Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](\[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.ClCCl>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](\[C:13]1[CH:18]=[CH:17][C:16]([C:25]#[C:24][CH2:23][N:22]([CH3:26])[CH3:21])=[CH:15][CH:14]=1)/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1ccc(Br)cc1
Reactant: C#CCN(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)/C=C(/c1ccccc1)c1ccc(C#CCN(C)C)cc1

Procedure:
A solution of (Z)-3-(4-bromo-phenyl)-3-phenyl-acrylic acid ethyl ester (1.200 g, 3.6 mmol), dimethyl-prop-2-ynyl-amine (0.9 ml, 10.88 mmol), bis(triphenylphosphine) palladium(II) chloride (0.102 g, 0.144 mmol), copper(I) iodide (2.06 mg, 0.0108 mmol) in dry triethyllamine (10 ml) were heated to 100° C. by microwave irradiation for 20 min. The cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (10 g) and evaporated in vacuo. The resulting residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving (Z)-3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-acrylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:10]2[N:11]=[CH:12][N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:14]=2)=[CH2:9])[N:3]=1>FC(F)(F)C(O)=O.[Pd]>[NH:13]1[CH:14]=[C:10]([CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=2)[CH3:9])[N:11]=[CH:12]1
Reactant: C=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc(C)n1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(C)c2c[nH]cn2)n1

Procedure:
A mixture of 2-methyl-6-[1-(1-trityl-1H-imidazol-4-yl)-vinyl]-pyridine (Intermediate D4) (460 mg, 1.1 mmol) in trifluoroacetic acid (TFA) (25 mL) was reduced by the action of 10% Pd/C (100 mg) under H2 at 35 psi for 20 h at rt. The mixture was filtered through Celite and freed of solvent under reduced pressure. The residue was purified by chromatography on silica gel with 5% NH3-MeOH:CH2Cl2 to give 2-[1-(1H-imidazol-4-yl)-ethyl]-6-methyl-pyridine (Intermediate D5) as a solid, 150 mg (93%).
Reaction SMILES: C([N:8]1[C:12]2=[N:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][C:16]([CH3:17])=[C:11]2[N:10]=[C:9]1[CH2:22][CH3:23])C1C=CC=CC=1.Cl>CO.[OH-].[OH-].[Pd+2]>[CH2:22]([C:9]1[N:8]=[C:12]2[NH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][C:16]([CH3:17])=[C:11]2[N:10]=1)[CH3:23]
Reactant: CCc1nc2c(C)cc(C(=O)OC)nc2n1Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCc1nc2[nH]c(C(=O)OC)cc(C)c-2n1
Reaction time: 24 h

Procedure:
A mixture of 750 mg of the crude product of Step F in MeOH (30 mL), concentration aqueous HCl (1 mL), and 100 mg of moist Pearlman's catalyst were shaken under 1 atm. H2 for 24 hours. The reaction was incomplete so 100 mg more of the catalyst was added and the reaction was shaken as described above for an additional 24 hours. Filtration, concentration, and extraction from dilute NH4OH with EtOAc followed by drying (Na2SO4), concentration, and purification (SiO2, 5 % MeOH/EtOAc) gave the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:16][CH2:15]3)=[CH:6][CH:5]=[C:4]([CH3:27])[N:3]=1.O.[Li+].[OH-].Cl>C1COCC1.CCO>[CH3:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:15]3)=[CH:6][CH:5]=[C:4]([CH3:27])[N:3]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCOc3ccc(C)nc3C)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OCCOc2ccc3c(c2)CC[C@H]3CC(=O)O)c(C)n1
Reaction time: 24 h
Yield: 88.4 %

Procedure:
To a solution of ethyl ((1S)-5-{2-[(2,6-dimethyl-3-pyridinyl)oxy]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 250, 43.1 mg, 0.12 mmol) in a mixture of THF (2 mL), water (2 mL), and EtOH (1 mL), was added LiOH (11.5 mg, 0.48 mmol). The reaction mixture was vigorously stirred for 24 h, acidified to pH ˜5 with HCl (1N aqueous solution), and then extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound as a white solid (36.2 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 1.72-1.75 (m, 1H), 2.33-2.44 (m, 2H), 2.37 (s, 3H), 2.41 (s, 3H), 2.68-2.85 (m, 3H), 3.52-3.55 (m, 1H), 4.19-4.25 (m, 4H), 6.67 (d, 1H), 6.74 (s, 1H) 6.85 (d, 1H), 6.99 (d, 1H), 7.01 (d, 1H); LC-MS: RT=2.41 min, (M+H)+ 342.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:41])[CH2:10][CH:11]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][N:12]1C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.N1CCNCC1.CO>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:41])[CH2:10][CH:11]1[NH:12][CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C(CC(=O)Nc2ccccc2Br)C1
Agent: C1CNCCN1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCNC(CC(=O)Nc2ccccc2Br)C1

Procedure:
To a solution of Example 1A (8.76 g, 14.12 mmol) in dichloromethane (100 mL) was added piperazine (3.65 g, 42.4 mmol). Methanol (50 mL) was added to the solution for solubility, and the resultant mixture was warmed to 40° C. for 14 hours. Once the reaction was complete, purification via flash chromatography (20-100% ethyl acetate/hexanes) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 7.83 (d, J=7.12 Hz, 1H), 7.64 (dd, J=7.97, 1.53 Hz, 1H), 7.35 (dd, 1H), 7.08 (dd, 1H), 3.69-3.85 (m, 2H), 2.70-2.99 (m, 3H), 2.53-2.67 (m, 2H), 2.42 (d, J=6.44 Hz, 2H), 1.34-1.46 (m, 9H); MS (APCI+) m/z 400.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][OH:13])[CH:8]=[C:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C1COCC1.CC(=O)OCC>[CH2:33]([O:32][C:30]([N:17]1[CH2:16][CH2:15][N:14]([C:7]2[CH:8]=[C:9]([CH2:11][CH2:12][OH:13])[N:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:6]=2)[CH2:19][CH2:18]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)c1nc(CCO)cc(N2CCNCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(CCO)cc(N2CCN(C(=O)OCc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of 2-tert-Butyl-4-(2-hydroxy-ethyl)-6-piperazin-1-yl-pyrimidine (5.1 g, 19.29 mmol) and N,N-diisopropylethylamine (7.48 g, 57.9 mmol) in THF (150 mL) was added benzyl chloroformate (CbzCl, 3.29 g, 19.29 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EA, washed with water, brine, dried over Na2SO4, filtered and concentrated to afford the crude title compound as an oil which was purified by column chromatography to afford the product (2.3 g, yield 29%) as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]([N:25]=1)=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:15]=[N:16][C:17]=2Cl)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CC(O)C>[C:19]1([C:14]2[N:15]=[N:16][CH:17]=[C:12]3[CH:11]=[CH:10][C:9](=[O:8])[NH:25][C:13]=23)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1nnc(-c2ccccc2)c2nc(OCc3ccccc3)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: O=c1ccc2cnnc(-c3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
2-Benzyloxy-5-chloro-8-phenylpyrido[2,3-d]pyridazine (250 mg), ammonium formate (115 mg) and 10% palladium on carbon catalyst (50 mg) were stirred together at reflux in propan-2-ol (50 ml) for 30 min. More ammonium formate (45 mg) was added, and the mixture was stirred as before for a further 30 min, and was then allowed to cool to room temperature. The catalyst was removed by filtration, was washed thoroughly with methanol, and the filtrate was concentrated in vacuo to yield 8-phenyl-1H-pyrido[2,3-d]pyridazin-2-one as a white solid (150 mg). 1H NMR (400 MHz, CDCl3) δ6.98 (1H, d, J=9.4 Hz), 7.63 (3H, m), 7.69 (2H, m), 7.85 (1H, d, J=9.5 Hz), 8.88 (1H, br s), 9.23 (1H, s); MS (ES+) m/e 224 [MH]+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]2[C:15](=[O:42])[N:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C@H:26]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)=[O:33])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH2:17][C:13]2=[CH:12][N:11]=1)(C(C)(C)C)(C)C.C(O)(=O)C.O>C1COCC1>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:32]([NH:31][C@@H:26]([C:24]([N:21]2[CH2:22][CH2:23][CH:18]([N:16]3[CH2:17][C:13]4=[CH:12][N:11]=[C:10]([CH2:9][OH:8])[N:14]4[C:15]3=[O:42])[CH2:19][CH2:20]2)=[O:25])[C:27]([CH3:29])([CH3:30])[CH3:28])=[O:33])=[CH:40][CH:39]=1
Reactant: CC(C)(C)[C@@H](NC(=O)Nc1ccc(Cl)cc1)C(=O)N1CCC(N2Cc3cnc(CO[Si](C)(C)C(C)(C)C)n3C2=O)CC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)[C@@H](NC(=O)Nc1ccc(Cl)cc1)C(=O)N1CCC(N2Cc3cnc(CO)n3C2=O)CC1
Yield: 83.1 %

Procedure:
N-((1R)-1-((4-(5-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperidinyl)carbonyl)-2,2-dimethylpropyl)-N′-(4-chlorophenyl)urea (0.31 g) obtained in Example 831) was dissolved in a solution (acetic acid:water:THF=4:1:1, 6 ml), and mixed at 60° C. for 4 hours. The solvent was distilled off under reduced pressure, and then to the residue were added ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was collected by separation, washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate to ethyl acetate:ethanol=10:1) to obtain the title compound as a colorless solid (0.21 g, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:13]=[CH:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)([OH:11])[CH3:10])=[CH:5][C:4]=1[F:36])#[N:2].[C:37]([O:41][CH3:42])(=[O:40])[CH2:38]O.C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[CH3:42][O:41][C:37](=[O:40])[CH2:38][N:13]1[C:12]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:36])[CH:5]=2)([OH:11])[CH3:10])=[CH:16][N:15]=[CH:14]1
Reactant: CC(O)(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)CO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cn1cncc1C(C)(O)c1ccc(C#N)c(F)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-cyano-3-fluorophenyl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol, as described above in Step C, (200 mg, 0.42 mmol), methyl glycolate (35 mg, 0.39 mmol), and N,N-diisopropylethylamine (65 mg, 0.51 mmol) in dry CH2Cl2 (10 mL), under argon, at −78° C., was added trifluoromethanesulfonic anhydride (110 mg, 0.39 mmol) dropwise. The mixture was allowed to warm slowly to ambient temperature, then the solvent was removed in vacuo. The residue was dissolved in MeOH (10 mL) and the solution was heated to reflux for 1 hour, then concentrated to dryness. The residue was purified by silica gel chromatography, eluting with 4% MeOH—0.4% NH4OH in CHCl3, to yield the titled product as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:17]1=[O:27].[CH3:36][N:37]=[C:38]=[O:39].C(N(CC)CC)C>C(Cl)Cl>[CH3:36][NH:37][C:38]([N:24]1[CH2:25][CH2:26][CH:21]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH2:15][C:14]3[C:13]([Cl:28])=[CH:12][C:11]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)=[CH:10][C:9]=3[Cl:8])[C:17]2=[O:27])[CH2:22][CH2:23]1)=[O:39]
Reactant: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1C1CCNCC1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(F)cc4)cc3Cl)C2=O)CC1
Yield: 106.7 %

Procedure:
Treat a solution of (R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-piperidin-4-yl-pyrrolidin-2-one trifluoroacetic acid (Preparation 29) (0.10 g, 0.19 mmol) in CH2Cl2 (3 mL) with methyl isocyanate (21 mg, 0.36 mmol) and triethylamine (0.07 mL, 0.48 mmol). Stir the reaction overnight at room temperature. Quench the reaction with 1N HCl and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute pure product. Remove the solvent to afford 0.097 g (84%) of product. MS (m/e): 478 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:17][C:16](=[O:18])[N:15]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=2)[CH:13]=1)[CH2:2][CH2:3]C.C(OC1C=CC=CC=1C(OC)=O)C=C>>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]2[CH:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:1][CH:2]=[CH2:3])[NH:17][C:16](=[O:18])[N:15]=2)=[CH:20][C:21]=1[CH3:26]
Reactant: CCCCOc1ccccc1-c1cc(-c2ccc(O)c(C)c2)nc(=O)[nH]1
Agent: C=CCOc1ccccc1C(=O)OC
Product: C=CCOc1ccccc1-c1cc(-c2ccc(O)c(C)c2)nc(=O)[nH]1

Procedure:
Using the same or analogous synthetic techniques described in Example 1, Using the same or analogous synthetic techniques described in Example 1, 6-[2-(butyloxy)phenyl]-4-(4-hydroxy-3-methylphenyl)pyrimidin-2-(1H)-one was prepared by replacing methyl 2-{[2-(methyloxy)ethyl]oxy}benzoate with methyl 2-(prop-2-en-yloxy)benzoate prepared according to Eissenstat, Michael A.; Bell, Malcolm R.; D'Ambra, Thomas E.; Alexander, E. John; Daum, Sol J.; Ackerman, James H.; Gruett, Monte D.; Kumar, Virendra; Estep, Kimberly G.; et al. Aminoalkylindoles: Structure-Activity Relationships of Novel Cannabinoid Mimetics. Journal of Medicinal Chemistry (1995), 38(16), 3094-105.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:13]3[C:14]([CH3:17])=[N:15][N:16]=[C:12]3[C:9]3([CH2:11][CH2:10]3)[CH2:8][NH:7][C:6]=2[CH:18]=1>[Pd].CO>[CH3:17][C:14]1[N:13]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:18][C:6]=3[NH:7][CH2:8][C:9]3([CH2:10][CH2:11]3)[C:12]2=[N:16][N:15]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1NCC21CC1
Agent: [Pd]
Solvent: CO
Product: Cc1nnc2n1-c1ccccc1NCC21CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
A mixture of 8-bromo-1-methyl-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane] (150 mg, 0.49 mmol) and palladium on carbon (40 mg) in methanol (10 mL) was stirred for 2 hours at 40° C. under hydrogen atmosphere. The solid was filtered and the filtrate was concentrated to give crude 1-methyl-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane] (100 mg, 91%) as yellow oil, used for the next step without further purification. LRMS (M+H+)+: calcd 226.12. found 226.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([NH:21][C:22]([O:24]C2C=CC=CC=2)=O)[CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][S:6]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH2+:14])=[O:11])(=[O:8])=[O:7].[C:31]1([CH3:49])[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=[C:39]([C:45]([F:48])([F:47])[F:46])[N:38]=2)[CH:32]=1>C(#N)C.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:20]=[C:19]([NH:21][C:22]([NH:44][CH2:43][C:42]2[C:37]([C:33]3[CH:32]=[C:31]([CH3:49])[CH:36]=[CH:35][CH:34]=3)=[N:38][C:39]([C:45]([F:48])([F:46])[F:47])=[CH:40][CH:41]=2)=[O:24])[CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][S:6]([NH:9][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:7])=[O:8]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: [CH2+]C(C)(C)OC(=O)NS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1F
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)Nc2ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)c(F)c2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
2-(N-(2-Fluoro-4-(phenoxycarbonylamino)benzyl)sulfamoylcarbamoyloxy)-2-methylpropan-1-ylium (100 mg, 0.225 mmol) was dissolved in acetonitrile. (2-m-Tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (60 mg, 0.225 mmol) and 4-dimethylaminopyridine (27 mg) were added to the solution. The reaction mixture was stirred for overnight at 50° C. The mixture was extracted with ethyl acetate and washed with brine. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave tert-butyl N-(2-fluoro-4-(3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)benzyl)sulfamoylcarbamate (70 mg, 51%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:10][CH2:9]1)=[O:7].[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[NH:19][C:18]2=[O:26])[CH2:13][CH2:12]1.C1C=CC=CC=1.CO>ClC(Cl)Cl>[O:26]=[C:18]1[N:17]([CH:14]2[CH2:13][CH2:12][N:11]([CH2:9][CH2:10][NH:8][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:16][CH2:15]2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19]1
Reactant: O=C(c1cccs1)N1CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1cccs1

Procedure:
A mixture of 7.7 parts of 1-(2-thienylcarbonyl)aziridine, 10.8 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 54 parts of benzene and 8 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and trichloromethane is added. The undissolved product is filtered off and stirred in 2,2'-oxybispropane. It is filtered off again and crystallized twice: first from a mixture of methanol and N,N-dimethylformamide and then from a mixture of trichloromethane and methanol, yielding 4 parts of N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-2-thiophenecarboxamide; mp. + 300° C (dec.).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([CH:24]([OH:26])[CH3:25])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[F:27][C:2]([F:1])([F:28])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([C:24](=[O:26])[CH3:25])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(O)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 1-[5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazol-2-yl]ethanol (0.30 g, 0.77 mmol) in dichloromethane (3 mL) was added a solution of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.65 g, 1.54 mmol) in dichloromethane (3 mL) at room temperature, and the resulting mixture was stirred overnight. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=17/3) and recrystallized from hexane/ethyl acetate to give the title compound (0.17 g, yield 57%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]#[N:14].[C-:15]#[N:16].[Na+]>CN(C)C=O>[NH2:14][CH:13]([CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1)[C:15]#[N:16]
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CC(N)C#N)c2c1
Yield: 43 %

Procedure:
Using the same method starting from 5.4 millimoles (1 g) of (5-methoxy-3-indolyl)-acetonitrile and replacing of cyanising agent by 20 ml of a normal solution of sodium cyanide in dimethylformamide, there are obtained, after purification by an acid-base extraction, 0.50 g of 2-amino-3-(5-methoxy-3-indolyl)-propionitrile with a yield of 43%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:8]([CH:17]([OH:31])[C@@H:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)[CH:7]=[CH:6][CH:5]=1.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].[NH4+].[Cl-]>C1COCC1>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:31][CH:17]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([F:3])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)[C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19]1)[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(-c2c(F)cccc2C(O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)COC(c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
To a suspension of NaH (0.42 g, 17.6 mmol) in THF (50 mL) at 0˜5° C. was added dropwise a solution of (3R)-tert-butyl 3-((6-fluoro-3′-methylbiphenyl-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (3.5 g, 8.8 mmol) in THF (30 mL) and the reaction mixture was stirred for 1 h at rt. A solution of ethyl bromoacetate (2.92 g, 17.6 mmol) in THF (30 mL) was added dropwise to the above mixture, and then refluxed for 12 h. Tlc showed the starting material had disappeared. The reaction mixture was poured into satd aq NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to afford (3R)-tert-butyl 3-((2-ethoxy-2-oxoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (1.1 g, 38%). 1H NMR (400 MHz, CDCl3): 1.26 (m, 3H), 1.40 (s, 9H), 2.10 (m, 1H), 2.39 (s, 3H), 2.51 (m, 1H), 3.51 (m, 1H), 3.78 (m, 1H), 3.96 (m, 2H), 4.16 (m, 3H), 4.23 (m, 2H), 4.69 (m, 2H), 6.97 (m, 2H), 7.06 (m, 1H), 7.20 (m, 1H), 7.29-7.41 (m, 3H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Reactant: CCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.498 g, 1.7 mmoles), 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Nonanoyl chloride (1.26 mL, 7.0 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in 25 mL ethyl acetate and undissolved salts were removed by filtration. After evaporation of the ethyl acetate, the residue was dissolved in methanol and passed over a silica gel column (4.8×13 cm). The product containing fractions were combined, concentrated, and chromatographed on a Chromatotron (4 mm silica gel plate) in a mixture of hexane:acetone (80:20). Two separate subsequent runs on the Chromatotron (4 mm silica gel plate) with a mixture of chloroform:acetone (95:5) and a mixture of hexane:acetone (85:15) followed by lyophilization afforded 0.236 g of 6-(cyclopropylmethylamino)-9-((2R,5S)-5-[(nonanoyloxy)methyl]-tetrahydro-2-furyl)-9H-purine as an oil (32% yield).