Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:20]1[N:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1F.[CH2:36]([O:38]C(=O)NCC)[CH3:37].[H-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[F:32][C:30]([F:33])([F:31])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:15]([F:18])([F:17])[F:16])[CH:29]=1)[CH2:6][N:7]([C:20]1[N:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:12]=[CH:11][C:10]=1[O:38][CH2:36][CH3:37]
Reactant: Fc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: CCNC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 140.3 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (300 mg) is dissolved in tetrahydrofuran (3 ml) and thereto are added ethyl-carbamic ethyl ester (67 mg) and sodium hydride (60%) (23 mg) and the mixture is stirred at 120° C. under a condition of 192 W by a microwave instrument for 1 hour and thereto are added ethyl-carbamic ethyl ester (134 mg) and sodium hydride (60%) (46 mg) and the mixture is stirred at 120° C. under a condition of 192 W by a microwave instrument for an additional 1 hour. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-ethoxy-5-trifluoromethyl-benzyl)-amine (220 mg). MS (m/z): 602/604 [M+H]+
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([CH:11]3[CH2:13][CH:12]3[C:14]#[N:15])[N:10]=2)[CH:7]=1.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][NH:27][C:26](=[O:30])[CH:25]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][N:27]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([CH3:16])=[C:9]([CH:11]5[CH2:13][CH:12]5[C:14]#[N:15])[N:10]=4)[CH:7]=3)[C:26](=[O:30])[CH:25]=2)=[CH:20][CH:19]=1
Reactant: Cc1c(C2CC2C#N)nc2ccc(I)cn12
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(C2CC2C#N)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cn12
Temperature: 110 °C
Yield: 43.3 %

Procedure:
To a mixture of 2-(6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)cyclopropanecarbonitrile (26 mg), 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (45 mg), potassium carbonate (58 mg) and dioxane (2 ml) were added CuI (7 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (5 mg), and the mixture was heated at 110° C. for 16 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM, washed with brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (15 mg) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]=2[CH:3]=1.C([Li])CCC.[C:36](=[O:38])=[O:37].Cl>O1CCCC1>[CH2:23]([C:5]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]2[CH:3]=[C:2]([C:36]([OH:38])=[O:37])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C=O
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(Br)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)O)cc21
Temperature: -60 °C
Reaction time: 1 h

Procedure:
Into a flask fitted with a nitrogen inlet and rubber septum were introduced 2-bromo-9,9-dioctylfluorene (34.18 g, 72.8 mmole) and dry tetrahydrofuran (300 mL). The solution was cooled to −60° C. and n-butyl lithium (29.1 mL, 2.5M in hexanes, 72.8 mmole) added via a syringe. The reaction mixture was observed to turn red. After stirring for 1 hour at −60° C., the reaction mixture was poured onto powdered dry-ice and left to stand overnight. The mixture was acidified with 1M HCl and extracted with chloroform. The chloroform extract was washed with water, dried over magnesium sulfate and concentrated to give the acid as an oil.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1>O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]([O:4][CH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: N#Cc1ccc(CBr)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)OCc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.7 %

Procedure:
Add iso-propanol (2.2 g, 25 mmol) and tetrabutylammonium sulfate (28 mg, 0.08 mmol) to a solution of potassium hydroxide (7.1 g, 127 mmol) in water (7 mL) and stir at room temperature for 15 min. Add 6-bromomethyl-pyridine-3-carbonitrile (1 g, 5.08 mmol) and stir the mixture for 24 h at room temperature. Add water (15 mL) and extract with DCM (15 mL). Filter through an IST® phase separator frit to separate the organic phase and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 1:1 gradient) to obtain the desired intermediate as a crystalline solid (0.4 g, 45%). MS (ES+) m/z: 177 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH3:36])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:43]>C(Cl)Cl.CCOCC>[ClH:43].[CH:38]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[C:29]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH3:36])[C:28]2=[O:37])[CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: CCOCCOc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOCCOc1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
4-{6-[8-Cyclopentyl-6-(2-ethoxy-ethoxy)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (70 mg, 0.12 mmol) was dissolved in CH2Cl2 (2.5 mL) and 2 M HCl in ether (2.5 mL) was added. This mixture was stirred for 2 h at room temperature and a yellow precipitate formed. The solvents were removed under reduced pressure and the resulting solid was suspended in ether and collected by filtration then dried overnight in vacuo at 50° C. to give 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt (30 mg, 52%). MS (APCI); M++1: Calc'd, 480.3. Found 480.4. Anal. Calc'd for C25H33N7O32HCl 3.44H2O: C, 48.87; H, 6.87; N, 15.96. Found; C, 48.48; H, 6.66; N, 15.66.
Reaction SMILES: [CH:1]([N:4]([CH3:17])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)(=[O:7])=[O:6])([CH3:3])[CH3:2].CO.O.NN>[Ni].ClCCl.C(OCC)(=O)C>[CH:1]([N:4]([CH3:17])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)N(C)S(=O)(=O)c1ccccc1N
Temperature: 0 °C

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer and an ice bath. The flask was charged with N-isopropyl-N-methyl-2-nitrobenzenesulfonamide (9.21 mmol), followed by methanol (100 mL). The solution was cooled to 0° C. Hydrazine monohydrate (92.1 mmol) was added, followed by Raney nickel (catalytic amount). After 5 hours TLC (9:1 dichloromethane/ethyl acetate) indicated that the reaction was complete. The reaction was filtered through celite and the catalyst recovered to a separate waste stream. The methanol was removed under reduced pressure and water (100 mL) added. The aqueous solution was extracted with ethyl acetate (100 mL), dried (Na2SO4), filtered, and the solvent removed under vacuum. The resultant yellow oil was purified by silica gel chromatography (1.5″ millimeter×18″ length, 9:1 dichloromethane/ethyl acetate). Fractions containing the desired product were combined and the solvent removed under vacuum to yield N-(isopropyl)-N-(methyl)-2-amino benzene sulfonamide as a clear yellow oil. 2.21 g, (81%). LC/MS: m/z 229.4 [C10H16N2O2S+H]+. 1H-NMR (CDCl3): δ 1.04-1.06 (d, 6H, J=6.7 Hz); 2.73 (s, 3H); 4.15-4.24 (m, 1H, J=6.7 Hz); 4.95 (b, 2H); 6.68-6.78 (m, 2H); 7.24-7.29 (t, 1H, J=7.7 Hz); 7.62-7.65 (d, 1H, J=8.0 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19](O)=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:13]([O:12][C:10]([N:17]1[CH2:24][CH2:23][CH2:22][CH:18]1[C:19](=[O:20])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: NCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NCc1ccc(Br)cc1
Reaction time: 0.75 h
Yield: 94.4 %

Procedure:
To a mixture of 4-Bromo-benzylamine (2.00 g), Boc-L-proline (2.01 g), and 4-methylmorpholine (3.26 mL) in DMF (40 mL) was added HATU (3.48 g). Reaction mixture was stirred for 45 minutes, then concentrated, diluted with dichloromethane and washed with 10:1 H2O/saturated sodium bicarbonate solution. The aqueous layer was back-extracted with dichloromethane and the combined organic layers were dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) to give 2-(4-Bromo-benzylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.38 g): LCMS-ESI+: calc'd for C17H24BrN2NaO3: 405.29 (M+Na+). Found: 405.0 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:25]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][O:27][CH2:26]2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O.O>[C@@H:29]12[N:32]([C:21]([C@H:9]3[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:23])[C@@H:25]([CH2:31][CH2:30]1)[CH2:26][O:27][CH2:28]2
Reactant: C1CC2COCC1N2
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2[C@@H]3CC[C@H]2COC3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
In a 250-mL round-bottomed flask, a solution of (R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.51 g, 4.57 mmol, ASW Medchem, New Brunswick, N.J.), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.684 g, 4.57 mmol, Advanced Chemblocks, Burlingame, Calif.), and Hünig's base (1.76 mL, 10.06 mmol) in 15 mL of DMF was stirred at 0° C. To this mixture was added HATU (1.912 g, 5.03 mmol, Oakwood Products, West Columbia, S.C.). The reaction was stirred for 3 h at room temperature. The mixture was then diluted with EtOAc (25 mL) and water (25 mL). The organic solution was then extracted with water (2×25 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was purified via column chromatography (about 40 g silica gel, 5% to 80% of EtOAc in hexanes) to give (R)-di-tert-butyl 2-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)piperazine-1,4-dicarboxylate (1.78 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Pd]>[OH:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Oc1cccc2occc12
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1cccc2c1CCO2
Yield: 101 %

Procedure:
At ambient temperature a rapidly stirred solution of 4-hydroxybenzofuran (2.0 g) (prepared by the method of G. Keen & P. Maddocks Syn. Comm., 16(13), 1635-1640 (1986)) in glacial acetic acid (30 ml) containing 30% palladium on carbon (0.2 g) was exposed to an atmosphere of hydrogen. When uptake of hydrogen had ceased the solution was filtered and the filter cake washed with glacial acetic acid. The combined filtrates were evaporated to dryness to give of 4-hydroxy-dihyrobenzofuran (2.05 g) 1H NMR (DMSO-d6, 300 MHz, ppm): 3.0(2H,t), 4.5(2H,t), 6.2(1H.d), 6.3(1H,d), 6.8(1H,t), 9.5(1H,b) m/Z 135 (M−H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Si:12]([O:29][C@@H:30]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[C@@H:32]([CH2:33][CH2:34][C@@H:35]3[C@@H:44]2[CH2:43][CH2:42][C@@:40]2([CH3:41])[C@H:36]3[CH2:37][CH2:38][C@@H:39]2[C:49]#[C:50][CH:51]([OH:53])[CH3:52])[CH2:31]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-][Si]([O-])=O.[Mg+2]>ClCCl>[Si:12]([O:29][C@@H:30]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[C@@H:32]([CH2:33][CH2:34][C@@H:35]3[C@@H:44]2[CH2:43][CH2:42][C@@:40]2([CH3:41])[C@H:36]3[CH2:37][CH2:38][C@@H:39]2[C:49]#[C:50][C:51](=[O:53])[CH3:52])[CH2:31]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(O)C#C[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(=O)C#C[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridinium chlorochromate (22 mg, 0.10 mmol) was added to anhydrous methylene chloride (1 mL) and to the resulting mixture was added a solution of 4[3α-(t-butyldiphenylsilyloxy)-5α-androstan-17β-yl]-3-butyn-2-ol (30 mg, 0.053 mmol) in dichloromethane (2.5 mL) and the resulting mixture was stirred for 3 h at RT. Subsequently the mixture was fitered through florisil, washed with ether and the solvent was removed in vavuo. Purification of the residue using flash column chromatography, petroleum ether/ethyl acetate 97/3 elution solvent, afforded the product mentioned above.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][N:22]=1)[CH2:13][C:14](=O)[CH2:15][C:16](=O)C)#[N:9].Cl.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1>C(O)C>[C:8]([C:10]1[CH:11]=[C:12]([C:13]2[N:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[N:32]=[C:15]([CH3:16])[CH:14]=2)[CH:20]=[CH:21][N:22]=1)#[N:9]
Reactant: CC(=O)CC(=O)Cc1ccnc(C#N)c1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccnc(C#N)c2)n(-c2ccc(F)cc2)n1
Yield: 52.8 %

Procedure:
Triethylamine (4.6 mL, 0.033 mol) was added dropwise to a mixture of 1-(2-cyanoisonicotinyl)-1,3-butanedione (6.0 g, 0.032 mol) and 4-fluorophenylhydrazine hydrochloride (5.37 g, 0.033 mol) in 100 mL of ethanol. The reaction mixture was heated at reflux overnight (about eighteen hours). The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by recrystallization from ether/hexane to give 4.7 g (53% yield) of product as a yellow solid: mp: 94-95° C.; Anal. Calc'd. for C16H11FN4: C, 69.06; H, 3.98; N, 20.13. Found: C, 68.52; H, 3.89; N, 19.73.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[C:19]([NH2:21])=[O:20].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:34][C:35](OC)=O)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31].CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH:25]=[C:24]([O:23][CH3:22])[C:29]=1[O:30][CH3:31])[CH2:34][C:35]1[NH:21][C:19](=[O:20])[C:3]2[C:4]([CH2:17][CH3:18])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=2[N:1]=1
Reactant: CCCCCCC(CCC)n1nc(CC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1cc(OC)c(OC)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CC)c2c(=O)[nH]c(Cc3cc(OC)c(OC)c(OC)c3)nc21
Yield: 56.7 %

Procedure:
6 mg (0.02 mmol) of 5-amino-3-ethyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.083 mmol) of methyl 3,4,5-trimethoxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate have been added, the phases are separated. Purification by chromatography gives 5.5 mg (55%) of a solid, Rf=0.47 (dichloromethane/methanol=15:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>CN(C=O)C>[O:26]=[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1)[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.1 %

Procedure:
To a solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (100 mg) in DMF (8 ml) was added succinic anhydride (79 mg). The reaction mixture was stirred at room temperature for 2.5 hr and a precipitate was collected, washed with DMF and ethanol, then dried to give the title compound (106 mg) as a beige-coloured solid: m.p. 263°264° C.; NMR (d6 -DMSO+CF3CO2H) δ2.68 (4H, m), 3.80 (4H, m), 4.19 (4H, m), 7.20 (2H, d), 7.56 (2H, d), 7.82 (2H, d), 8.21 (2H, d), 9.62 (1H, s); m/Z 355 (M+H)+ ; calculated for C19H22N4O3. 0.4 H2O: C, 63.1%; H, 6.36%; N, 15.5%; found: C, 63.1%; H, 6.4%; N, 15.7%.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([CH3:15])[O:12][N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:49][C:50]([F:62])([F:61])[O:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[C:55](O)=[O:56]>ClCCl.CN(C=O)C>[CH3:15][C:13]1[O:12][N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:55](=[O:56])[C:54]3[CH:58]=[CH:59][CH:60]=[C:52]([O:51][C:50]([F:49])([F:61])[F:62])[CH:53]=3)=[C:5]([NH:16][CH2:17][C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH:6]=2)[N:14]=1
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(CNC(=O)c3cccc(OC(F)(F)F)c3)c(NCC(=O)OCc3ccccc3)c2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of compound 58d (50 mg, 0.13 mmol), TEA (0.027 mL), HOAt (1.8 mg) and EDCI (37 mg, 0.19 mmol) in a mixture of dichloromethane (0.8 mL) and DMF (0.3 mL) was added 3-trifluoromethoxybenzoic acid (27 mg, 0.13 mmol). The resulting solution was stirred overnight at rt, and then concentrated. The residue was triturated with water, and then purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.1% TFA) to afford compound 58e (30 mg, 43%). ESI-MS m/e 541.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]=[CH:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Cl-].[Na+].CC(C)=O.[C:44]([OH:49])(=[O:48])[C:45]([OH:47])=[O:46]>CC(C)=O.CN(C)C=O>[C:44]([OH:49])(=[O:48])[C:45]([OH:47])=[O:46].[CH2:30]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([CH2:16][CH:15]=[CH:14][N:11]3[CH2:12][CH2:13][N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)[CH2:9][CH2:10]3)=[CH:26][CH:25]=2)[CH2:20][CH2:21][C:22]1=[O:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cccc(N2CCN(C=CCc3ccc4c(c3)CCC(=O)N4)CC2)c1
Agent: O=C(O)C(=O)O
Agent: [Cl-]
Agent: [H-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(N2CCN(C=CCc3ccc4c(c3)CCC(=O)N4Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.8 Grams of 6-{3-[4-(3-methylphenyl)-1-piperazinyl]-2-propenyl}-3,4-dihydrocarbostyril and 0.25 g of sodium hydride (50% in mineral oil) were mixed into 60 ml of dimethylformamide and the mixture was stirred at a room temperature for 2 hours then 0.7 g of benzyl chloride was added to the reaction mixture and stirred at a room temperature for 8 hours. The reaction mixture was poured into 150 ml of saturated sodium chloride aqueous solution and was extracted with chloroform, the chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was purified by a silica-gel column chromatography and an oily substance thus obtained was dissolved in 20 ml of acetone, then under stirring condition, the pH of the solution was adjusted to pH 3 to 4 by adding 5%-oxalic acid acetone solution to obtain precipitates. The precipitates were collected by filtration and washed with acetone then recrystallized from ethanol to obtain 2.2 g of 1-benzyl-6-{3-[4-(3-methylphenyl)-1-piperazinyl]-2-propenyl}-3,4-dihydrocarbostyril monooxalate in colorless needle-like crystals, having the melting point of 176°-178° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:44]=[O:45])=[C:24]2[C:28]=1[N:27]=[C:26]1[N:29]([C:33]3[C:34]([CH3:43])=[N:35][C:36]([CH:40]4[CH2:42][CH2:41]4)=[N:37][C:38]=3[CH3:39])[CH2:30][CH2:31][CH2:32][N:25]21.C[Si](C)(C)[C:48]([F:51])([F:50])[F:49].Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:19][C:20]1[C:28]2[N:27]=[C:26]3[N:29]([C:33]4[C:34]([CH3:43])=[N:35][C:36]([CH:40]5[CH2:41][CH2:42]5)=[N:37][C:38]=4[CH3:39])[CH2:30][CH2:31][CH2:32][N:25]3[C:24]=2[C:23]([CH:44]([OH:45])[C:48]([F:51])([F:50])[F:49])=[CH:22][CH:21]=1
Reactant: Cc1nc(C2CC2)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Cc1nc(C2CC2)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(O)C(F)(F)F)c12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 88.6 %

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.10 mL, 0.10 mmol) was added dropwise to a stirred solution of 9-chloro-1-(2-cyclopropyl-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (294 mg, 0.770 mmol) and trimethyl(trifluoromethyl)silane (219 mg, 1.54 mmol) in tetrahydrofuran (3.0 mL) at 0° C., and the mixture was stirred at 0° C. for 40 min. 1N hydrochloric acid (3.0 mL) was added to the mixture at 0° C., and the mixture was stirred at 0° C. for 30 min. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (308 mg, 0.682 mmol, 89%).