Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Si:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6](Br)[CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([N:42]3[C:54]4[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=4[C:48]4[C:43]3=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:39]=[CH:40][CH:41]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Br:1][C:2]1[CH:7]=[C:6]([C:40]2[CH:41]=[CH:36][CH:37]=[C:38]([N:42]3[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=4[C:49]4[C:54]3=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH:39]=2)[CH:5]=[C:4]([Si:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1
Reactant: CC1(C)OB(c2cccc(-n3c4ccccc4c4ccccc43)c2)OC1(C)C
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
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: O
Solvent: Cc1ccccc1
Product: Brc1cc(-c2cccc(-n3c4ccccc4c4ccccc43)c2)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A solution of (3,5-dibromophenyl)triphenylsilane (4.02 g, 8.12 mmol), 9-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9H-carbazole (1.500 g, 4.06 mmol), Pd(PPh3)4 (100 mg, 0.086 mmol), K2CO3 (1.123 g, 8.12 mmol) in toluene (100 mL) and water (20 mL) was refluxed under nitrogen for 24 h. After cooling to room temperature, the organic phase was isolated and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (9/1 to 4/1, v/v) as eluent and recrystallized from hexane/DCM (9/1, v/v) to yield 9-(3′-Bromo-5′-(triphenylsilyl)-[1,1′-biphenyl]-3-yl)-9H-carbazole (2.1 g, 79%) as white crystals.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O.[Cl-].[Na+].CN(C)[CH:23]=[O:24]>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:23]=[O:24])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)Oc1ccc(C(C)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)Oc1ccc(/C=C/C=O)cc1
Temperature: 0 °C

Procedure:
A solution of 1-(4-isopropyloxy phenyl) ethanol of formula 4 (4.8 g, 27 mmol) in dimethyl formamide (10 ml) is slowly added to phosphorus oxychloride (8 ml) in DMF (12 ml) with stirring at 0° C. The reaction mixture is stirred for 2 hours then allowed attaining room temperature followed by heating on an oil bath for 36 hour at 40° C. After the completion of the reaction as monitored by TLC, contents of the reaction mixture are poured into ice cold water (500 ml), neutralised with dilute alkali solution and saturated by adding sodium chloride. The aqueous portion is extracted with ethyl acetate (3×100 ml), organic layer washed with water, dried over anhydrous sodium sulphate and stripped off the solvent under vacuum to furnish crude product (4.8 g). It was purified by column chromatography over silica gel to yield a semisolid 3-(4-isopropyloxy phenyl)-2E-propenal of formula 3 (80%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C([O:30][C:31](=O)[C:32]([F:35])([F:34])[F:33])C>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH:15][C:31](=[O:30])[C:32]([F:35])([F:34])[F:33])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 130 h

Procedure:
112.5 g (0.41 mmol) of O-benzyltyrosine is suspended in 1 liter of dry methanol and combined at room temperature with 58.9 ml (0.42 mol) of triethylamine. After adding 67 ml (0.53 mol) of trifluoroacetic acid ethyl ester, the mixture is stirred at room temperature for 130 hours under exclusion of moisture. The mixture is separated from unreacted starting material and volatile components are removed by shaking with ethyl acetate/aqueous hydrochloric acid. The ethyl acetate phase is decolorized with activated carbon. Evaporation of the solvents yields 120.7 g (80% of theory) of colorless crystals. Melting point: 149°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.[H-].[Na+].F[C:15]1[C:20]([F:21])=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([O:10][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[C:20]([F:21])[CH:15]=2)[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(O)c1
Reactant: O=[N+]([O-])c1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(Oc2ccc([N+](=O)[O-])c(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.7 %

Procedure:
To an ice bath cooled solution of 5-hydroxynicotinic acid methyl ester (5.00 g, 32.65 mmol) in DMF (20 mL) was added sodium hydride (0.78 g, 32.65 mmol). The reaction mixture was stirred at room temperature for 2 hours, and 2,3-difluoro-4-nitrobenzene (5.12 g, 29.68 mmol) was added, and the reaction mixture was stirred at room temperature. After 3 hours the solvent was removed under reduced pressure, and the residue was partitioned between EtOAC (300 mL) and H2O (150 mL). The aqueous layer was extracted with EtOAc (100 mL), and the combined organic layers were dried over Na2SO4, filtered, and the filtrate removed under reduced pressure. The crude product was purified by column chromatography eluted with 50 to 75% EtOAc/Hex to give 2.4 g (28%) of 5-(4-nitro-3-fluorophenoxy)nicotinic acid methyl ester. 1H-NMR (CD3OD) δ 9.05 (d, J=1.8 Hz, 1H), 8.70 (d, J=2.7 Hz, 1H), 8.31 (dd, J=2.4, 10.5 Hz, 1H), 8.15-8.14 (m, 1H), 9.06 (dd, J=1.5, 2.1 Hz, 1H), 7.40 (dd, J=8.1, 9.0 Hz, 1H), 3.97 (s, 3H); MS LC-MS [M+H]+=293.1; RT=3.15 min.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[NH2:23][C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.CN1CCC(N)CC1>C(O)(=O)C>[CH3:24][N:23]1[CH2:3][CH2:2][CH:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: CN1CCC(N)CC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: CN1CCC(n2cnc3c(-c4ccccc4)csc3c2=O)CC1
Yield: 33.8 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 1-methylpiperidin-4-amine (0.124 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 47.3 mg (0.15 mmol, 33.8% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:10][CH2:11][CH2:12][CH2:13]I.O>CN(C)C=O>[Cl:10][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCOc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (5.00 g, 52.58 mmol) in N,N-dimethylformamide (DMF) (55 mL) was slowly added to a cold (0-5° C.), stirring slurry of sodium hydride (2.52 g of an 80% dispersion in mineral oil, 84.0 mmol) in DMF (10 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added 1-choro-3-iodopropane (12.90 g, 63.10 mmol), and the resulting dark-brown mixture was stirred at ambient temperature for 48 h. Cold water was added and the mixture was extracted with chloroform (4×100 mL). The combined chloroform extracts were washed with water (2×50 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation. Water (150 mL) was added, and the mixture was basified with 20% NaOH solution (5.0 mL). The alkaline solution was extracted with methyl t-butyl ether (MTBE) (5×100 mL). The combined MTBE extracts were washed with water (4×100 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 4.90 g (54.3%) of an oil. 1H NMR (CDCl3, 300 MHz): δ 8.34 (s, 1H), 8.24 (s, 1H), 7.22 (t, 2H, J=2.13 Hz), 4.18 (t, 2H, J=5.85 Hz), 3.77 (t, 2H, J=6.19 Hz), 2.27 (p, 2H, J=6.03 Hz). 13C NMR (CDCl3, 75 MHz): δ 154.99, 142.38, 138.07, 123.93, 121.09, 64.60, 41.22, 32.11. EI-MS: m/z (relative intensity) 171 (M+, 27.25%), 136 (4.66%), 95 (100.00%), 78 (17.98%), 41 (37.74%), 39 (34.23%).
Reaction SMILES: [OH-].[Na+].Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:26])[C:13]([CH2:23][CH2:24][CH3:25])=[C:14]([C:20](=[O:22])[CH:21]=2)[C:15]([O:17]CC)=[O:16])=[CH:7][CH:6]=1>O.C(O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([CH3:26])[C:13]([CH2:23][CH2:24][CH3:25])=[C:14]([C:20](=[O:22])[CH:21]=2)[C:15]([OH:17])=[O:16])=[CH:9][CH:10]=1
Reactant: CCCc1c(C(=O)OCC)c(=O)cc(-c2ccc(Cl)cc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1c(C(=O)O)c(=O)cc(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
4.0 g (0.05 mol) of 50% aqueous sodium hydroxide is added to a suspension of 2.7 g (0.01 mol) ethyl 6-(4-chlorophenyl)-1-methyl-2-n-propyl-4-oxonicotinate hydrochloride in 50 ml of water and 10 ml of ethanol. The mixture is refluxed and stirred for 3 hrs, allowed to stand at room temperature for 18 hrs., refluxed for an additional 1 hr. and cooled to room temperature. The solution formed is extracted with three 50 ml portions of methylene dichloride and the aqueous solution is acidified to pH 1 with 12N hydrochloric acid. The suspension formed is stirred at room temperature for 3 hrs. and is vacuum filtered. The filter cake is dried to afford 1.65 g (54% yield) of 6-(4-chlorophenyl)-1-methyl-2-n-propyl-4-oxonicotinic acid, mp 184°-187° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>CN(C=O)C>[CH2:1]([N:26]1[C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]2[C:22]1=[O:32])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCN1C(=O)c2ccccc2C1=O

Procedure:
Phytanyl bromide (12.34 g), potassium phthalimide (6.95 g) and DMF (50 ml) were heated at 120-130° C. for 4 hours. Most of the DMF was removed under reduced pressure and the crude product was dissolved in dichloromethane (100 ml), washed with water (2×50 ml), dried (MgSO4). The light yellow crude product was chromatographed on flash silica (dichloromethane/hexane as eluant) to yield pure N-phytanyl phthalimide in 11.89 g (80.9%) 1H-n.m.r. (CDCl3) δ0.82-1.8 (m, 39H), 3.73 (t, 2H, CH2N), 7.73 (m, 2H, ArH), 7.88 (m, 2H, ArH); m/z 431 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]2[CH:8]=[N+:9]([O-:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OO
Reactant: Clc1ccc(Oc2cccnc2)cc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: [O-][n+]1cccc(Oc2ccc(Cl)cc2)c1
Temperature: 70 °C

Procedure:
A solution of 93 g of 3-(p-chlorophenoxy)pyridine [Agr. Biol. Chem. 34, 68 (1970)] in 100 ml of glacial acetic acid is treated with 95 g of 40% peracetic acid in acetic acid in four equal portions. The mixture is heated at 35°-40° C. for 16 hours and than refluxed 1 hour. The mixture is cooled to 70° C., 100 ml of isopropanol is added and the reaction heated at 95° C. for 2 hours. The mixture is concentrated in vacuo and dissolved in 700 ml of dichloromethane. The solution is washed with 25 ml of 25% cold sodium hydroxide solution, dried over anhydrous MgSO4, concentrated at reduced pressure to yield crystalline 3-(p-chlorophenoxy)pyridine N-oxide, recrystallized from toluene; mp 138°-140° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.[OH:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:30](=[O:31])[C:29]([OH:28])([CH3:34])[CH3:33])[CH2:2]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: CC(C)(O)C(=O)O
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)C(C)(C)O)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol), 2-hydroxy-2-methylpropionic acid (47 mg, 0.455 mmol), HOAt (62 mg, 0.455 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (87 μL, 0.455 mmol) and 4-methylmorpholine (0.10 mL, 0.911 mmol) in anhydrous DCM (4 mL) was stirred at RT for 20 h. Volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) then triturated with diethyl ether affording 135 (65 mg, 35%). LCMS: RT 2.44 min [M+H]+ 449.1. 1H NMR (DMSO, 400 MHz): δ 8.24-7.90 (3H, m), 7.88-7.81 (1H, m), 7.67-7.56 (1H, m), 7.23-7.07 (2H, m), 5.90 (1H, s), 5.51 (1H, s), 5.30-3.76 (4H, br), 2.45-2.28 (1H, m), 1.93-1.61 (5H, m), 1.48-1.27 (6H, m), 1.20-1.08 (1H, m)
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[O:12])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:27][CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[ClH:39]>CO.ClCCl>[ClH:39].[ClH:39].[OH:38][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:11][C:10]3=[O:12])=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccccc3)CC2)cc1

Procedure:
The free base was prepared from 1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 28) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Intermediate 3) according to the procedure of Example 1. The free base was dissolved in methanol/dichloromethane and treated with hydrogen chloride gas. After concentrated the solvents the product was obtained as a yellowish solid; mp>160° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.60-1.90 (m, 2 H), 2.05-2.25 (m, 2 H), 2.80-3.30 (m, 7 H), 3.60-4.40 (m, 11H), 6.90-7.10(m, 3 H), 7.14(d, J=8.7 Hz, 2 H), 7.51 (d, J=8.7 Hz, 2 H), 7.57 (s, 1 H), 8.92(brs, 1 H), 9.36(brs, 1 H); MS (ES) m/z: 262.1 ((M+2H)2+, 100%); 523.1(MH+, 30%); HRMS Calcd. for C28H35N4O3S (MH+): 523.2379. Found: 523.2394.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH:15]=[C:16]([OH:19])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:48]1([CH2:54][CH2:55]O)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH:15]=[C:16]([O:19][CH2:55][CH2:54][N:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:28]
Reactant: OCCN1CCCCC1
Reactant: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2c(-c3ccc(F)cc3F)cc(OCCN3CCCCC3)cc2N1c1c(Cl)cccc1Cl
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of 10 mg of 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-hydroxy-2(1H)-quinolinone (INTERMEDIATE 3) dissolved in 2 mL of anhydrous THF was added 87 mg of Ph3P and 43 mg of 1-piperidine ethanol. The resulting mixture was heated to 65° C. for 10 min. Then 72 mg of diisopropyl azodicarboxylate was added dropwise over 2 min and the mixture was stirred for 1 h at 65° C. The resulting reaction mixture was concentrated and purified by preparative thin-layer chromatography, eluting with 100% EtOAc, to yield 1-(2,6-Dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-[2-(1-piperidinyl)ethoxy]-2(1H)-quinolinone. Mass spectrum (ESI) 531.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J=8 Hz, 2H); 7.38 (t, J=8 Hz, 1H); 7.31 (q, J=6.5 Hz, 1H); 6.98 (m, 2H); 6.54 (s, 1H); 5.90 (s, 1H); 4.08 (s, 2H); 2.83 (m, 6H); 2.61 (s, 4H); 1.68 (s, 4H); 1.48 (s, 2H).
Reaction SMILES: CI.[C:3]([O-])(O)=O.[Na+].Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([C:23]3([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24]3)[NH:16][CH2:15][CH2:14][C:13]2=1>C(O)C>[ClH:9].[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([C:23]3([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:25][CH2:26]3)[N:16]([CH3:3])[CH2:15][CH2:14][C:13]2=1
Reactant: O=C([O-])O
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CCOC(=O)C1(C2c3[nH]c4ccc(Cl)cc4c3CCN2C)CCC1

Procedure:
0.3 ml of methyl iodide and 0.8 g of NaHCO3 are added to a solution of 1 g of the compound of Example 1 in 25 ml of ethanol. After reaction for 24 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure and then the residue is taken up in a mixture of water and dichloromethane. After extraction, drying and filtration, the organic phase is concentrated under reduced pressure. Crystallisation from a solution of ethanol and ethereal hydrogen chloride enables the expected product to be obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4](F)=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.[O:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.[BH3-]C#N.[Na+]>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:14][CH2:13]3)[C:7]=2[CH:18]=1
Reactant: O=c1[nH]c2cc(F)c(Cl)cc2n1C1CCNCC1
Reactant: O=C1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2ccc(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Chloro-5-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (2.0 g), Ti(iPrO)4 (4.2 mL), and tetrahydro-4H-pyran-4-one (1.4 g) were stirred together at room temperature for 1 h; dry methanol (30 mL) followed by NaBH3CN (0.8 g) were added and the mixture was stirred at room temperature for 1 h. The crude mixture was then quenched with methanol and it was purified first by SCX column chromatography followed by filtration and silica gel chromatography (methanol-NH3-dichloromethane). Conversion to the hydrochloride gave the title compound, 950 mg, MH+=336 and 338, 1H NMR (HCl salt) (DMSO-d6) 1.72 (2H, m), 1.94 (2H, m), 2.03 (2H, m), 2.81 (2H, m), 3.20 (2H, m), 3.33 (2H, m), 3.44 (1H, m), 4.01 (2H, m), 4.61 (1H, m), 7.02 (2H, m), 7.66 (1H, s), 10.52 (1H, bs) and 11.12 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:16]([OH:18])[CH3:17])=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:50][O:51][C:52](=[O:63])[CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58](O)=[CH:57][C:56]=1[CH3:62]>C1(C)C=CC=CC=1>[CH3:50][O:51][C:52](=[O:63])[CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:18][CH:16]([C:10]2[O:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[N:12][C:11]=2[CH:13]([CH3:15])[CH3:14])[CH3:17])=[CH:57][C:56]=1[CH3:62]
Reactant: CC(C)c1nc(-c2ccc(Br)cc2)oc1C(C)O
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(Br)cc3)nc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
To a solution of 1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol (9.05 g, 29.2 mmol) in toluene (300 ml) at 0° C. is added tri-n-butylphosphine (7.70 g, 38.1 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (8.84 g, 35.0 mmol), followed by addition of 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (6.30 g, 32.1 mmol). The resulting mixture is stirred for 18 hours while warmed up to room temperature. The reaction is quenched with water (100 ml) and the aqueous layer is extracted with EtOAc (2×100 ml). The combined organics are dried over Na2SO4 and concentrated, purified by silica gel chromatography (Hexanes/EtOAc, 9/1 to 8.5/1.5) to afford the 3-(4-{1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic acid methyl ester as a colorless oil (11.4 g, 80%). MS (MH+): 488.1.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:9]([CH2:10][NH:11][CH2:12]3)[C:8]=2[CH:7]=[CH:6][C:5]=1[O:17][CH3:18].[CH2:19]=O>[Pd].CO>[ClH:1].[CH3:2][O:3][C:4]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:9]([CH2:10][N:11]([CH3:19])[CH2:12]3)[C:8]=2[CH:7]=[CH:6][C:5]=1[O:17][CH3:18]
Reactant: COc1ccc2c(c1OC)CC[C@@H]1CNC[C@@H]21
Reactant: C=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1OC)CC[C@@H]1CN(C)C[C@@H]21
Yield: 75 %

Procedure:
A solution of the product of example 46, formalin (5 mL), NaOAc.3H2O (0.45 g), and MeOH (95 mL) in the presence of Pd/C catalyst (0.45 g, 5%, wet) was hydrogenated under 3 atmospheres H2 pressure. The resulting solution was filtered and evaporated to dryness. Water/1N KOH were added and the solution was extracted with ether. The combined extracts were washed with water, saturated aqueous NaCl, dried (MgSO4), filtered, evaporated, and converted to the HCl salt. The crude product was triturated with ether/MeOH, filtered, and dried to yield 0.70 g gray powder, (75%); mp 228°-30° C.; M+ 247.