Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[C:12]([O:35][CH3:36])[CH:11]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[NH:28][CH:27]=4)[CH:23]=[CH:22][N:21]=3)=[C:12]([O:35][CH3:36])[CH:11]=2)[CH2:4]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Yield: 84.2 %

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (92 mg, 0.81 mmol) was added to a mixture of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 68, 404 mg, 0.73 mmol) and DIPEA (0.256 mL, 1.46 mmol) in DMA 3 mL. The mixture was then heated in a microwave at 140° C. for 0.5 h. Part-purification was achieved by ion-exchange chromatography, using an SCX column (20 g) and eluting with 0.35M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo to provide an orange/brown gum. This gum was triturated with ethanol (15 mL) to give a solid which was collected by filtration and dried under vacuum to give the title compound (291 mg, 84%) as an orange solid; 1H NMR: 1.82 (1H, dt), 2.12-2.20 (1H, m), 2.22 (6H, s), 2.73-2.83 (1H, m), 3.12-3.22 (2H, m), 3.22-3.27 (1H, m), 3.41-3.51 (1H, m), 3.97 (3H, s), 6.58 (1H, s), 7.07 (1H, t), 7.18 (1H, t), 7.26 (1H, d), 7.45 (1H, d), 8.00 (1H, s), 8.28-8.31 (2H, m), 8.35 (1H, d), 8.57 (1H, s), 11.78 (1H, s); m/z: ES+ MH+ 474.30.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:27]([CH2:33][CH2:34][CH3:35])=[N:26][C:20]=3[C:21]([NH2:25])=[N:22][C:23]=2[CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:25][C:21]1[C:20]2[N:26]=[C:27]([CH2:33][CH2:34][CH3:35])[N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])=[CH:24][C:23]=2[N:22]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(OCCCNS(C)(=O)=O)ccc3c2n1CC(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
Methanesulfonic anhydride (0.245 g, 1.41 mmol) was added in one portion to a suspension of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.41 mmol) in chloroform, and the reaction was stirred for 18 hours. Saturated aqueous sodium bicarbonate was added, and the reaction was stirred for 20 minutes. The aqueous layer was separated and extracted with chloroform. The combined organic fractions were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting off-white solid was dissolved in concentrated hydrochloric acid; the solution was then cooled to 0° C. and adjusted to pH 13 with the addition of 50% aqueous sodium hydroxide. The opaque solution was extracted with dichloromethane. The extract was washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was recrystallized from acetonitrile to yield 0.160 g of N-{3-[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}methanesulfonamide as a flocculent, white solid, mp 166.5-168.5° C.
Reaction SMILES: O([Si](C)(C)C)[K].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)=[O:9]>>[CH:7](/[C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH3:7])=[CH:11][CH:12]=1)=[CH:8]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(=O)c1ccc(I)cc1
Agent: C[Si](C)(C)O[K]
Product: CCCCC/C=C/c1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
Following General Procedure II, a mixture of KOSiMe3 (570 mg, 4.0 mmol, 2.0 equiv), (E)-21 (379 mg, 2.2 mmol, 1.1 equiv), 4-iodoacetophenone (492 mg, 2.0 mmol) and Pd(dba2) (58 mg, 0.1 mmol, 0.05 equiv) was stirred at room temperature for 9 h, and then was filtered through SiO2. Purification by column chromatography (RP C18, MeOH/H2O, 9/1) and Kugelrohr distillation afforded 354 mg (82%) of (E)-154c as colorless oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[S:17])[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr>C(Cl)Cl>[CH3:16][C:15]1[S:17][C:10]2[CH:9]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:13]=[CH:12][C:11]=2[N:14]=1
Reactant: CC(=S)Nc1ccc(Oc2ccccc2)cc1
Agent: BrBr
Solvent: ClCCl
Product: Cc1nc2ccc(Oc3ccccc3)cc2s1
Temperature: 45 °C
Yield: 10.4 %

Procedure:
To an ice-cold solution of N-(4-phenoxy-phenyl)-thioacetamide (0.78 g, 3.20 mmol) in 10 ml of DCM was added Br2 (0.32 ml, 6.40 mmol) dropwise. The reaction mixture was heated at 45° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated under reduced pressure. The residue was basified with NH4OH solution and extracted with ethyl acetate. The combined organics were, dried, (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (230-400 M) using ethyl acetate/hexane (3:97) as the eluent to provide the title compound (0.08 g, 10.3%).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[O:19][C:20]([F:23])([F:22])[F:21])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][CH2:8][CH2:7][C:6]1[CH:17]=[CH:18][C:3]([C:1]#[N:2])=[C:4]([O:19][C:20]([F:21])([F:22])[F:23])[CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C#N)c(OC(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CCN)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.8 %

Procedure:
To a solution of tert-butyl 4-cyano-3-(trifluoromethoxy)phenethylcarbamate (150 mg, 0.45 mmol) in DCM (3 mL) was added TFA (1.5 mL). The resulting reaction mixture was stirred at room temperature for 1.5 h. The mixture was concentrated to afford the crude title product (120 mg, crude), which was used directly for next step without further purification. MS (ESI) m/z 231.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: OCCN1CCCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OCCN2CCCC2)CC1

Procedure:
The title compound was prepared by using Mitsunobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 2-hydroxyethyl pyrrolidine.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12](CCl)=[CH:11][CH:10]=[CH:9][C:4]=1C(OC)=O.[NH2:15][C:16]1[C:25]([CH2:26][S:27]([CH3:29])=O)=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].ClCC1C=CC=CC=1[N:34](C)C>C(O)(C)C>[NH2:15][C:16]1[C:25]([CH2:26][S:27][C:29]2[NH:2][C:3]3[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=3[N:34]=2)=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CN(C)c1ccccc1CCl
Reactant: COC(=O)c1cccc(CCl)c1N
Reactant: COC(=O)c1cccc(CS(C)=O)c1N
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)c1cccc(CSc2nc3ccccc3[nH]2)c1N

Procedure:
The title compound was prepared by the method of Example 1 using 1.27 g of methyl 2-amino-3-(chloromethyl)benzoate hydrochloride (prepared from methyl 2-amino-3-(methylsulfinylmethyl)benzoate as reported by J. P. Chupp et al., J. Org. Chem., 49, 4711 (1984) instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol. Recrystallization of the title compound from diethyl ether gave 1.72 g of the title compound in three crops. Anal. Calc'd. for C16H15N3O2S: C, 61.32; H, 4.82; N,13.41; S, 10.23. Found: C, 60.73; H, 4.86; N, 12.87; S, 9.67.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:5]([OH:9])[C:6]([OH:8])=[O:7].[CH:17]1(O)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[ClH:1].[CH:17]1([O:7][C:6](=[O:8])[CH:5]([OH:9])[C@@H:4]([NH2:3])[CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OC1CCCC1
Reactant: N[C@@H](CC1CCCCC1)C(O)C(=O)O
Agent: Cl
Product: N[C@@H](CC1CCCCC1)C(O)C(=O)OC1CCCC1
Temperature: 90 °C

Procedure:
Hydrogen chloride was passed into a solution of 300 mg of (2RS, 3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid hydrochloride, which was prepared in Reference Example 2, in 5 ml of cyclopentyl alcohol with stirring under ice-cooling, and then the mixture was heated at 90° C. for 5 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=15/1 by volume). The eluate was acidified by adding hydrochloric acid, and then evaporated to dryness under reduced pressure to obtain 380 mg of (2RS, 3S)-3-amino-4-cyclohexyl-2hydroxybutyric acid cyclopentyl ester hydrochloride as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[F:72]>ClCCCl>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:65]([F:72])[CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)c(F)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.53 g, 0.92 mmol), was reacted with diisopropylethylamine (0.95 g, 7.4 mmol), diphenylphosphinic chloride (0.87 g, 3.7 mmol), then reacted with 4-amino-3-fluorobenzonitrile (Matrix) (0.13 g, 0.92 mmol) in 1,2-dichloroethane at 70° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-fluoro-phenyl)-amide as a off white solid (Yield 0.14 g, 26%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=1>>[F:23][C:22]([F:25])([F:24])[C:21]1[C:16]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: FC(F)(F)c1cccnc1Cl
Product: NC1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
The title compound was prepared from D7 and 2-chloro-3-trifluoromethyl-pyridine using the procedure outlined for Descriptions D11 and D12.
Reaction SMILES: C([Al](CC(C)C)CC(C)C)C(C)C.[OH:14][CH2:15]/[CH:16]=[C:17](/[CH3:24])\[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].C(=O)C1OC=CC=1>C1(C)C=CC=CC=1>[CH3:23][C:21](=[CH:20][CH2:19][CH2:18][C:17](=[CH:16][CH:15]=[O:14])[CH3:24])[CH3:22]
Reactant: CC(C)=CCC/C(C)=C\CO
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: O=Cc1ccco1
Solvent: Cc1ccccc1
Product: CC(C)=CCCC(C)=CC=O

Procedure:
This example illustrates the use of triisobutylaluminum to generate the aluminum alkoxide catalyst. A flask was charged with 80 grams of nerol and 10 ml of a 25% solution of triisobutylaluminum in toluene. To the solution was added 39 grams (0.75 equivalents) of furfural and the solution was allowed to react at ambient temperature for 18 hours. Analysis by glpc showed that 69% of the nerol had been consumed to give citral in 98+% yield.
Reaction SMILES: N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H](C(O)=O)CCC(=O)[OH:6].[CH2:28]1[CH2:33][CH2:32][CH:31]([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:30][CH2:29]1>O1CCCC1>[CH:37]1([NH:36][C:35]([NH:34][CH:31]2[CH2:30][CH2:29][CH2:28][CH2:33][CH2:32]2)=[O:6])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C(O)CC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Yield: 78 %

Procedure:
Fmoc-D-Glu-OH (59.8 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (THF) (324 mL). DCC (40.1 g, 1.2 eq) was then added while stirring in ice-water bath. The reaction mixture was allowed to warm to r.t and stirring was maintained for additional 8 h to produce 1,3-dicyclohexylurea (DCU). The precipitates were filtered off, and washed with small amount THF. Dry ammonia gas was then bubbled through the filtrate which was stirred in a NaCl salt-ice bath. The reaction was completed after 1.5 h when no more white solid was precipitated. Still standing for 30 min, small amount MeOH was added to dissolve the solid. The mixture was cooled in an ice-water bath again. Then 2.0 N HCl was added carefully and slowly to adjust pH to 2-3. The solvent was evaporated under vacuum. The resulting solid was dissolved in AcOEt and then washed with diluted HCl, saturated aqueous NaHCO3 solution, and H2O sequentially. The organic layer was separated and combined, then dried with MgSO4 overnight, filtered and evaporated under vacuum. Then residue was recrystallized with ethylacetate-cyclohexane system. After filtration, 46.5 g target product was obtained with a yield of 78%. m.p.=204˜205° C., [α]=−4.2° (C=10 mg/mL, DMF).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][C:5](=[O:7])[CH2:4][C@H:3]1[C:8]([O:10]C)=[O:9].[I-].[Na+].C[Si](C)(C)Cl.O>C(#N)C>[CH3:1][C@H:2]1[CH2:6][C:5](=[O:7])[CH2:4][C@H:3]1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)[C@@H]1CC(=O)C[C@@H]1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CC(=O)C[C@H]1C(=O)O
Temperature: 25 °C
Yield: 32.3 %

Procedure:
In acetonitrile (5 ml) were dissolved methyl cis-2-methyl-4-oxocyclopentanecarboxylate [K. Kojima et al., Chem. Pharm. Bull., 33, 2750 (1985)] (827 mg) and sodium iodide (3.175 g), and trimethylchlorosilane (2.69 ml) was added to the solution at room temperature. The mixture was refluxed under nitrogen atmosphere for one day. After the temperature was cooled to room temperature, water was added and the mixture was extracted with ether, followed by washing with an aqueous solution of sodium thiosulfate. The water layer was further extracted with ether. The organic layers were combined, dried over magnesium sulfate and concentrated to dryness. The residue was subjected to silica gel column chromatography with ethyl acetate:chloroform (1:1), and the eluted fractions were combined and concentrated to dryness to yield the title compound (243 mg).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CN(C)C=O.C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([Cl:33])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1cccc(C(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a suspension of 5.0 g of product from Example 23, 0.055 g of dimethylformamide and 70 ml of methylene chloride is added 1.96 ml of oxalyl chloride. The reaction is stirred at room temperature for 22 hours and concentrated. The residue is dissolved in diethyl ether, filtered and concentrated to give 5.28 g of the desired product as cream crystals.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:27])[CH3:26]
Reactant: CCOC(=O)C1=C(O)c2cc3ccccc3n2CC1C(=O)OCC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(OC(C)=O)c2cc3ccccc3n2CC1C(=O)OCC

Procedure:
From a mixture of 29.3 g of diethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-7,8-dicarboxylate, 100 ml of pyridine and 30 ml of acetic anhydride, the solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate and 2M hydrochloric acid. The organic extract was washed with saturated sodium bicarbonate solution and water, dried and evaporated to give 33 g of diethyl 9-acetoxy-6,7-dihydropyrido[1,2-a]indole-7,8-dicarboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:9][C:8]([C:18]2[O:19][C:20]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[C:21]=3[C:22]=2[CH3:23])=[N:7]1)=[O:5])[CH3:2]>C1(C)C=CC=CC=1.O.OO.[Ni]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:18]2[O:19][C:20]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][N:32]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[C:21]=3[C:22]=2[CH3:23])[O:9][C:10]=1[CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1N=C(c2oc3cccc(OCCCN(Cc4cccnc4)C(=O)OC(C)(C)C)c3c2C)O[C@H]1CC1CCCCC1
Agent: [Ni]
Agent: OO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1nc(-c2oc3cccc(OCCCN(Cc4cccnc4)C(=O)OC(C)(C)C)c3c2C)oc1CC1CCCCC1
Yield: 22.1 %

Procedure:
5-Cyclohexylmethyl-2-(3-methyl-4-{3-[tert-butoxycarbonyl-(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-yl)-trans-4,5-dihydro-oxazole-4-carboxylic acid ethyl ester (10.0 mg) and nickel peroxide hydrate (22 mg) in toluene (2 ml) was heated at 80° C. under the atmosphere of argon for 23 hours. The reaction mixture was directly poured onto silica gel column chromatography and eluted with 2:3 mixture of n-hexane and ethyl acetate to give 5-cyclohexylmethyl-2-(3-methyl-4-{3-[tert-butoxycarbonyl-(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-yl)-oxazole-4-carboxylic acid ethyl ester (2.2 mg). FAB-MS: m/z 632 (MH+).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:11](=[O:18])[CH:12]=[C:13]([Cl:17])[C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[Cl:9][C:10]1[C:11]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([OH:18])[CH:12]=[C:13]([Cl:17])[C:14](=[O:16])[CH:15]=1
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1C=C(Cl)C(=O)C=C1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C=C(Cl)C(=O)C=C1Cl
Yield: 92 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.59 g (3.33 mmol) of 2,5-dichloro-p-benzoquinone in 6.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate, and the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3, 1/2) afforded 0.81 g of the desired product (yield 92%).
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:25]2[C:26]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[CH:23][CH:24]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Reactant: Brc1cccc2ccccc12
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1c1cccc2ccccc12

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 1-bromonaphtalene were used for a similar reaction and treatment as Example 181, and the title compound was obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].Br[CH:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH:18]([CH2:17][CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(C)Br
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
A reaction vessel was charged with 2.02 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 1.56 g of ethyl 3-bromobutyrate, 1.11 g of potassium carbonate and 20 ml of N,N-dimethylformamide. After stirring at room temperature for 12 hours, the reaction mixture was poured into water and extracted twice with 50 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 2.54 g of ethyl 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxybutyrate (90% yield).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.ClC(OCC(C)C)=O.Cl.[NH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)Cl.C(Cl)(Cl)Cl.CCOCC>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)CNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
8.3 g (3.45 mmol) of Boc-Pro-OH were dissolved in 50 ml of CH2Cl2, cooled down to 5° C.; then, 38.45 mmol (5.38 ml) of TEA were added. The reaction mixture was cooled down to −25÷−30° C. At this temperature, 38.45 mmol (4.84 ml) of isobutyl chloroformate were added using a pipette. The reaction mixture temperature was kept in the range of −18÷−20° C. for 20 minutes. Simultaneously, a solution of 5.9 g (42.3 mmol) of 1.1-fold excess of HCl.H-Gly-OEt in 75 ml of chloroform, containing 5.92 ml of TEA. The solution was cooled down to −25° C. and, after formation of mixed anhydride in the first flask, its contents were poured to the ether solution right away. The reaction mixture was incubated for 1 hour at −10° C. and then stirred for 12 hours at 4° C. on a magnetic stirrer. The reaction mixture was evaporated, then 250 ml of ethyl acetate were added; then, ethyl acetate solution was washed 3 times with 25 ml of 0.1N HCl, 3 times with 25 ml H2O, and once with saturated solution of NaCl. The organic layer was dried over MgSO4, filtered and evaporated. The residue was dried under vacuum over P2O5/KOH and paraffin.