Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[OH:2][CH:3]([CH2:9][C:10]([O:12]C)=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6]>C(O)(CC)(C)C>[CH3:8][O:7][C:5](=[O:6])[CH2:4][C@@H:3]([OH:2])[CH2:9][C:10]([NH2:1])=[O:12]
Reactant: N
Reactant: COC(=O)CC(O)CC(=O)OC
Solvent: CCC(C)(C)O
Product: COC(=O)C[C@@H](O)CC(N)=O
Temperature: 20.5 °C
Reaction time: 18 h

Procedure:
Tert-pentanol (200 ml) was saturated with anhydrous ammonia at ambient pressure. This was cooled to ambient temperature and to this CaLB-T1-AMD enzyme (1.25 g) and dimethyl 3-hydroxyglutarate (25.3 g) were added. The resulting mixture was gently stirred with a magnetic stirrer at ambient temperature (20-21° C.) for 18 h. The enzyme was removed by filtration and washed with tert-pentanol (25 ml). The clear filtrate (200 g) was concentrated under reduced pressure at a maximum temperature of +50° C. to light brown oil. The oil was again dissolved in tert-pentanol (90 ml) and placed in a mechanically stirred 500 ml vessel. To this MTBE (Methyl tert-butyl ether) was slowly added under seeding with methyl (S)-3-hydroxyglutaramate (10 mg). The crystal suspension was cooled in an ice-bath to +5° C. The reaction mass was filtered, washed with MTBE and dried to yield (S)-methyl-3-hydroxyglutaramate.
Reaction SMILES: FC(F)(F)C1C=CC(OCC2C=CC(SC3C=CC(OCC(O)=O)=C(C)C=3)=CC=2)=CC=1.C([O:34][C:35](=[O:66])[CH2:36][O:37][C:38]1[CH:43]=[C:42]([CH3:44])[C:41]([S:45][C:46]2[CH:51]=[CH:50][C:49]([CH2:52][NH:53][C:54]3[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=3)=[CH:48][C:47]=2[CH3:64])=[CH:40][C:39]=1[CH3:65])C>>[CH3:65][C:39]1[CH:40]=[C:41]([S:45][C:46]2[CH:51]=[CH:50][C:49]([CH2:52][NH:53][C:54]3[CH:59]=[CH:58][C:57]([C:60]([F:62])([F:61])[F:63])=[CH:56][CH:55]=3)=[CH:48][C:47]=2[CH3:64])[C:42]([CH3:44])=[CH:43][C:38]=1[O:37][CH2:36][C:35]([OH:66])=[O:34]
Reactant: CCOC(=O)COc1cc(C)c(Sc2ccc(CNc3ccc(C(F)(F)F)cc3)cc2C)cc1C
Agent: Cc1cc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O
Product: Cc1cc(Sc2ccc(CNc3ccc(C(F)(F)F)cc3)cc2C)c(C)cc1OCC(=O)O

Procedure:
The title compound was prepared according to the method described for preparing compound 7, using compound 21.5 as starting material. MS APSI m/e: 474 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 12.86 (1H, brs); 7.33 (2H, d, J=8.6 Hz); 7.21 (1H, s); 7.12 (1H, s); 7.05 (1H, d, J=8.1 Hz); 6.87 (1H, s); 6.85 (1H, t, J=5.6 Hz); 6.65 (2H, d, J=8.6 Hz); 6.62 (1H, d, J=8.1 Hz); 4.72 (2H, s); 4.22 (2H, d, J=5.6 Hz); 2.30 (3H, s); 2.23 (3H, s); 2.11 (3H, s).
Reaction SMILES: [CH3:1][C:2](=[CH2:23])[CH2:3][C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[C:17]([N:22]=2)=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:7]=[C:8]([CH2:10][C:11]([CH3:13])=[CH2:12])[CH:9]=1.[H][H]>[Pd].CO>[CH2:3]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[C:17]([N:22]=2)=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:7]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH:9]=1)[CH:2]([CH3:1])[CH3:23]
Reactant: C=C(C)Cc1cc(CC(=C)C)cc(-c2nc3ncccc3o2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)Cc1cc(CC(C)C)cc(-c2nc3ncccc3o2)c1

Procedure:
The product from Step B (3 mmoles) is hydrogenated in 25 ml. of methanol in the presence of 500 mg. of 5% palladium on carbon under 3 atmospheres of hydrogen. The catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue is recrystallized from n-hexane to give 2-[3,5-di(isobutyl)phenyl]oxazolo[4,5-b]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH2:11])=[O:26]
Reactant: C=C(CSc1ccccc1Cl)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C=C(CS(=O)c1ccccc1Cl)c1ccccc1
Temperature: 0 °C
Yield: 60.2 %

Procedure:
1-[2'-Chlorophenylthio]-2-phenyl-2-propene (1.56 g, 0.006 mole) is dissolved in methylene chloride (50 cc) and cooled to 0° C. 55% strength mCPBA (1.9 g, 0.006 mole) in solution in methylene chloride (15 cc) is added dropwise over 30 min. After 1 hour at 0° C. the solution is washed with saturated sodium bicarbonate (75 cc), brine (2×75 cc) and is dried over MgSO4. The crude (1.6 g) is chromatographed on silica to give 1-[2'-chlorophenylsulphinyl]-2-phenyl-2-propene (1.0 g, 60%) in the form of an oil. nD25 =1.6250.
Reaction SMILES: O[C:2]1([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:13][C@@H:14]1[CH2:18]OS(=O)(=O)[N:15]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN(C)C=O>[CH3:13][C@@H:14]([NH:15][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:18][N:5]1[CH2:6][CH:7]=[C:2]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:4]1
Reactant: OC1(c2cccs2)CCNCC1
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Solvent: CN(C)C=O
Product: C[C@H](CN1CC=C(c2cccs2)CC1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A mixture of 4-hydroxy-4-thiophen-2-yl-piperidine (3.3 g, 18 mmol) and (R)-4-methyl-3-(pyrid-2-yl)-[1,2,3]-oxathiazolidine-2,2-dioxide (3.7 g, 17.5 mmol) was stirred in dimethylformamide (70 ml) at ambient temperature for 40 minutes, then evaporated to dryness in vacuo and the residue dissolved in tetrahydrofuran (30 m) and water (10 ml). Concentrated sulfuric acid (2.9 g) was dropwise added while maintaining room temperature. Thereafter sodium hydrogencarbonate (6.7 g) were added in a portion wise fashion and the resulting suspension stirred at ambient temperature overnight. Water (100 ml) and ethylacetate (100 ml) were added to the reaction mixture and the pH adjusted to 10 with the addition of 0.5N NaOH. The product was extracted with ethylacetate (3×100 ml) and the combined organic layer washed with brine (150 ml), dried over magnesium sulfate, filtered, and evaporated to dryness. The obtained residue was dissolved in acetic acid (300 ml) and heated to 140° C. bath temperature for 3 hours. After cooling to room temperature the mixture was evaporated in vacuo and the residue partitioned between chloroform and 5% aqueous sodium hydrogencarbonate. The organic layer was separated, dried over magnesium sulfate, filtered, and evaporated in vacuo. Column chromatography on 120 g of silica gel with 2% methanol/ethylacetate as eluant, followed by trituration in ether with the addition of two molequivalent of fumaric acid gave 4.2 g of the title compound as the fumarate salt hemihydrate, m.p. 63°-8° C.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:16]([C:19]1[CH:23]=[C:22]([NH2:24])[O:21][N:20]=1)([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.Cl>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](=[O:12])[NH:24][C:22]1[O:21][N:20]=[C:19]([CH:16]([CH3:18])[CH3:17])[CH:23]=1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)c1cc(N)on1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)c1cc(NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)on1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of Boc-L-proline (150 mg, 0.697 mmol), 3-isopropylisoxazol-5-amine (88 mg, 0.697 mmol) and HBTU (264 mg, 0.697 mmol) in DMF (7 mL) was added 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) (201 μl, 0.697 mmol) and the reaction mixture was stirred at RT under nitrogen for 48 h. The mixture was poured into HCl 1N and extracted three times with EtOAc. The combined organic layers were washed with an aqueous saturated solution of NaHCO3, with water, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 7-3) to give the title compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.6; MS (LC-MS): 324.1 [M+H]+, 346.1 [M+Na]+, 669.2 [2M+Na]+, 322.1 [M−H]−; tR (HPLC conditions a): 3.42 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[NH2:12].[CH3:13][O:14][CH2:15][C:16](OC)=[O:17]>COC(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C@H:7]2[NH:12][C:16](=[O:17])[CH2:15][O:14][CH3:13]
Reactant: COCC(=O)OC
Reactant: NC1CCOc2c(F)cccc21
Solvent: COC(C)(C)C
Product: COCC(=O)N[C@@H]1CCOc2c(F)cccc21
Yield: 16 %

Procedure:
A mixture of 8-fluorochroman-4-amine (3.40 g), methyl 2-methoxyacetate (2.44 g) and Novozyme 435 (Aldrich, 0.68 g) in anhydrous tert-butyl methyl ether (75 mL) was heated at reflux under argon for two hours (at which time the ratio of acylated to unacylated product was 1:1 by HPLC). The solid that formed upon cooling was collected via filtration and dissolved in EtOAc. The mixture was filtered to remove the biocatalyst and washed once with 0.5M HCl to remove any lingering (S)-amine. The solvent was evaporated and the product was recrystallized from tert-butyl methyl ether to yield (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.78 g). The reaction solvent and recrystallization mother liquor was washed three times with 0.5 M HCl and concentrated to yield additional (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.83 g). The combined acidic aqueous layers were made basic by NaOH and extracted with methylene chloride to yield (S)-8-fluorochroman-4-amine (5a) (1.6 g). A solution of (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.78 g) in 8M HCl in EtOH (50 mL) was heated at reflux for four hours. The solvents were removed from the cooled reaction mixture, the resulting solid was taken up in 50 mL of 0.5M NaOH, salted out with NaCl(s), and extracted four times with methylene chloride to yield (R)-8-fluorochroman-4-amine (0.48 g (87%)) (5b). The % ee was checked via chiral HPLC: Chiralcel OD-H (0.46×25 cm analytical column, Daicel Chemical Industries) method: isocratic 5% (0.05% TFA/EtOH) 95% (0.05% TFA/Hex), Rt=7.2 min (S)-enantiomer, Rt=9.2 min (R)-enantiomer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH3:11][N:12]1[CH2:16][CH2:15][C@H:14](O)[CH2:13]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:7]=1)[O:8][C@H:14]1[CH2:15][CH2:16][N:12]([CH3:11])[CH2:13]1
Reactant: COc1ccc(Br)cc1O
Reactant: CN1CC[C@H](O)C1
Product: COc1ccc(Br)cc1O[C@H]1CCN(C)C1
Yield: 30.5 %

Procedure:
The title compound was prepared by the method outlined for Preparative Example 63 using 5-bromo-2-methoxy-phenol (1.00 g, 4.93 mmol) and (S)-1-methyl-pyrrolidin-3-ol (593 mg, 5.86 mmol) to afford titled compound as a colorless solid (430 mg, 30%). LC/MS (Method B) 1.17 min, [M+1]+ 286/288.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S([O-])([O-])(=O)=O.[Mg+2].O>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH2:2]1[CH2:1][O:11][C:4]2([CH2:9][C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:18][C:7]=3[CH2:6][CH2:5]2)[O:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: NNc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: ClCCl
Product: c1ccc2c3c([nH]c2c1)CCC1(C3)OCCO1
Reaction time: 0.5 h

Procedure:
77.2 g (0.5 mol) of 1,4-cyclohexanedione monoethylene ketal are dissolved together with 48.4 ml (0.5 mol) of phenylhydrazine in 2 l of methylene chloride, and 300 g of magnesium sulphate are added, and the mixture is stirred for 30 min. The magnesium sulphate is then filtered off with suction, washed with methylene chloride, and the filtrate is evaporated. The residue is taken up in 1.5 l of benzene, and 62.1 g (0.46 mol) of anhydrous zinc chloride are added and the mixture is heated under reflux with a water separator for 3 h. The reaction solution is then concentrated, 2N sodium hydroxide solution is added, and the mixture is extracted 3 times with ethyl acetate. The combined ethyl acetate phases are dried with sodium sulphate and evaporated. The residue crystallizes from a little ether. In this way 3.5 g (72.9% of theory) of the product are obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:32])[C:19]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=3)([OH:24])[C:20]([F:23])([F:22])[F:21])=[C:14]([Cl:33])[CH:13]=2)=[N:9][CH:10]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[Cl:33][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[CH:18]([CH3:32])[C:19]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=1)([OH:24])[C:20]([F:23])([F:21])[F:22])[O:11][C:8]1[N:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=1
Reactant: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1ccc(Oc2ncc(C(=O)O)cn2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.4 %

Procedure:
2-{3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-pyrimidine-5-carboxylic acid methyl ester (27 mg) was dissolved in THF/methanol=5/1 (2.5 mL). The reaction mixture was cooled to 0° C. and aqueous LiOH solution (1.0 M, 0.092 mL) was added. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was poured into ice/water and acidified with 1M aqueous HCl to pH 1. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate:heptane=50:50 to 100:0) to give the title compound as a colorless amorphous foam (2.2 mg, 8.4%). MS (neg. ion, m/e)=486.4 [(M−H)−].
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34]O)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[C:8]([CH3:14])[CH:9]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)CC1
Reactant: Cc1cc(O)ccc1C1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 4-cyclohexyl-3-methyl-phenol (65 mg, 0.34 mmol, 1 eq.), 4-(4-Hydroxymethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.34 mmol, 1 eq.) and PPh3 (134 mg, 0.51 mmol, 1.5 eq.) in dry DCM (3 mL) is added 1,1′-(azodicarbonyl)-dipipperidine (129 mg, 0.51 mmol, 1.5 eq.) in DCM (1 mL). The mixture is stirred at room temperature for 12 hours. After concentration, the residue is purified by silica gel chromatography (10% EtOAc in hexanes) to give 4-[4-(4-cyclohexyl-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:29]=[CH:30][C:31]([O:37][CH3:38])=[C:32](B(O)O)[CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23]([C:30]3[CH:29]=[C:28]([F:27])[CH:33]=[CH:32][C:31]=3[O:37][CH3:38])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1ccc(F)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Temperature: 110 °C
Yield: 52.5 %

Procedure:
To a stirred mixture of 4-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (VIII) (0.60 g, 1.6 mmol) and 5-fluoro-2-methoxy-phenylboronic acid (0.300 g, 1.76 mmol) in saturated sodium carbonate solution (5 ml) and 1,4-dioxane (5 ml) was added palladium(II) acetate (0.072 g, 0.32 mmol) followed by triphenylphosphine (0.084 g, 0.32 mmol) at room temperature under an atmosphere of nitrogen. The resulting mixture was heated to reflux at 110° C. for one hour and the reaction monitored by TLC. The reaction mixture was filtered through a celite bed and the filtrate was extracted with ethyl acetate (3×100 ml). The organic layers were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, elution with 50% ethyl acetate/n-hexanes) to afford 4-[6-(5-fluoro-2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXI) (0.39 g, 52%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]([OH:37])[C:27]2([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]2)[CH:22]=[CH:23][C:24]=1[Cl:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C>[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([CH:26]([OH:37])[C:27]2([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:29][CH2:28]2)=[CH:20][C:19]=1[NH:18][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H]([C@H](C(=O)Nc1cc(C(O)C2(C(=O)OC(C)(C)C)CC2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F

Procedure:
A solution of 2.65 g (9.92 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 1.97 g (6.62 mmol) of tert-butyl 1-[(3-amino-4-chlorophenyl)(hydroxy)methyl]cyclopropane-carboxylate and 3.27 g (8.60 mmol) of 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) in 5 ml of pyridine and 10 ml of DMF was stirred at room temperature for three days. 100 ml of ethyl acetate were then added to the mixture, and the solution obtained was washed with 1 M hydrochloric acid and saturated sodium chloride solution. The solution was dried over magnesium sulphate and then filtered, and the filtrate was evaporated to dryness. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→40:1→30:1). The product obtained in this manner was taken up in 100 ml of ethyl acetate, and the solution was extracted three times with saturated sodium bicarbonate solution. The organic phase was washed once more with saturated sodium chloride solution, then dried over magnesium sulphate and finally concentrated to dryness under reduced pressure. This gave 2.75 g of the target compound (76% of theory).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][CH3:13])=[O:11])=[C:8]([F:16])[CH:7]=1.Cl[Sn]Cl>Cl>[NH:5]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][CH3:13])=[O:11])=[C:8]([F:16])[CH:7]=1)[NH2:1]
Reactant: CNC(=O)c1ccc(N)cc1F
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: CNC(=O)c1ccc(NN)cc1F
Reaction time: 0.5 h

Procedure:
2.5M Solution of NaNO2 (2.38 ml) was added dropwise to a solution of 4-amino-N-methyl-2-fluorobenzamide (1 g, 5.95 mmol) in B 5N HCl (3.1 ml), so that the temperature of the reaction mixture did not exceed 5° C. The mixture was stirred for additional 30 min at the same temperature, after that the prepared solution was added drop by drop to a suspension of SnCl2*2H2O (4.03 g, 17.9 mmol) in HCl (4.2 ml) at 0° C., and stirring was continued for 2 h at the same temperature. Precipitated solid was filtered off, dissolved in water (40 ml) and NaOH was added to strongly basic reaction. The mixture was extracted with ether (3*100 ml), dried over MgSO4 and evaporated in vacuo. It gave 4-hydrazino-N-methyl-2-fluorobenzamide 7 (R1=CH3). LCMS (M+H)+ 184. 1H NMR (CDCl3, 400 MHz): 7.96 (t, J=8.4 Hz, 1H), 6.64 (br. m, 1H), 6.60 (t, J=1.6 Hz, 1H), 6.57 (dd, J1=7.2 Hz, J2=2.0 Hz, 1H), 5.60 (br. s, 1H), 3.66 (br. s, 2H), 3.00 (dd, J1=4.8 Hz, J2=1.2 Hz, 1H). The solution of 4-isocyanato-2-(trifluoromethyl)benzonitrile (59 mg, 0.27 mmol) 3.1 in dioxane (2 ml) was added to a solution of 4-hydrazino-N-methyl-2-fluorobenzamide (54 mg, 0.29 mmol) 7 in dioxane (3 ml), and the resultant mixture was stirred for 2 h. Then dioxane was distilled in vacuo, the residue was crumbled with ether, filtered off and dried in vacuo. It gave 2-[(4-methylcarbamoyl)-3-fluorophenyl]-N-[3-(trifluoromethyl)-4-cyanophenyl]-hydrazine carboxamide 8(1) (R1=CH3). LCMS (M+H)+ 405. 1H NMR (DMSO-d6, 400 MHz): 9.65 (br. s, 1H), 8.72 (br. s, 1H), 8.37 (s, 1H), 8.25 (br. s, 1H), 8.03 (br. m, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.58 (m, 2H), 6.63 (d, J=8.4 Hz, 1H), 6.48 (d, J=14.0 Hz, 1H), 2.77 (d, J=4.4 Hz, 3H). Triethylamine (56 mkl, 0.4 mmol) and diphosgene (27 mkl, 0.22 mmol) were added one after another to 2-[(4-methylcarbamoyl)-3-fluorophenyl]-N-[3-(trifluoromethyl)-4-cyanophenyl]-hydrazine carboxamide (80 mg, 0.2 mmol) 8(1) in dichloroethane (2 ml). The reaction mixture was stirred in a closed vial at 80° C. for 15 h. The solvent was evaporated in vacuo and the residue was subjected to chromatography on SiO2 (eluent—CH2Cl2:MeOH, gradient from 100:1 till 20:1). It gave N-methyl-2-fluoro-4-[4-[3-(trifluoromethyl)-4-cyanophenyl]-3,5-dioxo-1,2,4-triazolidin-1-yl]benzamide 1.4 (R1=CH3). Ki1.4=55.2 nM, LCMS (M+H)+ 422. 1H NMR (DMSO-d6, 400 MHz): 11.53 (s, 1H), 8.22 (br. m, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.99 (dd, J1=8.8 Hz, J2=1.6 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.81 (t, J=8.4 Hz, 1H), 7.69 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.62 (dd, J1=12.0 Hz, J2=2.0 Hz, 1H), 2.79 (d, J=4.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH:5]([NH:12][C:13]1[C:14]([N+:28]([O-])=O)=[C:15]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.NN.[CH2:35](O)C>[Ni]>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH:5]([N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]3)[C:14]=2[N:28]=[CH:35]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCO
Reactant: COC(=O)CC(Nc1cccc(N2CCC(C(=O)O)CC2)c1[N+](=O)[O-])c1ccccc1
Agent: [Ni]
Agent: NN
Solvent: O
Product: COC(=O)CC(c1ccccc1)n1cnc2c(N3CCC(C(=O)O)CC3)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-{3-[(3-methoxy-3-oxo-1-phenylpropyl)amino]-2-nitrophenyl}-4-piperidinecarboxylic acid (696 mg, 1.63 mmol) in ethanol (5 mL) was added Raney-Nickel (catalytic, ca. 5 mg) and hydrazine hydrate (316 μL, 6.52 mmol). The solution was stirred at room temperature for 3 hours, filtered, and evaporated in vacuo. The residue (560 mg) was dissolved in triethylorthoformate (5 mL), and heated at 60° C. for 0.5 hour. The resulting solution was cooled to room temperature, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (92:8) to afford the title compound, 1H NMR: (CD3OD) 8.27 (s, 1H), 7.34-7.28 (m, 5H), 7.10 (t, J=8.06, 1H), 6.99 (br d, J=8.06, 1H), 6.68 (d, J=8.06, 1H), 6.08 (dd, J=9.16, 6.22, 1H), 3.95-3.91 (m, 2H), 3.59 (obs dd, J=16.11, 9.16, 1H), 3.59 (s, 3H), 3.45 (dd, J=16.11, 6.22, 1H), 2.86-2.80 (m, 2H), 2.47-2.43 (m, 1H), 2.06-1.98 (m, 4H).
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.B(F)(F)F.CCOCC>>[NH2:9][C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=[C:11]2[CH2:12][CH2:13][CH2:14][C:10]=12
Reactant: O=C1CCCC1
Reactant: N#Cc1ccccc1N
Agent: FB(F)F
Solvent: CCOCC
Product: Nc1c2c(nc3ccccc13)CCC2

Procedure:
Anthranilonitrile (5.0 g, 42.3 mmol), cyclopentanone (4.1 g, 46.7 mmol), boron trifluoride diethyl etherate (1M, 10 ml, 81.8mmol) were treated according to the general procedure to give the title compound.