Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]([F:19])([F:18])[C:9]1C(C(O)=O)=[CH:13][N:12]=[CH:11][CH:10]=1.CN(C)C=O>ClCCl>[F:7][C:8]([F:19])([F:18])[C:9]1[C:1]([C:2]([Cl:4])=[O:3])=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnccc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnccc1C(F)(F)F

Procedure:
Oxalyl chloride (6.4 ml, 2M) was added to a suspension of 4-trifluoromethylnicotinic acid (2 g) and a catalytic amount of N,N-dimethylformamide in dichloromethane, and stirred at 20° C. for 1 hour to give a solution of 4-trifluoromethylnicotinic acid chloride. N,N-Ethylenethiourea (2.23 g) was added to sodium hydride (0.82 g, 60% dispersion in mineral oil) in tetrahydrofuran, and the mixture was stirred at 20° C. for 1 hour, and then added to the above solution of 4-trifluoromethylnicotinic acid chloride with ice bath cooling, then stirred at 20° C. for 1 hour. Ethyl acetate was added and the mixture washed with water, dried (magnesium sulfate), evaporated and the residue crystallized (ethanol) to give N-(4-trifluoromethyl-3-pyridylcarbonyl)-imidazolin-2-thione (1.35 g, Compound S-356).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][N:8]=1)[NH2:6].Br[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.C(P(C(C)(C)C)C1N(C2C(C3C=CC=CC=3)=NN(C3C=CC=CC=3)C=2C2C=CC=CC=2)N=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(O)(C)(C)C>[F:20][C:2]([F:1])([F:19])[CH2:3][CH2:4][CH:5]([NH:6][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][N:8]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: NC(CCC(F)(F)F)c1ccc(-c2ccccc2)cn1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccnn1-c1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ccccc3)cn2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, a mixture of 4,4,4-trifluoro-1-(5-phenylpyridin-2-yl)butan-1-amine (125.1 mg) obtained in step E, ethyl 4-bromobenzoate (0.214 mL), tris(dibenzylideneacetone)dipalladium (82 mg), 5-(di-tert-butylphosphino)-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole (90 mg), sodium tert-butoxide (129 mg), tert-butanol (2.008 mL) and water (0.223 mL) was stirred at 70° C. overnight. To the reaction mixture was added water at room temperature, and the insoluble material was filtered off through celite. The filtrate was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was fractionated by HPLC(C18, mobile phase: water/acetonitrile (10 mM ammonium hydrogencarbonate-containing system)). The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (35.3 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C@@H:18]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:28][C@@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][CH2:20][CH2:19]4)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: N[C@H]1CCCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc2c(c1)CCC[C@@H]2NC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and (S)-1,2,3,4-tetrahydro-1-naphthylamine (74 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (9 mg) and a syn-form compound (14 mg).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][C:33]([N:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)=[CH:34][CH:35]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(N2CCCCC2)cc1

Procedure:
The title compound, white solid (116 mg, 90%), MS (ISP) m/z=516.3 [(M+H)+], mp 248° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-piperidin-1-yl-benzoic acid.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.CCN(CC)CC.O>C1COCC1>[Cl:15][C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)ccc([N+](=O)[O-])c1NCc1ccc(OC)cc1
Yield: 79.4 %

Procedure:
A solution of methyl 2,6-dichloro-3-nitrobenzoate (11.9 g, 47.4 mmol), p-methoxybenzylamine (8.13 g, 59.3 mmol; additional amounts of 1.63 g, 11.9 mmol added after 5 and 6.5 h), and Et3N (7.20 g, 71.1 mmol; additional amount of 1.20 g, 11.9 mmol added after 6.5 h) in THF (190 mL) was stirred at room temperature for 15 min then was heated to reflux for 10 h. Water (100 mL) was added to the mixture and most of the THF was removed under reduced pressure. The residue was partitioned between aqueous 1 N HCl solution (350 mL) and EtOAc (500 mL). The organic layer was washed with aqueous 1 N HCl solution (100 mL) and brine (100 mL), then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10-40μ silica gel; hexane:EtOAc 6:1) to give the title compound (13.2 g, 79% yield) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[CH:33][C:32]=1[N:46]1[N:55]=[CH:54][C:53]2[C:48](=[C:49]([F:60])[CH:50]=[C:51]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:52]=2)[C:47]1=[O:61])(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:26]([O:29][CH2:30][C:31]1[C:36]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:35][CH:34]=[CH:33][C:32]=1[N:46]1[N:55]=[CH:54][C:53]2[C:48](=[C:49]([F:60])[CH:50]=[C:51]([C:56]([CH3:58])([CH3:57])[CH3:59])[CH:52]=2)[C:47]1=[O:61])(=[O:28])[CH3:27]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: CC(C)N1CCN(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C(C)C)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 125 °C
Yield: 77.8 %

Procedure:
6-Chloro-4-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (123 mg, 340 μmol, Eq: 1.2), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (140 mg, 283 μmol, Eq: 1.00), potassium phosphate tribasic (180 mg, 850 μmol, Eq: 3.00) and X-PHOS (13.5 mg, 28.3 μmol, Eq: 0.10) were dissolved in dioxane (10 ml) and water (1.0 mL). The reaction was degassed with Ar. Pd2(dba)3 (13.0 mg, 14.2 μmol, Eq: 0.05) was added and the reaction was heated to 125° C. for 30 min in the microwave. The solution was dried over MgSO4 and filtered. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 5% MeOH/DCM gradient) to give 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (153 mg, 78%). LC/MS-ESI observed [M+H]+ 695.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH:7]=[CH:6]2)[CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C=CC2(CCCC2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCC2(CCCC2)CC1
Reaction time: 16 h

Procedure:
A solution of spiro[4.5]dec-6-en-8-one (442 mg, 2.94 mmol) in ethanol (15 mL) was flushed with nitrogen and treated with 10% Pd—C, 50% wet (Alfa Aesar, 38303) (313 mg, 2.94 mmol). The reaction mixture was stirred for 16 hours under an atmosphere of hydrogen and filtered through Celite®, rinsing with ethanol. The filtrate was concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:20]>O1CCOCC1>[NH2:20][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: COc1ccccc1NC(=O)c1c(Cl)ncnc1Cl
Reactant: N
Solvent: C1COCCO1
Product: COc1ccccc1NC(=O)c1c(N)ncnc1Cl
Temperature: 0 °C
Reaction time: 6 h
Yield: 95.8 %

Procedure:
4,6-Dichloro-N-(2-methoxyphenyl)pyrimidine-5-carboxamide (506 mg, 1.70 mmol) was dissolved in dioxane (8 ml) and cooled in an ice bath. Ammonia solution (1.25 ml, 8.75 mmol, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 6 h. After evaporation of the solvent under reduced pressure, the residue was suspended in ethyl acetate and filtered, washing successively with ethyl acetate. The solvent of the filtrate is evaporated under reduced pressure to yield the final compound as a solid (454 mg, 93% purity, 89% yield) which was used in the next synthetic step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][O:20][CH3:21].[NH4+].[Cl-]>CN(C=O)C.C(Cl)Cl>[CH3:13][O:12][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][N:1]2[CH2:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:5][CH:6]=1)=[O:11]
Reactant: COCCCBr
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCCn1ccc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl indole-6-carboxylate (5.0 g, 28.5 mmol) in DMF (25 mL) is added under nitrogen, NaH-60% dispersion in oil (1.25 g, 31.3 mmol), the mixture is heated at 60° C. for 2 h, cooled to RT and 1-bromo-3-methoxypropane (8.7 g, 57.0 mmol) is added. The mixture is further stirred at 60° C. overnight. The crude mixture is poured into an aqueous solution of NH4Cl and diluted with CH2Cl2. The layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to give the title product. MS (LC-MS): 248.0 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.69 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:35])=[CH:16]/[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1.[OH-].[Na+]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[CH3:35])=[CH:16]/[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])=[CH:23][CH:24]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(Cl)c3Cl)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(Cl)c3Cl)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (example 58) (0.325 g, 0.63 mmol) and sodium hydroxide (1M, 1.27 ml, 1.27 mmol) by a procedure analogous to that described in example 51, giving (E)-(S)-3-{4-[3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid as a gum, which contained 0.28 mol equivalents of ethyl acetate; 0.24 g (80%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25](COCC[Si](C)(C)C)[N:24]=[CH:23]3)[C:16]1=[O:37].CO>C(Cl)Cl.C(Cl)(Cl)Cl>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([N:17]3[CH2:18][CH2:19][N:15]([C:10]4[CH:11]=[N:12][CH:13]=[CH:14][C:9]=4[CH3:8])[C:16]3=[O:37])=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: Cc1ccncc1N1CCN(c2ccc3c(cnn3COCC[Si](C)(C)C)c2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc3[nH]ncc3c2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
TFA (0.096 g, 0.00084 mol) was added to solution of 1-(4-methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-imidazolidin-2-one (0.24 g, 0.00056 mol) in DCM (10 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated and the concentrate was purified by preparative HPLC to afford 42 mg of the product (19.47% yield).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])[CH3:9].[C:16]([OH:22])(=O)[CH2:17][C:18]([OH:20])=O>C(O)(=O)C>[CH2:8]([N:10]1[C:16](=[O:22])[CH2:17][C:18](=[O:20])[N:13]([CH2:14][CH3:15])[C:11]1=[O:12])[CH3:9]
Reactant: O=C(O)CC(=O)O
Reactant: CCNC(=O)NCC
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCN1C(=O)CC(=O)N(CC)C1=O
Temperature: 90 °C

Procedure:
Acetic anhydride (16 ml, 0.15 mole) was added dropwise over two hours to a solution of 1,3-diethylurea (5.3 g, 0.05 mole) and malonic acid (5.2 g, 0.05 mole) in acetic acid (40 ml) at 65° C. After the addition was complete, the temperature was raised to 90° C. and maintained there for three hours. The solvent was evaporated under reduced pressure and the residue boiled with ethanol for fifteen minutes. After some time, 1,3-diethyl-2,4,6-(1H,3H,5H)- pyrimidinetrione crystallized in cubic crystals, m.p. 52° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:26]2[C:32]([C:33](O)=[O:34])=[CH:31][N:30]=[C:27]2[S:28][CH:29]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[N:26]3[C:27]([S:28][CH:29]=[C:25]3[CH3:24])=[N:30][CH:31]=2)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1csc2ncc(C(=O)O)n12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3scc(C)n23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=492.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.O>CN(C)C=O>[OH:16][CH:15]([CH2:17][N:42]1[CH2:43][CH2:44][CH:39]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:40][CH2:41]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC(O)CN1CCC(N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (39 mg) and 4-(1-pyrrolidinyl)piperidine (41 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (38 mg, yield 73%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:22]=[CH:21][C:20]=1[C:31]([NH:33][CH2:34][C:35]([CH2:41][NH2:42])([OH:40])[C:36]([F:39])([F:38])[F:37])=[O:32].C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C)C=O>[NH2:18][C:19]1[N:23]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:22]=[CH:21][C:20]=1[C:31]([NH:33][CH2:34][C:35]([CH2:41][NH:42][C:4]([C:3]1[C:7]([Br:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1])=[O:6])([OH:40])[C:36]([F:39])([F:38])[F:37])=[O:32]
Reactant: O=C(O)c1c(Br)cccc1Br
Reactant: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1c(C(=O)NCC(O)(CNC(=O)c2c(Br)cccc2Br)C(F)(F)F)cnn1-c1ccc(F)cc1
Reaction time: 0.75 h
Yield: 90.8 %

Procedure:
To a solution of 2,6-dibromobenzoic acid (28 mg, 0.1 mmol) in anhydrous tetrahydrofuran (1 ml) was added anhydrous dimethylformamide (4 μl) followed by oxalyl chloride (100 μl of a 1 ml solution of 87 μl of oxalyl chloride in THF; 0.1 mmol). The mixture effervesced and was stirred under nitrogen for 45 minutes. A solution of 5-amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (25.3 mg, 0.07 mmole) in anhydrous tetrahydrofuran (0.5 ml) and diisopropylethylamine (52 μl, 0.3 mmol) was added. It was then stirred under nitrogen at 21° C. for 3 days. It was blown down, partitioned between dichloromethane (5 ml) and 2M hydrochloric acid (2 ml). The organic layer was blown down and the residue purified on a 5 g SPE silica cartridge. Elution with dichloromethane then cyclohexane:ethyl acetate (10:1), (5:1), (3:1), (2:1) (3 times) and finally (1:1) (3 times). The title product was eluted in the third (2:1) fraction and the first (1:1) fraction. These fractions were combined and evaporated to give the title product (39.6 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH2:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1.CO.CCCCCC>O1CCCC1.ClCCl>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH2:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CO
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenylacetyl chloride (21 μL, 0.16 mmol) was added to a suspension of 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.050 g, 0.16 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at ambient temperature for 1 hour by which time a solution was obtained. Thin layer chromatography (9:1 dichloromethane:methanol) showed one major new spot with a higher Rf and only a trace of starting material. Aminomethyl resin (100 mg) was added and the reaction mixture was stirred for 5 minutes. The solvent was removed under vacuum to provide a white powder. This material was placed on a short column of silica gel and purified by eluting first with dichloromethane and then with 9:1 dichloromethane:methanol. The cleanest fractions were combined and then concentrated under vacuum to provide a colorless oil. The oil was dissolved in dichloromethane, hexane was added just until the solution started to become cloudy, and then the solvent was removed to provide N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]phenylacetamide as a white powder. Analysis: Calculated for C25H30N6O2: %C, 67.24; %H, 6.77; %N, 18.82; Found: %C, 67.52; %H, 6.85; %N, 18.38. 1H NMR (300 MHz, CDCl3) δ 8.51 (dd, J 4.4, 1.5 Hz, 1H), 8.11 (dd, J=8.4, 1.4 Hz, 1H), 7.43 (dd, J=8.4, 4.4 Hz, 1H), 7.10-7.20 (m, 5H), 6.30 (br s, 2H), 5.83 (m, 1H), 4.72 (apparent t, J=7.8 Hz, 2H), 3.54 (s, 2H), 3.35 (apparent q, J=6.5 Hz, 2H), 2.88 (apparent t, J=7.8 Hz, 2H), 1.80-1.90 (m, 4H), 1.45-1.65 (m, 4H), 1.00 (t, J=7.3 Hz, 3H); HRMS (EI) calcd for C25H30N6O (M+) 430.2481, found 430.2490.