Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:18]1[C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](OC)=O)=[CH:27][CH:26]=2)=[N:21][N:20]=[N:19]1>C(O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:32]([CH2:31][C:28]4[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:22]5[NH:18][N:19]=[N:20][N:21]=5)=[CH:30][CH:29]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)Cc1ccc(OCc2nnn[nH]2)cc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: [Na]
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(OCc4nnn[nH]4)cc3)nc(=O)c1-2
Yield: 13.5 %

Procedure:
Sodium (0.253 g) was dissolved in ethanol (15 ml) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.813 g, 3.7 mmol) and methyl 4-(5-tetrazolylmethoxy)phenylacetate (17 g, 7.3 mmol) were added. The reaction mixture was refluxed for about 2 days, cooled, and then the solvent was removed in vacuo. The residue was treated with water and acetic acid and the precipitate which formed was collected by filtration and dried at 60° C. under vacuum. The product was then dissolved in ethyl acetate, extracted with Na2CO3 (4×200 ml) and the aqueous layer was acidified to pH 2.5 with concentrated HCl. The aqueous layer was then extracted with ethyl acetate (2×300 ml) and the organic layer was dried over MgSO4, filtered and concentrated in vacuo. The solid residue was recrystallized from ethyl acetate to afford 0.21 g of 1-cyclopentyl-3-ethyl-6-[4-(5-tetrazolylmethoxy)phenylmethyl]pyrazolo[3,4-d]pyrimidin-4-one.2/5 hydrate, m.p. 240°-242° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)([O-:15])=[O:14]>C(O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)c1cc(Cl)ccc1N
Solvent: CCO
Product: COC(=O)c1cc(Cl)ccc1N=Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A mixture of 2-amino-5-chloro-benzoic acid methyl ester (5.55 g, 30 mmol) and 3-nitro-benzaldehyde (4.99 g, 33 mmol) in ethanol (100 mL) was heated to reflux for 2 h. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-chloro-2-[(3-nitro-benzylidene)-amino]-benzoic acid methyl ester (7.2 g, 75%) as a white solid: LC/MS m/e calcd for C15H11ClN2O4 (M+H)+: 319.72, observed: 319.0.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([OH:22])=O)[NH:8]2)=[CH:4][CH:3]=1.[N:23]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([NH2:23])=[O:22])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
To a mixture of 6-chloro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.83 g), 1H-1,2,3-benzotriazol-1-ol (0.38 g) and N,N-dimethylformamide (10 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.54 g) at room temperature, and the mixture was stirred at 50° C. for 20 min, and allowed to cool to room temperature. 28% Aqueous ammonia (0.30 ml) was added, and the reaction mixture was stirred at room temperature for 1 hr, and acidified with 10% aqueous citric acid solution. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.80 g, yield 96%) as colorless crystals. melting point >300° C. (decomposition).
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH:9]=[CH:8][C@H:7]1[CH2:11][C:12]([O:14]C)=[O:13])(=O)=O.O1CCCC1.[OH-].[Na+:22]>O>[OH:5][C@H:6]1[CH2:10][CH:9]=[CH:8][C@H:7]1[CH2:11][C:12]([O-:14])=[O:13].[Na+:22]
Reactant: COC(=O)C[C@@H]1C=CC[C@H]1OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])C[C@@H]1C=CC[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.290 g. (0.00124 mole) of racemic methyl trans-2-methylsulfonyloxy-4-cyclopentene-1-acetate in 10 ml. of tetrahydrofuran and 4 ml. of water at 0° C. was added dropwise, 1.00 ml. (0.0020 mole) of 2 N sodium hydroxide solution. The two-phased solution was vigorously stirred at 0° C. for 1 hr. and at room temperature for 16 hrs. to form racemic sodium cis-2-hydroxy-4-cyclopentene-1-acetate in admixture with racemic cis-2-hydroxy-4-cyclopentene-1-acetic acid lactone.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]#[N:12])=[CH:6][CH:5]=1.Cl.Cl[CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>CN(C)C=O>[NH:25]1[CH:26]=[C:22]([CH2:21][C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:11]#[N:12])[N:23]=[CH:24]1
Reactant: N#CC(c1ccccc1)c1ccc(Cl)cc1
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(Cc1c[nH]cn1)(c1ccccc1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
As described in Example 1, 2.04 g. of 50% sodium hydride, 10.12 g. of 2-(4-chlorophenyl)-2-phenylacetonitrile, and 3.06 g. of 4-chloromethylimidazole hydrochloride were reacted in 50 ml. of dimethylformamide. The reaction mixture was stirred for one hour at 60° C. and then for 20 hours at ambient temperature. Evaporation of the solvent and work up as described in Example 1 produced 5.3 g. of the product named above, which was converted to the maleate salt and crystallized from acetone/diethyl ether to obtain 6.29 g. of the maleate salt of the desired product, m.p. 135°-136° C.
Reaction SMILES: [OH-].[Na+:2].C([O:6][C:7]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][C:8]=1[C:9]([NH:11][C:12]1[CH:21]=[C:20]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])=[O:10])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:20]1[CH:19]=[CH:18][C:13]([C:14]([O-:16])=[O:15])=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:27]=[C:28]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:29]=[CH:30][C:7]=2[OH:6])[CH:21]=1.[Na+:2]
Reactant: COC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(-c2cccnc2)ccc1OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2ccco2)ccc1C(=O)[O-])c1cc(-c2cccnc2)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dioxane (3 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.19 mL) were added to the obtained methyl 2-(2-acetoxy-5-(pyridin-3-yl)benzamido)-4-(furan-2-yl)benzoate (0.18 g), followed by stirring at room temperature for 3 hours and 10 minutes and then at 70° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature and adjusted to a pH of 6.0 with a 10% aqueous solution of citric acid. The solid substance was collected by filtration, and methanol (1.0 mL) and a 1 mol/L aqueous solution of sodium hydroxide (0.055 mL) were added thereto. The solid substance was collected by filtration to obtain 0.044 g of sodium 4-(furan-2-yl)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)benzoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:14])[F:15])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: Cn1nc(-n2nccc2N)cc1OC(F)F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1nc(-n2ncc([N+](=O)[O-])c2N)cc1OC(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
15 g (0.065 mol) 5-Amino-1-(5-difluoromethoxy-1-methyl-3-pyrazolyl)pyrazole was dissolved in 60 ml acetic acid and treated with 7.35 g (0.072 mol) acetic anhydride. After stirring at room temperature for 3 hours, the reaction mixture was cooled to 10° C. 4.95 g (0.078 mol) Fuming nitric acid was added dropwise and the mixture treated with 8.0 g (0.078 mol) acetic anhydride. After stirring for 18 hours at room temperature, the reaction mixture was added to 500 ml ice-water. It was extracted three times with ethyl acetate, the organic phases were washed with water and concentrated. The residue was treated with 80 ml ethanol and 40 ml concentrated hydrochloric acid. After heating for 8 hours under reflux, the ethanol was removed and the residue extracted with ethyl acetate. The concentrated ethyl acetate phases were washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated. The residue was recrystallised from diisopropyl ether and ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1N.N([O-])=[O:12].[Na+]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[OH:12]
Reactant: COc1ccc(C)c(N)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccc(C)c(O)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-5-(methyloxy)aniline (Intermediate 11, 6.0 g) in H2SO4 (5 M, 20 mL) was added portionwise NaNO2 (3.4 g, 49.3 mmol) at 0-5° C. The mixture was stirred at 50° C. for 1 hour and extracted with ethyl acetate (4 times 30 mL). The combined ethyl acetate layers were dried over sodium sulphate and concentrated under vacuum to give a residue, which was purified by column chromatography on silica gel (with EtOAc:PE=1:20 as eluents) to afford the title compound as a solid.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7](Cl)=[O:8])(=[O:3])[CH3:2].[F:10][C:11]([F:34])([F:33])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][CH:21]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[NH:20][N:19]=2)=[CH:14][CH:13]=1.C(OCC)C>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:20]1[N:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:34])([F:10])[F:33])=[CH:13][CH:14]=2)[S:22][CH:21]1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(OCc1ccccc1)C1NN=C(c2ccc(C(F)(F)F)cc2)S1
Reactant: CC(=O)SCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)SCCC(=O)N1N=C(c2ccc(C(F)(F)F)cc2)SC1C(=O)OCc1ccccc1

Procedure:
3-Acetylthiopropanoyl chloride (0.36 g), poly (4-vinyl pyridine) (0.8 g) and the product from step b) (0.8 g) were stirred together in dry toluene (30 ml) under an atmosphere of nitrogen for 20 hours. Diethyl ether was added and the solid was filtered off and washed with diethyl ether. The filtrate was evaporated under reduced pressure and the resulting product was crystallised from ethanol to yield the sub-title product (0.9 g) as a white solid. mp 120°-121°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH2:6][C:7]1[NH:8][C:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:11]=1)C.IC.[C:36]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:3][C:4](=[O:33])[CH:5]([C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH2:6][C:7]1[N:8]([CH3:36])[C:9]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(Cc1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)[nH]1)c1cccc(C)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(Cc1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C)c1cccc(C)c1
Temperature: 40 °C
Yield: 26.9 %

Procedure:
A solution of 3-(4,5-di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic acid ethyl ester (Example 30, step C; 50 mg, 0.11 mmol), iodomethane (17 mg, 0.12 mmol) and K2CO3 (79 mg, 0.55 mmol) in DMF (2.0 mL) was stirred and heated to 40° C. overnight. The solvent was removed under reduced pressure, and the crude residue was purified on silica gel (EtOAc/CH2Cl2) to give 3-(1-methyl-4,5-di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic acid methyl ester (13 mg, 26%). The methyl ester (18 mg, 0.042 mmol) was hydrolyzed using the conditions outlined in Example 30, step D to provide the title compound (12 mg, 69% yield). HPLC: Rt=2.64 (Method A). MS (ESI): mass calculated for C28H28N2O2, 424.22; m/z found, 425.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.28-7.23 (m, 4H), 7.21-7.04 (m, 6H), 6.98 (d, J=7.8 Hz, 2H), 4.38 (d, J=9.3 Hz, 1H), 3.54 (dd, J=16.1, 9.3 Hz, 1H), 3.22 (dd, J=16.1, 3.1 Hz, 1H), 3.17 (s, 3H), 2.42 (s, 3H), 2.30 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:28]1[CH:42]=[CH:41][C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37](F)=[CH:36][CH:35]=2)=[O:33])=[CH:30][CH:29]=1.C1(C)C=CC=CC=1>O.CN(C)C(=O)C>[CH2:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])[C:31]1[CH:41]=[CH:42][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: Oc1ccc(C2(c3ccc(O)cc3)CCCCC2)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In a three neck 500 mL round-bottom flask was weighed bisphenol-Z (35.0000 g, 130.42 mmol), potassium carbonate (36.0505 g, 260.45 mmol), 4,4′-difluorobenzophenone (28.4587 g, 130.42 mmol), toluene (115 g) and N,N-dimethylacetamide (233 g). The flask was fitted with a condenser and a thermometer. The light yellow mixture was stirred and heated to reflux. The water formed was azeotropically distilled with toluene. On complete removal of water and toluene, the solution was stirred at reflux for about 2 hours. The viscous polymer solution was precipitated in water, and a white fibrous polymer was isolated by filtration. The white polymer was stirred in boiling water for about 1 hour, filtered, and then stirred in boiling methanol for about 1 hour and filtered. The fibrous white polymer was then dried in an vacuum oven for about 16 hours at 100° C. The yield was about 54.35 g. The number average molecular weight of the polymer was about 11.5 K.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17]CC3C=CC(F)=CC=3F)=[C:12](Br)[C:11]2=[O:28])=[C:6]([Cl:29])[CH:5]=1.Cl>C1COCC1.O>[Cl:29][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[N:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]1=[O:28])[C:3]([O:2][CH3:1])=[O:30]
Reactant: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-n2c(C)cc(O)cc2=O)c(Cl)c1
Reaction time: 8 h
Yield: 110.8 %

Procedure:
Methyl-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoate (2.30 g, 4.61 mmol) was taken up in THF (20 ml) and H2O (4 ml). 2.5 N NAOH (9.2 ml) was added to the vessel and the reaction stirred overnight to completion. Concentrated HCl was added dropwise until reaction was made acidic (pH=1). H2O (100 ml) and THF (100 ml) were added to the mixture. The contents were poured into a separatory funnel and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4, the solvent removed in vacuo, and the residue was taken up in a 50% mixture of ethyl acetate/hexane. The precipitate was collected on a filter pad to yield a white powder (1.5 g, 67%). 1H NMR (300 MHz, DMSO) δ 13.59 (1H), 8.16 (d, J=1.81 Hz, 1H), 8.06 (dd, J=6.24, 1.81 Hz, 1H), 7.73 (app q, J=8.46, 1H), 7.68 (d, J=8.26 Hz, 1H), 7.38 (dt, J=9.48, 2.62 Hz, 1H), 7.26-7.18 (m, 1H), 6.80 (s, 1H), 5.39 (s, 2H), 3.93 (s, 3H), 1.96 (s, 3H); ES-MS m/z 483 (M+H). ES-HRMS m/z 483.9749 (M+H calcd for C20H14BrClF2NO4 requires 483.9757).
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[C:9]1[C:18](=[O:19])[CH2:17][CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10]1=[O:20])[CH2:7][CH3:8])[CH:2]=[CH2:3].[OH-].[Na+].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O.O>[CH2:1]([O:4][N:5]=[C:6]([C:9]1[C:10](=[O:20])[CH:11]2[CH:16]([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:17][C:18]=1[O:19][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCONC(CC)=C1C(=O)CC2CCCCC2C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C=CCON=C(CC)C1=C(OC(=O)c2ccccc2)CC2CCCCC2C1=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(1-allyloxyaminopropylidene)decaline-1,3-dione (2 g) in acetone (30 ml), sodium hydroxide (0.2 g) in water (1 ml) was added at room temperature and then benzoylchloride (0.7 g) was added. After stirring for 5 hours, the reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with one normal sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo and an oily substance (1.8 g) was obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([N:9]([CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C(NCCCn1ccnc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N(CCCn1ccnc1)Cc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 4.58 g. of N-[3-(1H-imidazol-1-yl)propyl]benzamide, 40 ml. of dimethylformamide, and 0.96 g. of 50% sodium hydride in oil was stirred for 2 hours and 2.62 g. of benzyl bromide was added. The mixture was stirred for 24 hours, concentrated to remove the dimethyl formamide, diluted with water and methylene chloride, and the layers separated. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The oil was twice washed with hexane and again concentrated. The desired product was obtained as an oil.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:33])[C:7](=[O:32])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]C1C=CC=CC=1)=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2].[C:34]1([CH2:40]CCCCI)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:1]([C:5]1[N:6]([CH3:33])[C:7](=[O:32])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: ICCCCCc1ccccc1
Reactant: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(OCCCCc3ccccc3)ccc2c1=O
Product: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(OCCCCCc3ccccc3)ccc2c1=O

Procedure:
Following the procedure for 3-tert-butyl-2-methyl-4-phenyl-6-(4-phenylbutoxy)isoquinolin-1(2H)-one, using 5-phenyl-1-iodopentane in place of 4-phenyl-1-iodobutane, the titled compound was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[CH:33]=[C:32]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:10]([O:21][CH2:23][C:24]2[CH:33]=[C:32]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCOc1cc(CCl)cc2ccccc12
Reactant: OC1CN(Cc2ccccc2)CCC1c1ccc(F)cc1
Product: C[Si](C)(C)CCOCOc1cc(COC2CN(Cc3ccccc3)CCC2c2ccc(F)cc2)cc2ccccc12

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating (3RS,4RS)-1-benzyl-4-(4-fluoro-phenyl)-piperidin-3-ol with 2-chloromethyl-4-(β-trimethylsilylethoxymethoxy)-naphthalene there was obtained (3RS,4RS)-1-benzyl-4-(4-fluoro-phenyl)-3-[4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine as a light yellow oil; MS: 572 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@H:7]1[C:12]([OH:14])=O)=[O:5])C.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[Cl:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1>CC#N.CCN(CC)CC>[CH3:1][O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@H:7]1[C:12](=[O:14])[NH:42][C:41]1[CH:43]=[CH:44][C:38]([Cl:37])=[CH:39][CH:40]=1)=[O:5]
Reactant: C=C1C[C@@H](C(=O)O)[C@H](C(=O)OCC)C1
Reactant: Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C1C[C@@H](C(=O)Nc2ccc(Cl)cc2)[C@H](C(=O)OC)C1
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
The crude mixture containing 1a (16.7 g) was dissolved in 500 ml of CH3CN and treated subsequently with 51 ml of NEt3, 25.0 g hydroxybenzotriazole and 31.3 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and stirring was continued at 22° C. for 30 min. The mixture was treated with 23.1 g of 4-chloroaniline and stirring was continued at 22° C. for 16 h and at 60° C. for 5 h. The mixture was evaporated and the residue partitioned between AcOEt and 0.1 N NaOH. The organic layer was washed with 0.1 N NaOH, 1 N HCl and brine, dried and evaporated to give 13.7 g of the crude title compound 1b.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C(OP([CH:21]([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])(OCC)=O)C.[CH3:28][C:29]([CH3:33])([CH3:32])[CH:30]=O>CCCCCC.O1CCCC1.O>[F:27]/[C:21](=[CH:28]\[C:29]([CH3:33])([CH3:32])[CH3:30])/[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(C)(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)/C(F)=C/C(C)(C)C
Temperature: 0 °C

Procedure:
n-Butyllithium (4.8 ml of a 1.6M solution in hexane) was added to a stirred solution of diisopropylamine (1.1 ml) in tetrahydrofuran (15 ml) at 0° C. under nitrogen. The resulting mixture was maintained at 0° C. for 0.5 hour and then cooled to -70° when a solution of ethyl diethylphosphonofluoroacetate (1.7 g) in tetrahydrofuran (5 ml) was added. After a further 0.5 hour at -70° trimethylacetaldehyde (0.76 ml) was added neat and the resulting mixture was allowed to warm to room temperature over 5 hours. After this time, water (5 ml) was added and the bulk of the solvent was removed under reduced pressure. The residue was partitioned between diethyl ether and water. The organic phase was separated, washed with water, 10% hydrochloric acid solution and brine before drying over anhydrous magnesium sulphate. The solvent was removed in vacuo to leave ethyl (Z)-2-Fluoro-4,4-dimethylpent-2-enoate as a pale green oil (1.0 g).