Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][O:10][C:11]2=[O:21])[CH2:3]1.CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C@@H:7]([CH2:6][C:5](=[O:24])[C:4]4[C@:17]3([CH3:20])[CH2:18][CH2:19][C:2](=[O:1])[CH:3]=4)[C@@H:8]1[CH2:9][O:10][C:11]2=[O:21]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)OC[C@@H]12
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: C[C@]12CCC(=O)C=C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)OC[C@@H]12

Procedure:
53 mg of 3β-hydroxy-16-oxaandrost-5-en-17-one was dissolved in 2.4 ml of acetone and the solution was cooled with ice. 60 μl of Jones reagent was added dropwise to this solution under ice cooling and stirring, and the mixture was stirred for 15 minutes. 2-propanol was added to the reaction mixture and the insoluble matters were removed by filtration. The filtrate was concentrated, water was added and the mixture was extracted with ethyl acetate. The extract was washed with 5% aqueous sodium bicarbonate solution, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled out, and the resultant crude product was purified by TLC [developing solvent; chloroform: acetone (19:1)] to obtain 9 mg of 16-oxaandrost-4-ene-3,6,17-trione.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[S:16])[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH2:23]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]3=[S:16])[CH2:5][CH2:6]2)=[O:32])=[CH:34][CH:35]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: S=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1ccc(C(=O)N2CCC(n3c(=S)[nH]c4ccccc43)CC2)cc1
Reaction time: 18 h
Yield: 85.4 %

Procedure:
A solution of 1-piperidin-4-yl-1,3-dihydro-benzoimidazole-2-thione (0.2 g, 0.84 mmol) in methylene chloride (20 mL) was treated with pyridine (0.040 mL, 0.497 mmol) and 4-n-butylbenzoyl chloride (0.093 mL, 0.497 mmol). The reaction mixture was stirred for 18 h then purified directly by column chromatography on silica gel using ethyl acetate as the eluent to give (4-butyl-phenyl)-[4-(2-thioxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (0.167 g; 86%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[N+:22]([O-])=O)[C:13]2=[O:25])[C:6]1=[O:26].[H][H]>[Pd].C1COCC1>[NH2:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:20](=[O:21])[N:12]([CH:7]1[CH2:8][CH2:9][C:10](=[O:11])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]1=[O:26])[C:13]2=[O:25]
Reactant: COCCN1C(=O)CCC(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COCCN1C(=O)CCC(N2C(=O)c3cccc(N)c3C2=O)C1=O
Yield: 91.4 %

Procedure:
10% Pd/C (50 mg) was added to a THF solution of 2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (260 mg). The reaction vessel was pressurized with hydrogen gas at 5 times the atmospheric pressure. After 6 hrs of reaction time, the catalyst was filtered off and solvent was removed by rotary evaporation in vacuo yielding 218 mg of light-yellow solid. MS (m/e): 332 (M+H+).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([N:8]2[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]2=[O:16])=[CH:5][O:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[Br:37][CH2:2][C:3]1[C:4]([N:8]2[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]2=[O:16])=[CH:5][O:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1nn(C)c(=O)n1-c1cocc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1nn(C)c(=O)n1-c1cocc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of the title compound of Step F (3.6 g), and triphenylphosphine (5.1 g) in methylene chloride (40 mL) under N2 at 0° C. was added carbon tetrabromide (8.0 g). The resulting orange solution was allowed to stir overnight at room temperature and then was concentrated under reduced pressure to give a brown oil. The residue was purified by flash chromatography (1:2 ethyl acetate:hexane as eluent) to afford 3.6 g (78%) of the title compound of Step G, a compound of the invention, as a white solid melting at 147-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][NH2:12]>C1COCC1.CCO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:12][CH3:11])=[O:9])[CH:3]=1
Reactant: CN
Reactant: O=C(Cl)c1cc(Cl)ccn1
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)c1cc(Cl)ccn1
Temperature: 3 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A 0° C. solution of 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 0.16 mol) in THF (100 mL) at was treated drop-wise with a solution of MeNH2 in EtOH, stirred at 3° C. for 4 h, then concentrated to dryness. The material was suspended in EtOAc, the solids removed via filtration and the filtrate was washed with brine (2×), dried and concentrated to yield 4-chloro-N-methylpicolinamide (16.4 g, 60%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (br s, 1H), 8.55 (d, J=5.2 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.66 (m, 1H), 2.82 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 171.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[N:8][O:9][CH2:10][O:11][CH3:12])[C:5]([CH3:7])=[O:6].C1(C)C=CC=CC=1.[CH3:21][N:22]([CH:24](OC)OC)[CH3:23]>C(OC(C)C)(C)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[N:8][O:9][CH2:10][O:11][CH3:12])[C:5]([CH:7]=[CH:21][N:22]([CH3:24])[CH3:23])=[O:6]
Reactant: COCON=C(C(C)=O)C(=O)OC
Reactant: COC(OC)N(C)C
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: COCON=C(C(=O)C=CN(C)C)C(=O)OC

Procedure:
6.4 g of 2-(methoxymethoxyimino)acetoacetic acid methyl ester in 30 of toluene are heated with 9 ml of N,N-dimethylformamidedimethylacetal for 5 hours at boiling. After cooling, the semi-crystalline residue is dissolved by heating in diisopropylether, the mixture is filtered. The precipitate obtained after cooling is filtered and dried to obtain the heading compound, m.p. 99°-100°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[NH:23])[NH:14][O:15]CC1C=CC=CC=1)=[O:11].[ClH:24].[H][H]>[Pd].[C].C(O)C>[ClH:24].[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[NH:23])[NH:14][OH:15])=[O:11]
Reactant: [H][H]
Reactant: Cc1cccc(C)c1NC(=O)NC(=N)NOCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)NC(=N)NO

Procedure:
To a solution of 6.0 g. (0.017 moles) of 1-(2,6-dimethylphenyl)-3-benzyloxyamidinourea in 160 ml. of absolute ethanol there is added 1.0 g. of 5% Pd/carbon and then 1 ml. of saturated ethanolic hydrogen chloride. The mixture is hydrogenated at room temperature and atmospheric pressure until one equivalent of hydrogen is taken up (1 hour). The suspension is filtered through a bed of celite and the filtrate evaporated to an off-white solid. The solid is recrystallized from 150 ml. of 7:1 acetonitri e:methanol to give 1-(2,6-dimethylphenyl)-3-hydroxyamidinourea hydrochloride, m.p. 191°-2° C.
Reaction SMILES: [N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[N:29]=[C:28]([CH3:30])[N:27](COCC[Si](C)(C)C)[C:24]5=[N:25][CH:26]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[N:29]=[C:28]([CH3:30])[NH:27][C:24]5=[N:25][CH:26]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc2cc(-c3ccc4ncnc(N5CCCc6ccccc65)c4c3)cnc2n1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cc(-c3ccc4ncnc(N5CCCc6ccccc65)c4c3)cnc2[nH]1
Yield: 21 %

Procedure:
0.19 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazoline and 200 μl of trifluoroacetic acid in 2 ml of dichloromethane are stirred at 25° C. in a flask until the reaction is complete (HPLC check, about 48 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is purified by means of preparative HPLC (gradient water:acetonitrile 1-50% in 14 min.), giving 0.03 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-(2-methyl-3H-imidazo-[4,5-b]pyridin-6-yl)quinazoline (“A5”) as white solid (yield 23%, content 99%); MS-FAB (M+H+)=393.1; Rf (polar method): 1.41 min;
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8]C)=[O:7].CC(C)([O-])C.O.[OH-].[Na+].[CH:26]1([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:17][C:4]1[C:3]([CH2:2][O:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: OC1CCCCC1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g (2.93 mmol) of methyl 3-bromomethyl-2-chloro-4-methylsulfonylbenzoate was dissolved in 10 ml of cyclohexanol and treated with 0.33 g (2.93 mmol) of potasisum tert-butoxide. The mixture was stirred overnight at room temperature and then concentrated on a rotary evaporator. The residue was dissolved in 16 ml of tetrahydrofuran and 8 ml of water and refluxed for 4 h together with 0.55 g of NaOH (13.74 mmol). It was then allowed to cool and was largely concentrated on a rotary evaporator and the aqueous residue was then treated with 2 M HCl. It was then extracted with methylene chloride, and the combined organic phase was dried over MgSO4 and completely concentrated on a rotary evaporator.
Reaction SMILES: [CH:1]1([C:7]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:28]CC(O)[CH2:25][CH2:24]1.[Na].[ClH:31]>C1(C)C=CC=CC=1.CCOCC>[ClH:31].[CH:1]1([C:7]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[C:8]([O:10][CH:11]2[CH2:25][CH2:24][N:23]([CH3:28])[CH2:22][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(O)CC1
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCCC1
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN1CCC(OC(=O)C(O)(C#Cc2ccccc2)C2CCCCC2)CC1

Procedure:
This ester was prepared by a method similar to the ones described above from the reaction of ethyl α-cyclohexyl-α-phenylethynyl-glycolate (4.3 g., 0.015 mole), 1-methyl-4-piperidinol (2.3 g., 0.020 mole) and sodium (~0.05 g.) in toluene. The chloroform extract of the basic phase of the reaction mixture, when stripped of volatile components in vacuo, yielded an oil. The oil was dissolved in dry ether and treated with HCl (gas) to give an oily solid. Recrystallization from a chloroform-benzene mixture gave about 0.6 g. (10%) of the desired hydrochloride, m.p. about 198°-200°.
Reaction SMILES: C([Li])CCC.CC(C)([O-])C.[K+].[CH3:12][C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.[F:22][C:23]([F:40])([F:39])[C:24](=[O:38])[CH2:25][C:26]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[O:36][CH3:37])([CH3:28])[CH3:27]>C(OCC)C>[F:40][C:23]([F:22])([F:39])[C:24]([CH2:12][C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:38])[CH2:25][C:26]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[O:36][CH3:37])([CH3:28])[CH3:27]
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2ccccc2[nH]1)C(F)(F)F
Reaction time: 0.12 h

Procedure:
n-Butyl lithium (0.673 mL, 1.6 M in hexanes) followed by potassium tert-butoxide (81 mg, 0.718 mmol) was added to a stirred solution of 2-methyl indole (47 mg, 0.359 mmol) in anhydrous diethyl ether (5 mL) at room temperature. Within 5 to 10 minutes, the reaction mixture turned bright orange. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (100 mg, 0.4 mmol) (Example 1) was then added dropwise as a solution in anhydrous diethyl ether (2 mL). The reaction was quenched with water after 1 hour, extracted with three 5 mL portions of EtOAc, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel affording 45 mg of the title compound as an oil.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.C(Cl)(Cl)Cl>C(OCC)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[CH:11]([Br:1])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)C(Br)c1ccc(Cl)cc1

Procedure:
Bromine (2 ml.) was added dropwise to a solution of p-chloro-2-(p-chlorophenyl)acetophenone (10 g.; 0.038 mole), chloroform (50 ml.) and diethyl ether (25 ml.). The mixture was heated at reflux for 0.5 hours and cooled (ca. 20°). Following a thorough washing with saturated sodium bicarbonate, the organic solution was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed at low pressure through silica gel 60 mesh (230-400) with 5% ethyl acetate in hexane. Recrystallization from hexane afforded 2.69 g.; m.p. 81.5°-83°.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][CH:29]1[C:34](=O)[CH2:33][CH2:32][O:31][CH2:30]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:34]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[5-(trifluoromethyl)-3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (9.0 mg, 0.024 mmol), 3-methyltetrahydro-4H-pyran-4-one (8.1 mg, 0.071 mmol) and triethylamine (0.0066 mL, 0.047 mmol) in dry methylene chloride (2.0 mL) was added sodium triacetoxyborohydride (15.0 mg, 0.071 mmol). After being stirred at room temperature overnight, the reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The organic layers were combined, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified by silica gel column (30:70 MeOH/EtOAc) to provide pure product. MS calculated for C26H36F3N3O2: (M+H) 480; found 480.1.
Reaction SMILES: [CH3:1][NH-:2].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10](Cl)=[O:11])[CH:5]=1.C(=O)([O-])O.[Na+]>O1CCCC1.[OH-].[Na+].ClCCl>[CH3:1][NH:2][C:10]([C:6]1[CH:5]=[C:4]([Cl:3])[N:9]=[CH:8][N:7]=1)=[O:11]
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: C[NH-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ncn1
Temperature: 25 °C

Procedure:
0.5 ml of a 2 M methylamide solution in tetrahydrofuran and 1 ml 1 N sodium hydroxide solution are added to 177 mg 6-chloro-pyrimidin-4-carboxylic acid chloride in 5 ml dichloromethane under an argon atmosphere and while cooling with a bath of ice/acetone. The reaction mixture is heated overnight with stirring to ambient temperature and then combined with some saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic phases are washed with 0.1 N hydrochloric acid and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[C:32]([O:40][CH2:41][C:42]1[S:43][CH:44]=[C:45](/[CH:47]=[CH:48]/[C:49]2[C:50]([OH:60])=[N:51][N:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:53]=2)[N:46]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:32]([O:40][CH2:41][C:42]1[S:43][CH:44]=[C:45](/[CH:47]=[CH:48]/[C:49]2[C:50]([O:60][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:51][N:52]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:53]=2)[N:46]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: O=C(OCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(COC(=O)c5ccccc5)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.68 g), {4-[(E)-2-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-1,3-thiazol-2-yl}methyl benzoate hydrochloride (0.73 g), potassium carbonate (0.45 g) and N,N-dimethylformamide (15 mL) was stirred at 90° C. for 10 min. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (10:90-30:70, v/v) to give {4-[(E)-2-(3-{[4-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)-3-methoxybenzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)ethenyl]-1,3-thiazol-2-yl}methyl benzoate as colorless crystals (0.55 g, yield 44%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 116-117° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][O:11][C:12]=1[CH3:13].[NH2:15][CH2:16][CH2:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=2)=[CH:20][CH:19]=1.[OH-].[Na+]>CN(C)C=O>[CH3:14][C:9]1[C:8]([CH2:7][NH:15][CH2:16][CH2:17][C:18]2[CH:33]=[CH:32][C:21]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=3)=[CH:20][CH:19]=2)=[C:12]([CH3:13])[O:11][N:10]=1
Reactant: Cc1noc(C)c1CCl
Reactant: NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1CNCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
Add sodium bicarbonate (0.0481 g, 0.573 mmol) to a stirred solution of 4-(chloromethyl)-3,5-dimethylisoxazole (0.054 mL, 0.435 mmol), and 6-[4-(2-amino-ethyl)-phenoxy]-nicotinamide (0.1004 g, 0.390 mmol), in dimethylformamide (4 mL). Heat the reaction to reflux under nitrogen for 4 h. Cool to room temperature, pour the reaction mixture into 1 N sodium hydroxide (50 mL), extract with diethyl ether (3×50 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.8% concentrated ammonium hydroxide/8% ethanol/chloroform to yield 0.0843 g (59%) of 6-(4-{2-[(3,5-dimethyl-isoxazol-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide: mass spectrum (ion spray): m/z=367.1 (M+1); 1H NMR (CDCl3): 8.57 (dd, 1H), 8.16 (dd, 1H), 7.26-7.22 (m, 4H), 7.09-7.05 (m, 2H), 6.96 (d, 1H), 3.54 (s, 2H), 2.88-2.79 (m, 4H), 2.33 (s, 3H), 2.20 (s, 3H), 1.50 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>O1CCCC1>[C:16]1([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13](=[O:14])[CH2:12][NH:11][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:10])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCC(=O)N(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
3-Methylphenyl isocyanate (0.59 g) is added at a temperature in the region of 25° C. to a solution of 2-amino-N,N-diphenylacetamide (1 g) in anhydrous tetrahydrofuran (20 cc). The suspension obtained is stirred for 4 hours at a temperature in the region of 25° C. and the insoluble product is separated by filtration. After recrystallization in acetonitrile, N,N-diphenyl-2-[3-(3-methylphenyl)ureido]acetamide (0.8 g), m.p. 240° C., is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=2)[CH2:18][CH2:17]1>ClCCl>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:27]2[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=[C:23]2[NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][NH:13][C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)=[O:12])[CH2:17][CH2:18]2)=[CH:30][CH:31]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: ClCCl
Product: O=C(NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
A mixture of 1.6 parts of 1H-indole-2-carboxylic acid, 3.67 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 2.1 parts of N,N'-methanetetraylbis[cyclohexanamine] and 195 parts of dichloromethane was stirred over weekend at room temperature. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1 parts (19.5%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-1H-indole-2-carboxamide; mp. 232.1° C. (compound 76).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH3:25][CH2:26][CH:27](Br)[CH2:28][CH3:29]>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:27]([CH2:28][CH3:29])[CH2:26][CH3:25])[N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC(Br)CC
Reactant: CCCCN1CCN(CCNC(=O)c2n[nH]c3ccccc23)CC1
Product: CCCCN1CCN(CCNC(=O)c2nn(C(CC)CC)c3ccccc23)CC1

Procedure:
The title compound was synthesized by using N-[2-(4-n-butyl-1-piperazinyl)ethyl]-1H-indazole-3-carboxamide obtained in Example 10 and 3-pentyl bromide according to the same process as in Example 12.