Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[N:4]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[C:37]1([C@H:2]([C@H:3]2[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH2:18][CH2:19][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[CH2:21][CH2:22]4)=[O:16])=[CH:11][CH:10]=3)[NH:4]2)[OH:1])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCN(Cc4ccccn4)CC3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1)N1CCN(Cc2ccccn2)CC1

Procedure:
A solution of 0.038 g (0.067 mmol) of the title compound from Step A above in 1 mL dichloromethane and 1 mL trifluoroacetic acid was stirred at ambient temperature for 1 h. All volatiles were removed in vacuo and the crude light brown residue was purified directly by reverse-phase HPLC to afford the title compound (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). 1H-NMR (500 MHz, CD4O) δ 8.70 (d, J=4.9 Hz, 1H), 7.99-7.98 (m, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.53-7.34 (m, 10H), 4.76 (d, J=8.8 Hz, 1H), 4.51 (s, 2H), 4.10-3.81 (m, 6H), 3.42-3.39 (m, 4H), 3.33-3.08 (m, 2H), 2.10-2.00 (m, 1H), 1.86-1.75 (m, 3H). LC/MS: m/z (ES) 471.3 (MH)+, 493.3 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])=[CH:4][CH:3]=1.[CH2:19]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]([C:14]([N:26]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:16])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])=[CH:17][CH:18]=1
Reactant: CSCC[C@H](NC(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: CCOC(=O)CCCNCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSCC[C@H](NC(=O)c1ccc(Cl)cc1)C(=O)N(CCCC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-L-methionine and ethyl 4-benzylaminobutyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-L-methionyl]-4-benzylaminobutyric acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:3][CH:2]=1.O(C)[Na]>CO>[NH:9]1[CH:10]=[CH:11][N:12]=[C:8]1[CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1
Reactant: c1cc(Cc2ncc[nH]2)ccn1
Agent: CO[Na]
Solvent: CO
Product: c1c[nH]c(CC2CCNCC2)n1
Reaction time: 0.17 h

Procedure:
2-(4-pyridylmethyl)imidazole (4 g, 0.025M) and platinum oxide (0.4 g) in ethanol (40 ml) and 2NHCl (50 ml) was hydrogenated at 45 psig for 4 hrs. The catalyst was removed by filtration and the filtrate was stripped to dryness. Crystallization from ethanol gave 4-(1H-imidazol-2-yl-methyl)piperidine as the dihydrochloride salt m.p. 251°-252° C. (5.2 g, 87% yield). The mixture of 2-(4-pyridylmethyl)-imidazole (2.38 g, 10 mM) and NaOCH3 (10 mM) in methanol (20 ml) was stirred for 10 min. and filtered. The filtrate was stripped to dryness and distilled from about 180° to about 200° C./0.3 mmHg to give the free base of 4-(1H-imidazol-2-yl-methyl)piperidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH3:25][C:26]([SH:29])([CH3:28])[CH3:27]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][S:29][C:26]([CH3:28])([CH3:27])[CH3:25])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Reactant: CC(C)(C)S
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CSC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 15, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and 2-methyl-2-propanethiol.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][N:7]=[N:6][N:5]=1)[CH2:2][CH3:3].N([CH2:12][C@H:13]1[O:17][C:16](=[O:18])[N:15]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([C:26]3[CH2:27][CH2:28][S:29](=[O:33])(=[O:32])[CH2:30][CH:31]=3)=[C:21]([F:34])[CH:20]=2)[CH2:14]1)=[N+]=[N-]>>[O:33]=[S:29]1(=[O:32])[CH2:28][CH:27]=[C:26]([C:22]2[C:23]([F:25])=[CH:24][C:19]([N:15]3[CH2:14][C@H:13]([CH2:12][N:6]4[N:7]=[N:8][C:4]([CH2:1][CH2:2][CH3:3])=[N:5]4)[O:17][C:16]3=[O:18])=[CH:20][C:21]=2[F:34])[CH2:31][CH2:30]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: CCCc1nnn[nH]1
Product: CCCc1nnn(C[C@H]2CN(c3cc(F)c(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)n1

Procedure:
This compound was prepared from 5-propyl-1H-tetrazole (0.187 g, 1.67 mmol) and (5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)oxazolidin-2-one (WO 01/81350 A1) (0.30 g, 0.84 mmol) as described for Example 29. The title compound was obtained as a colourless solid (0.25 g).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2cccnc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cccnc3)CC2)C1

Procedure:
The title compound was prepared as yellow solid using the procedure described in Step E of Example 1 from reductive amination of 4-Hydroxy-4-pyridin-3-yl-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:44])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([O:39]C(C)(C)C)=[O:38])=[O:31])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:37]([C@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:30](=[O:31])[CH2:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:44])([OH:39])=[O:38]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1ccccc1-c1ccccc1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1ccccc1-c1ccccc1OCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A solution of 87 mg (0.14 mmol) (R)-1-[[2′-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-biphenyl-2-yloxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 31 mg (44%) of the title compound as a light brown powder.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][C:15]=1[F:16].[Cl:20][C:21]1[CH:22]=[C:23]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1.Cl>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]([C:17](=[O:19])[CH2:18][C:28]([C:23]2[CH:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[CH:22]=2)([OH:33])[C:29]([F:32])([F:31])[F:30])[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(F)c(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
Lithium diisopropylamide (Aldrich Chemical Company, 2M in tetrahydrofuran/ethylbenzene 10.18 mL, 20.36 mmol) was added to tetrahydrofuran (8 mL) at −78° C. A solution of 1-(3-bromo-4-fluorophenyl)ethanone (4.01 g, 18.47 mmol) in tetrahydrofuran (8 mL) was added dropwise to the mixture. When the addition was complete the mixture was stirred at −78° C. for 30 min. Then a solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (4.50 g, 18.52 mmol) in tetrahydrofuran (8 mL) was added dropwise to the mixture so the temperature of the reaction mixture did not exceed −60° C. After the addition was complete the mixture was stirred at −78° C. for 60 min. The mixture was allowed to warm to 0° C. and then poured into 1N hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (2×100 mL), and the combined extracts were dried and evaporated. Chromatography of the residue on silica gel (eluted with 1:4 ethyl acetate/hexanes) gave the title product as a white solid (3.32 g, 39% yield) melting at 134-135° C. (after crystallization from ethyl acetate/hexanes).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([N+:36]([O-])=O)=[CH:34][CH:33]=[C:32]([C:39]([CH3:41])=[CH2:40])[N:31]=3)[C@H:14]2[CH3:42])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CCO.[Pd]>[NH2:36][C:35]1[C:30]([C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:20]=2[CH2:19][N:15]2[C@@H:14]([CH3:42])[C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:4]=3)[O:17][C:16]2=[O:18])=[N:31][C:32]([CH:39]([CH3:40])[CH3:41])=[CH:33][CH:34]=1
Reactant: C=C(C)c1ccc([N+](=O)[O-])c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1ccc(N)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reaction time: 1.5 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenyl-3-nitropyridin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (example 177) (19.3 mg, 0.0305 mmol) in EtOH (300 μL) was added 10% Pd/C (5 mg). The reaction was placed under a H2 atmosphere (balloon) and stirred vigorously. After 90 minutes, the mixture was loaded on to a PTLC plate and purified (30% EtOAc/hexanes, developed twice), affording (4S,5R)-3-[2-(3-amino-6-isopropylpyridin-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.63 (30% EtOAc/hexanes, developed twice). LCMS=606.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.84 (s, 1H), 7.78 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.69 (s, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.09-7.05 (m, 2H), 5.53-5.52 (m, 1H), 4.92 (d, J=5.5 Hz, 1H), 4.15-4.10 (m, 1H), 3.89-3.78 (m, 1H), 3.48 (s, 2H), 3.00-2.95 (m, 1H), 1.26-1.23 (m, 6H), 0.44 (d, J=5.1 Hz, 3H).
Reaction SMILES: C([N:4]1[CH2:8][CH:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:6]([C:14](OC)=[O:15])[CH2:5]1)C=C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[OH:15][CH2:14][CH:6]1[CH:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:8][NH:4][CH2:5]1
Reactant: C=CCN1CC(C(=O)OC)C(c2ccsc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CNCC1c1ccsc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6.1 g (24.5 mmol) of 1-allyl-3-(SR)-carbomethoxy-4-(RS)-(3-thienyl)pyrrolidine in 50 mL of TMF at 0° C. was added 49 mL (49 mmol) of a 1 M solution of lithium aluminum hydride in THF and the reaction was stirred at rt for 12 h. To the reaction mixture was then added 5 mL of water and 5 mL of 2N NaOH. The reaction mixture was extracted with ethyl acetate and the combined organic fractions were washed with sat'd NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated to give the title compound which was used without further purification. Mass spectrum (ESI) m/e=274 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C@@H](C2C=CC=CC=2)C)[CH2:4][C@@:3]1([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl.C(=O)([O-])O.[Na+].[CH2:29]([O:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C.C(OCC)C>[CH2:29]([O:36][C:37]([N:5]1[CH2:6][CH:2]([OH:1])[C@:3]([CH3:22])([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](c1ccccc1)N1CC(O)[C@](C)(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@]1(C)CN(C(=O)OCc2ccccc2)CC1O
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a solution of tert-butyl (3R)-4-hydroxy-3-methyl-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (2.00 g, 6.55 mmol) in ethanol (10 mL), 1N hydrochloric acid (6.88 mL, 6.88 mmol) was added at room temperature, and the mixture was stirred for 10 minutes. After concentrating the reaction mixture under reduced pressure and dissolving the residue in ethanol (50 mL), 10% palladium-carbon catalyst (200 mg) was added, and the suspension was stirred in an oil bath at 50° C. for 14 hours in hydrogen atmosphere. After filtering the reaction mixture, the filtrate was concentrated, and the diethylether (30 mL) and saturated sodium hydrogencarbonate (30 mL) were added to the residue, and benzyloxycarbonyl chloride (982 μl, 6.88 mmol) was added in an ice bath. The mixture was stirred at room temperature for 3 hours, and the reaction mixture was extracted with ethyl acetate (100 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (20 mL), and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography (hexane : ethyl acetate=2:1→1:2) to obtain 2.00 g (91.1%) of the title compound as a colorless oily substance.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Cl:5][C:6]1[CH:15]=[C:14]([I:16])[C:13]([OH:17])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[Cl:5][C:6]1[CH:15]=[C:14]([I:16])[C:13]([O:17][CH:2]([CH3:4])[CH3:3])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: Oc1c(I)cc(Cl)c2cccnc12
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)Oc1c(I)cc(Cl)c2cccnc12
Reaction time: 16 h
Yield: 93.3 %

Procedure:
2-Bromopropane (0.46 mL, 4.90 mmol) was added into a stirred mixture of the 5-chloro-7-iodo-quinolin-8-ol (1.00 g, 3.27 mmol), K2CO3 (1.86 g, 13.5 mmol) and DMSO (10 mL). After 16 h at RT, saturated NH4Cl (10 mL) was added and the mixture extracted with dichloromethane (10 mL×3). The extracts were combined and concentrated. Diethyl ether (40 mL) was added to the residue and the resulting mixture washed successively with 2 N NaOH, H2O and brine, and dried (Na2SO4). Subsequent column chromatography on silica (ethyl acetate/hexane, 1:1) afforded 5-chloro-7-iodo-8-isopropoxy-quinoline 5 as a solid (1.06 g, 93%). 5: 1H NMR (CDCl3): δ 8.93 (dd, J=1.5 and 4.2, 1 H), 8.52 (dd, J=1.5 and 8.4, 1 H), 7.98 (s, 1 H), 7.53 (dd, J=4.2 and 8.4, 1 H), 5.38 (m, 1 H), 1.43 (d, J=6.0, 6 H). To a stirred mixture of 5-chloro-7-iodo-8-isopropoxy-quinoline 5 (200 mg, 0.58 mmol), phenylboronic acid (77 mg, 0.62 mmol), 2 N Na2CO3 (7.2 mL), EtOH (1.2 mL) and benzene (6 mL) was added, under a blanket of argon, Pd(PPh3)4 (20 mg). The mixture was stirred under reflux for 16 h, cooled and concentrated. This provided, after column chromatography on silica (ethyl acetate/hexane, 1:9), 5-chloro-7-phenyl-8-isopropoxy-quinoline as a yellow solid. To a stirred solution of the 8-isopropoxy-quinoline (0.339 mmol) in dichloromethane (2 mL) at −78° C. was added BCl3 (1.36 mL of a 1 M solution in dichloromethane, 1.36 mmol). After 2 h, the reaction mixture was allowed to warm to RT and stirred for a further 2 h. MeOH (5 mL) was added and the mixture was concentrated to dryness. This process was repeated four times. Further washing of the remaining residue with diethyl ether (2 mL×3) provided K1 in 91% yield. Data in Table 4.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([CH2:19][O:20][CH3:21])[CH:16]=[C:15]([Cl:22])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)[CH:10]=[O:11].CC(=CC)C.Cl[O-:29].[Na+].Cl>C(O)(C)(C)C.O1CCCC1.P([O-])(O)(O)=O.[K+]>[Cl:1][C:2]1[CH:18]=[C:17]([CH2:19][O:20][CH3:21])[CH:16]=[C:15]([Cl:22])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)[C:10]([OH:29])=[O:11]
Reactant: [O-]Cl
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)c(C=O)c2)c(Cl)c1
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)O)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of the title compound of Step C (228 mg, 0.67 mmol) and 2-methyl-2-butene (2M in tetrahydrofuran, 5 ml, 10.0 mmol) in tert-butanol/tetrahydrofuran (1 ml/3 ml) was added slowly a solution of sodium hypochlorite (543 mg, 6.0 mmol) in potassium dihydrogen phosphate aqueous solution (0.6 M, 8 ml). The reaction mixture was stirred for one hour at room temperature. The mixture was acidified with 1N HCl and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with 1N HCl (2×40 ml), brine (40 mL), dried, filtered, and concentrated to afford the title compound (241 mg) as a viscous oil which was used in the next step without further purification. MS (APCI−) Calc: 356.0, found: 355.0 (M−1).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].I[CH2:16][C:17]([NH2:19])=[O:18].O>CN(C=O)C>[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][C:17]([NH2:19])=[O:18])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(O)ccc1N
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCC(N)=O)ccc1N
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a suspension of NaH (299 mg, 7.48 mmol) in DMF (20 ml) at 0° under argon atmosphere was added methyl 2-amino-5-hydroxybenzoate (1.25 g, 7.48 mmol) and 2-iodoacetamide (1.38 g, 7.48 mmol). The mixture was stirred at 0° for 1 hr and at r.t overnight. At 0° water was given to the reaction mixture. The product was extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography using a methylenchloride gradient to obtain the title compound (1.03 g, 64%) as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[N:4][N:5]2[C:10]([Cl:11])=[C:9]([CH:12]([OH:17])[C:13]([O:15][CH3:16])=[O:14])[C:8]([CH3:18])=[N:7][C:6]=12.C(Cl)Cl.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C.C(OCC)(=O)C>[C:9]([O:17][CH:12]([C:9]1[C:8]([CH3:18])=[N:7][C:6]2[N:5]([N:4]=[C:3]([CH3:19])[C:2]=2[Cl:1])[C:10]=1[Cl:11])[C:13]([O:15][CH3:16])=[O:14])([CH3:12])([CH3:10])[CH3:8]
Reactant: COC(=O)C(O)c1c(C)nc2c(Cl)c(C)nn2c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(Cl)c(C)nn2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 181.5 %

Procedure:
To a suspension of methyl 2-(3,7-dichloro-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (80 mg, 0.26 mmol) in tert-butyl acetate (1.5 mL) at room temperature was added CH2Cl2 (1.5 mL) followed by perchloric acid (40 mg, 2.1 mmol). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with ethyl acetate (15 mL). The organic phase was washed with saturated NaHCO3 (2×10 mL), followed by water (1×10 mL) and dried over sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (85 mg, 90%). Used as is in the next step.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[C:10]=1[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][C:26]([O:31][Si](C)(C)C)([C:29]#[N:30])[CH2:25][CH2:24]2)[C:20]([CH2:36][N:37]([CH3:48])[CH:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][CH2:40][CH2:39]2)=[C:19]([CH3:49])[N:18]=1)[CH3:8].O.[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.CCOC(C)=O>[NH2:30][CH2:29][C:26]1([OH:31])[CH2:27][CH2:28][N:23]([C:21]2[C:20]([CH2:36][N:37]([CH3:48])[C@@H:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:41][CH2:40][CH2:39]3)=[C:19]([CH3:49])[N:18]=[C:17]([C:10]3[C:9]([CH2:7][CH3:8])=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:15][CH3:16])[N:22]=2)[CH2:24][CH2:25]1
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)C2CCCc3ccccc32)c(N2CCC(C#N)(O[Si](C)(C)C)CC2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(N2CCC(O)(CN)CC2)n1
Temperature: 0 °C

Procedure:
To a flask containing LAH (132 mg, 3.0 eq., 3.18 mmol) in anhydrous THF (20 mL) is added 1-(2-(2,6-diethyl-phenyl)-6-methyl-5-{[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amino]-methyl}-pyrimidin-4-yl)-4-trimethylsilanyloxy-piperidine-4-carbonitrile 12 (0.63 g, 1.06 mmol) as a solution in THF (5 mL) over 10 min. The reaction is refluxed overnight. Following cooling to 0° C., water (0.132 mL) NaOH (15%, 0.132 mL) and water (0.396 mL) are added successively, followed by addition of EtOAc (100 mL) and MgSO4 (100 mg). The suspension is filtered through celite and the celite bed is washed with 20:1 EtOAc:MeOH (2×100 mL). Concentration affords the title compound as an off-white solid. [mass expected (527.74); mass found (527.27)].
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]=[O:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[C:8](=[O:11])[O:9][CH3:10].C[Si](C)(C)[C:44]([F:47])([F:46])[F:45].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:35]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([OH:30])[C:44]([F:47])([F:46])[F:45])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[C:8](=[O:11])[O:9][CH3:10]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C=O)ccc1OC
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(O)C(F)(F)F)ccc1OC
Temperature: 25 °C

Procedure:
To a solution of methyl [3,5-bis(trifluoromethyl)benzyl]{[5′-formyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 73, 184 mg, 0.31 mmol) in anhydrous tetrahydrofuran at 0° C., 0.5 M trimethyl(trifluoromethyl) silane (2.5 mL, 1.24 mmol) and a catalytic amount of tetrabutylammonium fluoride were added. The reaction was stirred with gradual warming to room temperature. Once the reaction was complete, it was quenched with saturated ammonium chloride solution. The organic was extracted with methylene chloride, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by preparative thin layer chromatography using 1:4 acetone:hexane. 1H NMR (CDCl3, 600 MHz) δ 7.74 (s, 1H), 7.61 (m, 1H), 7.15-7.56 (m, 6H), 6.99 (m, 1H), 4.97 (m, 1H), 4.19-4.38 (m, 4H), 3.61-3.76 (m, 6H). LC-MS (M+Na) 686.9 (4.28 min).