Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:9]1=[CH:10][C:11]([O:13][C:14]1=[O:15])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Al].C[OH:18]>>[CH:1](/[C:9](/[C:14]([OH:13])=[O:15])=[CH:10]/[C:11]([OH:18])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Reactant: CO
Agent: [Al]
Product: O=C(O)/C=C(/C=Cc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 30 h

Procedure:
2.2 g of the styrene-maleic anhydride polymer (molecular weight: 1600) was mixed with 3.3 g of the polyethyleneglycol (molecular weight: 600) and 7.8 g of polyethyleneglycol monomethyl ether (molecular weight: 750). The mixture was dropped on an aluminum plate and heated in an oven at 100° C. under nitrogen stream. After 30 hours, the mixture was cooled down to room temperature, immersed into methanol and dried. An ion-conducting thin membrane of styrene-maleic acid polyethyleneoxy ester crosslinked copolymer of an excellent adhesive strength and mechanical strength was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[C:12]3[CH:15]=[CH:16][C:17]4[N:18]=C(C)[O:20][C:21]=4[C:11]=3[O:10][C:9]=2[CH:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1.Cl>CO>[NH2:18][C:17]1[C:21]([OH:20])=[C:11]2[C:12]([C:13](=[O:14])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([CH:23]([CH3:24])[CH3:25])[O:10]2)=[CH:15][CH:16]=1
Reactant: Cc1nc2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c2o1
Agent: Cl
Solvent: CO
Product: CC(C)c1oc2c(O)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suspension of 7-(4-chlorophenyl)-8-isopropyl-2-methyl-chromeno[7,8-d]oxazol-6-one (650 mg, 1.84 mmol) in methanol (30 ml) is added concentrated HCl (5 ml). The reaction mixture is stirred at 70° C. for 1 h. The solvent is removed in vacuo, and the product is partitioned between CH2Cl2 and a saturated solution of NaHCO3. The organic phase is washed with water and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(#N)C>[C:1]1([CH2:7][CH2:8][C:9]2[NH:17][C:12]3=[N+:13]([O-:26])[CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(CCc2cc3cccnc3[nH]2)cc1
Solvent: CC#N
Product: [O-][n+]1cccc2cc(CCc3ccccc3)[nH]c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.4 %

Procedure:
To a solution of 2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine (1.97 g, 8.86 mmol) in acetonitrile (100 mL) was added m-chloroperbenzoic acid (2.82 g, 10.63 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 20 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=9/1-0/1) to give the title compound (1.17 g, yield 55%) as a yellow amorphous form.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14]>Cl.C1(NN)C=CC=CC=1.CO>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC(C)=O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: Cl
Solvent: CO
Solvent: NNc1ccccc1
Product: CC1(C)CC(=O)CC(C)(C)N1
Yield: 75 %

Procedure:
A flask with attached condenser was charged with 80 g of acetonine, 80 g of acetone, 16 g methanol and 1.6 g N-phenylhydrazine monohydrochloride and the mixture reacted at 50°-55° C. for 18 hours, while stirring. The reaction solution was stripped under reduced pressure, to obtain a light red residue. This residue was distilled in vacuo to obtain 60.4 g of triacetonamine. White crystals were obtained by recrystallization from petroleum ether having the melting point of 34°-36° C. The compound was confirmed to be the objective matter by IR spectrum and gas chromatography.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C([Li])CCC.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>O1CCCC1.CCCCCC>[S:4]1[CH:5]=[CH:6][C:2]([C:15]2([OH:19])[CH2:16][CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14]2)=[CH:3]1
Reactant: CC1CCCC(=O)C1
Reactant: Brc1ccsc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1CCCC(O)(c2ccsc2)C1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of 36.3 g (0.223 mol) of 3-bromothiophene in 50 mL of dry tetrahydrofuran was cooled to -78° C. in a dry ice-acetone bath. To this solution was added dropwise 139.4 mL (14.3 g, 0.223 mol, 1.6 M in hexane) of n-butyllithium in hexane over 30 minutes. Upon complete addition, the reaction mixture was stirred at -78° C. for 1.5 hours, then 25.0 g 0.223 mol, of 3-methylcyclohexanone was added dropwise during 20 minutes. Upon complete addition, the reaction mixture was stirred at -78° C. for two hours. The cooling bath was removed, and the reaction mixture was allowed to warm to ambient temperature during 1.5 hours, then was stirred for an additional one hour. Diethyl ether saturated with water (50 mL) was added with stirring, and the mixture was poured into a mixture of 50 g of ice and 20 mL of concentrated hydrochloric acid. The layers were separated, and the aqueous layer was washed with two portions of 200 mL each of diethyl ether. The washings were combined with the organic layer, and the whole was washed with 300 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 44.0 g of 1-(3-thienyl)-3-methylcyclohexanol. Volatile components were removed from the product by distillation at 50° C./0.25 mm using a Kugelrohr distilling system.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH:11]([CH:31]([CH3:33])[CH3:32])[C:12]([O:14]C(C#N)C1C=CC=C(OC2C=CC=CC=2)C=1)=[O:13]>>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C@H:11]([C:12]([OH:14])=[O:13])[CH:31]([CH3:33])[CH3:32]
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(C)C(Br)C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Product: CC(C)[C@H](Nc1ccc(Cl)cc1F)C(=O)O

Procedure:
Following the procedure of Example 6, 2-fluoro-4-chloroaniline is reacted with m-phenoxy-α-cyanobenzyl α-bromoisovalerate to give the m-phenoxy-α-cyanobenzyl ester of N-(2-fluoro-4-chlorophenyl)valine, MS m/e 452 (M+). Alternatively 2-fluoro-4-chloroaniline is reacted with the sodium salt of α-bromo-isovaleric acid to give N-(2-fluoro-4-chlorophenyl)valine, which is then esterified using m-phenoxy-α-cyanobenzyl bromide or mesylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[C:24]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][C:26]2[O:31][CH:30]=[C:29]([C:32](O)=[O:33])[O:28][C:27]=2[CH:35]=1>>[OH:22][C:23]1[C:24]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][C:26]2[O:31][CH:30]=[C:29]([C:32]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:33])[O:28][C:27]=2[CH:35]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)(C)c1cc2c(cc1O)OC(C(=O)O)=CO2
Product: CC(C)(C)c1cc2c(cc1O)OC(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)=CO2
Yield: 72 %

Procedure:
That compound is obtained in a yield of 72% starting from 1-[bis(4-fluorophenyl)methyl]piperazine and 7-hydroxy-6-tert-butyl-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:12][C:13]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:14]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:31](Cl)(=[O:33])[CH3:32].O>O1CCCC1.CN(C)C=O>[C:7]([O:6][C:5](=[O:11])[N:4]([CH2:12][C:13]1[CH:17]=[C:16]([N:18]([C:31](=[O:33])[CH3:32])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:14]=1)[CH3:3])([CH3:10])([CH3:8])[CH3:9]
Reactant: CN(Cc1cc(Nc2ccccc2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)N(c1ccccc1)c1cc(CN(C)C(=O)OC(C)(C)C)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.2 %

Procedure:
To a suspension of sodium hydride (17 mg) in tetrahydrofuran (2 mL) and N,N-dimethylformamide (1 mL) was added tert-butyl methyl{[1-phenyl-5-(phenylamino)-1H-pyrazol-3-yl]methyl}carbamate (108 mg). After stirring at room temperature for 15 min, acetyl chloride (45 mg) was added, and the mixture was further stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:1→3:1) to give the title compound as a colorless oil (yield 83 mg, yield 69%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([N:12]1[C:17]2=[C:18]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:20][N:16]2[CH2:15][CH2:14][NH:13]1)=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH2:9][C:10]([N:12]1[C:17]2=[C:18]([C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)[C:19]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[N:20][N:16]2[CH2:15][CH2:14][NH:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
2-tert-Butoxycarbonylaminoacetyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (50 mg) was dissolved in trifluoroacetic acid (0.5 ml). The solution was stirred at ambient temperature for 30 minutes and concentrated in vacuo. The residue was dissolved in water and the solution was neutralized with an aqueous saturated sodium bicarbonate solution. The separated oil was extracted with a mixture of dichloromethane and ethanol (7:3) and the extract was washed with water, dried and concentrated in vacuo. The residue was crystallized from ethyl acetate to give 2-aminoacetyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (30 mg).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@H:10]2[O:15]C(O)[C@H:13]([OH:17])[C@@H:12]([OH:18])[C@@H:11]2[OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].C(O)[C@H]1[O:30][C@H:29](OC[C@H]2O[C@H](OC[C@H]3OC(O)[C@H](O)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:29][OH:30])[O:18][C@H:12]([CH2:13][OH:17])[C@@H:11]([OH:19])[C@@H:10]2[OH:15])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](OC[C@H]2OC(O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: OC[C@H]1O[C@H](OC[C@H]2O[C@H](OC[C@H]3OC(O)[C@H](O)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O

Procedure:
acceptor: 50 g/l composition of the acceptor: isomaltose: 59% isomaltotriose: 36% glucose: 5%
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[C:10]([C:22]([F:25])([F:24])[F:23])[CH:9]=1)=[O:6].N#N.C(N(CC)C(C)C)(C)C.[CH3:41][Si:42]([C:45]#[CH:46])([CH3:44])[CH3:43]>[Cu]I.CCOC(C)=O.O.CN(C=O)C>[CH3:29][C:28]1[CH:27]=[CH:26][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[C:10]([C:22]([F:23])([F:25])[F:24])[CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:46]#[C:45][Si:42]([CH3:44])([CH3:43])[CH3:41]
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
3-iodo-4-methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide (2.59 g, 5 mmol), Pd[(PPh3)]4 (289 mg, 0.25 mmol), CuI (71 mg, 0.375 mmol) was placed in a schlenk flask. The flask was subjected to 3 cycles of vacuum-refilling with N2. To this mixture was added anhydrous N,N-diisopropylethylamine (1.1 mL, 6 mmol), DMF (5 mL), and trimethylsilylacetylene (0.92 mL, 6.5 mmol). This solution was stirred at rt for 24 h. Water and EtOAc were added to the reaction mixture to facilitate the extraction. The combined organic layers were dried over Na2SO4, filtered, and then concentrated on a rotavap and the residue was purified on a silica gel column (eluent: 5% MeOH in CH2Cl2, MeOH was pre-saturated with ammonia gas) to give the desired product as a light yellow solid in 82% yield (2.0 g).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][C:6]1[N:10]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[N:8][C:7]=1[CH2:30][CH:31]1[C:43](=[O:44])[C:42]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]=2[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:5][C:6]1[N:10]([C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=[N:8][C:7]=1[CH2:30][CH:31]1[C:43](=[O:44])[C:42]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH2:3][C:2]#[CH:1])[C:34]=2[CH2:33][CH2:32]1
Reactant: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C#CCn1c2c(c3ccccc31)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reaction time: 60 h

Procedure:
Propargyl bromide (0.086 ml) was added to a suspension of 1,2,3,9-tetrahydro-3-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl ]-4H-carbazol-4-one (500 mg) and potassium carbonate (265 mg) in acetone (10 ml) and the mixture was stirred under nitrogen for 60 h. More propargyl bromide (0.086 ml) was added and the mixture was stirred at room temperature for 24 h and then at reflux for 6 h. Water (50 ml) was added and the suspension was extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give a gum (650 mg) which was purified by FCC (column made up in ethyl acetate:hexane:triethylamine 80:19:1) eluting with ethyl acetate:hexane (4:1) to give the title compound (95 mg) as a foam, t.l.c. on Et3N impregnated SiO2 (ethyl acetate:hexane 4:1) Rf 0.30.
Reaction SMILES: [C:1]12([NH:11][C:12]#[N:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[NH2:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1>ClC1C=CC=CC=1>[C:1]12([NH:11][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])=[NH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: N#CNC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccccc1N
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1ccccc1NC(=N)NC12CC3CC(CC(C3)C1)C2

Procedure:
A suspension of adamantan-1-ylcyanamide (151 mg, 0.857 mmol) and o-toluidine hydrochloride (186 mg, 0.857 mmol) in dry chlorobenzene was heated between 100°-130° C. for 4.5 hrs. The chlorobenzene was evaporated in vacuo with heating and the residue (285 mg) taken up in 18 ml of water. A gummy, insoluble material was discarded. On adjusting the aqueous extract to pH 9-9.5, a precipitate formed (194 mg, 71%). Two recrystallizations from EtOH/H2O gave the analytical sample; mp 160°-161°, 1H (CD3OD) 1.742 (s, 6H), 2.050 (d, 6H, J=2.4 Hz), 2.029 (s, 3H), 6.956 (j, 1H, J=8.1 Hz), 7.056 (t, 1H, J=8.1Hz), 7.168 (t, 1H, J=7.5 Hz), 7.213 (d, 1H, J=7.5 Hz). Anal. Calcd for C18H25N3 : C, 76.28; H, 8.89; N, 14.83. Found: C, 76.25; H, 8.86; N, 14.60.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:18][CH3:19])=[O:9])=[CH:11][CH:12]=1
Reactant: CCO
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc(Cl)cc1
Reaction time: 96 h
Yield: 93 %

Procedure:
A solution of 4-chlorophenoxyacetic acid (Aldrich) (18.62 g, 99.8 mmoles) and concentrated sulfuric acid (Fisher) (2.5 mL) in ethanol (170 mL) was refluxed with stirring under a DRIERITE tube for 96 hours. The reaction solution was cooled in an ice-bath, and the volatiles were removed by spin evaporation in vacuo to a volume of about 100 mL. The liquid was dissolved in dichloromethane (225 mL) and washed with a solution of 5% aqueous sodium bicarbonate (4×100 mL) and finally with brine (1×50 mL). The solution was dried over sodium sulfate and spin evaporated in vacuo to give 19.97 g (93% yield) of ethyl 4-chlorophenoxyacetate as an amber liquid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:39])=[C:5]([C:32]([O:34]CCC#N)=[O:33])[CH:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][N:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:15])[N:9]=1.[OH-].[Na+]>COCCOC.O>[CH3:1][C:2]1[NH:3][C:4]([CH3:39])=[C:5]([C:32]([OH:34])=[O:33])[CH:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][N:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:15])[N:9]=1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc([N+](=O)[O-])c2)C(c2nc(CN(C)Cc3ccccc3)no2)=C(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(c2nc(CN(C)Cc3ccccc3)no2)=C(C)N1
Temperature: 25 °C
Reaction time: 7 h
Yield: 75 %

Procedure:
To a stirred solution of 1.06 g of 2-cyanoethyl 1,4-dihydro-2,6-dimetyl-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-4-(3-nitrophenyl)pyridine-5-carboxylate in 5 ml of ethylene glycol dimethyl ether was added a solution of 240 mg of sodium hydroxide in 10 ml of water. The reaction mixture was stirred at room temperature for 7 hours and then diluted by adding 5 ml of water. The mixture was washed with three 20 ml portions of methylene chloride and then acidified with dilute hydrochloric acid until the pH of the solution was about 1. The solution was decanted and the oily precipitate was dissolved in isopropyl alcohol. After the organic phase was concentrated in vacuo, the residue was chromatographed on silica gel using chloroform-isopropyl alcohol (10:1) as eluent to give 0.715 g of 1,4-dihydro-2,6-dimethyl-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-4-(3-nitrophenyl)pyridine-5-carboxylic acid as an amorphous solid. Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals, m.p. 171° C. (decomp.)
Reaction SMILES: C[O-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][OH:21])=[CH:14][CH:13]=1.[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCCC1.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[I:24][C:25]1[CH:30]=[CH:29][C:28](/[C:18](/[C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:22])([F:23])[F:10])=[CH:17][CH:16]=2)=[CH:19]\[CH2:20][OH:21])=[CH:27][CH:26]=1
Reactant: Ic1ccc(I)cc1
Reactant: OCC#Cc1ccc(C(F)(F)F)cc1
Agent: C[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC/C=C(\c1ccc(I)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (12.5 mg, 0.225 mmol) was added to 1 M solution of lithium aluminum hydride in tetrahydrofuran (5 mL, 5 mmol) under argon. The mixture was cooled to 0° C. and a solution of the above alcohol (1.00 g, 5 mmol) in tetrahydrofuran (12.5 mL) was added over 10 min. The reaction was stirred at 0° C. for 3 h; dry ethyl acetate (0.825 mL) was added and the whole mixture was stirred at ambient temperature for 15 min. A degassed solution of 1,4-diiodobenzene (2.15 g, 6.5 mmol) in dry tetrahydrofuran (5 mL), anhydrous zinc chloride (0.408 g, 3 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.103 g, 0.1 mmol), and tri(2-furyl)phosphine (92.5 mg, 0.4 mmol) were added; the mixture was degassed and then was heated at 65° C. for 15 h under nitrogen. The suspension was cooled down; methanol (2.5 mL) was added and the mixture was stirred for additional 1 h. The reaction was diluted with ether (50 mL) and saturated aqueous solution of ammonium chloride (1.25 mL) was added. The mixture was filtered through a paddle of silica gel and the paddle was thoroughly washed with ether (100 mL). The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 5:1) affording (Z)-3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)prop-2-en-1-ol as solidifying oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[K+].[C:26]1([CH:32]=[CH:33][S:34]([NH-:37])(=[O:36])=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)C>CS(C)=O>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:37][S:34]([CH:33]=[CH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:35])=[O:36])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: [NH-]S(=O)(=O)C=Cc1ccccc1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: [K+]
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.6 %

Procedure:
To 4,6-dichloro-5-p-tolyl-pyrimidine (2.0 g) disolved in DMSO (35 ml) was added di-isopropyl-ethyl-amine (1.46 ml) followed by 2-phenyl-ethenesulfonamide potassium salt (2.78 g). The mixture was stirred for 48 h at rt then poured onto water (500 ml) and diethylether (250 ml) was added and the solution was stirred for 30 minutes. The layers were separated and the water layer was acidified with acetic acid (2.0 ml) and cooled to 0° C. for 1 h. The precipitated product was filtered off and washed with water and diethylether and dried to give 2-phenyl-ethenesulfonic acid(6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (2.02 g). tR=5.32 (LC); M+=386.23 (ES+); M−=384.22 (ES−).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH:20][C:21]([OH:23])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][S:29][CH2:28][CH2:27]2)=[O:23])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccccc2C=CC(=O)O)=C(C)C1=O
Reactant: C1CSCCN1
Product: COC1=C(OC)C(=O)C(Cc2ccccc2C=CC(=O)N2CCSCC2)=C(C)C1=O
Yield: 39.7 %

Procedure:
3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (20 mg, 0.058 mmol) obtained in Example 67 and thiomorpholine (0.009 ml, 0.087 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (10 mg, 0.023 mmol, yield 40%).