Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13](=[O:24])[C:14]([C:17]2[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=2)([CH3:16])[CH3:15])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+]>O1CCOCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[C:14]([CH3:16])([CH3:15])[C:13]2=[O:24])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](NC(=O)C(C)(C)c2cccnc2Cl)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cccnc32)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Tert-butyl(trans-3-(2-(2-chloropyridin-3-yl)-2-methylpropanamido)cyclobutyl)carbamate (1074 mg, 2.92 mmol), sodium t-butoxide (561 mg, 5.84 mmol), and chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethyl-phenyl)]palladium(ii) methyl tert-butyl ether adduct (143 mg, 0.175 mmol) were sealed in a round-bottomed flask under nitrogen. Dry dioxane (5 mL) was added and the reaction heated at 80° C. After 2 hours, the mixture was cooled and partitioned between ethyl acetate, water, and saturated ammonium chloride. The organic was dried with magnesium sulfate and evaporated to dryness to give tert-butyl(trans-3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutyl)carbamate (980 mg, 2.96 mmol, quantitative) as light-yellow solid.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([CH2:22][OH:23])[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ClC(Cl)(Cl)C(=N)O[CH:28]1[O:53][C@H:52]([CH2:54][O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:43]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@H:34]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:29]1[O:30][C:31](=[O:33])[CH3:32]>>[CH2:1]([O:17][CH2:18][C@H:19]([CH2:22][O:23][C@@H:28]1[O:53][C@H:52]([CH2:54][O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C@@H:43]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@H:34]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C@H:29]1[O:30][C:31](=[O:33])[CH3:32])[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CO)OC
Reactant: CC(=O)O[C@H]1C(OC(=N)C(Cl)(Cl)Cl)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Product: CCCCCCCCCCCCCCCCOC[C@H](CO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OC(C)=O)OC
Yield: 76 %

Procedure:
1-O-Hexadecyl-2-O-methyl-sn-glycerol (433.3 mg, 1.3 mmol) prepared as described above, was glucosylated with 2-O-acetyl-3,4,6-tri-O-benzyl-α, β-D-glucopyranosyl trichloroacetimidate (930 mg, 1.4 mmol) to give 1-O-Hexadecyl-2-O-methyl-3-O-(2′-O-acetyl-3′,4′,6′-tri-O-benzyl-β-D-glucopyranosyl)-sn-glycerol in 76% yield (805 mg). [α]D −8.5 deg. 1H-NMR: δ7.32-7.15 (m, 15H, 3PhCH2) 4.99 (dd, 1H, J1′,2a′=2.5 Hz, J1′,2e′−1.0 Hz, H-1′), 3.93 (m, 1H, H-5′), 3.44 (s, 3H, OCH3), 2.15 (ddd, 1H, J2e′,3′=4.7 Hz, J2e′,2a′=11.5 Hz,H-2e′), 1.7 (ddd, 1H, H-2a′, 1.25 (s, 26H, CH2), 0.87 (t, 3H, CH3). 13C-NMR: δ98.05 (C-1′), 79.33, (C-5′), 62.07 (C-6′), 57.94 (OCH3), 37.36 (C-2′), 31.90, 29.64, 29.48, 29.31, 26.06, 22.67 (CH2), 14.06 (CH3).
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([Cl:13])=[C:10]([Cl:12])[N:11]=1.[CH2:22]=[O:23]>C1COCC1>[Cl:12][C:10]1[N:11]=[C:7]([CH2:22][OH:23])[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]=1[Cl:13]
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Cl)c1Cl
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(CO)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
nBuLi (2.0 mL, 3.2 mmol, 1.6 M in hexane) was added dropwise to a solution of 2-bromo-4,5-dichloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (1.1 g, 3.2 mmol) in THF (50 mL) at −78° C. under N2. The mixture was stirred for 30 min and paraformaldehyde (960 mg, 32 mmol) was then added. The mixture was allowed warm up to room temperature and stirred for 6 h and then quenched by aqueous NH4Cl. Extracted with EtOAc and the organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-30% EtOAc in hexane) to give the title compound (614 mg, 65%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.37 (2H, s) 4.70 (2H, d, J=1.2 Hz) 3.58 (2H, dd, J=8.9, 7.7 Hz) 0.89-0.96 (2H, m) 0.00 (9H, s). LCMS: m/z 297 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[CH:24][C:25]=2[CH3:26])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:30]>O1CCOCC1>[ClH:30].[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[CH:24][C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)ccn(C)c2=O)cc1
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of N-[(1,1-dimethylethoxyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (132 mg, 0.33 mmol) in dioxane (1 mL) was added 4 N HCl solution in dioxane (1.5 mL) at room temperature. The solution was stirred for 4 h and concentrated under vacuum. The residue was dissolved in methanol (5 ml) and toluene (5 mL) and concentrated under vacuum to give 111 mg (99% yield) of 4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride salt as an amorphous white solid. EI-HRMS m/e calcd for C17H20N2O3 (M+) 300.1474, found 300.1486.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:17][CH:18]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH3:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[C:11]1([CH:10]([NH:17][CH:18]([C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH3:19])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(NC(c1ccccc1)c1cccc([N+](=O)[O-])c1)c1cc(F)cc(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(NC(c1ccccc1)c1cccc(N)c1)c1cc(F)cc(F)c1
Yield: 96.8 %

Procedure:
In a similar manner to that described in Example (1b), a solution of isomer B of [(3-nitrophenyl)-phenylmethyl]-[1-(3,5-difluorophenyl)ethyl]amine (890 mg) in methanol (20 ml), nickel chloride hexahydrate (1.14 g) and sodium borohydride (363 mg) were reacted, to afford isomer B of the title compound (791 mg) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[N:22]1([CH2:2][CH2:3][CH2:4][C:5]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][CH:8]=[CH:7][CH2:6]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)C1(CCCCl)CC=CCC1c1ccccc1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCCN2CCCCC2)CC=CCC1c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
Ethyl 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxylate (6.35 g, 20.7 mmol) was dissolved in 50 ml of dimethylformamide (DMF) to which piperidine (10 equiv, 15 ml) was added. The contents were stirred under N2 at 50° C. for 16 hrs. The reaction was allowed to cool to ambient temperature, whereupon the DMF was removed on the rotovap at 3 mm pressure. To the residue was added 200 ml of ethyl ether and the organic material was washed three times with 100 ml of water. The organic fraction was dried over MgSO4, filtered and concentrated in vacuo to afford after distillation (155°-160° C./0.1 mm) ethyl 1-[3-(1-piperidinyl)propyl]-6-phenyl-3-cyclohexene-1-carboxylate as a clear viscous oil (6.61 g, 90% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[C:5]([NH:7][C@H:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:6].CO>C(O)C.[Pd]>[NH2:24][C:23]1[CH:22]=[CH:21][C:4]([C:5]([NH:7][C@H:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:6])=[CH:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])c(C)c1)C(=O)OCC
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)c(C)c1)C(=O)OCC
Reaction time: 2 h

Procedure:
A solution of diethyl N-(3-methyl-4-nitrobenzoyl)-(L)-glutamate (Cosulich, D. B. et al., J. Am. Chem. Soc., 1953, 75, 4675) (11.0 g, 30.0 mmoles) in 95% ethanol (250 mL) was mixed with 10% palladium on carbon (0.8 g) and placed on a Parr apparatus. The mixture was shaken under hydrogen atmosphere for 2 hours. The reaction mixture was filtered, spin evaporated, and dried to give a beige solid; yield, 10.1 g (100%); mp 79°-82° C.; 1H-NMR (DMSO-d6) δ 1.15 and 1.16 (2t overlapped, 6H), 2.00 (m, 2H), 2.06 (s, 3H), 2.39 (t, 2H), 4.03 and 4.06 (2q overlapped, 4H), 4.33 (m, 1H), 5.40 (s, 2H), 6.56 (d, Jo=8 Hz, 1H), 7.47 (d, Jo=8 Hz, 1H), 7.50 (s, 1H), 8.16 (d, 1H); uv (MeOH) 284 nm max (17000), 241 min (3020); mass spec (CI) m/e 337 (44%), 134 (100).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:31][CH2:32][CH3:33])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:34](Cl)([Cl:36])=[O:35]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:34]([Cl:36])=[O:35])[CH:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:31][CH2:32][CH3:33])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:33]([C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)#[N:34].O>CS(C)=O>[C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:5][CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)=[CH:37][CH:36]=1)#[N:34]
Reactant: N#Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OCCCC1CCN(CCCOc2ccc(C#N)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(OCCCC2CCN(CCCOc3ccc(C#N)cc3)CC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Into a solution of 91.9 g of 3-{1-[3-(4-cyanophenoxy)propyl]-4-piperidinyl}propyl methanesulfonate in 460 mL of dimethylsulfoxide, 66.9 g of potassium carbonate and 28.8 g of 4-cyanophenol were added at room temperature, and the solution was stirred at 60° C. for 2 hours. To the reaction mixture, after being cooled down to room temperature, 640 mL of water was dropped over 20 min, and then the mixture was stirred at room temperature for 35 min, and under water cooling for 30 min. The solid matter was collected by filtration, and washed twice with 180 mL of water and then 360 mL of 2-propanol to obtain 90.0 g of 4-(3-{4-[3-(4-cyanophenoxy)propyl]-1-piperidinyl}propoxy)benzonitrile as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:31][C:29]=2C=1.CCN(C(C)C)C(C)C.CN.CCO>C(Cl)Cl>[CH3:29][NH:31][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1
Reactant: CC1CCC(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)CC1
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNC(=O)[C@H](CC1CCC(C)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 46.7 %

Procedure:
A mixture of (S)-2-(tert-butoxycarbonylamino)-3-(4-methylcyclohexyl)propanoic acid (2.080 g, 7.29 mmol, 1.0 equiv), EDC (3.308 g, 2.37 equiv), HOBT (1.752 g, 1.78 equiv), DIEA (7.6 mL, 6 equiv) and 33% wt. methylamine in EtOH (2.771 g, 4 equiv) in CH2Cl2 (80 mL) was stirred at rt for 21 h. The solvents were removed in vacuo and 200 mL of 1 N HCl was added. The mixture was extracted three times with EtOAc, washed with brine, and dried over Na2SO4. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC to give 1.0167 g (47%) of (S)-tert-butyl 1-(methylamino)-3-(4-methylcyclohexyl)-1-oxopropan-2-ylcarbamate. MS ESI +ve m/z 321 (M+Na). 1H NMR (CDCl3, 400 MHz) δ 6.27 (br s, 1H), 4.91 (br s, 1H), 4.11-4.07 (m, 1H), 2.80, 2.79 (d, J=4.8 Hz, 3H), 1.85-1.20 (m, 21H), 0.88, 0.85 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH2:1]([C@@:17]1([CH2:22][O:23]CC2C=CC=CC=2)[NH:20][C:19](=[O:21])[CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>[Pd].CO.C(O)(=O)C>[CH2:1]([C@@:17]1([CH2:22][OH:23])[NH:20][C:19](=[O:21])[CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC[C@]1(COCc2ccccc2)CC(=O)N1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCCCCCCCCCCC[C@]1(CO)CC(=O)N1
Reaction time: 16 h
Yield: 95.8 %

Procedure:
A mixture of 400 mg of (R)-4-hexadecyl-4-[(phenylmethoxy)methyl]-2-azetidinone, 50 mg of 10% palladium-on-carbon and 20 ml of methanol:acetic acid (1:1) is hydrogenated for 16 hours, then filtered and evaporated. The residue is recrystallized from petroleum ether/ethyl acetate, to give 300 mg of the desired compound as a white solid, mp. 82° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:34][C:35]([NH2:42])([CH3:41])[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH:42][C:35]([CH3:41])([CH3:34])[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC(C)(C)CC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.620 g of the compound obtained in EXAMPLE 13, 1 ml of 1,1,3,3-tetramethylbutylamine, 0.7 g of BOP, 1 ml of DIPEA and 20 ml of DCM is stirred for 2 hours at RT. The reaction mixture is then washed with water, with a 1N solution of HCl and with a 1N solution of NaOH and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM as the eluent to give 0.28 g of the expected product in the form of white crystals. M.p.=180° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([NH:14][S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([N:14]([CH3:31])[S:15]([C:17]([CH3:20])([CH3:18])[CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)cc2)(NS(=O)C(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(S(=O)C(C)(C)C)C1(Cc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-4-(2-methylpropane-2-sulfinylamino)-piperidine-1-carboxylic acid tert-butyl ester (205 mg, 0.478 mmol) in DMF (4.8 mL) at 0° C. was added sodium hydride (25 mg of a 60% dispersion in mineral oil, 0.621 mmol). After 15 min methyl iodide (33 □l, 0.526 mmol) was added, and the solution warmed to rt. After 12 h, sodium hydride (120 mg, 60% dispersion in mineral oil, 3.00 mmol) and methyl iodide (165 □l, 2.65 mmol) were added. After 30 min water (20 mL) was added and the solution extracted with ethyl acetate (3×20 mL). Organic extracts were combined, dried over magnesium sulphate and the resulting crude product was purified by silica column chromatography, eluting with 66% ethyl acetate-hexanes, to give the title product as an oil (163 mg, 77%). LC-MS (LCT2) m/z 465 [M+Na+], Rt 8.41 min.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:34]([N:43]1[C:48](=[O:49])[C:47]([CH2:50]OS(C)(=O)=O)=[CH:46][C:45]([C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([CH3:63])[CH:57]=2)=[N:44]1)[CH:35]=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CN1CCNCC1>>[CH2:34]([N:43]1[C:48](=[O:49])[C:47]([CH2:50][N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[CH:46][C:45]([C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([CH3:63])[CH:57]=2)=[N:44]1)[CH:35]=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Agent: CN1CCNCC1
Product: Cc1cc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Yield: 80.1 %

Procedure:
Following the procedure of Example 1 (10), 2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 80.1%).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)[CH3:2].C([Li])CCC.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.CCCCCC>[C:15]1([S:21]([N:8]2[CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][C:7]2=[O:9])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC1CCC(=O)N1S(=O)(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 29.9 %

Procedure:
To 4.5 g of 5-ethoxypyrrolidin-2-one dissolved in 140 cm3 of anhydrous tetrahydrofuran, 21.8 cm3 of butyl-lithium in hexane (1.6M) is added drop by drop under an inert atmosphere, while cooling to about -10° C. After 45 minutes, 6.15 g of benzenesulphonyl chloride in tetrahydrofuran is added, and the whole is kept at -10° C. under agitation for 2 hours. It is then returned to ambient temperature, and the residue, after concentrating under reduced pressure, is taken up in 100° ethanol. By cooling and under agitation, the product precipitates, and is then filtered, washed abundantly with water, dried, and 2.8 g of the expected product is obtained after crystallizing from isopropanol, m.p. 112°-113° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[O:3]1.[CH3:19]O>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:18])([CH3:1])[O:3][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([O:15][CH3:19])=[O:14])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CO
Product: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Yield: 83 %

Procedure:
50 g (200 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 1,22 g (10 mmol) of N,N-dimethylpyridine are dissolved in 200 ml of methanol and refluxed for 5 hours. Removal of 150 ml of methanol by distillation gives 43.4 g (165 mmol, 83%) of product.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[CH2:10]=[O:11].C(N(CC)CC)C>CC(C)=O>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][N:5]([CH2:10][OH:11])[N:4]=1
Reactant: C=O
Reactant: FC(F)(F)c1cc[nH]n1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: OCn1ccc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
The mixture of 4.08 g of 3-(trifluoromethyl)-1H-pyrazole, 2.00 g of paraformaldehyde and 1 ml of triethylamine was stirred at 80° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure. Hexane was added to the residue, and then crystalline was formed. The crystalline was collected to obtain 4.31 g of 3-(trifluoromethyl)-1H-pyrazole-1-ylmethanol.
Reaction SMILES: Cl.Cl.[N:3]1([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH:25]1[CH2:29][CH2:28][O:27][C:26]1=[O:30].[H-].[Na+]>CN(C=O)C>[O:30]=[C:26]1[CH:25]([N:6]2[CH2:5][CH2:4][N:3]([NH:9][C:10]([C:12]3[CH:17]=[N:16][C:15]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][CH:13]=3)=[O:11])[CH2:8][CH2:7]2)[CH2:29][CH2:28][O:27]1
Reactant: O=C(NN1CCNCC1)c1cnc(-c2ccccc2)nc1
Reactant: O=C1OCCC1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NN1CCN(C2CCOC2=O)CC1)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
A solution of 2-phenyl-pyrimidine-5-carboxylic acid piperazin-1-ylamide dihydrochloride (0.45 mmol) and bromo-dihydro-furan-2-one (1.8 mmol) in DMF (10 mL) is stirred under N2 at 0° C. for 15 min, then NaH (60%, 1.8 mmol) is added and the mixture is warmed to rt and stirred overnight. The mixture is quenched with water, and extracted with EtOAC. The organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-2% methanol in DCM to afford give 2-phenyl-pyrimidine-5-carboxylic acid [4-(2-oxo-tetrahydro-furan-3-yl)-piperazin-1-yl]-amide (120 mg, 73%) as a solid. MS: 368 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.34 (s, 2H), 2.50-3.30 (m, 8H), 3.42-3.70 (m, H), 4.17-4.50 (m, 2H), 7.34-7.68 (m, 3H), 8.50 (d, 2H), 9.06-9.38 (d, 2H). IC50=26 nM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[CH2:11][CH2:10]1.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([C:33]3[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=3)=[CH:29][NH:30]2)=[CH:26][CH:25]=1.C(N(CC)CC)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:36]2[CH2:37][CH:38]=[C:33]([C:28]3[C:27]4[C:31](=[CH:32][C:24]([F:23])=[CH:25][CH:26]=4)[NH:30][CH:29]=3)[CH2:34][CH2:35]2)[CH2:11][CH2:10]1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: COc1ccccc1N1CCN(C(=O)CCCCCBr)CC1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C(=O)CCCCCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)CC1
Yield: 65.2 %

Procedure:
Following the same procedure reported in the Step 2 of EXAMPLE 13, the reaction of 1-(2-methoxyphenyl)-4-(6-bromohexanoyl)piperazine (2.37 mmol) with 6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (2.37 mmol) and triethylamine (2.87 mmol) gave the alkylation product (780 mg, 65%).