Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([Br:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C@H:6]([O:24]C(=O)C(C)(C)C)[C@H:5]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)C.[OH-].[K+].O.NN.CC(C)=O>CO>[Br:17][C:16]1[N:11]2[CH:10]=[CH:9][C:8]3[C@@H:7]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C@H:6]([OH:24])[C@@H:5]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:4][C:13]=3[C:12]2=[N:14][C:15]=1[CH3:18]
Reactant: COCCO[C@@H]1c2ccn3c(Br)c(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: COCCO[C@@H]1c2ccn3c(Br)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 60 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A suspension of 3.30 g (5.90 mmol) (7R,8R,9R)-10-acetyl-3-bromo-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine, 1.00 ml (6.00 mmol) aqueous potassium hydroxide (6 N) and 2.00 ml (51.40 mmol) hydrazine hydrate in methanol is stirred at 60° C. for 4 h. The methanol is removed in vacuo and the reaction mixture is diluted with water. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (toluene/dioxane/acetic acid: 8/1/1) to give 1.50 g (3.47 mmol, 59%) of the title compound as a light yellow solid with a melting point of 153-154° C. (acetone).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][CH2:11][C:10]=2[CH:20]=1>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]([C:1]([Cl:4])=[O:2])[CH2:11][C:10]=2[CH:20]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1ccc2c(c1)CNc1ccccc1O2
Product: O=C(Cl)N1Cc2cc(Cl)ccc2Oc2ccccc21

Procedure:
2-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carbonyl chloride (43) is prepared in the manner described in Example 2 using phosgene and 2-chloro-10,11-dihydrodibenz[b,f][1,4]-oxazepine (42), prepared in the manner described above in Example 42.
Reaction SMILES: C([N:3](CC)CC)C.[CH3:8][C:9](C)([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10](O)=O.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>O.CC(C)=O>[CH3:8][C:9]([NH2:3])([CH3:10])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(CC(C)(C)C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CC(C)(C)N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 46.2 %

Procedure:
Triethylamine (16.8 g, 166 mmol) and 2,2-dimethyl-3-(4-methoxyphenyl)propionic acid (32.6 g, 157 mmol) were dissolved in 30 mL of water and enough acetone to maintain solubility at 0° C. A solution of ethyl chloroformate (20.1 g, 185 mmol) in acetone (100 mL) was then added dropwise. An aqueous solution (95 mL) of sodium azide (12.9 g, 198 mmol) was then added dropwise and the resulting reaction mixture stirred 45 minutes at room temperature. The intermediate acyl azide was then extracted into toluene (200 mL). The organic extract was washed with water, dried over anhydrous magnesium sulfate, and heated at 100° C. until the evolution of nitrogen ceased (˜45 min). The toluene was removed under vacuum and replaced with benzyl alcohol. The solution was then heated at 100° C. for 16 hours. The excess benzyl alcohol was removed under vacuum. The resulting benzyl carbamate was dissolved in absolute ethanol (200 mL) and reduced in the presence of palladium hydroxide (2 g) under 90 p.s.i. hydrogen for 4 hours at room temperature. The reaction was filtered and concentrated to a yellow oil. Vacuum distillation afforded 13.0 g of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 180 (M+1, 1), 164 (5), 121 (25), 91 (5), 78 (19), 58 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16]CCC#N)=[O:15])=[C:12]([CH3:21])[NH:11][C:10]([CH:22]([O:25][CH3:26])[O:23][CH3:24])=[C:9]2[C:27](=[O:38])[NH:28][CH2:29][CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:21])[NH:11][C:10]([CH:22]([O:23][CH3:24])[O:25][CH3:26])=[C:9]2[C:27](=[O:38])[NH:28][CH2:29][CH:30]=[CH:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C1=C(C(=O)NCC=Cc2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COC(OC)C1=C(C(=O)NCC=Cc2ccccc2)C(c2cccc(Cl)c2)C(C(=O)O)=C(C)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
134 mg (1.16 mmol) of 5-(2-cyanoethyl) 4-(3-chlorophenyl)-2-dimethoxymethyl-6-methyl-3-(3-phenyl-2-propene-1-ylcarbamoyl)-1,4-dihydropyridine-5-carboxylate was dissolved in 2.5 ml of methanol. 0.25 ml of 1 N aqueous sodium hydroxide solution was added to the obtained solution, and they were stirred at room temperature for 3 hours. An aqueous potassium hydrogensulfate solution was added to the reaction mixture. After the solvent was evaporated under reduced pressure, the residue was washed with water and then dried under reduced pressure to obtain the title compound.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]([NH:22][C:23](=[O:25])[CH3:24])[C:6]=2[CH:26]=1.N([O-])=O.[Na+].[ClH:31]>C(O)C.O.[Cu]Cl>[Cl:31][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]([NH:22][C:23](=[O:25])[CH3:24])[C:6]=2[CH:26]=1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(N)cc1[C@@H](NC(C)=O)CC2
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc2c(c(OC)c1OC)-c1ccc(Cl)cc1[C@@H](NC(C)=O)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A solution of N-[(5S)-3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (0.712 g; 2 mmol) in ethanol (3.75 ml) and 36% hydrochloric acid (1.57 ml) was slowly added into a mixture of ice (6 ml) and 36% hydrochloric acid (1.57 ml). At 0° C. a solution of sodium nitrite (0.14 g; 2 mmol) in water (0.25 ml) was added. The mixture was stirred at 0° C. for 1 hour and then transferred into a separate flask containing a solution of copper(I) chloride (0.218 g; 2.2 mmol) in water (0.35 ml) and 36% hydrochloric acid (0.4 ml). The resulting mixture was stirred at 30° C. for 30 minutes and extracted with toluene/ethyl acetate (50/50). The organic phase was washed with water, dilute sodium hydroxide, and saturated sodium chloride solution, then dried and the volatiles were removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate to give N-[(5S)-3-chloro-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.[CH3:11][O:12][C:13]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:17][CH:16]=[CH:15][N:14]=1>>[CH3:11][O:12][C:13]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([C@H:25]([NH:27][S:7]([C:3]3[C:2]([Br:1])=[CH:6][S:5][CH:4]=3)(=[O:9])=[O:8])[CH3:26])=[CH:21][CH:20]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: COc1ncccc1-c1ccc(C(C)N)cc1
Reactant: O=S(=O)(Cl)c1cscc1Br
Product: COc1ncccc1-c1ccc([C@@H](C)NS(=O)(=O)c2cscc2Br)cc1

Procedure:
2M Aqueous sodium carbonate solution (3.25 ml, 6.50 mmol) was added to a mixture of 2-methoxypyridine-3-boronic acid (994 mg, 6.50 mmol), (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (650 mg, 2.16 mmol) and tetrakis(triphenylphosphine)palladium (0) (125 mg, 0.108 mmol) in 1,2 dimethoxyethane (27 ml). The mixture was heated at 95° C. for 16 h under nitrogen atmosphere. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed twice with brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting gum was chromatographed over silica gel eluting with heptane/dichloromethane and the solvent evaporated to give (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (593 mg, 1.71 mmol, 83.5%) as a crystalline solid. Trifluoroacetic acid (6.45 ml, 86.8 mmol) was added dropwise to a solution of (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl ester (645 mg, 1.97 mmol) in dichloromethane (6.45 ml) under a nitrogen atmosphere at 0° C. After stirring for 1 h at 0° C. the solvent was evaporated. Methanol (20 ml) was added and the mixture added to a Strata™ 5 g/20 ml SCX column. The intermediate amine was eluted with 2M ammonia in methanol. The solvent was evaporated to give (R)-1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethylamine as a gum (425 mg, 1.86 mmol, 94.6%). The title compound was then prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) using 4-bromo-3-thiophenesulfonyl chloride and 1-[4-(2-Methoxy-pyridin-3-yl)-phenyl]-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, 1H), 7.56 (d, 1H), 7.41, 7.20 (a/b, 4H), 7.38 (m, 1H), 6.99-6.92 (m, 2H), 5.27 (d, 1H), 4.60 (m, 1H), 3.97 (s, 3H), 1.54 (d, 3H) ppm; MS (ESI) m/z: 453 [M+H]+.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([CH:13]2[CH:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:28][CH2:29]3)=[O:23])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a stirred solution of [(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (130 mg, 0.24 mmol) in CH2Cl2 (5 ml) was added TFA (1 ml). The reaction mixture was stirred at RT for 2 hours, aqueous NaHCO3 was added until pH=8 and the product was extracted with CH2Cl2. The combined organic phase were dried over Na2SO4. Concentration under vacuo gave 100 mg (93%) of the title product as a light yellow oil. ES-MS m/e: 435.8 (M+H+).
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH2:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1>O1CCCC1>[Cl:1][S:2]([NH:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([O:17][CH3:18])[CH:12]=[C:13]([O:15][CH3:16])[N:14]=1)=[O:7])(=[O:4])=[O:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1cc(OC)nc(N)n1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Cl)n1
Reaction time: 0.5 h

Procedure:
A solution of 4.8 g of chlorosulfonyl isocyanate in 10 ml of tetrahydrofuran (THF) is added to a solution of 4.7 g of 2-amino-4,6-dimethoxypyrimidine in 80 ml of THF under ice cooling and stirred for 30 minutes to yield N-chlorosulfonyl-N'-(4,6-dimethoxy-2-pyrimidinyl)urea. A solution of 1.0 g of 2-methylpyrrolo[1,2-a]pyridine in 10 ml of THF and 1.0 g of aluminum chloride are added to the above mixture and stirred for an hour at room temperature. THF is distilled off. The residue after addition of water is extracted with ethyl acetate. The extract is dried and distilled to remove ethyl acetate. The residue is purified by silica gel chromatography (eluent: n-hexane-ethyl acetate) to give 0.71 g of the title compound (Compound No. 5) having mp. 197°-199° C. and 0.88 g of the title compound (Compound No. 6) having mp. 168°-169° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=[C:3]([C:2]([F:26])([F:1])[F:25])[CH:4]=1)=[N:38][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=1[Cl:34])#[N:24]
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: NCc1ccccc1Cl
Solvent: CCN(CC)CC
Product: N#CNC(=NCc1ccccc1Cl)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 72 %

Procedure:
By following a procedure analogous to the one described above in Example 1b, N-(3,5-bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea (0.300 g, 0.8 mmol) was treated with triethylamine (0.123 ml, 0.88 mmol) and 2-chlorobenzylamine (0.107 ml, 0.88 mmol) to give the title compound as a syrup. Yield 72% (0.234 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:10]N1C(=O)CCC1=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[C:7]([Cl:10])[CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccnc1N
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-2-aminopyridine (Wonda Science, cat #01683; 12.4 g, 0.01 mol) is dissolved by stirring in 500 ml of ethyl acetate. A thermometer is placed in the solution to monitor temperature. N-Chlorosuccinimide (13.3 g, 0.01 mol) is added in several portions to keep the solution at room temperature. The solution becomes dark in color and is stirred at room temperature overnight. The supernatant is decanted from the dark solids that formed and transferred to a separatory funnel. The organic solution is washed with 500 ml saturated aqueous sodium bisulfite and then 500 ml brine. The organic layer is dried with MgSO4 and concentrated on a rotovap. The dark brown crude product is chromatographed on 500 g of flash silica-gel eluting with 30% EtOAc/Hexanes. Concentration of the appropriate fractions on a rotovap gives a yellow solid. The solid is suspended in hexanes, stirred and filtered to give the product as a bright yellow solid. (MP 93-94° C.).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=C)=[CH:19][C:18]=2[F:25])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].CC(C)=[O:28].C(=O)=O.[BH4-].[Na+]>CO>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:28])=[CH:19][C:18]=2[F:25])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CC(C)=O
Reactant: C=Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(CO)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product of Example 4, 3,4-Difluoro-2-(2-fluoro-4-vinylanilino)-N-(2-hydroxyethoxy)benzamide (170 mg, 0.48 mmol) was dissolved in MeOH (50 mL) and the solution cooled to −78° C. (acetone/dry ice). Ozone was bubbled through the solution until a pale blue-grey solution was obtained, then nitrogen bubbled through the solution until the blue colour disappeared. A solution of NaBH4 (92 mg, 2.41 mmol) in MeOH (10 mL) was added, the reaction mixture removed from the cold bath and allowed to stir for 0.5 h. at RT. The MeOH was removed from the mixture under reduced pressure and the resulting residue partitioned between EtOAc (50 mL) and 1 M HCl (50 mL). The EtOAc layer was washed with water (50 mL) and brine (50 mL), then dried (Na2SO4) and the solvent removed under reduced pressure to afford an oil which was purified by chromatography on silica gel (10% EtOAc as eluant). 3,4-Difluoro-2-[2-fluoro-4-(hydroxymethyl)anilino]-N-(2-hydroxyethoxy)benzamide was isolated as a pale yellow crystalline solid (99 mg, 58%); m.p. (Et2O/hexane) 108-1 10C. 1H NMR [400 MHz, (CD3)2SO] δ 11.86 (br s, 1 H), 8.74 (br s, 1 H), 7.44-7.37 (m, 1 H), 7.16-7.08 (m, 2 H), 7.02-6.97 (m, 1 H), 6.86 (ddd, J=8.6, 8.6, 4.5 Hz, 1 H), 5.18 (t, J=5.7 Hz, 1 H), 4.71 (br s, 1 H), 4.43 (d, J=5.8 Hz, 2 H), 3.85 (t, J=4.7 Hz, 2 H), 3.60-3.52 (m, 2 H). Anal. calcd. for C16H15F3N2O4: C, 53.9; H, 4.2; N, 7.9. Found C, 54.2; H, 4.6; N, 7.6.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[N+:20]([C:23]1[C:30]([NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:29]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])([O-:22])=[O:21].C(O)(=O)C>O1CCCC1>[OH:26][CH:25]([C:24]1[CH:27]=[CH:28][C:29]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:30]([NH:31][C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:23]=1[N+:20]([O-:22])=[O:21])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C#CC(=O)OCC
Reactant: O=Cc1ccc(OCCCCc2ccccc2)c(NC(=O)c2ccccc2)c1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C#CC(O)c1ccc(OCCCCc2ccccc2)c(NC(=O)c2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 105 %

Procedure:
To a solution of diisopropylamine (0.6 ml, 4.26 mmol) in tetrahydrofuran (12 ml) was added, at -78° C. under an argon atmosphere, 1.5 N butyllithium (2.66 ml, 3.99 mmol). The mixture was stirred for 30 min. Ethyl propiolate (0.49 ml, 4.79 mmol) and a solution of 2-nitro-4-phenylbutoxybenzoylaminobenzaldehyde (1.1 g, 2.66 mmol) in tetrahydrofuran (3 ml) were added in that order, and the mixture was stirred at -78° C. for additional one hr. A solution of acetic acid (0.47 ml, 8.25 mmol) in tetrahydrofuran (3 ml) was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution, and saturated brine in that order. It was then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(2-nitro-4-phenylbutoxybenzoylaminophenyl)-2-butynoate as an oil (1.443 g). Ethyl 4-hydroxy-4-(2-nitro-4-phenylbutoxybenzoylaminophenyl)-2-butynoate thus prepared was dissolved in toluene (10 ml), 4-methoxybenzylazide (1.3 g, 7.98 mmol) was added to the solution, and the mixture was stirred at 100° C. for 5 hr. The reaction mixture was cooled to room temperature, and the resultant crystal was collected by filtration to give ethyl 4-hydroxy-1-(4-methoxybenzyl)-(2-nitro-4-phenylbutoxybenzoylaminophenyl)methyl-1,2,3-triazole-5-carboxylate (a-1) (550.4 mg, 26%). Further, the filtrate was concentrated, and the resultant powder was washed with hexane:ethyl acetate (1:1) and dried to give ethyl 5-hydroxy-1-(4-methoxybenzyl)-(2-nitro-4-phenylbutoxybenzoylaminophenyl)methyl-1,2,3-triazole-4-carboxylate (a-2) (466.3 mg, 30%).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[CH3:19][O:20][C:21]([CH2:23]P(=O)(OCC(F)(F)F)OCC(F)(F)F)=[O:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:48]([C:50]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[C:51]=1[C:52]([O:54][CH:55]([CH3:57])[CH3:56])=[O:53])=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:19][O:20][C:21](=[O:22])/[CH:23]=[CH:48]\[C:50]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[C:51]=1[C:52]([O:54][CH:55]([CH3:57])[CH3:56])=[O:53]
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: CC(C)OC(=O)c1c(C=O)cccc1C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1cccc(C(F)(F)F)c1C(=O)OC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 142.1 %

Procedure:
To a solution of 18-crown-6 (9.1 g, 34.6 mmol) in 100 mL of THF at −78° C. was added bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (4.13 g, 12.98 mmol). Potassium bis(trimethylsilyl)amide (19.6 mL of a 15 wt % solution in toluene, 12.98 mmol) was added dropwise over 20 min and the mixture was stirred an additional 1 h at −78° C. Then there was added isopropyl 2-formyl-6-(trifluoromethyl)benzoate (1.5 g, 5.74 mmol) in 10 mL of THF and the resulting cloudy mixture was stirred at −78° C. for 1 h. The reaction was quenched with sat'd aq NH4Cl, diluted with EtOAc, washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The residue was purified by flash chromatography (elution with 6:1 hexane/ethyl acetate) to afford 2.58 g (94%) of the title compound as an oil. 1H NMR (CDCl3): δ 7.66-7.62 (m, 2H), 7.51 (t, 1H, J=7.7 Hz), 7.11 (d, 1H, J=12.1 Hz), 6.11 (d, 1H, J=12.1 Hz), 5.26 (septet, 1H), 3.63 (s, 3H), 1.32 (d, 6H, J=6.0 Hz). LRMS (ESI): 339.19 (M+H+Na)+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[O:9][C:8]=1[CH2:15]Br.C[C]C>[Ag]=O>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][CH2:15][C:8]1[O:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][CH:7]=1
Reactant: CC(C)=CCO
Reactant: O=[N+]([O-])c1ccc(CBr)o1
Agent: O=[Ag]
Agent: C[C]C
Product: CC(C)=CCOCc1ccc([N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Freshly prepared silver oxide (34.8 g, 0.15 mol) was added to a mixture of 3-methyl-2-buten-1-ol (21.0 g, 25 mL, 0.24 mol) and 5-nitro-2-furfuryl bromide (18.8 g, 0.1 mol) and stirred at room temperature for 12 h. Silver salts were removed by filtration and the filter cake was washed with ether (200 mL). The filtrate and the washings were combined and evaporated to remove ether and excess 3-methyl-2-buten-1-ol. The oil obtained was purified by column chromatography (silica gel, hexane:ethyl acetate, 7:1). Fractions containing the product were collected and evaporated to give a light yellow oil. Yield 5.5 g. 1H NMR (CDCl3) ε 1.69 and 1.77 (s, 6H, CH3), 4.09 [d, 2H, (CH3)2C=CHCH2 --OCH2)], 4.64 [s, 2H, (CH3)2C=CHCH2 --OCH2)], 5.38 (t, 1H, (CH3)2C=CH--), 6.6 and 7.27 (d, 2H, ArH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(Br)cc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CCCCC3)cc2)C1
Yield: 42.5 %

Procedure:
A solution of (2S)-2-(4-bromophenyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (1.06 g, 2.40 mmol), piperidine (0.29 ml, 2.88 mmol), palladium acetate (22.0 mg, 0.096 mmol), sodium tert-butoxide (323 mg, 3.36 mmol) and 2-(di-t-butylphosphino)biphenyl (57.0 mg, 0.192 mmol) in toluene (16 ml) was stirred at 80° C. for 6 hours. Water and ethyl acetate were added to the solution and the solution was passed through Celite column. The whole was extracted with ethyl acetate and the organic lawyer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (2S)-2-(4-piperidin-1-yl-phenyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (455 mg, 43%) as white crystals.