Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.CCCCCCC>C1(OC)C=CC=CC=1>[CH:31]1[CH:30]=[CH:29][C:28]([CH2:27][NH:34][C:23]([CH2:22][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:11][CH:12]=3)=[CH:21][N:20]=2)=[O:24])=[CH:33][CH:32]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Reactant: NCc1ccccc1
Solvent: CCCCCCC
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Temperature: 150 °C

Procedure:
The procedure for the amide formation described for the medium scale reaction worked well on large scale. Methyl ester 7 and benzylamine (3 equiv.) were dissolved in anisole and heated at 150° C. for almost 2 days. However, the isolation of the product using the medium-scale procedure can result in a solid mass of product. To avoid this issue, the reaction mixture was not cooled to room temperature, but cooled to 45-50° C. before adding the anti-solvent. Toluene and heptane were used as anti-solvent in the original procedure. Using n-heptane alone provided adequate purity and increased yields from 81 to 90%. Further, the use of a single isomer of heptane was essential to adequately quantitate the residual solvent.
Reaction SMILES: Cl.[C:2]1(C(N)=O)[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[As](C)(C)(=O)[O-]>>[CH:9]1[C:8]2[C:17]3=[C:16]4[C:5](=[CH:6][CH:7]=2)[CH:4]=[CH:3][CH:2]=[C:15]4[CH:14]=[CH:13][C:12]3=[CH:11][CH:10]=1
Reactant: NC(=O)c1ccc2ccc3cccc4ccc1c2c34
Agent: C[As](C)(=O)[O-]
Agent: Cl
Product: c1cc2ccc3cccc4ccc(c1)c2c34

Procedure:
1-Pyrenemethanamide, hydrochloride was added to a cacodylate buffer solution (sodium cacodylate: 10 mM, pH 7.0; NaCl: 100 mM) at 10 μM, so that a solution thereof was obtained. The solution was irradiated with light having an excitation wavelength of 340 nm, and a fluorescence intensity was measured. A device used for measuring the fluorescence intensity and a slit width were the same as those in Example 13.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.C(=O)([O-])O.[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>O1CCCC1>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:1][CH:2]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
To a suspension of p-aminophenol (7.0 g, 63.9 mmol) in tetrahydrofuran (105 mL) was added saturated aqueous sodium hydrogen carbonate (70 mL), and benzyl chloroformate (12.0 g, 70.3 mmol) was added dropwise at 0° C. After stirring at room temperature for 16 hr, the reaction mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with hexane/ethyl acetate (=4/1) and collected by filtration to give the title compound (8.2 g, 53%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][CH:2]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[S:23][N:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]([N:29]2[CH2:28][CH2:27][N:26]([C:24]3[S:23][N:22]=[C:21]([C:17]4[S:16][CH:20]=[CH:19][CH:18]=4)[N:25]=3)[CH2:31][CH2:30]2)=[O:15])=[CH:5][CH:6]=1
Reactant: c1csc(-c2nsc(N3CCNCC3)n2)c1
Reactant: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccncc1)N1CCN(c2nc(-c3cccs3)ns2)CC1
Yield: 18.6 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-4-ylcarbamate (235 mg, 0.872 mmol), 1-[3-(2-thienyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.793 mmol) and diisopropylethylamine (0.152 ml, 0.872 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3.5 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate, followed by methanol:ethyl acetate=1:9) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 54.9 mg (18.6%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:24]([NH:28][CH2:29][C:30]1[CH:42]=[CH:41][C:33]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:32]([CH3:43])[CH:31]=1)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:24]([N:28]([CH2:29][C:30]1[CH:42]=[CH:41][C:33]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:32]([CH3:43])[CH:31]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: Clc1ccc(-c2cncc(Br)n2)cc1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Yield: 16.7 %

Procedure:
A mixture of 2-bromo-6-(4-chlorophenyl)pyrazine (0.27 g, 1 mmol), N,N-diisopropylethylamine (0.18 mL, 1 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.42 g, 1.5 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The reaction mixture was then allowed to come to room temperature and the residue dissolved in CH2Cl2 (50 mL), the organic extract was washed water (15 mL) and passed through a hydrophobic frit before concentrating in vacuo. Purification by Biotage™ chromatography (Si, 40 g) eluting 1:9–1:1.5 EtOAc:cyclohexane afforded the title compound as a pale yellow oil 78 mg.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].CCOC(C)=O.[ClH:25]>C(O)(=O)C.Cl[Cu]>[Cl:25][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: Cl
Reactant: COC(=O)c1ccc(C(=O)O)cc1N
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)O)cc1Cl
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a mixture of 3-amino-4-(methoxycarbonyl)benzoic acid (781 mg, 4.0 mmol) suspended in acetic acid (10 mL) and conc. HCl (10 mL) was added aq. NaNO2 (276 mg, 4.0 mmol, 5 mL) at 0° C. The resulting mixture was stirred for 30 minutes. CuCl (400 mg, 8.0 mmol) in 10 mL of conc. HCl. was added to the mixture at 0° C. The resulting mixture was stirred at 30° C. for 6 hours. Followed a standard aqueous/EtOAc workup procedure (800 mg, yield 93%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([O:15][C:16]([NH:18][C@H:19]([CH2:23][NH2:24])[C:20]([OH:22])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([O:15][C:16]([NH:18][C@H:19]([CH2:23][NH:24][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[C:20]([OH:22])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CN)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 2-fluoronitrobenzene (3.45 g) in N,N-dimethylformamide (60 mL), (R)-(−)-2-tert-butoxycarbonylamino-3-amino-propionic acid (5 g) and potassium carbonate (6.77 g) were added, followed by stirring overnight at 70° C. The reaction mixture was allowed to cool down, poured into ice water, and then extracted with ethyl acetate. After 1 N hydrochloric acid was added to the aqueous layer to adjust pH to 3, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. n-Hexane was added to the residue to for crystallization. The resultant crystals were collected by filtration, whereby the title compound (7.9 g) was obtained. Yield: 99%.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C[Si](C)(C)N[Si](C)(C)C.[Li].[C-]#[C-].[Li+].[Li+].[CH:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH3:1][Si:2]([C:5]#[C:6][CH:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:28])([CH3:4])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(O)c1ccccc1

Procedure:
In step a, trimethylsilylacetylene (1) can first be reacted with a non-nucleophilic base, such as lithium hexamethyldisilazane, in a suitable aprotic solvent, such as tetrahydrofuran. The resulting lithium acetylide can then be reacted with the appropriate benzaldehyde compound of structure 2 to give the corresponding α-[(trimethylsilyl)-ethynyl]-benzenemethanol compound of structure 3.
Reaction SMILES: N1(N=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3([OH:18])[CH2:17][O:16][CH2:15]3)=[CH:10][CH:9]=2)CCCC1>CO.[Pd]>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([OH:18])[CH2:15][O:16][CH2:17]2)=[CH:12][CH:13]=1
Reactant: OC1(c2ccc(N=NN3CCCC3)cc2)COC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C2(O)COC2)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
To a solution of 3-(4-(pyrrolidin-1-yldiazenyl)phenyl)oxetan-3-ol (500 mg, 2.02 mmol) in methanol (15 mL) was added Pd/C (10%, 250 mg) at RT. The reaction mixture was stirred under 1 atm H2 atmosphere (balloon) at 40° C. for 18 h. The mixture was filtered through a pad of Celite. The filtrate was concentrated to give a residue, which was purified by Prep-HPLC to afford the title compound (200 mg, yield 60%) as a white solid. MS (ES+) C9H11NO2 requires: 165, found 166 [M+H]+, purity: 96%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:19])[CH2:13][CH2:14][C:15](OC)=[O:16].[BH4-].[Na+].C(OCC)(=O)C>CO>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:19])[CH2:13][CH2:14][CH2:15][OH:16]
Reactant: COC(=O)CCC(=O)N1CCCc2c(Br)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(CCCO)N1CCCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a solution of methyl 4-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-oxobutanoate (0.9 g, 2.76 mmol) in MeOH (30 mL) was added sodium borohydride (2.088 g, 55.2 mmol), and the resulting mixture was stirred at room temperature for 30 min. After this time, additional sodium borohydride (1.566 g, 41.4 mmol) was added slowly and the reaction was stirred for another 30 min. The reaction mixture was quenched with HCl and extracted with ethyl acetate. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes then 10% CH3OH:ethyl acetate) to afford the title compound (0.6 g, 73% yield) as a colorless oil. LCMS, [M+H]+=298.0. 1H NMR (400 MHz, MeOD) δ 7.49 (d, J=8.1 Hz, 1H), 7.44 (br. s, 1H), 7.17 (t, J=8.1 Hz, 1H), 3.86-3.80 (m, 2H), 3.61 (t, J=6.2 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H), 2.68 (t, J=7.4 Hz, 2H), 2.10-2.01 (m, 2H), 1.95-1.85 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][CH3:18])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:17]([C:11]1([C:14]([OH:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:18]
Reactant: CCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1(C(=O)O)CCNCC1
Yield: 112.9 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-4-ethylpiperidine-4-carboxylic acid (above step 1, 4.5 g, 12.96 mmol) in DCM (50 ml) was cooled to 0° C. After ten minutes, trifluoro acetic acid (6.0 g) was added and stirred the reaction at room temperature for about 6 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (2.3 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.48-1.58 (m, 2H); 2.14-2.18 (m, 2H); 2.64-2.73 (m, 2H); 2.86 (s, 2H); 3.01-3.07 (m, 4H); ES Mass: 158 (100%), [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43].[Cl-].[NH4+]>C(Cl)Cl>[C:42]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:23])(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
141 mg (0.30 mmol) of (−)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-1a-1)) was dissolved in 6 ml of methylene chloride, followed by the addition of 29 μl (0.36 mmol) of pyridine and 24 μl (0.33 mmol) of acetyl chloride under 0° C. The reaction mixture was stirred at room temperature for 1 hour. To the reaction solution, 10 ml of saturated aqueous solution of ammonium chloride was added and extracted with 50 ml of methylene chloride. The extract was washed with 20 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:4 mixture of ethyl acetate and hexane) to obtain 155 mg of the titled compound.
Reaction SMILES: [CH2:1]1[O:31][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[CH:17][N:18]=4)[C:15]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]([O:28][CH3:29])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:30]=[C:3]2[O:2]1.FC(F)(F)C(O)=O.Br[CH2:40][CH2:41][CH2:42][OH:43].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N>C(#N)C>[CH2:1]1[O:31][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:40][CH2:41][CH2:42][OH:43])[N:18]=4)[C:15]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]([O:28][CH3:29])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:30]=[C:3]2[O:2]1
Reactant: OCCCBr
Reactant: COc1ccc2c(cnc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c(CCCO)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Temperature: 80 °C
Yield: 15 %

Procedure:
2,3-(Methylenedioxy)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (prepared by the process described in Japanese Patent KOKAI No. 5-208959, 1.228 g, 3.00 mmols) was suspended in acetonitrile (48 mL), and trifluoroacetic acid (231 μL, 3.00 mmols), 3-bromo-1-propanol (271 μL, 3.00 mmols) and tris(trimethylsilyl)silane (1.85 mL, 6.00 mmols) were added to the suspension. The mixture was stirred at 80° C. on an oil bath. After the suspension was dissolved, azobis(isobutyronitrile) (0.985 g, 6.00 mmols) was added to the solution followed by heating under reflux. 90 minutes later, the reaction mixture was cooled to room temperature. By separating the precipitated crystals through filtration, the starting material, 2,3-(methylenedioxy)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine, was recovered as the trifluoroacetate (0.680 g). The filtrate was concentrated in vacuo, and a saturated sodium hydrogencarbonate aqueous solution (40 mL) was added to the residue followed by extraction with methylene chloride (50 mL). After the organic layer was washed with water (50 mL) and dried over anhydrous sodium sulfate, the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (eluted with 10% ethyl acetate-toluene) to give 2,3-(methylenedioxy)-6-(3-hydroxypropyl)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (0.210 g, yield 15%) as light brown powders.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.C(N(CC)CC)C>C(O)(C)C>[CH3:14][C@H:15]1[CH2:20][N:19]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH2:11][CH2:12][CH2:13][C:3]=23)[CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 97.8 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (19.4 mg, 0.10 mmol), tert-butyl [(3S,5R)-5-methylpiperidin-3-yl]carbamate (22.0 mg, 0.10 mmol) and triethylamine (40.9 μL, 0.29 mmol) in isopropyl alcohol (0.224 mL) was stirred at 100° C. for 40 min. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography using CombiFlash® (0 to 50% EtOAc in hexanes) to give the sub-title compound as pale yellow powder (36.8 mg, 100%). LCMS calc. for C19H29N4O4 (M+H)+: m/z=377.1. Found: 377.1.
Reaction SMILES: [CH2:1]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BrH:18]>>[Br:18][CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Br
Reactant: CCCCCCCCC(CO)CCCCCC
Product: CCCCCCCCC(CBr)CCCCCC

Procedure:
1-Bromo-2-hexyldecane was prepared by reacting 2-hexyldecanol with hydrogen bromide gas, or with 47% aqueous hydrogen bromide, according to well known procedures. The crude product was purified by distillation, b.p. 152°-154° at 18 mm of mercury.
Reaction SMILES: C(OCC)C.C([O:8][C:9]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]=1)/[CH:18]=[CH:19]/[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[OH:8][CH2:9][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]=1)/[CH:18]=[CH:19]/[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: CCOC(=O)CCCOc1cccc(/C=C/c2nc3ccccc3s2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCCCOc1cccc(/C=C/c2nc3ccccc3s2)c1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To 40 ml of ethyl ether was added 1.0 g of 2-[trans-3-(3-ethoxycarbonylpropoxy)styryl]benzothiazole, and 114 mg of lithium aluminum hydride was added under ice-cooling. After the mixture was stirred at the same temperature for 30 minutes, then at room temperature for 40 minutes, 114 μl of water, 114 μl of 15% aqueous sodium hydroxide and 340 μl of water were successively added slowly to decompose the aluminum complex, followed by extraction with toluene. After drying over anhydrous magnesium sklfate, the solvent was evaporated under reduced pressure and the crude crystals formed were washed with ethyl ether under ice-cooling, followed by drying under reduced pressure to give 570 mg (yield 64%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]([NH:21][C@H:22]([C:24](O)=[O:25])[CH3:23])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:14]([NH:21][C@H:22]([C:24]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)=[O:25])[CH3:23])([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.4 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)glyoxylate (4.0 g) and Boc-L-alanine (5.67 g) were dissolved in 40 ml of N,N-dimethylformamide (hereafter abbreviated as DMF), and thereto was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (5.74 g) under ice-cooling followed by addition of 4-dimethylaminopyridine (0.4 g). The mixture was stirred at room temperature for 5 hours. Water (400 ml) was added thereto, and the mixture was extracted twice with ethyl acetate (300 ml). The ethyl acetate layer was washed with 10% aqueous solution of citric acid (200 ml), saturated aqueous solution of sodium bicarbonate (200 ml) and saturated brine (200 ml) in this order, and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography eluted with benzene-ethyl acetate. The object fraction was concentrated to give 5.30 g of ethyl 2-[2-(Boc-L-alanyl)aminothiazol-4-yl]glyoxylate.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCCCN1CCCC1=O
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C1CCCN1CCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 1-(3-aminopropyl)pyrrolidin-2-one according to general procedure 1 providing the intermediate (150 mg, 58%) as a white solid; Rf=0.58 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.55 (d, J=9.7 Hz, 1H), 7.39 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.53 (t, J=7.1 Hz, 2H), 3.43-3.38 (m, 4H), 2.39 (t, J=8.0 Hz, 2H), 2.08 (quin, J=7.6 Hz, 2H), 1.94 (quin, J=6.9 Hz, 2H); ES-MS: (M+H)=338, 340 m/z.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][C:3](Cl)=[O:4].[CH3:8][O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20]>ClC1C=CC=CC=1Cl>[CH3:8][O:9][CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:3](=[O:4])[CH2:2][C:1]1=[O:6]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: COCCCNc1ccccc1N
Solvent: Clc1ccccc1Cl
Product: COCCCN1C(=O)CC(=O)Nc2ccccc21
Temperature: 130 °C
Reaction time: 1.6 h

Procedure:
To a stirred mixture of 8 ml of malonyl dichloride and 90 ml of o-dichlorobenzene at 60° C., a solution containing 12.7 g of N-(3-methoxypropyl)-o-phenylenediamine in 10 ml of o-dichlorobenzene is added for 32 minutes in several times. The resulting mixture is stirred at 130° C. for 1.6 hours and then subjected to filtration during hot. The filtrate is concentrated and purified by silica gel column chromatography (ethyl acetate). n-hexane is added and precipitated crystals are separated by filtration and dried to obtain 9.8 g of (208).