Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:26]([O:28][C:29](Cl)=[O:30])[CH3:27]>O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[C:17]2=[O:25])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)n1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A suspension of 165 mg of sodium hydride in 10 ml of tetrahydrofuran is cooled at 0° C. To the suspension is added dropwise a solution of 2.2 g of 1-t-butyloxycarbonyl-4-(2-keto-1-benzimidazolinyl)-piperidine in 18 ml of tetrahydrofuran over 30 minutes in a stream of nitrogen. The mixture is stirred at room temperature for 2 hours and 760 mg of ethoxycarbonylchloride is added. The mixture is stirred at room temperature for one hour and 300 mg of ethoxycarbonylchloride is added. The mixture is stirred for 12 hours. The reaction solution is put into ice and the resulting oily product is extracted with ethyl acetate. The extract is washed and dried. Ethyl acetate is distilled away and the resulting residue is recrystallized from n-hexane to obtain 2.4 g of 1-t-butyloxycarbonyl-4-(2-keto-3-ethoxycarbonyl-1-benzimidazolinyl)-piperidine.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20]C)=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:26](=[O:28])[CH3:27])OC(=O)C)[CH3:2].[Li].N.CO>O1CCOCC1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[C:26](=[O:28])[CH3:27])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@]2(OC(C)=O)C(C)=O
Agent: N
Agent: [Li]
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2C(C)=O
Yield: 36.7 %

Procedure:
Add 13β-ethyl-3-methoxy-17α-acetyl-17β-acetoxy-gona-1,3,5(10)triene (0.24 g.) in dioxan (5 cc.) to a stirred solution of lithium (0.15 g.) in liquid ammonia (100 cc.). After 30 minutes add methanol (8 cc.) followed by lithium (0.5 g.) in small pieces. Add water, extract with ether and work up to a gum (0.218 g.). Reflux this product with 4N hydrochloric acid (5 cc.) and methanol (8 cc.) for 15 minutes. Add water, extract with ether, work up and dissolve the resulting gum in acetone (30 cc.) containing anhydrous magnesium sulphate (0.5 g.) and add 8N-chromic acid dropwise with swirling until the solution assumes a permanent yellowish-orange color. Add excess isopropanol and evaporate the solution almost to dryness. Add water, extract with ether, wash, dry and evaporate the organic solution, filter the product through alumina with benzene-ether and recrystallize the product from ethyl acetate to obtain the title product (0.072 g.), m.p. 138°-142°; infrared absorption peaks at 5.9, 6 μ.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([NH:21][C:22](=[O:24])[CH3:23])[CH2:9][C@@H:8]1[CH3:25])=[O:6])([CH3:3])[CH3:2].[F:26][C:27]([F:41])([F:40])[C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:31]Br.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[C@H:10]([N:21]([C:22](=[O:24])[CH3:23])[CH2:31][C:30]2[CH:33]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:35]=[C:28]([C:27]([F:26])([F:40])[F:41])[CH:29]=2)[CH2:9][C@@H:8]1[CH3:25])=[O:6])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(=O)N[C@@H]1C[C@H](C)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)nc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)nc21
Yield: 30 %

Procedure:
Prepare the title compound by essentially following the procedure described in Example 49, Step 2, by replacing (+/−)-N-(1-cyclopently-6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]napthyridin-4-yl)-acetamide with cis-4-acetylamino-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.065 g, 0.018 mmol), and using 3,5-bis trifluoromethyl benzylbromide and lithium hexamethyldisilazide. Purify using silica gel column chromatography (gradient eluent, neat ethyl acetate) to afford the title compound (0.031 g, 30%). MS (ES+): 586 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(C)C=CC=CC=1.Cl>O>[C:13]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid (5.0 g, 38.7 mmol) and NaOH (1.86 g, 46.5 mmol) in H2O (15 ml) was added dropwise a 50% solution of benzyl chloroformate in toluene (13.6 mL, 40.6 mmol) over a period of half an hour at 0° C. The reaction mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was acidified with dil. HCl (pH 3) and extracted with ethyl acetate (3×100 ml). The combined organic phases were dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (silica gel, elution with 30% ethyl acetate/n-hexanes) to afford piperidine-1,4-dicarboxylic acid monobenzyl ester (VI) (6.5 g, 64%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[NH:9][C:10]=2[CH:11]=1.O1CCC[CH2:17]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[N:9][N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[C:6]=2[O:15][CH3:17]
Reactant: O=c1c2ccc(Cl)cc2[nH]n2cccc12
Reactant: C1CCOC1
Product: COc1c2ccc(Cl)cc2nn2cccc12
Reaction time: 48 h

Procedure:
Diazomethane was prepared by adding Diazald® (21.4 g) in 200 ml of ether to potassium hydroxide (5.0 g) in 20 ml of 50% ethanol/water solution and then distilling. This procedure was followed three times to give a solution of diazomethane (16.25 g) in ether which was then added to a stirred slurry of 7-chloropyrrolo[1,2-b]cinnolin-10(5H)-one (37.0 g) in 250 ml of tetrahydrofuran. The mixture was allowed to stand at room temperature for 48 hours and then the volatiles were removed. The residue was taken up in dichloromethane and washed several times with water. The organic layer was dried (MgSO4), filtered and concentrated to a dark orange powder. The powder was purified by flash chromatography (silica, dichloromethane) to give 18.35 g of an orange powder. A five gram portion of this powder was recrystallized from ether to give 4.3 g of an orange fibrous material, mp 128°-129°.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[CH:12]=2)=[CH:5][CH:4]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:18])[CH3:19])[CH:12]=1)([CH3:22])[CH3:23]
Reactant: CC(C)c1cccc(NCc2ccc(N(C)C)cc2)c1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1cccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)c1
Yield: 22.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](3-isopropylphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (0.83 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(3-isopropylphenyl)urea (0.40 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].Cl>C1COCC1>[OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9]
Reactant: COCOc1ccc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)cc1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1c(O)c2c(-c3ccc(O)cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-hydroxy-3-[4-(methoxymethoxy)phenyl]-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.1 g, 0.305 mmol) in THF (10 mL) was added 1N HCl (20 mL) in a single portion at room temperature and stirred for 16 h at room temperature. The reaction mixture was concentrated and purified by RP-HPLC to afford the title compound. MS (ESI) m/e 282.9 (M−H)+; 1H NMR (500 MHz, DMSO-d6): δ ppm 12.56 (br s, 1H), 9.45 (br s, 1H), 7.22 (d, 2H), 6.89 (s, 1H), 6.74 (d, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])C1C=CC=CC=1.[H][H]>CN(C=O)C.C(Cl)Cl.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30]
Reactant: [H][H]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Yield: 43.9 %

Procedure:
A solution of 7-benzyloxy-4-(indol-5-yloxy)-6-methoxyquinazoline (8 g, 20 mmol) in DMF (50 ml) and methylene chloride (100 ml) containing 10% palladium on charcoal (2 g) was hydrogenated at 1.8 atmospheres pressure until uptake of hydrogen had ceased. The solution was filtered, the catalyst was washed with DMF and the filtrate was evaporated. The residue was purified by column chromatography eluting with methylene chloride, followed by methylene chloride/methanol (95/5 and 90/10). After evaporation of the solvent, the residue was triturated with ether, filtered and dried under vacuum to give 7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (2.7 g; 44%).
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]#[N:13])=[CH:4]1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]#[N:13])=[CH:4]1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cn(CO)cc1C(F)(F)F
Solvent: ClC(Cl)Cl
Product: N#Cc1cn(CCl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The obtained 1-hydroxymethyl-3-cyano-4-trifluoromethyl-1H-pyrole was dissolved to 3 ml of chloroform, and 3 ml of thionyl chloride was added, followed by stirring at room temperature for 1 hour. After the reaction mixture was cooled to 0° C., it was poured into ice-water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 800 mg of 1-chloromethyl-3-cyano-4-trifluoromethyl-1H-pyrole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[N:6]=[C:5]2[CH:14]1[CH2:17][CH2:16][CH2:15]1.C(OC([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)(C)(C)C>>[CH2:31]([C@@H:26]1[NH:25][CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]([CH3:13])[CH3:12])[N:6]=[C:5]3[CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH2:27]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Reactant: CC(C)n1nc(C2CCC2)c2cc(Br)ccc21
Product: CC(C)n1nc(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc21
Yield: 55 %

Procedure:
The title compound was prepared by the method outlined for Example 1 using 5-Bromo-3-cyclobutyl-1-isopropyl-1H-indazole as the aryl halide and (S)-2-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component to afford the title compound as a brown oil (780 mg, 55%). 1H NMR (MeOH-d4) 7.44-7.20 (m, 5H), 7.16-6.87 (m, 3H), 4.78 (td, J=13.4, 6.7 Hz, 1H), 3.95-3.83 (m, 1H), 3.46-3.33 (m, 2H), 3.20-3.05 (m, 2H), 3.03-2.91 (m, 1H), 2.82-2.75 (m, 3H), 2.57-2.36 (m, 6H), 2.24-2.09 (m, 1H), 1.50 (d, J=6.7 Hz, 6H). LC/MS (Method B) 2.79 min, [M+1]+ 389.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].[I:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1>>[I:9][C:10]1[CH:15]=[CH:14][C:13]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][O:3][C:2]=2[CH3:1])=[CH:12][CH:11]=1
Reactant: Oc1ccc(I)cc1
Reactant: Cc1occc1CO
Product: Cc1occc1COc1ccc(I)cc1

Procedure:
3-(4-Iodo-phenoxymethyl)-2-methyl-furan was prepared from (2-methyl-furan-3-yl)-methanol and 4-iodo-phenol in an analogous manner to that described in Example 14(a).
Reaction SMILES: FC(F)(F)C(OO)=[O:4].[C:9]1([CH2:15][CH2:16][CH2:17][C:18](=[CH2:22])[C:19]([OH:21])=[O:20])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.P([O-])([O-])(O)=O.[Na+].[Na+]>C(Cl)Cl>[C:9]1([CH2:15][CH2:16][CH2:17][C:18]2([C:19]([OH:21])=[O:20])[CH2:22][O:4]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OO)C(F)(F)F
Reactant: C=C(CCCc1ccccc1)C(=O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)C1(CCCc2ccccc2)CO1
Temperature: 0 °C

Procedure:
Alternatively, the compound is obtained as follows: a solution of trifluoroperacetic acid (prepared from 1.8 ml of 85% strength hydrogen peroxide, 17 g of trifluoroacetic anhydride and 15 ml of methylene chloride) is added dropwise to a boiling mixture of 9.5 g of 5-phenyl-2-methylenevaleric acid and 28 g of disodium hydrogen phosphate in 50 ml of methylene chloride. The mixture is boiled under reflux for a further 30 minutes; 150 ml of ice-water are added; *the organic phase is separated off and, after drying over sodium sulfate, is concentrated. The title compound remains as a viscous oil.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[N:10]=[CH:9]2)C=CC=CC=1.[C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][C:33]=1[F:40])#[N:31]>C(#N)C>[C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:10]2[C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:8]=[CH:9]2)=[CH:34][C:33]=1[F:40])#[N:31]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Product: COC(=O)Cc1cncn1Cc1ccc(C#N)c(F)c1
Temperature: 50 °C
Yield: 164.7 %

Procedure:
A solution of methyl 1-(triphenylmethyl)imidazol-4-ylacetate from Step B (0.536 g, 1.40 mmol) and 4-cyano-3-fluoro-benzylbromide from Example 1, Step D (0.300 g, 1.40 mmol) in dry acetonitrile (3 mL) was heated at 50° C. under argon for 2 hours, then the precipitate was collected by filtration. The filtrate was concentrated to a volume of 1 mL and then heated at 50° C. for a further 2 hours. The precipitate formed was collected and combined with the first crop to give a white solid (0.63 g). This solid was dissolved in MeOH (30 mL) and heated to reflux for 2 hours. The MeOH was removed under reduced pressure and the residue was partitioned between sat. aq. NaHCO3 (20 mL) and CHCl3 (30 mL). The aqueous layer was extracted further with CHCl3 (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 3% MeOH/0.3% NH4OH in CHCl3 to give the titled product as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:18]3[CH2:22][N:21]([C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[C:20](=[O:31])[CH2:19]3)[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:32].[Na+].OO>CCO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:18]3[CH2:22][N:21]([C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]([NH2:27])=[O:32])[C:20](=[O:31])[CH2:19]3)[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1cccc(N2CC(c3ccc(OCC4CC4)c(OC4CCCC4)c3)CC2=O)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc(N2CC(c3ccc(OCC4CC4)c(OC4CCCC4)c3)CC2=O)c1
Temperature: 47.5 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a dry round bottom flask was added 3-[4-(3-cyclopentyloxy-4-cyclopropylmethoxy-phenyl)-2-oxo-pyrrolidin-1-yl]benzonitrile (1 mmol) in 10 mL EtOH. This mixture was then heated, and 50 μL of 25% NaOH solution followed by 0.5 mL 30% H2O2 was added to the solution. The mixture was stirred at 45 to 50° C. for 4 h, cooled to r.t., and concentrated under reduced pressure. The residue was dissolved in EtOAc (or CH3Cl), washed with saturated NH4Cl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give pure product. Yield: 87%.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)=O.CN(C)C=O.[N-:32]=[N+:33]=[N-:34].[Na+]>O>[N:32]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N+:33]=[N-:34]
Reactant: CCOC(=O)CSC(CCCCOS(C)(=O)=O)CCCc1cccnc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSC(CCCCN=[N+]=[N-])CCCc1cccnc1

Procedure:
A mixture of 0.12 g (0.3 mmol) ethyl 8-methylsulfonyloxy-4-[3-(3-pyridyl)propyl]-3-thia-octanoate, 1,5 ml dimethylformamide and 0.062 g (0.95 mmol) sodium azide is heated at 60° for 18 h. The mixture is then poured into water and extracted with ether. The organic phase is washed with water, saturated brine, dried, filtered and evaporated to give ethyl 8-azido-4-[3-(3-pyridyl)propyl]-3-thia-octanoate; IR (CH2Cl2): 2099, 1732 cm-1.
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][S:10]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:16][C:17]([C:19]([CH3:21])=[CH2:20])=[CH2:18]>C(Cl)CCl>[CH3:16][C:17]1[CH2:18][CH:12]2[C:13](=[O:14])[N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[S:10](=[O:15])[CH:11]2[CH2:20][C:19]=1[CH3:21]
Reactant: CCCCCCCCN1C(=O)C=CS1=O
Reactant: C=C(C)C(=C)C
Solvent: ClCCCl
Product: CCCCCCCCN1C(=O)C2CC(C)=C(C)CC2S1=O
Temperature: 60 °C
Yield: 50.7 %

Procedure:
To a solution of 2.2 g (0.01 mole) of 2-n-octyl-4-isothiazolin-3-one 1-oxide in 15 ml of ethylene dichloride is added 1.1 g (0.012 mole) of 2,3-dimethyl-1,3-butadiene. The solution is stirred and maintained at 60° C. overnight. The mixture is concentrated to give a dark, thick oil. The oil is further purified by column chromatography (90% benzene, 10% acetone, silica) to yield 1.58 g (51%) of product as a yellow oil.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]2[CH2:11][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9](=[O:19])[CH2:8]2)C(=O)C2=CC=CC=C12.O.NN.C(O)(=O)/C=C/C(O)=O>C(O)C>[CH2:12]([N:10]1[CH2:11][CH:7]([CH2:6][NH2:5])[CH2:8][C:9]1=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CC(CN2C(=O)c3ccccc3C2=O)CN1Cc1ccccc1
Agent: NN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: O
Product: NCC1CC(=O)N(Cc2ccccc2)C1

Procedure:
54 g (0.16 mol) of 4-phthalimidomethyl-1-benzyl-pyrrolidin-2-one are stirred into 1.3 liters of ethyl alcohol after the addition of 32 g of hydrazine hydrate for 4 hours at ambient temperature. The precipitate (phthalic acid hydrazide) is suction filtered and the filtrate is concentrated by evaporation. 500 ml of methylene chloride are added to the residue and it is extracted three times with 100 ml of water. The organic phase is dried and evaporated. The residue remaining is dissolved in 500 ml of methanol and 20 g (0.17 mol) of solid fumaric acid are added in batches at boiling temperature with stirring. When the mixture cools, colourless crystals are precipitated which are suction filtered and then washed with methanol and ether. Yield: 20-25 g (48-60% of theory), m.p. 209°-211° C.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=1>ClCCl>[Br:1][CH:2]([CH2:6][CH3:7])[C:3]([C:18]1[S:17][C:16]2[CH:20]=[CH:21][C:13]([Cl:12])=[CH:14][C:15]=2[CH:19]=1)=[O:4]
Reactant: CCC(Br)C(=O)Cl
Reactant: Clc1ccc2sccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(Br)C(=O)c1cc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromobutyryl chloride (8 g) in dichloromethane (15 ml) was added dropwise under nitrogen at ambient temperature to a stirred suspension of anhydrous aluminium chloride (12 g) in dichloromethane (100 ml). When the addition was complete, a solution of 5-chlorobenzo[b]thiophene (5 g; prepared in a manner similar to that described in J. Heterocyclic Chem., 1988, 25, 1271) in dichloromethane (30 ml) was added dropwise, then the mixture was stirred at ambient temperature for 1 hour and added to ice-cold water (500 ml). The mixture was stirred at ambient temperature for 30 minutes then the product was extracted into dichloromethane (100 ml). The extract was washed with water (2×30 ml) and saturated aqueous sodium chloride solution (2×30 ml), then it was dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by repeated (5-fold) flash chromatography over silica using a 19:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-bromo-1-(5-chlorobenzo[b]thiophen-2-yl)butan-1-one (1.04 g) as an off-white solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[C-:10]#[N:11].[K+]>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[N:11])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: [C-]#N
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C#N)nc(Cl)n1
Yield: 22.5 %

Procedure:
24.5 g of 2,4-dichloro-6-methylpyrimidine and 9.8 g of potassium cyanide were dissolved in 150 ml of CH3CN and refluxed for 8 days. The solvent was evaporated, the residue was dissolved in 150 ml of ethyl acetate and extracted twice with 50 ml H2O. The organic layer was dried over Na2SO4, the solvent was evaporated and the residue was purified on silica gel using a 4:1 mixture of benzene and methyl tert.butyl ether as eluent to give 5.2 g (24.8%) of 2-chloro-4-cyano-6-methyl pyrimidine of m.p. 57° C.
Reaction SMILES: [C:1](=[CH:3][C@@:4]12[C@@H:20]([C:21](=[O:23])[CH3:22])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C@:8]3([CH3:25])[C:13]([CH2:14][CH2:15]1)=[CH:12][C:11](=O)[CH2:10][CH2:9]3)[CH2:6][CH2:5]2)=[CH2:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CO>[N:26]1([C:11]2[CH2:10][CH2:9][C@@:8]3([CH3:25])[C:13](=[CH:14][CH2:15][C@@H:16]4[C@@H:7]3[CH2:6][CH2:5][C@@:4]3([CH:3]=[C:1]=[CH2:2])[C@H:17]4[CH2:18][CH2:19][C@@H:20]3[C:21](=[O:23])[CH3:22])[CH:12]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C=C=C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(C)=O
Reactant: C1CCNC1
Solvent: CO
Product: C=C=C[C@]12CC[C@H]3[C@@H](CC=C4C=C(N5CCCC5)CC[C@@]43C)[C@@H]1CC[C@@H]2C(C)=O

Procedure:
A solution is prepared from 3.3 g of 18-vinylidenepregn-4-ene-3,20-dione in the minimum amount of hot methanol and 700 mg of pyrrolidine is added to the hot solution. When the product begins to crystallize, the mixture is chilled rapidly in ice water. The mixture is diluted with methanol and the solid is separated by filtration and dried under high vacuum to give 3-(1-pyrrolidinyl)-18-vinylidenepregna-3,5-dien-20-one which is used in the next step without further purification.