Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:6]=O)[CH2:2][CH2:3][CH3:4].[CH2:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.C1COCC1.CCCCCC>[Si:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=[CH2:21])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CCCCC(C=O)CCCCCO[Si](C)(C)C(C)(C)C
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(CCCC)CCCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
2-Butyl-7-(tert-butyldimethylsilyloxy)heptanaI (6.01 g, 20 mmol) in 15 ml of anhydrous THF was added dropwise to a freshly prepared solution of methylidene(triphenyl)phosphorane (22 mmol in 125 ml of anhydrous THF/hexane at 0° C. over a period of 15 min. The mixture was warmed to room temperature, stirred for 8 h, and poured into 300 ml of ice/water and extracted (3×75 ml) with ether. The combined organic extracts were washed with water and dried over anhydrous MgSO4. Solvents were removed by evaporation and pentane (250 ml) was added to the red oily residue. The mixture was chilled to 0° C. and the precipitated Ph3PO removed by filtration The precipitate was washed with ice-cold pentane and the filtrate concentrated in vacuo. The crude product was purified by PMPLC yielding 4.06 g (68%) of 8-(tert-butyldimethylsilyloxy)-3-butyloct-1-ene.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:24]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:16]3[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccccc1
Product: FC(F)(F)c1cccc2c(-c3cccc(N(Cc4ccccc4)Cc4ccccc4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 559.
Reaction SMILES: C([NH:8][CH:9]([CH3:28])[CH2:10][N:11]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:27])C1C=CC=CC=1.C(O)(=O)C.[H][H]>[C].[Pd].C(O)C>[NH2:8][CH:9]([CH3:28])[CH2:10][N:11]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:27]
Reactant: CC(Cn1cc(-c2ccccc2)c2ccccc2c1=O)NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(N)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Yield: 75.2 %

Procedure:
36.8 g of 2-(2-benzylaminopropyl)-4-phenyl-1(2H)-isoquinolone preapred as described above, 12 g of 5% palladium-carbon, 50 ml of glacial acetic acid and 200 ml of ethanol were mixed, and the mixture was catalytically reduced while introducing hydrogen gas into the mixture at 60° to 70° C. After completion of the reduction reaction, the mixture was filtered, and the solvent was distilled off from the filtrate. The resulting residue was dissolved in 5% hydrochloric acid and the solution was washed with ethyl acetate. The aqueous layer was separated and rendered neutral with a 10% aqueous solution of sodium hydroxide. The resulting precipitate was filtered and recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 20.9 g (75% yield) of 2-(2-aminopropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 104° C. as colorless prisms.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:6])[C:3]([NH2:5])=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH3:6][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:1])[C:3]#[N:5]
Reactant: CC(C)(Oc1ccccc1)C(N)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C#N)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-2-phenoxypropanamide from Step C (0.01 mol) in dry CH2Cl2 (50 mL) and triethylamine (3.03 g, 0.03 mol) at 0° C. was added trifluoroacetic anhydride (3.15 g, 0.015 mol). After the addition was complete, the solution was allowed to warm to room temperature and stirring was continued at ambient temperature overnight. The reaction mixture was then refluxed for 3 hours. After cooling to room temperature and dilution with CH2Cl2 (100 mL), the solution was washed with saturated aqueous NaHCO3 (50 mL×3), water, and brine and dried over sodium sulfated. Evaporation gave the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.32˜7.36 (m, 2H), 7.14˜7.20 (m, 3H), 1.71 (s, 6H).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.CO[CH:12](OC)[CH2:13][NH2:14].ClC(OCC)=O.P(OCC)(OCC)OCC>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:9][C:1]1[CH:6]=[C:5]2[C:4](=[CH:3][CH:2]=1)[CH:7]=[N:14][CH:13]=[CH:12]2
Reactant: COC(CN)OC
Reactant: Cc1ccc(C=O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CCOC(=O)Cl
Agent: CCOP(OCC)OCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc2cnccc2c1
Temperature: 90 °C
Yield: 66.5 %

Procedure:
p-Tolualdehyde (53 mL, 0.486 mol) was stirred in a solvent of chloroform (900 mL), slowly added with aminoacetaldehyde dimethyl acetal (59.3 mL, 0.486 mol), and stirred at 90° C. until about a half of the reaction solution had evaporated. The reaction solution was cooled to room temperature, and the yellow reaction solution was dissolved in chloroform (400 mL), followed by cooling to 0° C. or lower. The reaction solution was slowly added with ethyl chloroformate (48 mL, 0.486 mol) and triethyl phosphite (104 mL, 0.583 mol), followed by stirring for 24 hours at room temperature. The reaction solution was cooled to 0° C. or lower, slowly added with titanium tetrachloride (213.6 mL, 1.94 mol), and refluxed for 12 hours or more. The temperature of the reaction solution was adjusted to room temperature and stirred for over 12 hours. The reaction mixture was poured over an ice water to separate the organic layer and the aqueous layer, and the aqueous layer was washed with dichloromethane. The aqueous layer was poured into a saturated potassium sodium tartrate solution, and adjusted to have a pH value of 9 by adding an aqueous ammonia solution, and then extracted with dichloromethane. The combined organic layer thus obtained was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (46.3 g, 66%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[CH3:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH:18]=O>O.CO.[Pd]>[CH2:18]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])[CH2:17][C:16]([CH3:21])([CH3:20])[CH3:15]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: CC(C)(C)CC=O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)CCN[C@@H](CC(=O)O)C(=O)O
Reaction time: 48 h
Yield: 72.9 %

Procedure:
L-aspartic acid (4 g, 0.03 mol) was added to a Parr bottle containing a solution of sodium bicarbonate (5.04 g, 0.06 mol) in water (50 mL) to form a clear solution, with effervescence. A solution of 3,3-dimethylbutyraldehyde (3 g, 0.03 mol) in methanol (50 mL) was then added to the Parr bottle, followed by Pd/C (4% palladium on carbon, 50% wet, 0.4 g). The mixture was hydrogenated at 50 psi/room temperature for 2 days. If the reaction was not complete, fresh Pd/C (0.2 g) would be added and hydrogenation continued for an additional 8 hrs. The mixture was filtered through a Celite® bed, and the bed was washed with methanol (20 mL). The filtrate and washings were combined and concentrated under reduced pressure at 40-50° C. The pH of the remaining aqueous solution was adjusted to 3 with concentrated hydrochloric acid. The precipitated solid was filtered and dried in a vacuum oven at 50° C. for 4 hrs to give 4.75 g (73%) of crude N-neohexyl-L-aspartic acid. The crude product was slurried with aqueous ethanol (47.5, 80% ethanol, 20% water) for 15 minutes and filtered to give 3.3 g (51%) of >98% pure N-neohexyl-L-aspartic acid. M.P. 184-186° C.; [α]D +12.35 (c=1, water); NMR (D2O) δ3.37(t, 3H); 2.25-2.65 (m, 4H); 1.27-1.47 (m, 2H); 0.89(s, 9H); Anal. Calc'd. for C10H19NO4 ; C, 55.28; H, 8.81; N, 6.45; Found: C, 55.35; H, 8.86; N, 6.50.
Reaction SMILES: O[CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.S(Cl)([Cl:17])=O>>[ClH:17].[Cl:17][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCCCCC(O)CCn1ccnc1
Reactant: O=S(Cl)Cl
Product: CCCCCC(Cl)CCn1ccnc1
Product: Cl

Procedure:
A solution of 1.5 g of 1-(3-hydroxyoctyl)imidazole was treated with 5 ml. of thionyl chloride and the solution stirred at room temperature for one hour. Evaporation to dryness afforded 1-(3-chlorooctyl)imidazole hydrochloride.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11](CC3C=CC(OC)=CC=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.[C:36](O)([C:38]([F:41])([F:40])[F:39])=[O:37]>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C@H:25]([O:28][C:36](=[O:37])[C:38]([F:41])([F:40])[F:39])[CH2:24]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Cn2nnc3c(N4CC[C@H](O)C4)nc(C(C)(C)C)nc32)cc1
Agent: CC[SiH](CC)CC
Product: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Temperature: 70 °C

Procedure:
A mixture of (S)-1-[5-tert-Butyl-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-c]pyrimidin-7-yl]-pyrrolidin-3-ol (example 106) and triethylsilane in TFA was heated to 70° C. for 22 h and evaporated to dryness. The residue was used without further purification in the consecutive step.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)=[CH:5][C:4]=1[F:19].CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:29]([O:30][CH3:31])=[O:32])=[CH:5][C:4]=1[F:19]
Reactant: COC(=O)C1CCNC(c2ccc(Cl)c(F)c2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
Methyl 2-(4-chloro-3-fluorophenyl)piperidine-4-carboxylate hydrochloride (1.639 g, 5.32 mmol) and DIPEA (2.316 mL, 13.30 mmol) were dissolved in DCM (10 mL). Methyl carbonochloridate (0.503 mL, 6.38 mmol) was added dropwise and the reaction stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (100 mL) and washed with 0.1 M HCl (2×75 mL), sat. NaHCO3 (100 mL), dried through a phase separator and evaporated in vacuo yielding dimethyl 2-(4-chloro-3-fluorophenyl)piperidine-1,4-dicarboxylate (1.625 g, 93%) as a colorless oil. MS m/z 330 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][F:13])[C:8](=[O:14])[CH2:7]2.[Cl-].[NH4+]>C(O)C.O.ClCCl.[Fe]>[NH2:15][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[N:9]([CH2:11][CH2:12][F:13])[C:8](=[O:14])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1CCF
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c2c(c1)CC(=O)N2CCF
Temperature: 25 °C

Procedure:
Iron powder (0.416 g, 7.43 mmol) is added in small portions to 7-fluoro-1-(2-fluoro-ethyl)-5-nitro-1,3-dihydro-indol-2-one (Step 3, 0.45 g, 1.86 mmol) and ammonium chloride (0.987 g, 18.6 mmol) in ethanol (40 ml) and water (20 ml) at 90° C. The reaction mixture is stirred vigorously and heated for 30 min, cooled to room temperature, and diluted with dichloromethane (100 ml). The mixture is filtered through celite, the organic layer separated and washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a dark brown solid. HPLC r.t. 2.34 min; MS for C10H10F2N2O m/z 213.2 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[N+:15]([C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)([O-:17])=[O:16].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>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Boc-4-piperidinol (log, 50 mmol), 4-nitrophenol (7.0 g, 50 mmol) and triphenylphosphine (15.7 g, 60 mmol) were dissolved in dry tetrahydrofuran (150 mL), and cooled on the ice bath. Diisopropyl azodicarboxylate (11.8 mL, 60 mmol) was added slowly, and stirred for 2 days at room temperature. The solvent was distilled off under reduced pressure, diethyl ether was added, and the solid precipitate was filtered off. The filtrate was concentrated and the product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1). Trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour. After distillation under reduced pressure, 1N sodium hydroxide aqueous solution was added, and the mixture extracted with ethyl acetate. After drying with anhydrous sodium sulfate, the product was concentrated and dried to obtain the target substance (6.75 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOC1CCCCC1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOC2CCCCC2)C(=O)O)cs1
Yield: 66.2 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetate (syn isomer, 3.5 g.), 2N aqueous solution of sodium hydroxide (11.8 ml.), methanol (11.8 ml.) and tetrahydrofuran (11.8 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 2.1 g.), mp. 148° C. (dec.).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12])(=[O:3])[CH3:2].[C-:31]#[N:32].[K+]>CS(C)=O>[C:1]([O:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([C:31]#[N:32])=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2Cc2ccccc2)n(C)c1=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C#N)n2Cc2ccccc2)n(C)c1=O
Temperature: 75 °C
Reaction time: 4.5 h
Yield: 89.7 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-7-benzyl-8-bromo-3-methylxanthine (9.55 g, 20.0 mmol) in anhydrous dimethylsulfoxide was added potassium cyanide (1.43 g, 22.0 mmol). After stirring at 70-80° C. for 4.5 hours, the mixture was cooled to room temperature, quenched with water (500 ml) and extracted with ethyl acetate (4×150 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (45 ml), dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to provide (R)-1-(5-acetoxyhexyl)-7-benzyl-8-cyano-3-methylxanthine (7.60 g, 90% yield) as a beige powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43]CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=2)=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1NC(=O)OCCc1ccccn1
Yield: 75.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-(2-pyridyl)-1-ethanol (58 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (110 mg, yield 75%).
Reaction SMILES: [CH2:1]([C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12]([N:22]([CH:19]([CH3:21])[CH3:20])[NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccccc1Cc1ccccc1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccccc1Cc1ccccc1
Yield: 59.8 %

Procedure:
A solution of (2-benzyl-phenoxy)-acetic acid (1.15 g, 4.74 mmol), and benzoic acid N′-isopropyl-hydrazide (704 mg, 3.95 mmol) in DMF (30 ml), was treated with diisopropyl ethyl amine (1.8 ml, 9.88 mmol), and PyBroP (2.76 g, 5.93 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between 1N HCl and DCM. The organic layer was successively washed brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 50% ethyl acetate/hexanes to afford the product as a white solid (950 mg, 60%). MS m/e 403.25 (M+H+)
Reaction SMILES: [O:1]=[C:2]1[C@@:6]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:17])[NH:3]1.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[O:1]=[C:2]1[C@@:6]([N:12]2[CH:13]=[CH:14][CH:15]=[C:16]2[C:20](=[O:21])[C:19]([Cl:24])([Cl:23])[Cl:18])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:17])[NH:3]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@@]1(n2cccc2)CC(=O)NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@]1(n2cccc2C(=O)C(Cl)(Cl)Cl)CC(=O)NC1=O
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of ethyl (R)-2,5-dioxo-3-(pyrrol-1-yl)pyrrolidine-3-carboxylate (767 mg) in ethyl acetate (10 ml) was added trichloroacetyl chloride (1.1 ml) and this solution was heated under reflux overnight. This reaction mixture was allowed to cool to room temperature, and thereto was added trichloroacetyl chloride (1.1 ml) and this mixture was heated under reflux for 3 hours. This reaction mixture was allowed to water-cooling to room temperature and the residual trichloroacetyl chloride was decomposed carefully with saturated aqueous sodium bicarbonate solution. After the aqueous layer was confirmed to be alkali, this mixture was extracted with ethyl acetate (5 ml) three times and the combined extract was washed sequentially with water and saturated brine, dried over magnesium sulfate, filtered and then concentrated to give a crude product as oil. This was purified by a flash column chromatography (n-hexane:ethyl acetate=1:1) to give ethyl (R)-2,5-dioxo-3-(2-trichloroacetylpyrrol-1-yl)pyrrolidine-3-carboxylate (1.17 g, 94%).
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH3:57])[C:3]([O:5][CH:6]([C@:8]12[O:15][C@:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=4)[CH:17]=3)([O:13][CH2:14]1)[C@H:11]([O:33]CC1C=CC=CC=1)[C@@H:10]([O:41]CC1C=CC=CC=1)[C@@H:9]2[O:49]CC1C=CC=CC=1)[CH3:7])=[O:4].ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@:12]23[O:15][C@@:8]([CH:6]([O:5][C:3](=[O:4])[C:2]([CH3:58])([CH3:57])[CH3:1])[CH3:7])([CH2:14][O:13]2)[C@@H:9]([OH:49])[C@H:10]([OH:41])[C@H:11]3[OH:33])=[CH:17][C:18]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)C(C)(C)C)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)C(C)(C)C)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethyl 2,2-dimethyl propanoate 14a (120 mg, 0.15 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.08 mL, 0.72 mmol) and 10% Pd/C (19 mg, 0.02 mmol) in turn at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=4/1 to give the title compound 14 as a white solid (62.3 mg, 77.6%, HPLC: 85.3%). The compound was characterized by the following spectroscopic data: MS(ESI, pos. ion) m/z: 580.3[M+HCOO]−; and 1H NMR (600 MHz, DMSO-d6) δ(ppm): 7.42 (m, 2H), 7.32 (m, 1H), 7.08 (m, 2H), 6.82 (m, 2H), 5.38 (brs, 1H), 5.06 (m, 1H), 4.04 (d, 1H), 3.97 (m, 3H), 3.57 (d, 1H), 3.52 (d, 1H), 3.47 (m, 3H), 1.30 (t, 3H), 1.23 (d, 3H), 1.10 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:19]1[C:23]2[CH:24]=CC=C[C:22]=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C(N)(C)C>CN(C=O)C>[CH:23]([NH:19][C:15](=[O:17])[CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)([CH3:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)NC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[1-(Tert-butoxycarbonyl)piperidin-4-yl]acetic acid 46-1 (0.20 g, 0.82 mmol), 1-hydroxybenzotriazole (0.15 g, 0.99 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.21 g, 1.07 mmol), 4-methylmorpholine (0.33 g, 3.29 mmol) and isopropyl amine (0.053 g, 0.90 mmol) were dissolved in DMF and stirred at 25° C. for 18 hours. Evaporated off the DMF and partitioned between ethyl acetate and dilute KHSO4. The aqueous was drawn off and the organic was washed with dilute NaHCO3, brine, dried, filtered and evaporated to afford 46-2. 1H-NMR (CD3OD): 4.03(d, 2H); 3.95(m, 1H); 2.75(br s, 2H); 2.06(d, 2H); 1.91(m, 1H); 1.64 (d, 2H); 1.44(s, 9H); 1.12(complex, 8H).