Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:12]2[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]1=[O:14].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=1.O>O1CCCC1.C(OCC)C>[CH3:1][C:2]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[C:12]2[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]1=[O:14]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC1C(=O)c2cccc3cccc1c23
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC1(Cc2cccc(C#N)c2)C(=O)c2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-methyl-1-acenaphthenone (1.00 g, 0.005 mole) in tetrahydrofuran (20.0 ml) was added dropwise to a solution of sodium hydride (0.580 g, 0.024 mole, 50% oil dispersion) in tetrahydrofuran (35.0 ml) at 0°. The reaction mixture was stirred for 2 hours at room temperature. At 0°, α-Bromo-m-tolunitrile (1.37 g, 0.007 mole) in tetrahydrofuran (10.0 ml) was added dropwise. The mixture was stirred for 24 hours at room temperature, poured into water, and isolated by extraction with diethyl ether. The material was chromatographed on silica with ethylacetate/hexane providing the title compound as an oil (1.55 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Cl:12][C:13]1[CH:14]=[C:15](/[CH:16]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])\[C:9]#[N:10])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: O=Cc1cc(F)cc(Cl)c1
Reactant: N#CCc1ccc(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cc(F)cc(Cl)c1)c1ccc(Cl)cc1F
Yield: 88.7 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (3.4 g, 20 mmol) was reacted with 3-chloro-5-fluoro-benzaldehyde (Aldrich) (3.77 g, 24 mmol), methanolic solution (25 wt %) of sodium methoxide (4.99 mL, 22 mmol) in methanol (90 mL) at 50° C. for 3 h to give (Z)-3-(3-chloro-5-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (5.5 g, 90%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]([F:10])([F:9])[F:8].ClCCl.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:15](=[O:16])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: FC(F)(F)CNCCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)N(CCCCl)CC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 500-mL round-bottom flask, was placed (3-chloropropyl)(2,2,2-trifluoroethyl)amine (5 g, 28.48 mmol, 1.00 equiv), dichloromethane (300 mL), TEA (5.8 g, 57.32 mmol, 2.00 equiv), pyridine (0.5 mL). To this was added dropwise phenyl chloroformate (4.4 g, 28.10 mmol, 1.00 equiv) at 0° C. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was washed with 2×100 mL of H2O. The resulting mixture was washed with 2×100 mL of brine. The mixture was dried over sodium sulfate. The resulting mixture was concentrated under vacuum. This resulted in 1.4 g (crude) of phenyl N-(3-chloropropyl)-N-(2,2,2-trifluoroethyl)carbamate as a colorless liquide.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:9][C:10](=[O:12])[O-:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[CH3:13][O:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].COC(C)(C)C>FC(F)(F)C(O)=O>[CH3:13][O:14][CH2:15][CH2:16][CH2:17][C:18]([C:3]([CH2:9][C:10](=[O:11])[O-:12])([CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])[OH:2])=[O:19]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: COCCCC(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Product: COCCCC(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Temperature: 25 °C
Reaction time: 384 h
Yield: 50 %

Procedure:
4.5 g (0.02 moles) of carnitine hydrochloride were dissolved in 6 ml of trifluoroacetic acid. To this solution 4-methoxybutyryl chloride was added. The resulting mixture was kept under stirring at room temperature for 16 days. Subsequently tert-butyl methyl ether was added to the mixture. An oil precipitated which was treated with anhydrous acetonitrile in order to remove the undesired carnitine. To the acetonitrile solution tert-butyl methyl ether was added and 4-methoxybutyryl carnitine precipitated. Yield 50%.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([N:9]2[C:13]3=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][C:17](=[O:18])[N:12]3[CH2:11][CH2:10]2)[CH:6]=CN=1.[Cl:25]C1N=CC=C(Cl)N=1.C1(C2C=[C:41]3[NH:48]CCN3C(=O)C=2)C=CC=CC=1>>[Cl:25][C:3]1[N:8]=[C:7]([N:9]2[C:13]3=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][C:17](=[O:18])[N:12]3[CH2:11][CH2:10]2)[CH:6]=[N:48][CH:41]=1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCN2
Reactant: Clc1ccnc(Cl)n1
Reactant: CSc1nccc(N2CCn3c2cc(-c2ccccc2)cc3=O)n1
Product: O=c1cc(-c2ccccc2)cc2n1CCN2c1cncc(Cl)n1

Procedure:
Following the procedure described in the synthesis of 1-(2-methylsulfanyl-pyrimidin -4-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one, but using 2,6-dichloropyrimidine as the coupling component, 7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (0.5 g, 2.4 mmol) was converted into the title product as a pale yellow solid. MS m/e 325 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[CH2:17](N(CC)CC)[CH3:18]>C1COCC1>[OH:16][C@H:12]([CH2:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][N:8]=[CH:7]2)[C:13]([O:15][CH2:17][CH3:18])=[O:14]
Reactant: Cc1cc(CC(=O)C(=O)O)cc2cn[nH]c12
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](O)Cc1cc(C)c2[nH]ncc2c1
Temperature: -25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.31 g (7.2 mmol) (1R)—B-chlorodiisopinocampheylborane in 20 mL THF was added dropwise within 30 min to a solution of 1.3 g (5.96 mmol) 3-(7-methyl-1H-indazol-5-yl)-2-oxo-propionic acid and 0.84 mL (7.2 mmol) triethylamine in 50 mL THF cooled to approx. −25° C. and the reaction mixture was kept for 1.5 h at this temperature and then heated to RT within another hour. The mixture was evaporated down i.vac., the residue was taken up in 100 mL 4 M ethanolic HCl and stirred overnight at RT. 200 mL EtOAc and 200 mL 15% K2CO3 solution were added, the organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified chromatographically by HPLC.
Reaction SMILES: CN(C)C=O.[CH3:6][S-:7].[Na+].Cl[C:10]1[N:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:31])[CH:16]=2)[N:11]=1.Cl>O>[CH3:6][S:7][C:10]1[N:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:31])[CH:16]=2)[N:11]=1
Reactant: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
20 ml of N,N-dimethylformamide and 221 mg of sodium thiomethoxide were added to 1 g of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline. The obtained mixture was stirred at 110° C. for one hour, neutralized with 1N hydrochloric acid and stirred at room temperature for one hour, followed by the addition of water. The crystals thus precipitated were recovered by filtration to give 780 mg of the title compound.
Reaction SMILES: O[Li:2].O.C[O:5][C:6](=[O:46])[CH2:7][C:8]1[CH:45]=[CH:44][CH:43]=[CH:42][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]3)=[CH:25][CH:24]=2)[N:13]=1>C1COCC1.O.CO>[C:38]([O:37][C:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:42]=[CH:43][CH:44]=[CH:45][C:8]=4[CH2:7][C:6]([O-:46])=[O:5])[C:17]([C:18]([F:20])([F:19])[F:21])=[CH:16][N:15]=3)=[CH:28][CH:27]=2)[CH2:30]1)=[O:36])([CH3:41])([CH3:39])[CH3:40].[Li+:2]
Reactant: [Li]O
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)C1
Product: [Li+]
Temperature: 40 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
LiOH.H2O (0.052 g, 1.25 mmol) was added to tert-butyl 3-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I26) (0.249 g, 0.416 mmol) in THF (10 mL), water (2.5 mL) and methanol (1 mL). The resulting mixture was allowed to stir for 2 hours at 40° C. and then 20 hours at room temperature. The volatiles were removed in vacuo and the residue was diluted with EtOAc (70 mL) and 2 M aq. NaOH (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (70 mL), the organic layers were combined, washed with brine (70 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (I27) (0.250 g, 100% yield) as an off-white oily solid; 1H NMR (400 MHz, d6-DMSO) δ 10.23 (s, 1H), 8.64 (s, 1H), 7.72-7.60 (m, 2H), 7.25-7.00 (m, 6H), 4.01-3.88 (m, 2H), 3.48 (s, 2H), 3.13-2.92 (m, 4H), 2.86-2.63 (m, 2H), 1.91-1.81 (m, 1H), 1.72-1.54 (m, 2H), 1.48-1.34 (m, 10H). LCMS Method C: rt 6.71 min; m/z 585.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Li]CCCC.CCCCCC.[NH2:20][C:21]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:22]=1[C:23](N(OC)C)=[O:24].Cl>C1COCC1>[NH2:20][C:21]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:22]=1[C:23]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:24]
Reactant: CON(C)C(=O)c1cccc(C)c1N
Reactant: Fc1cccc(I)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc(C(=O)c2cccc(F)c2)c1N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
In a 500 mL round-bottomed flask a solution of 1-fluoro-3-iodobenzene (13.61 mL, 116 mmol) in THF (120 mL) was cooled in −78° C. bath. A solution BuLi, 2.5M in hexane (46.3 mL, 116 mmol) was added dropwise over 10 minutes to give a slightly cloudy yellow solution. The solution was stirred at −78° C. for 30 minutes and then treated with a solution of 2-amino-N-methoxy-N,3-dimethylbenzamide (6.43 g, 33.1 mmol) in THF (30 mL). After 1.5 hours the reaction mixture was added to a mixture of ice and 1N HCl (149 mL, 149 mmol) and reaction flask rinsed with THF (5 ml) and combined with the aqueous mixture. The resulting mixture was diluted with 10% aq LiCl and the pH was adjusted to 4.00 with 1N NaOH. The mixture was extracted with Et2O, washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified on silica gel column (220 g ISCO) eluting with a gradient from 10% EtOAc/hexane to 30% EtOAc/hexane. The product was collected and concentrated to give (2-amino-3-methylphenyl)(3-fluorophenyl)methanone (7.11 g, 94% yield) as an oil. MS(ES):m/z=230.1 [M+H+]; HPLC: RT=2.820 min Purity=99%. (H2O/MeOH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=4 min, wavelength=220 nm);
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@@H:13]([OH:19])[CH2:14][NH:15][CH:16]3[CH2:18][CH2:17]3)[O:11][C:10]([CH3:21])([CH3:20])[N:9]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:36]([O:43][C:44](ON1C(=O)CCC1=O)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:36]([O:43][C:44]([N:15]([CH2:14][C@@H:13]([C@@H:12]1[O:11][C:10]([CH3:21])([CH3:20])[N:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:8]1[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[OH:19])[CH:16]1[CH2:17][CH2:18]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)CNC2CC2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)CN(C(=O)OCc2ccccc2)C2CC2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.9 %

Procedure:
A mixture of 180 mg (0.45 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-2-(cyclopropylamino)-1-hydroxyethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, 0.126 ml (0.98 mmol) of triethylamine and 136 mg (0.545 mmol) of N-(benzyloxycarbonyloxy)succinimide in 5 ml of methylene chloride is stirred at room temperature for 2 hours. Subsequently, the residue is poured on to ice and 2N sodium bicarbonate solution and then extracted three times with 150 ml of ether each time. The organic phase is washed with 70 ml of water, then dried over magnesium sulphate and evaporated. There are obtained 296 mg of tert-butyl (4S,5R)-5-[(S)-2-[1-(benzyloxy)-N-cyclopropylformamido]-1-hydroxyethyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate as a colourless oil; MS: 531 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([O:23]CC)=O)=[C:6]2[CH2:20][CH2:19][C:9]3[N:10]=[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:12][C:8]=3[C:7]=12.[NH3:26].O>CO.O1CCCC1>[CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([NH2:26])=[O:23])=[C:6]2[CH2:20][CH2:19][C:9]3[N:10]=[C:11]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:12][C:8]=3[C:7]=12
Reactant: N
Reactant: CCOC(=O)c1sc(SC)c2c1CCc1nc(-c3ccccc3)[nH]c1-2
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CSc1sc(C(N)=O)c2c1-c1[nH]c(-c3ccccc3)nc1CC2
Yield: 14 %

Procedure:
A mixture of ethyl 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzimidazole-6-carboxylate (0.50 g), a 10% (w/w) ammonia solution (30 ml) in methanol and tetrahydrofuran (30 ml) was heated in a sealed tube at 100° C. for 3 days. The reaction mixture was poured over water and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (30:1, v/v) to yield 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzimidazole-6-carboxamide (65 mg, 14%), which was then recrystallized from ethanol. Colorless prisms. Melting point 206-207° C.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:23]2[S:24][CH:25]=[CH:26][N:27]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>CO>[CH3:22][S:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11]([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[CH:12]2)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(-c1nccs1)n2S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc2[nH]c(-c3nccs3)cc2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
To a solution of the compound obtained in the step of Example 2 (4) (39 mg) in methanol (1 ml), a 1N aqueous potassium hydroxide solution (0.2 ml) was added at 15 to 30° C. and the mixture was stirred at 60° C. for 1 hour. To the reaction mixture was added 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off under reduced pressure to obtain the desired product (27 mg).
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH3:13])[CH:8]([CH3:14])[CH2:7]1)(OCC)=O>[OH-].[Na+]>[CH3:13][NH:12][CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH:8]1[CH3:14]
Reactant: CCOC(=O)N1CCC(NC)C(C)C1
Agent: [Na+]
Agent: [OH-]
Product: CNC1CCNCC1C
Temperature: 110 °C
Reaction time: 24 h

Procedure:
1-Carbethoxy-4-methylamino-3-methylpiperidine (4.0 g, 18.34 mmol) was suspended in 5 M NaOH solution (15 ml), stirred at 110° C. for 24 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to dryness to afford 4-methylamino-3-methyl-piperidine. Yield 1.8 g (77%), C7H16N2, m/z 129 (M+1), PMR (CDCl3): 0.92 (dd, 3H), 1.54 (m, 1H), 2.12 (m, 2H), 2.38 (s, 3H), 2.6 (m, 1H), 2.8 (m, 1H), 3.02 (m,1H), 3.42 (m,1H), 3.68 (m,1H).
Reaction SMILES: C(OC(=O)C[CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][C:21]([O-])=[O:22])[C:10]2[CH:24]=[CH:25][CH:26]=[CH:27][C:9]1=2)(C)(C)C.F[C:30](F)(F)[C:31]([OH:33])=[O:32].[NH:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][NH2:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:31]([O:33][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][C:21]([NH:50][CH2:49][CH2:48][CH2:47][CH2:46][NH:45][C:37]2[NH:36][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=2)=[O:22])[C:10]2[CH:24]=[CH:25][CH:26]=[CH:27][C:9]1=2)(=[O:32])[CH3:30]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC1c2ccccc2C(=O)N(CC(=O)[O-])c2ccccc21
Reactant: NCCCCNc1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(=O)OC1c2ccccc2C(=O)N(CC(=O)NCCCCNc2nc3ccccc3[nH]2)c2ccccc21

Procedure:
Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-ylacetate (66) with N1-(1H-benzimidazol-2-yl)butane-1,4-diamine (trifluoroacetate) (49) using HATU as coupling reagent, cleavage of the tert-butyl ester and purification of the resulting crude product by RP-MPLC afforded 94 mg; ESI-MS [M+H+]=512.25.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5]([CH3:9])([CH3:8])[CH2:6][OH:7])[CH3:2].[CH3:11]I>CC#N>[CH2:1]([O:3][C:4](=[O:10])[C:5]([CH3:9])([CH3:8])[CH2:6][O:7][CH3:11])[CH3:2]
Reactant: CCOC(=O)C(C)(C)CO
Reactant: CI
Solvent: CC#N
Product: CCOC(=O)C(C)(C)COC
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.6 %

Procedure:
To a solution of 2,2-dimethyl-3-hydroxypropionic acid ethyl ester (1.3 g, 10.0 mmol) in CH3CN (30 mL) was added Ag2O (11.5 g, 50.0 mmol) and methyl iodide (0.56 mL, 11 mmol). The reaction mixture was stirred at rt for 12 h and quenched with a saturated aqueous NH4Cl. The mixture was filtered though Celite, the filtrate concentrated in vacuo, and the residue was purified by column chromatography (EtOAc/Hex=1/10) to give the title compound (1.34 g, 91.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[C:44]#[N:45]>CN(C=O)C.O>[C:44]([C:43]1[CH:42]=[C:41]([NH:40][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:48]=[CH:47][CH:46]=1)#[N:45]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: N#Cc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cccc(C#N)c2)cc1
Reaction time: 0.25 h

Procedure:
5.0 g (33 mmol) 4-methoxybenzoic acid were dissolved in 50 ml DMF. 12.8 g (66 mmol) EDCI, 9.2 g (66 mmol) HOBt and 14.8 ml (132 mmol) 4-methylmorpholine were added and the mixture was stirred for 15 min. Subsequently, 3.9 g (33 mmol) 3-aminobenzonitrile were added and the mixture was stirred for 48 h at room temperature and 6 h at 80° C. The reaction mixture was poured in 500 ml water and the precipitate was filtered, washed and dried.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[O:30]1[C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=[N:31]1>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:35]([C:34]3[O:30][N:31]=[CH:32][CH:33]=3)=[O:36])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccno1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccno4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (2.7 g, 8.4 mmol) in CH3CN (25 ml), were added triethyl amine (2.9 mL, 8.4 mmol) and isoxazole-5-carbonyl-chloride (1.07 g, 4.5 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH3CN (20 mL), water (2×20 mL) and EtOAc (20 mL). The solid was dissolved in CH2Cl2 (5 mL) and purified by ISCO silica gel flash chromatography (eluent: 2% MeOH in CH2Cl2) to afford isoxazole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a light yellow solid (0.87 g, 27%): mp, 257-259° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=5.62 (99%); 1H NMR (DMSO-d6): δ 2.04-2.11 (m, 1H), 2.53-2.64 (m, 2H), 2.85-2.97 (m, 1H), 4.93 (d, J=5.6 Hz, 2H), 5.17 (dd, J=6, 12 Hz, 1H), 7.14-8.78 (m, 5H), 9.60 (t, J=5.6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 37.96, 48.87, 106.26, 122.11, 127.25, 131.56, 133.14, 134.89, 138.00, 151.75, 155.95, 162.35, 166.90, 167.44, 169.80, 172.73. Anal Calcd for C18H14N4O6: C, 56.55; H, 3.69; N, 14.65. Found: C, 56.20; H, 3.36; N, 14.47.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)[CH3:2].[OH-].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][CH:11]=2)=[N:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ncc(OCC)cn2)cc1
Yield: 77.2 %

Procedure:
To a solution of 5-ethoxy-2-(4-hydroxyphenyl)pyrimidine (40 g) dissolved in ethanol (340 ml) were added potassium hydroxide (11.2 g) and octyl bromide (35.8 g), followed by keeping the mixture under reflux for 3 hours, distilling off ethanol (about 300 ml), extracting the residue with toluene (500 ml), washing the resulting organic layer with 2N--NaOH aqueous solution, further washing with water until the washing water became neutral, distilling off low boiling substances in the organic layer and recrystallizing the residue from ethanol to obtain 5-ethoxy-2-(4-octyloxyphenyl)pyrimidine (46.9 g). This product exhibited a phase transition of ##STR11##
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[CH2:9]([O:11][C:12](=[O:42])[C:13]([NH:38][C:39](=[O:41])[CH3:40])([CH2:19][C:20]1[O:24][N:23]=[C:22]([CH:25]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:21]=1)[C:14]([O:16]CC)=[O:15])[CH3:10].Cl>C(OCC)(=O)C>[CH2:9]([O:11][C:12](=[O:42])[C:13]([NH:38][C:39](=[O:41])[CH3:40])([CH2:19][C:20]1[O:24][N:23]=[C:22]([CH:25]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:21]=1)[C:14]([OH:16])=[O:15])[CH3:10]
Reactant: CCOC(=O)C(Cc1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1)(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1)(NC(C)=O)C(=O)O
Reaction time: 8 h

Procedure:
Sodium hydroxide, 1N, (20.5 mL, 20.5 mmol, 1.10 equivalents) was added to a dioxane solution of 2-acetylamino-2-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-ylmethyl]-malonic acid diethyl ester (8.99 g, 18.6 mmol, 1.0 equivalents) at room temperature over 30 minutes and the reaction was stirred overnight. The reaction was diluted with ethyl acetate (200 mL) and acidified to pH=1-1.5 with 1 N hydrochloric acid. The organic portion was washed with brine (200 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give 8.589 of a 1:1 mixture (by 1H NMR) of 2-Acetylamino-2-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-ylmethyl]-malonic acid monoethyl ester [MS (Cl) m/z 356.3 (M-99)] and the decarboxylated title compound [MS (CI) m/z 412.3 (M+1), 312.2 (M-99), 410.3(M−1)].