Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH2:21][CH2:22][CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH2:21][CH2:22][CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1
Reactant: CCCCC(Cc1ccc(OCCCN=[N+]=[N-])cc1)C(=O)OCC
Agent: [Pd]
Product: CCCCC(Cc1ccc(OCCCN)cc1)C(=O)OCC
Yield: 71.7 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-[4-(3-azidopropoxy)phenyl]-2-butylpropionate (2.45 g) and palladium on carbon (5%, 250 mg) and the reaction mixture was treated to afford the desired compound (1.62 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:6]=[C:7]([C:13]([CH3:15])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:13]([CH3:15])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=Cc1ccc(OC)c(OC)c1)C(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OC)c(OC)c1)C(C)=O
Yield: 80.4 %

Procedure:
Ethyl α-(3,4-dimethoxybenzylidene)acetoacetate (50 g) was catalytically reduced in a Parr low pressure apparatus in ethyl acetate (150 ml) in the presence of 5% palladium on charcoal catalyst (Pd/C)(3 g). The catalyst was removed by filtration; the solvent was removed under reduced pressure; and the residual oil was distilled to give ethyl α-(3,4-dimethoxybenzyl)-acetoacetate (40.5 g, b.p. 162°-164° C./0.4 mm Hg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:31]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:32])=[CH:9][C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:11]([CH:22]=2)[C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH:4]=[N:3]1.[OH-].[Li+].O.Cl>O1CCCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:31]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:32])=[CH:9][C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:11]([CH:22]=2)[C:12]([OH:14])=[O:13])[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc(C(=O)OCc3ccccc3)c(OCc3ccccc3)cc2C(=O)N2CCCCC2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(C(=O)O)c(OCc3ccccc3)cc2C(=O)N2CCCCC2)cn1
Reaction time: 18 h

Procedure:
To a solution of phenylmethyl 5-(1-methyl-1H-pyrazol-4-yl)-2-[(phenylmethyl)oxy]-4-(1-piperidinylcarbonyl)benzoate (may be prepared as described in Description 37; 194 mg, 0.38 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (33 mg, 1.38 mmol) and water (1 ml). The solution was stirred for 18 hours then 2M hydrochloric acid (0.69 ml, 1.38 mmol) was added and the solvent removed in vacuo to give the title compound as a gum. 170 mg.
Reaction SMILES: C(OC([NH:8][CH:9]([C:38]([OH:40])=[O:39])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:34](=[O:37])[CH:35]=[O:36])[CH:20]2[CH2:23][N:22]([CH:24]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[C:21]2=[O:33])=[CH:15][CH:14]=1)=O)(C)(C)C.C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(OCC)C>[NH2:8][CH:9]([C:38]([OH:40])=[O:39])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:34](=[O:37])[CH:35]=[O:36])[CH:20]2[CH2:23][N:22]([CH:24]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[C:21]2=[O:33])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3cccs3)C2=O)cc1)C(=O)O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NC(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3cccs3)C2=O)cc1)C(=O)O
Reaction time: 2.5 h
Yield: 71.5 %

Procedure:
2-[3-{4-(3-tert-Butoxycarbonylamino-3-carboxypropoxy)phenylglyoxyloylamino}-2-oxo-1-azetidinyl]-2-(2-thienyl)-acetic acid (0.830 g.) was added to a mixture of benzene (4 ml.) and anisol (1 ml.), and to the mixture, there was added 2,2,2-trifluoroacetic acid (2 ml.) under ice-cooling. The mixture was stirred at the same temperature for 2.5 hours, and diethyl ether (50 ml.) was added to the reaction mixture, whereafter the stirring was continued under ice-cooling for half an hour. Insoluble matrials were collected by filtration and suspended in ethyl acetate (30 ml.). The suspention was stirred for an hour, whereafter the insoluble materials were collected by filtration, washed with diethyl ether and then dried to give 2-[3-{4-(3-amino-3-carboxypropoxy) phenylglyoxyloylamino}-2-oxo-1-azetidinyl]-2-(2-thienyl) acetic acid (0.49 g.).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([N:22]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])S(CCC)(=O)=O)[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[F:35][C:15]1[C:14]([C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:11]3)=[O:13])=[C:19]([F:20])[C:18]([F:21])=[CH:17][C:16]=1[NH:22][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30]
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F)S(=O)(=O)CCC
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(-c4ccccc4)nc3c2)c1F
Temperature: 80 °C

Procedure:
A mixture of N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 0.1 mmol, 1.0 eq.), phenylboronic acid (13.5 mg, 0.011 mol, 1.1 eq.), Pd(dppf)2C12 (4.1 mg, 0.005 mmol, 0.05 eq.) and Na2CO3 (0.21 g, 0.2 mmol, 2.0 eq.) in dioxane and water (9 mL/1 mL) were heated at 80° C. for 4 h under N2 protection, then cooled and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford N-(2,4,5-trifluoro-3-(3-phenylquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide. 1H NMR (DMSO-d6, 400 MHz) δ 10.15 (brs, 1 H), 9.78 (s, 1 H), 8.62 (s, 1 H), 8.38 (m, 2 H), 8.32 (brs, 2 H), 7.79 (m, 1 H), 7.62 (brs, 3 H), 3.22 (t, 2 H), 1.74 (m, 2 H), 0.97 (t, 3 H).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][CH:3]=[CH2:4].ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl>[O:17]1[CH2:4][CH:3]1[CH2:2][CH2:1][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1
Reactant: C=CCCOC1CCCCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C1CCC(OCCC2CO2)OC1
Temperature: 0 °C
Yield: 96.2 %

Procedure:
Into a 500-mL flask containing 2-(3-butenyloxy)tetrahydropyran (49.0 g, 0.314 mol) in CH2Cl2 (500 mL) under a nitrogen atmosphere and cooled to 0° C. was added freshly crystallized m-chloroperoxybenzoic acid (95 g, 0.55 mol). The mixture was maintained at 0° C. for a period of 24 h. The precipitated benzoic acid was removed via vacuum filtration. The filtrate thus obtained was washed successively with 10% aqueous sodium hydroxide (500 mL) and saturated aqueous sodium sulfite (500 mL), respectively, the organic layer dried over anhydrous MgSO4 and concentrated in vacuo to afford tetrahydro-2-(oxiranylethoxy)-2H-pyran as a pure clear colorless liquid (52 g, 95%), which was used without any further purification: 1H NMR (CDCl3, 300 MHz) δ 4.62 (s, 1H], 3.86-3.92 [m, 2H], 3.52-3.55 [m, 2H], 3.08 [br, 1H], 2.78-2.81 [t, J=3 Hz, 1H], 2.53-2.55 [t, J=3 Hz, 1H], 1.53-1.88 [m, 8H].
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][N:12]2[C:15]([I:18])=[CH:16][N:17]=[C:11]2[CH:10]=1)=[O:8])=O.N1C=CC=CC=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[C:2]([C:3]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][N:12]3[C:15]([I:18])=[CH:16][N:17]=[C:11]3[CH:10]=2)=[N:6][N:5]=1)([CH3:20])([CH3:19])[CH3:1]
Reactant: CC(C)(C)C(=O)NNC(=O)c1ccn2c(I)cnc2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)c1nnc(-c2ccn3c(I)cnc3c2)o1
Temperature: 70 °C
Yield: 8.4 %

Procedure:
3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid N′-(2,2-di methyl propionyl) hydrazide (875 mg, 2.27 mmol) was suspended in anhydrous THF (15 mL) under a nitrogen atmosphere. Pyridine (0.388 mL, 4.76 mmol) and tosyl chloride (518 mg, 2.72 mmol) were added and the mixture was heated to 70° C. overnight. The reaction was cooled and partitioned between EtOAc and 1M HCl. The aqueous fraction was basified with 2M sodium carbonate solution and extracted with CH2Cl2. The organic phase was dried through a phase separation cartridge and evaporated to give 7-(5-tert-Butyl-[1,3,4]-oxadiazol-2-yl)-3-iodo-imidazo[1,2-a]pyridine (70 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:12][CH:11]=2)[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8]>[Ni].C(O)(C)C>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([CH:13]2[CH2:12][CH2:11][CH:10]([C:4]3[CH:5]=[C:6]([CH3:9])[C:7]([OH:8])=[C:2]([CH3:1])[CH:3]=3)[CH2:15][CH2:14]2)=[CH:21][CH:20]=1
Reactant: Cc1cc(C2=CCC(c3ccc(O)cc3)CC2)cc(C)c1O
Agent: [Ni]
Solvent: CC(C)O
Product: Cc1cc(C2CCC(c3ccc(O)cc3)CC2)cc(C)c1O
Yield: 99.6 %

Procedure:
19.6 g (0.063 mol) of 1-(3,5-dimethyl-4-hydroxyphenyl)-4-(4-hydroxyphenyl)-1-cyclohexene obtained in Example 5 of Example A, 300 g of isopropyl alcohol and 5.2 g of Raney nickel catalyst were placed in a reaction vessel (1L capacity autoclave), and then in the same manner as in Example 3, 18.6 g of 4-(4′-(4″-hydroxyphenyl)-cyclohexyl)-2,6-dimethyl-1-hydroxybenzene) was obtained as white crystals having a purity of 92.7% (high performance liquid chromatography). The yield was found to be 92.0 mol % based on the 1-(3,5-dimethyl-4-hydroxyphenyl)-4-(4-hydroxyphenyl)-1-cyclohexene used. The selectivity of trans-/cis-isomers of 4-(4′-(4″-hydroxyphenyl)cyclohexyl)-2,6-dimethyl-1-hydroxybenzene was found to be 69/31 (high performance liquid chromatography).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[CH3:11][CH:12]1[C:18]2=[N:19][C:20]3[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:21]=3[N:17]2[CH:16]=[CH:15][CH:14]=[CH:13]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([N:19]1[C:20]2[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:21]=2[N:17]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]([CH3:11])[CH:18]12)=[O:10]
Reactant: CC1C=CC=Cn2c1nc1c2CCCC1=O
Reactant: O=C=Nc1ccccc1F
Solvent: ClCCl
Product: CC1C=CC=CN2C3=C(C(=O)CCC3)N(C(=O)Nc3ccccc3F)C12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Fluorophenylisocyanate (0.28 g, 2.06 mmol) was added to a solution of 6-methyl-1,2,3,4-tetrahydro-4-oxo-6H-azepino(1,2-a)benzimidazole (0.4 g, 1.87 mmol; Ohta, S. et al. Chem. Pharm. Bull. 1990, 38(2), 301) in methylene chloride (5 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and purified by medium pressure chromatography, using EtOAc/MeOH as an eluent and recrystallization from EtOAc/methylene chloride to give the title compound as a solid: mp 139-141° C.; MS: 352 (MH+).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[N:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].[Li][AlH][SeH:12]>>[CH:1]([NH:4][C:5]([NH:6][CH:7]([CH3:9])[CH3:8])=[Se:12])([CH3:3])[CH3:2]
Reactant: [Li][AlH][SeH]
Reactant: CC(C)N=C=NC(C)C
Product: CC(C)NC(=[Se])NC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
N,N′-diisopropylcarbodiimide (0.15 mL, 1.0 mmol) was added to the solution of LiAlHSeH (1.0 mmol) prepared as described above in Example One. The reaction mixture was stirred at 0° C. for one hour. The mixture was extracted with diethyl ether and washed with saturated NaCl solution. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel with dichloromethane:n-hexane (40:1) to give 0.13 grams (62%) N,N′-diisopropylselenourea as a white crystal; mp 142.6–148.2° C.; C7H16N2Se; IR (KBr) 1515, 1570, 3195, 3246 cm−1; 1H NMR (CDCl3) δ 1.19 (12H, d, J=6.4 Hz, CH3), 4.21 (2H, br s), 6.10 (2H, br s); 13C NMR (CDCl3) δ 22.4, 47.9,176.2; MS (EI): m/z=208 [M+]; HRMS: m/z=208.0478 calcd for C7H16N2Se, found 208.0503.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[CH2:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15]>C1COCC1>[CH2:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)[CH2:18][CH2:17]1)[CH3:15]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCN1CCNCC1
Solvent: C1CCOC1
Product: CCN1CCN(c2ncc([N+](=O)[O-])cc2[N+](=O)[O-])CC1
Temperature: 60 °C
Yield: 120.9 %

Procedure:
3 g (14.7 mmol) of 2-chloro-3,5-dinitropyridine, 20 ml of THF and 30 mmol of 4-ethylpiperazine were placed in a round-bottomed flask. The mixture was maintained at 60° C. for two hours with stirring and was then poured into a mixture of ice-water with stirring. The precipitate formed was filtered off by suction and dried under vacuum to constant weight. 5 g of yellow powder were obtained.
Reaction SMILES: C(NC1CCCCC1)(C)C.[Li]CCCC.[CH3:16][C:17]1[N:18]=[CH:19][O:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([N-]C1CCCCC1)(C)C.[Li+].C(Cl)(Cl)(Cl)[Cl:39]>C1COCC1.CCCCCC.O>[Cl:39][C:19]1[O:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([CH3:16])[N:18]=1
Reactant: CCOC(=O)c1ocnc1C
Reactant: ClC(Cl)(Cl)Cl
Agent: CC(C)NC1CCCCC1
Agent: CC(C)[N-]C1CCCCC1
Agent: [Li+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1oc(Cl)nc1C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
To 1.50 g (0.016 mol) of N-isopropylcyclohexylamine in 20 ml of dry THF at -78° C. was added, under nitrogen, 4.1 ml of 2.4 M BuLi in hexane. The solution was stirred at -78° C. for 5 min. A solution of 1.55 g (0.01 mol) of the compound of Example 1, in 10 ml of THF, was added dropwise to the above lithium N-isopropylcyclohexylamide solution. The reaction mixture turned deep red. After 5 min. of stirring, 5 ml of CCl4 was added to the red solution and the reaction mixture was stirred at -78° C. for 1 hr. Thereafter, the reaction mixture was poured into water and extracted with 100 ml of ether. The ether solution was washed with 1 N HCl, dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel using 10% ether/petroleum ether as eluant. The first 800 ml of eluate gave a solid which was recrystallized from hexane at low temperature to give 200 mg of ethyl 2-chloro-4-methyl-5-oxazolecarboxylate as white solid, mp 61°-72° C. An additional 330 mg, mp 55°-58° C., was obtained by concentration of the mother liquor and distillation of the residue; total yield 29%.
Reaction SMILES: C.[F:2][C:3]([F:11])([F:10])[C:4]([C:6]([F:9])([F:8])[F:7])=[O:5]>[Pd]>[CH:4]([OH:5])([C:6]([F:9])([F:8])[F:7])[C:3]([F:11])([F:10])[F:2]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Product: OC(C(F)(F)F)C(F)(F)F

Procedure:
French Pat. No. 2,027,172 relates to a process for gas phase hydrogenation of perhaloketones over a palladium-based catalyst deposited on activated charcoal and particularly describes catalytic hydrogenation of hexafluoroacetone (CF3COCF3) to yield 1,1,1,3,3,3-hexafluoroisopropyl alcohol. The yield obtained (75%) and the difficulty of handling the starting material (b.p.: -27.4° C./760 torr) make the process uneconomical. French Pat. No. 2,479,803 carries out a gas phase catalytic hydrogenation of hexafluoroacetone to 1,1,1,3,3,3-hexafluoroisopropanol over a nickel-based catalyst. The catalyst life is not rated for a continuous operation time longer than 20 hours and, above all, this process requires the use of a pure starting material, which is difficult to obtain in the case of hexafluoroacetone. French Pat. No. 1,361,260 carries out the gas phase catalytic hydrogenation of hexafluoroacetone over a catalyst based on copper chromite. The yields of 1,1,1,3,3,3-hexafluoroisopropanol are mediocre (approximately 40%) for a partial conversion (83%) of the ketone used. This entails difficult and costly recycling.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6].[CH3:9][C:10]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:40])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[CH3:9][C:10]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:40])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:11][CH2:12][CH2:13][O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]
Reactant: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Reactant: OCC(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=CCCOCC(O)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
0.21 g (55%, 4.8 mmol) of sodium hydride was added to a solution of 0.44 g (4.8 mmol) of glycerol in dry N,N-dimethylformamide (5 mL) with cooling on ice. After the mixture was stirred for 30 min at 50° C., the above (4,8,12,16-tetramethylheptadec-3-enyl)tosylate was added dropwise with additional stirring for 12 hours at the same temperature. After addition of water at 0° C., the reaction mixture was extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 44 mg of the title compound (4% yield in 2 steps) as a colorless transparent viscous product. The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:6][CH:5]1[C:7]([O:9]CC)=[O:8])[CH3:2].[OH-].[Li+:13]>CO>[Li+:13].[CH2:1]([O:3][CH:4]1[CH2:6][CH:5]1[C:7]([O-:9])=[O:8])[CH3:2]
Reactant: CCOC(=O)C1CC1OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCOC1CC1C(=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 104 %

Procedure:
A solution of the crude ethyl 2-ethoxycyclopropanecarboxylate in methanol (10 mL) was treated with aqueous lithium hydroxide (8.6 mL, 1.0 M, 8.6 mmol, 1.0 equiv.), the mixture stirred at ambient temperature for 16 h, and concentrated in vacuo. The resulting orange syrup was twice redissolved in methanol and concentrated in vacuo to afford crude 2-ethoxycyclopropane-carboxylic acid lithium salt as an orange foam (1.21 g, 104%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][Cl:17])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[C:21]2[O:26][CH2:27][O:28][C:20]=12>>[Cl:17][CH2:16][CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]4[O:26][CH2:27][O:28][C:20]=34)=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: Nc1c(Cl)cnc2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCl
Product: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCCCl
Yield: 92 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-7-(2-chloroethoxy)6-methoxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 92% yield; NMR Spectrum: (DMSOd6 and CD3CO2D) 4.05 (s, 3H), 4.1 (t, 2H), 4.55 (t, 2H), 6.3 (s, 2H), 7.4 (s, 1H), 7.9 (s, 1H), 8.15 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 409 and 411.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:35]#[N:36])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18][CH:17]([C:25]([OH:27])=O)[CH:16]2[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[C:11]([F:37])[CH:10]=1.CC1(C)[O:43][C@@H:42]([CH2:44][CH2:45][NH2:46])[CH2:41][O:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:43][C@H:42]([CH2:41][OH:40])[CH2:44][CH2:45][NH:46][C:25]([CH:17]1[CH:16]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=2[F:37])([C:35]#[N:36])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18]1)=[O:27]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 47.2 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 64c (0.46 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 48%).
Reaction SMILES: [Cl-:1].C([O:4][C:5](=[O:15])[CH2:6][CH2:7][CH2:8][N+:9]([CH2:12][CH2:13][F:14])([CH3:11])[CH3:10])C.Cl>O1CCOCC1>[Cl-:1].[C:5]([CH2:6][CH2:7][CH2:8][N+:9]([CH2:12][CH2:13][F:14])([CH3:11])[CH3:10])([OH:15])=[O:4]
Reactant: CCOC(=O)CCC[N+](C)(C)CCF
Agent: Cl
Agent: [Cl-]
Solvent: C1COCCO1
Product: C[N+](C)(CCF)CCCC(=O)O
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a solution of 4-ethoxy-N-(2-fluoroethyl)-N,N-dimethyl-4-oxobutan-1-aminium chloride (4) from the preceding step (3.61 g, ≦514.2 mmol) in dioxane (10 ml) was added conc. HCl (5 ml) and the reaction mixture was stirred at 40° C. for 24 h. The mixture was evaporated, to the residue (3.02 g) was added conc.HCl (15 ml) and stirred at 70° C. for 2 h, then the mixture was evaporated again. The residue was triturated with acetonitrile in an ultrasound bath, then the mixture was decanted and the crystalline solid was washed with acetone. After drying in vacuo over P2O5 2.125 g of the 3-carboxy-N-(2-fluoroethyl)-N,N-dimethylpropan-1-aminium chloride (6) was obtained.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[NH:6][CH:7]=[CH:8][N:9]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>C(O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([S:4][C:5]2[NH:6][CH:7]=[CH:8][N:9]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Sc1ncc[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2ncc[nH]2)cc1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a mixture of 6.2 g (0.12 mmoles) of sodium methoxide and 90 ml of ethyl alcohol was added 5.8 g (0 058 mmoles) of 2-mercaptoimidazole. After stirring for 0.5 hour, 8.2 g (0.058 mole) of 1-fluoro-4-nitrobenzene was added and the mixture refluxed for 4 hours. The mixture was allowed to cool and filtered to give 5.0 g (39%) of the product. An additional 2.0 g (16%) of product was recovered from the filtrates. Recrystallization from dichloromethane/methanol gave the product as yellow rods. mp 207°-209° C.