Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]1[O:34][C:33]2[CH:32]=[CH:31][C:16]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([S:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][C:14]=2[O:13]1>C(Cl)(Cl)Cl>[CH2:12]1[O:34][C:33]2[CH:32]=[CH:31][C:16]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:30])=[O:9])[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][C:14]=2[O:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 80 %

Procedure:
A solution of 1.20 g (6.95 mmol) of m-chloroperbenzoic acid in 30 ml of chloroform was dropped into a solution of 1.80 g (5.53 mmol) of 4-(3,4-methylenedioxybenzyl)amino-6-methylthioquinazoline in 100 ml of chloroform under cooling with ice and stirring. The obtained mixture was stirred under cooling with ice for several hours, washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and filtered. The filtrate was purified by silica gel column chromatography (ethyl acetate/acetone) and recrystallized from chloroform/n-hexane to give 1.51 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:27])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24](O)=[O:25])[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:27])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[O:25])[N:22]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(C(=O)C2CCCC2)c1
Reactant: CN1CCNCC1
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)N3CCN(C)CC3)cs2)c(C(=O)C2CCCC2)c1

Procedure:
4-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazol-4-yl}-acetyl)-1-methyl-piperazine (337 mg) is prepared from 2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)ureido]-thiazol-4-ylacetic acid (386 mg, 1.0 mmol) and N-methylpiperazine following the general procedure K.
Reaction SMILES: [Si:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[NH:20][C:19]2[C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:35][CH3:36]>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[N:20]([CH2:35][CH3:36])[C:19]2[C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC/C=C/c1cc2ncnc(Oc3ccccc3)c2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(/C=C/CO[Si](C)(C)C(C)(C)C)cc2ncnc(Oc3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-((1E)-3-{[tert-Butyl(dimethyl)silyl]oxy}-1-propenyl)-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (100 mg) was dissolved in N,N-dimethylformamide (0.786 mL), cesium carbonate (102.6 mg) was added, and the mixture was stirred at room temperature for 20 min. Iodoethane (0.0231 mL) was added and the mixture was stirred at room temperature for 2 hrs and at 40° C. for 4 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with water (30 mL) and saturated brine (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→50:50) to give the title compound (79 mg) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[CH:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:32][CH2:31]2)=[O:24])=[N:19][CH:20]=1)=[O:14])(C)(C)C>ClCCl>[C:13]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[CH:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][N:33]([CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:34][CH2:35]2)=[O:24])=[N:19][CH:20]=1)([OH:14])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(C=CC(=O)NCCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C=Cc1ccc(C(=O)O)cn1)NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (6 ml) is cooled to 5° C., and a solution of 0.8 g of N-[3-(5-t-butoxycarbonyl-2-pyridyl)acryloyl]-4-(4-diphenylmethyl-1-piperazinyl)butylamine (the free base of the product of Example 24) in 3 ml of dichloromethane is slowly added below 20° C. The mixture is stirred at room temperature overnight and concentrated. The residue is dissolved in 10 ml of water and washed with diethyl ether. The aqueous solution is adjusted to pH 5 with aqueous ammonium hydroxide and extracted with three 40-ml portions of ethyl acetate. The combined extracts are dried over magnesium sulfate and the solvent is distilled off. The residue is chromatographed on silica gel with chloroform-methanol (10:1) to give the title compound. m.p. 214°-216° C. (recrystallized from methanol)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1ccccc1C(F)(F)F
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Yield: 70 %

Procedure:
Upon boiling a solution of 8.7 g 2-trifluoromethylbenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml of ethanol for two hours, 2,6-diamino-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 191° C (ethanol) is obtained.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]([Cl:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[C:22]([Cl:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Cl
Product: Cc1sc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c2c1Cl

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4,5-trichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2,5-dichloro-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:30].Cl>CO.Cl>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:30]
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: Cl
Solvent: CO
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Temperature: 25 °C
Reaction time: 26 h
Yield: 45.4 %

Procedure:
To a stirred solution of tert-butyl 4-({[(5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridin-8-yl)carbonyl]amino}methyl)piperidine-1-carboxylate (EXAMPLE 3, Step 3, 13.71 g, 31.44 mmol) in 10% hydrochloric acid methanol solution (314 mL) was added concentrated hydrochloric acid (10 mL). After stirring at room temperature for 26 h, the mixture was concentrated to about 50 mL in vacuo. The residue was basified with an excess of sodium carbonate and then insoluble material was filtered off. The filtrate was concentrated azeotropically with ethanol and diluted with a mixture of dichloromethane and methanol (5:1, 200 mL). The formed inorganic solid was filtered off again. The filtrate was concentrated in vacuo to give a pale yellow amorphous, which was crystallized from ethanol to afford 4.79 g (45%) of the title compound as an off-white solid. Furthermore, 5.09 g (48%) of the compound was obtained from the mother liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Cc1ccc(N)cc1Cl
Reactant: CCCC=O
Product: CCCCNc1ccc(C)c(Cl)c1
Yield: 97 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 3-chloro-p-toluidine (Aldrich, 430 μL, 3.53 mmol) and butyraldehyde (320 μL, 3.13 mmol) were converted to the title compound (600 mg, 79%). 1H NMR (CDCl3) δ 7.06-6.93 (m, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.43 (dd, J=8.1, 2.4 Hz, 1H), 3.56 (br s, 1H), 3.08 (t, J=7.2 Hz, 2H), 2.26 (s, 3H), 1.66-1.50 (m, 2H), 1.49-1.33 (m, 2H), 1.00-0.89 (m, 3H).
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])[CH3:2].[C:7]([O:13]C)([CH2:10][CH2:11][CH3:12])([CH3:9])[CH3:8]>>[C:7]([O:13][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH2:10][CH2:11][CH3:12])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OO
Reactant: CCCC(C)(C)OC
Product: CCCC(C)(C)OOC(C)(C)C

Procedure:
In similar manner, although optimal conditions may vary, hydrogen peroxide may be reacted with methyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with methyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with ethyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with ethyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with ethyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with n-propyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with n-propyl t-amyl ether to provide t-amyl hydroperoxide or di t-amyl peroxide; or with n-propyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide. Illustrative of reactions employing hydroperoxide reactants are the reaction of t-butyl hydroperoxide with methyl t-butyl ether to provide di-t-butyl peroxide; the reaction of t-hexyl hydroperoxide with methyl t-hexyl ether to provide di-t-hexyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-amyl ether to provide t-butyl t-amyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-hexyl ether to provide t-butyl t-hexyl peroxide; and the reaction of t-amyl hydroperoxide with ethyl t-hexyl ether to provide t-amyl t-hexyl peroxide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[O:30][C:31]=1[CH3:32])[CH2:7][O:8][C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[CH3:2].[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[O:30][C:31]=1[CH3:32])[CH2:7][O:8][C:9]1[C:13](/[CH:14]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:12][N:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:10]=1)[CH3:2]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(COc2nn(-c3ccccc3)cc2/C=C/P(=O)(OCC)OCC)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 60.9 %

Procedure:
To a mixture of 3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.44 g), tetraethyl methylenediphosphonate (0.31 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.34 g, yield 55%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[NH2:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1
Reactant: [N-]=[N+]=NC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: NC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 4-azido-1-(p-nitrobenzyloxycarbonyl)-piperidine (2.81 g, 9.17 mmol) (obtained as described in Reference Example 51(3)) in acetonitrile (84 ml) was added triphenylphosphine (2.53 g, 9.63 mmol), and the mixture was stirred in an oil bath (70° C.) for 3 hours. After checking the completion of the reaction, sodium sulfate decahydrate (3.10 g, 9.63 mmol) was added thereto and the reaction mixture was stirred for 3 hours. After checking the completion of the reaction, the reaction mixture was filtered and partitioned between methylene chloride and 0.1M aqueous hydrogen chloride solution. To the obtained aqueous layer were added methylene chloride and sodium hydrogencarbonate, and the aqueous layer was extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried under reduced pressure to give 4-amino-1-(p-nitrobenzyloxycarbonyl)-piperidine (2.33 g, yield 91%) as pale yellow crystals.
Reaction SMILES: B(F)(F)F.CCOCC.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)=O)=[CH:13][CH:12]=1.[NH2:27][N:28]1[C@@H:32]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:31][CH2:30][C:29]1=[O:42]>O1CCCC1>[CH2:35]([O:34][CH2:33][C@@H:32]1[N:28]([N:27]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[CH2:17][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[C:29](=[O:42])[CH2:30][CH2:31]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1cccc(C(=O)Cc2ccc(F)cc2)n1
Reactant: NN1C(=O)CC[C@@H]1COCc1ccccc1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C(Cc2ccc(F)cc2)=NN2C(=O)CC[C@@H]2COCc2ccccc2)n1
Reaction time: 0.5 h

Procedure:
Boron trifluoride etherate (0.25 mL, 1.98 mmol) is added to a solution of 2-(4-fluoro-phenyl)-1-(6-methyl-pyridin-2-yl)-ethanone (0.45 g, 1.98 mmol) in tetrahydrofuran (6.6 mL) under nitrogen and stirred for 30 min. A solution of (R)-1-amino-5-benzyloxymethyl-pyrrolidin-2-one (0.43 g, 1.98 mmol) in tetrahydrofuran (1.0 mL) is added and the resulting mixture is stirred for 1 h. The mixture is concentrated in vacuo and the residue chromatographed on a SiO2 column (30% ethyl acetate/hexanes) to yield the title compound, 380 mg (45%), as a yellow foam.
Reaction SMILES: [C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[C:20](O)=[O:21])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:32]([O:36][C:37](=[O:49])[NH:38][CH2:39][C@@H:40]([NH2:48])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:35])([CH3:34])[CH3:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:32]([O:36][C:37](=[O:49])[NH:38][CH2:39][C@@H:40]([NH:48][C:20]([C:8]1[C:9]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][CH:13]=[CH:12]3)[NH:19][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:21])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1)NC(=O)c1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a suspension of 2-phenyl-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid G2 (0.087 mmol) in DMF (1 mL), DIEA (0.26 mmol) and ((S)-2-amino-3-phenyl-propyl) -carbamic acid tert-butyl ester (0.13 mmol) were added. The mixture was cooled to 0° C., EDCI hydrochloride (0.13 mmol) and HOBT (0.13 mmol) were added and stirring was kept overnight at rt. The suspension was filtered and the solid was washed with aq saturated NaHCO3 and with water. After drying, the title compound was isolated in 43% yield. ESI (+) MS: m/z 521 (MH+). 1H NMR: 1.40 (s, 9H) 2.80-2.89 (m, 1H) 3.00-3.11 (m, 2H) 3.12-3.21 (m, 1H) 4.18-4.30 (m, 1H) 6.91-6.97 (m, 1H) 7.00-7.06 (m, 1H) 7.16-7.23 (m, 1H) 7.25-7.34 (m, 4H) 7.37-7.43 (m, 1H) 7.49-7.56 (m, 2H) 7.88 (d, J=7.62, 2H) 8.00 (d, J=9.00, 1H) 8.31 (d, J=9.00, 1H) 8.72 (s, 2H) 9.51 (s, 1H) 11.72 (bs, 1H).
Reaction SMILES: [CH2:1](O)C.[CH3:4][CH2:5][C@@:6]1([OH:29])[C:11](=[O:12])[O:10][CH2:9][C:8]2[C:13]([N:15]3[C:27](=[CH:28][C:7]1=2)[C:26]1[N:25]=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]2)=[CH:18][C:17]=1[CH2:16]3)=[O:14].S(=O)(=O)(O)O.OO>O>[CH3:4][CH2:5][C@@:6]1([OH:29])[C:11](=[O:12])[O:10][CH2:9][C:8]2[C:13]([N:15]3[C:27](=[CH:28][C:7]1=2)[C:26]1[C:17](=[C:18]([CH3:1])[C:19]2[C:24]([N:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16]3)=[O:14]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Ferrous sulfate heptahydrate (4.17 g, 15 m-mol) and ethanol (3 ml, 60 m-mol) were dissolved in water (30 ml). Camptothecin (700 mg, 2 m-mol) was suspended in the solution and dissolved therein by adding concentrated sulfuric acid (15 ml) in small portions to the suspension. To the mixture was added dropwise under ice-cooling and agitation a 30% aqueous solution of hydrogen peroxide (1.63 ml, 16 m-mol). After addition of the hydrogen peroxide, the mixture was stirred for 6 hours at room temperature. To the reaction mixture was added ferrous sulfate heptahydrate (2.0 g, 7.2 m-mol) and then was added dropwise under ice-cooling and agitation a 30% aqueous solution of hydrogen peroxide (1 ml, 9.8 m-mol). The agitation was continued for 15 hours at room temperature. To complete the reaction, additional ferrous sulfate heptahydrate (4.2 g, 15 m-mol) and a 30% aqueous solution of hydrogen peroxide (1.5 ml, 14.7 m-mol) were added to the reaction mixture and the whole was stirred for 8 hours at room temperature. The reaction mixture was diluted with ice water (2.5 liters) and extracted with chloroform (3 liters). The chloroform layer was dried with anhydrous magnesium sulfate, filtered and evaporated until dryness under reduced pressure. The residue was purified by way of column chromatography (chloroform) through silica gel (10 g) followed by recrystallization from n-hexane-chloroform whereby 127 mg (17.5%) of the objective compound were obtained as yellow needle crystals. M.P. 280°-281° C.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)(C)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:22]4[CH2:23][CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:21]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCc2ccccc2C1

Procedure:
A mixture of N-[3-(2,3-epoxy)propyl]-4-(6-fluoro-1,2-benzisoxaz-3-yl)piperidine (3.56 g, 12.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.06 g, 15.4 mmol) in isopropyl alcohol (150 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was removed. The residual oil was purified by flash chromatography over a silica gel column (SiO2, 45 g, eluted with 1% CH3OH: 99% methylene chloride). The product thus purified as a light oil, weighed 4.15 g. The oil was treated with a solution of fumaric acid (1.98 gm, 17 mmol) in ethanol. The white crystals so obtained were recrystallized in a large volume of hot ethanol (~150 ml). The recrystallized crystals weighed 2.75 g, m.p. 179°-181° C.
Reaction SMILES: C(N)C1C=CC=CC=1.C(O[C:17]([N:19]([CH2:21][C:22]([NH:24][C@H:25]([C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([P:38](=[O:41])([OH:40])[OH:39])[CH3:37])=[O:34])[CH3:32])=[O:29])[CH2:26][OH:27])=[O:23])C)=O)C1C=CC=CC=1>>[NH:19]([CH2:21][C:22]([NH:24][C@H:25]([C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([P:38](=[O:39])([OH:41])[OH:40])[CH3:37])=[O:34])[CH3:32])=[O:29])[CH2:26][OH:27])=[O:23])[CH3:17]
Reactant: C[C@H](NC(=O)[C@H](CO)NC(=O)CN(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CNCC(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 3(ii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-sarcosyl-L-seryl-L-alanyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(N-sarcosyl-L-seryl-L-alanylamino)-ethylphosphonic acid of melting point 249°-250° C. (decomposition); [α]D20 =-85.2°; [α]36520 =-301° (c=0.5% in water).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[N:22](COCC[Si](C)(C)C)[S:21]3(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH:13]=1.I[CH:57]([CH3:59])[CH3:58]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][N:52]([CH:57]([CH3:59])[CH3:58])[C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:34])=[O:35])=[CH:16][CH:15]=2)[CH:13]=1
Reactant: CC(C)I
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNC(=O)C5)cc4)cc3)cc2)S1(=O)=O
Product: CC(C)N1CCN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CC1=O

Procedure:
4-[4′-(4-(2,4-Dichloro-phenyl)-1-{4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxy methyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperazin-2-one (17 mg, 0.02 mmol) was treated as described in general procedure L (using 2-iodopropane) and general procedure W stepwise to give 4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-1-isopropyl-piperazin-2-one.