Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClCCl>[Br:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Temperature: 25 °C

Procedure:
A solution of methyl-o-toluate (0.93 mL, 6.6 mmol), N-bromosuccinimide (1.25 g, 7.0 mmol) and azaisobutryonitrile (11 mg, 0.07 mmol) in chloroform (10 mL) was heated at 65° for 16 h. After cooling to rt, the mixture was diluted with dichloromethane and washed with H2O and then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give methyl 2-(bromomethyl)benzoate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].Cl.Cl.[CH3:18][N:19]([CH3:29])[CH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH2:21][CH2:20][N:19]([CH3:18])[CH3:29])[CH2:23][CH2:24]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)CC[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CCN(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with trans-4-[2-(dimethylamino)ethyl]cyclohexanamine dihydrochloride (300 mg, 1.2 mmol) to afford the desired product (140 mg, 36%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 10.88 (br s, 1H), 8.93 (s, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 5.04-4.96 (m, 1H), 2.67 (s, 3H), 2.36-2.22 (m, 4H), 2.24 (s, 6 H), 1.93-1.83 (dd, J=13.9, 3.5 Hz, 2H), 1.49-1.31 (m, 5H), 1.27-1.15 (m, 2H); ESI MS m/z 375 [M+H]+
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([I:14])[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:15]([NH:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:16]>CN(C)C=O>[CH2:21]([N:20]([CH2:23][CH3:24])[CH2:19][CH2:18][NH:17][C:15]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:4]=1[F:1])=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[O:16])[CH3:22]
Reactant: [F-]
Reactant: CCN(CC)CCNC(=O)c1cnc2ccc(I)cc2c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cnc2ccc(I)cc2c1F
Temperature: 200 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
Potassium fluoride (674 mg, 11.6 mmol) was dried under vacuum and stirring, at 200° C. for 3 h. After cooling to room temperature, a solution of compound 95 (1.00 g, 2.32 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added. The mixture was then heated at 130° C., under argon, for 2 h. After cooling to room temperature, the solvent was evaporated under vacuum and the residue was chromatographed (Al2O3, AcOEt/cyclohexane, 9/1, v/v) to give compound 96 (0.50 g, 1.20 mmol) as a yellow solid. Yield 52%; Rf (Al2O3, AcOEt/cyclohexane, 9/1, v/v) 0.46; mp 88-90° C.; IR (KBr) ν 1105, 1342, 1518, 1656, 2830, 2966, 3405 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.07 (t, 6H, J=7.1 Hz), 2.59 (q, 4H, J=7.1 Hz), 2.69 (t, 2H, J=5.9 Hz), 3.57 (q, 2H, J=5.9 Hz), 7.58 (se, 1H), 7.86 (d, 1H, J=9.0 Hz), 8.06 (dd, 1H, J=1.8, 9.0 Hz), 8.54 (d, 1H, J=1.8 Hz), 9.44 (d, 1H, 4JH-F=10.6 Hz); MS m/z 415 (M+, 1), 299 (3), 145 (1), 118 (3), 86 (100), 58 (9).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6][C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2.[Cl-].[Na+].ClC1C=CC=C(C(OO)=[O:30])C=1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6]([C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1ccccc1CSc1nc2ncccc2[nH]1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNc1ccccc1CS(=O)c1nc2ncccc2[nH]1
Reaction time: 0.25 h

Procedure:
In a mixture of 1 ml of methanol and 30 ml of chloroform was dissolved 1.5 g of 2-[2-(methylamino)benzylthio]imidazo[4,5-b]pyridine. To the resulting solution was portionwise added under chilling with ice and aqueous sodium chloride solution to -5° C. 1.08 g of m-chloroperbenzoic acid (purity: 80%) over a period of 20 min., maintaining the temperature of the solution at -5° C.±3° C. The reaction mixture was stirred for additional 15 min. at the same temperature, and to the mixture was added a saturated NaHCO3 solution. The resulting mixture was then stirred. The organic phase was separated and extracted with two portions of 14 ml of 0.1N NaOH. The alkaline extracts were combined and neutralized by NH4Cl, and the deposited oil was extracted with chloroform. The chloroform extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and placed under reduced pressure to distill of the solvent. The residue was crystallized by addition of acetonitrile to give 2-[2-(methylamino)benzylsulfinyl]imidazo[4,5-b]-pyridine. m.p.: 120° C. (decompn.)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>O1CCCC1>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[CH:7]=2)=[CH:10][C:11]=1[Cl:16]
Reactant: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)Oc3ccccc3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (707 mg) as disclosed in WO 02/32872 was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere, and then triethylamine (0.523 ml) and phenyl chloroformate (0.470 ml) were added dropwise thereto while cooling in an ice bath, followed by raising the temperature gradually to room temperature while stirring. After 6 hrs, the reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:2) to provide a crude product of 4-(4-amino-3-chlorophenoxy)-2-phenoxycarbonylaminopyridine (920 mg). The crude product was dissolved in N,N-dimethylformamide (9 ml), and then 2 M solution of ethylamine in tetrahydrofuran (4.5 ml) was added thereto, followed by stirring at room temperature for 23 hrs. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2). Fractions containing the target compound were concentrated to give a residue, to which hexane-ethyl acetate (5:1) was added to precipitate crystals. The crystals were filtered, and dried under aeration to provide the titled compound (298 mg, 32%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[Cl:1][C:2]1[C:7]([N:8]([CH3:21])[C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:18])([F:19])[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cccnc1Cl)c1ccccc1C(F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: CN(C(=O)c1ccccc1C(F)(F)F)c1cccnc1Cl
Temperature: 25 °C
Yield: 99.2 %

Procedure:
8.0 g N-(2-chloro-pyridin-3-yl)-2-trifluoromethyl-benzamide (26.6 mmol), 1.1 g potassium carbonate (K2CO3) (80 mmol), and 100 mL ethanol were added and stirred in a round-bottomed flask. 5.7 g methyl iodide (MeI) (40 mmol) was then added and reacted for 12 hr. After cooling to room temperature, the reaction was quenched by water. After extraction three times by ethyl acetate, removal of water by magnesium sulphate (MgSO4), concentration, and purification by column, 8.3 g white solid was obtained, with a yield of 88%.
Reaction SMILES: N#[C:2][Br:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C[CH2:13][S:14][C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[CH:16]=1>C(Cl)(Cl)Cl.CO>[Br:3][CH2:2][CH2:13][S:14][C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[CH:16]=1
Reactant: N#CBr
Reactant: CN(C)CCSC1=Cc2ccccc2Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: BrCCSC1=Cc2ccccc2Oc2ccccc21

Procedure:
To a stirring solution of 0.36 g of cyanogen bromide, 2.28 g of potassium carbonate in 10 ml of chloroform is added dropwise a solution of 1.0 g of 10-[β-(dimethylamino)ethylthio]dibenz[b,f]oxepin, Example 8, in chloroform. After total addition the reaction mixture is refluxed for 2 hours and the solvent removed leaving an oil. The oil is dissolved in 10 ml of methanol and the methanolic solution refluxed for 10 minutes and again concentrated to recover the oil. The oil is chromatographed through a silica gel column with an eluant of ether. The top fraction is collected and concentrated leaving a white solid, mp 106°-107° C. of 10-[β-(bromo)ethylthio]dibenz[b,f]oxepin.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH2:13][Cl:14])[N:3]=1.O.[NH2:16][NH2:17].C(=O)([O-])O.[Na+]>O1CCCC1.O>[Cl:14][CH2:13][C:4]1[N:3]=[C:2]([NH:16][NH2:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=1
Reactant: NN
Reactant: Cc1ccc2nc(CCl)nc(Cl)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2nc(CCl)nc(NN)c2c1
Temperature: 10 °C
Reaction time: 0.13 h

Procedure:
3. 63.5 g of 4-chloro-2-(chloromethyl)-6-methylquinazoline are dissolved in 630 ml of absolute tetrahydrofuran at room temperature and then cooled to 10° C. 27.2 ml of hydrazine hydrate are added dropwise thereto within 8 min., whereby a solution results and the temperature rises to 15° C. The reaction mixture is stirred at 5° to 15° C. for 4 h. and then poured into a solution of 40 g of sodium hydrogen carbonate in 5 l of water. The mixture is extracted five times with 1.5 l of dichloromethane each time. The combined organic phases are washed with water, dried and concentrated (T<40° C.) in a vacuum to a volume of 0.5 l. 0.5 l of ethyl acetate is added thereto and the dichloromethane is evaporated completely in a vacuum, whereby the product crystallizes out. The mixture is left to stand at -25° C. overnight and the crystals are filtered off, washed with diethyl ether and dried at room temperature in a vacuum. There are obtained 38 g of 2-(chloromethyl)-4-hydrazino-6-methylquinazoline of m.p. above 140° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[C@@H:14]([CH3:26])[CH2:13]2)=[N:4][N:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[N:27]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:19])[C@@H:14]([CH3:26])[CH2:13]3)=[N:4][N:3]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: c1c[nH]cn1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)c1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H]1CN(c2nnc(-n3ccnc3)c3ccccc23)CCN1C(=O)c1ccccc1
Temperature: 110 °C

Procedure:
Compound 77 was prepared as described in general Method I. A 15 mL Schlenk tube was charged with (S)-(4-(4-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl)(phenyl)methanone JK-4 (100 mg, 0.273 mmol), 1H-imidazole (22.3 mg, 0.328 mmol), copper (I) iodide (2.6 mg, 0.0136 mmol), potassium phosphate (122 mg, 0.573 mmol), trans-cyclohexanediamine (3.3 μl, 0.0273 mmol), and dioxane (0.75 mL). The vessel was evacuated, backfilled with argon 5 times, and then heated at 110° C. for 22 hours. After cooling, the reaction was then taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-100% ethyl acetate gave a white solid, compound 77. MS (M+H)+=399.2.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH3:17])[C:10]=1[CH:18]1[C:26](=[O:27])[CH:25]2[CH:20]([CH:21]3[O:28][CH:24]2[CH2:23][CH2:22]3)[C:19]1=[O:29])[CH3:8].C(N(CC)CC)C>ClCCl>[CH2:5]([O:4][C:2](=[O:3])[O:29][C:19]1[CH:20]2[CH:25]([C:26](=[O:27])[C:18]=1[C:10]1[C:11]([CH2:16][CH3:17])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH2:7][CH3:8])[CH:24]1[O:28][CH:21]2[CH2:22][CH2:23]1)[CH3:6]
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)C2C3CCC(O3)C2C1=O
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2c(CC)cc(C)cc2CC)C(=O)C2C3CCC(O3)C12
Temperature: 25 °C

Procedure:
A solution of ethyl chloroformate (0.071 g, 0.65 mmol) in dichloromethane (0.5 ml) is added dropwise to a solution of (1RS,2SR,6RS,7SR)-4-(2,6-diethyl-4-methylphenyl)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (0.172 g, 0.55 mmol) in dichloromethane (2 ml) at 0° C. and the reaction mixture is stirred. A solution of triethylamine (0.066 g, 0.65 mmol) in dichloromethane (1 ml) is added and the reaction mixture is stirred at room temperature for 17 hours, warming slowly to room temperature. The reaction mixture is diluted with dichloromethane (3 ml) and washed with saturated aqueous sodium bicarbonate solution. The organic phase is separated, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give carbonic acid (1RS, 2SR,6RS,7SR)-5-oxo-4-(2,6-diethyl-4-methylphenyl)-10-oxatricyclo-[5.2.1.02,6]-dec-3-en-3-yl ester ethyl ester as a colourless solid.
Reaction SMILES: [CH2:1]([C:8]1[N:16]([CH2:17][CH2:18][NH:19][CH2:20][CH3:21])[C:15]2[C:14](=[O:22])[N:13]([CH2:23][CH2:24][CH3:25])[C:12](=[O:26])[N:11]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=3)[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[H][H]>[Pd]>[NH2:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH2:27][N:11]2[C:10]3[N:9]=[C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:16]([CH2:17][CH2:18][NH:19][CH2:20][CH3:21])[C:15]=3[C:14](=[O:22])[N:13]([CH2:23][CH2:24][CH3:25])[C:12]2=[O:26])=[CH:34][CH:33]=1
Reactant: [H][H]
Reactant: CCCn1c(=O)c2c(nc(Cc3ccccc3)n2CCNCC)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2c(nc(Cc3ccccc3)n2CCNCC)n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 3, 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine, is reacted with sodium carbonate, 1,2-dichloroethane and ethylamine to yield 8-benzyl-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By the method of Example 4, 8-benzyl-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-propylxanthine free base. The corresponding dihydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [CH3:1][C:2]1([CH:8]([OH:23])[CH:9]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28].O>O1CCCC1>[CH3:1][C:2]1([CH:8]([O:23][CH2:28][CH:27]=[CH2:26])[CH:9]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:3][O:4][CH2:5][O:6][CH2:7]1
Reactant: C=CCBr
Reactant: CC1(C(O)C(Cc2ccc(Cl)cc2)n2cncn2)COCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(C(Cc1ccc(Cl)cc1)n1cncn1)C1(C)COCOC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A solution of 23.6 g (0.07 mole) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-3-(4-chlorophenyl)-propan-1-ol in 100 ml of tetrahydrofuran is added dropwise to a suspension of 2.4 g of sodium hydride in 120 ml of dry tetrahydrofuran. After stirring the mixture for 12 hours at 25° C, a solution of 9.7 g (0.08 mole) of allyl bromide in 20 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred for 36 hours, 20 ml of water are then added cautiously, and the batch is evaporated down. The residue is taken up in 350 ml of methylene chloride, the solution is washed with three times 100 ml of water, and the organic phase is dried and evaporated down. The residue is mixed with 30 ml of petroleum ether and 10 ml of ether and left to stand overnight at +3° C. The crystalline, colorless precipitate is filtered off, washed with petroleum ether and dried. 22.6 g (87.5%) of 1-(5-methyl-1,3-dioxan-5-yl)-1-allyloxy-2-(1,2,4-triazol-1-yl)-3-(4-chlorophenyl)-propane, of melting point 113°-115° C., are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:8][C:7]=2[CH:33]=1.[H-].[Na+].[CH3:36]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]([CH3:36])[C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[S:8][C:7]=2[CH:33]=1
Reactant: CCOC(=O)/C=C/c1ccc(Nc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N(C)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a solution of (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)amino)phenyl)acrylate (69.0 mg, 0.15 mmol) in DMF (6.0 mL) at room temperature was added NaH (60% suspension in oil, 139 mg, 3.48 mmol). After 15 min, methyl iodide (0.272 mL, 4.35 mmol) was added and the resulting solution was allowed to stir at room temperature for 45 min after which time the reaction was quenched with brine and diluted with water. The resulting solution was then extracted with EtOAc (3×) and the combined organic layers were washed with brine (2×), passed through a phase separator and concentrated in vacuo to afford the crude product which was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford ((E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate (25.5 mg, 0.05 mmol, 36% yield) as a white solid. LC/MS (m/z, MH+): 474.3.
Reaction SMILES: [NH2:1][C:2](=[S:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=O>C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:1]=[C:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:9][CH:11]=2)=[CH:15][CH:16]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCOC(=O)CC(N)=S
Solvent: CCO
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)cs1
Yield: 83 %

Procedure:
To a stirred solution of ethyl 3-amino-3-thioxopropanoate (20.00 g, 135.9 mmol) in ethanol (120 mL) was added 2-bromo-4′-fluoroacetophenone (29.49 g, 135.9 mmol). The mixture was refluxed for 1 hour, concentrated and partitioned between ethyl acetate (300 mL) and aqueous NaHCO3 (400 mL). The organic layer was combined with a backextract of the aqueous layer (ethyl acetate, 1×100 mL), dried (Na2SO4) and concentrated. The resulting light brown solid was purified by flash chromatography using a hexane/ethyl acetate gradient to afford ethyl 2-(4-(4-fluorophenyl)thiazol-2-yl)acetate as an off-white solid (29.92 g, 83%).
Reaction SMILES: [CH2:1]1[CH2:9][N:8]2[C@@H:4]([C@H:5]([OH:11])[C@H:6]([OH:10])[CH2:7]2)[C@H:3]([OH:12])C1.C1(=O)O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](O)[C@@H]1[OH:15]>>[OH:12][CH:3]1[CH:4]2[N:8]([CH2:7][CH:6]([OH:10])[CH:5]2[OH:11])[CH2:9][CH:1]1[OH:15]
Reactant: O=C1O[C@@H]([C@H](O)[C@H](O)CO)[C@H](O)[C@@H]1O
Reactant: O[C@H]1[C@H]2[C@H](O)CCCN2C[C@H]1O
Product: OC1CN2CC(O)C(O)C2C1O

Procedure:
The tetrahydroxypyrrolizidone (1) is an analogue of 1,8-diepiswainsonine. A similar analogue of swainsonine can be made by analogous methods starting with D-glycero-D-talo-heptono-1,4-lactone to produce the novel (1S), 2R, 6R, 7S)-1,2,6,7-tetrahydroxypyrrolizidine.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[C:10]([NH:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:24]([NH2:26])=[O:25])=[C:19]([NH2:23])[NH:20]2)=[CH:16][CH:15]=1)(=[O:12])[CH3:11].N.CO>O1CCCC1>[C:10]([NH:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:24]([NH2:26])=[O:25])=[C:19]([NH:23][C:3]([NH2:5])=[O:4])[NH:20]2)=[CH:16][CH:15]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc2c(C(N)=O)c(N)[nH]c2c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
Trichloroacetyl isocyanate (48 μL, 0.36 mmol) was added to a solution of 6-acetylamino-2-aminoindole-3-carboxamide (Reference compound 15-1, 26 mg, 0.11 mmol) in anhydrous tetrahydrofuran (1.5 mL), and the mixture was stirred at room temperature for 18 hours. 2.0 M Ammonia in methanol solution (2.0 mL, 4.0 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hours. The precipitated solid was separated by filtration using methanol (0.5 mL), and dried under reduced pressure to give the title compound (13 mg) as a colorless solid (yield 43%).
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[NH2:32][CH:33]([CH2:45][CH3:46])[C@@H:34]([C:36]1[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[O:38][N:37]=1)[OH:35]>>[N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([NH:32][C@H:33]([C:34]([C:36]2[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[O:38][N:37]=2)=[O:35])[CH2:45][CH3:46])=[O:12])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Reactant: CCC(N)[C@H](O)c1noc(C(F)(F)F)n1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1noc(C(F)(F)F)n1

Procedure:
It is similarly prepared according to general procedure given for Example 2 above but using 4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyric acid and (S)-2-Amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoroacetic acid.