Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([O:31][C:28]3[CH:29]=[CH:30][C:25]([CH2:24][C:16]4[NH:15][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[N:17]=4)=[CH:26][CH:27]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Oc1ccc(Cc2nc3ccccc3[nH]2)cc1
Reactant: Cc1cc(-c2cccnc2F)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Cc1cc(-c2cccnc2Oc2ccc(Cc3nc4ccccc4[nH]3)cc2)ccn1
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-3-(2-methylpyridin-4-yl)pyridine (1.00 g, 5.31 mmol), 4-((1H-benzo[d]imidazol-2-yl)methyl)phenol (1.43 g, 6.38 mmol) and cesium carbonate (2.60 g, 7.97 mmol) was heated to 80° C. for 16 h. After cooling to room temperature, the mixture was diluted with H2O and extracted with 25% i-PrOH/CHCl3 (3×). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (Acetone/Hexanes=0→80%) to give the title compound. MS (ESI, pos. ion) m/z: 393 (M+1). IC50 (uM) ++++.
Reaction SMILES: Cl.[C:2]1(=[O:20])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[NH:13])[C:5](=[O:15])[C:4]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:3]12.C(N(CC)CC)C.Cl[C:29](=[CH2:32])[C:30]#[N:31]>CCO>[NH2:31][C:30]1[CH:29]=[CH:32][N:14]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]2[C:5](=[O:15])[C:4]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:3]3[C:2]2=[O:20])[N:13]=1
Reactant: C=C(Cl)C#N
Reactant: N=C(N)CCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ccnc(CCCCCN2C(=O)c3ccccc3C2=O)n1

Procedure:
A mixture of 6-phthalimidohexanamidine hydrochloride (71.1 g.), triethylamine (170 ml.) and 2-chloroacrylonitrile (57.4 ml.) in EtOH (500 ml.) was heated under reflux for 2 hours. The solvent was evaporated and the residue was partitioned between EtOAc and 2N aqueous HCl. The aqueous layer was basified with 10N aqueous NaOH and the product was extracted with EtOAc, dried (MgSO4) and evaporated to dryness. The residual gum was dissolved in EtOAc and treated with excess of a solution of maleic acid in EtOAc. The precipitated solid was dissolved in water, basified with 10N aqueous sodium hydroxide, extracted with EtOAc, the extract dried (MgSO4) and evaporated. The residual solid was triturated with acetonitrile to give 4-amino-2-(5-phthalimidopentyl)pyrimidine as a brown solid (37.9 g.), m.p. 101°-4°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N+:16]([O-])=O)[CH:10]=2)[CH:4]=1>O1CCCC1.C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH:10]=2)[NH2:16])[CH:4]=1
Reactant: COc1ccnc(-c2ccc(C)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccnc(-c2ccc(C)c(N)c2)c1
Yield: 96.5 %

Procedure:
A suspension of 4-(4-methoxypyridin-2-yl)-2-nitrotoluene (300 mg) in tetrahydrofuran (3 ml) and ethanol (3 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 150 mg) under a hydrogen atmosphere for 3 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 5-(4-methoxypyridin-2-yl)-2-methylaniline (254 mg).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([F:14])=[C:9]([F:15])[CH:8]=1.[C:16](=[O:18])=[O:17].Cl>O1CCCC1.O>[F:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([F:14])=[C:9]([F:15])[C:8]=1[C:16]([OH:18])=[O:17]
Reactant: Fc1cc(F)c(F)cc1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(F)cc(F)c1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.7M solution in n-hexane, 148 cm3) was added dropwise over a period of one hour to a stirred solution of 2,3,5,6-tetrafluorobenzene (60 g) in dry tetrahydrofuran (200 cm3) maintained at -70° C. under a nitrogen atmosphere, after which the mixture was stirred at -70° C. for a further one hour. Carbon dioxide gas was passed into the mixture over a period of 4 hours during which time the temperature was allowed to warm up to the ambient value (ca. 22° C.). After adding water and acidifying with dilute hydrochloric acid, the mixture was extracted with diethyl ether and the extracts dried over anhydrous magnesium sulphate. The product was obtained by removal of the solvent by evaporation under reduced pressure to give 2,3,5,6-tetrafluorobenzoic acid (42.5 g), mp. 152°-154° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:19][S:20]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCOCc1ccccc1
Reaction time: 3 h
Yield: 96.4 %

Procedure:
2-Benzyloxyethanol (85.0 g) and triethylamine (73.5 g) were dissolved in THF (500 mL) and methanesulfonyl chloride (76.8 g) was added dropwise at from 0° C. to 10° C. The mixture was stirred for 3 hr. 10% Aqueous sodium bicarbonate (300 mL) was poured into the reaction mixture, the mixture was partitioned and combined with an extract of the aqueous layer with MTBE (300 mL), and the mixture was washed with 10% aqueous sodium bicarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2-benzyloxyethyl methanesulfonate (124.0 g). The 2-benzyloxyethyl methanesulfonate (124.0 g) was dissolved in acetone (500 mL), and sodium iodide (130.0 g) was added. The mixture was stirred at from 50° C. to 60° C. for 3 hr. The reaction mixture was filtered and the solvent was evaporated. Water (300 mL) was added, and the mixture was extracted twice with toluene (300 mL). The toluene layer was washed successively with aqueous sodium hydrogen sulfite solution, water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (127.0 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:12](O)=[O:13])[C:3]1=[O:15].S(Cl)([Cl:18])=O>>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:12]([Cl:18])=[O:13])[C:3]1=[O:15]
Reactant: Cn1c(C(F)(F)F)ccc(C(=O)O)c1=O
Reactant: O=S(Cl)Cl
Product: Cn1c(C(F)(F)F)ccc(C(=O)Cl)c1=O

Procedure:
1,2-dihydro-1-methyl-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid (17.8 g, 80.5 mmol) was dissolved in thionyl chloride (70 mL), and this mixed solution was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 1,2-dihydro-1-methyl-2-oxo-6-(trifluoromethyl)pyridine-3-carbonyl chloride. The obtained acid chloride was dissolved in acetonitrile (80 mL), and added dropwise to a mixed solution of 5-hydroxy-1-methyl-1H-pyrazole hydrochloride (10.8 g, 80.3 mmol), triethylamine (20.4 g, 201 mmol) and acetonitrile (20 mL), under ice cooling. After stirring this mixed solution for a day at room temperature, acetonecyanhydrin (0.69 g, 8.05 mmol) and triethylamine (9.8 g, 96.6 mmol) were added thereto, and the mixture was stirred overnight at room temperature. To a residue obtained by concentrating the reaction solution under reduced pressure, a mixture of aqueous saturated sodium bicarbonate and ethyl acetate was added for extraction and separation. Thus obtained aqueous layer was added with diluted hydrochloric acid to give a pH of 3 to 4, and extracted with chloroform. The obtained organic layer was dried over anhydrous magnesium sulfate, and the inorganic substance was separated by filtration. The solvent was distilled off under reduced pressure to obtain 10.4 g of a crude product of a subject compound.
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]2[C:9]([CH3:16])([CH3:15])[CH2:8][CH2:7][C:6]([CH3:18])([CH3:17])[C:5]=2[C:4]=1[OH:19])=[O:2].[OH-].[K+].S(OC)(O[CH3:26])(=O)=O.Cl>C1(C)C=CC=CC=1>[CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]2[C:9]([CH3:15])([CH3:16])[CH2:8][CH2:7][C:6]([CH3:18])([CH3:17])[C:5]=2[C:4]=1[O:19][CH3:26])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: Cc1c(C)c2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1c(C=O)c(C)c(C)c2c1C(C)(C)CCC2(C)C
Temperature: 55 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
Methylation. 2-Formyl-1-hydroxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene (8.7 g, 0.0335 mol) was stirred with toluene (60 mL), and potassium hydroxide 85% (3.1 g, 0.047 mol) was added in one portion. The mixture was heated to 55° C., dimethyl sulfate (6.3 g, 0.05 mol) added during 0.5 h at 55°-60° C., and the heating continued at 55°-60° C. for 4 h. The mixture was cooled to 20° C., neutralized with 5% hydrochloric acid, then washed with water (10 mL), and finally washed with brine (10 mL). The solvent was removed by distillation and the residue distilled to give 2-formyl-1-methoxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene (5.8 g), GLC purity 97%. Crystallization from hexane gave 3.5 g material with GLC purity 100%. 1H-NMR (CDCl3) δ10.40 (1H, s), 3.78 (3H, s), 2.40 (3H, s), 2.37 (3H, s), 1.64 (4H, s), 1.45 (6H, s), 1.42 (6H, s). 13C-NMR (CDCl3) δ193.5 (1C, d), 162.9 (1C, s), 151.6 (1C, s), 137.7 (1C, s), 136.7 (1C, s), 132.5 (1C, s), 126.9 (1C, s), 65.7 (1C, q), 40.3 (1C, t), 38.2 (1C, t), 36.2 (1C, s), 35.2 (1C, s), 30.2 (2C, q), 29.8 (2C, q), 19.7 (1C, q), 15.8 (1C, q). IR (KBr) 1244, 1271, 1682 cm-1, MS (m/e) 274.2 (M+, 34.9), 259.1 (100.0), 260.2 (21.7), 189.1 (21.5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2C[C@H:9]2[C:11]([O:13]CC)=O)=[CH:4][CH:3]=1.[CH3:16][C@@H:17]1[C@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:20][C:19](=[O:28])[NH:18]1.CCN(CC)CC>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:11]([N:18]2[C@@H:17]([CH3:16])[C@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:20][C:19]2=[O:28])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-bromo-phenyl)-1-imidazol-1-yl-propenone (1.05 eq) from Step 1, (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (1.0 eq) or (−)-isomer and Et3N (1.2 eq) in CH3CN (0.2M) was refluxed overnight. The resulting mixture was cooled to rt, filtered on a pad of silica gel and concentrated. Crystallization in hexane:Et2O afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH2:30](O)[C:31]([CH3:34])([CH3:33])[CH3:32]>>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Reactant: CC(C)(C)CO
Product: CC(C)(C)COC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
Using the procedure of Step A of Example 15, 3.89 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 1 g of neopentyl alcohol were reacted and the mixture was stirred at room temperature for 4 hours and was filtered. The filtrate was washed with N hydrochloric acid, with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 3.8 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[2-neopentyloxycarbonyl-ethynyl]-cyclopropane-carboxylate melting at 67° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][C:10](=[O:13])[NH:11][CH2:12][C:6]=2[CH:5]=1.[CH3:16]I>CN(C)C=O>[CH3:16][N:11]1[C:10](=[O:13])[CH2:9][CH2:8][C:7]2[CH:14]=[CH:15][C:4]([CH3:3])=[CH:5][C:6]=2[CH2:12]1
Reactant: Cc1ccc2c(c1)CNC(=O)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)CN(C)C(=O)CC2
Temperature: 80 °C
Yield: 55 %

Procedure:
0.023 moles of sodium hydride is added slowly, while stirring, to a solution of 2.0 g. (0.011 moles) of 8-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one in 60 ml. of dimethylformamide, followed by heating at 80° C. for 80 minutes. The reaction mixture is cooled in an ice bath and 6.5 g. (0.046 moles) of methyl iodide added dropwise, the rate of addition being regulated so as to maintain the temperature of the reaction mixture at about 10° C. When the addition is complete, the temperature is raised slowly to 60° C. and then maintained at this level for 3 hours. The reaction mixture is evaporated to dryness in vacuo and the solid residue is extracted with chloroform. The organic solution is washed twice with water, dried over anhydrous sodium sulfate, filtered and then evaporated to dried over anhydrous sodium sulfate, filtered and then evaporated to dryness in vacuo. The solid residue is taken up in diisopropyl ether, filtered over active carbon and recrystallized from diisopropyl ether. 2,8-Dimethyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one is obtained in a yield of 55% of theory. M.P. 75°-76° C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>C(Cl)Cl>[CH2:18]([N:20]([CH2:21][CH3:22])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:19]
Reactant: CCNCC
Reactant: CC(C)(C)c1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1C(C)(C)C
Temperature: 0 °C

Procedure:
A solution of 2-tert-butylbenzoic acid (4.0 g, 22.5 mmol) in thionyl chloride (8.2 mL, 112 mmol) was stirred at RT for 2 h, then was concentrated three times from carbon tetrachloride to remove all traces of excess thionyl chloride. A solution of diethylamine (4.93 g, 67.4 mmol) in CH2Cl2 (10 mL) was added dropwise over 10 min to an ice water-cooled solution of the crude acid chloride in CH2Cl2 (35 mL). Ten min after addition was complete, the reaction was partitioned between ether and 10% HCl. The ether phase was then washed with sat aq NaHCO3, then was dried (MgSO4), and concentrated to afford a quantitative yield of N,N-diethyl-2-tert-butyl-benzamide as an off-white solid. m.p. 38.5°-40.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:51]Br>C(#N)C>[CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Br:51]
Reactant: Cc1cccc(CO)c1[N+](=O)[O-]
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1cccc(CBr)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A round bottomed flask was charged with 5.0 g (0.029 mol) of 3-methyl-2-nitrobenzyl alcohol and 100 mL of anhydrous acetonitrile. The reaction solution was cooled to 0° C. and treated, portionwise, with 13.2 g (0.031 mol) triphenylphosphine perbromide (Ph3P—Br2). The reaction was allowed to warm to rt overnight at which point the solvent was removed and the resulting solids triturated with 50:50 ether:hexanes. The wash solvent was filtered through a fine frit and then concentrated to give a quantitative yield (7.03 g) of the desired material as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.36–7.34 (m, 2H), 7.33–7.24 (m, 1H), 4.45 (s, 2H), 2.33 (s, 3H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[C:21]=1[NH2:22])=[O:16])[CH3:13].[CH:30]([S:33](Cl)(=[O:35])=[O:34])([CH3:32])[CH3:31].Cl>ClCCl>[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=2)[C:21]=1[NH:22][S:33]([CH:30]([CH3:32])[CH3:31])(=[O:35])=[O:34])=[O:16])[CH3:13]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1N
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1NS(=O)(=O)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
Add DBU (5.14 mL, 33.69 mmol) to a solution of 5-amino-1-(4-bromo-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.612 g, 8.42 mmol) in dichloromethane (25 mL) at 0° C. Stir for 15 min. at 0° C. and then add isopropylsulfonyl chloride (1.94 mL, 16.84 mmol). Immerse the mixture into a pre-heated oil bath (50° C.). After stirring for 5 min., add additional isopropylsulfonyl chloride (0.97 mL, 8.42 mmol). Stir overnight at 50° C. Add 1.0M HCl (aq) until pH 5, wash with water (2×50 mL), dry over sodium sulfate, filter, and concentrate. Adsorb the compound onto silica gel, and subject to silica gel flash column chromatography (15-30% EtOAc/n-hexane) to yield 1-(4-Bromo-phenyl)5-(propane-2-sulfonylamino)-1H-pyrazole-4-carboxylic acid ethyl ester (2.55 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][NH:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[Br:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=1[CH2:30][C:31](Cl)=[O:32].[Cl-].[NH4+]>C1COCC1>[Br:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=1[CH2:30][C:31]([N:9]1[CH:10]=[CH:11][C:12](=[O:14])[CH2:13][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:32]
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Reactant: COc1cc(CC(=O)Cl)c(Br)cc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(CC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(Br)cc1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (80 mg) in THF (1.5 mL) at −78° C. under argon was added n-butyllithium (0.184 mL, 2.5M in hexanes). After ten minutes a solution of (2-bromo-5-methoxy-4-methyl-phenyl)-acetic acid chloride (116 mg) in THF (1 mL) was added. The mixture was stirred at −78° C. for 30 minutes, then at room temperature for 30 minutes. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hexanes/ethyl acetate gradient) gave (S)-1-[2-(2-bromo-5-methoxy-4-methyl-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one as a foam. MS (M+H) 433.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[CH3:27][S:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:27][S:28][C:29]1[CH:34]=[C:33]([C:2]2[C:3]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[C:4]=3[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CSc1cccc(B(O)O)c1
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(F)cc1F
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: C1COCCO1
Product: CSc1cccc(-c2nc(NC(CO)CO)nc3c2ccc(=O)n3-c2ccc(F)cc2F)c1
Temperature: 150 °C
Yield: 90 %

Procedure:
A solution of 4-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2, 4-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.13 mmol) in dioxane/H2O (3:1, 4.8 mL) was mixed with 3-methylthiophenyl boronic acid (33.8 mg, 0.20 mmol) and K2CO3 (54.3 mg, 0.39 mmol). The resultant mixture was bubbled with argon for 5 minutes follwoed by the addition of Pd(PPh3)4 (3.0 mg, 0.0026 mmol). The reaction tube was sealed and heated with “Smith Creator” (microwave, 150° C.) for 15 minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (90%): MS (ES) m/z 471 (M+H)+; 1H-NMR(CDCl3) δ 2.40 (s, br, 2H), 2.40 (s, 3H), 3.90 (m, br, 5H), 6.00 (m, br, 1H), 6.45 (m, 1H), 7.15 (m, 2H), 7.40 (m, 5H), 7.85 (m, 1H).
Reaction SMILES: [Li+].C[CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].[C:9](#N)[C:10]([CH3:12])=O>C1COCC1>[NH:5]1[C:6]2[C:7](=[CH:9][CH:10]=[CH:12][CH:8]=2)[CH:4]=[CH:3]1
Reactant: CC(=O)C#N
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 1 (426 mg, 1.26 mmol) in THF (6 mL) at −78° C. was added dropwise a 1.8 M solution of LDA in THF (1.54 mL, 2.78 mmol) and the reaction stirred for 1 hour, then pyruvonitrile (0.208 mL, 2.78 mmol) was added dropwise and the reaction was stirred for 15 minutes turning homogeneous. The reaction was quenched by the addition of satd. NH4Cl (10 mL), the layers separated, and the aqueous extracted with Et2O (3×10 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on silica gel gradiently eluted with 20 to 40% EtOAc/hexanes to give 2 (230 mg, 48% yield) as an off-white solid. Rt=1.71 min using Phenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. [M+H]=380.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:18]=2[F:27])[CH2:12][CH2:11]1)=[O:9].O>CN(C)C=O>[N:1]1([CH2:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([O:16][C:17]3[C:18]([F:27])=[C:19]([F:26])[C:20]([F:25])=[C:21]([F:24])[C:22]=3[F:23])[CH2:14][CH2:15]2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCl)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1ccnc1)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 75 °C
Reaction time: 5 h
Yield: 46.9 %

Procedure:
A stirring solution of 7.11 g of imidazole in 100 ml of dimethylformamide was treated with a solution of 7.22 g of 1-(2-chloroacetyl)-4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 50 ml of dimethylformamide and then stirred at 75° C. for five hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was purified by means of high pressure liquid chromatography (silica gel; elution with 7.5% methanol/dichloromethane). Recrystallization of the resulting solid from ethyl acetate/hexane (10:1) afforded 3.70 g (47.0%) of 1-[(2-imidazol-1-yl)acetyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 95°-96° C.