Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2)(=[O:23])=[O:22]
Reactant: OCc1ccc2ncccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Hydroxymethylquinoline (0.4325 g, 2.72 mmoles) (prepared by the method of: C. E. Kaslow and W. R. Clark, J. Org. Chem., 1953, 18, 55-58.) and triethylamine (1.5147 mL, 10.87 mmoles) were dissolved in anhydrous dichloromethane (16 mL) and the mixture was cooled to 0° C. Methanesulfonyl chloride (0.421 mL, 5.43 mmoles) was added and the mixture was stirred under argon at 0° C. for 1 h. Additional triethylamine (0.758 mL, 5.435 mmoles) and methanesulfonyl chloride (0.211 mL, 2.72 mmoles) were added and the reaction was allowed to proceed for a further 1 h at 0° C. The mixture was evaporated to dryness to give the title compound which was used without further purification in the next step.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[C:20]([CH3:26])[CH:19]=2)=[C:11]([CH:16]=1)[CH2:12][N:13]([CH3:15])[CH3:14].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[CH3:15][N:13]([CH2:12][C:11]1[CH:16]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=[CH:9][C:10]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[C:20]([CH3:26])[CH:19]=1)[CH3:14]
Reactant: CSc1ccc(Oc2ccc(N)cc2CN(C)C)cc1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CSc1ccc(Oc2ccc(NS(C)(=O)=O)cc2CN(C)C)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (371 μL, 4.79 mmol) was added to a solution of the aniline of Example 103 (725 mg, 2.4 mmol) and Et3N (1 mL, 7.17 mmol) in DCM (10 mL) at 0° C. After stirring at 0° C. for 1 h the reaction was allowed to warm to room temperature before the solvent was removed in vacuo. 2M NaOH (10 mL) was added to the residue and the mixture was stirred overnight. The resulting clear solution was neutralised by the addition of sat aq NH4Cl and extracted with DCM (2×30 mL). The combined organic layers were dried (MgSO4) and evaporated to give an oil. This was taken up in EtOAc (10 mL), the HCl salt was precipitated by the addition of 1M ethereal HCl and the product (669 mg, 67%) was collected by filtration; δH (d6-DMSO, 400 MHz) 2.23 (3H, s), 2.42 (3H, s), 2.75 (6H, s), 3.04 (3H, s), 4.38 (2H, s), 6.84 (1H, d), 6.93 (1H, d), 6.98 (1H, s), 7.17-7.25 (2H, m), 7.50 (1H, s); MS m/z (ES+) 381 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21]>CN(C=O)C>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH3:21])=[CH:8][N:9]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a 500 mL flask equipped with addition funnel at 0° C. was added NaH (8.26 g, 95%, 327 mmol), followed by slow addition of DMF (100 mL). The mixture was stirred for 10 minutes. The addition funnel was then charged with 6-methyl-pyridin-3-ol (30.2 g, 277 mmol) and DMF (100 mL), and the solution in addition funnel was added to the flask dropwise over 45 minutes. The reaction mixture was stirred at 0° C. for another 30 minutes once the addition was finished. To the addition funnel was then added 4-fluoro-3-methyl-nitrobenzene (39.1 g, 252 mmol) and DMF (100 mL) and the resulting solution was added to the flask dropwise over 45 minutes. The cold bath was removed at the end of the addition and the reaction mixture was allowed to stir at room temperature for 15 hours. The red dark solution was cooled to 0° C. and water (100 mL) was added cautiously to the reaction mixture. The resulting solution was stirred for 30 minutes and solid product was purified by filtration and washed with cold water (500 mL). The wet solid was dried in vacuo to give product (49.8 g, 81%).
Reaction SMILES: ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[CH3:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:18](=[O:30])[NH:17][C:16]=1[C:31]1[N:35]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=2)[N:34]=[CH:33][CH:32]=1.[CH2:44]([N:46]([CH2:49]C)CC)[CH3:45].C(N)C>C(Cl)Cl.C1COCC1>[C:40]([C:39]1[CH:38]=[CH:37][C:36]([N:35]2[C:31]([C:16]3[N:17]([C:49]([NH:46][CH2:44][CH3:45])=[O:3])[C:18](=[O:30])[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[C:15]=3[CH3:14])=[CH:32][CH:33]=[N:34]2)=[CH:43][CH:42]=1)#[N:41]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Agent: CCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)n1c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 2.75 h

Procedure:
4-Nitrophenyl chloroformate (226 mg, 1.12 mmol) was added portion wise to a solution of 4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (409 mg, 1.0 mmol) and triethylamine (0.355 mL, 2.55 mmol) in DCM (12 mL) under a nitrogen atmosphere. The mixture was stirred for 2.75 h giving a yellow solution. A solution of ethylamine (3.0 mL of a 2M solution in THF, 6 mmol) was added. The mixture was stirred for a further 2.5 h then concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10-40% EtOAc in DCM then recolumned on silica gel with 25-60% EtOAc in cyclohexane to afford the title compound as a colourless foam after drying in vacuo.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1.S(Cl)(Cl)=O.C(Cl)Cl>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[CH2:16][C:17](=[O:19])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH2:1][C:8]=2[CH:13]=1
Reactant: COc1ccc(CC(=O)O)c(Cc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc2c(c1)Cc1ccccc1C(=O)C2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-benzyl-4-methoxyphenylacetic acid (14.2 g, 0.055 m) in benzene (120 mL) and thionyl chloride (28 mL) was refluxed for 1 hour and concentrated. The acid chloride was dissolved in dry methylene chloride (40 mL), and the solution was added dropwise under argon to a solution of AlCl3 (14.7 g, 0.11 mol) in methylene chloride (600 mL). The reaction was stirred under an argon atmosphere for 2.5 hours at room temperature, then was quenched with ice-water (200 mL). The layers were separated, and the organic phase was washed sequentially with 10% NaOH solution, water, and dil. HCl. The resulting solution was diluted with ether (200 mL), dried over MgSO4, and concentrated. The solid residue was triturated with ether/hexane (1:1) and 9.35 g of the title compound was collected by filtration: Mp 105-106° C.; 1H NMR (400 MHz, CDCl3) δ3.72 (s, 3H), 4.1 (s, 2H), 4.2 (s, 2H), 6.7 (d, 1H), 6.82 (s, 1H), 7.30 (m, 4H), 8.1 (d, 1H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH2:48][CH2:49][CH3:50])[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH2:48][CH2:49][CH3:50])[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(CCC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CCC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.0 g), sodium hydrogen carbonate (1.5 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C. for 30 min, 4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-6-oxo-2-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.59 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 mL), N,N′-carbonyldiimidazole (0.37 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography and recrystallized from dichloromethane and diisopropyl ether to give the title compound (0.61 g, 92%) as a colorless solid.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].I[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]>C(OCC)C.O1CCCC1>[C:1]1([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:4][CH2:3][CH:2]=1
Reactant: COC(=O)CCI
Reactant: c1cc[cH-]c1
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCC1=CC=CC1
Product: COC(=O)CCC1=CCC=C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
The above compounds were prepared using a modified literature method (16). A 2.0 M solution of sodium cyclopentadienide in tetrahydrofuran (105.10 mL, 210.28 mmol) was added dropwise over 15 minutes to a stirred solution of methyl 3-iodopropionate (45.00 g, 210.28 mmol) in anhydrous diethyl ether (280 mL) and anhydrous tetrahydrofuran (200 mL) under nitrogen at −78° C. The resulting reaction mixture was stirred at −78° C. for 2 hours and then stored at −20° C. for a further 15 hours. The resulting red suspension was quenched with 1 M ammonium chloride solution (800 mL), and the organic phase was extracted with diethyl ether (5×400 mL). The combined organic layer was washed with 1 M ammonium chloride solution (2×500 mL) and dried (anhydrous sodium sulfate), filtered and concentrated in vacuo. The crude oil was purified by flash chromatography on silica using 5% ethyl acetate in iso-hexane to afford methyl 3-cylopenta-1,3-dienylpropionate (1-alkylCp) and methyl 3-cylopenta-1,4-dienylpropionate (2-alkylCp) (14.72 g, 96.72 mmol, 46%) as yellow liquids in a 1.2:1 ratio.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.O[CH2:25][C:26]1[C:27]([CH3:37])=[N+:28]([O-:36])[C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:25][C:26]4[C:27]([CH3:37])=[N+:28]([O-:36])[C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(CO)ccc(C(F)(F)F)[n+]1[O-]
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)ccc(C(F)(F)F)[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a suspension of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (64 mg, 0.2 mmol), 3-(hydroxymethyl)-2-methyl-6-(trifluoromethyl)pyridine 1-oxide (41 mg, 0.2 mmol) and Ph3P (105 mg, 0.4 mmol) in anhydrous THF (3 mL) at room temperature was added dropwise a 40% solution of DEAD in toluene (0.091 mL, 0.4 mmol). The resulting clear, yellowish solution was then stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, then saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of ethyl acetate (40-100%) in hexanes to afford 70 mg (69%) of the title compound as a light yellow foam. A portion of the product (10 mg) was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 40% to 80% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 7.2 mg of the title compound as a light yellow powder. HPLC/MS: retention time=2.33 min, [M+H]+=512.0.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[O:7]1[CH2:8][CH2:9][O:10][C:11]2[C:2]([CH:24]([NH:23][S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: Brc1cccc2c1OCCO2
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1cccc2c1OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of commercially available 5-bromo-2,3-dihydrobenzo[b][1,4]dioxine (500 mg; 2.32 mmol) in anh. THF (5 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes. The resulting solution was further stirred at −78° C. for 10 min. A solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (542 mg; 2.32 mmol) in anh. THF (2 ml) was added to the cooled reaction mixture, and stirring at −78° C. was continued for 10 min., and then at −20° C. for 2 h. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (15 ml), Et2O (30 ml) and water (15 ml). The separated organic layer was then washed with brine (15 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded methyl 5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-(1,1-dimethylethylsulfinamido)-pentanoate as a yellow oil. LC-MS (conditions A): tR=0.73 min.; [M+H]+: 369.73 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][CH2:35][OH:36]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH2:33][CH2:34][CH2:35][OH:36])=[CH:14][C:13]=1[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: CCc1ccc(Oc2ccc(N)cc2F)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2ccc(NCCCO)cc2F)c(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 68.3 %

Procedure:
4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline (500 mg, 1.48 mmol), K2CO3 (1.23 g, 8.9 mmol) and 3-bromo-1-propanol (410 mg, 2.9 mmol) were taken in dry DMF (2 ml) in a microwave vial and was subjected to microwave at 180° C. for 2 h. The reaction mixture was filtered over celite and the residue washed thouroughly with ethyl acetate. The combined organic fractions including the filtrate were washed with water, brine, dried over Na2SO4 and concentrated. The crude obtained was combined with earlier crude products obtained from a 100 mg and 200 mg batches and purified together by column chromatography over silica gel using 40% ethylacetate in pet ether as eluant to get 400 mg (42.6%) of pure title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[C:5]#[N:6].[Cl-].[Na+].O.[C:15](Cl)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:15]([O:10][C:9]1[C:2]([Br:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[Br:11])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC(=O)Cl
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)Oc1c(Br)cc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
A mixture of 3,5-dibromo-4-hydroxybenzonitrile (27.69 g) sodium hydroxide (4.08 g), sodium chloride (43.4 g) and water (125 ml) was stirred at room temperature for 15 minutes. Toluene (30 ml) and benzyltributyl ammonium chloride (1.57 g) was added, and a solution of octanoyl chloride (17.06 g) in toluene (30 ml) was slowly added to the stirred mixture over a half an hour while the temperature was maintained at 20° C. After addition was completed, the mixture was stirred for 1 hour and the phases allowed to separate. After removing the aqueous phase, the organic phase was washed with water, then with 5% aqueous Na2O3 and again with water. The solution was dried over Na2O3 and evaporated to dryness, yielding 2,6-dibromo-4-cyanophenyl octanoate (40.08 g, 99.5%) as a brown crystalline solid.
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH:30]1([CH2:36][CH2:37]C=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:36][CH2:37][C:21]2[C:20]3[C:19]([F:22])=[CH:18][C:17]([F:23])=[CH:16][C:15]=3[N:14]=[C:13]3[C:24]4[N:10]([CH2:11][C:12]=23)[C:9](=[O:27])[C:8]2[CH2:7][O:6][C:5](=[O:28])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:29])[C:26]=2[CH:25]=4)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=CCCC1CCCCC1
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)cc(F)c1c2CCC1CCCCC1

Procedure:
The product of Example 100 is treated with 3-cyclohexylpropanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:6]=2[N:7]=1>C1CCCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][C:16]3[C:15](=[CH:4][CH:5]=[CH:6][CH:8]=3)[CH2:14]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCCCC2)c2ncnc(Cl)c2n1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1nc(N2CCc3ccccc3C2)c2ncnc(Cl)c2n1

Procedure:
2,8-dichloro-4-piperidino-pyrimido [5,4-d]-pyrimidine Rf value: 0.66 (silica gel; cyclohexane/ethyl acetate=2:1)
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:52]1(=[O:58])[NH:56][C:55](=[O:57])[CH:54]=[CH:53]1>C1COCC1.CN(C1C=CN=CC=1)C.CCOCC>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:56]3[C:52](=[O:58])[CH:53]=[CH:54][C:55]3=[O:57])=[O:17])=[CH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1C=CC(=O)N1
Reactant: O=C(O)c1ccc(C(OCCCc2ccccc2)(c2ccccc2)c2cccc(OCCO)c2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1C=CC(=O)N1C(=O)c1ccc(C(OCCCc2ccccc2)(c2ccccc2)c2cccc(OCCO)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of trityl acid 8 (280 mg, 0.42 mM) in dry THF (6 mL) was added dicyclohexyl carbodiimide (DDC, 400 mg, 1.95 mM). The reaction mixture was stirred for 30 min at r.t., and maleimide (100 mg, 1.1 mM) and a catalytic amount of DMAP was added and allowed to stir for overnight. The solvent was removed under rotaevaporator and the solid obtained was dissolved in dry ether. The precipitated DCU was filtered and the solvent ether was evaporated. Part of the product was purified by preparative TLC. Yield: 12 mg. 1H-NMR (500 MHz, CDCl3) δ ppm: 1.78 (m, 2H), 1.95 (m 2H), 2.9 (s, 4H), 3.51 (m, 2H), 3.93 (t, 2H), 4.02 (t, 2H), 6.8 (m, 5H), 7.25 (m, 5H), 7.29 (m, 5H), 7.37 (m, 3H), 7.48 (d, 2H), Mass: 561.3 (M+).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C[O:13][B:14](OC)[O:15]C>O1CCCC1.CCOCC>[CH2:5]([C:6]1[CH:11]=[CH:10][C:9]([B:14]([OH:15])[OH:13])=[CH:8][CH:7]=1)[CH2:4][CH3:3]
Reactant: BrCCCc1ccccc1
Reactant: COB(OC)OC
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium shavings (217 mg, 8.9 mmol) in 3 mL of dry tetrahydrofuran under argon, a crystal along with a solution of 4-bromopropylbenzene (1.69 g, 8.5 mmol) dissolved in 6 mL of tetrahydrofuran was added at such a rate that a gentle reflux was maintained. The solution was refluxed for an additional 0.5 h, cooled to room temperature and added in portions over 10 minutes to a solution of trimethylborate (924 mg, 8.9 mmol) previously dissolved in 4 mL of dry ether at -78° C. After 30 minutes, the solution was warmed to room temperature where stirring continued for 90 minutes, then the reaction was quenched by the addition of 2 mL of a 10% hydrochloric acid solution. The tetrahydrofuran was removed under reduced pressure and the remaining residue was extracted into diethyl ether (3×25 mL). The combined ether extracts was extracted with 1M NaOH (3×25 mL) and the resulting aqueous layer was acidified to pH 2.0 using 6N HCl, then reextracted back into diethyl ether (3×25 mL). The combined organic layers was washed with water (1×25 mL), brine (1×25 mL) and dried over magnesium sulfate. Evaporation of solvent left a brown solid which was filtered through a small plug of silica gel using 11.0 MeOH/CACl3. Evaporation left 448 mg (32%) of a brown solid, m.p. 90°-93° C.