether. The combined extracts were dried over MgSO4 and concentrated under reduced pressure. Further drying under vacuum gave 5.1 g of 2(R,S)-methyl-1-(benzyloxycarbonyl)-2,3-dihydro-4-pyridone as a greenish oil: TLC (25% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) 7.75 (d, 1H), 7.4 (s, 5H), 5.30 (d, 1H), 5.26 (s, 2H), 4.7 (m, 1H), 2.82 (dd, 1H), 2.38 (d, 2H), 1.25 (t, 3H).
Reaction SMILES: [OH:1][C@H:2]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:10]=[N:11][C:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:14]=2)[N:4]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[C:37]1([C@H:2]([C@H:3]2[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]3[CH:10]=[N:11][C:12]([C:15]([N:17]4[CH2:18][CH2:19][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[CH2:21][CH2:22]4)=[O:16])=[CH:13][CH:14]=3)[NH:4]2)[OH:1])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCN(Cc4ccccn4)CC3)nc2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cn1)N1CCN(Cc2ccccn2)CC1

Procedure:
A solution of 0.038 g (0.067 mmol) of the title compound from Step A above in 1 mL dichloromethane and 1 mL trifluoroacetic acid was stirred at ambient temperature for 1 h. All volatiles were removed in vacuo and the crude light brown residue was purified directly by reverse-phase HPLC to afford the title compound (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). 1H-NMR (500 MHz, CD4O)
Reaction SMILES: C([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:13]([OH:15])=[O:14])=O)C1C=CC=CC=1.S(Cl)(Cl)=O>C(Cl)Cl>[CH2:21]([O:20][C:18]([NH:17][CH2:16][C@H:12]1[C:13](=[O:15])[O:14][C:9](=[O:8])[NH:11]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(NC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(NC[C@@H]1NC(=O)OC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Suspend the product of Step A (2 g) in CH2Cl2 (25 mL) and treat with thionyl chloride (1.6 mL). Stir the resulting mixture at room temperature for 1 hr and then heat under reflux for 1.5 hr. Concentrate the mixture in vacuo and triturate with hexane (3 times). Dissolve the residue in CH2Cl2 (10 mL), treat with hexane (30 mL), and stir overnight. Filter to give 4(S)-benzyloxycarbonylaminomethyl-2,5-oxazolidinedione.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:29][CH2:28][CH2:27][C:22]2[C:23]([CH3:26])=[N:24][O:25][C:21]=2[C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Reactant: Clc1ccc(CBr)cc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCOCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 14, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-bromomethyl-4-chloro-benzene.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[C:3]=1[CH3:12].[CH3:13][CH2:14]O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:13]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[C:3]=1[CH3:12])=[CH2:14]
Reactant: COc1c(C#N)ccc(Br)c1C
Reactant: CCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: C=Cc1ccc(C#N)c(OC)c1C

Procedure:
The mixture of 4-bromo-3-methyl-2-(methyloxy)benzonitrile (8.10 g, 35.8 mmol), potassium vinyl trifluoroborate (6.24 g, 46.6 mmol) and PdCl2(dppf)2 (0.55 g, 0.70 mmol) in 160 mL of EtOH and 40 mL of TEA was refluxed under Ar for 4 hours. The mixture was concentrated, and the residue was purified by column chromatography (PE:EtOAc=20:1) to afford 4-ethenyl-3-methyl-2-(methyloxy)benzonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:20]1[CH2:24][CH2:23][N:22]([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[O:44][NH2:45].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:22]2[CH2:23][CH2:24][C@@H:20]([N:8]([C:9]3[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17](=[O:18])[NH:45][O:44][CH:39]4[CH2:40][CH2:41][CH2:42][CH2:43][O:38]4)=[CH:13][N:14]=3)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:21]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 58.8 %

Procedure:
To a stirred solution of (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (142 mg) in DMF (3 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (67 mg), HOBT (77 mg), and EDCI hydrochloride (109 mg), and the resulting mixture was stirred at ambient temperature for 7 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water, saturated NaHCO3 solution, and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=5:1) to give tert-butyl [(3R)-1-(diphenylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate (100 mg) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](O)=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[CH2:21]([C@H:17]([NH:16][C:14](=[O:15])[O:13][C:9]([CH3:11])([CH3:10])[CH3:12])[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(Br)cc1
Reaction time: 24 h
Yield: 97.7 %

Procedure:
To a solution of 4-bromoaniline (1.1 g), (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoic acid (1.87 g) and diisopropylethylamine (1.82 g) in N,N-dimethylformamide (30 mL) was added (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HATU) (2.68 g) and the mixture was stirred for 24 hours. Water was added and the mixture was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to afford tert-butyl {(1S)-1-benzyl-2-[(4-bromophenyl)amino]-2-oxoethyl}carbamate (2.62 g).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C@@H:8]([NH2:10])[CH3:9])=[CH:3][CH:2]=1.CI.[Cl:28][C:29]1[CH:30]=[C:31]([CH2:36][C@@H:37]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[C:43]([F:53])[CH:42]=2)[C@@H:38]([NH2:40])[CH3:39])[CH:32]=[CH:33][C:34]=1[Cl:35].[CH2:54](Cl)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([CH2:36][C@@H:37]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[C:43]([F:53])[CH:42]=2)[C@@H:38]([NH:40][CH3:1])[CH3:39])[CH:32]=[CH:33][C:34]=1[Cl:35].[CH2:54]([NH:10][C@@H:8]([CH3:9])[C@H:7]([C:4]1[CH:3]=[CH:2][C:1]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:6][CH:5]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)c(F)c1
Reactant: ClCc1ccccc1
Solvent: CI
Product: CN[C@@H](C)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)c(F)c1
Product: C[C@H](NCc1ccccc1)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1

Procedure:
The reaction was conducted in the same manner as in Example 121 except that (1S, 2S)-2-(4-biphenylyl)-3-(3,4-dichlorophenyl)-1-methylpropylamine or methyl iodide used in the above reaction was changed to (1S, 2S)-3-(3,4-dichlorophenyl)-2-(2-fluoro-4-biphenylyl)-1-methylpropylamine or benzyl chloride, to obtain (1S, 2S)-N-{3-(3,4-dichlorophenyl)-2-(2-fluoro-4-biphenylyl)-1-methylpropyl}methylamine and (1S, 2S)-N-benzyl-2-(4-biphenylyl)-3-(3,4-dichlorophenyl)-1-methylpropylamine.