Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:11]([NH:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2([C:37]2[CH:38]=[CH:39][C:40]3[N:41]([CH:43]=[CH:44][N:45]=3)[CH:42]=2)[C:24]([S:27]CC2C=CC(OC)=CC=2)=[N:25][CH3:26])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:1]1([S:11]([NH:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2([C:37]2[CH:38]=[CH:39][C:40]3[N:41]([CH:43]=[CH:44][N:45]=3)[CH:42]=2)[C:24](=[S:27])[NH:25][CH3:26])(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CN=C(SCc1ccc(OC)cc1)C1(c2ccc3nccn3c2)CCCCC1OCCNS(=O)(=O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=S)C1(c2ccc3nccn3c2)CCCCC1OCCNS(=O)(=O)c1cccc2ccccc12
Temperature: 0 °C
Yield: 64.6 %

Procedure:
A mixture comprising 0.4 g of the 2-(2-(1-naphthalenesulfonamido)ethoxy)-1-(imidazo[1,2-a]pyridin-6-yl)-1-((4-methoxybenzylthio)(methylimino)methyl)cyclohexane, 0.5 ml of anisole, 5 ml of trifluoroacetic acid and 5 ml of dichloromethane was stirred under cooling with ice for 1.5 hours, followed by the addition of ice-water. The resulting mixture was alkalinized with sodium carbonate and extracted with chloroform. The chloroform phase was dried over anhydrous magnesium sulfate and ditilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: a 80:1 dichloromethane/methanol mixture) and crystallized from ethyl acetate/n-hexane to give 0.21 g of the title compound as a white powder (yield: 65%).
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[O:11][CH:12]1[CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C.[N+]([NH:29][C:30](N)=[O:31])([O-])=O>CC(C)=O.O>[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[O:11][CH:12]1[CH2:15][N:14]([C:30]([NH2:29])=[O:31])[CH2:13]1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: Fc1cccc(OC2CNC2)c1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)N1CC(Oc2cccc(F)c2)C1
Reaction time: 1 h
Yield: 43.6 %

Procedure:
A stirred slurry of 3 g (0.012 mole) of 3-(3-fluorophenoxy)azetidine oxalate [1:1] in 20 ml of acetone was treated with 3 ml of triethylamine and stirred for 1 hr. The resulting solution was treated with 2.5 g (0.024 mole) of nitrourea and 2 ml of water then stirred for 16 hr. The reaction mixture was diluted with water and the product crystallized. Recrystallization from methanol-water yielded 1.1 g (43.6%) of a white crystalline solid, m.p. 169°-170° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:42]=[CH:41][C:17]([CH2:18][C:19]2[N:20]=[C:21]([O:37][CH2:38][CH2:39][CH3:40])[C:22]3[N:27]=[C:26]([C:28]4[CH:33]=[C:32]([CH3:34])[C:31]([OH:35])=[C:30]([CH3:36])[CH:29]=4)[O:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1.[CH3:43][C:44]1([CH3:51])[O:48][CH:47]([CH2:49]O)[CH2:46][O:45]1.C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[CH:42]=[CH:41][C:17]([CH2:18][C:19]2[N:20]=[C:21]([O:37][CH2:38][CH2:39][CH3:40])[C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[C:30]([CH3:36])[C:31]([O:35][CH2:49][CH:47]5[CH2:46][O:45][C:44]([CH3:51])([CH3:43])[O:48]5)=[C:32]([CH3:34])[CH:33]=4)[O:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Reactant: CC1(C)OCC(CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC4COC(C)(C)O4)c(C)c3)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 0.736 mmol of polystyrene-bound triphenylphosphine (Argonaut) and 128 mg of diethyl azodicarboxylate in 10 ml of tetrahydrofuran was stirred for 15 min at 0° C. Then 260 mg of 4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol, 81 mg of (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol and 85 μl of triethylamine were added. The reaction mixture was stirred at room temperature for 3 h. Then another 81 mg of (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol, 0.736 mmol of polystyrene-bound triphenylphosphine and 128 mg of diethyl azodicarboxylate were added and the reaction mixture was stirred for 18 h. The polymer was filtered off and washed thoroughly with tetrahydrofuran. The solvent was removed in vacuo and the title compound isolated by silica gel chromatography (method SC1) and then by preparative HPLC (method HPLC2).
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:8][CH:7]=[C:6]([C:9](O)=[O:10])[CH:5]=1)#[N:2].CSC.B.O>C1COCC1>[OH:10][CH2:9][C:6]1[CH:5]=[C:4]([CH2:3][C:1]#[N:2])[S:8][CH:7]=1
Reactant: N#CCc1cc(C(=O)O)cs1
Agent: B
Solvent: CSC
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1cc(CO)cs1
Yield: 68.9 %

Procedure:
A solution of 5-cyanomethyl-thiophene-3-carboxylic acid (2.7 g, 16.1 mmol) in THF (95 mL) is treated with borane dimethylsulfide (1.78 mL, 10.0 M, 17.8 mmol) in a dropwise maner. After the addition is complete, the solution is warmed to reflux for 1 h. After cooling, water is added and the mixture is extracted with dichloromethane (3×). The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, 30-50% ethyl acetate in heptane) to give (4-hydroxymethyl-thiophen-2-yl)-acetonitrile (1.7 g, 69%) as a white solid: mp 45-47° C.; 1H NMR (CDCl3, 300 MHz) δ 7.16 (s, 1 H), 7.02 (s, 1 H), 4.60 (s, 2 H), 3.84 (s, 2 H), 1.79 (s, 1 H).
Reaction SMILES: [Cl-].[Cl-].[C:3]1(P)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1(P(Cl)Cl)[CH:15]=CC=[CH:12][CH:11]=1.[P:19]([Cl:22])([Cl:21])[Cl:20].[Cl-].[Cl-].C1(C)C=CC(P)=CC=1.[O:33]=[P:34]([Cl:37])([Cl:36])[Cl:35]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[O:33]=[P:34]([Cl:37])([Cl:36])[Cl:35].[CH:7]1[C:8]2[C:3](=[CH:15][CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][CH:6]=1.[P:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: Pc1ccccc1
Reactant: ClP(Cl)c1ccccc1
Agent: Cc1ccc(P)cc1
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: c1ccc2ccccc2c1

Procedure:
Phenylphosphine dichloride, C6H5PCl2, was the only product detected when benzene and PCl3 were fed to the catalytic reactor. A mixture of o, m, and p-tolylphosphine dichloride, CH3C6H4PCl2, was the only organic product detected when toluene and PCl3 were used as the starting material. A small amount, < 1%, of POCl3 was observed. A mixture of α- and β-naphthylphosphine dichloride, C10H7PCl2, was produced, along with a small amount of POCl3 when naphthalene and PCl3 were used as the feed. A small amount of 2,5, dimethyl phenylphosphine dichloride was detected when p-xylene and PCl3 were used as the feed. Traces of toluene, POCl3 and an unidentified product were observed with the latter. The results are summarized in more detail in Table VI.
Reaction SMILES: [NH2:1][CH:2]([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>C(#N)C>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:1][CH:2]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(COCC(N)Cn2ccnc2)cc1
Reactant: COc1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(CNC(COCc2ccc(OC)cc2)Cn2ccnc2)cc1
Yield: 3.6 %

Procedure:
A solution of 1-[2-amino-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (1.70 g, 0.0065M) in dry acetonitrile (10 ml) containing triethylamine (0.5 ml) was treated with 4-methoxybenzyl chloride (1.12 g, 0.0072M) and heated under reflux for 18 hours under a stream of dry nitrogen. The solvent was evaporated off under reduced pressure and the residue was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and dried (MgSO4). The solvent was evaporated off under reduced pressure to give the crude product as an oil which was further purified by chromatography (silica gel), 10% ethanol in chloroform) to give N-[(4-methoxyphenyl)methyl]-α-[[(4-methoxyphenyl)methoxy]methyl]-1H-imidazole-1-ethanamine (0.09 g ) as a pale yellow oil.
Reaction SMILES: [C:1]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:25])[CH3:24]>>[C:1]([C:6](=[CH:12][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:25])[CH3:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)c1ccccc1N
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1ccccc1C(C)=O)C(=O)OCC

Procedure:
A mixture of ethyl 2-butyryl-3-ethoxyacrylate (23.5 g, 0.11 mol) and 2'-aminoacetophenone (13.5 g, 0.1 mol) was warmed on a steam bath for 10 minutes. Crystallisation from petroleum ether gave ethyl 2-butyryl-3-(2-acetylphenylamino)acrylate as a mixture of E/Z isomers (14.9 g, 49%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)=[CH:5][C:6]([C:10]([O:12]CC)=[O:11])=[N:7][C:8]=1[CH3:9])#[N:2].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[N:7][C:8]=1[CH3:9])#[N:2]
Reactant: CCOC(=O)c1cc(-c2cccc([N+](=O)[O-])c2)c(C#N)c(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C(=O)O)cc(-c2cccc([N+](=O)[O-])c2)c1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
To a solution of ethyl 5-cyano-6-methyl-4-(3-nitrophenyl)-2-pyridinecarboxylate (2.75 g) in ethanol (30 ml) was added a solution of sodium hydroxide (0.37 g) in water (6 ml). After the mixture was stirred at ambient temperature for 1.5 hours, the reaction mixture was adjusted to pH 2 with 6N hydrochloric acid. The resulting precipitates were filtered off, washed with water, and dried to give 5-cyano-6-methyl-4-(3-nitrophenyl)-2-pyridinecarboxylic acid (2.4 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>ClCCl.O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: OCCc1ccc2ccccc2n1
Reactant: BrCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: BrCCCCCOCCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(2-Hydroxyethyl)quinoline (2.00 g), TAB (200 mg) and 1,5-dibromopentane (8 ml) were dissolved in dichloromethane (6 ml) and 50% aqueous sodium hydroxide (8 ml) added. The mixture was vigorously stirred at room temperature for 24 h, diluted with water (50 ml) and extracted with diethyl ether (2×30 ml). The organic extracts were dried, filtered and evaporated in vacuo to afford an oil, which was purified by FCC eluting with cyclohexane-ether (1:1) and ether, to give the title compound as a yellow oil (2.67 g), t.l.c. (ether) Rf 0.40.
Reaction SMILES: [Cl:1][C:2]1[C:8]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH2:14][N:15]([CH3:17])[CH3:16])=[CH:7][C:5]([NH2:6])=[C:4]([N+:18]([O-])=O)[CH:3]=1>[Ni].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:6])=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:14][N:15]([CH3:16])[CH3:17]
Reactant: CN(C)CC1CCCN1c1cc(N)c([N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CN(C)CC1CCCN1c1cc(N)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-chloro-5-(2-dimethylaminomethyl-pyrrolidin-1-yl)-2-nitroaniline (150 mg, 0.5 mmol), EtOAc (10 mL) and Ra—Ni (50 mg) was stirred for 19 h at rt under a hydrogen atmosphere (3.0 bar). Further catalyst was added and the hydrogenation was continued for 6 h at 40° C. The catalyst was removed by filtration, the filtrate was acidified with 1.25 M HCl in EtOH and concentrated to give the sub-title compound.
Reaction SMILES: [CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C@H:2]1N.C(C1C(=O)C(=[O:28])C=C(C(C)(C)C)C=1)(C)(C)C.C(O)(=O)C(O)=O.[OH-].[NH4+]>CO.O>[CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C:2]1=[O:28]
Reactant: N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Agent: O=C(O)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
To a stirred solution of valiolamine (80 mg, 0.414 mmol), in 96% aq. methanol (5.2 mL) was added 3,5-di-t-butyl-1,2-benzoquinone (92 mg, 0.418 mmol) dissolved in methanol (2 mL) at room temperature. After stirring for 90 min, water (1 mL) was added, the pH lowered to 5.0 (pH paper control) with an aqueous solution of oxalic acid, and the mixture shaken vigorously for 45 min. Subsequently, the pH was adjusted to 8 with ammonium hydroxide. The mixture was diluted with water (80 mL) and extracted with chloroform (4×40 mL). The water phase was concentrated to approximately 5 mL in a vacuum and loaded onto an IRA-68 anion exchange column (40 mL, OH- -form). Elution with water gave a fraction containing the product. This solution was concentrated to 1 mL and further purified by chromatography on a weak cation exchanger (Wk-100, 40 mL, NH4+ -form, mobile phase: water) to give pure valiolone (42 mg, 0.219 mmol, 53% yield). 1H NMR (300 MHz, D2O), δ(ppm): 2.39 (d, 1H, J=14.6 Hz, HCH--C=O); 2.79 (d, 1H, J=14.6 Hz, HCH--C=O); 3.3 (d, 1H, J=11.5 Hz, HCH--C--OH); 3.62 (d, 1H, J=11.3 Hz, HCH--C--OH); 3.63 (t, 1H, J=9.5 Hz, HC-3); 3.84 (d, 1H, J=9.4 Hz, HC-4) and 4.19 (d, 1H, J=9.7 Hz, Hc-2). 13C NMR (75 MHz, D2O), δ (ppm): 45.45, 64.37, 72.91, 75.79, 76.01, 78.62 and 209.43.
Reaction SMILES: C(Cl)(=O)C.[C:5](Cl)(=[O:9])[O:6][CH2:7][CH3:8].[C:11]1([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][C:19]2[NH:20][CH2:21][CH2:22][N:23]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:7]([O:6][C:5]([N:23]1[CH2:22][CH2:21][N:20]=[C:19]1[CH2:18][CH:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9])[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(C(CC2=NCCN2)c2ccccc2)cc1
Solvent: CC(=O)Cl
Product: CCOC(=O)N1CCN=C1CC(c1ccccc1)c1ccccc1

Procedure:
In place of acetyl chloride in Example 53, ethyl chlorocarbonate was reacted with 2-(2,2-diphenyl ethyl)-2-imidazoline to give 1-ethoxycarbonyl-2-(2,2-diphenyl ethyl)-2-imidazoline having a melting point of 78° to 80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: Cc1ccc2c(Cl)ncnc2c1
Product: Cc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Yield: 14 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 14% yield from 6-chloro-indoline and 4-chloro-7-methyl-quinazoline. (M.P. 265° C.; LC-MS: 296 (MH+)).
Reaction SMILES: O=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13](C4C=CC(C=O)=CC=4)[CH:14](C4C=CC(C=O)=CC=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[BH4-].[Na+].[CH3:33][OH:34]>>[CH3:13][NH:12][CH2:7][C:6]1[CH:11]=[CH:10][C:2]([N:3]2[N:4]=[C:5]3[CH2:14][CH2:13][NH:12][C:7]4[C:6]3=[C:11]([CH:10]=[CH:9][CH:8]=4)[C:33]2=[O:34])=[CH:14][CH:5]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C=O)cc2)cc1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CNCc1ccc(-n2nc3c4c(cccc4c2=O)NCC3)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 33 %

Procedure:
A mixture of 4,4′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzaldehyde (80 mg, 0.21 mmol) and 27% methylamine alcohol solution (94 mg, 0.82 mmol) in methanol (10 mL) was stirred at room temperature for 40 min. The mixture was then cooled to 0° C. Sodium borohydride (24 mg, 0.64 mmol) was added. After the addition, the mixture was stirred at room temperature for 4 hr. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate and filtered. The filtrate was concentrated to give 8,9-bis(4-((methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (29.5 mg, yield 33%) as a light yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 2.20 (d, J=8.8 Hz, 6H), 3.52-3.53 (d, J=2.4 Hz, 4H), 4.31-4.33 (d, J=6.4 Hz, 1H), 4.76-4.77 (d, J=6.4 Hz, 1H), 7.06-7.08 (d, J=6.4 Hz, 2H), 7.12-7.17 (m, 5H), 7.35-7.38 (t, J=6.4 Hz, 2H), 7.49-7.57 (t, J=10.0 Hz, 1H); LC-MS (ESI) m/z: 426(M+1)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:21])[CH2:7][NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:10]([O:12][CH3:13])=[O:11].[CH2:22]=O>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:21][CH2:22][N:8]([CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:7]=1
Reactant: COC(=O)C(NCC(O)c1cccs1)c1ccccc1Cl
Reactant: C=O
Solvent: CCO
Product: COC(=O)C(c1ccccc1Cl)N1C=C(c2cccs2)OC1
Temperature: 40 °C
Yield: 90.1 %

Procedure:
Methyl N-(2-(2-thienyl)-2-hydoxyethyl)-2-o-chlorophenylglycinate (21) (2.5 g, 7.6 mmol) was dissolved in ethanol and treated with 37% formaline (1.85 g, 22.8 mmol), then heated at 40° C. over the night under nitrogen. The ethanol is evaporated under vacuum and the residual water was removed by azeotropic distillation with toluene to provide 2.3 g of desired product as a mixture of diastereoisomers. 1H-NMR (CDCl3, ppm) 7.72 (1H, m), 7.43 (1H, m), 7.2-7.3 (2H, m), 7.15 (1H, m), 6.95 (2H, m), 5.35 (1H, q), 5.15 and 5.05 (2H, 2s), 4.55 (2H, q), 4.40 (2H, q), 3.75 and 3.70 (3H, 2s), 3.3-3.5 (1H, m), 2.9-3.1 (1H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:14][CH2:13]1)[CH:7]=O)([O-:3])=[O:2].[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16][CH2:17]1)[CH2:7][N:28]1[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]1)([O-:3])=[O:2]
Reactant: OC1CCNCC1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(CN2CCC(O)CC2)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 64 and 4-hydroxypiperidine.
Reaction SMILES: BrCCBr.I[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cu]C#N.[Cl-].[Li+].C(Cl)(=O)OCC.[C:24]([O:32][CH3:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.[S]>O1CCCC1.C(=O)([O-])O.[Na+].[Zn].Cl[Si](C)(C)C.C1(C)C(C)=CC=CC=1>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH2:6][C:30]1[C:25]([C:24]([O:32][CH3:33])=[O:31])=[CH:26][N:27]=[CH:28][CH:29]=1)[CH3:12]
Reactant: COC(=O)c1cccnc1
Reactant: CCOC(=O)CCI
Agent: N#C[Cu]
Agent: CCOC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Solvent: BrCCBr
Product: CCOC(=O)CCc1ccncc1C(=O)OC
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 42.6 %

Procedure:
Under an argon gas atmosphere, a mixture of zinc (21.0 g, 321 mmol) and 1,2-dibromoethane (1.40 mL, 16.2 mmol) in tetrahydrofuran (105 mL) was stirred at 80° C. for 20 min. After cooling to room temperature, chlorotrimethylsilane (400 μL, 3.13 mmol) was added at room temperature, and the mixture was stirred for 30 min. A solution of ethyl 3-iodopropanoate (60.0 g, 263 mmol) in tetrahydrofuran (53 mL) was added dropwise to the mixture at room temperature, and the mixture was stirred at 40° C. for 3 hr. A solution of copper(I) cyanide (19.2 g, 214 mmol) and lithium chloride (18.3 g, 432 mmol) in tetrahydrofuran (50 mL) was added dropwise to the mixture at 0° C., and the mixture was stirred for 30 min. This mixture was added dropwise at −78° C. under an argon gas atmosphere to a mixture obtained by stirring a solution of ethyl chlorocarbonate (19.4 mL, 203 mmol) and methyl nicotinate (27.8 g, 203 mmol) in tetrahydrofuran (105 mL) at 0° C. for 30 min, and the mixture was stirred for 12 hr while heating to room temperature. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the insoluble material was filtered off. The filtrate was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Xylene (105 mL) and sulfur (20.0 g, 624 mmol) were added to the residue, and the mixture was stirred at 140° C. for 12 hr. After cooling to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (20.5 g, yield 43%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:16]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:29])[C:19]2=[CH:30][CH:31]=[C:32]([Cl:33])[N:18]2[N:17]=1)[CH:13]1[CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:42]1([CH3:51])[CH:47]=[CH:46][C:45]([C:48](Cl)=[O:49])=[CH:44][CH:43]=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:16]1[N:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:20](=[O:29])[C:19]2=[CH:30][CH:31]=[C:32]([Cl:33])[N:18]2[N:17]=1)[CH:13]1[CH2:14][CH2:15]1)[C:48](=[O:49])[C:45]1[CH:46]=[CH:47][C:42]([CH3:51])=[CH:43][CH:44]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCNC(c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1)C1CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nn3c(Cl)ccc3c(=O)n2Cc2ccccc2)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 65.1 %

Procedure:
To a solution of (±)-(3-{[(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]-triazin-2-yl)-cyclopropyl-methyl]-amino}propyl)carbamic acid tert-butyl ester (0.30 g, 0.62 mmol) and Et3N (0.13 mL, 0.93 mmol) in CH2Cl2 (10 mL) at rt was added p-toluoyl chloride (0.10 mL, 0.76 mmol) under N2 and it was stirred at rt for 50 min. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 solution, and dried over MgSO4. Concentration and purification of the residue by flash column chromatography (SiO2, EtOAc/hexane 1:4) gave the title compound as an oil (0.244 g, 66%): 1H NMR (CDCl3) δ 7.22 (m, 2H), 7.13 (m, 3H), 7.04 (d, 1H, J=4.4 Hz), 6.48 (d, 1H, J=4.4 Hz), 5.90 (d, 1H, J=15.95 Hz), 5.12 (d, 1H, J=9.9 Hz), 4.83 (d, 1H, J=15.95 Hz), 4.03 (m, 1H), 3.54 (m, 1H), 3.45 (m, 1H), 2.74 (m, 2H), 2.31 (s, 3H), 1.66 (m, 2H), 1.29 (s, 9H), 1.19 (m, 3H), 0.80 (m, 1H), 0.42 (m, 1H), 0.32 (m, 2H); 3C NMR (CDCl3) δ 172.9, 155.7, 154.6, 148.8, 139.8, 136.8, 133.2, 129.2, 128.8, 127.7, 126.8, 126.3, 117.7, 117.2, 110.3, 108.5, 57.9, 44.4, 42.7, 37.9, 30.9, 28.2, 21.4, 13.4, 5.24, 3.80; MS (ESI+) 626.16, 628.14 (M++Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:18])[S:10]([CH2:13][CH3:14])(=[O:11])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)Cc1cncc(Br)c1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (0.21 g, 0.752 mmol), prepared as described in Example 11a, in DMF (6 mL) at −10° C., was added sodium hydride (60% oil dispersion, 39 mg, 0.98 mmol). The reaction was stirred for 15 minutes at which time iodomethane (0.056 ml, 0.903 mmol) dissolved in DMF (1 mL) was added. The reaction was stirred at −10° C. for an additional 15 minutes and was then quenched with ammonia hydroxide (2 mL). The reaction was diluted with brine and extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate, 0 to 80%) to provide ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-methyl-amide; MS: (ES+) m/z 293.1 (M+H)+.