Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].O.[Cl-].[Na+]>N1C=CC=CC=1.Cl>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:18][CH2:17][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:9]=2)[NH:13][CH:12]=1
Reactant: NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Methanesulphonyl chloride (0.23 ml) was added to an ice cooled, stirred solution of 2-[2-[5-(aminomethyl)-1H-indole-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione, hemisulphate, hydrate (0.84 g) in dry pyridine (25 ml). After 20 h at room temperature, a further portion of methanesulphonyl chloride (0.14 ml) was added. The mixture was stirred for 2 h, water (10 ml) was added and the solution was stirred for a further 1 h. The solution was diluted with hydrochloric acid (2N; 250 ml) containing sodium chloride (30 g) and ice. The product was extracted into ethyl acetate (2×80 ml) and the extract was washed with brine (2×60 ml), dried (Na2SO4) and evaporated in vacuo to leave a yellow foam (0.85 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O.Cl.[NH2:37][CH:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1>ClCCl>[CH2:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:46][CH:38]1[NH:37][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:22]
Reactant: COc1ccc(CCNC(=O)CCCCC(=O)O)cc1OC
Reactant: NC1Cc2ccccc2C1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)CCCCC(=O)NC2Cc3ccccc3C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
6-[2-(3,4-Dimethoxyphenyl)ethylamino]-6-oxohexanoic acid (6.0 g, 0.019 mole) was dissolved in dry dichloromethane (200 ml) and triethylamine (2.28 g, 0.021 mole) added followed by ethyl chloroformate (1.86 ml, 0.019 mole) at 0°. The solution was stirred at 0° for 30 min and a solution of 2-aminoindane hydrochloride (3.3 g, 0.019 mole) and triethylamine (2.52 ml 0.019) in dry dichloromethane (200 ml) added, allowed to warm to room temperature and stirred for a further 18 hr. The reaction mixture was washed with water, dried (MgSO4) and evaporated and the residue recrystallised from methanol to give the sub-title compound as a white solid (6.4 g), mp 162°-4°.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH3:16])[CH:10]1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].CN(C=O)C.N1C=NCC=1>CN(C)C1C=CN=CC=1.CCOCC>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH3:16])[CH:10]1[O:17][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1CCCC(OCc2ccccc2)C1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: C1=NC=NC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC1CCCC(OCc2ccccc2)C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyloxy-3-methoxy-cyclohexan-2-ol, 51d, (2.31 g, 9.78 mmol), tert-butyl-chlorodimethyl-silane (2.21 g, 2.73 mL, 14.66 mmol) in 20 dry DMF at room temperature was added 4H-imidazole (1.997 g, 29.33 mmol) and a catalytic amount of 4-dimethylaminopyridine (0.12 g, 0.98 mmol). The resulting mixture was stirred at room temperature overnight. It was then diluted with ether, washed with water, aqueous saturated citric acid solution and water again. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The colorless crude oil was used directly in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[F:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][C:39]=1F)[C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>C(#N)C>[F:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][C:39]=1[O:7][C:8]1[CH:9]=[C:10]([C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)=[O:12])[CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:32]([N:34]([CH3:36])[CH3:35])=[O:33]
Reactant: CN(C)C(=O)c1ccc(F)c(F)c1
Reactant: C[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N(C)C)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
Potassium carbonate (276 mg) was added to a solution of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (291 mg) and 3,4-difluoro-N,N-dimethylbenzamide (204 mg) in acetonitrile (3.5 mL) and the stirred mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 15 h. The mixture was allowed to return to ambient temperature and pressure, the acetonitrile evaporated, and the residue chromatographed on silica, eluting with 0-5% methanol in ethyl acetate, to give the desired compound (63 mg). 1H NMR δ (d6-DMSO): 1.22 (d, 3H), 2.94 (s, 6H), 3.49 (m, 2H), 3.76 (s, 3H), 4.54 (m, 1H), 4.83 (t, 1H), 6.53 (m, 1H), 6.76 (m, 1H), 7.14 (s, 1H), 7.24 (m, 2H), 7.40 (s, 1H), 7.47 (d, 1H), 7.57 (m, 1H), 10.83 (br s, 1H). m/z 457 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[C:17]2[C:12]([C:13](=[O:38])[C:14]([CH3:37])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:41]([F:44])([F:43])[F:42].C(OCC)(=O)C>CS(C)=O>[CH2:1]([O:8][C:9]1[C:18]([CH:19]([OH:20])[C:41]([F:44])([F:43])[F:42])=[C:17]2[C:12]([C:13](=[O:38])[C:14]([CH3:37])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:28])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1c(C2CCN(C(=O)OCc3ccccc3)CC2)oc2c(C=O)c(OCc3ccccc3)ccc2c1=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1c(C2CCN(C(=O)OCc3ccccc3)CC2)oc2c(C(O)C(F)(F)F)c(OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of benzyl 4-[7-(benzyloxy)-8-formyl-3-methyl-4-oxo-4H-chromen-2-yl]piperidine-1-carboxylate (378 mg, 0.74 mmol) obtained in Example 36-1 in dimethyl sulfoxide (10 mL), molecular sieves 4A (1.0 g) and trimethyl(trifluoromethyl)silane (1.09 mL, 7.39 mmol) were added, and then the mixture was stirred at room temperature for 3 hours. Ethyl acetate (80 mL) was added to the reaction solution, and insoluble matter was removed by filtration through celite. The filtrate was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. A 1 N aqueous hydrochloric acid solution (3 mL) and methanol (12 mL) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue. The organic layer was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=80/20→40/60) to obtain 392 mg of the title compound (yield: 91%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:4][CH2:3]1.O[C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>>[CH2:32]([O:31][C:29](=[O:30])[C:28]1[CH:34]=[CH:35][C:25]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=3[O:20][CH:21]([CH3:23])[CH3:22])[CH2:6][CH2:7]2)=[CH:26][CH:27]=1)[CH3:33]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Reactant: CCOC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OC2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)cc1
Yield: 28 %

Procedure:
Prepared in analogy to Example 4 from (4-hydroxy-piperidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 3(a)) and ethyl 4-hydroxybenzoate. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 28%). MS (m/e): 490.5 (M+H+, 100%).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH2:19][CH2:20][CH2:21][Cl:22])[C@H:9]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(O)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:22][CH2:21][CH2:20][CH2:19][N:10]1[C:9]2[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[C:5](=[O:6])[C:8]=2[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:18]
Reactant: COc1ccc([C@H]2[C@@H](C(=O)O)c3ccccc3C(=O)N2CCCCl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(=O)c1c-2n(CCCCl)c(=O)c2ccccc12
Temperature: 25 °C
Yield: 17 %

Procedure:
Thionyl chloride (2 mL) was added to a solution of cis-4-carboxy-N-(3-chloropropyl)-3,4-dihydro-3-(4-methoxyphenyl)-1(2H)isoquinolone (8a) (0.510 g, 1.364 mmol) in benzene (40 mL). The reaction mixture was heated at reflux for 30 min, allowed to cool to room temperature, and concentrated. The residue was diluted with nitrobenzene (20 mL), chilled in an ice bath, and aluminum chloride (0.364 g, 2.728 mmol) was added. The reaction mixture was removed from the bath and heated at 100° C. for 1.5 h. Ice water (100 mL) was added and the solution was extracted with CHCl3 (3×50 mL). The combined organic layer was washed with sat NaHCO3 (3×50 mL), sat NaCl (50 mL), and dried over sodium sulfate. The solution was concentrated, hexanes (250 mL) were added, and liquid was decanted. The obtained solid was washed with hexanes (100 mL) and the liquid was again decanted. The solid was purified by flash column chromatography (SiO2), eluting with chloroform, to provide a purple-red solid (0.082 g, 17%) that was precipitated from EtOAc/hexanes: mp 195-198° C. IR (KBr) 1662, 1611, 1505, 1481, 1432, and 1299 cm−1; 1H NMR (CDCl3) δ 8.67 (d, J=8.1 Hz, 1 H), 8.31 (dd, J=8.2 Hz and 0.7 Hz, 1 H), 7.73 (m, 1 H), 7.66 (d, J=8.4 Hz, 1 H), 7.45 (m, 1 H), 7.22 (d, J=2.6 Hz, 1 H), 6.86 (dd, J=8.4 Hz and 2.6 Hz, 1 H), 4.67 (m, 2 H), 3.89 (s, 3 H), 3.83 (m, 2 H), 2.43 (m, 2 H); CIMS m/z (rel intensity) 354/356 (MH+, 100/30). Anal. (C20H16ClNO3) C, H, N.
Reaction SMILES: [C:1]([NH:8][OH:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:12]([O:14][C:15](=[O:30])[CH:16](OS(C)(=O)=O)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:13]>CN(C=O)C>[CH2:12]([O:14][C:15](=[O:30])[CH:16]([O:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:13]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CCOC(=O)C(CCc1ccccc1)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccccc1)ONC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.5 %

Procedure:
To a solution of BocNHOH (958 mg, 7.2 mmol) in DMF (15 mL) was added NaH (60% in mineral oil, 320 mg, 8 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 15 min. The compound from Step 9a (1.81 g, 6 mmol) was added to the mixture at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc (3×15 mL), dried (Na2SO4) and filtered. The organic solvent was removed under reduced pressure and residue was purified by flash chromatography (Hexanes/EtOAc=3/1), giving 1 g (50%) of the title compound. 13C NMR (CDCl3): δ17172.0, 156.6, 141.3, 128.8, 128.7, 126.3, 83.3, 82.2, 61.5, 33.0, 31.7, 28.5, 14.5.
Reaction SMILES: [CH:1]1([CH:7]([OH:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](O)=[O:11]>>[CH:10]([O:9][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:8])=[O:11]
Reactant: CC(O)C1CCCCC1
Reactant: O=CO
Product: CC(OC=O)C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 12.8 g. (0.1 moles) 1-cyclohexyl-1-ethanol and 13.8 g. (0.3 moles) formic acid was refluxed for two hours and then cooled to room temperature. It was poured in 200 ml. cold water, the organic material extracted in ether and the ether extract washed thoroughly with water, sodium bicarbonate, water and brine and dried over molecular sieves. 15.4 g. crude product of 97.9% purity was recovered--major impurity is residual solvent. The crude product was distilled through a short Vigreux-column. The product is a mobile, colorless liquid, b.p. 94° C./16 mm., nD25 =1.4437. Yield 13.6 g.=87.1%, purity 99.2% (by GLC) of 1-cyclohexyl-1-ethyl formate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C>[C:24]([Si:21]([CH3:23])([CH3:22])[O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.2 %

Procedure:
To a solution of N-(3-hydroxypropyl)phthalimide (5.25 g, 24.36 mmol) in DMF (20 mL) was added imidazole (16.6 g, 240 mmol) and tert-butyldimethylsilyl chloride (19 g, 120 mmol). The reaction was stirred at room temperature for 18 hours before the volatiles were removed in vacuo and a portion of the crude product was subjected to column chromatography (SiO2, 1:1 DCM/hexanes) to give 2-[3-(tert-butyldimethyl-silanyloxy)propyl]isoindole-1,3-dione as a clear oil (5 g). 2-[3-(tert-Butyldimethyl-silanyloxy)propyl]isoindole-1,3-dione (5 g, 26.4 mmol) was dissolved in ethanol (50 ml) and methyl hydrazine (2.94 ml, 55.4 mmol) added. The reaction was heated to 75° C. for 8 hours before concentration in vacuo. The crude residue was triturated with a mixture of diethyl ether (150 mL) and hexanes (50 mL) and the resultant solid removed by filtration. The solvents were removed in vacuo to give the title compound as a pale yellow oil (1.8 g, 61%). δH (DMSO-d6) 4.58 (2H, br s), 3.63-3.58 (2H, m), 2.67-2.62 (2H, m), 1.60-1.55 (2H, m), 0.83 (9H, d, J=1.1 Hz), 0.00 (6H, d, J=1.2 Hz). LCMS (ES+) RT 1.77 minutes, 190 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([CH2:28][CH2:29][C:30]([OH:32])=O)[CH:3]=1.[NH2:33][C:34]1[C:39]([NH2:40])=[CH:38][C:37]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)=[CH:36][N:35]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[NH2:33][C:34]1[C:39]([NH:40][C:30](=[O:32])[CH2:29][CH2:28][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:5]=2)=[CH:38][C:37]([C:41]2[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=2)=[CH:36][N:35]=1
Reactant: Cc1cc(CCC(=O)O)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: Nc1cc(-c2ccc(Cl)cc2)cnc1N
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCC(=O)Nc2cc(-c3ccc(Cl)cc3)cnc2N)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 40 °C
Yield: 91.4 %

Procedure:
300 mg of 3-[4-methyl-6-(trityl-amino)-pyridin-2-yl]propionic acid (compound C4) and 156 mg of 2,3-diamino-5-(4-chlorophenyl)-pyridine (compound F4) are dissolved in 13 ml of pyridine and sequentially treated with 280 mg of O-[(ethoxycarbonyl)canomethylene-amino]-N,N,N′,N′-tetramethyl-uronium tetrafluoroborate and 153 μl of diisopropylethyl amine. The reaction mixture is warmed to 40° C. for 120 h. Purification of the crude product by chromatography on silica gel (eluent: dichloromethane/methanol 8:1) afforded 405 mg of the title compound as an oil. ESI-MS: 624.1/626.1 (MH+, 100%/38%). TLC: Rf=0.32 (dichloromethane/methanol 8:1).
Reaction SMILES: Cl[CH2:2][O:3][C:4]([O:6][CH:7]([CH2:24][O:25][C:26](=[O:39])[C@H:27]([CH:36]([CH3:38])[CH3:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][O:9][C:10](=[O:23])[C@H:11]([CH:20]([CH3:22])[CH3:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5].[Na+].[I-:41]>C(#N)C>[I:41][CH2:2][O:3][C:4]([O:6][CH:7]([CH2:24][O:25][C:26](=[O:39])[C@H:27]([CH:36]([CH3:38])[CH3:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][O:9][C:10](=[O:23])[C@H:11]([CH:20]([CH3:22])[CH3:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCI
Yield: 92 %

Procedure:
A solution of 2-O-chloromethoxycarbonyl-1,3-di-O-(N-tertbutoxycarbonyl-L-valyl)propane-1,2,3-triol (7.86 g, 13.5 mmol) and NaI (8.09 g, 54.0 mmol) in 135 mL dry acetonitrile was refluxed at 80° C. for 4 h under N2. The reaction mixture was concentrated under vacuum, and then partitioned between 150 mL diethyl ether and 50 mL H2O. The aqueous layer was reextracted with 2×25 mL ether. The combined organic phases were washed successively with 25 mL aqueous Na2S2O3 and 50 mL brine, dried over Na2SO4, and concentrated. Flash column chromatography (silica gel, 2/1 hexane-ethyl acetate gave 8.38 g (92%) title product (alternative name: 2-iodomethoxycarbonyloxy-1,3-bis-(N-tert-butoxycarbonyl-L-valyloxy)propane or 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl iodomethyl carbonate) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[N:17]=O.[H][H]>C(O)C.O=[Pt]=O>[CH2:9]([N:5]1[C:4](=[O:16])[C:3]([NH2:17])=[C:2]([NH2:1])[NH:7][C:6]1=[O:8])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: Nc1[nH]c(=O)n(Cc2ccccc2)c(=O)c1N=O
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1[nH]c(=O)n(Cc2ccccc2)c(=O)c1N

Procedure:
This compound can also be prepared by a method similar to that of Wells et al. as described in J. Med. Chem. 1981, 24(8), 954. Catalytic reduction of 6-amino-3-benzyl-5-nitroso-1H-pyrimidine-2,4-dione using PtO2 in ethanol at 50 psi of hydrogen at room temperature. Once the reduction is complete the catalyst is filtered off through a pad of Celite and the filtrate concentrated to give 3-benzyl-5,6-diamino-1H-pyrimidine-2,4-dione as a tan solid.
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([O-:9])=[O:8].Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[N+:7]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccs1
Reactant: CCOC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccsc1[N+](=O)[O-]
Temperature: -50 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
Potassium tertiary-butoxide (652 mg, 5.81 mmol) was dissolved in tetrahydrofuran (150 ml) and the solution cooled to −50° C. A solution of 2-nitrothiophene (250 mg, 1.94 mmol) (Avocado) and ethyl chloroacetate (0.22 ml, 1.94 mmol) (Aldrich) was added dropwise in dry tetrahydrofuran (4 ml) over 5 minutes. The reaction mixture was stirred at −50° C. for 1 hour then quenched with acetic acid (0.5 ml), then washed with water (20 ml). The aqueous phase was extracted with ethyl acetate and the combined organic fractions were washed with saturated brine solution. The organic phase was dried over magnesium sulfate, evaporated to dryness and the residue chromatographed on silica gel using hexane/ethyl acetate (4:1) as eluent to give 261 mg of ethyl 2-nitrothiophene-3-acetate as a red/brown viscous oil. MS(ES): mn/e 216 [M+H].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2[NH:22][C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][C:24]=1[Cl:30]>CS(C)=O>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:25][C:24]=1[Cl:30]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Nc1ccc(F)cc1Cl
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(Nc3c([N+](=O)[O-])cnc4ccc(Br)cc34)c(Cl)c2)CC1
Temperature: 180 °C

Procedure:
5 ml of N-methylpiperazine are added to a solution of 600 mg (1.5 mmol) of (6-bromo-3-nitro-quinolin-4-yl)-(2-chloro-4-fluoro-phenyl)-amine (Example 63b) in 2 ml of DMSO. The reaction is heated at 180° C. for 1 h in a microwave oven (Emrys Optimizer, Personal Chemistry). After this time, the solution is concentrated to dryness and the crude compound is purified by preparative MPLC. Title compound: ES-MS: 476.3, 478.3, 480.3 (M+H)+; analytical HPLC: tret=4.28 minutes (Grad 2).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH2:6]([N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]2[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23]([CH2:25]Br)[N:24]=[C:14]12)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[CH2:6]([N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]2[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23]([CH2:25][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:24]=[C:14]12)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCNCC
Reactant: CCOC(=O)c1c(CBr)nc2n(Cc3ccccc3)c3ccccc3n12
Solvent: c1ccccc1
Product: CCOC(=O)c1c(CN(CC)CC)nc2n(Cc3ccccc3)c3ccccc3n12
Yield: 96 %

Procedure:
Add 1.04 ml (10 mmol) of diethylamine to a hot solution of 9-benzyl-2-bromomethyl-3-ethoxycarbonylimidazo[1,2-a]benzimidazole (2.01 g, 5 mmol), prepared as described for the alkylated analogues in Khim. Farm. ZH 88, 22 (7), 815-9, in 20 ml of benzene. Heat at reflux for one hour, cool. Remove the resulting precipitate, evaporate the benzene, and the residue is recrystallised by hexane to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([OH:12])=[O:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C>C1(C)C=CC=CC=1>[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=2)=[CH:15][CH:14]=1)([OH:12])=[O:11]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(C=Nc2cc(Cl)cc(Cl)c2)cc1

Procedure:
To a reaction flask, equipped with a Dean-Stark trap, is added 3,5-dichloroaniline (16.2 g., 0.10 mole), p-carboxybenzaldehyde (0.10 moles), p-toluenesulfonic acid monohydrate (0.2 g), and toluene (100 ml.). The reaction mixture is then warmed to reflux and the water (1.65 ml.) collected by azeotroping. The cooled reaction mixture is treated with charcoal and the filtrate reduced to vacuo to give an amber oil that crystallizes on standing to give N-(p-carboxybenzylidene)-3,5-dichloroaniline which is recrystallized from pentane.