Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](O)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.ClCC(OC(=O)CCl)=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28]>ClC(Cl)C>[C:1]1([C:7]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[C:22]([O:27][CH3:28])[CH:23]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COc1ccccc1OC
Reactant: O=C(O)C1=CCCCC1
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)C2=CCCCC2)cc1OC
Temperature: 75 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
In 50 ml of dichloroethane were dissolved 6.31 g (0.05 mole) of 1-cyclohexene-1-carboxylic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 8.98 g (0.065 mole) of 1,2-dimethoxybenzene and 0.71 g of boron trifluoridediethyl ether complex and the resulting mixture was then stirred at 75° C. for 6 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over, anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 7.27 g of 4-(1-cyclohexenoyl)-1,2-dimethoxybenzene.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:2]3[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[N:20]2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1Br
Reactant: COc1ccc(NN)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(-n2ncc3ccccc32)cc1
Temperature: 100 °C

Procedure:
2-Bromobenzaldehyde (74 mg, 0.4 mmol), 4-methoxyphenylhydrazine hydrochloride (70 mg, 0.4 mmol), sodium tert-butoxide (115 mg, 1.2 mmol), palladium(II) acetate (18 mg, 0.08 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (44 mg, 0.08 mmol) were dissolved in toluene (0.6 mL) and heated to 100° C. overnight. The mixture was filtered through Celite with ethyl acetate, and the filtrate was concentrated. SiO2 chromatography (5-20% ethyl acetate/hexanes) gave the desired product, 30 mg. LC-MS (C14H12N2O calculated 224) m/z 225 (M+H).
Reaction SMILES: [I-].[CH2:2]([N+:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7]([CH3:8])=[CH:6][CH:5]=1)[CH3:3].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[N+:25]([O-:27])=[O:26].C(N(C(C)C)CC)(C)C>C(#N)C>[N+:22]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:25]([O-:27])=[O:26])[C:16]=1[CH:8]=[C:7]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:2][CH3:3])[CH:5]=[CH:6]1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CC[n+]1ccc(C)c2ccccc21
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN1C=CC(=Cc2c([N+](=O)[O-])cccc2[N+](=O)[O-])c2ccccc21
Reaction time: 8 h
Yield: 25 %

Procedure:
1-Ethyllepidinium iodide (3.0 g., 10 mmole) and 1-chloro-2,6-dinitrobenzene (2.5 g., 12 mmole) are warmed in acetonitrile (50 ml.) and diisopropylethylamine (2.6 g., 20 mmole) is added. The resulting dark mixture is allowed to cool and stand overnight. The precipitate of dye is filtered off and washed with acetonitrile and ether. On recrystallization from acetonitrile, a 25% yield (0.85 g.) of purified dye is obtained with a m.p. of 154°-155° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][C:29]2=[O:33])=[CH:23][CH:22]=1>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C@@H:28]2[CH2:32][CH2:31][CH2:30][C@@H:29]2[OH:33])=[CH:23][CH:22]=1
Reactant: O=C1CCCC1Oc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O[C@@H]4CCC[C@@H]4O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(2-oxo-cyclopent-1-yloxy)-benzyl]-benzene (0.10 g) in dry tetrahydrofuran (3 mL) chilled to −78° C. is added L-selelctride (1 mol/l in tetrahydrofuran, 0.33 mL). The resulting solution is stirred at −78° C. for 2 h, then diluted with dichloromethane and quenched with aqueous hydrochloric acid (1 mol/l). The organic layer is separated and the aqueous phase is extracted with dichloromethane. The combined organic layers are dried (Na2SO4), the solvent is removed in vacuo and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→4:1).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[S:14][C:13]([S:15]([OH:18])(=O)=[O:16])=[CH:12][CH:11]=2)[CH:6]=1)([F:4])[CH3:3].CN(C)C=O.S(Cl)([Cl:26])=O>>[F:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[S:14][C:13]([S:15]([Cl:26])(=[O:18])=[O:16])=[CH:12][CH:11]=2)[CH:6]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1cc(-c2ccc(S(=O)(=O)O)s2)no1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(F)(F)c1cc(-c2ccc(S(=O)(=O)Cl)s2)no1
Temperature: 80 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a suspension of 5-[5-(1,1-difluoroethyl)-isoxazol-3-yl]-thiophene-2-sulfonic acid (9.5 g, 32 mmol) obtained in Preparation Example 5-10-c) in thionyl chloride (50 mL) was added dimethylformamide (1.0 mL) under argon atmosphere, and the suspension was stirred at 80° C. for 16 hours. The obtained solution was concentrated, and chloroform (100 mL) was added. After azeotropic removal of residual solvent with chloroform, chloroform (50 mL) was added to the residue. The obtained mixture was extracted twice, sequentially washed with water (20 mL) and saturated aqueous sodium chloride solution (10 mL), and dried over magnesium sulfate. After filtration and evaporation, the obtained residue was separated and purified by silica gel chromatography (hexane:ethyl acetate=15:1) to give the title compound (6.9 g, 68%) as a yellow solid.
Reaction SMILES: [C:1]1([NH:11][C:12]2[O:13][C:14]3[C:20]([F:21])=[C:19]([CH2:22][C:23]([O:25]C)=[O:24])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([NH:11][C:12]2[O:13][C:14]3[C:20]([F:21])=[C:19]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3cccc4ccccc34)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc2nc(Nc3cccc4ccccc34)oc2c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 106.5 %

Procedure:
Methyl (2-(1-naphthylamino)-7-fluoro-6-benzoxazolyl)acetate (1.41 g, 4.02 mmol) was dissolved in THF/methanol (21, 30 ml). To the resulting solution was added 1N NaOH (10 ml). After stirring at room temperature for 12 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(1-naphthylamino)-7-fluoro-6-benzoxazolyl)acetic acid (1.44 g, 100%) as a brown solid.
Reaction SMILES: Br[C:2]1C=C[C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[NH:37]1C=CC(C(=O)C)=C1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:7]=[CH:2][NH:37][CH:5]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1cc[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc[nH]c4)ccc3c1)n2C1CCCCC1
Yield: 8 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(1H-pyrrol-3-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (10 mg, 8% yield).
Reaction SMILES: C([O:4][C@@:5]1([CH2:38][CH3:39])[C:35]2[CH:34]=[C:33]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:20]([N:26]([CH3:28])[CH3:27])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:36])[C:9]=2[CH2:8][O:7][C:6]1=[O:37])(=O)C.NN.[ClH:42]>CO.O1CCOCC1>[ClH:42].[CH3:28][N:26]([CH3:27])[C:20]1[N:19]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:18]2=[C:13]3[CH2:12][N:11]4[C:33](=[CH:34][C:35]5[C@:5]([CH2:38][CH3:39])([OH:4])[C:6](=[O:37])[O:7][CH2:8][C:9]=5[C:10]4=[O:36])[C:14]3=[N:15][C:16]3[C:17]2=[C:22]([CH:23]=[CH:24][CH:25]=3)[N:21]=1
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2N(CC(C)C)C(N(C)C)=N3
Agent: Cl
Agent: NN
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2N(CC(C)C)C(N(C)C)=N3
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of (9S)-9-acetoxy-2-(dimethylamino)-9-ethyl-1-(2-methylpropyl)-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (8.7 mg, 0.023 mmol) in methanol (2 ml) and 1,4-dioxane(2 ml) cooled in an ice-bath was added anhydrous hydrazine (100 μl). The mixture was warmed to room temperature and stirred for 3 hr. 10% HCl in methanol was added dropwise to acidify the reaction mixture and the mixture was stirred at room temperature for 2 h. After concentrated under reduced pressure, the obtaining residue was purified by reversed phase column chromatography (water/methanol=1/0-1/2) to give the product (7.4 mg, 85%) as a yellow powder.
Reaction SMILES: O.[Na].[C:3](=O)([O:6]C)[O:4][CH3:5].[H-].[Na+].[C:11]([C:14]1([CH3:22])[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16][CH2:15]1)(=[O:13])[CH3:12]>O1CCCC1.O.C(O)(=O)C.CO>[CH3:20][C:17]1([CH3:21])[O:18][CH2:19][C:14]([CH3:22])([C:11](=[O:13])[CH2:12][C:3]([O:4][CH3:5])=[O:6])[CH2:15][O:16]1
Reactant: COC(=O)OC
Reactant: CC(=O)C1(C)COC(C)(C)OC1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(=O)C1(C)COC(C)(C)OC1
Temperature: 25 °C

Procedure:
Sodium hydrate—60% in oil dispersion (100.0 g, 2.5 mol) was weighed into a 5-liter three-necked reaction flask and the metal hydride washed three times with 300-mL portions of pentane under nitrogen. The washed sodium hydride was covered with a solution of dry reagent grade tetrahydrofuran (900 mL) and dimethyl carbonate (900 g, 10.0 mol). The sodium hydride was activated by the dropwise addition of anhydrous methanol (1.5 mL) followed by a few grams of 5-acetyl-2,2,5-trimethyl-1,3-dioxane in tetrahydrofuran. The reaction mixture was held under reflux with constant stirring in a nitrogen atmosphere while 5-acetyl-2,2,5-trimethyl-1,3-dioxane dissolved in tetrahydrofuran (800 mL) was added dropwise (ca. 0.5 hr.). The reaction was stirred for another hour after which time the mixture was allowed to cool to room temperature. Anhydrous methanol (100 mL) was added to the mixture to decompose residual sodium hydride followed by glacial acetic acid (150 mL) to quench the anion. The quenched reaction was poured into one liter of cold water and the product extracted with ligroin. The ligroin extract was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, and flash evaporated in vacuio to yield 203 g of crude product. The brown-colored mobile oil was purified to yield a water white liquid by distillation; b.p. 102-5° C.; 130 g, 57% of theoretical yield; H-NMR spectra were consistent. Elemental Analysis calculated for C11H18O5: C,57.38; H, 7.88. Found: C, 57.67; H, 7.98.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].C(O[C:14]([CH3:17])([CH3:16])[CH3:15])(=O)C.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:15][C:14]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[NH2:1])([CH3:17])[CH3:16]
Reactant: CCCC[C@H](N)C(=O)O
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCC[C@H](N)C(=O)OC(C)(C)C
Temperature: 20 °C
Yield: 76.4 %

Procedure:
To a suspension of L-norleucine (commercial product) (13.1 g; 0.1 mol) in t-butyl acetate (600 mL; 4.45 mol) maintained at 20° C., 70% aq. HClO4 (10.3 mL; 0.12 mol) was added in 10 min. The reaction was maintained at r.t. for 7 h. Saturated aq. Na2CO3 was slowly added until pH 9 was reached and the organic phase was separated and concentrated. The oily residue was dissolved in Et2O (250 mL) and extracted with 1N HCl (120 mL). The aqueous phase was basified to pH 10 with 1 N NaOH and extracted with Et2O (400 mL). The organic layer, dried over Na2SO4, was concentrated to give the desired compound (14.3 g; 76.4 mmol). Yield 76%.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][C:7](=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)[CH3:3].[BH4-].[Na+]>CO>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)[CH3:1]
Reactant: CC(C)N1CCC(=Nc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CCC(Nc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a stirred and warmed (30°-40° C.) solution of 72 parts of N-[1-(1-methylethyl)-4-piperidinylidene]benzenamine in 480 parts of methanol are added portionwise20 parts of sodium borohydride. Upon completion, stirring is continued overnight at at room temperature. The reaction mixture is evaporated and the residue is dissolved in water. The solution is extracted with 4-methyl-2-pentanone. The extract is washed with water and acidified with a diluted hydrochloric acid solution. The aqueous acid phase is alkalized with a diluted sodium hydroxide solution till pH 9 and the product is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated. The residue is distilled (bp. 135°-140° C. at 0.2 mm. pressure) and the distillate is crystallized from petroleumether, yielding 21 parts of 1-(1-methylethyl)-N-phenyl-4-piperidinamine; mp. 69.3° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH:14]1[C:19]([CH2:20][CH:21]([NH2:25])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=[C:16]([F:26])[CH:15]=1>>[F:26][C:16]1[CH:15]=[CH:14][C:19]([CH2:20][CH:21]([NH:25][C:11]([C:10]2[C:6]3[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=3[S:8][CH:9]=2)=[O:13])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=C(O)c1csc2c1CCCC2=O
Reactant: NC(Cc1ccc(F)cc1)C(=O)O
Product: O=C(NC(Cc1ccc(F)cc1)C(=O)O)c1csc2c1CCCC2=O

Procedure:
From 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (the compound of Preparation Example 4) (105 mg) and DL-4-fluorophenylalanine, the title compound (190 mg) was obtained as a viscous yellow oily substance, in the same way as Preparation Example 116.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10](Br)=[C:11]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)(=[O:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1.C(N(CC)CC)C>[Pd].[C]>[CH3:1][O:2][C:3](=[O:34])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)(=[O:15])=[O:16])[CH:12]=2)[CH:7]=[CH:6]1
Reactant: COC(=O)Cn1ccc2cc(Br)c(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc21
Agent: [Pd]
Solvent: CCN(CC)CC
Product: COC(=O)Cn1ccc2ccc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc21
Yield: 83.1 %

Procedure:
{5-Bromo-6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid methyl ester (135 mg, 0.24 mmol), triethylamine (40 μL, 0.29 mmol) and 10% Pd/carbon (cat) were stirred under an atmosphere of hydrogen until all the starting material was gone. The reaction was then filtered through celite, concentrated and purified by flash column chromatography (60% hexanes in ethyl acetate) to afford {6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid methyl ester (96 mg, 83%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.76(d, 1H) 7.75 (d, 1H), 7.51 (dd, 1H), 7.44 (dd, 2H), 7.31 (d, 1H), 6.84 (d, 2H), 6.67 (d, 1H), 4.11 (dd, 2H), 3.78 (s, 3H), 3.33 (m, 4H), 3.16 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH2:11](OC1C=CC(C(=O)CCC)=CC=1)C1C=CC=CC=1.C(OC1C=CC(C(=O)CC)=CC=1)C1C=CC=CC=1>>[CH2:1]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1)[CH3:11]
Reactant: CCCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1c[nH]c2ccccc12
Agent: CCC(=O)c1ccc(OCc2ccccc2)cc1
Product: CCc1c[nH]c2ccccc12

Procedure:
This compound was synthesized in exact analogy to the xample given for 3-methylindole, supra, using methods a and 2–8. the only difference is that the starting material used is 4′-(benzyloxy)-Butyrophenone CAS No. [26945-71-1] instead of 4′-(benzyloxy)-Propiophenone. Data for intermediates is as follows.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:26])[C:10]3[CH:11]=[CH:12][CH:13]=[C:14]4[C:23]=3[N:22]([CH:24]=2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]4=[O:25])[CH:2]=1.[CH:27](=O)C1C=CC=CC=1>>[CH2:7]([C:8]1[C:9](=[O:26])[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[N:22]([CH:24]=1)[C:23]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]3=[O:25])[C:3]1[CH:2]=[CH:27][CH:6]=[CH:5][CH:4]=1
Reactant: O=c1c(Cc2cccnc2)cn2c3ccccc3c(=O)c3cccc1c32
Reactant: O=Cc1ccccc1
Product: O=c1c(Cc2ccccc2)cn2c3ccccc3c(=O)c3cccc1c32
Yield: 72 %

Procedure:
According to Example 1<step 4>, the compound (200 mg) obtained in Example 18<step 2>was reacted with benzaldehyde (0.13 mL) to obtain the title compound (194 mg; 72%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]([CH2:31][OH:32])=[CH:21]2)=[CH:17][CH:16]=1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22]([CH:31]=[O:32])=[CH:21]2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(-c3ccccc3)c2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3ccccc3)c2)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 71.9 %

Procedure:
A mixture of [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]methanol (3.98 g), activated manganese dioxide (8.00 g), and toluene (50 ml) was stirred at 80° C. for 10 hours. After the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenylpyrrole-3-carbaldehyde (2.85 g, yield: 72%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 117–118° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.Cl.[CH:16]12[NH:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17]2.C(N(CC)CC)C>C(#N)C>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([N:22]2[CH:16]3[CH2:21][CH2:20][CH:19]2[CH2:18][CH2:17]3)=[N:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Br)nc1C(F)(F)F
Reactant: C1CC2CCC1N2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)nc1C(F)(F)F
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A solution of 6-bromo-3-nitro-2-(trifluoromethyl)pyridine (300 mg, 1.107 mmol), 7-azabicyclo[2.2.1]heptane hydrochloride (177.4 mg, 1.328 mmol) and triethylamine (224.0 mg, 308.5 μL, 2.214 mmol) in acetonitrile (3 mL) was heated at 80° C. overnight. The reaction was cooled to room temperature and quenched with water. The resulting precipitate was filtered, washed with water and dried under vacuum to provide 7-[5-nitro-6-(trifluoromethyl)-2-pyridyl]-7-azabicyclo[2.2.1]heptane (300 mg, 94% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.27 (d, J=9.2 Hz, 1H), 7.20 (d, J=9.3 Hz, 1H), 4.71 (s, 2H), 1.71 (d, J=7.7 Hz, 4H), 1.55 (d, J=6.9 Hz, 4H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)[C:4](=[O:13])[CH2:3]1.[H-].[Na+].I[CH3:17]>C1COCC1.O>[CH3:17][O:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)[C:4](=[O:13])[CH2:3]1
Reactant: CI
Reactant: Cn1ccc(N2C[C@@H](O)CC2=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1CC(=O)N(c2ccn(C)n2)C1

Procedure:
To a solution of (4S)-4-hydroxy-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (97 mg) in THF (3.0 mL) was added a sodium hydride 60% dispersion in mineral oil (24 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 10 min. Iodomethane (50 μL) was added to the reaction mixture under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (30 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]#[N:9])[CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[C:18](=O)([O:22]CC)[O:19][CH2:20][CH3:21].Cl>C1COCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]#[N:9])([C:18]([O:19][CH2:20][CH3:21])=[O:22])[CH2:3]1
Reactant: CC1CCCC(C#N)C1
Reactant: CCOC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C#N)CCCC(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 17 g of 3-methylcyclohexanecarbonitrile in 140 ml of THF has added to it, at -78°, a lithium diisopropylamide solution (prepared from 140 ml of THF, 16 g of diisopropylamine and 100 ml of 1.6-molar butyllithium solution in hexane), followed, after 2 hours, by 25 g of diethyl carbonate, and stirring is continued for one hour. After heating to room temperature and pouring onto 300 ml of ice-water the mixture is neutralized with dilute hydrochloric acid. Customary working up and distillation gives ethyl 3-methyl-1-cyanocyclohexanecarboxylate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[NH:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH3:22])(=O)=O.Cl.[CH:27]([O:30][NH2:31])([CH3:29])[CH3:28]>C(O)(C)C>[CH2:19]([C:18]1[N:31]([O:30][CH:27]([CH3:29])[CH3:28])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CC(C)ON
Reactant: CCCCC(=O)Nc1cnc2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CC(C)O
Product: CCCCc1nc2cnc3cccnc3c2n1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A solution of 3-(pentanoylamino)[1,5]naphthyridin-4-yl trifluoromethanesulfonate (2.7 g, 7.2 mmol), O-isopropylhydroxylamine hydrochloride (1.1 g, 9.9 mmol), and isopropanol (50 mL) was heated at reflux for six hours, allowed to cool to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was stirred with dichloromethane (100 mL) and saturated aqueous sodium carbonate (50 mL) for 15 minutes. The organic layer was separated and dried over potassium carbonate, filtered, and concentrated under reduced pressure. The crude product (2.3 g) was purified by column chromatography on silica gel (eluting with 5% methanol in dichloromethane containing 2 mL of aqueous ammonium hydroxide per liter of eluent) to provide 0.40 g of 2-butyl-1-isopropoxy-1H-imidazo[4,5-c][1,5]naphthyridine as an oil.