Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:12]=[N:11][NH:10][C:9](=[O:13])[C:8]=1Cl)(=[O:3])[CH3:2].C(O)=O.C([O-])=O.[NH4+]>[Pd].C(O)C>[C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:12]=[N:11][NH:10][C:9](=[O:13])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1Oc1cn[nH]c(=O)c1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O=CO
Product: CC(=O)c1ccccc1Oc1cn[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
A suspension of 5-(2-acetyl-phenoxy)-4-chloro-2H-pyridazin-3-one (6 g, 0.0227 mol) and palladium on carbon (2.5 g) in ethanol (180 mL) was heated to reflux and then treated with formic acid (1.2 g, 0.023 mol). The reaction stirred for 10 min at reflux and then ammonium formate (1.43 g, 0.023 mol) was added. The reaction stirred at reflux for another 10 min. At this time, a second portion of ammonium formate (0.3 g, 0.0048 mol) was added. After 5 min, the reaction was cooled to 25° C. and filtered. The filtrate was concentrated in vacuo to afford 5-(2-acetyl-phenoxy)-2H-pyridazin-3-one (4.7 g, 90%); ESI-MS 231 [M+H+].
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]3[CH3:22])=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[CH:46]1([S:49]([NH2:52])(=[O:51])=[O:50])[CH2:48][CH2:47]1.Cl>O1CCCC1>[CH:1]1([C:4]2[C:5]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]3[CH3:22])=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([NH:52][S:49]([CH:46]2[CH2:48][CH2:47]2)(=[O:51])=[O:50])=[O:11])[CH2:2][CH2:3]1
Reactant: CC1CCCCC1COc1cc(F)c(C(=O)O)cc1C1CC1
Reactant: NS(=O)(=O)C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC1CCCCC1COc1cc(F)c(C(=O)NS(=O)(=O)C2CC2)cc1C1CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred solution of 5-cyclopropyl-2-fluoro-4-((2-methylcyclohexyl)-methoxy)benzoic acid (0.093 g, 0.305 mmol) in tetrahydrofuran (2 mL) under an atmosphere of nitrogen was added carbonyldiimidazole (0.074 g, 0.457 mmol) and the reaction mixture was stirred at 70° C. for 1 hour. The mixture was cooled to room temperature and 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.07 mL, 0.45 mmol) was added followed by cyclopropanesulfonamide (0.06 mg, 0.52 mmol). Stirring was continued at ambient temperature for 18 hours. 5% aqueous hydrochloric acid solution (0.15 mL) was added and the mixture was concentrated and directly purified by column chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.05 g, 43%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.79-8.58 (m, 1H), 7.56 (d, J=9.1 Hz, 1H), 6.57 (d, J=14.5 Hz, 1H), 3.87 (dd, J=7.0, 2.7 Hz, 2H), 3.08 (tt, J=8.1, 8.1, 4.8, 4.8 Hz, 1H), 2.21-1.93 (m, 3H), 1.76-1.35 (m, 9H), 1.13 (dq, J=6.20, 6.08, 1.31 Hz, 2H), 0.98-0.86 (m, 5H), 0.68-0.59 (m, 2H); MS (ES+) m/z 410.1 (M+1); MS (ES−) m/z 408.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11]O>Cl>[CH3:11][O:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1)=[O:10]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a slurry of 2.0 g of 6-chloro-3-pyridinecarboxylic acid (Aldrich, 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233 USA) in methanol (200 ml) was added two drops of concentrated aqueous hydrochloric acid and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated to give 1.5 g (71%) of product as a white solid. mp 90°-92° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8](/[CH:15]=[CH:16]/[CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[CH:36]=[C:35]([CH2:37]Cl)[CH:34]=[CH:33][C:32]=1[C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[C:32]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:33][CH:34]=[C:35]([CH2:37][O:1][C:2]2[CH:3]=[CH:4][C:5]([C@H:8](/[CH:15]=[CH:16]/[CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)[CH:36]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOc1ccc(OC)cc1-c1cc(CCl)ccc1C(C)(C)C
Reactant: C/C=C/[C@H](CC(=O)OCC)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C/C=C/[C@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3OCCCC)c2)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of compound B (11 mg, 47 μmol), compound C (17 mg, 47 μmol), and cesium carbonate (23 mg, 70 μmol) in DMF (1.0 mL) was stirred for 16 hours at 23° C. The mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford compound 11.1 (21 mg, 81% yield) as a colorless oil. MS ESI (pos.) m/e: 576 (M+H2O), 581 (M+Na).
Reaction SMILES: [CH2:1]1[CH2:11]C[N:9]2[C:4](=NCCC2)[CH2:3][CH2:2]1.[C:12]([O:16][C:17](=[O:21])CC#N)([CH3:15])([CH3:14])[CH3:13].BrCCCBr>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C:17]([C:3]1([C:4]#[N:9])[CH2:2][CH2:1][CH2:11]1)=[O:21])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1(C#N)CCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
DBU (23.5 mL) was added slowly to a solution of cyano-acetic acid tert-butyl ester (8.84 g) in DMF (100 mL) at rt, followed by addition of 1,3-dibromopropane (13.9 g); then the reaction mixture was stirred in an oil bath (bath temperature=80° C.) overnight. The reaction was cooled, diluted with EtOAc, then washed with cold water, dil. NaCl solution; EtOAc phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was column purified to give title compound (6.58 g). 1H NMR in CDCl3, δ in ppm: 2.8-2.5 (m, 4H), 2.4-2.2 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:13][CH2:14][C@:15]1([F:28])[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:12][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([NH:13][CH2:14][C@:15]2([F:28])[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16]2)[N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CN)C1
Reactant: Clc1cc2ncccc2c(Cl)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(CNc2nc(Cl)cc3ncccc23)C1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To 5,7-dichloro-1,6-naphthyridine (5.01 g, 25.2 mmol) and 1,1-dimethylethyl (3R)-3-(aminomethyl)-3-fluoro-1-piperidinecarboxylate (5.32 g, 22.90 mmol) in NMP (20 ml) was added DIPEA (8.00 ml, 45.8 mmol) and the mixture was stirred at 100° C. for 72 h under nitrogen. The reaction was cooled and partitioned between ethyl acetate and water (200 ml each). The aqueous was washed with ethyl acetate. The combined organics were washed with water and the solvent was removed. The residue was dissolved in DCM and loaded onto a 100 g silica SNAP column and purified on the SP4 eluting with 0-50% ethyl acetate in cyclohexane over 17 CVs. Appropriate fractions were combined and the solvent was removed to give the title compound as a pale orange solid which was dried under high vacuum for 2 h (7.61 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][C@H:17]([CH3:19])[C@@H:16]([CH3:20])[C@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1.CCCC1C2C3OC(C)(C)C=CC=3C3O[C@@H](C)[C@H](C)[C@@H](O)C=3C=2OC(=O)C=1.CCCCCC.C(OCC)(=O)C>CCCCCC.C(O)C>[CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][CH:17]([CH3:19])[CH:16]([CH3:20])[CH:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@H](C)[C@@H](C)[C@@H]3O
Agent: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@@H](C)[C@H](C)[C@H]3O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)OC(C)C(C)C3O

Procedure:
The synthetic (±)-1 was resolved into enantiomers, (+)-calanolide A and (-) calanolide A, by preparative HPLC. Thus, using a normal phase silica gel HPLC column (250 mm×4.6 mm I.D. Zorbasil, 5 μm particle size, MAC-MOD Analytical, Inc., Pennsylvania, USA), the synthetic (±)-1 appeared as one peak with a retention time of 10.15 minutes when hexane/ethyl acetate (70:30) was used as the mobile phase at a flow rate of 1.5 mL/min and a wavelength of 290 nm was used as the uv detector setting. However, on a chiral HPLC column packed with amylose carbamate (250 mm×4.6 mm I.D. Chiralpak AD, 10 μm particle size, Chiral Technologies, Inc., Pennsylvania, USA), two peaks with retention times of 6.39 and 7.15 minutes in a ratio of 1:1 were observed at a flow rate of 1.5 mL/min. The mobile phase was hexane/ethanol (95:5) and the uv detector was set at a wavelength of 254 nm. These two components were separated using a semi-preparative chiral HPLC column, providing the pure enantiomers of calanolide A. The chemical structures of the separated enantiomers, which were assigned based on their optical rotations and compared with the reported natural product, were characterized by spectroscopic data. HPLC chromatograms (±)-calanolide A and its optical forms are shown in FIG. 6.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:22])[C:8]([CH2:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+].O>C(O)(=O)C.CO>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:22])[C:8]([CH2:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc(N)cc2)c(C#N)c(CC)n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(NCc3ccccc3)cc2)c(C#N)c(CC)n1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add 3-(4-amino-phenyl)-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.297 g, 1.0 mmol, prepared in example E-153), benzaldehyde (0.106 g, 1.0 mmol), and one drop of acetic acid in methanol with stirring at room temperature. After 4 hours, add sodium borohydride (0.075 g, 2.0 mmol) portionwise and continue stirring at room temperature. After 18 hours, pour the reaction mixture into water and extract with EtOAc. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 388.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10](Cl)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16]>C(O)CCC>[C:1]1([C:7]2[N:12]=[N:11][C:10]([NH:16][NH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Product: CCOC(=O)NNc1ccc(-c2ccccc2)nn1

Procedure:
A mixture of 15.0 g. of 6-phenyl-3-chloropyridazine, 16.3 g. of ethyl carbazate, and 250 ml. of n-butanol is refluxed for 3 hours. The solvent is removed under vacuum and the residue triturated with cold water. Filtration gives 18.6 g. of cream colored crystals. Recrystallization gives white crystals, m.p. 158°-160° C.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[S:5].[Cl:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:18][CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][C:2]([CH3:1])([CH3:17])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[S:5]
Reactant: CCOC(=S)CC(C)(C)CCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=S)CC(C)(C)CC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.06 g (3.09 mmol) of ethyl 3,3-dimethyl-5-phenylthiopentanoate in 10 mL of carbon tetrachloride was added 590 mg (4.4 mmol) of 1-chloro-2,5-pyrrolidinedione, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate concentrated to give ethyl 5-chloro-3,3-dimethyl-5-phenylthiopentanoate as an oil. The product was used without further purification in the reaction described in Example 3 below. NMR Data (CDCl3):
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C([N:12]([CH2:15]C)CC)C.C(OC(Cl)=O)C(C)C.C[N:26](C)C=O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:9][N:12]=[CH:15][N:26]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccccn1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: c1ccc(-c2ncno2)nc1
Reaction time: 2 h

Procedure:
A mixture of picolinic acid (62 mg, 0.5 mmol) and triethylamine (202 mg, 2 mmol) in tetrahydrofuran (1 mL) was treated with isobutylchloroformate (0.059 ml, 0.55 mmol) at room temperature. The mixture was stirred for 2 hours and treated with 3-fluoro-5-(1H-imidazol-1-yl)]phenyl-amidoxime (100 mg, 0.45 mmol). The mixture was then heated in dimethylformamide (1 mL) at 130° C. overnight. Standard work up, afforded 24.4 mg (17.6%) 3-[3-fluoro-5-(1H-imidazol-1-yl)]phenyl]-5-(2-pyridyl)-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 8.90 (d, 1H), 8.32 (d, 1H), 8.10 (s, 1H), 7.7.98 (m, 3H), 7.58 (dd, 1H), 7.39 (s, 1H), 7.29 (m, 2H).
Reaction SMILES: C(OCC)(=O)CC(OCC)=O.[CH2:12]([CH:16]([C:22]([O:24]CC)=[O:23])[C:17]([O:19]CC)=[O:18])[CH:13]([CH3:15])[CH3:14].[OH-].[K+]>CO.O>[CH2:12]([CH:16]([C:22]([OH:24])=[O:23])[C:17]([OH:19])=[O:18])[CH:13]([CH3:15])[CH3:14]
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: O
Solvent: CO
Product: CC(C)CC(C(=O)O)C(=O)O
Yield: 83.9 %

Procedure:
To a solution of sodium ethoxide obtained from 46.0 g (2.00 mol) of sodium lump and 1000 cm3 of anhydrous ethanol 320 g (2.00 mol) of diethyl malonate was added at room temperature. The obtained mixture was stirred for 30 min at this temperature, and then 274 g (2.00 mol) of isobutylbromide was added. The resulting mixture was refluxed for 5 h, and then ethanol was distilled off. To the cooled residue 1500 ml of cold water and 500 ml of ethyl acetate were added. The organic layer was separated, dried over Na2SO4 and then evaporated to dryness. Fractional rectification of the residue gave 357 g of colorless liquid, bp 177-187° C./220 mm Hg. This product contained ca. 10% of diethyl malonate. To a solution of 117.3 g (542 mmol) of diethyl isobutylmalonate in 500 ml of methanol a solution of 125 g of potassium hydroxide in 1000 cm3 of water was added. The resulting mixture was refluxed for 5 h, then ethanol and methanol were distilled off. Further on, 1000 cm3 of water was added, and then this mixture was acidified by 12 M HCl to pH 1.0. Isobutylmalonic acid was extracted by 4×500 ml of ether. The combined extract was evaporated to dryness. To the residue 300 ml of toluene was added. Again, the obtained mixture was evaporated to dryness to remove moisture. To a solution of the residue in 150 ml of toluene 500 ml of hexanes was added. The formed precipitate was filtered off, washed by 50 ml of hexanes and dried in vacuum. This procedure gave 72.8 g (84%) of the title product as white crystalline solid.
Reaction SMILES: [S:1]([CH2:10][CH2:11][NH:12][C:13](=[O:16])[CH2:14]Cl)[S:2][CH2:3][CH2:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8].[N:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>CN1C(=O)CCC1>[Cl-:8].[Cl-:8].[S:1]([CH2:10][CH2:11][NH:12][C:13](=[O:16])[CH2:14][N+:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[S:2][CH2:3][CH2:4][NH:5][C:6](=[O:9])[CH2:7][N+:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1
Reactant: O=C(CCl)NCCSSCCNC(=O)CCl
Reactant: Cc1ccncc1
Solvent: CN1CCCC1=O
Product: Cc1cc[n+](CC(=O)NCCSSCCNC(=O)C[n+]2ccc(C)cc2)cc1
Product: [Cl-]
Reaction time: 19 h

Procedure:
6.1 g of N,N′-(disulfanediyldiethane-2,1-diyl)bis(2-chloroacetamide) and 4.5 g of 4-picoline was dissolved in 50 ml of NMP and brought to 80° C. for 19 h. After cooling the mixture, with successive precipitations from acetone and drying under vacuum, 9.2 g of salts were recovered. The analyses showed that the product was in conformity. 1H NMR (400 MHz, D2O): 2.61 (s, 6H), 2.82 (t, 4H), 3.56 (t, 4H), 5.31 (s, 4H), 7.85 (d, 4H), 8.51 (d, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[N:5][CH:4]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C>CS(C)=O.O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[C:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[N:5][CH:4]=[C:3]2[CH2:2][N:39]1[CH2:40][CH2:41][N:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])[CH2:37][CH2:38]1
Reactant: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Reactant: COc1ccccc1N1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(Cc2ncc(CN3CCN(c4ccccc4OC)CC3)c3cc(OC)c(OC)cc23)cc1OC
Yield: 79.2 %

Procedure:
A mixture of 10.0 g of 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline, 5.5 g of 1-(2-methoxyphenyl)piperazine, and 7.6 ml of triethylamine in 100 ml of dimethylsulfoxide was heated at 80° for one hour under argon. The cooled solution was then diluted with water and extracted with methylene chloride. The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, charcoaled, and evaporated. The residue was crystallized from ethanol to give 11.1 g of 6,7-dimethoxy-1-{(3,4-dimethoxyphenyl)methyl}-4-([4-(2-methoxyphenyl)-1-piperazinyl]methyl)isoquinoline as a yellow solid, mp 117°-119°.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][OH:15])[N:12]=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:20][C:19]([F:21])([F:22])[C:17]1[CH:16]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:18]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][O:15][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)[N:12]=1
Reactant: OCCn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(CNc2nnn(CCOC3CCCCO3)n2)cc(C(F)(F)F)c1

Procedure:
A mixture of 2-(5-{N-[3,5-bis(trifluoromethyl)benzyl]amino}tetrazol-2-yl)ethanol (0.68 g, 1.9 mmol), 3,4-dihydro-2H-pyran (DHP, 0.35 g, 4.2 mmol) and a catalytic amount of pyridinium p-toluene sulfonate (PPTS, 0.050 g, 0.20 mmol) in CH2Cl2 (10 mL) is stirred at room temperature for 10 hours. The resulting mixture is quenched by addition of sat. NaHCO3 aq. and extracted with EtOAc. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give N-[3,5-bis(trifluoromethyl)benzyl]-N-{2-[2-(tetrahydropyran-2-yloxy)ethyl]-2H-tetrazol-5-yl}amine.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[ClH:6]>>[Cl:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5].[Cl:6][C:3]([CH3:4])([CH:2]=[CH2:1])[CH3:5]
Reactant: Cl
Reactant: C=CC(=C)C
Product: C=CC(C)(C)Cl
Product: CC(C)=CCCl

Procedure:
The chlorination of isoprene under normal conditions is less than straightforward and results in the formation of a variety of products. In a simple addition reaction involving loss of one double bond, dichlorides are formed such as 1,4-dichloro-2-methyl-2-butene and 1,2-dichloro-2-methyl-3-butene. A competing reaction, however, is one of substitution rather than addition in which a hydrogen ion is given up resulting in the formation of monochlorides such as 2-chloromethyl-1,3-butadiene and 1-chloro-2-methyl-1,3-butadiene. The substitution reaction produces HCl as a by-product which in turn reacts with unreacted isoprene in an HCl addition reaction to give hydrochlorides or monochlorobutenes such as 1-chloro-3-methyl-2-butene and 2-chloro-2-methyl-3-butene. In the preparation of the dichloride addition products, the formation of these monochloride substitution and HCl addition products constitutes an undesirable loss. Chlorination under conditions reported in the literature was found to result in discouragingly low weight yields of the 1,4- and 1,2-dichlorides, e.g., less than 50-60%, based on the weight of isoprene consumed. On a theory yield basis, which is moles of dichloride product per mole of isoprene consumed, this amounts to a yield of less than about 25-30%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27]Cl)[CH:20]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[Na].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)[CH:20]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: COc1cccc(-c2cn(-c3cccc(OCCCl)c3)c3ncnc(N)c23)c1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.8 g of 5-(3-methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine and 0.24 g of sodium imidazole are heated to 80° C. in 20 ml of DMF and stirred for 5 h. The mixture is then cooled to RT and treated with water, extracted 3 times with methylene chloride and concentrated. After chromatography on silica gel using methylene chloride/methanol 15:2 and crystallization from ether/methylene chloride, 5-(3-methoxy-phenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 138°-140° C. is obtained.
Reaction SMILES: [C:1]([C:4]1[C:5]([F:19])=[C:6]2[O:10][C:9]([CH:11]3[CH2:13][CH2:12]3)=[N:8][C:7]2=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16])(=O)[CH3:2].[C:20](OCC)(=O)C>O1CCCC1.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[CH:11]1([C:9]2[O:10][C:6]3[C:7](=[C:14]([C:17]#[N:18])[C:15]([CH3:16])=[C:4]([C:1]([CH3:20])=[CH2:2])[C:5]=3[F:19])[N:8]=2)[CH2:13][CH2:12]1
Reactant: CC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Reactant: CCOC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C(C)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
Under nitrogen atmosphere, zinc (520 mg, 0.79 mmol) was suspended in tetrahydrofuran (8 ml), then diiodomethyl (320 μl, 3.97 mmol) was added to the suspension, followed by stirring at room temperature for 30 minutes. The reaction liquid was cooled to 0° C. then titanium tetrachloride (794 μl 0794 mmol) was dropwise added, followed by stirring at room temperature for 30 minutes. After 30 minutes, 6-acetyl-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-82) (205 mg, 0-794 mmol) dissolved in tetrahydrofuran (2 ml) was dropwise added to the reaction liquid, followed by stirring at room temperature for 30 minutes. Ethyl acetate was added to the reaction liquid, followed by washing with 1 N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=4:1, v/v) to obtain the entitled compound (35 mg, 17%) as a white crystal.