Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][C:9]([CH2:11][C:12](=[O:24])[C:13](=[N+:22]=[N-:23])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl[C@@H:26]1[N:29](C(=O)C(OCOC(=O)C(C)(C)C)=O)[C:28](=[O:43])[C@H:27]1[C:44]([OH:47])([CH3:46])[CH3:45].C(O)(=O)C>ClCCl>[C:4]([O:8][C:9]([CH:11]([C@H:26]1[NH:29][C:28](=[O:43])[C@@H:27]1[C:44]([OH:47])([CH3:46])[CH3:45])[C:12](=[O:24])[C:13](=[N+:22]=[N-:23])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)C(=O)OCOC(=O)C(=O)N1C(=O)[C@@H](C(C)(C)O)[C@@H]1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)C(=[N+]=[N-])C(=O)OCC(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C(C(=O)C(=[N+]=[N-])C(=O)OCC(Cl)(Cl)Cl)[C@H]1NC(=O)[C@@H]1C(C)(C)O
Temperature: -78 °C

Procedure:
To 50 ml of 0.2 M methanolic sodium methoxide solution stirred and cooled at -78° C., are successively added 3.43 g of 2,2,2-trichloroethyl 4-t-butyloxycarbonyl-2-diazo-3-oxobutyrate in 30 ml of dichloromethane and 10 mMol equivalent of pivaloyloxymethyl [3R,4S]-2-[4-chloro-3-(1-hydroxyisopropyl)-2-oxoazetidin-1-yl]-2-oxoacetate, which is prepared according to the procedure of Example 1, in 30 ml of dichloromethane. After a few minutes, 0.6 ml of acetic acid is added to the solution and the solution is evaporated to dryness under reduced pressure. The residue is taken into 50 ml of ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure to give the crude product. The product is subjected to silica-gel column chromatography by use of n-hexane-ethyl acetate=1:2 for elution. The fractions containing the desired compound are combined and concentrated to give 2.6 g of the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C:19](=[O:30])[C@@H:20]5[O:29][C@@H:21]53)[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.[BH4-].[Na+].Cl>C(O)C.O>[CH3:31][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C@H:19]([OH:30])[C@@H:20]5[O:29][C@@H:21]53)[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
In 200 mL of ethanol was dissolved 13.0 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one, followed by addition of 1.0 g of sodium borohydride under ice-cooling. The mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was neutralized with diluted hydrochloric acid under ice-cooling, diluted with water and extracted with methylene chloride. The extract was washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure to recover 12.1 g of a crude product. Purification of this crude product by silica gel chromatography gave 10.6 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3α-ol (yield: 81%) having the following physical properties.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH3:17])=[O:15])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>>[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:14]([NH:16][CH3:17])=[O:15])[CH:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CNC(=O)c1cc(Br)cc(-c2ccccc2)c1
Product: CNC(=O)c1cc(-c2ccccc2)cc(-c2ccc(C=O)cc2)c1

Procedure:
In a manner similar to that of Example 1(e), by reacting 2 g (7 mmol) of 5-bromo-N-methyl-3-biphenylcarboxamide and 1.4 g (9.3 mmol) of 4-formylbenzene boronic acid, and after purification by recrystallization from acetonitrile, 1.4 g (63%) of the expected product are obtained in the form of a beige-colored solid.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4].[H][H]>[Pd].C(OCC)(=O)C>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CC(C)(C#N)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1ccc(N)cc1
Yield: 92.6 %

Procedure:
2-methyl-2-(4-nitrophenyl) propanenitrile (4.5 g, 23.6 mmol) was added to a reaction vessel, to which were successively added Pd/C (450 mg) and 50 mL ethyl acetate. The system was vacuumed and hydrogen was introduced. The resulting mixture is reacted at room temperature for 15 hrs. The resulting reaction was filtered with Celite, and washed with ethyl acetate. The resulting filtrate was concentrated to obtain a colorless oil of 2-(4-aminophenyl)-2-methyl propanenitrile (3.5 g).
Reaction SMILES: O.[CH3:2][O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]2[CH:10]=[C:11]3[O:21][CH2:20][CH2:19][O:18][C:12]3=[CH:13][C:14]=2[C:15]=1[CH2:16][Cl:17])=[O:5].P(Cl)(Cl)([Cl:25])=O>>[CH3:2][O:3][C:4]([C:6]1[C:7]([Cl:25])=[N:8][C:9]2[CH:10]=[C:11]3[O:21][CH2:20][CH2:19][O:18][C:12]3=[CH:13][C:14]=2[C:15]=1[CH2:16][Cl:17])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c(CCl)c2cc3c(cc2[nH]c1=O)OCCO3
Solvent: O
Product: COC(=O)c1c(Cl)nc2cc3c(cc2c1CCl)OCCO3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 4-necked 5-L round-bottom flask is equipped with a mechanical stirrer and water-cooled condenser. Under nitrogen, the flask is charged with 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester (Intermediate 5, 360 g, 1.16 mol), as a suspension in phosphorus oxychloride (1.8 kg). The mixture is heated to reflux Generating a black solution. After being heated at reflux for 20 h, the reaction mixture is allowed to cool to ambient temperature and transferred to a 25-L separatory funnel containing 18 L of ice water. After being stirred vigorously for 1.5 h, the precipitate is collected on a Buchner funnel, washed with water (3 L) and dried in vacuo at 50° C. yielding 7-chloro-9-chloromethyl-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxlic acid methyl ester as a dark crystalline solid: mp 130-132° C. 1H NMR (CDCl3, 200 MHz) d 4.05 (s, 3H), 4.42 (s, 4H), 4.81 (s, 2H), 7.50 (s, 2H). Elemental analysis: Calculated for C14H11Cl2NO4: C 51.24, H 3.38, N 4.27. Found: C 51.10, H 3.34, N 4.33.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][N:7]([C:9]3[N:14]=[CH:13][C:12]([NH:15][CH:16]([CH:33]4[CH2:36][C:35]([CH3:38])([CH3:37])[CH2:34]4)[C:17]4[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[CH:19][CH:18]=4)=[CH:11][CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Li+]>CO>[CH:1]1([C:4]2[CH:5]=[N:6][N:7]([C:9]3[N:14]=[CH:13][C:12]([NH:15][CH:16]([CH:33]4[CH2:36][C:35]([CH3:38])([CH3:37])[CH2:34]4)[C:17]4[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=4)=[CH:11][CH:10]=3)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cc(C4CC4)cn3)nc2)C2CC(C)(C)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(C(Nc2ccc(-n3cc(C4CC4)cn3)nc2)c2ccc(C(=O)NCCC(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of crude (+/−)-ethyl N-{4-[{[6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]amino}(3,3-dimethylcyclobutyl)methyl]benzoyl}-beta-alaninate (2.48 g, 4.91 mmol) was dissolved in methanol (4.8 ml) and tetrahydrofuran (2.4 ml) and treated with aqueous 2.0M lithium hydroxide (4.8 ml, 9.6 mmol). The mixture was stirred at ambient temperature for 12 hours. The reaction was concentrated in vacuo, then diluted with water and acidified with aqueous 1.0M hydrochloric acid. A yellow precipitate formed and was collected by filtration. The two enantiomeric products were separated by chiral SFC Column: Chiralpak AD-H. Dimensions: 21×250 mm. Mobile Phase: 50/50 CO2/methanol, (peak 1, 638 mg, 27% and peak 2, 682 g, 29%). Flow Rate: 65 mL/min. Modifier: none. Analytical SFC: Chiralpak AD-H, 4.6 mm×25 cm; SFC Mobile Phase 50:50 CO2/Methanol, 2.5 mL/min, analytical retention time: 3.90 min (Isomer 2) and 9.30 (Isomer 1). 1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.60 (d, J=2.5 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 6.84 (dd, J=8.8, 2.7 Hz, 1H), 4.14 (d, J=9.4 Hz, 1H), 3.56-3.67 (m, 2H), 2.40-2.47 (m, 2H), 1.96 (ddd, J=11.2, 8.0, 3.9 Hz, 1H), 1.60-1.74 (m, 3H), 1.54 (ddd, J=11.9, 8.4, 3.7 Hz, 1H), 1.28-1.34 (m, 1H), 1.09 (s, 3H), 1.07 (s, 3H), 0.81-0.86 (m, 2H), 0.50-0.56 (m, 2H) MS (M+1): 488.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([C:14](=O)[CH3:15])=[CH:12][C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.[CH3:17][Mg]Br>C1COCC1>[CH:14]([C:13]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1)([CH3:15])[CH3:17]
Reactant: COc1cc2c(cc1C(C)=O)N(C)CCO2
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc2c(cc1C(C)C)N(C)CCO2
Temperature: 0 °C
Yield: 30 %

Procedure:
1-(7-Methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethanone (10.48 g, 0.473 mol) was dissolved in 25 mL dry THF and the reaction mixture was stirred at 0° C. under nitrogen. Methyl magnesium bromide (22 mL of 3M solution in Et2O, 0.15 mol) was added dropwise, and the reaction mixture was stirred at 0° C. for two hours. The reaction was quenched by dropwise addition of 50 mL 10% aqueous ammonium chloride, followed by water. The aqueous mixture was extracted with EtOAc, and the combined organic layers were dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was taken up in 95 mL acetic acid, and the reaction mixture was stirred at room temperature under nitrogen. Ammonium formate (14.92 g) and 10% Palladium on activated carbon (1.0 g) were added, and the reaction mixture was heated to 120° C. for three hours. The reaction mixture was cooled, solids were removed by filtration, and the filtrate was diluted with water, and made neutral by addition of solid sodium bicarbonate. The resulting aqueous solution was extracted with EtOAc, and the combined organic layers were dried (MgSO4), filtered, and evaporated under reduced pressure to yield 9.97 g of 6-Isopropyl-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[C:24]1[CH:28]=[C:27]([S:29][CH3:30])[N:26]([CH3:31])[N:25]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:23][C:15]1[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]([Cl:12])[C:14]=1[C:24]1[CH:28]=[C:27]([S:29]([CH3:30])=[O:9])[N:26]([CH3:31])[N:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S(C)=O

Procedure:
A 0.3 g quantity of 70% m-chloroperbenzoic acid was slowly added to 0.3 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-5-methylsulfenylpyrazole (compound 1) in 20 ml of anhydrous chloroform at room temperature with stirring, followed by stirring for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, an organic layer was then separated off, washed with 5% aqueous sodium hydroxide solution and with brine and dried over anhydrous magnesium sulfate. The solvent was thereafter distilled off under reduced pressure, giving 0.3 g of the desired compound in the form of white crystals (quantitative crude yield).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=1[O:38][CH3:39])=[O:14])(C)(C)C>C(Cl)Cl>[C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=1[O:38][CH3:39])([OH:14])=[O:12]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(/C=C(\C)C(=O)OC(C)(C)C)cc23)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(/C=C(\C)C(=O)O)cc23)c(OC)c1
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Trifluoroacetic acid (50 ml) was added to a solution of methyl E-4-[5-[2-(t-butoxycarbonyl)-1-propenyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoate (6.4 g) in a small volume of methylene chloride (10 ml) cooled in an ice-bath. After 1.5 hr, the solution was evaporated (at approximately room temperature), and the residue was crystallized from methanol to give methyl E-4-[5-(2-carboxy-1-propenyl)-1-methylindol-3-ylmethyl]-3-methoxybenzoate (4.2 g, 75%) as a white powder: mp 182°-183° C.: partial NMR (250 MHz, DMSO-d6): 2.03(s, 3H, CCH3), 3.75(s, 3H), 3.83(s, 3H), 3.90 (s, 3H), 4.06(s, 2H, ArCH2Ar').
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].[CH3:19][O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[O:38][CH3:39].C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:19][O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:3]=2[CH2:4][N:5]2[CH2:9][CH2:8][O:7][C:6]2=[O:10])[CH:26]=[CH:25][C:24]=1[O:38][CH3:39]
Reactant: O=C1OCCN1Cc1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
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: COCCOC
Product: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN2CCOC2=O)ccc1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
3-(2-Bromo-5-trifluoromethyl-benzyl)-oxazolidin-2-one (0.085 g, 0.26 mmol), [2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester (0.120 g, 0.39 mmol), potassium carbonate (0.091 g, 0.66 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.030 g, 0.03 mmol) were combined in DME:H2O (2:1; 10 mL), and the mixture was purged with N2. The reaction was stirred at 90° C. for 3 hours, until no starting material was seen by analytical LCMS. After cooling to room temperature, the mixture was worked-up with EtOAc and brine and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [ClH:1].[CH2:2]([CH:4]([CH2:33][CH3:34])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[O:19])=[CH:13][CH:12]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH3:3].[OH-].[Na+]>CCOC(C)=O>[ClH:1].[CH2:33]([CH:4]([CH2:2][CH3:3])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[O:19])=[CH:13][CH:12]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH3:34]
Reactant: CCC(CC)C(c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1)n1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCC(CC)C(c1ccc(NC(=O)C2CCNCC2)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
HCl conc. (3.6 ml) was added at RT to a mixture of (±)-1,1-dimethylethyl 4-[[[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]phenyl]amino]carbonyl]-1-piperidinecarboxylate (0.0032 mol) in EtOAc (30 ml). The mixture was stirred at RT for 4 hours, then basified with a concentrated NaOH solution and extracted with EtOAc and then CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (1 g) was converted into the hydrochloric acid salt (1:1) in 2-propanol. The precipitate was filtered off and dried, yielding 0.85 g (68%) (±)-N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]-phenyl]4-piperidinecarboxamide monohydrochloride (compound 57).
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[C:17]([O:23]C(C)(C)C)[CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[C:17]([OH:23])[CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(SCc2ccc(C(C)(C)C)cc2)oc2cccc(OC(C)(C)C)c2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(SCc2ccc(C(C)(C)C)cc2)oc2cccc(O)c2c1=O

Procedure:
A 50 mL round bottomed flask is charged with 2-(4-tertbutylbenzylmercapto)-3-methyl-5-tertbutoxy chromen-4-one (10 g, 24.3 mmol). To this is then added anhydrous trifluoroacetic acid (15 mL) and the reaction mixture is stirred for 8 hours at 0° C. Dichloromethane is then added to the flask and the mixture poured into a separatory funnel. It is then washed with water and then with brine and dried over sodium sulfate and filtered. The filtrate is then concentrated in vacuo and the residue obtained is purified by silica gel flash chromatography (ethyl acetate:hexanes) to obtain the desired product.
Reaction SMILES: [CH:1]([OH:3])=O.[F:4][C:5]1([F:22])[O:10][C:9]2[CH:11]=[C:12]([F:17])[C:13]([NH:15][NH2:16])=[CH:14][C:8]=2[N:7]([CH2:18][C:19]#[CH:20])[C:6]1=[O:21]>ClCCl>[F:22][C:5]1([F:4])[C:6](=[O:21])[N:7]([CH2:18][C:19]#[CH:20])[C:8]2[CH:14]=[C:13]([NH:15][NH:16][CH:1]=[O:3])[C:12]([F:17])=[CH:11][C:9]=2[O:10]1
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(NN)cc21
Reactant: O=CO
Solvent: ClCCl
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(NNC=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Formic acid (0.157 ml, 4.09 mmol) was added to 2,2,7-trifluoro-6-hydrazinyl-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (the product of Step 1.7 above, 1.0 g, 3.69 mmol) in dichloromethane at room temperature under stirring. The mixture was then stirred overnight at room temperature. The resulting precipitate was isolated over a glass filter and washed with diisopropyl either to yield 858 mg of product (>95% purity), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:56][O:57][C:58]([C:60]1[O:61][C:62]2[CH:68]=[CH:67][C:66]([NH2:69])=[CH:65][C:63]=2[CH:64]=1)=[O:59]>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@H:9]2[C:28]([NH:69][C:66]2[CH:67]=[CH:68][C:62]3[O:61][C:60]([C:58]([O:57][CH3:56])=[O:59])=[CH:64][C:63]=3[CH:65]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2o1
Reaction time: 0.33 h

Procedure:
A solution of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.9 mg, 0.130 mmol) in dichloromethane (3 ml) was reacted with DIPEA (66.8 mg, 0.517 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (75.8 mg, 0.320 mmol) and stirred for 20 min under argon. 5-AMINO-BENZOFURAN-2-CARBOXYLIC ACID METHYL ESTER (26.0 mg, 0.136 mmol, Biofine,) was added and stirred 2.5 hrs. The reaction mixture was diluted with dichloromethane and washed with water, sat. NaHCO3 and brine. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral-methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylate (46.2 mg., 55.4%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 640.15. found: 640.0.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:32]2[CH2:33][CH2:34][N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:30][CH2:31]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(Cc5ccccc5)CC4)cc3nc21
Yield: 48.1 %

Procedure:
7-Fluoro-8-[4-benzylpiperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions of Example 2, but from 2 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 4.6 g of N-benzylpiperazine in 20 cm3 of pyridine. After recrystallizing twice from 25 cm3 of dimethylformamide on each occasion, 1.4 g of 7-fluoro-8-[4-benzylpiperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 311° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH:9]([C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[O:20][C:16]([CH:17]([CH3:19])[CH3:18])=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1C(C)C
Yield: 60.7 %

Procedure:
7.0 g of ethyl 3-(4-fluorobenzoylamino)-3-isobutyrylpropionate, 35 ml of dimethylformamide and 5.7 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 4.0 g of ethyl 2-[2-(4-fluorophenyl)-5-isopropyl-4-oxazolyl]acetate are thereby obtained. Yield: 60.6%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][CH:10]([CH2:12]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O-:17])(=[O:16])[CH3:15].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:11][CH:10]([CH2:12][O:17][C:14](=[O:16])[CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: ClCC1CN(Cc2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC1CN(Cc2ccccc2)C1
Reaction time: 2.25 h

Procedure:
195.5 g of 1 was added, drop-by-drop over 45 minutes, to a stirred mixture of 164 g of anhydrous sodium acetate and 1.8 liters of dimethylformamide, at 130° C. The mixture was held at 130° C. for an additional 2.25 hours, then most of the solvent was evaporated under reduced pressure and the cooled residue and treated with sufficient of an ice/water mixture to dissolve the salts therein. The resulting mixture was extracted with ether, the extract was washed with water, and the solvent was evaporated to give 2, as a pale yellow oil, b.p.: 94° C., 0.1 Torr.