Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4]([NH:15][C@@H:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])[N:3]=1.[F:22][C:23]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:22][C:23]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:2]3[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4]([NH:15][C@@H:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])[N:3]=3)=[CH:30][CH:29]=2)=[CH:25][CH:24]=1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Reactant: COC(=O)[C@H](C)Nc1cc(C(=O)OC(C)(C)C)nc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)[C@H](C)Nc1cc(C(=O)OC(C)(C)C)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 80 °C
Yield: 61.5 %

Procedure:
To a mixture of the (S)-tert-butyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate (0.347 g, 1.10 mmol) in dioxane (10 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.348 g, 1.11 mmol), 2M aqueous Na2CO3 (1.10 mL, 2.20 mmol) and PdCl2(dppf) (0.050 g, 0.061 mmol). The reaction vessel was flushed with argon, sealed, and heated at 80° C. for 2 days. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 10-40% EtOAc in hexanes. The product fractions were evaporated in vacuo to give (S)-tert-butyl 2-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate as an off-white foam (0.316 g, 0.676 mmol, 61% yield). 1H NMR (400 MHz, DMSO-d6): 8.31-8.25 (3H, m), 7.32-7.24 (2H, m), 7.19-7.14 (2H, m), 7.06 (2H, d, J=9.0 Hz), 7.04 (1H, s), 4.60-4.51 (1H, m), 3.63 (3H, s), 1.56 (9H, s), 1.44 (3H, d, J=7.2 Hz). LC/MS: m/z=468.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[C:46](=[O:58])[N:47]([CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[N:48]([CH3:51])[C:49]=1[CH3:50].C(N(CC)CC)C>CN1C(=O)CCC1.CS(C)=O>[CH:52]1([N:47]2[C:46](=[O:58])[C:45]([NH:44][C:17]([C:3]3[C:2]([CH3:1])=[C:6]([CH:7]4[CH2:8][CH2:9][C:10]5([O:11][CH2:12][CH2:13][O:14]5)[CH2:15][CH2:16]4)[O:5][N:4]=3)=[O:19])=[C:49]([CH3:50])[N:48]2[CH3:51])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)O)noc1C1CCC2(CC1)OCCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-methyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)isoxazole-3-carboxylic acid (239 mg, 0.894 mmol) in dry NMP (3 mL), HATU (374 mg, 0.984 mmol) was added followed by 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (206 mg, 0.984 mmol) and triethylamine (0.274 mL, 1.967 mmol). The mixture was stirred at room temperature for 16 hours. The resulting mixture was partitioned between EtOAc (20 mL) and 1M NaOH (20 mL). The organic phase was washed with water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-2% MeOH in DCM afforded crude material. Isolated material was dissolved in DMSO (2 mL) and triturated with water (30 mL). The resulting suspension was filtered under reduced pressure and the solid was washed with water (20 mL) and allowed to dry under vacuum to afford the title compound;
Reaction SMILES: C([O:8][C:9](=[O:26])[CH:10]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C1C=CC=CC=1.[OH-].[Na+].Cl>CO>[C:19]([NH:18][O:17][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:9]([OH:26])=[O:8])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)NOC(C(=O)OCc1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NOC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
A mixture of the compound from Step 4c (2.8 g, 7.8 mmol) and 1 N NaOH (15 mL, 15 mmol) in MeOH (30 mL) was stirred at room temperature for 3 hours. The reaction mixture was neutralized by 2 N HCl to pH ˜2. The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic phases were washed with NH4Cl and brine, dried (Na2SO4) and filtered. The filtrate was concentrated and residue was purified by flash chromatography (silica gel, EtOAc/CH2Cl2=1/4) giving 0.6 g (29%) of the title compound.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:25][CH2:24][C:13]2([CH:15]([NH:16]C(OC(C)(C)C)=O)[CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.[NH2:26][C:27]1[C:36]([F:37])=C(F)[C:34]([F:39])=[C:33]2[C:28]=1[C:29](=[O:47])[C:30]([C:44]([OH:46])=[O:45])=[CH:31][N:32]2[C@@H:40]1[CH2:42][C@@H:41]1[F:43].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:26][C:27]1[C:36]([F:37])=[C:9]([N:11]2[CH2:25][CH2:24][C:13]3([CH:15]([NH2:16])[CH2:14]3)[CH2:12]2)[C:34]([F:39])=[C:33]2[C:28]=1[C:29](=[O:47])[C:30]([C:44]([OH:46])=[O:45])=[CH:31][N:32]2[C@@H:40]1[CH2:42][C@@H:41]1[F:43]
Reactant: CC(C)(C)OC(=O)NC1CC12CCN(C(=O)OCc1ccccc1)C2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1c(F)c(N2CCC3(CC3N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
A 346 mg (1.00 mmol) portion of 5-benzyloxycarbonyl-1-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (1-b) was dissolved in 30 ml of ethanol, and the solution was mixed with 350 mg of 10% palladium-carbon and subjected to 4 hours of hydrogenation under atmospheric pressure. After completion of the reaction, 10% palladium-carbon was removed by filtration and ethanol was evaporated. The thus obtained residue was suspended in 10 ml of acetonitrile, and the suspension was mixed with 210 mg (0.67 mmol) of 5-amino-6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.93 ml (6.67 mmol) of triethylamine, and heated under reflux for 18 hours. After evaporation of the solvent, the thus obtained residue was mixed with chloroform, washed with water, 10% citric acid aqueous solution and saturated brine in that order, and then dried over anhydrous sodium sulfate, subsequently evaporating the solvent. The thus obtained tert-butylcarbamate compound was mixed with 5 ml of concentrated hydrochloric acid, stirred at room temperature for 30 minutes, adjusted to pH 7.4 with sodium hydroxide aqueous solution and then extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was recrystallized from ethanol-ether to yield 198 mg (78%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[C:16](=O)([O:22]C(C)(C)C)[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.2 %

Procedure:
To a solution of 4-(4-nitrophenyl)piperidine (412 mg, 2 mmol) in CH2Cl2 (100 mL) was added di-tert-butyl carbonate (480 mg, 2.2 mmol) and N,N-dimethylpyridin-4-amine (50 mg, 0.4 mmol). The mixture was stirred for 20 h at room temperature. The mixture was added saturated NaHCO3 (100 mL). The organic layer was separated and aqueous was extracted with CH2Cl2 (50 mL×2). The combined organic solution was dried and concentrated in vacuo. The residue was dissolved in MeOH and bubbled with Ar for 2 min. before adding 10% Pd—C. The hydrogenation was finished in 4 h. The catalyst was removed by filtration and solvent was removed in vacuo to afford title compound (460 mg, 83%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([P:12](=[O:15])([OH:14])[OH:13])([OH:11])[PH2:9]=[O:10])=[CH:4][CH:3]=1.C([Si](C)(C)[O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][C:33]([F:40])=[N:34][C:35]=3Cl)[CH:25]=[CH:26][CH:27]=1)(C)(C)C.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:40][C:33]1[N:32]=[C:31]2[C:36]([N:37]=[CH:38][N:30]2[CH2:29][CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=2)=[C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([P:12](=[O:13])([OH:14])[OH:15])([OH:11])[PH2:9]=[O:10])=[CH:6][CH:7]=2)[N:34]=1
Reactant: Nc1ccc(C(O)([PH2]=O)P(=O)(O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CCn2cnc3c(Cl)nc(F)nc32)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=[PH2]C(O)(c1ccc(Nc2nc(F)nc3c2ncn3CCc2cccc(O)c2)cc1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
A sealed pressure flask, flushed with N2, containing a mixture of crude [(4-Amino-phenyl)-hydroxy-phosphinoylmethyl]-phosphonic acid (8.29 mmol), 9-{2-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-ethyl}-6-chloro-2-fluoro-9H-purine (3.37 g, 8.29 mmol), and N,N-diisopropylethylamine (7.2 mL, 41.5 mmol) in 45.0 mL DMSO was heated at 110–120° C. for 13 h. Upon removing excess N,N-diisopropylethylamine (N2 flow, slight heat) the slightly brown solution was cooled to ambient temperature and added ˜500 mL of H2O to produce a milky, off-white solution. Further precipitation occurred upon addition of TFA (final pH=1–2), at which time the mixture was heated (100° C. hot plate) and stirred vigorously for ˜20 min, filtered while hot, then washed with acidified H2O (TFA, pH=1–2; 4×20 mL), EtOH (2×20 mL), and Et2O (4×20 mL). Isolation of a second crop from the concentrated filtrate in the same manner as described above, followed by removal of excess solvent (in vacuo) provided 2.47 g of an off-white solid: m/z 506 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:28][C:29]1[S:30][CH:31]=[N:32][N:33]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:18][C:19]([NH:28][C:29]4[S:30][CH:31]=[N:32][N:33]=4)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1nncs1
Reactant: O=C(O)CC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: O=C(CC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1)Nc1nncs1
Yield: 50 %

Procedure:
Example 136 was prepared from 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoic acid (504 mg, 1.4 mmol) and 2-amino-1,3,4-thiadiazole using General Coupling Method A to give 310 mg (50% yield). MS found: (M+H)+=444. Resolution of this compound into its enantiomers could be accomplished using chiral HPLC as described above.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15](Cl)=[N:14][C:13]([NH:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([O:8][CH:9]([CH3:10])[CH3:18])=[N:14][C:13]([NH:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OCc1ccccc1
Solvent: CC(C)O
Product: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OCc1ccccc1

Procedure:
Similar procedure as described in example 10 was used, starting from (6-Benzyloxy-1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-propanol to give (6-benzyloxy-1-isopropoxy-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 419(MH+).
Reaction SMILES: CO[C:3]1[C:4](C)=[C:5](C)[C:6]2[O:11][C:10](CCN3CCNCC3)(C)[CH2:9][CH2:8][C:7]=2[C:21]=1C.O1CCCC1.C([Li])CCC.O>CCCCCC>[O:11]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:21][C:7]=2[CH2:8][CH2:9][CH2:10]1
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCN1CCNCC1)O2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C

Procedure:
A solution composed of 2 g (6.02 mmol) of the 3,4-dihydro-6-methoxy-2-[2-(piperazin-1-yl)ethyl]-2,5,7,8-tetramethyl-2H-benzopyran obtained by the process of Example 12 and 50 ml of tetrahydrofuran was cooled to -40° C. in a nitrogen atmosphere and, to this solution, 4.7 ml of a 15% solution of n-butyllithium in hexane was added gradually. The resultant mixture was stirred at -40° C. for 30 minutes. Then, 6.65 millimoles of the halogenated terpene compound (X') was added gradually thereto, and the resultant mixture was stirred at -40° C. for 30 minutes. After raising the temperature gradually to room temperature, the reaction mixture was poured into water and extracted with diethyl ether. The ether layer was dried over anhydrous sodium sulfate, and low-boiling substances were distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the corresponding 3,4-dihydrobenzopyran derivative. The yield and physical characteristics for each derivative thus obtained are shown in Table 19.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][NH:26]3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:26]1[C:27]2[C:23](=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:31][C:32]4[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=4)[N:3]=3)[CH:30]=[CH:29][CH:28]=2)[CH:24]=[N:25]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc5[nH]ncc45)nc(Cl)nc32)cc1
Reactant: NC(=O)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc5[nH]ncc45)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Temperature: 120 °C
Yield: 11 %

Procedure:
To a mixture of 2-chloro-N-(1H-indazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.12 g, 0.27 mmol) and 4-aminobenzamide (0.055 g, 0.4 mmol) in nBuOH (1 ml) was added TMSCl (0.017 ml, 0.14 mmol). After heating at 120° C. for 24 h, the mixture was purified by preparative HPLC to give 4-(4-(1H-indazol-4-ylamino)-7-tosyl-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (0.016 g).
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].S(OC)(O[CH3:21])(=O)=O.[OH-].[Na+]>>[CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([O:16][CH3:21])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)NCCc1c[nH]c2ccc(O)cc12
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2[nH]cc(CCNC(C)=O)c2c1

Procedure:
To the aqueous alcoholic solution containing N-acetyl serotonine prepared in Example 2, there were added slowly and simultaneously 36 g of dimethyl sulphate and 20 g of 30% sodium hydroxide so that the pH was maintained at 12.5, while ensuring that the temperature did not exceed 40° C. During this operation, a part of the melatonine formed crystallised and this was filtered after neutralisation. The mother-liquor of crystallisation was decolourised with activated carbon, concentrated to eliminate the ethanol, then extracted with dichloromethane. After separation of the aqueous phase, the organic phase was concentrated to dryness which allowed the recuperation of a further 28 g of crude melatonine. The two fractions, which totalled 42 g, were mixed and purified by recrystallisation in a mixture containing water and ethanol in a 75:25 ratio. 30 g of white crystals of melatonine were obtained having a purity of 98.6%.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11](O)(=[O:14])[CH:12]=[CH2:13]>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:11](=[O:14])[CH2:12][CH2:13][C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: C=CC(=O)O
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC(=O)CC2

Procedure:
Prepared analogously to Example G from 1-amino- 5,5-dimethyl-cyclohexen-3-one and acrylic acid at 140° C. for 3 hours.
Reaction SMILES: [O:1]=[C:2]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C@@H:6]1[C:18](O)=[O:19].S(Cl)(Cl)=O.[CH3:37][OH:38]>>[O:1]=[C:2]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:18]([O:38][CH3:37])=[O:19]
Reactant: COc1ccc2nccc(C(=O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)O)c2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: -30 °C

Procedure:
A solution of 19.4 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(t-butyloxycarbonyl)piperidine-3-carboxylic acid (80% content) in 355 cm3 of methanol is cooled to a temperature in the region of −30° C. Thionyl chloride (7.7 cm3)is added with stirring while maintaining the temperature between −25 and −30° C. After the addition, the mixture is maintained in the vicinity of −30° C. for 30 minutes and then the temperature is allowed to return to the vicinity of 20° C. After stirring at ambient temperature for 19 hours, the reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 30° C. The residue is taken up in 300 cm3 of water to which 200 cm3 of dichloromethane have been added, and then stirred. The organic phase is separated by settling; the aqueous phase is again extracted with 200 cm3 of dichloromethane. The aqueous solution is brought to pH 8 by gradual addition of solid sodium hydrogen carbonate. After extracting the alkaline solution 3 times with 200 cm3 of dichloromethane, the combined organic extracts are washed 2 times with 200 cm3 of water and then dried over magnesium sulfate. After filtering through a paper filter, the organic solution is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. to afford 4.51 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][OH:11])[C:5]#[N:6]>ClCCl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])[C:5]#[N:6]
Reactant: N#Cc1ccc(CO)c(F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: N#Cc1ccc(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (6.62 mmol) of 3-fluoro-4-(hydroxymethyl)benzonitrile are dissolved in 50 ml of dichloromethane, and 9.20 g (105.9 mmol) of manganese(IV) oxide are added. The mixture is stirred at room temperature overnight and then filtered through a short kieselguhr column. The solvent is distilled out under reduced pressure, and the residue is purified by column chromatography (silica gel, mobile phase: dichloromethane). 120 mg (12.1% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:10]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH:11]=1)=[O:6].[CH3:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH:37]=3)=[CH:14][CH:13]=2)[CH:11]=1)=[O:6]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=C(NCC(F)(F)F)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NCC(F)(F)F)nc3-c3ccccc3Cl)cc2)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a 50 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 1-(4-Bromo-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (249 mg, 540 μmol), 3-methylsulfonylphenyl boronic acid (130 mg, 650 μmol), PdCl2 dppf (40 mg, 10 mol %), K2CO3 (260 mg, 1.90 mmol), 1,2-dimethoxyethane (14 mL) and H2O (2 mL). The reaction solution was allowed to stir at 75° C. for 2 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4 Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 2% EtOAc to 90% EtOAc to afford 212 mg (74% yield) of the title compound. MS (ES): 534 [M+H]+, 557 [M+Na]+. 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 7.99 (s, 1H), 7.92 (d, 1H), 7.65 (t, 1H), 7.57 (d, 2H), 7.52 (d, 2H), 7.41-7.34 (m, 3H), 7.24 (d, 2H), 4.11 (q, 2H), 3.08 (s, 3H); 19F NMR (400 MHz, CDCl3) 6-72.4 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4]([C:20]1[C:28](O)=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)([CH2:18][OH:19])[C:5](=[O:17])[N:6]2[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4]1([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:28]3[O:19][CH2:18]1)[C:5](=[O:17])[N:6]2[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Cl)ccc(Cl)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
To a solution of 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one (0.69 g, 1.57 mmol) in anhydrous tetrahydrofuran (15.0 mL) was added triphenylphosphine (0.54 g, 2.04 mmol) followed by slow addition of diisopropyl azodicarboxylate (0.41 g, 2.04 mmol) at 0° C. The brown reaction mixture was stirred at ambient temperature for 16 h and quenched with ammonium chloride solution (2.00 mL). The organic solvent was removed in vacuo. The residue was dissolved in ethyl acetate (20.0 mL), washed with 10% aqueous HCl solution (10.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (35%) to give a solid, which was crystallized from ethyl acetate/ether to give the title compound (0.13 g, 20%) as a colorless solid: mp 106-108° C.; 1H NMR (300 MHz, CDCl3) δ 7.24-7.16 (m, 1H), 6.81 (d, 1H), 6.44 (s, 1H), 6.07 (s, 1H), 5.86 (dd, 2H), 4.87 (dd, 2H), 4.12-4.07 (m, 2H), 1.76-1.66 (m, 2H) 1.36-1.31 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.5, 157.0, 149.2, 142.1, 140.0, 132.3, 131.0, 130.2, 124.6, 116.0, 113.8, 102.3, 101.5, 93.3, 77.2, 58.5, 42.1, 29.5, 28.7, 22.3, 14.0; MS (ES+) m/z 420.4 (M+1).