Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([F:26])=[C:13]([C:15]2[NH:24][C:23](=O)[C:22]3[C:17](=[N:18][CH:19]=[CH:20][N:21]=3)[N:16]=2)[CH:14]=1.[NH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([F:26])=[C:13]([C:15]2[N:24]=[C:23]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:22]3[C:17](=[N:18][CH:19]=[CH:20][N:21]=3)[N:16]=2)[CH:14]=1
Reactant: Nc1ccncc1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(Br)cc1-c1nc(Nc2ccncc2)c2nccnc2n1
Reaction time: 12 h
Yield: 32.9 %

Procedure:
Triethylamine (1.04 mL, 7.17 mmol) was added to a solution of 2-(5-bromo-2-fluoro-phenyl)pteridin-4-one 104 (800 mg, 2.49 mmol), 4-aminopyridine (469 mg, 4.98 mmol) and PyBOP (2.59 g, 4.98 mmol) in CH2Cl2. After 12 h, the reaction mixture was partitioned between CH2Cl2/Petroleum ether (2:1, 300 mL) and ice-cold 1N HCl (300 mL). The pH of the water phase was adjust to 12 with conc. NaOH and extracted with AcOEt, dried (Na2SO4) and evaporated. The residue was triturated in CH2Cl2/Petroleum ether (2:1, 15 mL), filtered off, and washed with ether. The product was purified by column chromatography (AcOEt/CH2Cl2/MeOH, 5:4:1) to give 325 mg of the title product 1 as a yellow powder (LCMS analysis).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[S:5][CH:6]=1.CO.[Br:22]N1C(=O)CCC1=O>[Pd].C(OCC)(=O)C>[Br:22][C:6]1[S:5][C:4]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1Br
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To Compound 1062 (1.67 g, 5.98 mmol) in a solution of methanol and ethyl acetate (40 mL, 1:1) was added palladium on carbon (1 g, 10%, Degussa type). The reaction was shaken under hydrogen atmosphere at 45 psi on a Parr apparatus for 1 hour, filtered through diatomaceous earth, and concentrated under reduced pressure. The resulting material was dissolved in acetonitrile (30 mL) and treated with N-bromosuccinimide (1.14 g, 6.4 mmol). The reaction mixture was stirred for 30 minutes at room temperature and quenched with a saturated solution of sodium sulfite. The crude product was extracted with EtOAc (2×30 mL) and the combined organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified via silica gel chromatography to provide 1.26 g of tert-butyl 4-(5-bromo-4-methylthiophen-2-yl)piperidine-1-carboxylate Compound 1063) as a pale yellow solid; 1H NMR (300 MHz, CDCl3): δ 6.42 (s, H), 4.20-4.01 (m, 2H), 2.77-2.68 (m, 3H), 2.05 (s, 3H), 1.84 (d, J=12.3 Hz, 2H) and 1.50-1.39 (m, 11H).
Reaction SMILES: [CH:1]#C.[C:3]([O:7][K])([CH3:6])([CH3:5])[CH3:4].[C:9]1(=[CH:14][CH2:15]CC(=O)C)[CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:9]1(=[CH:14][CH2:15][CH2:4][C:3]([CH3:6])([OH:7])[C:5]#[CH:1])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)O[K]
Reactant: C#C
Reactant: CC(=O)CCC=C1CCCC1
Product: C#CC(C)(O)CCC=C1CCCC1
Temperature: 25 °C
Yield: 81 %

Procedure:
Acetylene was bubbled for 50 minutes through a solution of tBuOK (33.8 g; 0.30 mol) in TBF (240 ml) at 0° C. The resulting beige suspension was treated with 5-cyclopentylidenepentan-2-one (41.7 g; 0.27 mol) added dropwise for 15 minutes at 0° C. The resulting mixture was warmed gently to room temperature and quenched with saturated NH4Cl (180 ml). The aqueous phase was separated and extracted with MTBE (2×120 ml). The combined organic layers were washed with H2O (240 ml), brine (100 ml), dried over MgSO4, and concentrated in vacuo. Distillation (69° C.-71° C./0.09 torr) afforded 38.95 g (81% yield) of 6-cyclopentylidene-3-methylhex-1-yn-3-ol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CC)CC)C>O1CCCC1.O>[CH2:26]([O:25][C:23]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Yield: 635.3 %

Procedure:
To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (5.00 g, 1.68 mmol) in tetrahydrofuran (150 ml) was added ethyl chloroformate (1.82 g, 16.8 mmol) and triethylamine (1.70 g, 16.8 mmol) and the mixture was stirred under reflux for 2 hr. After cooling, the reaction mixture was diluted with water, then extracted with ethyl acetate. The extracts were washed with 1N-HCl and water, dried, then evaporated under reduced pressure to a residue, which was chromatographed to afford 2-ethoxycarbonylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl) thiazole (3.954 g, 64% yield): NMR(CDCl3)δ1.31(t, 3H), 1.60(t, 3H), 4.25(m, 3H), 6.58(s, 1H), 6.95-7.58(m, 8H) ppm; IR(nujol) 3280, 1720, 1290, 1230, 1080 cm-1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]#[N:14])[C@@H:2]1[O:4][CH2:3]1.[CH3:15][C:16]([NH2:27])([CH3:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[ClH:12].[OH:4][C@@H:2]([CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]#[N:14])[CH2:3][NH:27][C:16]([CH3:26])([CH3:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: N#Cc1c(Cl)cccc1OC[C@H]1CO1
Product: COc1ccc(CC(C)(C)NC[C@@H](O)COc2cccc(Cl)c2C#N)cc1
Product: Cl
Yield: 80.2 %

Procedure:
Using the method of Example 6, supra, (R)-3-chloro-2-cyanophenyl glycidyl ether (0.7 g, 3.34 mmol) and 1,1-dimethyl-(4-methoxyphenyl)ethylamine (0.72 g, 4.0 mmol) were used to prepare 570 mg of the title compound as a white solid: 1H-NMR (CDCl3) 9.65 (1H, br s), 8.2 (1H, br s), 7.4 (1H, t), 7.15 (2H, d), 7.03 (1H, d), 6.95 (1H, d), 6.8 (2H, d), 4.8 (1H, m), 4.3 (2H, d), 3.75 (3H, s), 3.4 (2H, m), 3.13 (2H, dd), 1.44 (3H, s), 1.40 (3H, s); 13C-NMR 161.9, 159.4, 138.2, 135.1, 132.4, 126.8, 122.8, 114.4, 114.2, 111.6, 104.0, 71.8, 66.0, 61.9, 55.8, 45.4, 43.9, 23.5, 23.3.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[C:32](O)(=[O:35])[CH2:33][CH3:34]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:28][CH2:27]2)[N:10]=1
Reactant: CCC(=O)O
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 20 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and propionic acid (Aldrich), to give 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-propan-1-one. HRMS, observed: 384.2034; Calcd for (M+H)+: 384.2030.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[CH2:34]([C:36]1[S:40][C:39]([NH2:41])=[N:38][N:37]=1)[CH3:35]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:41][C:39]2[S:40][C:36]([CH2:34][CH3:35])=[N:37][N:38]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCc1nnc(N)s1
Product: CCc1nnc(NC(=O)[C@@H]2CC(=NOC)CN2C(=O)c2ccc(-c3ccccc3)cc2)s1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 5-ethyl-1,3,4-thiadiazol-2-amine the title compound was obtained in 89% purity by LC/MS. MS(ESI+): m/z=450.2.
Reaction SMILES: C1(C2C=CC(C(=O)C[Cl:13])=CC=2)C=CC=CC=1.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[CH2:20][Mg:21]Cl>CCOCC>[Mg:21].[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[CH2:20][Cl:13]
Reactant: Cl[Mg]Cc1ccc(Cl)cc1Cl
Reactant: O=C(CCl)c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: ClCc1ccc(Cl)cc1Cl
Product: [Mg]

Procedure:
69.3 g (0.3 mol) of 4-phenylphenacyl chloride are added in portions to a solution of 0.6 mol of 2,4-dichlorobenzyl-magnesium chloride, obtained from 15.9 g (0.65 mol) of magnesium and 117.3 g (0.6 mol) of 2,4-dichlorobenzyl chloride in 300 ml of ether. The reaction mixture is then poured onto aqueous ammonium chloride solution and the ether phase is seperated off, washed with water, dried over sodium sulphate and evaporated. The oil which remains is extracted with petroleum ether and the petroleum ether solution is evaporated. The crystals are filtered off and dried. 62 g (53% of theory) of 2-(4-biphenylyl)-3-chloro-1-(2,4-dichlorophenyl)-propan-2-ol of melting point 84° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[CH:4]=[C:3]1[C:10]([OH:12])=[O:11].[H][H].[C:15](=O)([O-])[O-:16].[Na+].[Na+]>[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][CH:15]=[O:16])[CH:4]=[C:3]1[C:10]([OH:12])=[O:11]
Reactant: [H][H]
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Product: Cn1cc(NC=O)cc1C(=O)O
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
1-methyl-4-nitro-2-pyrrolecarboxylic acid (III) (1.0 g, 6.0 mmol) is dissolved in 20 mL of a 1 M sodium carbonate aqueous solution and hydrogenated in presence of 250 mg of 10% Pd/C catalyst. When the uptake of hydrogen has stopped, the catalyst is removed by filtration and the resulting yellow solution, containing the aminoacid (VI), is slowly added to a freshly prepared benzene solution of N-formylimidazole with vigorous stirring. After the addition, the resulting two layers are stirred for additional 15 min and then the organic layer is separated and discarded. The aqueous yellow solution, cooled to 0-5° C., is carefully acidified with formic acid (pH 3.5) with vigorous stirring. The precipitated acid (V) is filtered off and washed with small portions of ice-cold water. There are obtained 0.81 g (yield 80%) of product (V): m.p. 208-210° C.; NMR (DMSO-d6), ppm: 3.85 (s, 3H); 6.75 (d, 1H); 7.35 (d, 1H); 8.15 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C@H:17]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH3:18])=[CH:13][C:12]=2[C:32]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3C2CCCCO2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O.F[C:56](F)(F)[S:57](O)(=[O:59])=[O:58].CS(Cl)(=O)=O>C(Cl)Cl.O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:12]([C:32]3[N:40]=[C:39]([CH3:41])[N:38]=[C:37]4[C:33]=3[N:34]=[CH:35][NH:36]4)=[CH:13][C:14]([C@H:17]([N:19]3[CH2:24][CH2:23][N:22]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:21][CH2:20]3)[CH3:18])=[CH:15][N:16]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COc1ncc(Nc2ncc([C@@H](C)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cc1F
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc([C@@H](C)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc3[nH]cnc23)cc1F
Reaction time: 1 h
Yield: 2.66 %

Procedure:
A mixture of tert-butyl 4-((1R)-1-(6-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (0.450 g, 0.695 mmol) and trifluoroacetic acid (0.803 mL, 10.42 mmol) in DCM (25 mL) was treated with trifluoromethanesulfonic acid (0.01 mL) and allowed to stir under inert atmosphere for 1 h. The mixture was concentrated in vacuo. The residue was diluted with DCM (10 mL), then sodium carbonate (2.50 g) was added to the mixture and allowed to stir 10 min. Then methanesulfonyl chloride (0.271 mL, 3.47 mmol) was added slowly via syringe into the mixture. The mixture was allowed to stir under inert atmosphere overnight. The mixture was diluted with dichloromethane (20 mL), water (20 mL) and brine solution (10 mL). The organic layer was extracted with dichloromethane (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 10 micron, C18(2), 100 Å, 250×50 mm, (Varian, 5-70% acetonitrile in water with trifluoroacetic acid additive 0.1% v/v in each solvent) and then further purified by normal phase silica-gel chromatography on an Interchim puriflash (25 g) column eluting with 10% methanol in dichloromethane to give N-(5-fluoro-6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((R)-1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-amine (0.010 g, 0.018 mmol, 2.66% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ 12.69 (s, 1H) 9.77 (d, J=1.96 Hz, 1H) 8.39 (dd, J=12.52, 2.15 Hz, 1H) 8.32 (d, J=2.15 Hz, 1H) 8.21 (s, 1H) 8.11 (d, J=2.15 Hz, 1H) 4.04 (s, 3H) 3.67-3.73 (m, 1H) 3.26 (t, J=4.69 Hz, 4H) 2.94 (s, 3H) 2.77 (s, 3H) 2.62-2.71 (m, 4H) 1.51 (d, J=6.65 Hz, 3H). m/z (ESI, +ve ion) 542.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:7]=1[CH2:8][N:9]([CH3:14])[C:10](=[O:13])[CH:11]=[CH2:12])[CH:2]([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.Br[C:31]1[CH:44]=[N:43][C:34]2[NH:35][C:36](=[O:42])[C:37]([CH3:41])([CH3:40])[NH:38][CH2:39][C:33]=2[CH:32]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:40][C:37]1([CH3:41])[C:36](=[O:42])[NH:35][C:34]2[N:43]=[CH:44][C:31](/[CH:12]=[CH:11]/[C:10]([N:9]([CH2:8][C:7]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:6]=3[O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH3:14])=[O:13])=[CH:32][C:33]=2[CH2:39][NH:38]1
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1cccc(OC)c1OCC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)c1OCC(C)C
Yield: 36.7 %

Procedure:
A solution of N-(2-isobutoxy-3-methoxybenzyl)-N-methylacrylamide (0.407 g, 1.47 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.40 mL, 2.33 mmol) and 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.11 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.024 g, 0.11 mmol) and P(o-tol)3 (0.067 g, 0.22 mmol) were then added and the solution was deoxygenated with Ar for 20 min. The solution was heated to reflux for 18 h, then allowed to cool. The solution was diluted with EtOAc (30 mL) and was washed with H2O (3×50 mL). The organic layer was washed with brine (2×50 mL), dried (Na2SO4) and concentrated to an orange oil. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 98:2) gave the title compound (0.19 g, 32%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 9.79-9.77 (m, 1H), 8.40-8.35 (m, 1H), 8.00-7.92 (m, 1H), 7.54-7.48 (m, 1H), 7.29-7.22 (m, 1H), 7.04-6.96 (m, 2H), 6.66-6.63 (m, 1H), 4.79-4.64 (m, 2H), 3.89-3.83 (m, 2H), 3.79 (s, 3H), 3.72-3.67 (m, 2H), 3.11-2.87 (m, 4H), 2.04-1.99 (m, 1H), 1.31-1.29 (m, 6H), 1.00-0.97 (m, 6H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[CH3:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=1[NH2:30]>O>[CH3:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][C:29]=1[NH:30][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: C[C@H]1CCCCN1c1ccc(C(F)(F)F)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H]1CCCCN1c1ccc(C(F)(F)F)cc1NC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 93.4 %

Procedure:
Isonicotinoyl chloride hydrochloride (466 mg, 2.61 mmol, commercially available product) and triethylamine (600 μl, 4.30 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of (S)-2-(2-methyl-1-piperidinyl)-5-(trifluoromethyl)aniline (223 mg, 0.863 mmol), obtained as described in [Referential Example 2-2]. The resulting mixture was warmed to room temperature and stirred for 19.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25 g, hexane/ethyl acetate=1.5/1). Thus, (S)—N-[2-(2-methyl-1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0613) (293 mg, 93.4%) was yielded as an colorless oily material.
Reaction SMILES: CCC[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](O)=[CH:14][CH:15]=1.[CH:17]([OH:20])([CH3:19])[CH3:18].[OH-].[Na+].[CH2:23](Cl)[CH:24]=[CH2:25]>O>[CH2:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:20][C:17]1[CH:19]=[CH:25][CH:24]=[CH:23][CH:18]=1)[CH:5]=[CH2:4]
Reactant: CC(C)O
Reactant: C=CCCl
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCCCCCCCCCCOc1ccccc1
Reaction time: 5 h

Procedure:
Commercially available nonylphenol was mixed with 300 g isopropyl alcohol and 60 g of 50% NaOH to give a homogeneous solution. Allyl chloride (80 ml=1.2 equiv.) was added dropwise at 40° C. over 20 minutes. The mixture was digested five hours at 75° C. Water, 150 g, was added to dissolve the precipitated salt. The resulting mixture separated into two phases. The top layer was stripped of solvent to give 197 g crude product of hydroxyl value 0.19 meq/g. Conversion was calculated to be 95%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CO.[CH3:8][CH2:9][OH:10].[C:11](O)(=O)[CH3:12]>[Pd].[Pt]=O>[C:9]1([OH:10])[CH:5]=[CH:4][CH:12]=[CH:11][CH:8]=1.[NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)O
Reactant: CCO
Agent: O=[Pt]
Agent: [Pd]
Agent: c1c[nH]cn1
Solvent: CO
Product: Oc1ccccc1

Procedure:
As shown in Method E, imidazole 10 (R8 =CH3) is treated with any ether cleaving reagent such as 48% HBr in acetic acid, pyridine-HCl, AlCl3 /C6H6, and BBr3 /CH2Cl2 at 0° to the reflux temperature of the solvent for about 1-24 hours to obtain imidazole phenol 11 (X=CH2). Imidazole 10 (R8 =CH2C6H5) is treated with a suitable solvent such as an alcohol (CH3OH, EtOH, and the like) or acetic acid at ambient temperature for a period of about 15 minutes to about 15 hours in the presence of a suitable catalyst such as 10% Pd on carbon, platinum oxide, and the like, at a pressure of up to about 60 psi to afford imidazole 11 (X=CH2 or X=O when m and n are >1). ##STR16##
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.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>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:22])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: Cc1ccccc1B(O)O
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccccc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Yield: 93 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (25 mg, 0.068 mmol), (2-methylphenyl)boronic acid (11.97 mg, 0.088 mmol), potassium carbonate (28.1 mg, 0.203 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.91 mg, 3.39 μmol) in ethanol (1 mL) and toluene (1 mL) was degassed under house vacuum and quenched several times with nitrogen, and then was heated at 100° C. for 30 min before being cooled to room temperature. The mixture was filtered through celite and the insoluble washed with EtOH. Most of the solvent was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 30 to 60% AcOEt in hexanes) gave 1-methylethyl [(2S,4R)-1-acetyl-2-methyl-6-(2-methylphenyl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (24 mg, 0.063 mmol, 93%) as a colourless solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:28]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])=[C:9](Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CO.C1COCC1>[N:1]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:28]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])=[CH:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
3-{[4-(Azetidin-1-ylcarbonyl)-2-chlorophenyl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (104 mg, 0.215 mmol) was dissolved in methanol (3 mL) and THF (3 mL). Triethylamine (65 mg, 0.644 mmol) was added and the flask evacuated and purged with nitrogen (3 times). 10% Palladium on carbon (25 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 16 hours until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off, the filtrate concentrated in vacuo and dissolved in ethyl acetate (10 mL), washed with water (2×10 mL, saturated aqueous sodium chloride solution (10 mL) and dried (MgSO4) to give the title compound (95 mg).