Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][C:28](=[O:35])[N:29]2[C:32]([NH2:34])=[O:33])=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]([C:7]([C:4]3[CH:3]=[C:2]([Br:1])[O:6][CH:5]=3)=[O:9])[C:28](=[O:35])[N:29]2[C:32]([NH2:34])=[O:33])=[CH:25][CH:24]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: NC(=O)N1C(=O)Cc2ccc(Cl)cc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Product: NC(=O)N1C(=O)C(C(=O)c2coc(Br)c2)c2ccc(Cl)cc21
Yield: 11 %

Procedure:
The experimental procedure used to produce the title compound was adopted from Example 55. A 750 mg (3.93 mmole) portion of 5-bromo-3-furoic acid (prepared according to Amaral, L., et al., J.O.C., 41, 2350 (1976)) was transformed into the acyl imidazole by reaction with 690 mg (4.25 mmole) of 1,1'-carbonyldiimidazole. The intermediate 5-bromo-3-furan-(1-imidazo)carboxamide coupled directly with 689 mg (3.27 mmole) of 6-chloro-2-oxindole-1-carboxamide in the presence of 1.08 g (8.83 mmole) of 4-(N,N-dimethyl-amino)pyridine to give 500 mg (40% yield) of crude greenish-yellow solid. Recrystallization gave 143 mg (0.37 mmole, 11% yield) of pure title compound as a greenish solid, m.p. 232-4° C. (acetic acid).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6]C=[CH:4][C:3]=1C.[C:10]([C:14]1[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=1[O:16][C:17]1[C:22]([N:23]=[C:24]=S)=[CH:21][CH:20]=[CH:19][N:18]=1)([CH3:13])([CH3:12])[CH3:11].Cl[CH2:31][CH2:32]Cl>>[C:10]([C:14]1[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=1[O:16][C:17]1[C:22]([NH:23][C:24]2[NH:8][C:7]3[CH:6]=[C:31]([CH3:32])[CH:4]=[CH:3][C:2]=3[N:1]=2)=[CH:21][CH:20]=[CH:19][N:18]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Reactant: Cc1cccc(N)c1N
Reactant: ClCCCl
Product: Cc1ccc2nc(Nc3cccnc3Oc3ccccc3C(C)(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,3-diamino toluene (45 mg, 0.368 mmol) in DCE (2 mL) was slowly added 1c (50 mg, 0.176 mmol). The reaction was stirred 18 h at rt and concentrated. The crude mixture containing 1d and 1d′ was used in the next step without further purification. [M+H]+=407.4.
Reaction SMILES: ClCCCC([O:11]C(=O)C)CCCCC.ClCCCC(OC(=O)C)C(C)(C)CCCC.C([O:34][CH:35]([C:53](C)(C)[CH2:54][CH2:55][CH2:56][CH3:57])[CH2:36][CH2:37][CH2:38][N:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50]CC)=[O:49])[C:40]#[N:41])(=O)C>>[OH:34][C@H:35]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:36]#[C:37][CH2:38][N:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[C:40]#[N:41].[OH:34][C@H:35]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:36]#[C:37][CH2:38][N:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[C:40]([NH2:41])=[O:11]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: CCCCC(C)(C)C(CCCN(C#N)CCCCCCC(=O)OCC)OC(C)=O
Agent: CCCCC(C)(C)C(CCCCl)OC(C)=O
Product: CCCCC[C@@H](O)C#CCN(C#N)CCCCCCC(=O)O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-5,5-dimethylnonane (Example G). The product of Step A is thus ethyl 7-[N-(4-acetoxy-5,5-dimethylnonyl)cyanamido]heptanoate. The subsequent steps yield 7-[N-(4-hydroxy-5,5-dimethylnonyl)cyanamido]heptanoic acid (B) and 7-[1-(4-hydroxy-5,5-dimethylnonyl)ureido]heptanoic acid (C).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][NH:26][CH2:27][CH3:28])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[O:31]1[CH2:34][C:33](=O)[CH2:32]1>>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][N:26]([CH2:27][CH3:28])[CH:33]3[CH2:34][O:31][CH2:32]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: O=C1COC1
Reactant: CCNCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Product: CCN(CCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12)C1COC1

Procedure:
The title compound was prepared in analogy to Example 44-1 in Scheme 20 by using N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-ethylethane-1,2-diamine (prepared in analogy to Example 3-37) and oxetan-3-one. MS obsd. (ESI+) [(M+H)+] 481, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 (d, J=7.6 Hz, 1 H), 7.87 (d, J=7.2 Hz, 1 H), 7.66 (t, 2 H), 7.50 (t, 2 H), 7.36 (d, J=7.6 Hz, 1 H), 6.04 (s, 1 H), 5.20 (s, 2 H), 4.68-4.50 (m, 6 H), 4.07-4.00 (m, 1 H), 3.65 (s, 2 H), 3.45 (t, J=12.4 Hz, 2 H), 2.84 (t, J=12.8 Hz, 2 H), 2.73-2.67 (m, 2 H), 2.45 (s, 3 H), 1.07 (t, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:15]3[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:17][CH:9]2[CH2:10]4)[CH2:14]3)=[CH:4][CH:3]=1.[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl.[OH-].[Na+].C[CH2:33][C:34]([CH3:36])=[O:35]>CC(CC(C)=O)C.CS(C)=O>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:33][CH:34]4[O:35][CH2:36]4)=[CH:22][CH:23]=3)[CH:9]3[CH2:17][CH:13]4[CH2:12][CH:11]([CH2:16][CH:15]2[CH2:14]4)[CH2:10]3)=[CH:6][CH:7]=1)[CH:27]1[O:29][CH2:28]1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)C3CC4CC(C3)CC2C4)cc1
Reactant: CCC(C)=O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(=O)CC(C)C
Product: c1cc(C2(c3ccc(OCC4CO4)cc3)C3CC4CC(C3)CC2C4)ccc1OCC1CO1
Temperature: 45 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
In a separable flask having an inner volume of 300 ml, equipped with a reflux condenser, a stirrer, and a thermometer were charged 20.0 g (0.06 mol) of 2,2-bis(4-hydroxyphenyl)adamantane, 46 g (0.50 mol) of epichlorohydrin, 30 mL of MIBK, and 60 mL of DMSO, and the mixture was heated to 45° C. Then, 5.5 g (0.14 mol) of sodium hydroxide was added into this solution by small portions during a period of 1.5 hours. After completion of the addition, the reaction temperature was raised to 75° C., and the reaction was carried out for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, added by 25 mL of MIBK, and washed by water until the aqueous layer became neutral. The resulting organic layer was concentrated to obtain pale yellow solids. The pale yellow solids were dissolved in 285 g of MEK, added by 3.4 g of 25% by mass of aqueous sodium hydroxide solution, and then the mixture was stirred for 2 hours under reflux. Thereafter, the solution was cooled to room temperature, and washed by water until the aqueous layer became neutral from alkaline. The water-washing was performed two more times, and then the organic layer was concentrated. The resulting pale yellow solids were recrystallized by a mixed solvent of THF and isopropyl ether to obtain 23.2 g of 2,2-bis(4-glycidyloxyphenyl)adamantane having the following formula (96% purity by LC, epoxy equivalent of 224).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[Na+].S(O[CH2:22][CH2:23][S:24][C@H:25]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@:31]3([OH:49])[CH2:32][CH2:33][C@@H:34]2[C:44]2[CH:48]=[CH:47][O:46][CH:45]=2)[CH2:26]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[N:4]1([CH2:3][CH2:2][O:1][CH2:22][CH2:23][S:24][C@H:25]2[CH2:42][CH2:41][C@@:40]3([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]4[C@@H:39]3[CH2:38][CH2:37][C@@:35]3([CH3:36])[C@:31]4([OH:49])[CH2:32][CH2:33][C@@H:34]3[C:44]3[CH:48]=[CH:47][O:46][CH:45]=3)[CH2:26]2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCN1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCS[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12CC[C@H](SCCOCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Yield: 69.8 %

Procedure:
To a solution of 0.21 g of 1-(2-hydroxyethyl)pyrrolidine in 5 ml of dimethylformamide, 0.076 g of NaH (60% dispersion in mineral oil) were added and the mixture was kept at reflux for 2 hrs, then 0.35 g of 3β-(2-tosyloxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol in 2 ml of dimethylformamide was added, the mixture was kept at reflux temperature for 4 hrs and 5 ml of water were added. The residue was extracted with methylene chloride, the organic layer was washed with water to neutral pH, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using methylene chloride/methanol 95/5 as eluant to give 0.22 g of the title compound (I-bz) as a white pasty solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]([NH2:20])=[CH:18][C:17]([C:21]([CH3:42])([CH3:41])[CH2:22][O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:16]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:20][C:19]1[N:15]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[N:16]=[C:17]([C:21]([CH3:42])([CH3:41])[CH2:22][O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:18]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCc3ccccc3)c2)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(O)c2)n1
Yield: 52 %

Procedure:
A solution of Intermediate 153c (1.21 g, 2.1 mmol) in ethanol (IMS grade, 20 mL) was treated with water (1 mL) and ammonium formate (1.33 g, 21 mmol). The mixture was purged with N2 then 10% Pd/C (0.67 g, 0.63 mmol Pd) was added. The mixture was heated to reflux for 1 h then filtered through celite and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC, using 0-40% EtOAc in cyclohexane, to give the title compound (0.53 g, 41% over 2 steps) as a golden gum. LCMS (Method 3): Rt 4.55 min, m/z 486.5 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:30])[CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.CCCCCC.C(OCC)C>[F:30][C:4]1[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:42])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]3[CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)c(F)c1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)c(F)c1
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 4-[2-(azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (71 mg) in N,N-dimethylformamide (2 ml) was added a solution of 0.25 M 2-phenylacetyl isocyanate in hexane (2.05 ml) under a nitrogen atmosphere, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (1.5 ml) and hexane (3 ml). The solid was filtered off and dried under aeration to provide the titled compound (63.0 mg, 64.0%) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[CH3:13][C:14](C)([O-])[CH3:15].[K+].C(Br)(C)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[CH:14]([CH3:15])[CH3:13]
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)Br
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The (4-bromophenyl)acetic acid methyl ester in the Step 1 and potassium t-butoxide (4.8 g, 1 eq) were dissolved in 200 ml DMF at 0° C. Isopropyl bromide (4 ml. 1 eq) was added into the mixture and stirred at room temperature for 3 hours. When the reaction was completed, the mixture was extracted 3 times with ethyl acetate and water, and washed with saline solution. After the organic layer was dried with anhydrous and the solvent was removed at low pressures, the target compound 2-(4-bromophenyl)3-methylbutyric acid methyl ester was obtained by separation and purification of the mixture using a column chromatography (ethyl acetate:n-hexane=1:10) (6.60 g, 57%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.[OH-].[K+].S(O[CH2:23][C@H:24]([CH3:33])[NH:25]C(OCCCC)=O)(=O)(=O)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CS(C)=O.O>[NH2:25][C@@H:24]([CH3:33])[CH2:23][N:10]1[CH:9]=[N:8][C:7]2[C:11]1=[N:12][C:13]([NH2:15])=[N:14][C:6]=2[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)N[C@@H](C)COS(C)(=O)=O
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](N)Cn1cnc2c(-c3ccco3)nc(N)nc21
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
A solution of the 6-(2-furyl)-1H-purine-2-amine (0.1 g, 0.5 mmol) in DMSO was treated with freshly ground KOH (112 mg, 2 mmol), shaken for 10 min, treated with N-butoxycarbonyl-L-alaninol mesylate (316 mg, 3 mmol), shaken at 40° C. for a further 17 h, treated with di-tert-butyl dicarbonate (655 mg, 3 mmol), shaken for a further 30 min, diluted with H2O, extracted with EtOAc and the extracts dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; (EtOAc)]. The resulting gelatinous solid was dissolved in MeOH (3 mL), treated with HCl solution (4-M in dioxan, 0.5 mL), stirred for 17 h, diluted with Et2O and filtered to give the title compound (67 mg, 45%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.I[CH3:22]>>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:22])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CI
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Product: COC(=O)c1cc(OC)cc(OCc2ccccc2)c1

Procedure:
Following the procedure of Example 80(a) except substituting methyl 3-hydroxy-5-methoxybenzoate for methyl 3,5-dihydroxybenzoate and benzyl bromide for iodomethane, the title compound was prepared as a tan oil (1.2 g, 4.4 mmol). 1H NMR (400 MHz, CDCl3)δ7.45-7.31 (m, 6 H), 7.24 (s, 1 H), 6.76 (m, 1 H), 5.09 (s, 2 H), 3.95 (s, 3 H), 3.84 (s, 3 H).
Reaction SMILES: CC(C[NH:5][C:6](/[CH:8]=[CH:9]/[CH:10]=[CH:11]/C1C=CC2OCOC=2C=1)=O)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][CH2:31][C:32]([OH:34])=O)=[CH:29][C:24]=2[O:23][CH2:22]1.N1CCCCC1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][CH2:31][C:32]([N:5]3[CH2:6][CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:34])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: O=C(O)CCc1ccc2c(c1)OCO2
Reactant: CC(C)CNC(=O)/C=C/C=C/c1ccc2c(c1)OCO2
Agent: CS(=O)(=O)Cl
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc2c(c1)OCO2)N1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
The method was adapted from that reported for piperlonguminine (section 2.2) but utilising 3-benzo-1,3-dioxol-5-ylpropionic acid and piperidine as the acid and amine components respectively. A mixture of 3-benzo-1,3-dioxol-5-ylpropionic acid (200 mg, 0.0026 mole, 1 eq) and triethylamine (0.27 ml, 0.002 mole, 2 eq) in dichloromethane (50 ml) was stirred for 15 min at 0° C. To this mixture methanesulfonyl chloride (0.11 ml, 0.0015 mole, 1.5 eq) was added and stirred for further 30 min at 0° C. Piperidine (0.15 ml, 0.0015 mole, 1.5 eq) was added to the mixture and stirred for 1 h at 0° C. and 1 h at room temperature. Dichloromethane (50 ml) was added to the mixture which was then washed with 5% HCl (3×100 ml), saturated aqueous NaHCO3 (3×100 ml) and water (3×100 ml). The organic fraction was dried over anhydrous sodium sulphate, filtered and rotary evaporated to yield brown oil (65% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C.[NH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: OCCC1CCN(c2cc(Cl)nnc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a 50 mL round bottom flask, 9.18 g (0.05 mol) of 3,4,6-trichloro-pyridazine, 5.30 g (0.05 mol) of anhydrous sodium carbonate and 20 mL of N,N-dimethylacetamide (DMA) were added, stirred at room temperature, then 6.54 g (0.05 mol) of 2-(piperidin-4-yl)-ethanol (dissolved in 10 mL DMA) was added dropwise slowly, after the dropwise addition, the agitation was kept overnight, the reaction liquid was poured into 100 mL of distilled water on the next day, extracted for three times by using total 200 mL of dichloromethane, the extract solutions were combined together, dried over anhydrous Na2SO4, concentrated, and separated by using column chromatograph (eluent, petroleum ether:acetone=10:3) to obtain 6 g of 2-[1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-ethanol, yield: 43.6%, 1H-NMR (400MHz, DMSO-D6) δppm: 1.21˜1.31(m, 2H), 1.39˜1.43(m, 2H), 1.59˜1.67(m, 1H), 1.76˜1.79(dbrs, 2H), 2.82˜2.88(dt, 2H, J=11Hz), 3.45˜3.49(m, 2H), 3.70˜3.73(dbrs, 2H), 4.40˜4.42(t, 1H, J=5Hz), 7.35(s, 1H).
Reaction SMILES: F[C:2]1[C:7]2[C:8](=[O:17])[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:6]=2[C:5](F)=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>O1CCCC1>[NH2:21][CH2:20][CH2:19][NH:22][C:2]1[C:7]2[C:8](=[O:17])[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:6]=2[C:5]([NH:21][CH2:20][CH2:19][NH2:22])=[CH:4][CH:3]=1
Reactant: O=C1c2ccncc2C(=O)c2c(F)ccc(F)c21
Reactant: NCCN
Solvent: C1CCOC1
Product: NCCNc1ccc(NCCN)c2c1C(=O)c1ccncc1C2=O

Procedure:
reacting 6,9-difluorobenzo[g]isoquinoline-5,10-dione with ethylenediamine by slowly adding the 6,9-difluorobenzo[g]isoquinoline-5,10-dione to a solution of the diamine in tetrahydrofuran (THF) wherein the diamine is in large molar excess to the dione to form the dihydrofluoride salt of 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione;
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][SH:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1>[OH-].[Na+]>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[CH2:14]([N:10]1[CH2:11][CH2:12][CH2:13][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=2)[CH2:8][CH2:9]1)[CH2:15][CH2:16][S:17][S:17][CH2:16][CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][N:7]([CH2:6][C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:8][CH2:9]1
Reactant: SCCCN1CCCN(Cc2ccc(Cl)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: Cl
Product: Clc1ccc(CN2CCCN(CCCSSCCCN3CCCN(Cc4ccc(Cl)cc4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A mixture of 3-[4-(4-chlorobenzyl)homopiperazin-1-yl]-propanethiol (4.0 g) and 2N sodium hydroxide (50 ml) is stirred at room temperature for 8 days. The product is extracted with ether, dried, and concentrated to give a yellow oil, which is purified on a silica gel column (methylene chloride:methanol, 95:5). The resulting yellow oil (1.5 g) is dissolved in ether and the salt precipitated with ethereal hydrochloric acid. Recrystallization from ethanol provided 1,1'-(dithiodi-3,1-propanediyl)bis[4-(4-chlorobenzyl) homopiperizine] tetrahydrochloride as a white crystalline solid, m.p. >170° (dec.).
Reaction SMILES: [OH:1][CH:2]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:12]=[CH:11][C:10]=2[NH:21][C:22]([C:24]2[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=2)[CH2:27][S:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:23])[CH:4]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>ClCCl>[N:15]1([C:13]2[CH:12]=[CH:11][C:10]([NH:21][C:22]([C:24]3[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=3)[CH2:27][S:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:23])=[C:9]([C:5]3[CH:4]=[C:3]([C:2](=[O:1])[C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:48])[F:49])[CH:42]=4)[CH:8]=[CH:7][N:6]=3)[CH:14]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(O)c3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)c3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h
Yield: 41.4 %

Procedure:
A −10° C. solution of 23 mg of tert-butyl 3-((3-((2-(4-(hydroxy(3-(trifluoromethyl)phenyl)methyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzyl)thio)propanoate 5.2d, 17 mg of diisopropylethylamine, and 10 mg of DMSO in 0.4 mL of dichloromethane was treated with 10 mg of pyridine sulfur trioxide complex. After stirring for 1 h the reaction mixture was applied directly to a silica gel column and eluted with a gradient of 0% to 10% ethyl acetate in dichloromethane. Evaporation of the solvent yielded 9.5 mg of product. MS (ES, m/z) 704.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1ON=C(C(C2C=CC=CC=2)C(O)=O)C=1)CCCCCCCCCCC.[CH3:55][CH:56]([C:58]1[CH:64]=[CH:63][CH:62]=[C:61]([CH:65]([CH3:67])[CH3:66])[C:59]=1[NH2:60])[CH3:57]>>[CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH:60][C:59]2[C:61]([CH:65]([CH3:66])[CH3:67])=[CH:62][CH:63]=[CH:64][C:58]=2[CH:56]([CH3:57])[CH3:55])=[O:21])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)on1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)no1
Product: CCCCCCCCCCCCc1cc(C(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccccc2)on1

Procedure:
In a manner similar to Example 128, a mixture of 3-dodecyl-α-phenyl-5-isoxazole acetic acid and 5-dodecyl-α-phenyl-3-isoxazole acetic acid was condensed with 2,6-bis(1-methylethyl)aniline to give after chromatography pure title compound; mp 115°-117° C.