Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[C:4]([C:19](=O)[CH3:20])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[NH2:28][CH:19]([C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)[CH3:20]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2ccccc2c1N1CCC(O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2ccccc2c1N1CCC(O)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-1-(4-hydroxypiperidin-1-yl)-2-naphthyl]ethanone (74 mg, 0.24 mmol) and ammonium acetate (188 mg, 2.44 mmol) in methanol (1.4 mL) and acetonitrile (1.4 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (30.6 mg, 0.487 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude amine was used directly in the next step. LCMS calculated for C17H22ClN2O (M+H)+: m/z=305.1; Found: 305.1.
Reaction SMILES: C(C(CCCC)C(O)CC(O)=O)C=C.[OH:15][C:16]([CH3:27])([CH:22]([CH3:26])[CH2:23][CH:24]=[CH2:25])[CH2:17][C:18]([O:20]C)=[O:19]>>[OH:15][C:16]([CH3:27])([CH:22]([CH3:26])[CH2:23][CH:24]=[CH2:25])[CH2:17][C:18]([OH:20])=[O:19]
Reactant: C=CCC(C)C(C)(O)CC(=O)OC
Agent: C=CCC(CCCC)C(O)CC(=O)O
Product: C=CCC(C)C(C)(O)CC(=O)O

Procedure:
The compound of interest (10.1 g) was obtained as an oil substance in the same way as in paragraph (10-b) using methyl 3-hydroxy-3,4-dimethyl-6-heptenoate (11.7 g, 63 mmol). This compound was used in the next reaction without being purified.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[NH:21][N:20]=[C:19]4[CH2:22][CH2:23][S:24][CH2:25][C:18]=34)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.OO.C(=O)([O-])[O-:29].[K+].[K+]>C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[NH:21][N:20]=[C:19]4[CH2:22][CH2:23][S:24](=[O:29])[CH2:25][C:18]=34)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCN(CCCc3[nH]nc4c3CSCC4)CC2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O=CO
Product: O=S1CCc2n[nH]c(CCCN3CCN(c4ccc(F)cc4)CC3)c2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(3-(4-(4-Fluorophenyl)piperazin-1-yl)propyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole (0.5 g) obtained in Example 138 was dissolved in formic acid (5 ml) and 30% hydrogen peroxide (0.27 ml) was dropwise added under ice-cooling, and the mixture was stirred for 30 minutes at not more than 5° C. The reaction mixture was poured into ice water, made alkaline with potassium carbonate and extracted with ethyl acetate. After drying over magnesium sulfate, the solution was concentrated and recrystallized from isopropyl alcohol:isopropyl ether (1:2) to give 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-2,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazole 5-oxide, m.p. 140-142° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C1COCC1.CS(O)(=O)=O.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)[N:3]=1
Reactant: C1=COCCC1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccc2c(I)nn(C3CCCCO3)c2c1
Reaction time: 8 h
Yield: 24.4 %

Procedure:
An oven-dried round bottom flask under Ar was charged with 3-iodo-1H-indazole-6-carbaldehyde (50 mg, 0.184 mmol), THF (1.5 mL) and CH2Cl2 (1.0 mL). Methanesulfonic acid (1.4 uL, 0.0221 mmol) was added and the solution cooled with an ice-water bath. A solution of 3,4-dihydro-2H-pyran (41 uL, 0.460 mmol) in CH2Cl2 (0.5 mL) was then added dropwise over 15 minutes and the reaction stirred overnight. The solvents were removed in vacuo and the residue purified by column chromatography (silica gel, 99:1 to 98:2 CH2Cl2/MeOH) to give the title compound as a white powder (16 mg, 25%). 1H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 8.13 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 5.84-5.77 (m, 1H), 4.07-4.02 (m, 1H), 3.83-3.75 (m, 1H), 2.62-2.51 (m, 1H), 2.20-2.10 (m, 2H), 1.86-1.70 (m, 3H); MS ESI 378.9 [M+Na]+, calcd for [C13H13IN2O2+Na]+ 378.99.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH2:15][CH:16](CC)CC)#[N:14].C(OCC)=O.[NH2:26][NH:27][C:28]([NH2:30])=[S:29]>C1COCC1.C(O)C.O.C(O)(=O)C>[NH2:14][C:13]1[N:27]([C:28](=[S:29])[NH2:30])[N:26]=[CH:16][CH:15]=1
Reactant: NNC(N)=S
Reactant: CCC(CC)CC#N
Agent: [Li]CCCC
Solvent: CCOC=O
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: NC(=S)n1nccc1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 122.4 %

Procedure:
To a stirring solution of diisopropylamine (3.72 mL, 28.35 mmol) in anhydrous THF (75 mL) at −78° C. was added 11.4 mL of a 2.5M solution of n-butyllithium in hexanes. The solution was allowed to warm to 0° C., then cooled back down to −78° C. A solution of 1-cyano-2-ethylbutane (3 g, 27 mmol) in anhydrous THF (15 mL) was added to the cooled solution. After stirring for 10 min., ethyl formate (2.7 mL, 32.4 mmol) was added and the resulting reaction mixture was stirred at −78° C. for 1 h, then allowed to slowly warm to room temperature over 3 h. The reaction mixture was then partitioned between Et2O and water. The organic layer was washed with water and the aqueous layers were combined and acidified with 1N HCl. The resulting acidic aqueous mixture was extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to yield a colorless oil. This residue was dissolved in ethanol (15 mL) and to the resulting solution was added water (10 mL), thiosemicarbazide (2.71 g, 29.7 mmol), and acetic acid (5.5 mL). The resulting mixture was stirred under reflux for 3 hr., then cooled and diluted with water (25 mL). The off-white precipitate which formed was collected by vacuum filtration to yield 4.7 g of the 5-amino-1-thiocarbamoylpyrazole. 1H NMR (300 mHz, CDCl3): δ7.2 (bs, 1H), 7.17 (d, 1H, J=4.4 Hz), 6.37 (bs, 1H), 3.65 (t, 1H, J=4.4, 4.8 Hz), 1.71 (m, 1H), 1.53 (m, 4H), 0.97 (m, 6H). Spectrum corresponds to imine tautomer. 1H NMR (300 mHz, dmso-d6): δ8.3 (bs, 1H), 7.4 (bs, 1H), 7.36 (d, 1H, J=4.8 Hz), 3.93 (t, 1H, J=5.13, 4.8 Hz), 1.76 (m, 1H), 1.4 (m, 4H), 0.89 (m, 6H). Spectrum corresponds to imine tautomer.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:8]=2)[C:3]1=O.[BH4-].[Na+].Cl>O1CCCC1.CO>[CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=2
Reactant: CC1Cc2ccc(C(C)(C)C)cc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=Cc2ccc(C(C)(C)C)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
5.3 g (26 mmol) of 8 were dissolved in 50 ml of tetrahydrofuran/methanol (2:1), 1.5 g of sodium borohydride were added at 0° C. with magnetic stirring, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured onto ice, conc. HCl was added to pH 1, and the mixture was extracted a number of times with diethyl ether. The combined organic phases were washed with saturated aqueous NaHCO3 solution and NaCl solution and dried (MgSO4). The solvent was removed in vacuo, and the crude product, without further purification, was taken up in 300 ml of toluene, 0.1 g of p-TsOH was added, and the mixture was refluxed for 1 hour. The reaction mixture was washed with 100 ml of saturated aqueous NaHCO3 solution, and the solvent was removed in vacuo. The crude product was purified by filtration through 200 g of silica gel (hexane), giving 4.8 g (99%) of 9 as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)C.C[O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][C@@H:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:19][C:17]2=[O:18])=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>ClCCl>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][C@@H:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:19][C:17]2=[O:18])=[CH:12][CH:11]=1
Reactant: CCCCCC[C@@H]1C[C@H](c2ccc(OC)cc2)C(=O)O1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CCCCCC[C@@H]1C[C@H](c2ccc(O)cc2)C(=O)O1
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a solution of 1.6 g of aluminium chloride and 2 ml of ethanethiol in 15 ml of dichloromethane was added, at 0° C, a solution of 440 mg of (2R,4R)-2-(4-methoxyphenyl)-4-decanolide dissolved in 5 ml of dichloromethane. This mixture was stirred for 4 hours. A saturated sodium bicarbonate aq. solution was then added, and the resulting mixture was subjected to extraction with dichloromethane, followed by column chromatography (Kieselgel 60, hexane/ethyl acetate = 3/1), thereby obtaining 374 mg (yield 90%) of (2R,4R)-2-(4-hydroxyphenyl)-4-decanolide. Identification data for this product are as follows. Melting point 87-88° C. [α]D20 +3.2° (c=1.27, MeOH).
Reaction SMILES: [Li+].[BH4-].C([O:5][C:6](=O)[C:7]([NH:30][C:31](=[O:33])[CH3:32])([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:19]=2)[CH2:14]1)[C:8](OCC)=[O:9])C>>[OH:9][CH2:8][C:7]([NH:30][C:31](=[O:33])[CH3:32])([CH2:6][OH:5])[CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:19]=2)[CH2:14]1
Reactant: CCCCCCCCc1ccc2c(c1)CC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2
Agent: [BH4-]
Agent: [Li+]
Product: CCCCCCCCc1ccc2c(c1)CC(C(CO)(CO)NC(C)=O)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 2 %

Procedure:
To a solution of LiBH4 (0.564 mL, 1.127 mmol) at 0° C. was added 5 (0.1 g, 0.225 mmol). The mixture was allowed to stir at room temperature for 2 days. The reaction was quenched with water and extracted with EtOAc. The product was purified with silica gel chromatography eluding with 5% MeOH and 95% CH2Cl2. The reaction provided 6 (8 mg, 0.0029 mmol, 2%) and also 8 (5 mg, 0.0017 mmol, 0.74%).
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:24]1[CH2:29][CH2:28][N:27]([C:30](OC(C)(C)C)=O)[CH2:26]C1)[CH2:19][CH2:18]2.[Li+].C[Si]([N-:42][Si](C)(C)C)(C)C>C1COCC1.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]>[CH3:30][N:27]1[CH2:28][CH2:29][CH:24]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([NH2:42])=[CH:23][CH:22]=3)[CH2:18][CH2:19]2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(Br)ccc32)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CN1CCC(N2CCc3cc(N)ccc32)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 104.8 %

Procedure:
A solution of Pd2(dba)3 (0.08 g, 0.087 mmol) in dry THF (5 mL) was treated with PtBu3 (1.06 mL, 0.351 mmol, 10% in hexanes), followed by compound 3 (0.67 g, 1.757 mmol) in dry THF (5 mL) and LiHMDS (3.51 mL, 3.514 mmol) at room temperature. The resulting mixture was stirred at 100° C. in a seal tube for 3 h. The reaction was brought to room temperature and quenched with TBAF (5 mL, 1 M solution in THF). After stirring for 15 min., solution was basified with 1 N NaOH solution (50 mL) and product was extracted into CH2Cl2 (3×20 mL). The combined CH2Cl2 layer was dried (Na2SO4) and evaporated to obtain the crude product. The crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5:97.5) to obtain compound 4 (0.4 g, 72%) as a foam.
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1)=[O:2].O=C(N1CCNCC1)COC1C=C(C=CC=1)C=O>>[O:10]=[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(C=O)cc2)CC1
Agent: O=Cc1cccc(OCC(=O)N2CCNCC2)c1
Product: O=Cc1ccc(OCC(=O)N2CCNCC2)cc1
Yield: 60 %

Procedure:
tert-Butyl 4-(2-(4-formylphenoxy)acetyl)piperazine-1-carboxylate (54) was treated in an analogous manner to compound 50 to yield the desired product (60%) as a pale yellow solid. LCMS: 97% (M++1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][OH:10])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[O:10][CH2:9][C@@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(N[C@@H](CO)c1ccccc1)c1cccc(I)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Reaction time: 18 h
Yield: 55.9 %

Procedure:
To a mixture of (+)-2-(3-iodobenzamido)-2(R)-phenylethan-1-ol (14.70 g, 40 mmol) and triphenylphosphine (13.64 g, 52 mmol) in dry tetrahydrofuran (350 ml) was added dropwise a solution of diethyl azodicarboxylate (10.52 g, 52 mmol) in dry tetrahydrofuran (15 ml). The reaction mixture was stirred for 18 h and volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (1:8) to afford (+)-4,5-dihydro-2-(3-iodophenyl)-4(R)-phenyloxazole (7.81 g, 56%) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=[O:29])[CH2:21][NH:22][C:23](=O)[CH2:24][O:25][CH2:26][CH3:27])=[CH:16][CH:15]=3.O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[O:29][C:23]([CH2:24][O:25][CH2:26][CH3:27])=[N:22][CH:21]=1)=[CH:16][CH:15]=3
Reactant: CCOCC(=O)NCC(=O)c1ccc2[nH]c3c(cc(-c4ccc(Cl)cc4Cl)c(=O)n3C)c2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOCc1ncc(-c2ccc3[nH]c4c(cc(-c5ccc(Cl)cc5Cl)c(=O)n4C)c3c2)o1

Procedure:
A solution of compound A N-{2-[3-(2,4-dichlorophenyl)-1-methyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-2-oxoethyl}-2-ethoxyacetamide (841 mg, 1.73 mmol) in 2 ml of H2SO4 is stirred at ambient temperature for 20 h. H2O is added, the mixture ie extracted with EtOAc and CH2Cl2, and the product is concentrated without drying. The product is adsorbed onto silica and purification is carried out by chromatography on a silica column, elution being carried out with EtOAc. The residue is taken up in Et2O, and the product is filtered and washed with a minimum amount of Et2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(COc2ccc(Cl)c([N+](=O)[O-])c2)cc1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 4-Bromomethyl-benzonitrile using the conditions described in Example 10C to provide 4-(4-Chloro-3-nitro-phenoxymethyl)-benzonitrile which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH2:38][CH2:39][O:40][CH2:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:40]1[CH2:39][CH:38]=[C:37]([C:2]2[C:3]([F:28])=[C:4]([N:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]4[N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:20]=[CH:19][CH:18]=4)=[N:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:42][CH2:41]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COc1cn(-c2cccc(Br)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1cn(-c2cccc(C3=CCOCC3)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 85.5 %

Procedure:
A mixture of 1-(3-bromo-2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (441 mg, 1.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (231 mg, 1.1 mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol) and Na2CO3 (233 mg, 2.2 mmol) in DME (8.8 mL) and water (2.2 mL) was heated to reflux for 15 h under N2. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with EtOH/hexane to yield the title compound (380 mg, 85% yield) as a white solid: mp 138-141° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.42 (2H, brs), 3.74-3.89 (5H, m), 4.21-4.29 (2H, m), 6.15 (1H, brs), 6.92-7.10 (2H, m), 7.17-7.59 (7H, m), 7.78 (1H, d, J=1.9 Hz), 8.52 (1H, s). Anal. Calcd for C25H21FN4O3: C, 67.56; H, 4.76; N, 12.61. Found: C, 67.42; H, 4.83; N, 12.44.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:5]([N:8]1[C:16](=[O:17])[NH:15][C:14]2[C:13]([CH3:18])=[N:12][C:11]3=[C:19]([C:23]4[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[CH3:31])[C:20]([CH3:22])=[N:21][N:10]3[C:9]1=2)[CH2:6][CH3:7])[CH3:4].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[CH2:32]([N:15]1[C:14]2[C:13]([CH3:18])=[N:12][C:11]3=[C:19]([C:23]4[C:24]([CH3:31])=[CH:25][C:26]([CH3:30])=[CH:27][C:28]=4[CH3:29])[C:20]([CH3:22])=[N:21][N:10]3[C:9]=2[N:8]([CH:5]([CH2:6][CH3:7])[CH2:3][CH3:4])[C:16]1=[O:17])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCC(CC)n1c(=O)[nH]c2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)n1c(=O)n(Cc2ccccc2)c2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Sodium hydride (28 mg, 0.71 mmol) was added to a solution of 1-(1-ethylpropyl)-6-mesityl-4,7-dimethyl-2,3-dihydro-1H-pyrazolo[5,1-b]purin-2-one (230 mg, 0.59 mmol) in N,N-dimethylformamide (5 mL) at room temperature. After 30 minutes, benzyl bromide (0.079 mL, 0.65 mmol) was added, followed by stirring at 70° C. for one hour. Water was added under ice-cooling, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (15-20% ethyl acetate/hexane) to give the title compound (259 mg) as brown crystals.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[N:12]=[C:11]([CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]([CH:24]([CH3:26])[CH3:25])[C:16]3=[O:27])[N:10]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C:5]1[C:13]2[N:12]=[C:11]([CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]([CH:24]([CH3:25])[CH3:26])[C:16]3=[O:27])[N:10]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(CN=[N+]=[N-])cccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(CN)cccc21

Procedure:
A mixture of 1-[4-azidomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (108 mg, 0.250 mmol) and palladium black (10 mg) in methanol (20 mL) was rocked under a hydrogen atmosphere (50 psi) for 3 hrs. The residue obtained after filtration and concentration was purified by preparative HPLC (50-70% B 20 min) to give 1-[4-aminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one; HCl salt as an off white solid after conversion into the hydrochloric acid salt (49 mg, 44%) along with 1-isopropyl-3-[4-methoxymethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-1,3-dihydro-benzoimidazol-2-one (4 mg, 3%) as a white solid:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28][CH3:29])[N:14]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>Cl.CCO>[NH2:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:28][CH3:29]
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
Tert-butyl 2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (9.35 g, 23.4 mmol) was suspended in 150 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 2 h, the reaction was cooled to room temperature and the HCl salt of the product was collected by vacuum filtration and rinsed with ether. The free base was made by dissolving the HCl salt in water and treating with 10% NaOH solution until the mixture was pH 12. The aqueous suspension was extracted with CH2Cl2 (10×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give 6.62 g of 1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](Cl)[CH:11]=[C:10]([Cl:15])[N:9]=2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([Cl:15])[CH:11]=[C:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccc(Br)cc2)n1
Reactant: NCCCN1CCOCC1
Product: Clc1cc(NCCCN2CCOCC2)nc(-c2ccc(Br)cc2)n1

Procedure:
Similarly, 2-(4-bromophenyl)-4,6-dichloropyrimidine is reacted with N-(3-aminopropyl)-morpholine to afford 2-(4-bromophenyl)-4-chloro-6-[3-(morpholino)propylamino]pyrimidine which is then reacted with p-chlorothiophenol to produce 2-(4-bromophenyl)-4-(4-chlorophenylthio)-6-[3-(morpholinopropyl)amino]-pyrimidine.