Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH3:2].[NH:23]1[CH:27]=[CH:26][CH:25]=[N:24]1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:21][C:5]([S:17]([CH3:20])(=[O:19])=[O:18])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)=[CH:10][CH:9]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: CCOC(=O)C(C)(CCc1ccc(B(O)O)cc1)S(C)(=O)=O
Reactant: c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(CCc1ccc(-n2cccn2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of {4-[4-ethoxy-3-methyl-3-(methylsulfonyl)-4-oxobutyl]phenyl}boronic acid which may be prepared as in Example 10, Step, A (597 mg, 1.82 mmol) in methylene chloride (3 mL) was added pyrazole (62 mg, 0.91 mmol), pyridine (147 uL, 1.82 mmol) and copper (II) acetate (157 mg, 0.866 mmol). The mixture was stirred at ambient temperature under an open atmosphere for 2 days. Silica gel was added, the mixture was concentrated to dryness and purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(1H-pyrazol-1-yl)phenyl]butanoate as an oil. 316.9 mg. LCMS: (M+1) 351.2.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([Cl:21])[CH:14]=1)[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH4-].[Na+]>CCO>[Cl:21][C:15]1[CH:14]=[C:13]([NH:12][C@H:3]([CH2:2][NH:1][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:4][C:5]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[CH:18]=[CH:17][C:16]=1[C:19]#[N:20]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@@H](CN)Nc1ccc(C#N)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CNCc1ccccc1)Nc1ccc(C#N)c(Cl)c1
Reaction time: 1 h
Yield: 58.7 %

Procedure:
1,1-Dimethylethyl (3S)-4-amino-3-[(3-chloro-4-cyanophenyl)amino]butanoate (0.355 g, 1.15 mmol), benzaldehyde (0.12 g, 1.15 mmol), and 4 Å molecular sieves in EtOH (4 mL) were stirred at room temperature for 3 h. To this mixture, NaBH4 (excess amount) was added and the reaction was stirred for additional 1 h. The reaction was filtered. The filtrate was diluted with H2O and extracted with Et2O (2×). The organic extracts were washed with H2O, dried over Na2SO4, filtered, concentrated, and purified via silica gel chromatography with 0% MeOH in CH2Cl2 grading to 5% MeOH in CH2Cl2 to yield the titled product (0.27 g, 59%) as a white solid. LC-MS (ES) m/e 400.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH2:31][CH2:32][OH:33]>>[CH3:29][N:30]([CH2:21][CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:1])[F:27])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:31][CH2:32][OH:33]
Reactant: CNCCO
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CN(CCO)CCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1; Methanesulfonic acid 4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and 2-Methylaminoethanol were converted to yield 2-(Methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-amino)-ethanol as light yellow oil, MS: 409 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>C1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 62.6 %

Procedure:
42 g (0.3 mole) of 3-amino-5-t-butylpyrazole prepared in Example 1 was dissolved in 200 ml of benzene, and 30.6 g of acetic anhydride was added dropwise thereto at 20° to 40° C. while cooling with water. After completion of the dropwise addition, the mixture was allowed to react at 50° to 60° C. for 3 hours. Thereafter, the reaction product was cooled, and water was added to form a precipitate. The precipitate was collected by filtration, and washed with water and benzene to obtain 34 g of 3-acetylamino-5-t-butylpyrazole. This product was recrystallized from hydrous methanol and found to have a melting point of 194° to 195° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C@H:8]1[NH:11][C:10](=[O:12])[C@@H:9]1[C@H:13]([O:15]C(OCC1C=CC=CC=1)=O)[CH3:14])=[CH2:7])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:6]([C@H:8]1[NH:11][C:10](=[O:12])[C@@H:9]1[C@H:13]([OH:15])[CH3:14])[CH3:7])=[O:5])[CH3:2]
Reactant: C=C(C(=O)OCC)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O

Procedure:
A solution of (3S,4S)-4-(1-ethoxycarbonylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone (40.0 g) in ethanol (600 ml) was hydrogenated under hydrogen atmosphere in the presence of 10% Pd/C (20.0 g) at room temperature for 3 hours. The mixture was filtered, and the filtrate was evaporated in vacuo to give (3S,4S)-4-(1-ethoxycarbonylethyl)-3-(1-(R)-hydroxyethyl)-2-azetidinone as a yellowish oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:9][CH:8]=3.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C1(C)C=CC=CC=1>C(O)C>[C:15]1([C:10]2[CH:9]=[CH:8][C:7]3[N:6]([C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:5]4[C:13]([C:12]=3[CH:11]=2)=[CH:14][C:2]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)=[CH:3][CH:4]=4)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(-n2c3ccc(Br)cc3c3cc(-c4ccccc4)ccc32)cc1
Reactant: COc1ccc(B(O)O)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3c(c2)c2cc(-c4ccccc4)ccc2n3-c2ccc(C)cc2)cc1
Yield: 67.4 %

Procedure:
The 3-bromo-6-phenyl-N-(4-methylphenyl)carbazole (3.20 g) and 4-methoxyphenylboronic acid (1.65 g) were added to a solvent mixture of toluene (30 mL) and ethanol (8 mL), followed by bubbling with nitrogen. Then, tetrakistriphenylphosphine palladium (150 mg) and 21.2% aqueous sodium carbonate solution (7.80 g) were added to the mixture, and the resultant mixture was refluxed under nitrogen flow for 3 hours. The mixture was diluted with toluene. The toluene layer was washed with water and dried and the toluene was evaporated. The residue was treated through silica gel column chromatography (eluent: toluene), to thereby obtain 2.30 g of 3-phenyl-6-(4-methoxyphenyl)-N-(4-methylphenyl)carbazole as colorless powder.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15](Cl)=[O:16].[Cl:23][C:24]1[CH:25]=[C:26]([NH2:33])[C:27](=[CH:31][CH:32]=1)[C:28]([OH:30])=[O:29]>O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15]([NH:33][C:26]1[C:27](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=1)[C:28]([OH:30])=[O:29])=[O:16]
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)Nc2cc(Cl)ccc2C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
In a mixture of 3.4 g of 4-chloroanthranilic acid in 50 ml of tetrahydrofuran is dissolved 3 ml of triethylamine, to this mixture is added slowly a solution of 4.5 g of 3,4-dimethoxycinnamoylchloride in tetrahydrofuran under room temperature, and this solution is stirred at room temperature for 5 hours. The reaction mixture is concentrated under a reduced pressure, to the residue is added water and hydrochloric acid is added to make the mixture the weakly acidic. The precipitated crystals are collected by filtration and recrystallized from a mixture of dimethylformamide and water to obtain 5.9 g of N-(3,4-dimethoxycinnamoyl)-4-chloroanthranilic acid as colorless prisms.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[OH-:17].[Na+]>C(O)C>[CH2:1]([C:3]1[C:8]([C:9]([NH2:10])=[O:17])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCc1c(C#N)cccc1-c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCc1c(C(N)=O)cccc1-c1ccccc1

Procedure:
Under a dry nitrogen atmosphere a mixture of 3-chloro-2-ethyl-[1,1'-biphenyl] (2.3 g, 0.0106 mole), copper cyanide (1.4 g, 0.0016 mole) and pyridine (1.2 g, 0.016 mole) was heated at 195° for approximately 18 hours. The reaction mixture was cooled to room temperature to give a solid. The solid was dissolved in 300 ml of methylene chloride and washed with 25% aqueous ammonium hydroxide and the aqueous phase extracted with 250 ml of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carbonitrile as a solid. A mixture of ethyl-[1,1'-biphenyl]-3-carbonitrile (2.2 g, 0.0106 mole), 40 ml of 10N aqueous sodium hydroxide, and 40 ml of ethanol was heated at reflux for approximately 18 hours. The reaction mixture was cooled and the ethanol evaporated under reduced pressure. The remaining aqueous portion was diluted with 100 ml of water, then extracted with three 150 ml portions of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carboxamide (2.4 g).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:16][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:14]2)[CH:8]=1)C.[Li+].[OH-]>CO>[C:28]([C:15]1[CH:16]=[C:17]([NH:18][C:19](=[O:27])[C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[N:13]([C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:32])=[O:3])[CH:12]=[CH:11][CH:10]=2)[N:14]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc(Cl)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)c2ccc(Cl)cc2)n(-c2cccc(CCC(=O)O)c2)n1
Yield: 90.4 %

Procedure:
A solution of Example 158 (45 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH=4, and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine, and dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-{3-[3-t-butyl-5-(4-chloro-benzoylamino)-pyrazol-1-yl]-phenyl}-propionic acid, (38.5 mg, 87%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=O.[C:15](#[N:18])[CH:16]=[CH2:17].C1N2CCN(CC2)C1>CCOCC>[F:12][C:11]([F:14])([F:13])[O:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[O:1][CH2:17][C:16]([C:15]#[N:18])=[CH:4]2
Reactant: C=CC#N
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: N#CC1=Cc2cc(OC(F)(F)F)ccc2OC1
Temperature: 130 °C
Yield: 49.8 %

Procedure:
To a microwave tube was added 2-hydroxy-5-trifluoromethoxybenzaldehyde (1 g, 5.0 mmol), 2-propenenitrile (1.6 mL, 24.3 mmol) and triethylenediamine (136 mg, 1.2 mmol). The reaction was heated in the microwave at 130° C. for 1 hour. After cooling, the resulting solution was diluted with ether (100 mL) and washed with 1N NaOH (50 mL), 1N HCl (50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 15% EtOAc in hexanes over 1 hour) gave the product (600 mg) as a solid. m/z=242.4 (M+1), r.t.=3.72 mins. 1H NMR (400 MHz; CDCl3) δ 7.14-7.12 (2H, m), 7.00 (1H, s), 6.89 (1H, d), 4.85 (2H, s).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][NH:13][C:12]2=[O:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:17][C:18]#[N:19].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:18]([CH2:17][N:13]1[CH2:14][CH:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:15])#[N:19]
Reactant: O=C(Cc1ccccc1)NC1CNC1=O
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCN1CC(NC(=O)Cc2ccccc2)C1=O
Temperature: 25 °C
Yield: 11.6 %

Procedure:
3-(2-Phenylacetamido)-2-azetidinone (408 mg.) and 2-chloroacetonitrile (152 mg.) was dissolved in N,N-dimethylformamide (15 ml.), and to the solution was added sodium hydride (50% oily) (105 mg.) under stirring at ambient temperature, whereafter the reaction mixture was stirred for an hour at room temperature, and ethyl acetate (100 ml.) was added to the reaction mixture. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off from the solution under reduced pressure. The oily residue (0.25 g.) obtained was subjected to column chromatography using silica.gel. 1-Cyanomethyl-3-(2-phenylacetamido)-2-azetidinone (56.3 mg.) was obtained from fractions eluted with chloroform. Mp 108° to 109° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[CH:5]2.[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18]OS(C)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[CH:5]2
Reactant: O=c1occc2cc(O)ccc12
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1occc2cc(OC[C@@H]3CCCO3)ccc12
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To a solution of 6-hydroxyisochromen-1-one (2 g) in DMF (50 ml) were added methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester (2.7 g) and cesium carbonate (12 g), and the mixture was stirred at 80° C. for 7 hours. After water had been added, the mixture was extracted with dichloromethane. The organic phases were dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 246.27 (C14H14O4); MS (ESI): 247 (M+H+).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:7]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6](C2C=CC(OC)=CC=2)[C:5]1=[O:24])=[N+:2]=[N-:3]>O.C(#N)C>[N:1]([C@H:4]1[C@@H:7]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:6][C:5]1=[O:24])=[N+:2]=[N-:3]
Reactant: COc1ccc(N2C(=O)[C@@H](N=[N+]=[N-])[C@H]2C=Cc2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: [N-]=[N+]=N[C@@H]1C(=O)N[C@@H]1C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
To a solution of 10.22 g of ceric ammonium nitrate in 13 ml of water at 0° C. is added 1.99 g of (±)-(cis)-3-azido-1-(4-methoxyphenyl)-2-oxo-4-(2-phenylethenyl)azetidine dissolved in 65 ml of acetonitrile during a 15 minute period (additional 10 ml of acetonitrile is used for rinse). The mixture is stirred for an additional 15 minutes at 0° C., diluted with 750 ml of ethyl acetate, washed with water (six 600 ml portions), dried over anhydrous sodium sulfate, and stripped of solvent to give an oil. The crude product is chromatographed on 90 g of silica gel, eluting first with 250 ml of 30% ethyl acetate/petroleum ether, then 50% ethyl acetate/petroleum ether. Fractions (50 ml each) 11-16 are combined and evaporated to give 802 mg of the title compound as an oil.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[C:16]([OH:18])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:22])=O>ClCCl.CN(C)C=O>[C:1]1([S:7]([NH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[C:16]([Cl:22])=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1sccc1NS(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1sccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
3-Benzenesulfonylaminothiophene-2-carboxylic acid (0.61 g, 2.15 mmol) was suspended in dichloromethane (8.6 mL). The resulting mixture was sequentially treated with N,N-dimethylformamide (1 drop), and, in two portions, oxalyl chloride (0.42 mL, 4.8 mmol). After stirring briefly at room temperature, the foaming subsided and the solution was refluxed until the reaction was complete. The mixture was concentrated to dryness, re-dissolved in dichloromethane, and filtered through very small pad of course silica gel, eluting with dichloromethane. Upon concentration of the eluent, the desired 3-benzenesulfonylaminothiophene-2-carboxylic acid chloride was obtained as a yellow solid (0.32 g, 49%), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].B(F)(F)F.CCOCC.[CH:19]([O:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([N:29]2[CH2:34][CH2:33][C:32](=[CH:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:30]2)=[O:28])=[CH:25][C:24]=1[CH3:41])([CH3:21])[CH3:20]>ClCCl>[F:1][C:2]1[CH:9]=[C:6]([CH:7]([OH:8])[CH2:37][C:36](=[O:38])[CH:35]=[C:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[C:26]3[CH:39]=[CH:40][C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[C:24]([CH3:41])[CH:25]=3)[CH2:30][CH2:31]2)[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cncc(F)c1
Reactant: CC(=O)C=C1CCN(C(=O)c2ccc(OC(C)C)c(C)c2)CC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C(=O)N2CCC(=CC(=O)CC(O)c3cncc(F)c3)CC2)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-fluoronicotinaldehyde (51 mg, 0.41 mmol) in dichloromethane (1.7 mL) was cooled to −78° C. and boron trifluoride diethyl etherate (164 μL, 0.82 mmol) was added. The mixture was stirred at −78° C. for 5 min. The solution from step 1 was added. The mixture was stirred at −78° C. for 5 min, quenched with a buffer solution of pH=7. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified on silica gel utilizing a gradient of 60-100% ethyl acetate in hexanes to afford 4-(5-fluoro-3-pyridyl)-4-hydroxy-1-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]butan-2-one (105 mg). 1H NMR (400 MHz, CDCl3) δ 8.46-8.31 (m, 2H), 7.53-7.49 (m, 1H), 7.24-7.22 (m, 2H), 6.83 (d, J=8.1 Hz, 1H), 6.09 (s, 1H), 5.26 (dd, J=8.9, 5.9 Hz, 1H), 4.62-4.53 (m, 1H), 4.13-4.12 (m, 1H), 3.69 (br d, 4H), 3.00 (br s, 2H), 2.88 (d, J=6.2 Hz, 2H), 2.37 (br s, 2H), 2.21 (s, 3H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 440.21, found 441.4 (M+1)+; Retention time: 1.65 minutes (3 min run).
Reaction SMILES: [Si]([O:18][C:19]1[CH:51]=[CH:50][C:22]([O:23][CH2:24][C@@H:25]([OH:49])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]([C:45]([CH3:47])=[CH2:46])[C:37]3=[O:48])=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:49][C@H:25]([CH2:24][O:23][C:22]1[CH:50]=[CH:51][C:19]([OH:18])=[CH:20][CH:21]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:40]3=[N:41][CH:42]=[CH:43][CH:44]=[C:39]3[N:38]([C:45]([CH3:47])=[CH2:46])[C:37]2=[O:48])=[CH:32][CH:31]=1
Reactant: C=C(C)n1c(=O)n(-c2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)c2ncccc21
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=C(C)n1c(=O)n(-c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)c2ncccc21
Yield: 86 %

Procedure:
3-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)phenyl]-1-isopropenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.19 g, 0.272 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.108 g, 0.234 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH2:8][CH:9]=O)[CH:7]=1.[CH3:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH2:8][CH2:9][N:26]2[CH2:27][CH2:28][N:23]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:20]=3[CH:21]=[CH:22][C:13]([CH3:12])=[N:14]4)[CH2:24][CH2:25]2)[CH:7]=1
Reactant: O=CCc1cc(Br)ccc1F
Reactant: Cc1ccc2c(N3CCNCC3)cccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1ccc2c(N3CCN(CCc4cc(Br)ccc4F)CC3)cccc2n1
Yield: 95 %

Procedure:
The title compound was prepared in 95% yield from (5-bromo-2-fluorophenyl)acetaldehyde (0.98 g), 2-methyl-5-(1-piperazinyl)quinoline (0.51 g) and sodium triacetoxyborohydride (0.95 g) according to the procedure described for Example 131.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([Cl:22])[CH:15]=2)[C:8]([O:12][CH3:13])=[C:9]([F:11])[CH:10]=1)=[O:4].CO.[OH-].[Na+].OS([O-])(=O)=O.[Na+]>O>[Cl:22][C:16]1[CH:15]=[C:14]([C:7]2[C:8]([O:12][CH3:13])=[C:9]([F:11])[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COC(=O)c1cc(F)c(OC)c(-c2ccc(OC)c(Cl)c2)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc(C(=O)O)cc(F)c2OC)cc1Cl
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
500 mg of 3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carboxylic acid methyl ester were dissolved using 10 ml of methanol and 1.8 ml of a 1M aqueous NaOH-solution added. The reaction mixture was stirred at 60° C. for 5 h and was then allowed to cool to room temperature. The reaction mixture was then poured into 25 ml of water and acidified to pH=4 using aqueous NaHSO4-solution. The mixture was extracted three times using 20 ml of EA each. The organic layer was dried using MgSO4 and evaporated to yield 430 mg of the title compound that was used without further purification.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([N:18]([CH2:19][CH3:20])[C:2]1[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1)[CH3:17]
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1oc(N(CC)CC)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
To a reaction vessel containing a stirred mixture of 3.15 g (13 mmol) of ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate in 25 ml of toluene, there was added 3 ml (29 mmol) of diethylamine. The reactionmixture was stirred at ambient temperature for 4 hours and then suction filtered. The filtrate was washed with 5% hydrochloric acid, then with saturated brine, then dried over sodium sulfate and concentrated under reduced pressure to yield 3.3 g of a pale yellow oil. This oil was subjected to Kugelrohr distillation (60° C. @ 3 mm Hg) to remove trace amounts of starting material. Further Kugelrohr distillation provided 2.9 g of colorless oil (b.p. 110° C. @ 3 mm Hg) identified in Table I.