Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:12])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=[CH:20][C:21](=[O:23])[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CS(O)(=O)=O.O>C(#N)C>[C:1]1([C:7]2[NH:8][C:9](=[O:12])[O:10][C:11]=2[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][C:21](=[O:23])[CH3:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: O=c1[nH]c(-c2ccccc2)co1
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: O
Product: CC(=O)CC(c1ccccc1)c1oc(=O)[nH]c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of 4-phenyl-2-oxo-4-oxazoline (1.61 g) and benzalacetone (1.46 g) in acetonitrile (20 ml) was added dropwise methanesulfonic acid (0.96 g). After stirring the obtained mixture at room temperature for 30 min, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried (MgSO4), and the solvent was evaporated. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:1). The solvent was evaporated. Crystallization from isopropyl ether gave 4-(4-phenyl-2-oxo-4-oxazolin-5-yl)-4-phenyl-2-butanone (2.65 g; yield 86.3%). Recrystallization from ethanol gave colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Br:1][C:2]1[CH:7]=[C:6]([S:16]([Cl:15])(=[O:18])=[O:17])[CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:11])[F:12]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(Nc1ccccc1Br)C(F)(F)F
Product: O=C(Nc1ccc(S(=O)(=O)Cl)cc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
3.0 g N-(2-Bromo-phenyl)-2,2,2-trifluoro-acetamide was added in three portions to 3.74 mL (5.0 equiv.) chlorosulfonic acid under cooling in an ice-bath. The ice-bath was removed, the mixture was warmed to room temperature, and subsequently stirred for 1 hour at 80° C. After cooling, the clear brown reaction mixture was poured into ice and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness to give 3.36 g (80%) of an oil that solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J=9.0, 2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.69 (d, J=9.0 Hz, 1H), 8.71 (br.s., 1H).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1>>[CH3:3][CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CCCC(C)Br
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(OC(C)CCCC(C)C)cc1

Procedure:
2-bromo-6-methyl-heptane was reacted with p-hydroxy-acetophenone to obtain p-[(1,5-dimethyl-hexyl)-oxy]-acetophenone (boiling point = 200° C/1.0 mmHg);
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C=O)[CH2:6][CH2:5]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25](N)([CH3:27])[CH3:26].[O-]CC.[Na+]>C(O)C>[CH3:26][C:25]1([CH3:27])[NH:2][C:1]([CH2:3][CH:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]2)=[N:23][CH2:24]1
Reactant: N#CCC1CCN(C=O)CC1
Reactant: CC(C)(N)CN
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CN=C(CC2CCNCC2)N1
Temperature: 185 °C
Yield: 69 %

Procedure:
A mixture containing 4(cyanomethyl)-1-piperidinecarboxaldehyde (3.5 g, 0.023M) and 1,2-diamino-2-methylpropane mono-p-toluenesulfonate (12.4 g, 0.047M) was heated at 185° C. under nitrogen for 5 hrs. The reaction mixture was dissolved in ethanol (20 ml), basified with sodium ethoxide (0.052M), filtered and stripped to dryness. The residue was distilled at 150° C. to about 185° C., 0.02 mmHg, to give (3.1 g, 63%) 4-[(4,5-dihydro-5,5-dimethyl-1H-imidazol-2-yl)methyl]-piperidine.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@:9]([C@H:18]1[CH2:22][O:21][CH2:20][C@H:19]1[OH:23])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[CH3:10].[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25]>ClCCl.CN(C)C1C=CN=CC=1>[C:24]([Si:28]([CH3:31])([CH3:30])[O:23][C@@H:19]1[CH2:20][O:21][CH2:22][C@@H:18]1[C@:9]([NH2:8])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[CH3:10])([CH3:27])([CH3:26])[CH3:25]
Reactant: C[C@@](N)(c1ccccc1F)[C@H]1COC[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1COC[C@@H]1[C@](C)(N)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Triethylamine (8.05 g, 79.6 mmol) was added to a solution of rel-(3S,4S)-4-((S)-1-amino-1-(2-fluorophenyl)ethyl)tetrahydrofuran-3-ol (5.6 g, 24.9 mmol) in dichloromethane (100 ml) at 0° C., then 4-dimethylaminopyridine (1.52 g, 12.4 mmol) followed by tert-butyldimethylchlorosilane (7.49 g, 49.7 mmol). The reaction mixture was stirred at room temperature overnight. For the workup, the reaction mixture was extracted with a saturated solution of sodium hydrogencarbonate and brine. The organic layer was dried over sodium sulphate and evaporated. The crude material was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 50:50 as the eluent. The rel-(S)-1-[(3S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-yl]-1-(2-fluoro-phenyl)-ethylamine (8.13 g, 96% yield) was obtained as a colorless oil. MS (ISP): m/z=340.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([Cl:12])[CH:3]=1.[CH:13](OCC)(OCC)OCC>>[Cl:11][C:6]1[C:7]2[C:8](=[O:9])[NH:10][CH:13]=[N:1][C:2]=2[CH:3]=[C:4]([Cl:12])[N:5]=1
Reactant: NC(=O)c1c(N)cc(Cl)nc1Cl
Reactant: CCOC(OCC)OCC
Product: O=c1[nH]cnc2cc(Cl)nc(Cl)c12
Temperature: 150 °C

Procedure:
A mixture of 4-Amino-2,6-dichloronicotinamide (2.06 g, 10.0 mmol) and triethyl orthoformate (20 mL) was heated at 150° C. in a ChemGlass pressure vessel (heavy wall, 150 mL) for 6 hours and evaporated under reduced pressure to afford the crude title compound. 1H NMR (DMSO-d6) δ 7.72 (s, 1H), 8.31 (1H); ESI-MS m/z 216.0 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])=[O:6])C.[OH-].[K+]>C(O)C.O>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[NH:12][C:11]1[CH:10]=[CH:9][S:8][C:7]=1[C:5](=[O:6])[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C(=O)c1sccc1Nc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)c1sccc1Nc1c(Cl)cccc1Cl
Reaction time: 0.17 h

Procedure:
3.44 g (10 mmoles) of 3-(2,6-dichloroanilino)-2-thiophenglyoxylic acid ethyl ester are dissolved in 10 ml of ethanol with 1 g of potassium hydroxide until a homogeneous solution has formed--after 10 minutes. The solution is diluted with 50 ml of water, acidified and extracted with ethyl acetate; the organic phase is dried and concentrated. Recrystallization from cyclohexane with a little toluene yields 3-(2,6-dichloroanilino)-2-thiophenglyoxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([S:13]([C:16]3[CH:17]=[C:18]([NH2:25])[C:19](=[CH:23][CH:24]=3)[C:20]([OH:22])=[O:21])(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+:28].O>C1COCC1>[Na+:28].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([S:13]([C:16]3[CH:17]=[C:18]([NH2:25])[C:19](=[CH:23][CH:24]=3)[C:20]([O-:22])=[O:21])(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)ccc1C(=O)[O-]

Procedure:
50 mg (0.13 mmol) of Compound 17 was suspended in approximately 1 ml of THF, then 126 μl of 1N sodium hydroxide aqueous solution was added dropwise. The solution was confirmed to have become uniform, then 30 ml of water was added and the mixture was freeze-dried to quantitatively obtain the above-identified compound in an amorphous state in an amount of 52 mg. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 7.11-7.22 (3H, m), 7.37 (1H, s), 7.83 (1H, d), 7.91 (1H, d).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH:24]1[CH:29]=[C:28]([CH:30]=O)[C:27]([OH:32])=[CH:26][CH:25]=1>C(O)C>[O:32]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:29][C:28]=2[CH:30]=[C:2]1[C:3]([C:5]1[CH:6]=[C:7]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: CCOC(=O)C(C)c1cccc(C(=O)CBr)c1
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)c1cccc(C(=O)c2cc3ccccc3o2)c1
Yield: 25 %

Procedure:
Ethyl 2-[meta-(α-bromo-acetyl)-phenyl]propionate (0.1 mole) is mixed with dry potassium carbonate (0.2 mole), salicylic aldehyde (0.1 mole) and ethanol (200 cc). The mixture is refluxed for 5 hours, with vigorous stirring. The initially yellow reaction medium turns brown during the heating step. The reaction mixture is then allowed to cool and the resulting precipitate is suction filtered. The alcohol is removed in vacuo. The resulting material is taken up into ethyl acetate, after which it is washed to neutral pH, dried and evaporated. The distilled residue gives a thick oil, b.p.0.05 = 210°-220°C. A second distillation gives the pure product (Yield: 25%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][NH2:14])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:21](Cl)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[C:24]1([CH:23]=[CH:22][C:21]([NH:14][CH2:13][CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=2)=[O:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCOc1cccc(CCN)c1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cccc(CCNC(=O)C=Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 95.6 %

Procedure:
To a solution of 2-(3-butyloxyphenyl)ethylamine (1.0 g) in acetonitrile (40 cm3) was added powdered potassium carbonate (0.80 g). Cinnamoyl chloride (1.03 g) was then added portionwise over a period of fifteen minutes and the reaction mixture was then stirred at room temperature for 6.5 hours after which distilled water (40 cm3) was added. The mixture was left to stand overnight and was then filtered and extracted several times with ethyl acetate. The combined ethyl acetate extracts were washed successively with potassium bicarbonate solution, water and 0.5M hydrochloric acid before drying over sodium sulphate and then evaporating down to give the product as a tan coloured oil (1.60 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=2)[CH:15]=1)=[O:8].[CH2:31](O)[CH2:32][OH:33].O.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([O:27][CH2:31][CH2:32][OH:33])=[O:26])[CH:21]=2)[CH:15]=1)=[O:8]
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)c1
Reactant: OCCO
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)OCCO)c[nH]3)c2)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (70 mg, 0.17 mmol), ethylene glycol (1 ml), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HCl, 40 mg, 0.21 mmol) and 4-dimethylaminopyridine (DMAP, 10 mg, 0.08 mmol) in anhydrous DMF (10 ml) was stirred at 70° C. for 3 hours then room temperature for 16 hours. The mixture was poured into 100 ml of water. Saturated NaHCO3 solution was added until pH=9. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 3˜4% MeOH/CHCl3 to give 2-hydroxyethyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate as white solid. Yield: 40 mg, 51%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[C:4]=1[F:13].[C:14]([O-:17])(=[O:16])[CH3:15].[K+]>CN(C)C=O>[C:14]([O:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[C:4]=1[F:13])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: COc1ccc(CCl)c(F)c1OC
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(C)=O)c(F)c1OC
Temperature: 0 °C

Procedure:
5.5 g of α-chloro-2-fluoro-3,4-dimethoxytoluene and 4.05 g of potassium acetate are stirred at 80° for 25 hours in 50 ml of dimethylformamide. The reaction mixture is subsequently poured into 150 ml of ice-water and extracted with ether. The ether phases are washed with sodium chloride solution, dried over sodium sulfate and evaporated, 2-fluoro-3,4-dimethoxybenzyl acetate is obtained as an oil.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[CH2:32][C:33](O)=[O:34]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[CH2:32][C@@H:28]5[CH2:29][CH2:30][CH2:31][O:27]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C[C@@H]1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(C[C@@H]1CCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (72 mg, 65%), MS (ISP) m/z=441.4 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (S)-2-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH:14]([CH3:16])[CH3:15].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]([CH3:16])[CH3:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(Br)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of methyl 3-bromo-4-hydroxybenzoate (15.0 g, 64.9 mmol), 2-bromopropane (7.68 mL, 77.9 mmol) and potassium iodide (1.0 g, 6.49 mmol) in N,N-dimethylformamide (200 mL) was added potassium carbonate (13.5 g, 97.4 mmol) and the mixture was stirred at 80° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure. Brine was added to the obtained residue and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-hexane/ethyl acetate=9/1) to give the title compound (14.6 g, yield 83%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=1>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc2cc(-c3ccc(F)cc3)ccc2c1O
Temperature: 120 °C
Yield: 55 %

Procedure:
7-Bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (250 mg, 0.8443 mmol) was dissolved in dry DMF and 4 Å molecular sieves were added to maintain dryness. 4-fluorophenyl-tri-n-butylstannane (392 mg, 1.013 mmol) and bis(triphenylphosphine)palladium(II) dichloride (71 mg, 0.1013 mmol) were added sequentially and the reaction heated to 120° C. in an oil bath. Upon completion, the reaction was cooled and diluted with ethyl acetate. The solution was washed with water then brine and the organic phase dried over sodium sulfate. The crude material was purified by medium pressure liquid chromatography (15 to 45% ethyl acetate in hexanes) to give the desired material in 55% yield as a thick yellow oil. 1H NMR (200 MHz, CDCl3): δ ppm=11.88 (s, 1H), 8.83 (s, 1H), 8.41 (d, 1H), 8.05 (s, 1H), 7.93 (d, 1H), 7.66 (m, 2H), 7.18 (t, 2H), 4.57 (q, 2H), 1.52 (t, 3H.)
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[C:29]#[N:30].C([O-])(O)=O.[Na+]>>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][C:29](=[NH:30])[C:28]2[CH:31]=[CH:32][C:33]([F:34])=[C:26]([Cl:25])[CH:27]=2)[CH:16]=1
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(OC)c(NC(=N)c2ccc(F)c(Cl)c2)c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
Anhydrous p-toluene sulfonic acid (10 g, 52.57 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (3.88 g, 21.44 mmol) obtained in step 1 of Preparation Example 1 and 3-chloro-4-fluorobenzonitrile (5.0 g, 32.14 mol) were added thereto and stirred at 160° C. for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO3 thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.24 g, 9.62 mmol) in a yield of 45%.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[C:18]([CH3:20])[N:17]([CH3:21])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=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>[C:22]([N:6]1[C:5]2[CH:26]=[CH:27][C:2]([C:32]3[CH:33]=[N:34][C:29]([NH2:28])=[N:30][CH:31]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]=[C:18]([CH3:20])[N:17]([CH3:21])[N:16]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)nn1C
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: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)nn1C
Temperature: 110 °C
Yield: 76 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(1,5-dimethyl-1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (38 mg, 0.09 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (24 mg, 0.109 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.01 mmol) and 2 M aqueous Na2CO3 (0.2 mL, 0.4 mmol). The reaction mixture is heated under Argon at 110° C. for 3 hours. The residue is diluted with EtOAc (20 mL), washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-10% MeOH/CH2Cl2 as the eluent to afford the title compound (30 mg, 76%) as an off-white solid. LCMS (ESMS): m/z 439.72 (M++1).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:14]([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:19]#[N:20])=[C:13]([F:25])[C:12]([CH3:26])=[CH:11][CH:10]=1.[ClH:27].CCOC(C)=O>C(#N)C>[Cl:24][C:22]1[CH:21]=[C:18]([CH:17]=[C:16]([O:15][C:14]2[C:9]([Cl:27])=[CH:10][CH:11]=[C:12]([CH3:26])[C:13]=2[F:25])[CH:23]=1)[C:19]#[N:20]
Reactant: Cl
Reactant: Cc1ccc(N)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To an oven dried flask was added CuCl2 (2.5 g, 18.0 mmol). The flask was placed under high vacuum, flushed with nitrogen and acetonitrile (10 ml) was added. t-Butyl nitrite (2.7 mL, 22.5 mmol) was added dropwise. The stirred solution was placed in a an oil bath at 50° C. under gentle stream of nitrogen and 3-[(6-amino-2-fluoro-3-methylphenyl)oxy]-5-chlorobenzonitrile dissolved in acetonitrile (15 mL) was added dropwise. The reaction was stirred for 0.5 h, cooled to RT and poured into ice cold, aqueous HCl (0.5 N, 100 mL). EtOAc (100 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. Purification was accomplished by column chromatography (hexane/EtOAc) to afford the title compound (1.8 g, 67%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.79 (s, 1H), 7.48 (s, 1H), 7.44 (t, 1H), 7.41 (d, 1H), 7.31 (t, 1H), 2.27 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])[CH3:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([C:28](=[O:30])[CH3:29])[CH:36]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cccc(C(C)=O)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 3-acetylphenylboronic acid (90 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(3-acetyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a colorless oil.