Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][C:10]([O-])(C)[CH3:11].[K+].C([O-])([O-])=O.[K+].[K+].IC(C)C>COCCOC.O>[I:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:10]([CH3:11])[CH3:9])[CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: Oc1ccc(I)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CC(C)I
Product: CC(C)n1cc(I)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a stirred solution 5-iodopyridin-2-ol (0.4 g, 1.80 mmol) in DME (10 mL) was added t-BuOK (0.604 g, 5.4 mmol). The mixture was stirred for 30 min at rt, K2CO3 (0.621 g, 4.5 mmol) and 2-iodopropane (0.35 mL, 3.6 mmol) were added, and the reaction was heated at reflux for about 3 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane as eluent to afford 5-iodo-1-isopropylpyridin-2(1H)-one as an off-white solid (0.41 g, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.90 (s, 1H), 7.49 (dd, 1H), 6.21 (d, 1H), 4.94 (t, 1H), 1.25 (t, 6H), LC-MS m/z calcd for [M+H]+ 263.98. found 264.0.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([CH3:18])([CH3:17])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)=[O:6].Cl>C(O)(C)C>[CH3:3][C:4]([CH3:17])([CH3:18])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=1)[OH:6]
Reactant: CC(C)Cc1ccc(C(=O)C(C)(C)C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Cc1ccc(C(O)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Sodium borohydride (4.72 g) was added to a solution of 2,2-dimethyl-4'-isobutylpropiophenone (22.7 g) in isopropyl alcohol (150 ml), The mixture was stirred at 50° C. for 2 hours and poured into ice water. After acidified with 6N-hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated to give 2,2-dimethyl-l-(4-isobutylphenyl)propanol as a colourless oil (21.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:28][CH2:27][C:23]2([CH2:26][NH:25][CH2:24]2)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:25]3[CH2:26][C:23]4([CH2:27][CH2:28][N:20]([CH3:19])[CH2:21][CH2:22]4)[CH2:24]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC2(CC1)CNC2
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (72 mg, 0.254 mmol) in DCE (7 mL) was added 7-methyl-2,7-diaza-spiro[3.5]nonane (45 mg, 0.321 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (81 mg, 0.382 mmol) was added and stirring was continued for 3 h. To the reaction mixture was added water and the resulting solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted with 2 M NH3 in MeOH an concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow oil (31 mg, 30%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](=O)[O:11][C:12](=[O:14])[CH:13]=2)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(CC#[N:28])=CC=1.O.C(O)(=O)C=O.C(=O)([O-])[O-].[K+:41].[K+]>CO>[K+:41].[C:10]([C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=1)=[CH:13][C:12]([O-:11])=[O:14])#[N:28]
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: O=C1C=C(c2ccc(C(F)(F)F)cc2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: O=CC(=O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CC(=CC(=O)[O-])c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(4-Trifluoromethyl-phenyl)-furan-2,5-dione. A mixture of 4-(trifluoromethyl)phenylacetonitrile (9.26 g, 50 mmol), glyoxylic acid monohydrate (6.9 g, 75 mmol), and potassium carbonate (17 g, 125 mmol) in methanol (100 mL) was stirred at room temperature for 3-5 h. The resulting thick solid precipitate was filtered and washed with dichloromethane. This solid was suspended in 250 mL of water, stirred overnight, and filtered and air-dried to provide 3-cyano-3-(4-trifluoromethyl-phenyl)-acrylic acid potassium salt. This was dissolved in 88% formic acid (ca. 200 mL) containing concentrated sulfuric acid (15 mL). This mixture was heated at reflux for 2-3 h and cooled and poured into ice water. The resulting precipitate was collected by filtration, washed with water, and air dried to provide the title compound. 1H NMR (DMSO-d6) δ 7.94 (s, 1H), 7.97 (d, J=8.2 Hz, 2H), 8.24 (d, J=8.2 Hz, 2H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=1)=O.O=P(Cl)(Cl)Cl>C1COCC1>[N+:3]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])=[CH:6][CH:5]=1)#[C-:1]
Reactant: CC(C)(C)OC(=O)c1ccc(NC=O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: [C-]#[N+]c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 64.6 %

Procedure:
To Intermediate 1A in THF (300 mL) was added TEA (33 mL, 238 mmol) and, after cooling to 0° C., POCl3 (7.3 mL, 79 mmol) was slowly added and the reaction was stirred at room temperature. After 24 h, the reaction was partitioned between EtOAc (200 mL) and aqueous NaHCO3 (100 mL). The aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL) and dried (MgSO4). Purification by normal phase chromatography afforded 10.4 g (64.6%) of Intermediate 1 as a green solid. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.59 Hz, 2H), 7.41 (d, J=8.34 Hz, 2H), 1.60 (s, 9H) ppm.
Reaction SMILES: OO[S:3]([O-:5])=[O:4].[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[CH3:15][CH:16]([N:18]1[CH2:23][C:22]2[CH:24]=[C:25](SC)[CH:26]=[CH:27][C:21]=2[NH:20][S:19]1(=[O:31])=[O:30])[CH3:17].[C:32](OCC)(=O)C>O.CC(C)=O.O>[CH3:15][CH:16]([N:18]1[CH2:23][C:22]2[CH:24]=[C:25]([S:3]([CH3:32])(=[O:5])=[O:4])[CH:26]=[CH:27][C:21]=2[NH:20][S:19]1(=[O:31])=[O:30])[CH3:17]
Reactant: CSc1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2
Reactant: CCOC(C)=O
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)N1Cc2cc(S(C)(=O)=O)ccc2NS1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of OXONE® (potassium peroxymonosulfate) (5.65 g, 0.0092 mol) in water was added to a solution of 3,4-dihydro-3-(1-methylethyl)-6-(methylthio)-1H-2,1,3-benzothiadiazine-2,2-dioxide (1 g, 0.0037 mol) in acetone/water (25 ml/2.5 ml) stirring at room temperature. After 30 mins, water (25 ml) and ethyl acetate (50 ml) were added to the mixture. The two layers were separated and the organic layer was then dried (MgSO4) and concentrated in vacuo to afford 3,4-dihydro-3-(1-methylethyl)-6-(methylsulfonyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide as a pale yellow solid. δ(1H NMR, CDCl3, 300 MHz, ppm): 1.0 (3H, d), 2.9 (3H, s), 4.1 (1H, m), 4.6 (2H, s), 6.8 (1H, d), 7.6 (2H, m), 9.9 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1(C2OC3C=CC=CC=3C=2)[CH2:10][CH:9]1CO)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[CH:28]=1.C(OC(C1([Li])CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([C:8]1([CH2:23][C:24]2[O:25][C:26]3[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=3[CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)C1(c2cc3ccccc3o2)CC1CO
Agent: [Li]C1(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)C1(Cc2cc3ccccc3o2)CC1

Procedure:
An appropriately substituted bromobenzofuran is converted to the corresponding aldehyde as described supra. This aldehyde is then reacted with 1-tert-butoxycarbonylcyclopropyllithium essentially as described by Haener et al. (Helvetica Chimica Acta, 69, 1655–65 (1986)) to provide the corresponding 1-tert-butoxycarbonyl-1-(benzofuryl)hydroxymethylcyclopropane. The alcohol is reduced to methylene by treating the corresponding acetate with samarium(II) iodide as described supra. The resulting tertbutyl ester is subjected to standard Curtius rearrangement conditions to provide the corresponding N-tert-butoxycarbonyl 1-amino-1-(benzofuryl)methylcyclopropane. This compound is deprotected by treatment with acid to provide the compounds of the present invention. If necessary or desired, the starting aldehyde may be reduced to the corresponding alcohol and then converted to the corresponding bromomethylbenzofuran. This reagent is then reacted with 1-tert-butoxycarbonylcyclopropyllithium essentially as described by Haener, to provide 1-tert-butoxycarbonyl-1-(benzofuryl)methylcyclopropane which is then subjected to the Curtius rearrangement/deprotection sequence described supra to provide the compounds of the present invention.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25](C=O)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:31].Cl.[C:36]1([S:42]([CH2:45][CH2:46][NH2:47])(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[CH3:48]CN(CC)CC.[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4([CH2:48][NH:47][CH2:46][CH2:45][S:42]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)(=[O:43])=[O:44])[CH2:23][CH:24]=[CH:25][O:26]4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:31]
Reactant: CCN(CC)CC
Reactant: NCCS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(CCNCC1(c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)CC=CO1)c1ccccc1

Procedure:
The title compound and its hydrochloride salt are prepared according to Procedure D utilizing 5-{4-[4-(3-fluoro-benzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furaldehyde (0.317 mmol, 0.15 g), Phenylsulfonylethyl amine hydrochloride salt (0.475 mmol, 0.105 g) in the presence of Et3N (0.51 mmol, 0.067 mL) and NaBH4 (0.79 mmol, 0.029 g) in THF/MeOH. 1H NMR (DMSO-d6) 11.76 (bs, 1H); 9.82 (bs, 2H); 9.59 (s, 1H); 8.91 (s, 1H); 8.37 (d, 1H); 8.04 (m, 1H); 7.98-7.89 (m, 3H); 7.78 (m, 2H); 7.67 (m, 2H); 7.48 (m, 1H); 7.37-7.27 (m, 4H); 7.19 (m, 1H); 6.78 (m, 1H); 5.31 (s, 2H); 4.41 (s, 2H); 3.89 (m, 2H); 3.27 (m, 2H). Electrospray MS 643.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=O)=[CH:6][CH:5]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20]C#N)[CH:17]=[CH:18][CH:19]=1.O>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:9]=1)=[C:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=1)[O:12][N:10]=2
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: N#CCc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
Sodium hydroxide (0.62 mol) was dissolved in methanol (100 ml) and the mixture was cooled till room temperature. 1-Bromo-4-nitro-benzene (0.124 mol), followed by 3-chloro-benzeneacetonitrile (0.223 mol) was added dropwise, the temperature rose till 50° C. and the mixture was stirred at room temperature for one night. The mixture was poured into water and ice, the precipitate was filtered off, washed with water and extracted with DCM and methanol. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The residue was taken up in diethylether, filtered off and dried, yielding 13.2 g (34.8%) of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole, mp. 163° C. (intermediate 1).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])[C:4]([C:12]#[N:13])=[C:5]([C:10]#[N:11])[C:6](=[O:9])[C:7]=1[Cl:8]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[C:5]([C:10]#[N:11])=[C:4]([C:12]#[N:13])[C:3]=1[OH:14]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: N#Cc1c(O)c(Cl)c(Cl)c(O)c1C#N
Temperature: 0 °C

Procedure:
By way of general guidance, a toluene solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is added to a toluene solution of a compound of formula (III-i) while maintaining a reaction temperature of about 0° C. to about 10° C. after which the reaction temperature is maintained at about 0° C. for about 1 hour to form a toluene slurry of 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene and a compound of formula (IV-i). The slurry is filtered to remove the 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene; the resulting waste cake of the 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene is washed with toluene. The filtrate and toluene washings are combined and concentrated in vacuo with addition of methanol to remove most of the toluene and produce the compound of formula (IV-i) in methanol at a temperature of about 40° C. to about 45° C. To this solution an aqueous solution of sodium hydroxide is added dropwise to form a clear solution of the amino alcohol (V-i) and p-methoxy-benzaldehyde upon which a solution of NaBH4 in an aqueous solution of sodium hydroxide is added dropwise, all the time maintaining a reaction temperature of about 40° C. to about 45° C. Upon addition of the solution of NaBH4 in an aqueous solution of sodium hydroxide, the reaction solution is stirred for about 30 minutes after which glacial acetic acid is added to neutralize the reaction to a pH of about 8 to about 9. Upon neutralization water is added to form a slurry and the slurry is cooled to about -15° C. to about 0° C. for about 1 hour. The cooled slurry of the amino alcohol (V-i) is filtered and washed with water to give the crude crystalline amino alcohol (V-i) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][NH:22][CH2:23][CH3:24])[CH:8]=[CH:9][CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][C:12]=2[CH2:21][N:22]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH3:24])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)OC)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:24])[CH2:14][CH:15]([C:20]([F:23])([F:22])[F:21])[CH2:16][C:17](O)=[O:18])=[C:4]([F:25])[CH:3]=1.[Na].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:24])[CH2:14][CH:15]([C:20]([F:22])([F:21])[F:23])[CH2:16][CH2:17][OH:18])=[C:4]([F:25])[CH:3]=1
Reactant: CC(C)Oc1cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(F)cc1Cl
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(NC(=O)CC(CCO)C(F)(F)F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 150 h
Yield: 39.2 %

Procedure:
To a solution of N-(4'-chloro-2'-fluoro-5'-isopropyloxy-phenyl)-3-(trifluoromethyl)glutaramic acid (4.32 g, 11.4 mmol) in 20 ml of tetrahydrofuran, (freshly distilled from sodium/benzophenone) was slowly added 10M borane-methyl sulfide complex (1.18 ml) via syringe. The temperature was maintained at 10°-20° C. with an ice bath while vigorous bubbling was evident. The mixture was allowed to warm slowly to room temperature and stirred 150 hrs while kept under nitrogen, heated to 55° C. for 6 hours, then cooled to room temperature and allowed to stand for 16 hours. The flask was cooled in an ice/water bath, then 7 ml of methanol (MeOH) were added slowly via addition funnel. The reaction mixture became too thick to continue stirring. It was allowed to warm slowly to room temperature, when the stir bar was again able to stir the mixture. The MeOH and THF were removed in vacuo (20-50 Torr) and the residue was flash chromatographed (2"×7" column, 3:1 hexanes/ethyl acetate, 75 ml fractions). Fractions 18-45 were combined and the solvent was removed in vacuo. The residue was dried in vacuo at 50° C. to yield 1.66 g (39% yield) of the pentanamide as a nearly colorless oil.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:34][Cl:35]>O>[ClH:35].[ClH:35].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:34][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:2][CH2:3]1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: COc1ccc(CCl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1OC
Product: Cl
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a mixture of 1.2 g of 5-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.17 g of potassium carbonate and 20 ml of DMF was added 858 mg of 3,4-dimethoxybenzyl chloride and the mixture was stirred at 70°-80° C. for 2 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography. The residue was converted to hydrochloric acid salt to give 610 mg of 5-[4-(3,4-dimethoxybenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril dihydrochloride, m.p. 270°-272.5° C. (decomp.).
Reaction SMILES: C([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=O)=[CH:17][CH:16]=2)[N:10]=1)CCCCCCC.[CH2:24](Cl)[CH2:25]Cl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:22]([C:14]1[CH:13]=[N:12][C:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:21])=[CH:22][CH:23]=2)=[N:10][CH:9]=1)[CH2:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:24][CH3:25]
Reactant: CCCCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1
Reactant: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCCCCCCc1cnc(-c2ccc(C#N)cc2)nc1

Procedure:
1.84 G. of 4-(4-n-octylpyrimid-2-yl)-benzoic acid amide are maintained at reflux for 80 minutes in a mixture of 40 ml. of ethylene chloride and 0.63 ml. of phosphorus oxychloride with stirring. The mixture, diluted with ether, is washed with 2-N sodium hydroxide and then with water until neutral. The organic phase is dried over sodium sulfate and evaporated to give 1.91 g. of 5-octyl-2-(4-cyanophenyl)-pyrimidine which are distilled in a high vacuum; melting point 66.1°-66.5° C; clearing point 47.5° C.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][C:19]=1[Cl:29].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([Cl:29])[CH:20]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)c(Cl)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (32.50 g, 0.135 mol) in CH2Cl2 (70 mL) was added drop wise, over a 30 minutes period, to a stirred solution of 1,2-dichloro-4-((E)-2-nitro-vinyl)-benzene (19.60 g, 0.09 mol) and trifluoroacetic acid (1.54 mL, 0.013 mol) in CH2Cl2 (160 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:6) afforded 25.0 g (79%) of the title compound as a yellow oil. ES-MS m/e: 351.0 (M+H+).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([P:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH3:11]>CC(C)=O>[CH2:17]([P:12]([CH2:8][CH2:9][CH2:10][CH3:11])([CH2:13][CH2:14][CH2:15][CH3:16])=[C:2]1[CH2:3][C:4](=[O:5])[O:6][C:1]1=[O:7])[CH2:18][CH2:19][CH3:20]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCP(CCCC)CCCC
Solvent: CC(C)=O
Product: CCCCP(CCCC)(CCCC)=C1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
Maleic anhydride (9.81 g; 0.1 mole) in 25 ml acetone and tri-n-butylphosphine (20.23 g; 0.1 mole) in acetone were blended at 0°-5° C. under a blanket of dry nitrogen. The resulting red solution was stirred for 1 hour at room temperature and then placed under vacuum to remove the bulk of the acetone solvent. The resulting red viscous liquid gave 15 g of yellow-brown crystalline product. This solid was separated by filtration and washed with cold acetone giving a yellow crystalline product which melts at 70° C., resolidifies and melts again at 85° C. with gassing. The infrared (IR) and nuclear magnetic resonance (NMR) spectra and elemental analysis of the product were consistent with a compound represented by the structure ##STR7##
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Li+].[Cl-].C[CH2:15][O:16]C(C)=O>FC(F)(F)C(O)=O.CO.Cl[Pd]Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]2[C:15](=[O:16])[O:10][CH2:9][C:4]=2[C:3]=1[CH3:11]
Reactant: Cc1cc(Br)c(C)c(CO)c1
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(Br)c(C)c2c1C(=O)OC2
Reaction time: 8 h

Procedure:
To a solution of (3-bromo-2,5-dimethylphenyl)methanol (1.6 g, 7.4 mmol) in trifluoroacetic acid (20 mL) was added Tl(OOCF3)3 (4 g, 7.4 mmol) at r.t, then the reaction was stirred at r.t overnight under N2. The mixture was concentrated under pressure. The residue solids, LiCl (0.6 g, 14.9 mmol), MgO (0.6 g, 14.9 mmol) and PdCl2 (0.13 g, 0.74 mmol) in MeOH were stirred under CO at 1 Mpa over night. EtOAc was added to the mixture and filtered. The organic phase was concentrated to afford 5-bromo-4,7-dimethyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=O)[CH2:9][CH2:8]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[N:14]1([C:10]2[CH2:9][CH2:8][C:7]3[C:12]([CH:11]=2)=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc2c1CC(=O)CC2
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: COc1cccc2c1C=C(N1CCCC1)CC2

Procedure:
To 75 mL of toluene were added 3.52 gm (20 mMol) of 8-methoxy-2-tetralone followed by 2.5 gm of pyrrolidine. The mixture was heated to reflux for 3 hours after which the solvent was evaporated in vacuo to give 3-pyrrolidino-5-methoxy-1,2-dihydronaphthalene as a dark oil.