Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:4]=1[F:20])=[O:28]
Reactant: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 86.7 %

Procedure:
2-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (0.056 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.05 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. for 6 h with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 16 h. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was triturated with boiling IPA, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(6-chloro-4-cyano-2-pyridinyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.069 g, 0.157 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br. s., 1H), 8.28 (br. s., 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.49 (d, J=8.38 Hz, 1H), 7.30-7.41 (m, 1H), 4.46-4.61 (m, 2H). LC-MS (ES−) m/z 438.02, 440.05, 442.05 [M−1]. LC-MS (ES+) m/z 439.93, 441.90, 443.94 [M+H]
Reaction SMILES: [C:1]([P:3](=[O:10])([O:7]CC)[O:4][CH2:5][CH3:6])#[N:2].C[C:12]([N:14]([CH3:16])[CH3:15])=O>[Cl-].C[N+](C)(C)C>[CH2:5]([O:4][P:3]([C:1]#[N:2])(=[O:7])[O-:10])[CH3:6].[CH3:12][N+:14]([CH3:16])([CH3:1])[CH3:15]
Reactant: CC(=O)N(C)C
Reactant: CCOP(=O)(C#N)OCC
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: CCOP(=O)([O-])C#N
Temperature: 80 °C
Yield: 70 %

Procedure:
Diethyl cyanophosphonate (0.50 g, 3.06 mmol) and tetramethylammonium chloride (0.338 g, 3.06 mmol) were added to dimethylacetamide (0.5 mL) which was heated to 80° C. for 3 hours. Then dimethylacetamide was removed under vacuum to give 0.45 g (70% yield) of a viscous residue which was analyzed by NMR and mass spectrometry without additional purification. 31P NMR (CD3CN) δ (ppm) major peak (87%) -22.4 (t, 3JPH =8.8 Hz), minor peaks: -13.0 to -14.0 (10%), -3.0 (3%); 1H NMR (D2O) δ (ppm) 1.30 (t), 3.20 (s), and 4.05 (qnt); 13C NMR (D2O) δ (ppm) 119.7 (d, 1JCP =175.5 Hz), 63.9 (d, 2JCP =6.3 Hz), 55.8 (t, J=4.0 Hz) 16.0 (d, 3J CP =6.87 Hz). Mass spectral analysis (FAB+, thioglycerol) detected a peak at m/z 282.3, corresponding to the complex species [[+N(CH3)4 ]2-O(OC2H5)POCN]+ !, the presence of a cation at m/z 74.1 [[N(CH3)4 ]+ ] and an anionic species (FAB- thioglycerol) at m/z 133.9 [NCP(O)(OC2H5)O- ], and to the cluster [[+N(CH3)4 ] O(OC2H5)POCN- [O(OC2H5)POCN]- at m/z 342.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Sc2cccc3ccccc23)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2cccc3ccccc23)cc1
Yield: 91.8 %

Procedure:
1-(4-Nitrophenylthio)naphthalene (39.0 mmoles, 11.0 g) was dissolved in 200 ml ethyl acetate and hydrogenated over 8 g of 5% Pd/C at 40 psi for 1 hr at room temperature. The solution was filtered through celite and the solvent removed to yield 1-(4-aminophenylthio)naphthalene 9.0 g, 92%. Mass spec (FD) 251. Calculated for C15H17NS: C, 76.46; H, 5.21, N, 5.57 Found: C, 76.71; H, 5.39; N, 5.47.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][CH:6]([C:10]([O:12]CC2C=CC=CC=2)=[O:11])[CH2:5]1)(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][O:7][CH:6]([C:10]([OH:12])=[O:11])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCOC(C(=O)O)C1
Yield: 24.3 %

Procedure:
Phenylmethyl 4-acetyl-2-morpholinecarboxylate (313 mg, 1.189 mmol) was dissolved in ethanol (5 ml) and hydrogenated at 30 bar on H-Cube using 10% palladium on carbon. The mixture was blown to dryness under a stream of nitrogen to give the starting material. The starting material was dissolved in ethanol (5 ml) and hydrogenated at 50 bar on H-Cube using10% palladium on carbon. The mixture was blown to dryness under a stream of nitrogen to give the title compound (50 mg) as a colourless oil.
Reaction SMILES: [CH3:1][O-].[Na+].CI.[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2>CN(C)C=O>[CH3:1][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: Cc1ccc(-c2cc3ccccc3[nH]2)c(O)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1-c1cc2ccccc2[nH]1
Reaction time: 2 h
Yield: 70 %

Procedure:
At a temperature of 25° C. 54 g (1 mol) of sodium methylate and 170 g (1.2 mol) of methyl iodide were added to a solution of 223 g (1 mol) of 2-(2'-hydroxy-4'-methyl-phenyl)-indole, prepared as in Example 1, in 1200 ml of N,N-dimethylformamide. The solution was then stirred for 2 hours and the crude product was precipitated by adding water. After recrystallization from benzene, 166 g of 2-(2'-methoxy-4'-methyl-phenyl)-indole were obtained. M.P.: 125° C. Yield: 70%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:6][C:5]=1[CH2:18][OH:19].[Br:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:19][CH2:18][C:5]2[CH:6]=[CH:7][C:8]([C:14]([F:15])([F:16])[F:17])=[C:9]([O:10][CH2:11][O:12][CH3:13])[C:4]=2[CH:3]([O:2][CH3:1])[O:20][CH3:21])=[CH:25][CH:24]=1
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Reactant: Oc1ccc(Br)cc1
Product: COCOc1c(C(F)(F)F)ccc(COc2ccc(Br)cc2)c1C(OC)OC
Yield: 77 %

Procedure:
According to a method similar to Example (6-7), from [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (3.00 g, 9.66 mmol) obtained in Example (6-6) and 4-bromophenol (2.00 g, 11.6 mmol), 1-[(4-bromophenoxy)methyl]-2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzene was obtained (3.46 g, yield: 77%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C@@H:9]([C:23]([OH:25])=O)[CH2:10][CH2:11][C@@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[F:22])[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:12]1[CH2:13][NH:14][C:23](=[O:25])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](CN)c1cccc(F)c1F)C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Reaction time: 1 h

Procedure:
To a solution (5S)—N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine from Step D (22.0 g, 48.0 mmol) in CH2Cl2 (700 mL) were added EDC (11.0 g, 57.6 mmol) and HOAT (3.27 g, 24.0 mmol) followed by triethylamine (10.0 mL, 72.0 mmol). After 1 h, aqueous NaHCO3 was added, the layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—90:10, to give the title compound. MS: m/z=341 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1.S(Cl)(Cl)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[C:5]([N:10]2[CH2:11][CH2:12][CH:13]([C:16](=[O:18])[C:26]#[C:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: C#Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(C#Cc1ccccc1)C1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
To a solution of Compound 258b in anhydrous toluene (10 mL), thionyl chloride (0.29 mL, 3.98 mmol was added and the resulting mixture was stirred at reflux for 1 hour, cooled to r.t and evaporated to dryness in vacuo. The residue was dissolved in anhydrous toluene (5 mL); to this solution was added phenylacetylene (0.09 mL, 0.80 mmol), palladium(II)acetate (18 mg, 0.08 mmol), triethylamine (0.34 mL, 2.4 mmol). The mixture was stirred in a microwave oven at 110° C. for 1 hour, cooled to r.t., poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 25:75) affording the title product (77 mg).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)[C:5]([O:23][CH3:24])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C(C)O)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of tert-butyl 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (1.3 g, 3.7 mmol) in methanol (20 mL) stirring at 0° C. was added sodium tetrahydroborate (0.167 g, 4.41 mmol). The mixture was stirred at 0˜5° C. for 1 hour. The reaction was quenched with water and extracted with EtOAc (3×). The combined extracts were dried over MgSO4, filtered and concentrated to give 1.3 g (100%) of the desired product. LCMS calculated for C18H26ClNO4Na (M+Na)+: m/z=378.2; Found: 378.1. 1H NMR (400 MHz, CDCl3): δ 7.37 (s, 1H), 5.10 (q, 1H), 4.30 (m, 2H), 4.14 (m, 3H), 3.63 (s, 3H), 2.25 (s, 3H), 1.48 (d, 3H), 1.44 (s, 9H) ppm.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:14]=[C:13]1[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:15])[N:1]1[C@H:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CSCC[C@@H](N)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSCC[C@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Yield: 93.2 %

Procedure:
A solution of (R)-2-amino-4-(methylthio)butanoic acid (50 g, 335 mmol), finely ground phthalic anhydride (49.6 g, 335 mmol) and triethlamine (4.67 ml, 33.5 mmol) in toluene (450 ml) was stirred and heated under vigorous reflux in a Dean-Stark apparatus for 2.5 h. Volatiles were evaporated and to the residue was added 600 ml water and 6 ml hydrochloric acid and the mixture stirred vigorously with a mechanical stirrer. After stirring for 30 minutes, the suspension was filtered and filtrate evaporated under vacuum to give the title compound (87.24 g=92% yield).
Reaction SMILES: [Br-:1].[OH:2][CH:3]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N+:10]([CH3:13])([CH3:12])[CH3:11].C1(C)C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>>[Br-:1].[C:41]([O:2][CH:3]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N+:10]([CH3:11])([CH3:13])[CH3:12])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCC[N+](C)(C)C)OC(C)=O

Procedure:
A solution of 580 mg of 4-[2-hydroxy-3-(octadecyloxy)-propoxy]-N,N,N-trimethyl-1-butanaminium bromide in 5 ml of acetic anhydride is stirred at reflux under inert gas for 15 minutes. Toluene is added and the solvents evaporated followed by several additional toluene evaporations. The residue is stirred with ether and stored at 0° C. for several days. The resulting solid is collected and dried to give 480 mg of the desired product.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([O:13][C:14](=[O:23])[C:15]1[C:20](F)=[CH:19][N:18]=[C:17]([Br:22])[CH:16]=1)[CH3:12].O>O1CCCC1>[CH2:11]([O:13][C:14](=[O:23])[C:15]1[C:20]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:19][N:18]=[C:17]([Br:22])[CH:16]=1)[CH3:12]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)c1cc(Br)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)ncc1OCc1ccccc1
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
To a solution of benzylalcohol (1.5 g) in tetrahydrofuran (30 mL) was added sodium hydride (55%, 0.3 g) under ice cooling, and this mixture was stirred at same temperature for 5 minutes. To this reaction mixture was added a solution of 2-bromo-5-fluoroisonicotinic acid ethyl ester (2.9 g) in tetrahydrofuran (30 mL), and this mixture was stirred at room temperature for 2 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give the title compound (2.4 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=3[F:27])[N:20]=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:18]=2[CH3:35])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+].[NH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:27][C:25]1[CH:24]=[C:23]([F:28])[CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:4]1[C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)=[N:6][CH:7]=[C:2]([N:76]3[CH2:81][CH2:80][O:79][CH2:78][CH2:77]3)[CH:3]=1)=[C:18]([CH3:35])[C:19]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[N:20]2
Reactant: COc1ccc(-c2ncc(Br)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)cc1
Temperature: 100 °C
Reaction time: 23.5 h

Procedure:
A stirred mixture of mostly N-(5-bromo-2-(4-methoxyphenyl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.093 g, 0.18 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (0.017 g, 0.035 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.017 g, 0.018 mmol), and sodium tert-butoxide (0.058 g, 0.60 mmol) in dry toluene (3.0 mL) was purged three times with argon and placed under vacuum three times, then morpholine (0.2 mL, 2.30 mmol) was added to the mixture by syringe. Upon complete addition, the mixture was heated to 100° C. After 23.5 h, the reaction was cooled to rt, then treated with 1M Na2CO3 solution. After extracting twice with DCM:MeOH (95:5), the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on silica gel (0-40% of 89:9:1 DCM:MeOH:ammonium hydroxide solution in DCM) to afford an impure light yellow film. This film was submitted to analytical group for SFC purification. After concentration, the residue was identified as 5,7-difluoro-N-(2-(4-methoxyphenyl)-5-(4-morpholinyl)-3-pyridinyl)-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (1H, m), 8.05 (1H, m), 7.94 (2H, m), 7.76 (2H, m), 7.64 (1H, m), 7.42 (1H, m), 7.07 (3H, m), 6.99 (1H, m), 6.54 (1H, m), 3.92 (7H, m), 3.22 (4H, m), 2.22 (3H, s). Mass Spectrum ESI (pos.) m/e: 540.3 (M+H)+.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1/[CH:27]=[CH:28]/[CH:29]=[O:30]>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:29](=[O:30])[CH:28]([CH2:27][C:23]3[O:22][CH:26]=[CH:25][CH:24]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: O=C/C=C/c1ccco1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1ccco1
Yield: 66 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(furan-2-yl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 16 as an off-white solid (80 mg, 66%). Analytical data for 16: 1H NMR (500 MHz, CDCl3) δ 9.45 (d, J=8.1 Hz, 1H), 7.90 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.37 (ap d, J=1.2 Hz, 1H), 7.37-7.27 (m, 3H), 7.11-7.01 (m, 3H), 7.01-6.94 (m, 1H), 6.34 (dd, J=3.2, 1.9 Hz, 1H), 6.02 (d, J=2.9 Hz, 1H), 4.20 (d, J=6.9 Hz, 1H), 3.70 (ddd, J=10.3, 6.8, 4.1 Hz, 1H), 3.30 (ddd, J=15.9, 4.2, 1.2 Hz, 1H), 2.48 (dd, J=15.8, 10.4 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.4, 159.1 (d, JCF=243.8 Hz), 155.4 (dd, JCF=241.2, 2.2 Hz), 151.8, 149.1, 141.6, 136.7, 136.5, 129.2, 128.3, 128.0, 118.4 (dd, JCF=12.8, 9.2 Hz), 117.1 (dd, JCF=25.6, 8.8 Hz), 116.6 (dd, JCF=24.9, 9.6 Hz), 114.5 (dd, JCF=26.9, 3.7 Hz), 110.7 (d, JCF=3.9 Hz), 110.4, 107.6, 44.9, 38.5, 25.6; IR (film) cm−1 1770, 1636, 1620, 1529, 1482, 1464, 1452, 1173, 1117, 1008, 919, 902, 885, 875, 814, 766, 736, 700; LRMS (ESI): Mass calcd for [M+H]+ C23H17F2N2O3: 407.1. found 407.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 5% IPA/3% MeOH/hexanes 0.5 mL/min, 280 nm), Rt1 (major)=32.4, Rt2 (minor)=36.4 min; er=98:2.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[OH:16][C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:7](=[O:8])[C:6]1[CH:17]=[C:2]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)[C:3]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:4][CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1Br
Product: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was synthesised in analogy to the Suzuki reaction procedure described for the preparation of Example 1, from 5-bromo-N-(trans-2-hydroxy-cyclohexyl)-6-(2-methoxy-ethoxy)-nicotinamide and 4-trifluoromethyl-phenylboronic acid (commercially available). MS (m/e): 439.3 (MH+).
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[Cl:9][CH2:10][CH2:11]O>>[OH:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3]([O:5][CH2:11][CH2:10][Cl:9])=[O:4]
Reactant: CCC(C)(O)C(=O)O
Reactant: OCCCl
Product: CCC(C)(O)C(=O)OCCCl

Procedure:
2-Chloroethyl 2-hydroxy-2-methylbutyrate was prepared from 2-hydroxy-2-methylbutyric acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1: b.p. 108° C./20 mm Hg; 1H NMR δ0.90 (t, 3H, J=7.4 Hz), δ1.44 (s, 3H), δca. 1.70 (m, 1H), δca. 1.83 (m, 1H), δ3.10 (s, 1H), δ3.72 (t, 2H, J=5.6 Hz), δ4.43 (dd, 2H, J=5.6 Hz and 1.5 Hz); HRMS calcd for C6H9ClO3Tms (M-CH3) 237.0714, obsd 237.0750.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.[C:18]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)CCl.CCN(CC)CC.Cl>C(Cl)Cl.O>[C:19]1([C:18]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([C:35]([N:1]4[CH2:2][CH:3]([N:5]5[CH2:6][CH2:7][N:8]([C:11]([C:13]6[S:14][CH:15]=[CH:16][N:17]=6)=[O:12])[CH2:9][CH2:10]5)[CH2:4]4)=[O:36])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Reactant: O=C(O)c1ccc2c(c1)CCN2C(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc2c(c1)CCN2C(=O)c1ccccc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a solution of compound 5e (115.9 mg, 0.34 mmol), compound 55h (82 mg, 0.31 mmol) and EDC (87.9 mg, 0.46 mmol) in CH2Cl2 (5 mL) was added Et3N (0.13 mL, 0.92 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O and the water layer was acidified to pH˜6 with 1 N aqueous HCl. The organic solution was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, 2% MeOH/EtOAc) to give compound Cpd 724 (64.4 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=3.2 Hz, 1H), 7.31-7.63 (m, 9H), 4.38-4.63 (m, 2H), 4.03-4.37 (m, 6H), 3.74-3.96 (m, 2H), 3.20-3.29 (m, 1H), 3.16 (t, J=8.3 Hz, 2H), 2.38-2.61 (m, 4H). MS m/z (M+H+) 502.0.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[OH:10])=[CH2:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH2:2]
Reactant: C=Cc1cc(F)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=Cc1cc(F)ccc1OCc1ccccc1

Procedure:
A mixture of 2-ethenyl-4-fluorophenol (C16) (1.03 g, 7.46 mmol) and potassium carbonate (3.12 g, 22.4 mmol) in acetone (35 mL) was treated with benzyl bromide (1.78 mL, 14.9 mmol) and stirred at reflux for 3 hours. The mixture was concentrated in vacuo, ethyl acetate (100 mL) was added and the mixture was washed with water (2×50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 15% ethyl acetate in heptane) afforded the title compound as a colorless oil. Yield: 1.64 g, 7.23 mmol, 97%. GCMS m/z 228 (M+). 1H NMR (400 MHz, CDCl3) δ 5.08 (s, 2H), 5.33 (dd, J=11.1, 1.0 Hz, 1H), 5.76 (dd, J=17.8, 1.0 Hz, 1H), 6.85-6.95 (m, 2H), 7.11 (ddd, J=17.8, 11.1, 1.5 Hz, 1H), 7.23 (dd, J=9.4, 2.9 Hz, 1H), 7.33-7.48 (m, 5H).