Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:3][CH2:4][C:5]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:14][C:13](=[O:15])[C:12]2[C:7](=[C:8]([CH3:19])[C:9]([CH3:18])=[C:10]([OH:17])[C:11]=2[CH3:16])[O:6]1.[C:37](OC(=O)C)(=[O:39])[CH3:38].N1C=CC=CC=1>C1C=CC=CC=1>[C:37]([O:17][C:10]1[C:11]([CH3:16])=[C:12]2[C:7](=[C:8]([CH3:19])[C:9]=1[CH3:18])[O:6][C:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[CH2:14][C:13]2=[O:15])(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(CCC(C)CCCC(C)C)(COc1ccc([N+](=O)[O-])cc1)O2
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(CCC(C)CCCC(C)C)(COc1ccc([N+](=O)[O-])cc1)O2

Procedure:
Following the same procedure as described in Preparation 16, 1.8 g of 2-(3,7-dimethyloctyl)-6-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 30), 0.5 g of acetic anhydride, 5 ml of pyridine and 10 ml of benzene were reacted, to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.CN(C=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH3:21])=[CH:19][CH:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: Cc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1H-indole-2-carboxylate and 4-methylbenzyl bromide in substantially the same manner, as described in Step 1 of Example 25. The product was obtained as a semi-solid contained 0.8 mole equivalent DMF. Mass spectrum (ESI, [M+H]+) m/z 372. 1H NMR (400 MHz, DMSO-d6) δ7.93 (d, 1H, J=7.94 Hz), 7.55 (d, 1H, J=9.01 Hz), 7.40 (dd, 1H, J=8.85 and 1.98 Hz), 7.32 (s, 1H), 7.04 (d, 2H, J=7.96 Hz), 6.90 (d, 2H, J=7.94 Hz), 5.79 (s, 2H), 4.28 (q, 2H), 2.20 (s, 3H), and 1.28 ppm (t, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:21][NH2:22]>C(O)C>[N:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([NH:21][NH2:22])=[O:18])=[CH:13][CH:12]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NCCN2CCCC2)s1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(C(=O)NCCN2CCCC2)s1
Temperature: 25 °C
Yield: 38 %

Procedure:
Methyl 5-[2-(pyrrolidin-1-yl)ethylcarbamoyl]-thiophene-2-carboxylate (56 mg, 0.2 mmol) in ethanol (2.0 mL) was refluxed with heating with hydrazine monohydrate (0.10 mL) for 10 hours and allowed to cool to room temperature, and the precipitated solid was collected by filtration, washed with water and dried to give 21 mg of the desired product (yield 38%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].CC1C=CC(S(O[CH2:29][CH:30]2[CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH:30]1[CH2:29][S:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)OCC2COCCOCCOCCO2)cc1
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(CCSCC1COCCOCCOCCO1)NC(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (242 mg, 0.955 mmol) in N,N-dimethylformamide (1 ml) was added (1,4,7,10-tetraoxacyclododecan-2-yl)methyl 4-methylbenzenesulfonate (218.4 mg, 0.6060 mmol) and cesium carbonate (253 mg, 0.776 mmol). The solution was heated to 60° C. for 15 hours, cooled to room temperature, concentrated in vacuo, and the residue purified by flash chromatography (30%-100% ethylacetate in hexanes) to afford the title compound as a clear oil (quantitative); LRMS (ESI/APCI) m/z 442 [M]+.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37])[C:27](O)=O.[NH2:38][NH2:39]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:39][N:38]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37]
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: NN
Reactant: O=C(O)C(CCCCCl)c1ccc(Cl)cc1Cl
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(Cl)cc3Cl)n2)ccc1-n1cnc(Cl)c1
Yield: 16 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (500 mg, 1.685 mmol, from preparation A) and 6-chloro-2-(2,4-dichlorophenyl)hexanoic acid (498 mg, 1.685 mmol, from preparation AG) were coupled and then reacted with hydrazine (0.212 mL, 6.74 mmol) using a procedure analogous to Step A of Example 13. The crude products were purified using silica gel chromatography (40-100% ethyl acetate/chloroform) to afford 5-(5-chloro-1-(2,4-dichlorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (173 mg, 0.272 mmol, 16% yield) as a pink foamy solid. LC-MS (M+H)+ 539.0.
Reaction SMILES: C1(N=C=O)C=CC(N=C=O)=CC=1.C(N(CC)CC)C.COC1C=C[C:25]([C:28]#[C:29][C:30]([F:33])([F:32])[F:31])=CC=1.COC(=O)CCC[N+:40]([O-])=[O:41]>C1(C)C=CC=CC=1>[F:31][C:30]([C:29]1[CH:28]=[CH:25][O:41][N:40]=1)([F:33])[F:32]
Reactant: COc1ccc(C#CC(F)(F)F)cc1
Reactant: COC(=O)CCC[N+](=O)[O-]
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccon1
Temperature: 150 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
1,4-Phenylene diisocyanate (597.1 mg, 3.73 mol) and triethylamine (780 μL, 5.60 mmol) were added to a solution of 1-methoxy-4-trifluoropropynylbenzene (373.2 mg, 1.86 mmol) and 4-nitrobutanoic acid methyl ester (441.5 mg, 2.80 mmol) in toluene (10 mL). Using a microwave reactor, the obtained mixture was stirred at 150° C. for 2 hours. The reaction solution was filtered with celite, and the solvent was then distilled away. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain a trifluoromethyl isoxazole compound (144.0 mg, yield: 25%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C@H:14]([OH:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C@H:14]([O:16][S:27]([CH3:26])(=[O:29])=[O:28])[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](O)c1cccc(C(=O)OC(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](OS(C)(=O)=O)c1cccc(C(=O)OC(C)(C)C)c1
Yield: 102.5 %

Procedure:
(R)-1-(3-Tert-butyloxycarbonylphenyl)ethanol (3.28 mmol) was dissolved in CH2Cl2 (10 mL), diisopropylethylamine (4.92 mmol) added and the resultant solution cooled to 0° C. This mixture was stirred as methanesulfonyl chloride (3.94 mmol) was added dropwise. After 45 min the mixture was poured into water and extracted 3× with diethyl ether. The organic extracts were combined, washed with brine, dried (MgSO4) and concentrated under reduced pressure to yield 1.01 g of an oil which was used with out further purification. 1H NMR (500 MHz, CDCl3): δ 8.03 (m, 1H); 8.01 (m, 1H); 7.60 (m, 1H); 7.48 (t, J=7.6 Hz, 1H); 5.80 (q, J=6.6 Hz, 1H); 2.81 (s, 3H); 1.76 (d, J=6.6 Hz, 3H); 1.63 (s, 9H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C:16](=[CH2:18])[CH2:15][NH:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>O.C(Cl)Cl.O>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C:16](=[CH2:18])[CH2:15][N:14]1[C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: C=C1CNN(C(=O)OCc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C=C1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Yield: 62 %

Procedure:
Sodium hydroxide (0.12 g, 3 mmol) is dissolved in a 1:2 water/methylene chloride solution (30 mL) with rapid stirring followed by the addition of 4-methylene-pyrazolidine-1-carboxylic acid 1-benzyl ester, 2, (0.62 g, 2.8 mmol) at room temperature. (4-Fluorophenyl)acetyl chloride (0.39 mL, 4.2 mmol) is added and the reaction is allowed to stir for 18 hours after which time the reaction mixture is diluted with water (10 mL) and the layers allowed to separate. The aqueous layer is extracted with methylene chloride, the organic layers combined, dried, and filtered. Concentration in vacuo affords the crude product which is purified over silica (1:3 ethyl acetate/hexane) to provide 0.54 g (62% yield) of the desired product.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH2:15][NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])(=[O:19])=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-:30].[Cl-].[Cl-].[Cl:33][CH2:34][CH2:35][C:36](Cl)=[O:37].Cl>C1([N+]([O-])=O)C=CC=CC=1>[Cl:33][CH2:34][CH2:35][C:36]([C:3]1[CH:2]=[CH:1][C:13]2[N:12]([CH2:14][CH2:15][NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])(=[O:18])=[O:19])[C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][C:8]([C:36](=[O:37])[CH2:35][CH2:34][Cl:30])=[CH:9][CH:10]=3)=[O:37]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCn1c2ccccc2c2ccccc21
Reactant: O=C(Cl)CCCl
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(CCCl)c1ccc2c(c1)c1cc(C(=O)CCCl)ccc1n2CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.67 h

Procedure:
Compound 51 (20.0 g, 50.6 mmol) was dissolved in PhNO2 (130 mL) and the solution was cooled in an ice bath. Then AlCl3 (34.0 g, 254.7 mmol) and after that, 3-chloropropionyl chloride (25.0 mL, 259.8 mmol) were added. The mixture was kept for 40 min (LC/MS monitoring), poured in a mixture of diluted HCl and ice, extracted with CHCl3, and left for 16 h. The straw-colored precipitated obtained was filtered and washed with ether. Yield of 57: 18.47 g (63%).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)=[O:6].[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1.C(OC(=O)C)(=O)C.Cl>>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:5]1([C:4]2[CH:16]=[CH:17][C:18]([N:20]([CH3:22])[CH3:21])=[CH:19][C:3]=2[N:2]([CH3:1])[CH3:23])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:11])[O:6]1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)c(N(C)C)c1
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c(N(C)C)c1

Procedure:
A mixture of crude 2-(2,4-bis(dimethylamino)benzoyl)benzoic acid (7 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (1.64 g.) and acetic anhydride was warmed (at 25°-35° C.) during two to three hours, then poured into dilute hydrochloric acid (10%). The resulting mixture was basified and filtered with a filter aid. The filter cake was extracted with hot toluene. Dilution of the toluene extract with hexane afforded 3,3-bis(2,4-bis(dimethylamino)phenyl)phthalide (I: X=Y2 =Y4 =(CH3)2N, Z4 =Z5 =Z6 =Z7 =H) (m.p. 186°-188° C.).
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[O:23]=[C:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:23]=[C:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH2:30][C:31]([N:20]1[CH2:21][CH2:22][CH:17]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C@@H:11]4[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]4[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH2:18][CH2:19]1)=[O:32]
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCN(C2CCNCC2)CC1
Reactant: O=C(O)CCN1CCCC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN1CCC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To the solution of (3aR,7aR)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one (0.25 mmol) in dry DMF (3 mL) was added 3-(2-oxopyrrolidin-1-yl)propanoic acid (47 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol). The mixture was stirred at room temperature for 1 h, and the reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. The crude product was purified with High pH prep-LCMS to provide the title compound (53 mg, 47%) as white powders. 1H NMR (400 MHz, METHANOL-D4): δ ppm 1.26-1.51 (m, 6H), 1.55-1.73 (m, 2H), 1.75-2.08 (m, 9H), 2.19-2.37 (m, 5H), 2.56 (t, J=11.91 Hz, 2H), 2.64 (t, J=7.03 Hz, 2H), 2.87-3.14 (m, 5H), 3.43-3.55 (m, 4H), 3.55-3.69 (m, 1H), 3.99 (d, J=13.28 Hz, 1H), 4.54 (d, J=13.28 Hz, 1H). MS (M+1): 446.3
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[CH2:27]([N:30]([CH2:32][CH2:33][CH3:34])O)[CH2:28][CH3:29].[H-].[Na+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:30]([CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2]
Reactant: CCCN(O)CCC
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [H-]
Agent: [Na+]
Product: CCCN(CCC)Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 15, 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine is treated with a cold mixture of N,N-dipropylhydroxylamine and sodium hydride in dimethylformimide to give 8-nitro-1-[(dipropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=O.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(O)(=O)C>CN(C=O)C.N1CCCCC1>[CH2:18]([O:17][C:15]([C:14]1[C:13](=[O:20])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=2)=[O:16])[CH3:19]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cc(C=O)c(O)cc1O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(OC)c(O)cc2oc1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-dihydroxy-5-methoxybenzaldehyde (1.68 g) and diethyl malonate (1.76 g) in DMF (5 ml) was treated with a few drops of piperidine and acetic acid and kept at 80-95° C. overnight. The reaction mixture was poured into ice water, acidified and filtered. Yield: 2.2. g.
Reaction SMILES: [C:1]1([CH3:50])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][N:13]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH2:14][CH2:15][N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:54][CH2:55][O:56][CH2:57][CH2:58]Cl.O>CN(C=O)C>[C:26]1([CH3:29])[CH:27]=[CH:28][C:23]([S:20]([N:19]2[CH2:18][CH2:17][N:16]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[CH2:15][CH2:14][N:13]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:41])=[O:42])[CH2:12][CH2:11][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:50])=[CH:2][CH:3]=3)(=[O:8])=[O:9])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)NCCN(CCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCOCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a stirred solution of 1,4,7,10-tetra(p-toluenesulfonyl)-1,4,7,10-tetraazadecane prepared as in Example 15B (35.3 g, 0.0463 mole) in anhydrous DMF (460 ml) was added sodium hydride (2.77 g-80% in mineral oil, 0.0925 mole) in portions and the resulting mixture was stirred for 30 minutes under a dry argon atmosphere. The solution was then heated to 100° C. and a solution of 2-chloroethyl ether (6.61 g, 0.0463 mole) in anhydrous DMF (90 ml) was added dropwise over a 1.5 h period, maintaining the temperature at 100° C. After stirring the solution an additional 1.5 h at 100° C., H2O (3 l) was added while cooling (ice bath) to crystallize the product. The resulting tan solid was filtered and dried in vacuo. The crude product was purified by crystallization from CH2Cl2 -hexane to give 13.2 g (34% yield) of the product as an off-white solid: mp 197.5°-201°C.; 1H NMR (CDCl3) δ 2.44 (s, 12H), 3.28 (m, 16H), 3.57 (m, 4H), 7.35 (m, 8H), 7.69 (m, 8H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH:21]([Mg]Cl)([CH3:23])[CH3:22].Cl.O>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([OH:20])[CH:21]([CH3:23])[CH3:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.0 g of the aldehyde of Example 4 was dissolved in 20 ml of dry tetrahydrofuran under argon and added to 8.5 ml of 2 M isopropylmagnesium chloride in tetrahydrofuran that had previously been added under argon gas to a flask that had been dried in vacuo overnight. Reaction temperature was maintained at 10°-15° C. with an ice bath. When addition was complete, the reaction mixture was allowed warm to room temperature and stirred for 3 hours. 2 N hydrochloric acid (2 ml) was added followed by 50 ml of water and the mixture extracted with ethyl acetate three times. The organic extracts were combined, washed with water twice and dried over sodium sulfate. The solvent was removed in vacuo after filtration and the crude product chromatographed on silica to give the title compound.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[O:17])[CH:13]=[CH:12][C:11]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[Cl:34])[O:27][C:11]1[CH:12]=[CH:13][C:14]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH:24]([CH3:25])[CH3:26])[CH2:22][CH2:23]2)=[O:17])=[CH:15][C:10]=1[CH2:9][NH:7][CH3:6]
Reactant: CC(C)N1CCN(C(=O)c2ccc(Oc3ccc(Cl)c(Cl)c3)c(CN(C)C(=O)OC(C)(C)C)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(C(=O)N2CCN(C(C)C)CC2)ccc1Oc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of [2-(3,4-dichloro-phenoxy)-5-(4-isopropyl-piperazine-1-carbonyl)-benzyl]-methyl-carbamic acid tert-butyl ester (212.5 mg, 0.40 mmol) in DCM (2 mL) was added TFA (1 mL). After 30 min, the mixture was concentrated and the residue was purified by FCC to give the desired product (119.3 mg, 69%). MS (ESI): mass calcd. for C22H27Cl2N3O2, 435.15; m/z found, 436.3 [M+H]+. 1H NMR (CDCl3): 7.50 (d, J=2.0, 1H), 7.38 (d, J=8.8, 1H), 7.30 (dd, J=8.3, 2.1, 1H), 7.06 (d, J=2.8, 1H), 6.88 (d, J=8.3, 1H), 6.82 (dd, J=8.8, 2.8, 1H), 3.81-3.69 (m, 4H), 3.53-3.37 (m, 2H), 2.78-2.68 (m, 1H), 2.64-2.43 (m, 4H), 2.43 (s, 3H), 1.93 (br s, 1H), 1.04 (d, J=6.5, 6H).
Reaction SMILES: C(O)C.CNC.C([Li])CCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(Br)(Br)(Br)[Br:21]>O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([Br:21])[CH:15]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccncc1
Agent: CNC
Agent: [Li]CCCC
Solvent: O
Solvent: CCO
Product: COc1ccnc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
A solution of N,N-dimethylamine ethanol (78.086 g, 0.876 mole) in anhydrous hexanes(1241 mL.) was cooled to 0° C. and butyllithium (2M soln. 876 mL., 1.757 mole) was added by use of an addition funnel. After 30 minutes at 0° C., 4-methoxypyridine(47.87 g, 0.438 mole) was added. Stirring continued at 0° C. for one hour before the reaction mixture was cooled to −78° C. and a solution of CBr4 (363 g, 1.093 mole) was added. The reaction temperature was maintained at 0° C. for 2.5 hours. The water was then added to quench the reaction. The aqueous layer was then separated and extracted with methylene chloride. The organic extractions were washed with brine, dried over magnesium sulfate and evaporated to give crude product. The crude product was purified by column chromatography using 80/20 ethyl acetate/hexanes as the eluants. The purified product was collected and concentrated to give 4-methoxy-2-bromopyridine (17 g. 22% yield).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Cl>>[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCc1ccccc1Cl
Product: Clc1ccc(-c2nn(Cc3ccccc3Cl)c3c2CCNCC3)cc1
Yield: 13.4 %

Procedure:
The title compound (0.01 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-chlorobenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C17H22ClN3O, 371.10; found, m/z 372.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.43-7.41 (m, 2H), 7.32-7.30 (m, 2H), 7.32 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 5.23 (s, 2H), 2.94-2.91 (br m, 4H), 2.79-7.77 (br m, 2H), 2.73-7.71 (br m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.Br[CH2:17][CH2:18][CH2:19][C:20]#[N:21].C(=O)([O-])[O-:23].[K+].[K+]>CN1CCCC1=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][C:20]([NH2:21])=[O:23])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: N#CCCCBr
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: NC(=O)CCCN1CCN(c2ccc(N)cc2)CC1

Procedure:
1-(4-Nitrophenyl)piperazine and 4-bromobutyronitrile were allowed to undergo the reaction under heating in 1-methyl-2-pyrrolidone in the presence of potassium carbonate. The resulting compound was allowed to react with polyphosphoric acid under heating and then subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 4-[4-(4-aminophenyl)piperazin-1-yl]butanamide. F: 263.