Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][CH2:8]1.O.NN>C(O)C>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:11][CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2ccccc2-c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCN1CCN(c2ccccc2-c2ccccc2)CC1

Procedure:
Batch size: 20.8 g (47.3 mol) 2-[4-(4-biphenyl-2-yl-piper-azin-1-yl)-butyl]-isoindolin-1,3-dione and 4.6 ml (94.6 mmol) hydrazine-hydrate in 185 ml ethanol.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[CH3:3][CH2:2][CH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:17]([CH3:18])=[O:19])=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: CCCc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
4-n-Propylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (862 mg) and acetyl chloride (692 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed therefrom by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give 4-n-propylphenyl acetate (1.09 g, yield 100%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:18][N:19]=[C:20]=[S:21]>>[CH3:18][NH:19][C:20]([NH:1][CH:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)=[S:21]
Reactant: CN=C=S
Reactant: NC1CCCc2ccc(-c3ccccc3)nc21
Product: CNC(=S)NC1CCCc2ccc(-c3ccccc3)nc21

Procedure:
The 8-amino-compound of Example 23 may be treated with methylisothiocyanate to give the title compound following the procedure of Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[C:4]([C:17]2[CH:18]=[N:19][C:20](S(CCC)(=O)=O)=[N:21][CH:22]=2)[CH:3]=1.Cl.[CH3:30][NH2:31]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:17]2[CH:22]=[N:21][C:20]([NH:31][CH3:30])=[N:19][CH:18]=2)[CH:3]=1
Reactant: CCCS(=O)(=O)c1ncc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cn1
Reactant: CN
Agent: Cl
Product: CNc1ncc(-c2cc(Cl)ccc2OCC(=O)O)cn1

Procedure:
The title compound was prepared from the product of example 20 step (iv) and methylamine hydrochloride by the method of example 20 step (v).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[N:11](C(OC(C)(C)C)=O)[C:10]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:26])[N:9]([CH2:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccc(Cl)cc21

Procedure:
A solution of 1.8 g (4.70 mmol) of tert-butyl 3-tert-butoxycarbonylmethyl-5-chloro-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIIg) in 100 ml of 2% trifluoroacetic acid in dichloromethane was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was dried in vacuo. Yield: 1.32 g (100%) of colorless solid
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18](=O)[CH:19]([O:22][CH3:23])[O:20][CH3:21].C(OCC)(=O)C>CN(C=O)C.O>[CH3:21][O:20][CH:19]([O:22][CH3:23])[C:18]1[N:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:9][CH:17]=1
Reactant: COC(OC)C(=O)CBr
Reactant: N=C(N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(OC)c1c[nH]c(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
To a solution of benzamidine 207 (1.44 g, 12 mmol) and potassium carbonate (4.1 g, 30 mmol) in anhydrous DMF (25 mL) is slowly added a solution of 3-bromo-1,1-dimethoxy-propan-2-one 206 (1.97 g, 10 mmol) in anhydrous DMF (10 mL) over 30 min. The mixture is then heated at 50–60° C. for 2 h. After cooling to room temperature, ethyl acetate (100 mL) and water (100 mL) were added. The organic phase is separated and the aqueous phase is extracted with ethyl acetate twice and the combined organic phase is washed with water (3×20 mL) and brine. Removal of solvents under reduced pressure and purification of the residue by column chromatography affords the desired product as a white solid. Yield: 2.08 g; LC-MS (MH+): 219. 1H NMR (300 MHz, CDCl3) δ 7.88–7.85 (m, 2H), 7.37–7.46 (m, 4H), 5.49 (s, 1H), 3.36 (s, 6H).
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:10])[CH2:7][C:8]#[N:9].[CH3:11][CH:12]=[CH:13][C:14](=[O:17])[CH2:15][CH3:16]>CO>[CH3:16][CH:15]1[C:14](=[O:17])[CH2:13][CH:12]([CH3:11])[CH:7]([C:8]#[N:9])[C:6]1=[O:10]
Reactant: CC=CC(=O)CC
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1C(=O)CC(C)C(C#N)C1=O
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To a solution of sodium methoxide (162 grams, 3 moles) in 400 mls of anhydrous methanol is added, dropwise, 276 grams (3.2 moles) of methylcyanoacetate over a period of 1 hour at 60° C. with stirring. The resulting slurry is stirred at 60° C. for 10 minutes, whereupon 288 grams (3.0 moles) of 2-hexen-4-one is added over a 20 minute period. The resulting reaction mixture is stirred and heated at reflux for six hours, whereupon a distillation take-off condenser is affixed to the reaction flask and 240 mls of methanol are removed under reduced pressure (65 mm Hg). The reaction mixture is then cooled to room temperature and poured into 2 liters of water. Toluene (500 ml) is added and the mixture is transferred to a separatory funnel. The aqueous layer is removed and again extracted with toluene (500 mls). To the aqueous solution, 500 mls of 18% HCl are added with external cooling at 25° C., whereupon a solid material precipitates. The solid is filtered, dried and recrystallized from aqueous methanol to afford colorless needles of 3,6-dimethyl-2,4-dioxocyclohexanecarbonitrile (388 grams, 68.3% yield based on 2-hexen-4-one); m.p. 178°-179° C. The resulting product is represented by the following equilibrium mixture: ##STR22##
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[Li]CCCC.[I:20]I>C1COCC1>[CH3:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([I:20])[CH:6]=1
Reactant: CC(C)(C)C#Cc1ccc(C(=O)O)s1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cc(I)c(C(=O)O)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid (6.2 g, 30 mmol; see patent application U.S. Pat. No. 5,861,421) in THF (100 mL) was added a solution of nBuLi (2.0M in pentane, 33 mL, 66 mmol) via an addition funnel at −78° C. After addition, the reaction was stirred at −78° C. for 1 h. A solution of I2 (7.7 g, 30 mmol) in THF (100 mL) was added slowly (ca. 15 min) to the flask. After a further 10 mins, the reaction was quenched with 1N HCl (50 mL) and warmed to room temperature. The volatiles were removed in vacuo and the residue was dissolved in ether (500 mL). The organic solution was washed with 1M Na2S2O3 (100 mL×2), brine (100 mL) and dried over Na2SO4. After concentrated in vacuo, the residue was purified by silica gel chromatography (EtOAc/hexanes) to give 5-(3,3-dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid (5.9 g, 65%) as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14](Cl)=O.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=C.C(N(CC[CH2:35][CH3:36])CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:22]([O:21][C:17]([CH:18]=[CH:11][C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH:14]=[CH:18][C:17]([O:21][CH2:35][CH3:36])=[O:20])[CH:1]=2)[CH:6]=1)=[O:20])[CH3:23]
Reactant: CCCCN(CCCC)CCCC
Reactant: O=C(Cl)c1ccc2cc(C(=O)Cl)ccc2c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)C=Cc1ccc2cc(C=CC(=O)OCC)ccc2c1

Procedure:
0.1683 g (0.75 millimol) of palladium acetate, 9.49 g (37.5 millimols) of naphthalene-2,6-dicarboxylic acid dichloride, 9.38 g (93.75 millimols) of ethyl acrylate and 13.89 g (75 millimols) of tri-n-butylamine, in 150 ml of p-xylene, are stirred for 2 hours at 120° C. The crude product is chromatographed on silica gel in methylene chloride, and is then recrystallised from cyclohexane. 4.11 g (34% of theory) of yellow crystals, of melting point 150°-51° C., are obtained. Analysis for C20H20O4 : calculated C 74.06%, H 6.22%, O 19.73%; found C 73.85%, H 6.41%, O 19.56%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.Br[CH2:28][C:29]#[N:30]>C1(C)C=CC=CC=1>[C:29]([CH2:28][N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)#[N:30]
Reactant: N#CCBr
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2nn(CC#N)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 190 °C
Yield: 1.8 %

Procedure:
A mixture of 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (Example 1, step 3)(0.10 g), 4.2 g of bromoacetonitrile and 3 mL of toluene was heated at reflux for 2 hours. Toluene was distilled off and the mixture was heated at 190° C. for 24 hours. The reaction mixture was diluted with methylene chloride and filtered through silica gel. The filtrate was concentrated in vacuo and the residue was purified by HPLC (30% ethyl acetate-hexane). The second fraction eluted with 40% ethyl acetate-hexane yielding 1-cyanomethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (1 2 mg, 11%): mp 192°-194° C.
Reaction SMILES: [F:1][CH:2]=[C:3](CBr)[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[OH:26].[H-].[Na+].[CH3:29]COCC>CN(C)C=O.[Cl-].[Na+].O>[F:1]/[C:2](/[CH2:29][O:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[Cl:18])=[CH:3]\[CH2:4][N:5]1[C:6](=[O:15])[C:7]2=[CH:14][CH:13]=[CH:12][CH:11]=[C:8]2[C:9]1=[O:10]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCOCC
Reactant: O=C1c2ccccc2C(=O)N1CC(=CF)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C/C=C(\F)COc1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 88 %

Procedure:
Solid 1-fluoro-2-bromomethyl-3-phthalimidopropene (0.60 g) is added to a previously prepared mixture of 2,4-dichlorophenol (0.33 g) and sodium hydride dispersion (96 mg of 55-60% oil dispersion) in dimethylformamide (10 ml) at room temperature. Stirring is continued for 3 hours, then brine is added and the product is isolated by ether extraction. The extracted material is essentially pure (Z)-1-fluoro-(2',4'-dichlorophenoxy)methyl -3-phthalimidopropene (0.67 g; 88% yield). A small portion is recrystallized from hexane/dichloromethane whereupon the analytical sample is obtained as colorless plates; mp. 115°-116° C.
Reaction SMILES: C(S)CCCCCCC.C([Li])CCC.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([CH2:32][O:33][C:34]3[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][CH:35]=3)([OH:31])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1)#[N:16]>CCCCCC.CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][C:28]([CH2:32][O:33][C:34]3[CH:35]=[CH:36][C:37]([C:38]([OH:40])=[O:39])=[CH:42][CH:43]=3)([OH:31])[CH2:29][CH2:30]2)=[CH:21][CH:22]=1)#[N:16]
Reactant: COC(=O)c1ccc(OCC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Agent: CCCCCCCCS
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(CCN2CCC(O)(COc3ccc(C(=O)O)cc3)CC2)cc1
Temperature: 0 °C
Yield: 75.9 %

Procedure:
To a solution of n-octanethiol (2.04 g) in a mixture of anhydrous tetrahydrofuran (10 mL) and anhydrous hexamethylphosphoric triamide (HMPA) (5 mL), a 1.59 M solution of n-butyl lithium in hexane (8.74 mL) was added dropwise under cooling with ice-water under nitrogen atmosphere. After stirring at the same temperature for fifteen minutes, a solution of the compound (2.50 g) obtained in Example 13 in a mixture of anhydrous tetrahydrofuran (10 mL) and anhydrous HMPA (5 mL) was added dropwise thereto over ten minutes, followed by stirring at the same temperature for thirty minutes and further stirring at room temperature for seventeen hours. After the completion of reaction, the reaction mixture was mixed with an ice water (20 mL) under cooling with ice-water and was washed with ethyl acetate (25 mL×2). Small portions of 3 N hydrochloric acid were gradually added to the aqueous layer with stirring under cooling with ice-water, to adjust the pH of the mixture to 5.6. The precipitated crystals were collected by filtration and were sequentially washed with water and ethanol. The resulting crystals were suspended in a mixture of methanol (50 mL) and water (10 mL), followed by heating under reflux for thirty minutes. After standing to cool, the crystals were collected by filtration and were washed with methanol, and dried under reduced pressure to yield the titled compound (1.83 g) as crystals.
Reaction SMILES: [CH3:1][C:2]([O:14][CH2:15][CH2:16][CH3:17])([CH3:13])[CH2:3][NH:4][C:5]1[N:6]=[CH:7][NH:8][C:9]=1[C:10]([NH2:12])=[O:11].C(N=[C:27]=[S:28])(=O)C1C=CC=CC=1>ClCCl>[CH2:15]([O:14][C:2]([CH3:1])([CH3:13])[CH2:3][N:4]1[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[C:10](=[O:11])[NH:12][C:27]1=[S:28])[CH2:16][CH3:17]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCCOC(C)(C)CNc1nc[nH]c1C(N)=O
Solvent: ClCCl
Product: CCCOC(C)(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-[(2-Methyl-2-propoxypropyl)amino]-1H-imidazole-5-carboxamide obtained from Example 2(c) was dissolved (0.19 g, 0.78 mmol) in 7 mL of dichloromethane. The obtained solution was stirred at ambient temperature. Benzoyl isothiocyanate (0.50 g, 3.1 mmol) was added in portions during 6 h. The reaction mixture was stirred over night and the solvent was then removed in vacuo. Ammonia in methanol (7 mL of 7 M solution) was added and the obtained solution was heated at 50° C. for 3 h and then at 80° C. for 3 h in a pressure flask. The cooled reaction mixture was concentrated and the crude product was purified by reverse phase HPLC. The product was obtained in 22% (48 mg) yield.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:17])([F:16])[F:15])[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:15])([F:16])[F:17])[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])[CH2:46][CH2:45]1)=[O:20]
Reactant: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)O
Reactant: COc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3ccccc3OC(F)(F)F)noc2N)CC1
Yield: 65.8 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (559 mg, 1.21 mmol, 66%) was obtained.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13](=[O:17])[CH2:14][CH2:15][CH3:16]>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:13]([CH:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:1]([O:10][CH2:11][CH3:12])=[O:9])(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC=O
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCCC(=O)C(CC(=O)OCC)C(=O)OCC
Yield: 85.6 %

Procedure:
A mixture of 86 g of diethyl maleate, 144 g of butyraldehyde and 4 g of dibenzoyl peroxide was boiled at reflux for 20 hours. After completion of the reaction, the excess butyraldehyde was firstly distilled off over a Vigreux column and then the yellow coloured crude product was taken up in 250 ml of hexane and washed with 200 ml of 5% (wt./vol.) sodium hydrogen carbonate solution and 200 ml of water. The aqueous phases were back-extracted with a small amount of hexane. The combined organic phases were dried over sodium sulphate and freed from solvent on a rotary evaporator. Distillation of the resulting crude product in a high vacuum over a Vigreux column gave 104.5 g (85.6%) of diethyl 2-butyrylsuccinate as a slightly yellow coloured liquid; b.p. 84°-90° C./0.08 Torr.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[N:13]([CH2:31][CH2:32][CH3:33])[C:14](=[O:30])[C:15]3[NH:16][C:17]([C:21]45[CH2:28][CH:27]6[CH2:29][CH:23]([CH2:24][CH:25]4[CH2:26]6)[CH2:22]5)=[N:18][C:19]=3[N:20]=2)[CH:6]=1)C.[OH-].[Na+]>C(O)C.C1COCC1>[CH2:24]1[CH:25]2[C:21]3([C:17]4[NH:16][C:15]5[C:14](=[O:30])[N:13]([CH2:31][CH2:32][CH3:33])[C:12]([O:11][C:7]6[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=6)[C:4]([OH:34])=[O:3])=[N:20][C:19]=5[N:18]=4)[CH2:28][CH:27]([CH2:29][CH:23]1[CH2:22]3)[CH2:26]2
Reactant: CCCn1c(Oc2cccc(C(=O)OCC)c2)nc2nc(C34CC5CC(CC3C5)C4)[nH]c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCn1c(Oc2cccc(C(=O)O)c2)nc2nc(C34CC5CC(CC3C5)C4)[nH]c2c1=O
Temperature: 50 °C
Yield: 60.1 %

Procedure:
To a solution of 3-[8-(Hexahydro-2,5-methano-pentalen-3a-yl)-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-yloxy]-benzoic acid ethyl ester (prepared by following similar, procedure as Example 1, 0.073 g, 0.157 mmol) in a mixture of ethanol (5 ml) water (5 ml) and THF (5 ml) was added sodium hydroxide (0.019 g, 0.473 mmol) and the reaction mixture was heated at 50° C. overnight. The reaction mixture after cooling to room temperature was concentrated under vacuum to remove THF. The aqueous layer was acidified with 1N HCl. The precipitate obtained was extracted with ethylacetate. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography using 5% methanol in DCM as the eluant to give the product (0.041 g, 59%) as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([CH3:8])[CH2:5][C:6]#N.C1C[O:13]CC1.C1CCCCCCCCCCC1.CC1CCOC1=O>O>[CH3:8][CH:4]([CH2:5][CH2:6][OH:13])[C:3]([O:2][CH3:1])=[O:9]
Reactant: C1CCOC1
Reactant: COC(=O)C(C)CC#N
Agent: C1CCCCCCCCCCC1
Agent: CC1CCOC1=O
Solvent: O
Product: COC(=O)C(C)CCO
Temperature: 100 °C
Reaction time: 3.2 h

Procedure:
A mixture of 0.05 mmol RuHCi(H2)(PCy3)2, 0.54 mmol methyl-3-cyanoisobutyrate (prepared by addition of HCN to methyl methacrylate), 17.7 g THF, 15.3 g water, and 0.0596 g cyclododecane (internal standard for gc analysis) was stirred in an autoclave and heated to 100° C. under 7000 kPa H2. After 3.2 hours, the nitrile was completely and cleanly converted to methyl-butyrolactone, which formed by transesterification/cyclization of the intermediate hydroxyester, methyl 2-methyl-4-hydroxybutyrate.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[C:11](#[N:14])[CH:12]=[CH2:13].S(=O)(=O)(O)O>O>[C:1]1([S:7]([CH2:13][CH2:12][C:11]#[N:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])c1ccccc1
Reactant: C=CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: N#CCCS(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
650 ml of water are introduced into the flask and are heated to 80° to 90° C., and 935 g (4 mols) of 70% strength sodium benzenesulphinate are added to the water. 215 g (4.04 mols) of acrylonitrile and 382 g (1.95 mols) of 50% strength sulphuric acid are then added simultaneously, in the course of about 1 hour at 100° C., at such a rate that the pH value remains at 6 to 7. The mixture is stirred for 30 minutes at 100° C. and the pH value is again readjusted. Excess acrylonitrile is distilled off over a Vigreux column in an azeotropic mixture with water at normal pressure, and 255 g of xylene are then added and the phases are separated at about 95° C. This is carried out by sucking off the lower aqueous phase with a suction tube. The salt precipitate remains for the most part in the flask. 800 ml of washing water is now stirred in at >95° C. and the phases are separated as described above. In this process most of the salt is dissolved, and the remainder does not interfere in the following reaction. A further 17 g of 3-phenylsulphonyl-propionitrile are isolated from the combined aqueous phases. 255 g (300 ml) of xylene are now added to the organic phase in the flask, at 95° to 100° C., and the remaining water is distilled off azeotropically with xylene (boiling point 92° C.) The remaining xylene is completely removed in vacuo at a trough temperature of 100° to 120° C. The trough now contains 730 g (94%) of 3-phenylsulphonyl-propionitrile in 97% purity, and 50 g of salt.
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\CCCC(O)=O)[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24].C(OC(Cl)=O)C(C)C.C([N:36](CC)CC)C>>[OH:23][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([NH2:36])=[O:24]
Reactant: CCN(CC)CC
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CC(C)COC(=O)Cl
Product: NC(=O)c1ccccc1O

Procedure:
Following the procedure of Example 1 but using 0.738 g. of PGF2 α , 0.306 ml. of triethylamine, 0.288 ml. of isobutylchloroformate, and 0.299 g. of o-hydroxybenzamide, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-acetone-water (25:75:1). The residue obtained by concentration of selected fractions, 0.296 g., is crystallized from ethyl acetate diluted with 1.5 volumes of hexane as the title compound, white free-flowing crystals, m.p., 98.5°-100.1° C. having Rf 0.55 (TLC on silica gel in ethyl acetate-acetone (1:3)).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(CC)CC>C1COCC1>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=1)[CH3:10]
Reactant: C1CCNC1
Reactant: CCOc1ccnc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccnc(N2CCCC2)n1

Procedure:
To a solution of 2-chloro-4-ethoxypyrimidine (3 g, 19 mol) in THF (410 mL) was added pyrrolidine (2.7 g, 38 mmol) and Et3N (5.8 g, 57 mmol) and the reaction mixture was heated to reflux overnight. The solvent was evaporated and the residue was partioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give the title compound.