Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.OC1C=CC=CN=1.[C:14]([O:18][C:19](=[O:48])[NH:20][C@H:21]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:46])[CH3:45])[C:41](=[O:47])[O:40]1)[CH2:22][N:23]1[CH2:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH2:25][C:24]1([CH3:38])[CH3:37])([CH3:17])([CH3:16])[CH3:15]>O>[C:14]([O:18][C:19](=[O:48])[NH:20][C@@H:21]([CH2:22][N:23]1[CH2:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH2:25][C:24]1([CH3:37])[CH3:38])[C@@H:39]([OH:40])[CH2:43][C@H:42]([C:41](=[O:47])[NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:44]([CH3:46])[CH3:45])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reactant: NC1CCCC1
Agent: Oc1ccccn1
Solvent: O
Product: CC(C)[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NC1CCCC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 83.4 %

Procedure:
0.17 g of cyclopentylamine (2.0 mmol) and 37 mg of 2-hydroxypyridine (0.39 mmol) were added to 200 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (1m) (0.39 mmol), and the mixture was stirred at 80° C. for six hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 193 mg of the title compound (yield: 83%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]([N:17]([CH3:19])[CH3:18])[C:6]1([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:3].[Br:20]([OH:23])(=[O:22])=[O:21]>C(OCC)(=O)C>[CH3:3][CH:2]([CH2:4][CH:5]([N:17]([CH3:18])[CH3:19])[C:6]1([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:7][CH2:8][CH2:9]1)[CH3:1].[Br:20]([O-:23])(=[O:22])=[O:21]
Reactant: [O-][Br+2]([O-])O
Agent: CC(C)CC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Solvent: CCOC(C)=O
Product: [O-][Br+2]([O-])[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sibutramine (28.0 g, 0.1 mol) was dissolved in 280 ml of ethyl acetate with agitation. After the solution was adjusted to 25° C., 17.2 g of 47% bromic acid was slowly added in droplets to the solution to form crystals. The resulting mixture was agitated at 25° C. for 2 hrs and further agitated at 4° C. for 1 hr. The generated solid was recovered by filtration under pressure, washed with 100 ml of ethyl acetate, and vacuum-dried at 40° C., thus obtaining 33.1 g (yield: 92%) of a target compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][N:7]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)C>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)=[N:7][CH:6]=1
Reactant: OC1CCNCC1
Reactant: Clc1ncc(-c2ccccc2Cl)nn1
Solvent: CCO
Product: OC1CCN(c2ncc(-c3ccccc3Cl)nn2)CC1

Procedure:
7.4 g of 3-chloro-6-(2-chlorophenyl)-1,2,4-triazine, prepared according to J. Het. Chem. 16, 1402 (1979), and 9 g of 4-hydroxypiperidine are heated under reflux in 150 ml of ethanol for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][C:24]=1[CH3:25])=[CH:16][CH:15]=3.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[C:24]([CH3:25])=[CH:23][N:22]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cn(C(=O)C(C)(C)C)nc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.14 g (0.32 mmol) of compound from Example 53, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(4-methyl-2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one is dissolved in 5 ml of pyridine. 0.2 ml (1.6 mmol) of pivaloyl chloride is added. The mixture is stirred at ambient temperature for 2 hours. The reaction medium is poured into water, and extracted with EtOAc. Washing with a saturated NaCl solution, drying over Na2SO4 and then adsorbing onto silica are performed. Purification is carried out by chromatography on a silica column, elution being carried out with a 75/25 EtOAc/cyclohexane mixture and then with pure EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7](O)[C:6]=2[CH:11]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:7]1[C:6]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1noc2ccc(Cl)cc12
Solvent: c1ccncc1
Product: Clc1ccc2onc(Cl)c2c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a suspension of 5-chloro-3-hydroxy-1,2-benzisoxazole (100 g) in phosphorus oxychloride (80 ml) was added pyridine (48 ml) dropwise over 1 hours with stirring at room temperature, and the mixture was then refluxed for 5 hours. The reaction mixture was added to ice water (500 ml) and extracted with ethyl acetate and the combined extracts were dried over anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure and the title compound (102 g, 92%) was obtained by recrystallizing the residue from petroleum ether as a colorless needle.
Reaction SMILES: [N+:1]([O-])([O-])=O.[Na+].[I:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[Sn](Cl)Cl>O.Cl>[I:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1ccc(I)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(I)cc1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
The title compound was synthesized in accordance with Reaction Scheme 2. The product obtained had the formula of compound (13), in which X and X1 represent C(CH3)2, R/R1 represent C22H14 /C45H29 and A represents Cl. 4-iodophenylhydrazine was prepared by the procedure of Blaikie et al., J. Chem. Soc., 313:296 (1924). Sodium nitrate (16.56 g, 0.24 mol, Aldrich) dissolved in water (100 ml) was added dropwise within 45 mins. to a solution of 4-iodoaniline (43.9 g, 0.20 mol, Aldrich) in ice-water (600 ml) and concentrated hydrochloric acid (200 ml) which was cooled to 0°-2° C. The reaction mixture was stirred for a further 30 minutess at 0°-2° C. then tin(II) chloride (151.68 g, 0.8 mol, Aldrich) in c.HCl (150 ml) was added dropwise over 90 mins. while maintaining the temp. of the reaction mixture between 0°-2° C. Following the addition, the resulting solution was warmed to room temperature and stirred for 3 hours. The yellow solid which had separated from the solution was then collected by filtration, placed in ice water (800 ml) and the pH adjusted to 10 with 25% aqueous potassium hydroxide solution. The resulting solid was collected by filtration, washed with a small amount of water and dried under vacuum. The product was then placed in toluene (400 ml) and filtered to remove insoluble impurities. Hexane (1200 ml) was added and upon cooling in the refrigerator yellow needles separated which were collected by filtration, washed with hexane (100 ml) and dried under high vacuum to give pure 4-Iodophenylhydrazine (23.36 g, 50%), m.p.=94° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)=[N:7][C:6]=2[CH:16]=1.[C:17](Cl)(Cl)=[S:18].C(=O)([O-])[O-].[Ca+2].O>C(Cl)(Cl)Cl>[CH3:15][N:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([N:1]=[C:17]=[S:18])=[CH:16][C:6]=2[N:7]=1
Reactant: S=C(Cl)Cl
Reactant: Cn1cccc1-c1nc2cc(N)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1cccc1-c1nc2cc(N=C=S)ccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g of 5-amino-2-(1-methyl-2-pyrrolyl)benzoxazole (0.0047 mole) is dissolved in 50 ml of chloroform and slowly added to the following cold mixture: 0.54 g of thiophosgene (0.0047 mole), 0.47 g of calcium carbonate (0.0047 mole), 100 ml of chloroform and 25 ml of water. After the addition is complete the reaction is stirred at room temperature for 2 hr. The chloroform layer is separated, dried over anhyd. MgSO4 and evaporated under vacuum yielding a light brown solid. This material is crystallized from petroleum ether yielding 0.650 g of tan crystals, mp 105°-106° (54%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=O)[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[OH-].[NH4+]>>[CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH:6]=[C:5]([C:16]2[CH:17]=[CH:18][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: Oc1ccccc1
Reactant: CN1C(C)(C)CC(=O)CC1(C)C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CN1C(C)(C)C=C(c2ccc(O)cc2)CC1(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 33.5 %

Procedure:
1,2,2,6,6-Pentamethyl-piperidin-4-one (8.64 g, 50.00 mmol) and phenol (4.98 g, 53.00 mmol) were melted together at 60° C. in a 100 mL round bottomed flask after which 13.5 mL of concentrated hydrochloric acid was added dropwise. The yellow solution was stirred at 70° C. for 24 hours. The mixture was poured into a beaker containing ice. Ammonium hydroxide was added carefully while stirring until the pH reached 7˜8. The mixture was extracted with EtOAc five times. The organic phases were combined, dried (Na2SO4) and concentrated. The residue was purified by chromatography on a silica gel column, eluting with 7N NH3 in methanol/dichloromethane to give 4-(1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydropyridin-4-yl)-phenol (4.11 g, 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:19]1([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C:25]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][C:9]3=[O:12])=[CH:4][CH:3]=2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CC1CCCC1)Nc1ccc2c(c1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
To a mixture of 7-amino-1-tetralone (13.2 g) (prepared as described above and used without further purification) and pyridine (8.4 ml) in methylene chloride (130 ml) at 0° C. was added a solution of cyclopentylacetyl chloride (13.2 g) in methylene chloride (20 ml). The reaction was stirred for 30 min and at room temperature for 1.5 h. The mixture was evaporated and the residue was diluted with ethyl acetate, washed (saturated sodium bicarbonate, 1N HCl, brine), dried (MgSO4) and evaporated. The residue was flash chromatographed, eluting with ethyl acetate:methylene chloride (5:95, 7.5:92.5, and 1:9, successively), to give 7-cyclopentylacetamido-1-tetralone (16.6 g, 74%) as a colorless solid; mp 117.0°-118.0° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[C:12]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:11][O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: CCOC(=O)CBr
Reactant: C#CCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCCOCC(=O)OCC
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of 5-hexyn-1-ol (2.0 g, 20.4 mmol) in N,N-dimethylformamide (40 ml) was added sodium hydride (815 g, 60% in oil, 20.41 mmol) at 0° C. The mixture was stirred for 1 hour, and ethyl bromoacetate (3.4 ml, 30.5 mmol) was added thereto. The mixture was stirred at the same temperature for 1 hour. After the reaction was completed, water was added thereto. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (1.38 g, yield: 37%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]([CH2:10][C:11](=[O:13])[CH3:12])(=[O:9])[CH3:8].[Na]>>[CH3:6][O:5][C:1](=[O:4])[CH2:2][CH2:3][CH:10]([C:11](=[O:13])[CH3:12])[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)CC(C)=O
Reactant: C=CC(=O)OC
Agent: [Na]
Product: COC(=O)CCC(C(C)=O)C(C)=O

Procedure:
4-acetyl-5-oxohexanoic acid methyl ester was prepared through the Michael addition of methyl acrylate to acetyl acetone in the presence of metallic sodium. The crude product was purified by vacuum distillation and received in a purity of approximately 99%.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Br[CH2:11][CH2:12][C:13]#[N:14].[H-].[Na+]>>[C:13]([CH2:12][CH2:11][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][CH:9]=2)#[N:14]
Reactant: N#CCCBr
Reactant: c1ncc2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Product: N#CCCn1cnc2cncnc21

Procedure:
More specifically, a purine compound is alkylated with 3-bromopropionitrile in the presence of NaH to give N9-cyanoethyl purine intermediate. Reaction of this intermediate with a methyliodo-ester and lithium 2,2,6,6-tetramethylpiperidine affords a mixture of N7-alkylated and N9-alkylated ester-containing products. Reduction of the ester in N9-alkylated product gives another intermediate, which is converted to a desired purine compound of formula (I) by an alkylation reaction or by reacting with a phosphonate in the presence of tert-butoxide. Similarly, reduction of the ester in N7-alkylated product gives a compound, which reacts with a phosphonate to produce an N7-substituted phosphonate-purine.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)=O.[C:22](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)#[CH:22]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C=O)cc2)C1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
(S)-tert-Butyl 2-(4-formylphenyl)morpholine-4-carboxylate (120 mg, 0.41 mmol) was dissolved in methanol (5 ml), then potassium carbonate (114 mg, 0.824 mmol) was added, followed by dimethyl 1-diazo-2-oxopropylphosphonate (99 mg, 0.515 mmol). The mixture was stirred for 2 h at room temperature. Ethyl acetate (50 ml) and sodium bicarbonate solution (50 ml) were added, the aqueous phase re-extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography (10 g silica gel, 10 to 20% ethyl acetate in heptane) to yield a colorless oil (103 mg, 87%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:15]([O:17][C:18](=[O:25])[C@H:19]([CH2:21][CH2:22][S:23][CH3:24])[NH2:20])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:25])[C@H:19]([CH2:21][CH2:22][S:23][CH3:24])[NH:20][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:16]
Reactant: CCOC(=O)[C@@H](N)CCSC
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CCOC(=O)[C@H](CCSC)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure BG above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=[C:4]2[CH:3]=1.C(OCC)(=O)C.C([O-])(=O)C.[Na+]>C(O)C.[Pd]>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[CH:3][C:4]3[N:5]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=3)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cn2c(cc(Cl)c3ccc(OC)cc32)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn2c(ccc3ccc(OC)cc32)n1
Reaction time: 4 h

Procedure:
5 g of ethyl 5-chloro-8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate were suspended in 75 ml of ethanol and 75 ml of ethyl acetate and then 2.5 g of anhydrous sodium acetate and 250 mg of 5% palladium on charcoal were added. The mixture was hydrogenated at 50° C. under atmospheric pressure for 4 hours and the catalyst was filtered off. Then, the solvent was removed under vacuum and the residue was partitioned between chloroform and 2 N sodium carbonate solution. The organic solution was dried over magnesium sulfate and was reduced in volume under vacuum and ether was added to obtain pale cream crystals of ethyl 8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 152°-153° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:39]([O:41][C:42](=[O:67])[CH2:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]Br)[C:48]=1[CH2:60][CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH3:40]>CC(C)=O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:32])[C:16]2[CH:21]=[C:20]([O:22][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([O:46][CH2:45][CH2:44][CH2:43][C:42]([O:41][CH2:39][CH3:40])=[O:67])[C:48]=3[CH2:60][CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH:19]=[C:18]([C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc(O)cc(-c3ccc4c(c3)OCO4)c2)CC1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(3-benzo[1,3]dioxol-5-yl-5-hydroxy-benzoyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (400 mg) in a mixture of acetone and DMF (2:1, 3 mL) were added potassium carbonate (10 eq.) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.1 eq). The resulting mixture was stirred at 75° C. for 2 days. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 4-(3-benzo[1,3]dioxol-5-yl-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (556 mg). The total amount of material from the previous step was dissolved in EtOH (3 mL), followed by addition of 10 M NaOH solution (10 eq.). The resulting reaction mixture was stirred at room temperature for 3 h. Then it was neutralized with 3 N HCl and extracted into ethyl acetate. The organic extract was washed with water and brine and dried over anhydrous sodium sulfate. The crude material was concentrated under reduced pressure and redissolved in a mixture of TFA and dichloromethane (1:1, 2 mL) and stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the crude material was purified on reverse-phase HPLC to yield the title compound.
Reaction SMILES: [CH3:1][CH:2]([C@:4]([OH:30])(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:29])[CH2:20][CH2:21]2)=[CH:16][CH:15]=3)[CH2:12][CH2:11]1)[CH3:9])[CH3:5])[CH3:3].C1C=CC=CC=1.O>CCOCC>[CH3:9][C@@H:8]([C@@H:10]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][CH2:24]/[C:14](=[CH:15]\[CH:16]=[C:17]3\[CH2:18][C@@H:19]([OH:29])[CH2:20][CH2:21][C:22]\3=[CH2:23])/[C@@H:13]2[CH2:12][CH2:11]1)/[CH:7]=[CH:6]/[C:4]([OH:30])([CH:2]([CH3:1])[CH3:3])[CH3:5]
Reactant: CC(C)[C@](C)(O)/C=C/[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)/C=C/C(C)(O)C(C)C)CC[C@@H]12
Yield: 55.5 %

Procedure:
One gram (2.4 mmol) of (7) was dissolved in 250 ml of ether and benzene (4:1) and irradiated with stirring under nitrogen in a water-cooled quartz immersion well using a Hanovia medium-pressure UV lamp for 2 hrs. The solution was concentrated in vacuo, redissolved in 100 ml of ethanol and heated under reflux overnight. The solution was concentrated to dryness in vacuo and the residue was purified on a silica gel column using 30% ethyl acetate in hexane to yield 0.55 g (55%) of (8).
Reaction SMILES: [C:1]([N:9]([C:11](=[O:16])[C:12]([NH:14][NH2:15])=[O:13])[NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>CC(N(C)C)=O>[C:1]([N:9]([C:11](=[O:16])[C:12]([NH:14][NH2:15])=[O:13])[NH:10][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)Cl
Reactant: NNC(=O)C(=O)N(N)C(=O)c1ccccc1
Solvent: CC(=O)N(C)C
Product: CCCC(=O)NN(C(=O)C(=O)NN)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
11.1 g (0.05 mols) of N-benzoyloxalic acid dihydrazide are suspended in 250 ml of dimethylacetamide and dropwise admixed, while stirring, with 5.8 g (0.055 mols) of butyric acid chloride. The reaction mixture is stirred for 3 hours at 60°-70° C., then 500 ml of ice water are added and filtering under suction is carried out at 5°-10° C. The resultant product is recrystallised from methylcellosolve. There is obtained N-benzoyl-N'-butyroyloxalic acid dihydrazide (stabiliser 44), M.P. 254° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[C:17]1([C:23]2[CH:27]=[CH:26][O:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:28]([C:24]4[O:25][CH:26]=[CH:27][C:23]=4[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[O:29])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1occc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4occc4-c4ccccc4)CC3C2)n1
Yield: 27.6 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0 mg, 0.28 mmol), 3-phenyl-furan-2-carboxylic acid (61.8 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (107.0 mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Dionex HPLC to yield pure title compound (30.0 mg, 28.0%). MS (ESI) mass calcd. for C23H24N4O2, 388.47; m/z found 389.2 [M+H]+. 1H NMR (CDCl3): 7.56-7.50 (m, 2H), 7.46 (d, J=1.8, 1H), 7.37-7.30 (m, 2H), 7.25-7.19 (m, 1H), 6.61 (d, J=1.8, 1H), 6.29 (s, 1H), 3.95-3.80 (m, 2H), 3.75-3.60 (m, 3H), 3.51 (dd, J=11.6, 5.0 1H), 3.42 (dd, J=11.6, 4.1, 1H), 3.33 (dd, J=11.6, 5.4, 1H), 3.02-2.81 (m, 2H), 2.35-2.22 (m, 6H).