Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][NH:18][C:17](=[O:21])[CH:16]1[CH2:22][CH2:23][S:24][CH3:25])=O)(C)(C)C>C(SCC)C>[CH3:25][S:24][CH2:23][CH2:22][CH:16]1[NH:15][CH2:20][CH2:19][NH:18][C:17]1=[O:21]
Reactant: CSCCC1C(=O)NCCN1C(=O)OC(C)(C)C
Solvent: CCSCC
Solvent: O=C(O)C(F)(F)F
Product: CSCCC1NCCNC1=O

Procedure:
Trifluoroacetic acid (30 ml.) is added at 0° to a stirred solution of 4-t-butoxycarbonyl-3-[2-(methylthio)ethyl]piperazinone (XVII, Example 43, 2.6 g., 0.0095 mole) in diethyl sulfide (20 ml.). After 1 hour the solvents are removed and the residual oil is partitioned between chloroform (300 ml.) and 5N sodium hydrochloride solution (10 ml.). The chloroform is washed with water (2×10 ml.) and the chloroform is removed under reduced pressure. The residual oil is chromatographed on silica gel eluted with methanol:chloroform (1:9), the appropriate fractions are pooled and concentrated to give a solid which upon recrystallization from ethyl acetate:SSB gives the title compound, m.p. 68°-70°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:11][C:8]2=[N:9][CH:10]=1)(=[O:4])=[O:3].[H-].[Na+].[CH:22]1([CH2:28]Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:22]1([CH2:28][N:11]2[C:8]3=[N:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]3[CH:13]=[C:12]2[C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1cnc2[nH]c(-c3ncccn3)cc2c1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncccn1)n2CC1CCCCC1
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a suspension of 5-methanesulfonyl-2-(2-pyrimidinyl)-1H-pyrrolo[2,3-b]pyridine (150 mg) in N,N-dimethylformamide (5.5 ml), 60% sodium hydride (32.8 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. Subsequently, to the mixture was added cyclohexylmethyl bromide (154 mg) at 0° C. and the mixture was stirred at 60° C. for 2 hours, followed by addition of cyclohexylmethyl bromide (77 mg) and stirring of the mixture at the same temperature for 1 hour. Further, to the mixture was added cyclohexylmethyl bromide (77 mg) and the mixture was stirred at 60° C. for 15 hours. Subsequently, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (methanol:chloroform=1:20) and further recrystallized (chloroform/hexane) to obtain 109 mg of the desired product as a white needle-like crystal.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH:21]([CH2:59][CH3:60])[CH2:22][O:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[C:35](=[O:36])[C:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][CH:39]=3)=[C:33]([CH2:52][CH2:53][CH3:54])[N:32]3[N:55]=[C:56]([CH3:58])[N:57]=[C:31]23)[CH2:26][CH2:25]1)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[OH:20][CH:21]([CH2:59][CH3:60])[CH2:22][O:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[C:35](=[O:36])[C:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]4[NH:51][C:4](=[O:7])[O:5][N:3]=4)=[CH:40][CH:39]=3)=[C:33]([CH2:52][CH2:53][CH3:54])[N:32]3[N:55]=[C:56]([CH3:58])[N:57]=[C:31]23)[CH2:26][CH2:25]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(CC)O[Si](C)(C)C(C)(C)C)CC2)c2nc(C)nn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)CC)CC2)c2nc(C)nn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.46 g), sodium hydrogen carbonate (0.74 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-({4-[trans-4-(2-{[tert-butyl(dimethyl)silyl]oxy}butoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.29 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water 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 dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.086) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.073 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 1.1 mL) was added, and the mixture was stirred at room temperature for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was solidified with diisopropyl ether to give the title compound as a colorless solid (0.12 g, 45%).
Reaction SMILES: CN[CH:3]([C:6]1C=C[CH:9]=[CH:8][C:7]=1C)[CH2:4]N.[CH2:13]([N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][N:17]=[C:16]1[NH:26][C:27]([O:29][CH3:30])=[O:28])C>>[CH3:13][N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][C:23]([CH2:4][CH2:3][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:22][CH:21]=2)[CH2:18][N:17]=[C:16]1[NH:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: CNC(CN)c1ccccc1C
Reactant: CCN1C(NC(=O)OC)=NCC1c1ccccc1
Product: CCCCCCc1ccc(C2CN=C(NC(=O)OC)N2C)cc1

Procedure:
Similarly, by following the same procedure of part A but respectively replacing the β-methylamino-β-(2-methylphenyl)-ethylamine with other β-alkylamino-β-phenylethylamino or β-alkylamino-(substituted phenyl)-ethylamino such as β-ethylamino-β-phenylethylamine β-isopropylamino-β-(substituted phenyl)-ethylamine, β-t-butylamino-β-(substituted phenyl)-ethylamine, β-isoamylamino-β-(substituted phenyl)-ethylamine, β-2'-t-butylethylamino-β-(substituted phenyl)-ethylamine, or β-n-hexylamino-β-(substituted phenyl)-ethylamine, the corresponding 1-alkyl-4,5-dihydro-5-(substituted phenyl)-2-methoxycarbonylaminoimidazole or 1-alkyl-4,5-dihydro-5-phenyl-2-methoxycarbonylaminoimidazoles such as 1-ethyl-4,5-dihydro-5-phenyl-2-methoxycarbonylaminoimidazole, m.p. 115°-116° C;
Reaction SMILES: C1CO[CH:20]2[CH:3]([CH2:4][C:5]34O[C@H:6]3[C:7](=[CH2:30])[C@@H:8]3[C@@H:17]([C@@:18]4([CH3:24])[C@@H:19]2[CH3:23])[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C@:11]3([F:29])OCC[O:25][CH:12]32)[O:2]1.[Mg].[CH3:33]I>C1C=CC=CC=1.C(OCC)C>[F:29][C@@H:11]1[CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]2([CH3:14])[C:12]1=[O:25])[C@:18]1([CH3:24])[C:5](=[CH:4][C:3](=[O:2])[CH2:20][C@H:19]1[CH3:23])[C@H:6]([CH3:33])[C:7]3=[CH2:30]
Reactant: C=C1[C@@H]2[C@H](CC[C@]3(C)C4OCCO[C@@]4(F)C[C@@H]23)[C@@]2(C)[C@H](C)C3OCCOC3CC23O[C@@H]13
Reactant: CI
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=C1[C@@H](C)C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Reaction time: 3 h
Yield: 80.5 %

Procedure:
3,17-bis(ethylenedioxy)-5,6α-epoxy-16α-fluoro-1β-methyl-7-methylenandrostane (431 mg) in benzene solution (40 ml), is added to a Grignard mixture prepared from magnesium (122 mg) and methyl iodide (710 mg) in diethylether (10 ml). Solvent is removed until the boiling point reaches ~78° C. Heating is then continued for a further 3 hrs. Ice and saturated ammonium chloride solution are added, the product extracted with ethyl acetate and the organic layer is evaporated in vacuo after having washed and dried it. The residue is dissolved in a 2:1 mixture of acetic acid and water (10 ml) and the solution heated for about 6 hrs at 40°-50° C. Then water is added and the product extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate solution, dried and evaporated in vacuo. The residue is submitted to column chromatography thus giving pure 16α-fluoro-1β,6β-dimethyl-7-methylenandrost-4-ene-3,17-dione (275 mg).
Reaction SMILES: [CH2:1]([CH:4]([CH2:12][CH2:13][CH3:14])[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6])[CH2:2][CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37].C(N(CC)CC)C>C(Cl)Cl>[NH3:7].[CH2:12]([CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([NH:7][CH2:8][C:9]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[O:11])=[O:6])[CH2:13][CH3:14]
Reactant: CCCC(CCC)C(=O)NCC(=O)O
Reactant: NCCCCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CCC)C(=O)NCC(=O)NCCCCCCN
Product: N
Reaction time: 0.5 h
Yield: 28 %
Yield: 129.7 %

Procedure:
To a suspension in which 2.01 g of N-(2-n-propyl-n-pentanoyl)glycine was supended in 30 ml of methylene chloride which was cooled in an ice-salt bath was added 2.06 g (10 mmole) of dicyclohexylcarbodiimide in the state of crystal as such, and the mixture was stirred for about 30 minutes while cooling. The suspension thus prepared was added to a solution in which 2.32 g (20 mmole) of hexamethylenediamine and 2.02 g (20 mmole) of triethylamine dissolved in 20 ml of methylene chloride. the mixture was stirred under cooling by ice-cold water for about 2 hours and then at room temperature for about 3 hours, and then allowed to stand overnight. Precipitated dicyclohexylurea was filtered off and the resulting filtrate having red-brownish color was washed with 50 ml of water three times. The methylene chloride solution thus obtained was dried over anhydrous sodium sulfate, and then condensed under reduced pressure to give red-brownish oily product. This material was purified by silica gel (Wako gel C-200, trade name, produced by Wako Jun-yaku Co.) column chromotagraphy using a developing solution comprising a mixed solvent of methanol: 28% aqueous ammonia=9:1 to give 1.94 g (Yield: 68%) of the title compound as red-brownish oily product.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].Br.Br[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:10]1)=[O:8]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: BrCc1cccnc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C2CN(Cc3cccnc3)c3ccccc3C2=O)cc1C
Yield: 25.3 %

Procedure:
Compound 4o was prepared following the procedure outlined in Step 3 of Example 1 using 32 mg (0.8 mmol) of sodium hydride (60%), 86 mg (0.31 mmol) of 3-(3,4-dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a, 3 mL of anhydrous dimethylformamide, and 101.2 mg (0.40 mmol) of 3-bromomethylpyridine hydrobromide. The crude product was purified by flash chromatography to yield 29 mg of pale yellow solid 4o: LC-MSD, m/z for C24H20N2O2, [M+H]+=369.4, [M+2H]+=370.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.436 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.30 (d, 6H), 5.4 (s, 2H), 7.17 (d, 1H), 7.26-7.32 (m, 2H), 7.40 (t, 1H), 7.52-7.64 (m, 3H), 8.27 (s, 1H), 8.46 (d, 1H), 8.58-8.64 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:13])[NH:9][CH2:10][CH2:11][OH:12])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:15][C:16]([CH2:18]Cl)=[CH2:17]>CN1CCCC1=O.O>[C:3]([O:7][C:8]([N:9]1[CH2:18][C:16](=[CH2:15])[CH2:17][O:12][CH2:11][CH2:10]1)=[O:13])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: C=C(CCl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=C1COCCN(C(=O)OC(C)(C)C)C1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (992.6 mg, 60% in mineral oil, 24.8 mmol) was added portionwise to a solution of (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (2 g, 12.4 mmol) in 1-methyl-2-pyrrolidinone (20 ml) at −2° C., in order to maintain the temperature below 5° C. The mixture was then stirred for 30 minutes, cooled to −5° C., and a solution of 3-chloro-2-chloromethyl-1-propene (1.44 ml, 12.4 mmol) in 1-methyl-2-pyrrolidinone (10 ml) added dropwise in order to maintain the temperature below 3° C. Once addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for a further 18 hours. The reaction mixture was diluted with water and extracted with ether (2×50 ml). The combined organic extracts were dried over magnesium sulphate and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using ethyl acetate:pentane (10:90) to give the title compound as a clear oil, 713 mg.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])C.[C:8]([O:11][CH2:12][CH:13]1[CH:17]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[O:16][CH2:15][O:14]1)(=[O:10])[CH3:9].[C:23](O)(=O)C>[Cl-].[Zn+2].[Cl-]>[C:5]([O:4][CH2:1][O:3][CH:13]([CH:17]([O:16][C:15](=[O:14])[CH3:23])[CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:12][O:11][C:8](=[O:10])[CH3:9])(=[O:7])[CH3:6]
Reactant: CC(=O)OCC1OCOC1COC(C)=O
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)OCOC(COC(C)=O)C(COC(C)=O)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
20 ml of acetic anhydride was added to 12.2 g of (4RS,5SR)-4,5-bis(acetoxymethyl)-1,3-dioxolane obtained in Example 20. The mixture was mixed to dissolution at room temperature. To this were added 0.7 g of anhydrous zinc chloride and 2 ml of glacial acetic acid. The mixture was stirred overnight at room temperature and extracted with 300 ml of ethyl acetate. The extract was neutralized with saturated aqueous solution of sodium hydrogen carbonate. After washing with water and drying over anhydrous sodium sulfate, the product was filtered and the solvent was evaporated to obtain 19.0 g (yield: 92.0%) of the title compound.
Reaction SMILES: [O:1]=[C:2]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[N:23][C:9]1=2)[CH:3]([CH3:7])[CH2:4][C:5]#[CH:6].C=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[C:33](O)(=O)/C=C\C(O)=O>O.[Cu]Cl.O1CCOCC1>[O:1]=[C:2]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[N:23][C:9]1=2)[CH:3]([CH3:7])[CH2:4][C:5]#[C:6][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: C#CCC(C)C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cl[Cu]
Agent: C=O
Solvent: O
Solvent: C1COCCO1
Product: CC(CC#CCN1CCN(C)CC1)C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A reaction mixture consisting of 36.6 g (0.12 mol) of 5,11-dihydro-11-[1-oxo-2-methyl-4-pentynyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 4 g (0.13 mol) of paraformaldehyde, 13.2 g (0.13 mol) of N-methylpiperazine, 0.2 g of copper(I) chloride and 600 ml of dioxan is refluxed for 2 hours. After the reaction has ended the mixture is filtered over activated charcoal to remove the insoluble components and the filtrate is evaporated to dryness in vacuo. In order to purify it, the crude product is suspended in a solution of 15.4 g (0.13 mol) of maleic acid in 600 ml of water and stirred for 1 hour at ambient temperature. The insoluble matter is filtered off, the filtrate is made alkaline by the addition of potassium carbonate and the resin precipitated is taken up in 600 ml of methylene chloride. After drying over magnesium sulphate, the solution is evaporated to dryness in vacuo. The crystalline residue is decocted with 150 ml of ethyl acetate and suction filtered after cooling. By digesting it in a little ethyl acetate a crystalline product is obtained which melts at 212° to 214° C. after washing with ether.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:18]([C:23]2[N:24]=[N:25][N:26]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=2)[CH:19]=[CH:20][CH:21]=[O:22])=[CH:13][CH:12]=1>O1CCCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:18]([C:23]2[N:24]=[N:25][N:26]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=2)[CH:19]=[CH:20][CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:13][CH:12]=1
Reactant: COCCOCn1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(COCCOC)n1
Reaction time: 1 h

Procedure:
Ethyl acetoacetate dianion (2.1 mL of freshly prepared 1M solution as described in Example 10) was added to a solution of 5,5-bis(4-fluorophenyl)-4-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2,4-pentadienal (0.9 g, 2.0 mmoles) in 15 mL of tetrahydrofuran at -50 ° C. After stirring for 1 hours, another 1 mL of dianion solution was added and the mixture stirred for an additional 30 minutes. The reaction mixture was quenched with 1N HCl and then extracted with methylene chloride. The organic extracts were dried (MgSo4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride to give 0.55 g of the title compound. MS (CI): m/e=557 for M+H)+ ;
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8](S(O)(=O)=O)=[CH:7][CH:6]=1.[C:16]1(C)[CH:21]=CC=C[CH:17]=1>>[CH2:5]([CH:15]1[O:4][CH2:1][CH2:2][O:3]1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:17][CH2:16][CH3:21]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1
Reactant: OCCO
Product: CCCCCCCCCC1OCCO1
Yield: 77.4 %

Procedure:
Following example I from 78.77 g of decylaldehyde (0.5 mole), 37.22 g (0.6 mole) of ethyleneglycol, 0.5 g of p-toluenesulfonic acid in 100 ml toluene there is obtained 78 g (77.4%) of a colorless product; b.p. 80°-81° C./0.5 mm. nD20 =1.4392.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C:13](=[O:33])[C@H:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:15][C:16](OCC1C=CC=CC=1)=[O:17])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:46][CH:47]([CH3:61])[CH2:48][CH2:49][C:50]([NH:52][C@H:53](C(O)=O)[CH2:54][C:55](=[O:57])[NH2:56])=[O:51]>[Pd]>[C:1]([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C:13](=[O:33])[C@H:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:15][C:16](=[O:17])[C@H:53]([CH2:54][C:55](=[O:57])[NH2:56])[NH:52][C:50](=[O:51])[CH2:49][CH2:48][CH:47]([CH3:46])[CH3:61])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)CCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)CN1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 27.8 %

Procedure:
0.71 g (1.52 mmol) of N-[[N-(benzyloxycarbonyl)-L-phenylalanyl]methyl]-L-proline tert.butyl ester was hydrogenated in the presence of 0.58 g (3.05 mmol) of toluene-4-sulphonic acid over 5% palladium-on-carbon and the product was coupled with 0.35 g (1.52 mmol) of N-(4-methylvaleryl)-L-asparagine in an analogous manner to that described in Example 1. The crude product was purified by chromatography on silica gel using isopropanol in ethyl acetate (5%-8% gradient) for the elution. There was obtained 0.23 g of N-[[N-[N-(4-methylvaleryl)-L-asparaginyl]-L-phenylalanyl]methyl]-L-proline tert.butyl ester as a solid; MS: m/e 545 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:12]#[N:13])=[N:9][C:10]=1[CH3:11]>C(O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:12](=[NH:13])[NH:2][NH2:3])=[N:9][C:10]=1[CH3:11]
Reactant: NN
Reactant: Cc1nc(C#N)ccc1Br
Solvent: CCO
Solvent: O
Product: Cc1nc(C(=N)NN)ccc1Br
Temperature: 50 °C
Yield: 89 %

Procedure:
Hydrazine monohydrate (2 equiv) was added to a stirring 1.2 M suspension of 5-bromo-6-methylpicolinonitrile (1 equiv) in ethanol under nitrogen. The reaction mixture was heated at 50° C. for 24 h. The reaction was cooled to room temperature and then filtered. The collected solid was washed with cold ethanol followed by cold t-butyl methyl ether. The washed solid was dried under vacuum to provide the title compound in 89% yield, as a yellow solid. MS (ESI) m/z 228.9 [M]+, 230.9 [M+2]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH2:24]Br)[C:18]([CH2:22]Br)=[C:19]([F:21])[CH:20]=1.O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[C:19]([F:21])[CH:20]=1)[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:24]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Fc1cc(Br)cc(CBr)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2Cc3cc(Br)cc(F)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
In 30 ml of N,N-dimethylformamide was suspended 1.30 g of sodium hydride (purity: 60%), and 15 ml of a N,N-dimethylformamide solution containing 2.80 g of p-toluenesulfonamide was added thereto at room temperature, after which the resulting mixture was stirred at the same temperature for 30 minutes and then at 60° C. for 1 hour. A solution of 5.70 g of 5-bromo-2,3-di(bromomethyl)fluorobenzene in 15 ml of N,N-dimethylformamide was added to the reaction mixture at 60° C. and the resulting mixture was stirred at the same temperature for 10 minutes. The reaction mixture was added to 200 ml of water and the precipitate was collected by filtration to obtain 2.40 g of 5-bromo-7-fluoro-2-(p-toluenesulfonyl)isoindoline as colorless crystals.