Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[C:12]([F:14])[CH:13]=1)(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[C:12]([F:14])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnc(Cl)c(F)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnc(-c2cccnc2)c(F)c1

Procedure:
By carrying out the operation analogously to example 213, starting from 6-chloro-5-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XI, and 3-pyridineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6](=[N:7]O)[CH2:5][N:4]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:3]1=[O:17]>CO.[Ni]>[NH2:7][CH:6]1[CH2:5][N:4]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:3](=[O:17])[C:2]1([CH3:1])[CH3:18]
Reactant: C[C@H](c1ccccc1)N1CC(=NO)C(C)(C)C1=O
Agent: [Ni]
Solvent: CO
Product: C[C@H](c1ccccc1)N1CC(N)C(C)(C)C1=O
Reaction time: 16 h
Yield: 94 %

Procedure:
In 300 ml of methanol was dissolved 11.5 g of 3,3-dimethyl-4-hydroxyimino-1-[1-(R)-phenylethyl]-Pyrrolidin-2-one, and about 20 ml of Raney nickel washed with methanol was added to the solution. Reduction was conducted at room temperature for 16 hours in an egg-plant type flask. The catalyst was removed by filtration, and the solvent of filtrate was removed under reduced pressure. The residue was subjected to silica gel (400 g) column chromatography using a 30:1 (by volume) mixture of chloroform and methanol as an eluent to yield 3.75 g of Fraction 1 (lower polar material) and 10.2 g of a mixture of Fraction 1 and Fraction 2 (higher polar material).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:5]2
Reactant: O=C1NCc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc(Br)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
Under nitrogen atmosphere, 70 mg of 5-bromo-1-oxo-isoindoline was dissolved in 2 ml of tetrahydrofuran, cooled down to 0° C., and then 4 mg of N,N-dimethylaminopyridine and 144 mg of di-tert-butylcarbonate were added. The mixture was stirred at room temperature for 30 min. Methanol was added to the reaction solution, and the solvents were distilled outunder reduced pressure. Water was added to the residues, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, the residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=1/2), to obtain 51.2 mg of the above compound as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:14][CH2:15][C:16](OC)(OC)OC>>[Cl:14][CH2:15][C:16]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: NNC(=O)c1ccc2c(c1)CCO2
Reactant: COC(CCl)(OC)OC
Product: ClCc1nnc(-c2ccc3c(c2)CCO3)o1
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
A mixture of 2,3-dihydro-1-benzofuran-5-carbohydrazide (2.02 g, 11.3 mmol) and 2-chloro-1,1,1-trimethoxyethane (7.92 ml, 56.7 mmol) was tightly sealed in a vial, and microwave was irradiated thereon at 160° C. for 5 min. The reaction mixture was recrystallized from hexane to give the title compound (2.01 g, yield 75%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([C:39]1[CH:40]=[CH:41][C:42]([OH:50])=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:44]=1)[OH:38]>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][CH:31]([NH:35][CH2:36][CH:37]([C:39]5[CH:40]=[CH:41][C:42]([OH:50])=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:44]=5)[OH:38])[CH2:32][CH2:33]4)=[CH:26][CH:27]=3)[C:18](=[O:20])[N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(NC4CCN(Cc5ccccc5)CC4)=NC3=O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(NC5CCN(Cc6ccccc6)CC5)=NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl)-piperidin-4-one (which was obtained in Intermediate 21) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Intermediate 9) according to the procedure of Example 1 as a pale yellowish solid; mp>210° C. (dec.); 1 H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H), 2.06 (brt, J=9.8 Hz, 2 H), 2.50-3.50 (m, 6 H), 2.92 (s, 3 H), 3.47 (s, 2 H), 3.70-4.00 (m, 2 H), 4.47 (dd, J=7.9, 4.3 Hz, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.95-7.05 (m, 2 H), 7.17 (d, J=1.9 Hz, 1 H), 7.20-7.55 (m, 8 H); MS (ES) m/z:353.1 ((M+2H)2+, 100%); 705.1 (MH+, 5%); HRMS Calcd. for C36H45N6O5S2 (MH+): 705.2893. Found: 705.2921.
Reaction SMILES: [NH2:1][C@H:2]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:23][O:24][B:25](OC)OC>O1CCCC1>[CH:17]1([C@@H:2]2[C:3]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:4][B:25]([O:24][CH3:23])[NH:1]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N[C@H](C1CCCCC1)C(O)(c1ccccc1)c1ccccc1
Reactant: COB(OC)OC
Solvent: C1CCOC1
Product: COB1N[C@H](C2CCCCC2)C(c2ccccc2)(c2ccccc2)O1
Reaction time: 1.5 h

Procedure:
(R)-2-amino-2-cyclohexyl-1,1-diphenylethanol (59 mg, 0.2 mmol), dry tetrahydrofuran (2 mL) and trimethylborate (27.2 μL, 0.24 mmol) were added to a dry flask and stirred under an atmosphere of nitrogen for 1.5 hours to form a solution of (R)-4-cyclohexyl-5,5-diphenyl-2-methoxy-1,3,2-oxazaborolidine. To this solution was added borane dimethylsulfide complex (100 μL, 1.0 mmol) and the mixture was stirred at room temperature for a further 30 minutes. A solution of 1-tetralone (133 μL, 1.0 mmol) in tetrahydrofuran (5 mL) was added by means of a syringe pump at a rate of 16 mL/min and the reaction was then stirred for a further 1 hour. Thin layer chromatography (silica gel/hexane/ethyl acetate 4:1) showed no starting material. The reaction was quenched by addition of methanol. The solvent was evaporated under vacuum and the residue was dissolved in ethyl acetate and washed 3 times with IN HCl. The ethyl acetate solution was dried over magnesium sulfate, filtered through a plug of silica gel and concentrated to give (S)-1-hydroxy-1,2,3,4-tetrahydronaphthalene with an ee of 96.5%. The enantiomer ratio was determined by HPLC using a Chiralcel OB 25 cm×4.6 mm column with hexane/2-propanol (9:1) mobile phase at 0.5 mL/min at 25° C. Detection with UV was at 254 nm.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:12])[S:5]([CH2:8][CH2:9][CH2:10][OH:11])(=[O:7])=[O:6].Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1.Cl>CN(C)C=O>[CH3:3][N:4]([CH3:12])[S:5]([CH2:8][CH2:9][CH2:10][O:11][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1)(=[O:7])=[O:6]
Reactant: CN(C)S(=O)(=O)CCCO
Reactant: Clc1ccc2ncnn2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)CCCOc1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
In 10 ml of dimethylformamide was suspended 0.252 g of 60% sodium hydride in oil followed by addition of 1.0 g of N,N-dimethyl-3-hydroxypropane-1-sulfonamide and the mixture was stirred under reduced pressure at room temperature for 30 minutes. Then, 0.928 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture was further stirred at room temperature for 1.5 hours. Following addition of 30 ml of ice water, the reaction mixture was adjusted to pH 4.0 with 1N-hydrochloric acid and the resulting crystals were collected by filtration and recrystallized from hot methanol to provide 1.255 g of the title compound. m.p. 151°-153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:16][CH:15]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:21][CH:20]=3)=O)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].NN>C(O)COCCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:14][CH:15]([CH2:17][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:21][CH:20]=3)[CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CC(C(=O)c3ccc(-n4ccnc4)cc3)C2)cc1OC
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: COc1ccc(CCN2CC(Cc3ccc(-n4ccnc4)cc3)C2)cc1OC

Procedure:
In a manner similar to Example 28, react [1-[2-(3,4-dimethoxyphenyl)ethyl]azetidin-3-yl][4-(1H-imidazol-1-yl)-phenyl]methanone with potassium hydroxide and hydrazine in diethylene glycol to obtain the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].[OH-].[Na+].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>O.C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: Brc1ccccn1
Agent: [NH2-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phenylacetonitrile 46.8 grams (0.40 mole) was added dropwise to a stirred suspension of 31.2 g. (0.80 mole) of powdered sodium amide in 200 ml. of dry toluene in an oven-dried, 2-liter, three-neck round bottom flask, equipped with dropping funnel, thermometer, stirrer and sodium hydroxide-protected condenser. During the addition, the temperature was maintained at 30°-35°C. with ice bath cooling. Afterwards, the mixture was brought slowly to reflux and maintained there for 41/2 hours with continuous stirring. Then 63.6 grams (0.40 mole) of 2-bromopyridine in 100 ml. of toluene was added dropwise at a rate which maintained refluxing of the solution. After complete addition, stirring and refluxing was continued for 3 hours. The mixture was then cooled at 25°C. and ca. 300 ml. of water was added, at first very cautiously and then in a steady stream. The phases were separated and the toluene layer extracted with ca. 150 ml. of water, and then with several portions of cold 6 N hydrochloric acid. The acid extracts were basified with 50% sodium hydroxide with cooling and extracted with ether. The ether extract was washed with water, dried over sodium sulfate and concentrated, and the residue was distilled. Yield, 41.7 g. (54 %); b.p. 134°-136°C./0.07 mm. The distillate crystallized and after recrystallization from isopropyl ether melted at 87°-88.5°C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:13])C(=O)[NH:9]2)=[CH:5][CH:4]=1)[CH3:2].[OH-:14].[Na+].OO.Cl>>[CH2:1]([C:3]1[CH:11]=[C:10]([NH2:9])[C:6](=[CH:5][CH:4]=1)[C:7]([OH:13])=[O:14])[CH3:2]
Reactant: [OH-]
Reactant: CCc1ccc2c(c1)NC(=O)C2=O
Agent: Cl
Agent: OO
Agent: [Na+]
Product: CCc1ccc(C(=O)O)c(N)c1
Temperature: 50 °C

Procedure:
In a 500 ml flask, was placed 16.84 gm of 6-ethyl isatin which was covered with 216 ml of 1.5M sodium hydroxide solution. With stirring, the mixture was warmed to 50° C. Heating was discontinued and the solution was treated with a 30% solution of hydrogen peroxide (24 ml) which was added at such a rate to maintain the temperature at between 50° to 65° C. The mixture was left to slowly cool to room temperature and was then acidified to pH 4 with concentrated hydrochloric acid. The precipitated product was then collected by filtration: mp. 117°-120° C.; yield 8.93 gm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([O-])([OH:14])=[O:13]>O>[OH:1][C:2]1[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccccc1O
Solvent: O
Product: O=C(O)Cc1ccc([N+](=O)[O-])cc1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a suspension of o-hydroxy phenylacetic acid (15.0 g, 0.099 mol) in H2O (39 mL) at 0° C. was added a solution of nitric acid (12 mL of 65% in 8 mL H2O) slowly via pipette. The solution was stirred for an additional 1.5 h at 0° C. The mixture was then warmed to ambient temperature and allowed to stir for an additional 0.5 h. The heterogeneous solution was poured over ice (10 g) and filtered to remove the insoluble ortho-nitro isomer. The reddish solution was concentrated under reduced pressure, and the thick residue was redissolved in 6N HCl and filtered through celite. The solvent was again removed under reduced pressure to provide the desired 2-hydroxy-4-nitro-phenylacetic acid as a light, brownish-red solid (40% yield). The product (IV-a) was used in the next step without further purification.
Reaction SMILES: [NH:1]([CH2:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[N:17]#[C:18]Br>C(O)C>[NH:17]=[C:18]1[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:8][C:9](=[NH:11])[O:10]1
Reactant: NC(=O)CNc1ccccc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Product: N=C1CN(c2ccccc2)C(=N)O1

Procedure:
To a mixture of 3.75 g. of anilinoacetamide, 2.5 g. of potassium bicarbonate and 50 ml. of ethanol was added rapidly 2.7 g. of cyanogen bromide in 20 ml. of ethanol. The reaction mixture was heated to reflux. After heating overnight and cooling, a small amount of precipitate was in the flask. This was filtered and the ethanolic filtrate shown to be slightly acidic. The ethanol filtrate was concentrated down to dryness leaving a solid which was washed with ethanol. The yield of product, m.p. 117°-9° C., was 3.9 g. (88%). The mass spectrum of the product gives a parent ion at m/e 175. This product is used to prepare intermediate III.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:19][N:18]=1>C(N(CC)CC)C.ClCCl>[CH2:5]([O:4][C:2]([N:19]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[C:17]([C:13]2[NH:12][CH:16]=[CH:15][CH:14]=2)=[N:18]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1c[nH]c(-c2n[nH]c3ncccc23)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)n1nc(-c2ccc[nH]2)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (150 mg) (Aldrich, Milwaukee, Wis.) was added to a mixture of 3-(1H-pyrrol-2-yl)-1H-pyrazolo[3,4-b]pyridine (120 mg) (from Example 2) and triethylamine (3 drops) in dichloromethane (DCM). After stirring at room temperature for one hour, the reaction was concentrated and purified on a silica gel column to give 3-(1H-pyrrol-2-yl)-pyrazolo[3,4-b]pyridine-1-carboxylic acid benzyl ester. It was then combined with di-morpholine methane (300 mg) (Aldrich, Milwaukee, Wis.), THF (2 mL), water (0.2 mL) and acetic acid (2 drops). The mixture was heated at 90° C. for 20 hours. The reaction was concentrated and purified on a silica gel column to give 30 mg of the titled compound as a white solid.
Reaction SMILES: C1C[O:4][CH2:3]C1.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1.[Li]CCCC.CN(C=O)C>CCCCCC>[F:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH:3]=[O:4])=[CH:8][CH:9]=2)=[CH:17][CH:18]=1
Reactant: C1CCOC1
Reactant: Fc1ccc(OCCc2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(CCOc2ccc(F)cc2)cc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a THF (100 mL) solution of 1-bromo-4-[2-(4-fluorophenoxy)ethyl]benzene (3.05 g) was added 1.6 M solution of n-BuLi in n-hexane (6.80 mL) dropwise at −70° C. under an argon atmosphere. After stirring for 30 minutes, DMF (1.20 mL) was slowly added at −70° C. The resultant mixture was stirred and slowly warmed to −40° C. for 3 hours. The reaction mixture was quenched by addition of saturated aqueous NH4Cl, and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=9/1 to 1/1) to afford 4-[2-(4-fluorophenoxy)ethyl]benzaldehyde as a light yellow solid (1.63 g).
Reaction SMILES: [C:1]([C:9]1[N:10]([N:14]2C(=O)C3=CC=CC=C3C2=O)[CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN>C(O)C.O>[NH2:14][N:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cccn1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CCO
Solvent: O
Product: Nn1cccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
To a suspension of 2-benzoyl-1-phthalimidopyrrole (35 g, 0.11 mole) in 350 ml ethanol was slowly added 45 ml methylamine (40% solution in water). After stirring two hours at ambient temperature, the mixture was diluted with 40 ml water and extracted with ether. The ether extract was washed with water and saturated NaCl solution, dried over anhydrous MgSO4, filtered and evaporated to 28 g oil which upon trituration with hexanes gave 21 g (99%) solid, m.p. 65°-69°. 3.5 g of this material was purified by HPLC (silica gel, 4% ethyl acetate/dichloromethane) to give 2.8 g solid, which was recrystallized from hexanes to give 2.4 solid, m.p. 65°-67°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13](=O)(OC)OC.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C#N)c1cccc([N+](=O)[O-])c1
Temperature: 170 °C

Procedure:
A mixture of 62 mmol (10 g) of 3-nitrophenylacetonitrile, 1.11 mol (100 g) of dimethyl carbonate and 3.1 mmol (0.43 g) of potassium carbonate is heated for 6 hours at 170° C. in an autoclave. After cooling, 200 ml of dichloromethane are added and the organic phase is washed with 100 ml of water and then with 100 ml of a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulphate and concentrated. The residue obtained is purified by chromatography on silica gel, using as eluant a 90/10 cyclohexane/ethyl acetate mixture, to yield the expected product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:41][CH2:42][CH:43]([C:50]([F:53])([F:52])[F:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])(=O)=O)=CC=1>C1COCC1.CN(C)C=O>[F:51][C:50]([F:52])([F:53])[CH:43]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:42][CH2:41][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)cc3)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCC(CCCCCC)C(F)(F)F)cc3)nc2)cc1
Yield: 45.6 %

Procedure:
In a 30 ml-round-bottomed flask, a solution of 0.188 g (0.50 mM) of 2-(4-hydroxyphenyl)-5-(4-octyloxyphenyl)pyrimidine in dry THF and 2 ml of dry N,N-dimethylformamide were placed and sufficiently stirred. To the mixture, 40 mg of 60%-sodium hydride was added and 0.183 g (0.50 mM) of (-)-3-trifluoromethylnonyl p-toluene sulfonate was further added dropwise, followed by stirring for 6 hours at 130° C. After the reaction, distilled water was added to the reaction mixture and extracted with ether, followed by drying with anhydrous sodium sulfate and purification by thin-layer chromatography (developing solvent: hexane/ethyl acetate =3/1 (first) and 4/1 (second)) to obtain 0.13 g (0.23 mM) of 2-{4-(3-trifluoromethylnonyloxy)phenyl}-5-(4-octyloxyphenyl)pyrimidine (Yield: 46.0%). ##STR86##
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH:6]=[CH:5][C@H:4]([O:8][C:9]([CH3:11])=[O:10])[C@H:3]1[O:12][C:13]([CH3:15])=[O:14].[OH2:16].[Br-].[Li+].O>C(#N)C>[C:9]([O:8][C@@H:4]1[C@@H:3]([O:12][C:13](=[O:14])[CH3:15])[C@H:2]([CH3:1])[O:7][CH:6]([OH:16])[CH2:5]1)(=[O:10])[CH3:11]
Reactant: O
Reactant: CC(=O)O[C@H]1[C@H](C)OC=C[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: CC(=O)O[C@H]1[C@H](C)OC(O)C[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.2 %

Procedure:
To a solution of 3,4-di-O-acetyl-L-rhamnal (5.0 g) and lithium bromide hydrate (5.0 g) in acetonitrile (150 ml), activated resin prepared as in Example 1 (3.0 g) and water (6 ml) were added and stirred at room temperature for 15 min. The product was isolated as described for Example 1. Purification by chromatography on a column of Silica Gel using ethyl acetate-hexane 3:8) as eluant gave the title compound (3.75 g). α:β=2:1. [α]D20 =-96.8°±2° (c 0 96. CHCl3). 1H NMR δ: 5.36 (H-1α), 5.33 (m, H-3α), 4.98 (m, H-3β), 4.90 (dd, H-1β), 4.75 (t, H-4), 4.12 (m, H-5α), 3.54 (m, H-5β), 2.39 and 2.26 (m, H-2eq), 1.77 and 1.66 (m, H-2ax), 1.23 and 1.17 (d, CH3). MS (calc. mass=232). Obs. m/e 231.13, 215.12, 155.09 (100 %).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:38])[C:10]([N:12]([CH3:37])[C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:25]([O:27]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:14]2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41].O>CN1CCCC1=O>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]([CH3:38])[C:10]([N:12]([C@H:13]2[C@H:17]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:16][N:15]([C:25]([N:46]3[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:44][CH2:45]3)=[O:27])[CH2:14]2)[CH3:37])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@H]1c1ccc(F)cc1)c1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(Cl)cc(Cl)c1
Yield: 49.4 %

Procedure:
A solution of the compound (0.31 g) obtained in Example 419 and 1-(methylsulfonyl)piperazine (0.14 g) in 1-methyl-2-pyrrolidone (5 mL) was stirred at 110° C. for 24 hr and at 135° C. for 14 hr. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 75→100% ethyl acetate/hexane) to give the title compound (0.16 g, 48%) as a pale-yellow powder.