Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].[H-].C([Al+]CC(C)C)C(C)C>COCCOC.C1(C)C=CC=CC=1>[C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CC(=O)N[C@H](C=O)Cc1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
N-Acetylphenylalanine methyl ester (4.2 g, 19 mmol) was dissolved in ethylene glycol dimethyl ether. The solution was cooled to -70° C. and diisobutylaluminum hydride (25.3 mL of a 1.5M solution in toluene, 39 mmol) was added. The resulting reaction mixture was stirred at -70° C. for 2 hours. The reaction was quenched by addition of 2N hydrochloric acid. The mixture was extracted 4 times with cold ethyl acetate and 4 times with toluene. The extracts were combined, washed with brine and dried over magnesium sulfate. Concentration in vacuo followed by silica gel chromatography furnished 2.7 g of a white solid. The NMR was identical to that reported in the literature, Biochemistry, 1979, 18, 921-926.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[I:9]([O-])(=O)=O.[K+].[I-].[K+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: [O-][I+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Nc1ncc(Br)cc1I
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 179.8 %

Procedure:
A stirred solution of 5-bromo-pyridin-2-ylamine (50 g, 289 mmol) in 2M sulfuric acid (500 mL) was treated portionwise with potassium iodate (30.8 g, 144 mmol) and the mixture heated to 100° C. A solution of potassium iodide (26.5 g, 160 mmol) in water (50 mL) was added dropwise over ca. 1 hour. The mixture was allowed to stir for a further 30 minutes then cooled to ambient temperature. The pH of the aqueous phase was adjusted to 8-9 and the mixture extracted with ethyl acetate (×3). The combined organic layer was washed with aqueous sodium thiosulfate solution, water and brine, dried (Na2SO4) and evaporated to afford the title compound as a brown solid (77.4 g, 90%). 1H NMR (300 MHz, CDCl3): 8.06 (d, J=2.2 Hz, 1H), 7.96 (d, J=2.2 Hz, 1H), 4.96 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)[N:20]=[C:19]([CH3:31])[N:18]=2>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:32][CH2:33][NH2:34])[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1)[N:20]=[C:19]([CH3:31])[N:18]=2
Reactant: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(CCNC(=O)OC(C)(C)C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(CCN)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Add trifluoroacetic acid (5 mL) to a solution of tert-butyl N-[2-[8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)purin-9-yl]ethyl]carbamate (0.51 g, 0.001 mol) in dichloromethane (5 mL) at 0° C. Allow the reaction to warm to room temperature and stir for 2 h. Quench the reaction mixture with saturated aqueous sodium bicarbonate solution and then extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give 2-[8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)purin-9-yl]ethanamine (0.39 g). ES/MS m/z 386 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.O[CH:11]([C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]=2[CH:14]=1)[CH3:12]>C(Cl)Cl>[Cl:3][CH:11]([C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]=2[CH:14]=1)[CH3:12]
Reactant: CC(O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Cl)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.1 ml) and catalytically effective amount of N,N-dimethylformamide were added to a solution of 2-(1-hydroxyethyl)-9H-fluorene (1.05 g) in methylene chloride (15 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes and then heated under reflux for 1 hour. By evaporating the solvent under reduced pressure, 2-(1-chloroethyl)-9H-fluorene was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[CH:24]=1)[C:19](O)=[O:20].N1C=CC=CC=1.[NH2:37][C:38]1[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=1>C(Cl)Cl>[Cl:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([C:19]([NH:37][C:38]2[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=2)=[O:20])[CH:22]=[C:23]([O:25][C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[CH:24]=1
Reactant: CN1CCOc2c(ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)O)c3)c2Cl)C1=O
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCOc2c(ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)Nc4ccn(C(=O)OC(C)(C)C)n4)c3)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 52.5 %

Procedure:
1-Chloro-N,N-2-trimethylpropenylamine (0.09 mL, 0.37 mmol) was added to a solution of 3-[(9-chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (145 mg, 0.34 mmol) in DCM (5 mL) and the reaction stirred at RT for 30-40 minutes. Pyridine (0.055 mL, 0.67 mmol) and 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (123 mg, 0.67 mmol) were added and the reaction stirred for 2 hours at RT. The reaction mixture was evaporated in vacuo and water (20 mL) added. The mixture was extracted with ethyl acetate (3×20 mL), washed with 1N hydrochloric acid (20 mL), a saturated solution of sodium hydrogen carbonate (20 mL), brine (20 mL), dried (MgSO4) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound as a pale yellow oil (107 mg). m/z 611 (M−H)−
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]([C:26]([S:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:7][P:8]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)=[O:9])[CH3:2].ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]([C:26]([S:28]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:45])=[O:27])[CH2:7][P:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)=[O:9])[CH3:2]
Reactant: CCOC(=O)CN(CP(=O)(Oc1cccc(C)c1)Oc1cccc(C)c1)C(=O)SCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)CN(CP(=O)(Oc1cccc(C)c1)Oc1cccc(C)c1)C(=O)S(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 5.25 h

Procedure:
To a solution of ethyl-N-[(benzylthio)carbonyl]-N-[bis(3-methylphenoxy)phosphinylmethyl]-glycinate (2.6 g.; 0.005 mol.) dissolved in 25 ml. of methylene chloride at 0° C. was added metachloroperbenzoic acid (1.02 g.; 0.005 mol.). The reaction mixture was stirred at 0° C. for 5.25 hours, filtered and the filtrate was washed with 5% sodium hydroxide, dried, and concentrated in vacuo. To remove any remaining solvent, the residue was concentrated at 25° C. and 0.05 mm. and yielded ethyl-N-[(benzylsulfinyl)carbonyl]-N-[bis(3-methylphenoxy)phosphinylmethyl]-glycinate as an oil (nD25 =1.5584) having the following analysis:
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:5][P@@:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[NH2:20][O:21][K].Cl>>[OH:21][NH:20][C:3](=[O:2])[C@H:4]([NH:5][P@@:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: NO[K]
Reactant: COC(=O)[C@@H](CC(C)C)N[P@](C)(=O)c1ccccc1
Agent: Cl
Product: CC(C)C[C@@H](N[P@](C)(=O)c1ccccc1)C(=O)NO
Reaction time: 7 h

Procedure:
N-((R)-Methylphenylphosphinyl)-D-leucine methyl ester (60 mg, 0.21 mmol) is treated with a solution of NH2OK (0.57 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 7 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The residue is purified by silica gel flash chromatography (95:5 ethyl acetate:ethanol) to give N-hydroxy-2(R)-[[(R)-methylphenylphosphinyl]amino]-4-methylpentanamide as a colorless solid: MS-IS m/z 285 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=2[F:22])[CH2:7][C@@H:6]1[C:23]([O:25]C)=[O:24].Cl.O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[O:1]=[C:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=2[F:22])[CH2:7][C@@H:6]1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2nccc(C(=O)CC[C@@H]3CCN(CC#Cc4cc(F)cc(F)c4F)C[C@@H]3C(=O)O)c2c1
Yield: 59.9 %

Procedure:
A solution of 1 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylate in 10 cm3 of a 5N aqueous hydrochloric acid solution is stirred for 4 hours at a temperature in the region of 80° C. After cooling to a temperature in the region of 20° C., 10 cm3 of water, then 10 cm3 of chloroform, and then 1.9 g of powdered sodium hydrogen carbonate are added. The mixture is extracted with 3 times 10 cm3 of chloroform. The organic phases are pooled, dried over sodium sulfate, filtered, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is purified by chromatography under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20–45μ; diameter 2.5 cm; 30 g), eluting with a mixture of dichloromethane-methanol (96/4 by volume) and collecting first a fraction of 150 cm3, and then fractions of 10 cm3. Fractions 5 to 22 are pooled, and then concentrated as above. 0.583 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid, in the form of a green-colored solid which melts at around 70° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1.C[O-].[Na+].[CH2:30]([OH:32])[CH3:31]>>[Cl:1][C:2]1[N:3]=[C:4]([O:32][CH2:30][CH3:31])[C:5]2[S:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1
Reactant: CCO
Reactant: COc1ccc(-c2cc(C)c3c(n2)sc2c(Cl)nc(Cl)nc23)cc1OC
Agent: C[O-]
Agent: [Na+]
Product: CCOc1nc(Cl)nc2c1sc1nc(-c3ccc(OC)c(OC)c3)cc(C)c12
Yield: 90 %

Procedure:
1.5 g (3.7 mmol) 2,4-dichloro-7-(3,4-dimethoxyphenyl)-9-methyl-pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidine and 0.7 g (11.1 mmol) sodium methylate are added by stirring to 50 ml absolute ethanol at room temperature for 24 h. Then, the precipitate is sucked off, washed with about 40 ml water, suck dried and dried in vacuo at 50° C. 1.38 g (90%) 2-chloro-4-ethoxy-7-(3,4-dimethoxyphenyl)-9-methyl-pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidine is obtained.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[N+:10]([CH:13]([CH3:15])[CH3:14])([O-:12])=[O:11].CC(C)([O-])C.[K+]>COCCOCCOC>[CH3:14][C:13]([N+:10]([O-:12])=[O:11])([CH3:15])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: OCc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Yield: 82.2 %

Procedure:
A mixture of 4-(hydroxymethyl)phenol (1.0 g, 8.1 mmol) and 2-nitropropane (4.0 g, 45 mmol) in diglyme (50 mL) was cooled in an ice bath. Potassium tert -butoxide (0.45 g, 4.0 mmol) was added in portions, then the reaction mixture was heated to reflux overnight. After cooling, the mixture was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give 4-(2-methyl-2-nitropropyl)phenol (1.3 g, 83% yield) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([CH:11]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)[CH:2]=[CH2:3].[CH:33](OCC)=[O:34]>>[CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[O:24])=[CH:30][CH:31]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH:33]=[O:34])[CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: CCOC=O
Reactant: C=CCN1C[C@H](C)N(C(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(N)c2)C[C@H]1C
Product: C=CCN1C[C@H](C)N(C(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NC=O)c2)C[C@H]1C
Yield: 51 %

Procedure:
(±)-4-(α-(trans-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-aminobenzyl)-N,N-diethylbenzamide (0.42 g, 0.97 mmol) (Example 32, infra) was dissolved in 15 mL of ethyl formate and heated at reflux overnight under nitrogen. The reaction was concentrated to dryness and purified by chromatography on silica gel with ethanol (0-10%) in dichloromethane to give 0.23 g (51%) of (±)-trans-4-(α-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-formamidobenzyl)-N,N-diethylbenzamide. NMR (300 MHz, CDCl3): δ 1.0 (m, 3H) ; 1.2 (d, m, 9H); 1.8-2.2 (m, 3H); 2.4-2.9 (m, 5H); 3.2-3.6 (m, 5H); 5.1-5.3 (m, 3H) 5.8 (m, 1H); 6.7-7.8 (m, 8H); 7.9-8.1 (m, 1H), 8.6-8.9 (m, 1H). The amine was dissolved in ethanol and converted to the monohydrochloride salt by titration with ethanolic hydrogen chloride. The solution was concentrated to dryness. The resulting foam was dissolved in a minimal amount of ethanol and precipitated with diethyl ether to give 0.96 g of the hydrated monohydrochloride salt as an off-white solid. Calc. for C28H38N4O2HCl 1.5 H2O: C, 63.92; H, 8.05; N, 10.65; Cl, 6.74. Found: C, 64.21; H, 7.96; N, 10.77; Cl, 6.92.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[N:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[S:11](Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:10][C:4]1[C:5]([Cl:9])=[N:6][C:7]2=[N:8][S:11][N:1]=[C:2]2[N:3]=1
Reactant: Nc1nc(Cl)c(Cl)nc1N
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: Clc1nc2nsnc2nc1Cl

Procedure:
The cyclization reaction of o-diaminobenzene (compound II) in an aqueous solution of glyoxal and sodium hydrogen sulfite gives quinoxaline (compound III; See R. G. Jones et al., Org. Syn. Collective Vol. IV, page 824). Quinoxaline is in turn oxidized by an aqueous solution of potassium permanganate to produce 2,3-pyrazinedicarboxylic acid (compound IV; See R. G. Jones et al., Org. Syn. Collective Vol. IV, page 824). 2,3-pyrazinedicarboxylic acid is then chlorinated with phosphorus pentachloride at 300° C. to produce 2,3,5,6-tetrachloropyrazine (compound V; See C. G. Allison et al., J. Chem. Soc. (C), 1970, page 1023). The reaction of 2,3,5,6-tetrachloropyrazine with ammonium chloride at a temperature of 120° C. gives 2,3-diamino-5,6-dichloropyrazine (compound VI; See Palamidess et al., Ed. Sc. XXI-fasc, 11, 1966, page 810). The cyclization reaction of 2,3-diamino-5,6-dichloropyrazine with thionyl chloride in the presence of pyridine in xylene produces 5,6-dichloro-[1,2,5]thiadiazolo[3,4-b]pyrazine (compound VII; See Y. C. Tong, J. Heterocyclic Chem., 12, 1975, page 451 ). The 5,6-dichloro-[1,2,5]thiadiazolo[3,4-b]pyrazine is reacted with potassium phthalimide in the presence of dimethyl formamide (DMF) at a temperature of 60° C. to produce 5,6-diphthalimido[1,2,5]thiadiazolo[3,4-b]pyrazine (compound VIII; See Example 1). The 5,6-diphthalimido-[1,2,5]thiadiazolo[3,4-b]pyrazine is then reacted with an aqueous solution of hydrazine at 0° C. to produce 5,6-diamino-[1,2,5]thiadiazolo[3,4-b]pyrazine (compound IX; See Example 2). Finally the cyclization reaction of 5,6-diamino[1,2,5]thiadiazolo[3,4-b]pyrazine with thionyl chloride in the presence of pyridine in methylene chloride gives bis[1,2,5]thiadiazolo[3,4-b:3',4'-e]pyrazine (compound I; See Example 3).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH:27]([CH3:28])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=3)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9]C.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[F:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:14]([S:11]([C:5]1[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=1)(=[O:13])=[O:12])[CH:27]2[CH3:28]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(O)c1
Yield: 49.7 %

Procedure:
The title compound was prepared from 5-[(3,4-dimethoxyphenyl)sulfonyl]-8-fluoro-6-methyl-5,6-dihydrophenanthridine (0.50 g, 1.2 mmol), cyclohexene (4.4 mL, 44 mmol), and 1 M boron tribromide in dichloromethane (14.5 mL, 14.5 mmol) according to the procedure and in the same manner as described in Example 47, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:1 to 7:3 gradient), followed by re-crystallization from a mixture of dichloromethane-hexane (2×), to yield 4-[(8-fluoro-6-methylphenanthridin-5(6H)-yl)sulfonyl]benzene-1,2-diol as a homogeneous solid (0.23 g, 50%), m.p. 165-170° C.;
Reaction SMILES: [Cl:1][C:2]1C=C[C:5](C)=[C:6](N2CCN(C/C=C/CN)CC2)[CH:7]=1.[K].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>>[Cl:1][CH2:2]/[CH:7]=[CH:6]/[CH2:5][N:25]1[C:21](=[O:31])[C:22]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:23]2[C:24]1=[O:26]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(Cl)cc1N1CCN(C/C=C/CN)CC1
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1C/C=C/CCl

Procedure:
Trans-4-[4-(5-chloro-2-methylphenyl)piperazinyl]-2-buten-1-amine: according to the method of Example 1, phthalimide potassium salt was reacted with trans-1,4-dihydro-2-butene to obtain N-(trans-4-chloro-2-buten-1-yl)phthalimide, mp: 108-110° C.; which was then reacted with 5-chloro-2-methylphenylpiperazine to obtain N-{4-[4-(5-chloro-2-methylphenyl)piperazinyl]-trans-2-buten-1-yl}phthalimide, which was then reacted with hydrazine hydrate to obtain the product. Yield: 89.3%. Hydrochloride mp: 140-142° C. 1HNMR (ppm, CDCl3) δ: 1.46 (br-s, 4H), 2.25 (s, 3H), 2.61 (br-s, 2H, NH2), 2.93 (m, 4H), 3.10 (d, J=7.0 Hz), 3.39 (d, J=6.72 Hz, 2H), 5.58 (m, 1H), 5.71 (m, 1H), 6.96 (m, 2H), 7.06 (d, J=7.84, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]=[CH:1][C:3]2[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1
Reactant: Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COc1ccc(C=Nc2ccc(F)cc2)cc1
Yield: 101.2 %

Procedure:
tert-Butyl (4-formylphenoxy)acetate (21.6 g, 0.09 mol) was dissolved in dry toluene (150 ml) and 4-fluoroaniline (8.8 ml, 0.091 mol) was added. The mixture was refluxed in a Dean-Stark apparatus for 23 hours, cooled and concentrated under reduced pressure. Addition of hexane and concentration under reduced pressure afforded 30.0 g (quant. yield) of the title compound as an off-white solid. NMR (200 MHz): 1.5 (s, 9H), 4.6 (s, 2H), 7.0-7.2 (m, 6H), 7.8 (d, 2H), 8.4 (s, 1H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][C:16](O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:19][C@H:20]([C:25]([OH:27])=[O:26])[C:21]([CH3:24])([CH3:23])[CH3:22]>S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>[CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][C:16]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CC(C)(C)[C@H](NC(=O)CCC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
A solution of 3-(fluoren-9-yl)propionic acid (2.4 g, 10 mmol) in thionyl chloride was refluxed for two hours. The reaction mixture was cooled down and the solvent was removed in vacuum. A solution of the resulting 3-(fluoren-9-yl)propionic acid chloride was dissolved in dioxane (20 mL) and added into a solution of L-tert-leucine (4 g, 30.5 mmol) in 10% aqueous sodium carbonate (40 mL). The reaction mixture was monitored by quenching an aliquot with methanol than monitor the resulting methyl ester by TLC (10% MeOH in chloroform). After an 1.5 hr water was added and most of the dioxane was removed in vacuum. The aqueous layer was washed with diethyl ether (×3) then was acidified to pH 1 with 10% HCl. The resulting precipitate was purified by a short path chromatography (silica, 5% MeOH in chloroform) to yield 1.5 g (42.1%), mp 79°-83° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)[N:16]=1.C(#N)C>O>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:19]2[N:18]=[C:17]3[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=4)=[N:16]3)=[CH:21][CH:20]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(-c2ccc3ccc(N)nc3n2)cc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2ccc3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)nc3n2)cc1
Temperature: 4 °C
Yield: 57 %

Procedure:
The procedure is analogous to that described in Example 1 below but starting with 4-trifluoromethylbenzoic acid (2.7 g), N,N'-carbonyldiimidazole (2.3 g) and 2-amino-7-(4-methoxyphenyl)-1,8-naphthyridine (2.5 g). The product obtained by precipitation in water (3.3 g; m.p. 144°-146° C.) is dissolved in boiling acetonitrile (100 cc). After cooling for 3 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Methoxyphenyl)-1,8-naphthyridin-2-yl]-4-trifluoromethylbenzamide (2.4 g), m.p. 148° C., is obtained.