Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([F:16])[C@:13]([CH3:24])([C:17]([O:19]C(C)(C)C)=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([F:16])[C@:13]([CH3:24])([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@]1(C)CN(C(=O)OCc2ccccc2)CC1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(C(=O)O)CN(C(=O)OCc2ccccc2)CC1F
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3S)-1-benzyloxycarbonyl-4-fluoro-3-methylpyrrolidine-3-carboxylate (isomer A) (1.80 g, 5.33 mmol) in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added dropwise and, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and saturated aqueous solution of sodium hydrogencarbonate (30 mL) was added to the concentrate under reduced pressure. The aqueous solution was washed with diethylether (50 mL), and to the aqueous layer was added 1 mol/l hydrochloric acid to pH 2 to 3, and the mixture was extracted with chloroform (200 mL×2). The organic layer was dried with anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The concentrate was azeotropically distilled by adding toluene (20 mL), and dried under reduced pressure to obtain 1.86 g (quantitative) of the title compound (isomer A) as a colorless oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(=[N:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)C1C=CC=CC=1.S([O-])(O)(=O)=O.[K+]>ClCCl>[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH2:21][CH2:20]1
Reactant: O=C(O)c1ccccn1
Reactant: C(=NCC1CCNCC1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: NCC1CCN(C(=O)c2ccccn2)CC1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
N,N'-Carbonyl diimidazole (6.58 g) was added to a suspension of pyridine-2-carboxylic acid (5.0 g) in dichloromethane (75 ml) stirring under nitrogen at ambient temperature. Stirring continued until gas evolution had ceased (~2 hours) then N-benzylidene-1-(4-piperidyl)methylamine (8.2 g) was added and the reaction mixture stirred for 18 hours. The solvent was evaporated to give a viscous yellow oil, which was then stirred with aqueous potassium hydrogen sulphate solution (1 M; 200 ml) for 18 hours. The mixture was washed with dichloromethane (2×250 ml) and adjusted to pH 14 with aqueous sodium hydroxide solution (5 M) then extracted with methane (3×250 ml). The combined extracts were dried over magnesium and the the solvent removed in vacuo to give 4-(aminomethyl)-1-(2-pyridylcarbonyl)piperidine (5.2 g) as a viscous yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:19][C:16]([CH3:18])([CH3:17])[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=3)=[CH:3][C:4]2=[O:22])=[CH:9][C:10]=1[O:20][CH3:21]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(-n2ccc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc(-c3ccc(OC(F)(F)F)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 60 °C
Reaction time: 17 h
Yield: 63.6 %

Procedure:
A mixture of 4-chloro-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one Part D (25 mg, 0.08 mmol), 4-(trifluoromethoxy)phenylboronic acid (28 mg, 0.14 mmol), tribasic potassium phosphate (49 mg, 0.23 mmol), and palladium tetrakis (9 mg, 7.7 μmol) in DMF (0.4 mL) was stirred at 60° C. under nitrogen for 17 hours. The reaction mixture was diluted with CH2Cl2, filtered and concentrated. The crude was purified using preparative HPLC (C18 column/10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA). This material further purified by ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient) to afford the title compound 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(4-(trifluoromethoxy)-phenyl)pyridin-2(1H)-one B-1 (23.2 mg, 0.049 mmol, 63.6% yield) as a light yellow solid. LC/MS 450 (M+H)+, tR 0.95 min (method 5). 1H NMR (500 MHz, chloroform-d) δ 7.65 (2H, d, J=8.88 Hz), 7.43 (1H, d, J=7.49 Hz), 7.34 (2H, d, J=8.05 Hz), 6.97-7.02 (2H, m), 6.93 (1H, dd), 6.85 (1H, s), 6.48 (1H, dd), 3.89 (3H, s), 3.88 (2H, s), 1.37 (6H, s).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.C(COC)OC.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](Br)=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=2)=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 80 °C
Yield: 82.6 %

Procedure:
To a stirring mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (16.45 g, 53 mmol), dimethoxyethane (200 mL) and water (50 mL) was added 1-(benzyloxy)-4-bromobenzene (14 g, 53 mmol), sodium carbonate (16.9 g, 160 mmol) and bis-(triphenylphosphine)palladium(II) chloride (1.867 g, 2.66 mmol) at rt. The reaction mixture was purged with nitrogen for 15 min, then heated at 80° C. for 4 h. The mixture was allowed to cool to rt and then was filtered through Celite and diluted with 200 mL of water. The mixture was then extracted three times with 200 mL of ethyl acetate and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was subjected to silica gel chromatography eluting with 20% ethyl acetate/petroleum ether to obtain 16 g of tert-butyl 4-(4-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (16 g, 82% yield) as an off-white solid. LCMS (method O) RT 1.32 min, m/z 366 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ 1.47 (s, 9H), 2.42 (d, J=1.50 Hz, 2H), 3.52 (t, J=11.40 Hz, 2H), 3.97 (s, 2H), 5.11 (s, 2H), 6.04 (s, 1H), 6.98 (d, J=9.00 Hz, 2H), 7.30-7.46 (m, 7H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.Br[C:24]1[NH:28][CH:27]=[N:26][N:25]=1.C(OCC)C>CO>[N:25]1[N:26]=[C:27]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([NH:16][C:3]3[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=4)[N:4]=3)[CH2:18]2)[NH:28][CH:24]=1
Reactant: Brc1nnc[nH]1
Reactant: O=c1[nH]cccc1Nc1ncc(F)c(N[C@@H]2CCCNC2)n1
Solvent: CCOCC
Solvent: CO
Product: O=c1[nH]cccc1Nc1ncc(F)c(N[C@@H]2CCCN(c3nnc[nH]3)C2)n1
Temperature: 150 °C
Yield: 40.4 %

Procedure:
A mixture of (R)-3-(5-fluoro-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridin-2(1H)-one (Preparation 22c, 50 mg, 0.16 mmol) and 3-bromo-4H-1,2,4-triazole (prepared as described in J. Med. Chem. 2004, 47(19), 4645, 12.2 mg, 0.08 mmol) was stirred and heated overnight at 150° C. The reaction mixture was cooled to ambient temperature and diluted with methanol. Diethyl ether was then added and the precipitate that formed was filtered. The filtrate was concentrated under reduced pressure and the resulting semisolid was suspended in diethyl ether and filtered to yield the title compound (12 mg, 40%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:16][CH3:17])[C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:5][N:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[F:24][C:25]([F:31])([F:30])[CH2:26][C:27](O)=[O:28].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:6]([N:7]([CH2:16][CH3:17])[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:27](=[O:28])[CH2:26][C:25]([F:31])([F:30])[F:24])[CH2:12][CH2:11]2)=[O:9])=[CH:5][N:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: CCN(C(=O)C1CCNCC1)c1cn(-c2cccnc2)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: CCN(C(=O)C1CCN(C(=O)CC(F)(F)F)CC1)c1cn(-c2cccnc2)nc1Cl

Procedure:
In an appropriate reaction vessel, to N-(3-chloro-1-(pyridin-3-yl)-1H -pyrazol-4-yl)-N-ethylpiperidine-4-carboxamide may be added 3,3,3-trifluoropropanoic acid (about 1.0 to about 2.0 eq), DMAP (about 2.0 to about 3.0 eq), and EDCI (about 1.5 to about 3.0 eq) in a solvent, such as CH2Cl2 (at a concentration between about 0.01 M to about 1 M). The reaction may be stirred at a temperature from about 0° C. to about 50° C. until determined to be completed. After completion of the reaction, the product may be obtained using standard organic chemistry techniques for workup and purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:31])([F:30])[F:29])=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[N:15]1[CH:16]=[C:17]([NH:20][C:21]([C:23]2[N:24]=[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:26][C:27]=2[C:28]([F:30])([F:31])[F:29])=[O:22])[CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C2CCNCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (535 mg) from above was dissolved in a mixture of methylene chloride (35 mL) and trifluoroacetic acid (9 mL). The mixture was stirred at room temperature for 2 hrs. The solvents were evaporated and the residues were partitioned between methylene chloride and dilute sodium hydroxide solution. The organic layer was washed with brine and dried over sodium sulfate. Evaporation of solvents gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)-amide (360 mg) as a solid. LC-MS calcd for C21H19F3N4O2 (m/e) 416.1, obsd 417.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([O:22][CH2:23][C:24]([O:26]CC=C)=[O:25])=[O:21])=[C:9]2[CH3:30])=[O:7])=[CH:4][CH:3]=1.N1CCCCC1.Cl>O1CCCC1>[CH3:30][C:9]1[N:8]([C:6]([C:5]2[CH:31]=[CH:32][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:7])[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH3:18])=[CH:12][C:11]=2[C:10]=1[CH2:19][C:20]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21]
Reactant: C=CCOC(=O)COC(=O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Agent: Cl
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
0.003 mole of tetrakis-triphenylphosphine-palladium-(O) is added to 0.03 mole of acemetacin allyl ester in 50 ml of tetrahydrofuran, under nitrogen. 0.3 mole of piperidine is added dropwise at 20°-25° C., with stirring, and stirring is then continued for 2 hours at room temperature (check by thin layer chromatography). 200 ml of half-concentrated hydrochloric acid are added dropwise with cooling, the phases are separated off, the aqueous phase is extracted twice with methylene chloride and the combined organic phases are evaporated in vacuo. The residue is recrystallised from toluene.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].CC1(C)C(C)(C)OB([C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH2:22])O1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]2[C:3](=[C:4]([NH2:5])[N:22]=[C:21]3[C:20]=2[CH:26]=[CH:25][CH:24]=[CH:23]3)[CH:6]=1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: COc1ccc(Br)c(C#N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)c(N)nc1ccccc12
Yield: 68 %

Procedure:
2-Bromo-5-methoxybenzonitrile (1.32 g, 6.23 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.36 g, 6.23 mmol), bis(triphenylphosphine)palladiumdichloride (0.437 g, 0.623 mmol) and potassium phosphate monohydrate (4.30 g, 18.68 mmol) were added to toluene (30 mL) and water (3 mL). The reaction mixture was degassed with bubbled nitrogen gas for 30 minutes before being refluxed under nitrogen for 15 h. After cooling, the reaction mixture was filtered through Celite® and the organic layer was extracted with ethyl acetate. After removal of the solvents, the crude material was triturated with 40 mL of DCM followed by 50 mL of hexanes to give 8-methoxyphenanthridin-6-amine (0.95 g, 68%) as a light yellow solid. The product was confirmed by GC/MS and NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9]N1C(C1C=CC=CC=1)C(O)=O.[CH2:37]([CH2:39][NH2:40])[OH:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:40]1[CH:39]([C:3]1[CH:4]=[CH:5][CH:32]=[CH:33][CH:34]=1)[C:37]([NH:40][CH2:39][CH2:37][OH:38])=[O:38]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCCO
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCO)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with ethanolamine.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:24]([F:27])([F:26])[F:25])=[N:19][C:20]([C:21](=[O:23])[CH3:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:39]>C(OCC)(=O)C>[ClH:39].[C:21]([C:20]1[N:19]=[C:18]([C:24]([F:27])([F:26])[F:25])[N:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=3[F:37])[CH2:13][C:14]=12)(=[O:23])[CH3:22]
Reactant: CC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Yield: 57 %

Procedure:
(R)-[3-(1-Acetyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 27h (0.3 g, 0.55 mmol) was dissolved in 2 mL of ethyl acetate under stirring. A solution of 2.4 N hydrochloric acid in 5 mL of ethyl acetate was then added to the above solution. The reaction mixture was reacted at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-1-(1-acetyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-amino-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 27 (0.15 g, yield 57%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:16]=3[O:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:3]1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:32]=2[C:33]([NH:35][CH2:36][C:37]#[CH:38])=[O:34])[C:27]([Cl:44])=[CH:26][N:25]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][C:20]([NH:22][C:24]4[N:29]=[C:28]([NH:30][C:31]5[C:32]([C:33](=[O:34])[NH:35][CH2:36][C:37]#[CH:38])=[CH:39][CH:40]=[CH:41][C:42]=5[F:43])[C:27]([Cl:44])=[CH:26][N:25]=4)=[CH:21][C:16]=3[O:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:3]1
Reactant: CN1CCCC(OC(=O)N2CCCOc3cc(N)ccc32)C1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC2CCCN(C)C2)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 1-methyl-piperidin-3-yl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1410. Product isolated as an orange foam (107 mg, 54%). LCMS (m/e) 608 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.68-8.42 (m, 1H), 8.10 (s, 1H), 7.46-7.18 (m, 4H), 7.15-6.94 (m, 2H), 6.93-6.78 (m, 1H), 6.56-6.43 (m, 1H), 4.92-4.70 (m, 1H), 4.20-3.97 (m, 4H), 3.85-3.55 (m, 2H), 2.89-2.77 (m, 1H), 2.64-2.48 (m, 1H), 2.37-2.12 (m, 5H), 2.11-1.73 (m, 5H), 1.65-1.40 (m, 1H), 1.30-1.12 (m, 1H); 19F-NMR (CDCl3, 400 MHz) 6-113.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].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>CN(C)C=O.O>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC[C@H](CC3CCCCC3)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a solution of methyl 4-(4-hydroxyphenyl)benzoate (0.94 g), (S)-(−)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-1-propanol (1.00 g) and triphenylphosphine (1.62 g) in N,N-dimethylformamide (20 ml) was added dropwise diisopropyl azodicarboxylate (1.21 ml) for 10 minutes under ice-cooling in a stream of nitrogen. The solution was stirred for 16 hours at ambient temperature, and then water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixed solvent of n-hexane-ethyl acetate (from 0% to 20% gradient elution) to give methyl (S)-4-[4-[2-(tert-butoxycarbonylamino)-3-cyclohexylpropyloxy]phenyl]benzoate (290 mg) as a white solid.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH2:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl.O>CS(C)=O>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[CH2:7]
Reactant: C=C(c1ccccc1O)n1ccnc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=C(c1ccccc1OCc1ccc(Cl)cc1Cl)n1ccnc1
Yield: 93.9 %

Procedure:
To a solution of 500 g (2.69 mol) of 2-[1-(1H-imidazol-1-yl)vinyl]phenol 4 in 3 L of DMSO was added 210 g (3.22 mol) of potassium hydroxide (pellet) with stirring and the mixture was stirred at room temperature for 1 hour. The solution was cooled to 12°-18° C. and there was dropwise added a solution of 577 g (2.95 mol) of 2,4-dichlorobenzyl chloride 9 in 100 ml of DMSO in 1 hour. The mixture was allowed to stand at the same temperature with stirring for 2 hours. To the reaction mixture was dropwise added 4.5 L of water with ice-cooling in 45 minutes. The resulting mixture was stirred for 1 hour, and the precipitating crystals were collected by filtration, washed with water (0.75 L×4) and then with n-hexane (0.7 L×3), and dried in air to give 872 g (yield: 94.1%) of the titled compound 10, m.p., 90.5°-93° C.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10](C(OCC)=O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>C(O)C.O>[C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1C=NN(c2ccccc2)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Yield: 50.8 %

Procedure:
To a mixture of 2,4-dihydro-2-phenyl-4-ethoxycarbonyl-3H-pyrazol-3-one (5.8 g; 25 mmol) in 16 ml of ethanol/water (1:1) 4 g of KOH was added and the resulting mixture was heated at reflux for 4 hours. The mixture was cooled in an ice/bath, conc. HCl solution was added (until pH=1-2), and the resulting mixture was refluxed overnight. The reaction mixture was cooled, concentrated in vacuo, and the residue was dissolved in water. The aqueous layer was extracted with ethyl acetate (2×), the combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residual yellow oil was purified by silica gel column chromatography (25-30% ethyl acetate/hexane) to afford 1.5 g (38%) of 2,4-dihydro-2-phenyl-3H-pyrazol-3-one (Formula III: R1 =Ph; R2 =H; R3 =H) as a solid, m.p. 113°-114° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:19]([F:22])([F:21])[F:20].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:29][CH:30]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:19]([F:22])([F:20])[F:21]
Reactant: Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc(CC(=O)O)cc2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
3-[3-Methyl-8-(trifluoromethyl)quinolin-4-yl]phenol (1.13 g, 3.73 mmol) and 4-bromomethylphenylacetic acid (1.02 g, 4.47 mmol) in CH2Cl2 (60 mL) is treated with Cs2CO3 (4.86 g, 14.9 mmol) and the reaction is stirred overnight. The solvent is removed and the residue dissolved in THF and 2N aq NaOH. After heating at 70° C. for 1 h, the reaction is cooled and the layers separated. The aqueous layer is further extracted with ethyl acetate. The combined organics are dried (Na2SO4) and concentrated. The residue is chromatographed eluting with 20:80 ethyl acetate:hexane and then 5:95 methanol:methylene chloride to afford the title product.