Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1Br.C([Mg]Cl)(C)C.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][CH:6]=1
Reactant: COC(=O)c1cc(Br)c(Br)o1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)co1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of methyl 4,5-dibromo-2-furancarboxylate (1 g, 3.52 mmol) in tetrahydrofuran (14.1 ml) at −40° C. was added isopropylmagnesium chloride (1.85 ml, 3.70 mmol). After 2 h, H2O (3.52 ml) was added and the solution warmed to 25° C. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (3% EtOAc in hexanes) affording methyl 4-bromo-2-furancarboxylate (470 mg, 2.04 mmol, 58% yield) as a white solid: LCMS (ES) m/e 204, 206 (M, M+2)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)[CH3:2].[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:21][CH:22]=[CH2:23].C(N(CC)CC)C>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]([S:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:20][CH2:21][CH:22]=[CH2:23])=[CH:30][CH:29]=1)(=[O:33])=[O:32])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: C=CCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CNCc1ccc(-n2cncn2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)OCC)Cc2ccc(-n3cncn3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2 g (7.683 mmol) of (4-[1,2,4]triazol-1-yl-benzylamino)-acetic acid ethyl ester in 15 ml of dioxane and 15 ml of H2O, 2.3 g (9.22 mmol) of 4-but-3-enyloxy-benzenesulfonyl chloride and 1.3 ml (9.22 mmol) of triethyl amine are successively added at 0-5° C. After being stirred for 18 h at r.t., the reaction mixture is diluted with H2O and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give the title compound. 1H-NMR (400 MHz, CDCl3): 1.17 (t, 3H, J=7.04 Hz), 2.55-2.65 (m, 2H), 3.95 (s, 2H), 4.07 (t, 2H, J=7.04 Hz), 4.09 (t, 2H, J=6.56 Hz), 4.53 (s, 2H), 5.10-5.25 (m, 2H), 5.85-5.95 (m, 1H), 6.99 (d, 2H, J=8.04 Hz), 7.44 (d, 2H, J=7.56 Hz), 7.64 (d, 2H, J=8.04 Hz), 7.82 (d, 2H, J=7.56 Hz), 8.11 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: [CH2:1]([CH:3]1[NH:8][CH2:7][CH2:6][CH2:5][S:4]1)[CH3:2].[Cl:9][C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[S:18])[CH:13]=[CH:14][CH:15]=1.C1C=CC=CC=1>CCCCCC>[Cl:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([N:8]2[CH2:7][CH2:6][CH2:5][S:4][CH:3]2[CH2:1][CH3:2])=[S:18])[CH:13]=[CH:14][CH:15]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: CCC1NCCCS1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCC1SCCCN1C(=S)Nc1cccc(Cl)c1
Reaction time: 64 h

Procedure:
A mixture of 2.6 g. of 2-ethyltetrahydro-2H-1,3-thiazine, 3.4 g. of 3-chlorophenyl isothiocyanate, and 30 ml. of benzene was stirred, after an initial exotherm, at ambient temperature for about 64 hours. To the reaction mixture was added about 10 ml. of hexane, which caused white crystals to form. The mixture was cooled and filtered, and the solid was washed with hexane. The solid was recrystallized from about 500 ml. of 10:1 hexane:carbon tetrachloride to give N-(3-chlorophenyl)-2-ethyltetrahydro2H-1,3-thiazine-3-carbothioamide, m.p. 69°-73°. The following elemental microanalysis was obtained:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH:19]([CH2:28][C:29]([O-:31])=O)[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:6][O:7][C:8]=2[CH:9]2[CH2:12][CH:11]([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:10]2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:54][C:55]1[CH:60]=[C:59]([CH3:61])[CH:58]=[CH:57][C:56]=1[NH2:62]>C(OCC)(=O)C.O.CN(C=O)C>[Cl:54][C:55]1[CH:60]=[C:59]([CH3:61])[CH:58]=[CH:57][C:56]=1[NH:62][C:29]([CH2:28][CH:19]([C:5]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:8]([CH:9]2[CH2:10][CH:11]([CH2:13][CH:14]([CH2:15][CH3:16])[CH2:17][CH3:18])[CH2:12]2)[O:7][N:6]=1)[CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[O:31]
Reactant: CCC(CC)CC1CC(c2onc(C(CC(=O)[O-])CC(=O)OC(C)(C)C)c2C2CC2)C1
Reactant: Cc1ccc(N)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)CC1CC(c2onc(C(CC(=O)Nc3ccc(C)cc3Cl)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mono-tert-butyl 3-{4-cyclopropyl-5-[3-(2-ethylbutyl)cyclobutyl]isoxazol-3-yl}glutarate (150 mg) and DMF (1.5 mL) were mixed. To the mixture were added HOBt.H2O (63.5 mg), WSC.HCl (79.6 mg) and 2-chloro-4-methylphenylamine (0.0512 mL). The mixture was stirred at RT overnight. To the reaction mixture was added ethyl acetate. The mixture was washed with aqueous 10 w/v % citric acid, water, saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: ethyl acetate/hexane=1/6) to give the title compound (122 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[C:24]([O:23][C:21]([NH:20][C:14]1([C:17]([O:19][CH3:28])=[O:18])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.4 %

Procedure:
To an ice-cold solution of 1-((benzyloxy)carbonyl)-4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylic acid (0.50 g, 1.32 mmol) in ACN (15 mL) was added Cs2CO3 (0.52 g, 1.59 mmol) and the resulting reaction mixture stirred at the same temperature for 10 min followed by addition of MeI (0.4 mL, 4.2 mmol). The reaction mixture was stirred for 1 h at rt. After completion of reaction (by TLC), the mixture was passed through celite and solvent was evaporated under reduced pressure to obtain a white solid compound (0.52 g, 96% yield). MS: 393.31 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12]Cl)[CH2:8]CCl)([CH3:4])([CH3:3])[CH3:2].[C:15]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:27])[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[C:36](=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:20]([O:19][C:17]([C:16]1([C:15]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[CH2:36][CH2:12][CH2:11][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14])[CH2:8]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: O=C([O-])[O-]
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)OCc2ccccc2)(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of N,N-bis(2-chloroethyl)carbamic acid tert-butyl ester (1.22 g 5 mmol), dibenzyl malonate (1.42 g 5 mmol), potassium carbonate (1.38 g 10 mmol) and tetrabutylammonium bromide (0.5 g 1.55 mmol) in toluene (20 mL) is heated under reflux. Additional portion of tetrabutylammonium bromide (0.5 g 1.55 mmol) is added after 2 h reflux (twice). After further heating for 2 h (overall 6 h heating) the mixture is cooled back to room temperature and diethyl oxyde is added (50 mL). The organic phase is washed with water, dried and concentrated under reduced pressure. Purification by column chromatography affords piperidine-1,3,3-tricarboxylic acid 1-tert-butyl 3,3-dibenzyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([CH3:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1.ClC1C=CC(OCC(Cl)=O)=C(C)C=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]4[C:30]5[C:35]([CH:36]=[CH:37][C:22]3=4)=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:17][CH:16]=2)=[O:10])=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1OCC(=O)O
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: Cc1cc(Cl)ccc1OCC(=O)Cl
Product: Cc1cc(Cl)ccc1OCC(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 99 %

Procedure:
(4-Chloro-2-methylphenoxy)acetic acid (38 mg, 0.189 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, and (4-chloro-2-methylphenoxy)acetic acid chloride mentioned above, the title compound (47 mg, yield 99%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [OH-].[Na+].[CH:3]([CH:6]([C@H:16]1[CH2:19][C@H:18](C2C=C([N+]([O-])=O)C=CC=2C([O-])=O)[CH2:17]1)[C:7]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[O:8][SiH3:9])([CH3:5])[CH3:4].CC(O)=[O:34]>O1CCOCC1>[CH:3]([CH:6]([C@H:16]1[CH2:17][C@H:18]([OH:34])[CH2:19]1)[C:7]([CH:10]([CH3:11])[CH3:12])([CH:13]([CH3:15])[CH3:14])[O:8][SiH3:9])([CH3:4])[CH3:5]
Reactant: CC(=O)O
Reactant: CC(C)C([C@H]1C[C@H](c2cc([N+](=O)[O-])ccc2C(=O)[O-])C1)C(O[SiH3])(C(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)C([C@H]1C[C@H](O)C1)C(O[SiH3])(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
Aqueous NaOH (0.4 mol/L, 12 mL, 4.56 mmol) was added to a stirred solution of trans-3-(triisopropyl-siloxyethyl)cyclobutyl-4-nitrobenzoate (0.96 g, 2.28 mmol) in 18 mL 1,4-dioxane at ambient temperature. After 1 hr, AcOH was added drop by drop. After 5 min, the reaction mixture was concentrated by rotovap. The residue was partitioned between EtOAc (10 mL) and saturated NaHCO3 (2×10 mL). The organic phase was dried over MgSO4 and solvent evaporation gave light yellow oil (0.57 g, 92.3%, Rf=0.23 (Hexane:EtOAc=9:1)). 1H NMR (CDCl3, 300 MHz): δ 1.00-1.07 (m, 21H), 1.63-1.70 (m, 2H), 1.78 (bs, 1H), 1.99-2.10 (m, 4H), 2.24-2.38 (m, 1H), 3.61-3.65 (t, J=6.6, 2H), 4.35-4.44 (m, 1H). 13C NMR (CDCl3, 75 MHz): δ 12.23, 18.29, 24.24, 38.05, 39.37, 62.27, 66.82. MS (FAB): expected for C15H32O2Si (M+H)+ 273.50. Found 273.22456.
Reaction SMILES: [C:1]1([NH:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][Cl:19]>C1(C)C(C)=CC=CC=1>[Cl:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][Cl:19])[S:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)Nc1ccccc1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=S(=O)(Nc1ccccc1)N(CCCl)CCCl
Temperature: 100 °C

Procedure:
66 g of the product obtained in Step 1 above are added to a suspension of 38.6 g of N,N-bis(2-chloroethyl)amine hydrochloride in 265 ml of xylene heated to 100° C. The reaction mixture is heated at 140° C. for 12 hours and, after cooling, filtered over a frit. The filtrate is concentrated and then purified by flash chromatography (eluant CH2Cl2/AcOEt: 95/5) to yield the expected product.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+:9].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([O-:12])=[O:11].C(O)(=O)CC(O)=O>CC(O)C>[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([C@@H:17]([CH2:2][C:1]([OH:4])=[O:3])[NH2:9])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: [NH4+]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: O=C(O)CC(=O)O
Solvent: CC(C)O
Product: N[C@H](CC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 85 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
Acetic acid (110 ml) was mixed with 20.4 g of ammonium acetate (264 mmol) and heated to 85° C. After ammonium acetate was dissolved, the mixture was further mixed with 20.0 g of p-nitro-benzaldehyde (132 mmol) and 27.8 g of malonic acid (264 mmol) and heated at 90° C. with stirring for 5 hours. After being cooled to room temperature, the filtrate was mixed with 300 ml of 2-propanol. The precipitated crystal was filtered, subjected to slurry washing with 100 ml of ethanol, filtered again and dried under reduced pressure to give 14.4 g of p-nitro-β-phenylalanine at a yield of 52.0%.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[P:20](Cl)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21].C(O)(=O)C>C1COCC1.CCOCC>[O:10]=[C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH:11]1[P:20](=[O:21])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOP(=O)(Cl)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C1CCc2ccccc2C1=O
Temperature: -65 °C

Procedure:
A solution of α-tetralone (10 g, 68 mmol) in anhydrous THF (120 ml) is added dropwise to 1M lithium diisopropylamide solution (75 .mol, 75 ml) stirred at -65° C. under nitrogen. After stirring for 45 minutes, diethyl chlorophosphate (12.90 g, 75 mmol) is added to the enolate formed and the temperature of the mixture is progressively raised to 0° C. over a period of 50 minutes. After cooling to -70° C., the mixture is transferred to 2M lithium diisopropylamide solution (150 mmol, 75 ml). The solution obtained is stirred for 2 hours at 10° C. and then treated with acetic acid (272 mmol, 15.5 ml) in ether (250 ml). The mixture is filtered and the filtrate is concentrated. The title compound is obtained by purification on a flash column (eluant: cyclohexane/EtOAc=60/40).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[N:10]2[CH3:22])=[CH:5][C:4]=1[S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26].O>CO.C(N(CC)CC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:22])[C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[S:12][CH:13]=2)=[CH:5][C:4]=1[S:24](=[O:29])(=[O:28])[N:25]([CH3:26])[CH3:27]
Reactant: CN1C(=Nc2ccccc2Cl)SCC1(O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Agent: Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccccc3Cl)n2C)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.8 g of 4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(2-chlorophenyl-imino)-3-methylthiazolidin-4-ol hydrobromide are heated at the boil in a mixture of 100 ml of methanol and 10 ml of triethylamine for 30 minutes and the reaction mixture is then poured into an equal volume of water. The resulting mixture is stirred for about 2 hours at room temperature and the crystals are filtered off and recrystallized from ethanol. Melting point 153°-156° C.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:4].[Li][CH2:19]CCC.CI>O1CCCC1>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[C:7]=1[CH3:19])=[O:4]
Reactant: [Li]CCCC
Reactant: CC(C)(C)C(=O)Nc1cccc(C(F)(F)F)c1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(NC(=O)C(C)(C)C)cccc1C(F)(F)F
Temperature: 5 °C
Yield: 80 %

Procedure:
A solution of 2,2-dimethyl-3'-trifluoromethyl-propionanilide (6.1 g, 25 mmol) in 100 ml dry tetrahydrofuran was cooled to 0° C. under nitrogen atmosphere and a solution of n-BuLi (1.6M in hexane, 50 ml, 75 mmol) was added dropwise in such a rate that the internal temperature did not rise above 10° C. (about 20 min.) and it was stirred at that temperature for 10 more minutes during which time a grayish turbidity appeared. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2.5 hours. It was cooled to about 5° C. again and a solution of methyl iodide (4.258 g, 30 mmol) in tetrahydrofuran (10 ml.) was slowly transferred via a canula. It was stirred at room temperature for 4 hours and then quenched with water. The solution was concentrated in vacuo and then diluted with water and acidified with dilute HCl. It was then extracted with ether, and the ethereal extracts were washed with water followed by brine. The ether extract was dried with MgSO4 and concentrated to give a light yellow creamy solid (6.2 g., 95%). This was purified by crystallization from dichloromethane and petroleum ether mixture to afford colorless needles of 2,2,2'-trimethyl-3'-trifluoromethyl-propionanilide (80-85%, m.p. 122.5° C.).
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH3:6])(=O)C>CO.[OH-].[Na+]>[OH:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][N:14]=2)=[CH:11][CH:12]=1)[CH3:6]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)OC(C)=O)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
4 g of the above product (-)-(4-(1-acetoxy-ethyl)phenyl)-5-decyloxypyrimidine was dissolved in a mixture of 50 ml of methanol and 10 ml of a 20% sodium hydroxide solution, stirred at 30° C. for 2 hours and hydrolyzed, and the resulting reaction solution was extracted by adding 200 ml of water and 200 ml of toluene, followed by liquid separation. The obtained organic layer was dried over anhydrous magnesium sulfate and cleared of solvent in vacuo to yield 3.5 g of (-)-(4-(1-hydroxy-ethyl)phenyl)-5-decyloxypyrimidine as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[CH3:24][O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[CH3:24][O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4
Reactant: COC(=O)CCCBr
Reactant: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)CCCOc1ccc2c(c1)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
9-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound J5, 30 mg, 0.099 mmol), 4-bromo-butyric acid methyl ester (24.9 μl, 0.198 mmol) and cesium carbonate (64.5 mg, 0.198 mmol) were dissolved in DMA (0.20 ml) and stirred at room temperature for 4 hr. Water was added to the reaction solution, which was then extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The yellow solid obtained after concentration under reduced pressure was purified by silica gel column chromatography (methylene chloride/MeOH) to obtain 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-butyric acid methyl ester as an intermediate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)CCC>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]2)[N:3]=1
Reactant: O=C(O)CC1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2nc(N3CCC(CC(=O)O)CC3)nc(N)c2cc1OC
Yield: 74.3 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (17.3 g), piperidine-4-acetic acid hydrochloride (12.0 g) and triethylamine (20 ml) in n-butanol (500 ml) were stirred under reflux for 20 hours. The mixture was then cooled to 0°-4° and the separated product collected. The solid was slurried with acetone (100 ml), filtered, slurried with chloroform (100 ml), filtered and washed with ether to give 4-amino-2-(4-carboxymethylpiperidino)-6,7-dimethoxyquinazoline hydrochloride (19.0 g). A sample was recrystallised from acetic acid and had an m.p. of 250°-252°.
Reaction SMILES: O1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8]C#N.[OH-:11].[Na+:12].[C:13](=[O:15])=[O:14]>C(O)C.C(#N)C>[O:11]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:13]([O-:15])=[O:14].[Na+:12]
Reactant: N#CCOC1CCCCO1
Reactant: O=C=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: O=C([O-])COC1CCCCO1

Procedure:
To a solution of tetrahydropyran-2-yloxyethanonitrile (6.0 g, 42.49 mmol) in ethanol (15 ml) was added aqueous sodium hydroxide solution (10M, 15 ml). Following the initial exothermic reaction the solution was heated under reflux for 1.5 hours, diluted with ethanol (30 ml) and the pH adjusted to 8 by the addition of carbon dioxide pellets. The resulting gelatinous suspension was diluted with acetonitrile (60 ml), filtered at 60° C. through diatomaceous earth and the insoluble material extracted in a similar manner with a mixture of acetonitrile/ethanol/water (4:3:1, 2×120 ml). The crude product was purified by dissolution in warm isopropanol, filtration at 0° C. through diatomaceous earth, evaporation of the solvent in vacuo and trituration of the residue with acetone at 0° C. to yield sodium tetrahydropyran-2-yloxyethanoate (6.24 g, 34.26 mmol) as a colorless powder, m.p. 198°-205° C.;
Reaction SMILES: C([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=O.CC1C([P+](OC(C)=O)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=CC=1.O>C1(C)C=CC=CC=1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:3]=1
Reactant: O=Cc1ccc2ccccc2n1
Agent: CC(=O)O[P+](c1ccccc1)(c1ccccc1)c1ccccc1C
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2ncccc2c1

Procedure:
0.2 g (1.27 mmol) of 2-formylquinoline is dissolved in 10 ml of anhydrous toluene, in a dry round-bottomed flask equipped with a magnetic stirrer and a nitrogen inlet. 0.51 g (1.52 mmol) of methyl(triphenylphosphoranylidene) acetate is added. The reaction mixture is brought to the reflux temperature of toluene for 90 minutes, and the solution is then slowly returned to ambient temperature and hydrolyzed with 10 ml of water.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[CH2:13])=[CH:7][C:6]=1[O:14][CH3:15])=[O:3].[CH2:16]([OH:20])[CH2:17][CH2:18][OH:19]>>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([CH2:11][CH:12]=[CH2:13])[CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:19][CH2:18][CH2:17][CH2:16][OH:20])=[O:3]
Reactant: C=CCc1ccc(OC(=O)Cl)c(OC)c1
Reactant: OCCCO
Product: C=CCc1ccc(OC(=O)OCCCO)c(OC)c1

Procedure:
The reaction of 2-methoxy-4-allylphenyl chloroformate with 1,3-propanediol yields 1-(2-methoxy-4-allylphenoxycarbonyloxy)-3-propanol.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].CCOCC.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O:5][CH2:4][CH:2]1[O:3][CH2:1]1)=[O:15]
Reactant: OCC1CO1
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCC1CO1)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A mixture containing 37 g (0.5 mole) of glycidol, 500 ml of anhydrous ether, 500 ml of pyridine and 80 g (0.5 mole) of o-fluoro-benzoyl chloride was stirred at 0° C. for 1 hour and 25° C. for 2 hours. The mixture was filtered and the ethanol filtrate was washed with 100 ml of 5% HCl. Evaporation of the ether gave an oil which was distilled to give 69.5 g (71%) of product, b.p. 115° C./0.5 mmHg. The NMR and IR spectra were consistent with the assigned structure.