Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O.CC(O)=O>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]2([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:29][C:28](=[O:30])[N:27]([C:31]3[C:32]([CH3:38])=[CH:33][CH:34]=[CH:35][C:36]=3[CH3:37])[CH2:26]2)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: COC(=O)C1(COCc2ccccc2)CC(=O)N(c2c(C)cccc2C)C1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cccc(C)c1N1CC(COCc2ccccc2)(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 25 °C
Yield: 10 %

Procedure:
n-BuLi (2.8 M solution in hexanes, 183 μL, 0.513 mmol) was added to a cooled (−50° C.) solution of 3,5-bis-trifluoromethylaniline (84.5 μL, 0.545 mmol) in THF (3 mL). The resulting dark brown colored solution was slowly warmed to room temperature and stirred for an hour. A solution of 3-benzyloxymethyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 100 mg, 0.27 mmol) in THF (2 mL) was added and the solution was stirred for 2 h at 70° C. The reaction mixture was then cooled to room temperature, AcOH (100 μL) was added and the solution was purified by automated flash chromatography (SiO2, 10→50% EtOAc/hexanes) followed by preparative HPLC (15→85% gradient of MeCN—H2O with 0.1% TFA). The pure fractions were lyophilized to afford 3-benzyloxymethyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide (15 mg, 10% yield). LC-MS: Rt (retention time): 3.38 min, MS: (ES) m/z 565.2 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 8.28 (s, 2H), 7.8 (s, 1H), 7.2-7.28 (m, 5H), 7.05-7.15 (m, 3H), 4.5-4.58 (m, 2H), 4.03 (d, 1H, J=8 Hz), 3.86-3.92 (m, 2H), 3.6 (d, 1H, J=8 Hz), 3.08 (d, 1H, J=16 Hz), 2.64 (d, 1H, J=16 Hz), 2.05 (s, 3H), 2.06 (s, 3H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:9]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Oc1cccc(O)c1
Reactant: CCCCCBr
Product: CCCCCOc1cccc(O)c1
Yield: 39.9 %

Procedure:
Prepared according to the method described in Example A above from resorcinol (55 g; 0.5 mol) and n-pentylbromide (83.1 g; 0.55 mol) to yield 36.0 g (40%) of the title compound as an oil (92% purity). bp 128-131° C. (5 mm Hg) MW=180 (GC-MS)
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9]O)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][N:3]=1.C(Cl)(Cl)[Cl:18]>O(Cl)Cl.[P]>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][Cl:18])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCCc1c(Cl)ncnc1-c1ccccc1
Reactant: ClC(Cl)Cl
Agent: ClOCl
Agent: [P]
Product: ClCCc1c(Cl)ncnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(4-chloro-6-phenylpyrimidin-5-yl)ethanol (340 mg) in dry chloroform (10 mL), phosphorus oxy chloride (2 mL) was slowly added under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 2 hours and solvents were removed under reduced pressure. The resulting oil was diluted with dichloromethane (50 mL), washed with 10% NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to gave crude 4-chloro-5-(2-chloroethyl)-6-phenylpyrimidine (150 mg) as viscous liquid, which was used as was. 1H NMR (DMSO-d6): δ 2.89-2.94 (t, 2H), 3.54-3.55 (t, 2H), 7.48-7.59 (m, 5H), 8.91 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:14])[CH2:12]Br)[CH:5]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[CH3:26])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:12][C:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([O:2][CH3:1])=[O:15])=[O:14])=[CH:21][C:20]=1[CH3:26])([CH3:18])[CH3:17]
Reactant: COC(=O)c1cccc(NC(=O)CBr)c1
Reactant: Cc1cc(O)ccc1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cccc(NC(=O)COc2ccc(C(C)C)c(C)c2)c1
Reaction time: 12 h

Procedure:
A solution of 3-(2-bromo-acetylamino)-benzoic acid methyl ester (1.80 g, 6.61 mmol), 4-isopropyl-3-methylphenol (1.00 g, 6.61 mmol) and potassium carbonate (1.00 g, 7.23 mmol) in 2-butanone (15 mL) was heated to reflux under inert atmosphere with stirring for 12 h. After cooling, the mixture was partitioned between water and ethyl acetate (50 mL each). The aqueous phase was extracted with ethyl acetate, and the extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The residual material was separated on a column (silica gel) with 20:80 ethyl acetate-hexane, and the eluant containing the product was evaporated to afford pure methyl 3-[2-(4-isopropyl-3-methyl-phenoxy)acetylamino]benzoate, as a glassy solid (1.64 g, 4.80 mmol, 73%). TLC RF 0.41 (30:70 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): δ 8.39 (1H, br s), 8.05 (1H, t, J=1.8 Hz), 7.99 (1H, ddd, J=8.0, 2.2, 1.1 Hz), 7.80 (1H, dt, J=7.7, 1.3 Hz), 7.42 (1H, t, J=7.9 Hz), 7.18 (1H, d, J=8.8 Hz), 6.81-6.77 (2H, m), 4.57 (2H, s), 3.90 (3H, s), 3.07 (1H, heptet, J=7.0 Hz), 2.32 (3H, s), 1.18 (6H, d, J=7.0 Hz). MS (ESI): m/e 344 (3), 343 (22), 342 (100).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].S(Cl)(Cl)=O.C(N(CC)CC)C.[C:23]1([C:29]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]3[CH2:34][NH:35][CH2:36][CH2:37][N:32]3[C:31](=[O:38])[O:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.O1CCCC1.O>[O:38]=[C:31]1[N:32]2[CH2:37][CH2:36][N:35]([C:6]([C:5]3[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=3)[CH:1]=[O:2])=[O:8])[CH2:34][CH:33]2[C:29]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:30]1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=Cc1cccc(C(=O)O)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=Cc1cccc(C(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
3-Formylbenzoic acid (0.10 g, 0.67 mmol) was dissolved in toluene (7 mL). Thionyl chloride (0.80 g, 6.7 mmol) was added thereto, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated, and the residue was dissolved in tetrahydrofuran (5 mL). The resulting solution was added dropwise to a solution of triethylamine (69 mg, 0.68 mmol) and hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.20 g, 0.68 mmol) in tetrahydrofuran (3 mL) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was sequentially washed with 1 N hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate), and the fractions were collected and concentrated. The residue was collected by filtration and washed with diisopropyl ether to obtain the title compound (0.19 g, yield 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([SH:11])[N:4]=1.[CH3:12][N:13]1[C:17](Br)=[C:16]([N+:19]([O-:21])=[O:20])[N:15]=[C:14]1[CH3:22]>[OH-].[Na+].C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([S:11][C:17]2[N:13]([CH3:12])[C:14]([CH3:22])=[N:15][C:16]=2[N+:19]([O-:21])=[O:20])[N:6]=1
Reactant: Cc1nc([N+](=O)[O-])c(Br)n1C
Reactant: COc1cc(OC)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)nc(Sc2c([N+](=O)[O-])nc(C)n2C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
4,6-Dimethoxy-2-mercaptopyrimidine (3.0 g) was dissolved in an aqueous solution of sodium hydroxide (0.7 g in 100 ml water). 1,2-Dimethyl-5-bromo-4-nitro-1H-imidazole (3.9 g) dissolved in ethanol (50 ml) was added dropwise, and the mixture was stirred at room temperature 10 for 6 hours. The precipitated product was filtered, washed with water, dried and recrystallised from acetonitrile to give 3.1 g of the desired product, mp 228°-30° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[N:24][C:23]=2[CH:32]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[N:24][C:23]=3[CH:32]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Oc1cccc(CCCCn2ccnc2)c1
Reactant: ClCc1ccc2oc(-c3cccs3)nc2c1
Product: c1cc(CCCCn2ccnc2)cc(OCc2ccc3oc(-c4cccs4)nc3c2)c1
Yield: 70 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(3-hydroxyphenyl)butyl]imidazole was allowed to react with 5-chloromethyl-2-(2-thienyl)benzoxazole to give 5-[3-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)benzoxazole. The yield was 70%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 97-98° C.
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:35]=[CH:34][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([O:29]CC)=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3C#N)=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.O[Li].O.[ClH:45]>C1COCC1>[C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:35]=[CH:34][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[Cl:45])=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1
Reactant: Cl
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(-c5ccccc5)cc4)cc3)c(C#N)cc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.2 %

Procedure:
Ethyl 7-(4-(2-(biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (62.5 mg, 0.1124 mmol) was dissolved in THF (1 ml) and 1M solution of LiOH—H2O (224.8 μL, 0.2248 mmol) was added. The mixture was stirred for 3 days at ambient temperature. The mixture was quenched with 1M HCl solution (400 μL, 0.400 mmol). The crude mixture was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 48.8 mg of the title compound as a white solid (82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:3]=1.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:33]=[C:34]([CH2:38][C:39](O)=[O:40])[CH:35]=[CH:36][CH:37]=1>>[Si:22]([O:21][CH2:20][CH:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:42])([F:30])[F:43])[CH:33]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Product: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(NC(=O)Cc3cccc(C(F)(F)F)c3)ccn2)c2cnccc21

Procedure:
Prepared according to Method Z (Preparation 8) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 30) and 3-trifluoromethylphenylacetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[B-](F)(F)(F)[C:10]([CH3:12])=[CH2:11].[K+].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:8][C:5]1[CH:4]=[CH:3][C:2]([C:10]([CH3:12])=[CH2:11])=[CH:7][N:6]=1
Reactant: Fc1ccc(Br)cn1
Reactant: C=C(C)[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1ccc(F)nc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
A burgundy-colored solution of 5-bromo-2-fluoropyridine (Acros, Morris Plains, N.J.; 1.737 mL, 16.88 mmol), potassium trifluoro(prop-1-en-2-yl)borate (Aldrich, St. Louis, Mo.; 3.75 g, 25.3 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.; 0.239 g, 0.338 mmol), and potassium carbonate (7.00 g, 50.6 mmol) in a mixture of dioxane (40 mL) and water (10.00 mL) was stirred at 80° C. for 2.5 h. The reaction mixture was then cooled to 25° C. and partitioned between CH2Cl2 (300 mL) and water (100 mL). The aqueous layer was extracted with CH2Cl2 (2×100 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0 to 20% EtOAc/hexanes) furnished 2-fluoro-5-(prop-1-en-2-yl)pyridine (2.06 g, 15.02 mmol, 89% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (d, J=2.5 Hz, 1H), 7.81-7.89 (m, 1H), 6.89 (dd, J=8.5, 3.0 Hz, 1H), 5.36 (s, 1H), 5.16 (s, 1H), 2.15 (s, 3H). 19F NMR (377 MHz, CDCl3) δ −70.28 (br. s., 1F). m/z (ESI, +ve) 138.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][S:10][CH2:9][CH:8]1[C:13]([O:15]CC)=[O:14])=[O:6])[CH:2]=[CH2:3].CO.O1CCCC1.Cl>[OH-].[Na+]>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][S:10][CH2:9][CH:8]1[C:13]([OH:15])=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCSCC1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CCSCC1C(=O)O
Yield: 101.9 %

Procedure:
A solution of ethyl 4-(allyloxycarbonyl)thiomorpholine-3-carboxylate (15.4 g) in a mixture of 4N aqueous sodium hydroxide (30 ml), methanol (30 ml) and tetrahydrofuran (75 ml) was refluxed for 90 minutes. The organic solvents were evaporated to give an aqueous solution. The aqueous solution was adjusted to pH 2 with concentrated hydrochloric acid, extracted with ethyl acetate (200 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give 4-(allyloxycarbonyl)thiomorpholine-3-carboxylic acid (14.0 g) as a syrup.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:20]([CH3:30])([CH3:29])[C:21]([C:23]1[CH:24]=[N:25][CH:26]=[N:27][CH:28]=1)=[O:22].O>CS(C)=O>[CH3:29][C:20]([O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1)([CH3:30])[C:21]([C:23]1[CH:28]=[N:27][CH:26]=[N:25][CH:24]=1)=[O:22]
Reactant: CC(C)(Br)C(=O)c1cncnc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(Oc1ccc(OC(F)(F)F)cc1)C(=O)c1cncnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4.4 g (25.0 mmol) of 4-trifluoromethoxyphenol and 15.5 g (112.5 mmol) of potassium carbonate in 37.5 ml of dry dimethyl sulphoxide was stirred at room temperature for 2 h. The reaction mixture was subsequently warmed to 60° C., and 25.7 g (112.5 mmol) of 2-bromo-2-methyl-1-(pyrimidin-5-yl)propan-1-one, dissolved in 12.5 ml of dimethyl sulphoxide, were added. After the addition had ended, the reaction mixture was stirred overnight. The reaction mixture was poured into 250 ml of water and extracted with 250 ml of ethyl acetate. The organic phase was separated off and then washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The crude product was then purified by column chromatography. This gave 1.24 g (14%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[NH:12][CH2:13][CH2:14][OH:15].[CH:16](O)=O>>[F:9][C:8]([F:10])([F:11])[C:4]1[C:3]2[N:12]([CH2:13][CH2:14][OH:15])[CH:16]=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(C(F)(F)F)c1NCCO
Reactant: O=CO
Product: OCCn1cnc2cccc(C(F)(F)F)c21
Yield: 55 %

Procedure:
A solution of 2-{[2-amino-6-(trifluoromethyl)phenyl]amino}ethanol (0.57 g) in formic acid (20 mL) was heated at reflux for 20 min. The excess of formic acid was removed in vacuo; the residue was dissolved in a 2 M hydrochloric acid, and heated at reflux for 10 min. The solution was concentrated in vacuum and the residue was co-evaporated with acetonitrile and ethanol. The residue was treated with a saturated solution of sodium bicarbonate and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography on silica using ethyl acetate as an eluent affording 2-[7-(trifluoromethyl)-1H-benzimidazol-1-yl]ethanol, 0.36 g (55% yield) as a white solid. MS (ESI) m/z 231 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.74-3.70 (m, 2H), 4.37 (t, J=5.3 Hz, 2H), 5.06 (t, J=4.8 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 8.33 (s, 1H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][NH2:22])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[NH4+]>O.CO.C(Cl)Cl.O1CCOCC1>[CH3:11][O:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@H:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:21][NH:22][C:7](=[O:8])[C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)N[C@@H](CN)c2ccccc2)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)N[C@@H](CNC(=O)c2ccc(C)cc2)c2ccccc2)cc1
Yield: 73.1 %

Procedure:
(Acylation Method A) p-Toluoyl chloride (0.22 mL, 1.6 mmol) was added via syringe to a 15° C. stirring mixture of (R)-2-(4-methoxybenzoylamino)-2-phenylethylamine (0.40 g, 1.48 mmol), potassium carbonate (0.27 g, 1.9 mmol), 1,4-dioxane (8 mL), and water (4 mL). TLC analysis (80% methylene chloride, 18% methanol, 2% ammonium hydroxide) indicated reaction completion within 1 h. The solution was diluted with water, and the precipitated solid was collected by vacuum filtration. The precipitate was recrystallized from methanol and dried under vacuum at 50° C. overnight to afford the title compound (0.42 g, 72%) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19](Br)=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(Cl)Cl.[CH3:68][O:69][C:70]1[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=1[NH2:72]>O1CCOCC1.CCN(CC)CC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([NH:72][C:71]5[CH:73]=[CH:74][CH:75]=[CH:76][C:70]=5[O:69][CH3:68])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1N
Reactant: O=C(Nc1ccc(Br)nc1)C1(c2ccc3c(c2)OCO3)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1Nc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1
Temperature: 150 °C

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-3-yl)cyclopropanecarboxamide (72 mg, 0.2 mmol) in dioxane (0.400 mL), XANTPHOS (2.3 mg, 0.004 mmol), KtBuO (31 mg, 0.28 mmol), (DPPF)2PdCl2.CH2Cl2 (3.00 mg, 0.004 mmol), and 2-methoxyaniline (30 mg, 0.24 mmol), and Et3N (0.200 mL) were added. The reaction mixture was heated to 150° C. in a microwave reactor for 10 minutes. The resulting material was cooled to room temperature. The crude product was purified by column chromatography on silica gel to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxyphenylamino)pyridin-3-yl)cyclopropanecarboxamide which was then treated with HCl in MeOH to form the HCl salt (2.3 mg, 0.0053 mmol, 2.7%). ESI-MS m/z calc. 403.2, found; 404.5 (M+1)+ Retention time 2.29 minutes.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][C:16]([O:18]CC)=O)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1COCC1.[CH3:26][NH2:27]>O>[N:1]1([CH2:14][CH2:15][C:16]([NH:27][CH3:26])=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CN
Reactant: CCOC(=O)CCn1cnc2cnc3ccccc3c21
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)CCn1cnc2cnc3ccccc3c21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 3-(1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.70 g, 17.5 mmol), THF (5 mL), and methylamine (available as a 40% solution in water, 10 mL) was sealed in a high-pressure vessel, stirred at 100° C. overnight, and concentrated under reduced pressure to provide 4.4 g of 3-(1H-imidazo[4,5-c]quinolin-1-yl)-N-methylpropanamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([OH:12])=O.C(C#N)(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OC([N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([CH:55]([NH2:57])[CH3:56])[CH:53]=2)[CH2:48][CH2:47][CH2:46]1)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:57][CH:55]([C:52]1[CH:53]=[C:54]2[C:49]([CH2:48][CH2:47][CH2:46][NH:45]2)=[CH:50][CH:51]=1)[CH3:56])=[O:12]
Reactant: CC(N)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Reactant: O=C(O)C=Cc1ccccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: N#CC(Cl)(Cl)Cl
Product: CC(NC(=O)C=Cc1ccccc1F)c1ccc2c(c1)NCCC2
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 3-(2-fluoro-phenyl)-acrylic acid (166 mg, 1 mmol), CCl3CN (289 mg, 2 mmol) and PPh3 (52 mg, 2 mmol) in CH2Cl2 (10 mL) was stirred at 23° C. for 1.5 hours. Then 7-(1-amino-ethyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester, Preparation 29 (276 mg, 1 mmol) was introduced followed by triethylamine (304 mg, 3 mmol). After stirring for 1 hour, the solvent was evaporated, the residue was re-dissolved in a mixture of MeOH (5 mL) and 1M HCl in Et2O (5 mL), and stirred at 23° C. for 24 hours. The solvent was evaporated and the residual material was partitioned between EtOAc and aqueous NaHCO3. The organic phase was washed with water, dried (MgSO4) and evaporated. The crude product was purified by chromatography (SiO2, 10-50% EtOAc in hexane) to give 267 mg (82%) of the title compound as a tan solid.