Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH:23]1([CH2:29][CH2:30][C:31](O)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>ClCCl>[CH:23]1([CH2:29][CH2:30][C:31]([O:1][C:2]2[CH:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=3)=[N:6][CH:7]=2)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)CCC1CCCCC1
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ncc(OC(=O)CCC3CCCCC3)cn2)cc1
Yield: 57.5 %

Procedure:
3.00 g (10.0 mmol) of 5-hydroxy-2-(4-octyloxyphenyl)pyrimidin, 1.56 g (10.0 mmol) of 3-cyclohexylpropionic acid, 2.06 g (10.0 mmol) of N,N-dicyclohexylcarbodiimide and 0.1 g of 4-N,N-dimethylaminopyridine in 80 ml of dichloromethane are stirred at room temperature for 18 hours. Insoluble constituents are then filtered off, the mixture is evaporated, and the residue is purified by chromatography (silica gel/dichloromethane) and recrystallization from hexane, giving 2.52 g of 2-(4-octyloxyphenyl)pyrimidin-5-yl 3-cyclohexylpropionate. ##STR12##
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:17])[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:17])[C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(C)CCOC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCN(C)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
To a solution (10 ml) of ethyl 4-[(2-methoxyethyl)(methyl)amino]benzoate (467 mg, 1.97 mmol) in methanol was added 1M aqueous sodium hydroxide solution (10 ml), and the mixture was stirred at 50° C. for 3 hrs. The reaction mixture was concentrated under reduced pressure, and water and diethyl ether were added to the residue. The organic layer was separated. The aqueous layer was neutralized with 1M hydrochloric acid (10 ml) and extracted with ethyl acetate. The extract was dried over anhydrous MgSO4 and concentrated under reduced pressure to give the title compound (340 mg, 82%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])[CH3:2].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])([CH3:7])[CH3:6])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Yield: 32 %

Procedure:
To a stirring solution of ethyl-2-bromoisobutyrate (2.65 g, 13.6 mmol) in anhydrous acetonitrile (25 mL) at room temperature was added tert-butyl-1-piperazinecarboxylate (2.48 g, 13.3 mmol) followed by potassium carbonate (1.88 g, 13.6 mmol). The mixture was heated to 85° C. overnight. The cooled reaction mixture was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, separated and dried (MgSO4). The crude product was purified by column chromatography to yield 4-(1-ethoxycarbonyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester as a colourless oil (1.28 g).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].[CH2:17]([C:21]1[CH:32]=[CH:31][C:24]([CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1)[CH2:18][C:19]#[CH:20].C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[N:9][C:2]([C:20]#[C:19][CH2:18][CH2:17][C:21]3[CH:32]=[CH:31][C:24]([CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:23][CH:22]=3)=[C:3]([CH:6]=2)[C:4]#[N:5])=[CH:11][CH:12]=1
Reactant: C#CCCc1ccc(CN2CCCC2)cc1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)cnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(-c2ccc(Cl)cc2)cnc1C#CCCc1ccc(CN2CCCC2)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Under an argon atmosphere 1.9 mg (0.1 mmol) CuI and 7 mg (0.1 mmol) Pd(PPh3)2Cl2 are added to a solution of 50 mg (0.2 mmol) 2-chloro-5-(4-chloro-phenyl)-nicotinonitrile and 43 mg (0.2 mmol) 1-(4-but-3-ynyl-benzyl)-pyrrolidine in 2 mL DMF and 5 mL (20 mmol) triethylamine and the reaction mixture is stirred for 18 h at 50° C. The mixture is evaporated down i. vac., the residue is taken up in water, extracted exhaustively with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is is purified by HPLC.
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C([N:25](CC)CC)C.N>ClCCl>[NH2:25][C:20]([CH:17]1[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15][CH2:16]1)=[O:22]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Temperature: 0 °C

Procedure:
Ethyl chloroformate (4.6 ml, 48.3 mmol) was added slowly to a solution of 1-(tert-butoxycarbonyl)4-piperidinecarboxylic acid (10 g, 43.6 mmol) in dichloromethane (100 ml) stirred at 0° C. Triethylamine (7.6 ml, 52.3 mmol) was added with stirring over two minutes. 0.88 Ammonia solution (40 ml) was added and the mixture allowed to warm to room temperature with stirring. The mixture was washed with water, 1M citric acid solution and brine, dried (MgSO4), filtered and evaporated under reduced pressure gave the title compound as white solid, 8.94 g.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH2:16]([O:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]2[CH:23]=[N:24][C:19]([O:18][CH2:16][CH3:17])=[CH:20][CH:21]=2)[C:11]=1[CH3:12]
Reactant: CCOc1ccc(B(O)O)cn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)cn1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 6-ethoxypyridin-3-ylboronic acid (0.337 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 18 h to give 4-chloro-2-(6-ethoxypyridin-3-yl)-5,7-difluoro-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=335.0 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[C:11]([C:26]2[O:27][CH:28]=[CH:29][N:30]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1.[Ni]>[CH2:1]([NH:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[C:11]([C:26]2[O:27][CH:28]=[CH:29][N:30]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(-c2ncco2)nc1NCc1ccccc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1c(NCc2ccccc2)cc(-c2ncco2)nc1NCc1ccccc1
Yield: 100.1 %

Procedure:
N*2*,N*4*-Dibenzyl-3-nitro-6-oxazol-2-yl-pyridine-2,4-diamine (1.02 g, 2.54 mmol) was dissolved in THF (60 ml) then MeOH (60 ml) was added. The solution was hydrogenated over Raney nickel (210 mg, 0.25 mmol) under a hydrogen atmosphere (80 psi) for 1 hour. The reaction mixture was filtered through a Celite pad then evaporated to yield the title compound as a brown gum (944 mg, 100%). Taken on without further purification due to stability concerns.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]1=O.Cl.[CH2:12]([O:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH2:12]([O:19][N:20]=[C:3]1[C:4]2[CH:8]=[CH:7][S:6][C:5]=2[CH2:9][CH:2]1[OH:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1c2ccsc2CC1O
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: OC1Cc2sccc2C1=NOCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5-hydroxy-5,6-dihydro-cyclopenta[b]thiophen-4-one (33.4 g, 0.216 mol) in pyridine (300 mL) was added O-benzylhydroxylamine hydrochloride (38.3 g, 0.240 mol) and the mixture was stirred at room temperature over weekend. The mixture was evaporated under reduced pressure and co-evaporated two times with toluene. Ethyl acetate was added and the organic phase was washed with 5% citric acid and brine. The organic phase was dried with sodium sulphate and evaporated under reduced pressure. Yield. 55.1 g=98%
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(OC([NH:20][CH2:21][CH2:22][CH2:23]Br)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([CH2:23][CH2:22][CH2:21][NH2:20])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: c1ccc(C2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: NCCCN1CCC(c2ccccn2)CC1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To 1-benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in dry methanol (25 mL), 10% palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 mL EtOAc and 50 mL water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (hexane: EtOAc, 4.5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane (20 mL), N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution was refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 mL chloroform and 5 mL water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate: methanol, 4:1) to yield 1.86 g (49%) of the required product as a colorless oil; 1H-NMR (CDCl3): δ1.45 (s, 9 H), 1.54-1.69 (m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80 (m, 1 H), 3.02-3.22 (m, 4 H), 5.41 ( s, 1 H), 7.13-7.17 (m, 1 H), 7.33 (d, J=7.93 Hz, 1 H), 7.63 (t, J=7.6 Hz, 1 H), 8.54 (d, J=4.6 Hz, 1 H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15 g, 0.45 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added and the solution was stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 0.098 g (100%) of 3-[4-2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:37])[C@@H:12]([NH:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C(OCC1C=CC=CC=1)=O)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[H][H]>C(O)C.[Pd]>[CH3:9][C:2]([NH:10][C:11](=[O:37])[C@@H:12]([NH:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CC(C)(NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(NC(=O)[C@H](CCCCN)NC(=O)c1ccccc1)c1ccccc1
Yield: 106.5 %

Procedure:
1.73 g of (2S)-N-(α,α-dimethylbenzyl)-2-benzoylamino-6-(benzyloxycarbonylamino)hexanamide (prepared as described in Example 8) dissolved in 80 ml of ethanol and 4 ml of 1N hydrochloric acid was catalytically reduced by hydrogen gas in the presence of 0.33 g of 10% w/w palladium-on-carbon at room temperature. After filtering off the catalyst, the filtrate was concentrated by evaporation under reduced pressure to afford 1.35 g of the title compound as an amorphous substance melting at 94°-101° C. (with decomposition)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[N:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.CN(C)[CH:24]=[O:25]>>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[N:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13]([CH:24]=[O:25])=[CH:12]1
Reactant: COc1ccc2c(ccn2CCCCBr)n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(n1)c(C=O)cn2CCCCBr
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon and in an anhydrous medium, 730 μl (7.95 mmol) of phosphorus oxychloride are added dropwise to 12.5 ml of N,N-dimethylformamide maintained at 0° C.; after 30 minutes' stirring, 1.50 g (5.3 mmol) of the compound obtained in Step A dissolved in 25 ml of N,N-dimethylformamide are added by transfer. The reaction, mixture is stirred for 30 minutes at 0° C. and then for 3 hours at room temperature. The reaction mixture is evaporated to dryness and then taken up in water; the aqueous phase is rendered alkaline with a 6N sodium hydroxide solution and extracted several times with ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and then evaporated. After washing with a petroleum ether/diethyl ether mixture, the title compound is obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:12]Br>C(O)(=O)C>[C:1]([C:4]1[N:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[C:6]([Br:12])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N)c(Cl)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)c1cc(Br)c(N)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
15 g (88 mmol) of 6-acetyl-3-amino-2-chloropyridine are suspended in 88 ml of glacial acetic acid and 4.5 ml (88 mmol) of bromine are added dropwise. The mixture is subsequently stirred at room temperature for a further 30 minutes and then filtered off with suction and the filter cake is partitioned between NaHCO3 solution and CHCl3. The organic phase is separated off, dried with Na2SO4 and evaporated.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[C:10](Cl)(=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CCCCCCCCC(=O)Cl
Product: CCCCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Yield: 97.2 %

Procedure:
Following the procedure described in Referential Example 3, but using 4-(S)-isopropyl-2-oxazolidinone (4.99 g) and nonanoyl chloride (7.16 g), the desired compound (10.12 g) was obtained.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]([F:36])([F:35])[CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][C:29]([F:36])([F:35])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)CCC(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(CCC(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (106 mg, 93%), MS (ISP) m/z=455.3 [(M+H)+], mp 204.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4,4,4-trifluoro-butanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4].[CH3:23][O:24][C:25](=[O:30])[CH2:26][C:27](Cl)=[O:28]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]([C:27](=[O:28])[CH2:26][C:25]([O:24][CH3:23])=[O:30])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)cn1NCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)N(Cc1ccc(C(F)(F)F)cc1)n1cc(Br)cc1C(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 4-bromo-1-(4-trifluoromethyl-benzylamino)-1H-pyrrole-2-carboxylic acid methyl ester (1.0 eq.) and chlorocarbonyl-acetic acid methyl ester (1.5 eq.). ESI (m/z): 477 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(OS([C:15]1[CH:20]=[CH:19][C:18](C)=CC=1)(=O)=O)CCC.[CH:22]([N:25]1[C:30](=[O:31])[CH:29]=[C:28]([Cl:32])[NH:27][C:26]1=[O:33])([CH3:24])[CH3:23]>CN(C)C=O>[CH2:15]([N:27]1[C:28]([Cl:32])=[CH:29][C:30](=[O:31])[N:25]([CH:22]([CH3:24])[CH3:23])[C:26]1=[O:33])[CH2:20][CH2:19][CH3:18]
Reactant: CC(C)n1c(=O)cc(Cl)[nH]c1=O
Reactant: CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(Cl)cc(=O)n(C(C)C)c1=O
Yield: 98.1 %

Procedure:
16.6 g (0.12 mole) of potassium carbonate and 24 g (0.105 mole) of butyl-p-toluene sulphonate are added to a solution of 19 g (0.10 mole) of 3-isopropyl-6-chlorouracil in 200 ml of dimethyl formamide. The mixture is heated for 1 hour to 80° C. After evaporation of the solvent, the residue is taken up in water, followed by extraction with CH2Cl2. The extract is dried over Na2SO4 and the solvent is evaporated, leaving 24 g of a pale yellow oily product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:11]([CH:12]=[C:25]2[NH:19][C:20](=[O:21])[NH:22][C:23]2=[O:24])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1OCc1ccccc1

Procedure:
This compound is prepared from 3-benzyloxy-4methoxybenzaldehyde (Aldrich) and hydantoin by the procedure described in Example 3; mp 242°-244° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][C:16]([O:18]CC)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:27]=[CH:26][NH:25][N:24]=1>ClCCl>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[C:16]([OH:18])[N:24]3[N:25]=[CH:26][CH:27]=[C:23]3[N:22]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)C1CCC(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(c2cc(O)n3nccc3n2)CC1
Temperature: 100 °C

Procedure:
4-(2-Ethoxycarbonyl-acetyl)-cyclohexanecarboxylic acid t-butyl ester (8.5 g) and 3-amino-1H-pyrazole (Int-7a, 26.5 mmol, 2.2 g) were mixed and heated neat at 100° C. for 16 hours. The resulting residue was dissolved in dichloromethane (100 mL) and concentrated in vacuo to remove water formed during cyclization. This solid was taken forward without further purification. LC-MS: 318 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17](O)=[O:18])[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:18])[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O
Product: CN1CCN(C(=O)CN2CCCn3c2cc(OCc2ccc(F)c(F)c2)nc3=O)CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E13 starting from 2-(8-((3,4-difluorobenzyl)oxy)-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl)acetic acid and 1-methylpiperazine.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.[OH-].[Na+]>CO>[CH2:1]([CH:8]1[CH2:12][CH2:11]/[C:10](=[CH:18]\[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][CH3:14])/[C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCC1Cc1ccccc1
Reactant: COc1ccccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1/C=C1\CCC(Cc2ccccc2)C1=O

Procedure:
A Stork reaction between benzyl chloride and the pyrrolidine enamine of cyclopentanone gave 2-benzylcyclopentanone. The boiling point of this intermediate compound was determined to be 121°-125° C. at a pressure of 2 mm Hg. To a solution containing 32 mmole of 2-benzylcyclopentanone and 48 mmole of 2-methoxybenzaldehyde in 20 ml of methanol was added 12 ml of 5% NaOH with stirring at about room temperature. After about 2 hours of stirring, the mixture was cooled and the precipitate was collected by filtration and washed with water. The solid was recrystallized in ethanol to give 2-benzyl-5-(E)-[(2-methoxy) benzylidene] cyclopentanone. The melting point of this intermediate product was determined to be 65°-67° C. A mixture containing 20 mmole of this intermediate, 38 mmole of dimethylamine hydrochloride, 2.4 g of paraformaldehyde and 4 drops of concentrated HCl in 50 ml of ethanol was refluxed with stirring. After about 12 hours, 1.8 g of paraformaldehyde was added and refluxing was continued for about 12 additional hours. The resulting solution was concentrated in vacuo to give a residue. Then 100 ml of water was added to the residue and stirred for about 15 minutes at about room temperature. The precipitate was removed by filtration. The resulting filtrate was treated with 10% NaOH to about pH 10 and extracted with ether. The extract was dried over anhydrous MgSO4 and acidified with ethanolic HCl to give a precipitate. The precipitate was recrystallized in a mixture of methanol and acetone to yield the 2-Benzyl-2-dimethylaminomethyl-5-(E)-[(2-methoxy) benzylidene] cyclopentanone hydrochloride. The melting point of the product was determined to be 175°-177° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]([O-:29])=O)=[CH:26][C:21]=2[N:20]=[N:19]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:27]([C:25]2[CH:24]=[CH:23][C:22]3[N:18]([CH3:17])[N:19]=[N:20][C:21]=3[CH:26]=2)=[O:29])=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:27]([C:25]2[CH:24]=[CH:23][C:22]3[N:18]([CH3:17])[N:19]=[N:20][C:21]=3[CH:26]=2)=[O:29])=[CH:3][CH:4]=1)=[O:7]
Reactant: Cn1nnc2cc(C(=O)[O-])ccc21
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: Cn1nnc2cc(C(=O)Nc3ccc(C(=O)c4ccc(NC(=O)c5ccc6c(c5)nnn6C)cc4)cc3)ccc21

Procedure:
Compound 403 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 1-methyl-1H-benzotriazole-5-carboxylate. [M+H]+ calcd for C29H22N8O3: 531.06; found: 531.05.