Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11](=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH2:16][NH2:17].[BH4-].[Na+].ClCCl>CO.ClCCl.C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([NH:17][CH2:16][CH:15]([OH:14])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CC(C)=O)cc1F
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1F

Procedure:
1-(3-Fluoro-4-methoxyphenyl)propan-2-one (2.73 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (2.58 g) were condensed and subsequently reduced with sodium borohydride (2.0 g) by a procedure analogous to that described in Example 1, except dichloromethane was used instead of ethyl acetate in the work-up. Chromatography of the residue on silica gel in 5% methanol-dichloromethane gave N-[2-(3-fluoro-4-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine, mp 93°-5° C. (diethyl ether) as a 55:45 mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH:22][OH:23])[CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:22]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[O-:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ONC1CCCC1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: [O-][N+](=Cc1ccc(OCc2ccccc2)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.1 %

Procedure:
A mixture of 4-benzyloxybenzaldehyde (20 g, 94.23 mmol), N-cyclopentylhydroxylamine (14.3 g, 141.34 mmol), molecular sieves (60 g, 4A) and silica gel (15 g) in chloroform (300 mL) was stirred at room temperature under argon atmosphere for 48 hrs and then was refluxed for an additional 3 hrs. The mixture was filtered and rotary evaporated to give crystals which were recrystallized from hexanes and EtOAc to provide the title compound as white crystals, 23.7 g, 85.1% yield), m.p. 115.1° C. (Rf=0.35 on a silica gel plate using hexanes:EtOAc, 1:1, v:v, as an eluant).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[C:10](O)(=[O:14])[CH:11]([CH3:13])[CH3:12].CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)C(=O)O
Reactant: NCc1ccc(Br)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of (5-bromopyridin-2-yl)methanamine (200 mg, 1.069 mmol), isobutyric acid (0.159 mL, 1.711 mmol), BOP-reagent (757 mg, 1.711 mmol) and diisopropylethylamine (0.747 mL, 4.28 mmol) in DMF (6 mL) was stirred at rt for 2 hr. The reaction mixture was partitioned between EtOAc (60 ml) and saturated NaHCO3 solution (60 ml). The organic layer was washed with 10% LiCl solution (2×50 ml) and brine (50 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to afford an orange oil that was chromatographed on a 24 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford N-((5-bromopyridin-2-yl)methyl)isobutyramide (230 mg, 0.894 mmol, 84% yield) as an orange oil. 1H NMR (400 MHz, METHANOL-d4) δ 8.57 (d, J=2.2 Hz, 1H), 7.95 (dd, J=8.4, 2.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 4.42 (s, 2H), 2.53 (dt, J=13.8, 6.8 Hz, 1H), 1.15 (d, J=6.8 Hz, 6H). MS (ES+) m/z: 257.0, 259.0 (M+H); LC retention time: 1.200 min (analytical HPLC Method O).
Reaction SMILES: [CH2:1]1[CH2:24][O:23][C:3]2([CH2:8][CH2:7][C@H:6]3[C@H:9]4[C@H:19]([CH2:20][CH2:21][C@:4]23[CH3:5])[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:22])[CH:15]=[CH:16]2)=[CH:11][CH2:10]4)[O:2]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:22][C@H:14]1[CH:15]=[CH:16][C@@:17]2([CH3:18])[C:12](=[CH:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C:3]32[O:2][CH2:1][CH2:24][O:23]3)[CH2:13]1)(=[O:27])[CH3:26]
Reactant: C[C@]12C=C[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C=C[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC23OCCO3)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of crude 17,17-ethylenedioxyandrosta-1.5-dien-3β-ol (4, 1.2 g) in pyridine (10 ml) and acetic anhydride (3 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-water and the compound was extracted with ether. The organic layer was washed with ice-water several times followed by brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo below 35° C. gave 1.0 g of crude solid. Recrystallization from methanol gave 3β-acetoxy-17,17-ethylenedioxyandrosta-1,5-diene (5). Mp. 105-6° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:32])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](=[O:31])[CH3:30])=[CH:20][CH:19]=1)#[N:2].[BH4-].[Na+].C(Cl)(Cl)Cl>O1CCCC1.CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:32])[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([OH:31])[CH3:30])=[CH:22][CH:23]=1)#[N:2]
Reactant: CC(=O)CCCCOc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(O)CCCCOc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 94.2 %

Procedure:
In 30 ml of tetrahydrofuran was suspended 3.33 g of N-[2-(2-cyanophenylthio)phenyl]-4-(5-oxohexyloxy)benz-amide (prepared in accordance with Reference Example 6, Step 2) followed by addition of a solution of 0.31 g of sodium borohydride in methanol, and the mixture was stirred for 1 hour. To the reaction mixture was added chloroform and the mixture was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate-n-hexane to give 3.15 g of the title compound as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([C:17]1[CH:18]=[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=[C:21]([CH2:23][CH2:24][CH3:25])[CH:22]=1)[CH2:15][CH3:16]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:29]2[CH2:30][CH2:31][N:26]([C:19]3[CH:20]=[C:21]([CH2:23][CH2:24][CH3:25])[CH:22]=[C:17]([CH2:14][CH2:15][CH3:16])[CH:18]=3)[CH2:27][CH2:28]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCc1cc(CCC)cc(N2CCNCC2)c1
Solvent: CCN(CC)CC
Product: CCCc1cc(CCC)cc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-(3,5-dipropylphenyl)-piperazine and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)sulfonyl]-4-(3,5-dipropylphenyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([OH:22])=O)[O:19][C:15]=2[C:14]([O:23][CH3:24])=[CH:13][CH:12]=1)=[O:10].O.ON1C2C=CC=CC=2N=N1.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:22])[O:19][C:15]=2[C:14]([O:23][CH3:24])=[CH:13][CH:12]=1)=[O:10]
Reactant: C1CNCCN1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)O)oc12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)N3CCNCC3)oc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
Compound M (4.12 g) obtained in Reference Example 3 was dissolved in DMF (150 ml), 1-hydroxybenzotriazole monohydrate (5.8 g) and N-ethyl-N-′3-dimethylaminopropylcarbodiimide monohydrochloride (8.2 g) were added thereto, and the mixture was stirred at room temperature for 10 minutes. The mixture was dropwise added to a solution of piperazine (18.6 g) in DMF (300 ml) and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure and the residue was extracted with chloroform. The extract was washed a saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvent was distilled off. The resulting residue was suspended in ethanol and the precipitated crystals were collected by filtration to give the desired compound (3.54 g, 73%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:10][O:9]1)([O-])=O.[H][H].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(C(C)C)C(C)C)C>C(OCC)(=O)C.[Pt]>[O:9]1[CH2:10][C@H:8]1[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=1[NH:1][C:17](=[O:19])[CH3:18]
Reactant: O=[N+]([O-])c1ccccc1OC[C@@H]1CO1
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Agent: [Pt]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
(2S)-2-[(2-nitrophenoxy)methyl]oxirane (1.17 g, 6 mmol) was dissolved in ethyl acetate (50 ml). Platinum on charcoal (0.50 g) was added, and the mixture was stirred in the atmosphere of hydrogen for 3 h at room temperature and atmospheric pressure. The catalyst was filtered and washed on the filter with ethyl acetate (10 ml). Acetic anhydride (1.23 g, 1.13 ml, 12 mmol) and ethyldi(i-propyl)amine (1.55 g, 2.05 ml, 12 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 3 h, then washed with 1M NaOH (2×50 ml) and brine (2×50 ml), and dried with Na2SO4. Evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (from 25 to 75%) afforded the title compound (0.74 g, 3.57 mmol, 60%) as colourless crystals.
Reaction SMILES: [F:1][C@:2]12[C@@H:21]([OH:22])[CH2:20][C@@:19]3([CH3:23])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:18])[CH3:17])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:25])[CH:4]=[CH:5][C:6](=[O:24])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:38]([O-])(=[O:40])[CH3:39].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:38]([O:22][C@H:21]1[CH2:20][C@@:19]2([CH3:23])[C@@H:12]([CH2:13][CH:14]=[C:15]2[C:16](=[O:18])[CH3:17])[C@H:11]2[C@@:2]1([F:1])[C@:3]1([CH3:25])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:24])[CH:5]=[CH:4]1)(=[O:40])[CH3:39]
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@H]1C[C@]2(C)C(C(C)=O)=CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Temperature: 25 °C
Reaction time: 60 h
Yield: 80.2 %

Procedure:
A solution of 9-fluoro-11β-hydroxypregna-1,4,16-triene-3,20-dione (1.0g) in a mixture of acetic acid (70 ml) and acetic anhydride (70 ml) containing p-toluenesulfonic acid hydrate (500 mg) is stirred at room temperature for 60 hours. Sodium acetate (2.0g) is added and the mixture is concentrated in vacuo. The residue is mixed with water and washed with a dilute sodium bicarbonate solution and water, dried and the residue is crystallized from ethyl acetate-hexane to afford 0.9g of the title compound, melting point 202°-203° C.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:46][C:47]([F:57])([F:56])[C:48]1[CH:55]=[CH:54][C:51]([CH2:52]O)=[CH:50][CH:49]=1>CN(C=O)C.C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:52][C:51]3[CH:50]=[CH:49][C:48]([C:47]([F:46])([F:56])[F:57])=[CH:55][CH:54]=3)=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCN(C(=O)OCc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 0.08 h
Yield: 61.9 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 393 (1.87 g, 5.09 mmol) and methylene chloride (20 ml) was added trifluoroacetic acid (20 ml) followed by stirring for 5 minutes, and then concentrated under reduced pressure. The residue was dissolved in DMF (20 ml). To the solution, a mixture of 1,1′-carbonyldiimidazole (1.76 g, 10.9 mmol), 4-(trifluoromethyl)benzyl alcohol (1.92 g, 10.9 mmol) and DMF (20 ml) stirred at room temperature for 3 hours was added followed by stirring at room temperature overnight. The reaction mixture was extracted with ethyl acetate. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/acetone=3/1), recrystallized from isopropyl alcohol. The resulting solids were filtered off and then dried under reduced pressure to afford 4-trifluoromethylbenzyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (1.48 g, yield 53%) as a light yellow powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[N:7][N:8]=1.C(N(CC)C(C)C)(C)C.[CH:19]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20]1>CN(C)C=O.N1C=CC=CC=1>[O:9]=[C:4]1[C:3]([CH2:2][NH:1][C:23]([CH:19]2[CH2:22][CH2:21][CH2:20]2)=[O:24])=[N:8][N:7]=[CH:6][NH:5]1
Reactant: O=C(Cl)C1CCC1
Reactant: NCc1nnc[nH]c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(NCc1nnc[nH]c1=O)C1CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-aminomethyl-4H-[1,2,4]triazin-5-one (500 mg, 3.96 mmol) and N,N-diisopropylethylamine (DIEA) (0.829 mL, 4.76 mmol) in anhydrous N,N-dimethylforamide (DMF) (20 mL) and anhydrous pyridine (2 mL) was dropwise charged with cyclobutanecarbonyl chloride (0.451 mL, 3.96 mmol) at 0° C. then warmed to rt and stirred for an additional 1.5 h. The reaction mixture was quenched with H2O (2 mL) and concentrated in vacuo and was purified by chromatography on silica gel [eluting with 5% MeOH in DCM (200 mL)→10% MeOH in DCM (800 mL)], affording the title compound; 1H NMR (DMSO-d6, 400 MHz) δ 1.7-1.82 (m, 1H), 1.70-1.92 (m, 1H); 1.97-2.07 (m, 2H); 2.07-2.19 (m, 2H); 3.55-3.67 (m, 1H); 4.19 (d, 2H); 7.97 (brt, J=5.6 Hz, 1H); 8.67 (s, 1H); MS (ES+): m/z 209.25 (100) [MH+], HPLC: tR=1.56 min (MicromassZQ, polar—5 min).
Reaction SMILES: [H-].[Na+].[C:3]([CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])([O:5][CH2:6][CH3:7])=[O:4].[F:14]N1CC2CCC(C2(C)C)(C)CS1(=O)=O.C(O)(=O)C(O)=O>O1CCCC1>[F:14][C:8]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:12][CH2:11][CH2:10][C:9]1=[O:13]
Reactant: CC12CCC(CN(F)S(=O)(=O)C1)C2(C)C
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(F)CCCC1=O
Reaction time: 3 h

Procedure:
To a suspension of 1.56 mmol of sodium hydride in 5 ml of tetrahydrofuran are added, at 0° C., 1.3 mmol of 1-carboethoxycyclopentan-2-one and the mixture is stirred for 1 hour at 0° C. Then a solution of 1.4 mmol of (-)-N-fluorocamphor sultam (Example 4) is added dropwise, and stirring is continued for 3 hours at 0° C. The reaction mixture is then poured into 50 ml of 1M oxalic acid and extracted with diethyl ether. The organic phases are washed with 10% NaHCO3 solution and with a saturated solution of NaCl. The resultant mixture is purified over a column of silica gel, affording (+)-1-fluoro-1-carboethoxycyclopentan-2-one in high purity (ee=70%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.[Cl:50]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:50][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[C:24]=3[N:23]=[CH:12]2)=[CH:2][CH:3]=1
Reactant: COC(=O)c1scc(-c2ccc(F)cc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccc(F)cc3)c2ncn1-c1ccc(Cl)cc1
Yield: 40 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(4-fluorophenyl)thiophene-2-carboxylate (80 mg, 0.32 mmol), triethyl orthoformate (2 ml), 4-chloroaniline (74.45 mg, 0.59 mmol), and acetic acid (0.08 ml) were used to give 46 mg (0.13 mmol, 40% yield) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[O:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]=1[C:12]([C:14]1[CH:15]=[C:16]([Br:22])[C:17]([OH:21])=[C:18]([Br:20])[CH:19]=1)=[O:13].C1COCC1.Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]>C([O-])(O)=O.[Na+]>[Br:22][C:16]1[CH:15]=[C:14]([C:12]([C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:3]=2[CH2:2][CH3:1])=[O:13])[CH:19]=[C:18]([Br:20])[C:17]=1[O:21][S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCc1oc2ccccc2c1C(=O)c1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1oc2ccccc2c1C(=O)c1cc(Br)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(Br)c1
Reaction time: 18 h
Yield: 39.1 %

Procedure:
At ambient temperature, to a stirred solution of commercial benzbromarone (0.243 g, 0.574 mmol) in 0.5M aq. NaHCO3:THF (8 mL; 1:1) was added portionwise 4-chlorosulphonyl-2-hydroxybenzoic acid (0.271 g, 1.15 mmol) while maintaining the pH at 8 with the simultaneous addition of 0.5M aq. NaHCO3. After the addition was complete the reaction was stirred for 18 h. To the reaction was added 4-chlorosulphonyl-2-hydroxybenzoic acid (0.271 g, 1.15 mmol) while maintaining the pH at 8 with the simultaneous addition of 0.5M aq. NaHCO3. After 2 h, the reaction was quenched with 2N HCl (25 mL), extracted with EtOAc and concentrated. The crude product was purified by preparative HPLC (C18, eluting with 75% CH3CN/H2O containing 0.1% TFA) and crystallized from EtOAc/hexane to give 0.14 g (39%) of the title compound as a white solid, mp 173° C.; 1H NMR (DMSO-d6) δ 1.25 (t, 3H), 2.76 (q, 2H), 7.30 (dt, 1H), 7.36 (dt, 1H), 7.44-7.49 (m, 3H), 7.66 (d, 1H), 8.03 (d, 1H), 8.08 (s, 2H). IR (KBr) 3400, 2950, 1680, 1650, 1400 and 1180 cm−1. mass spectrum (−ESI), m/z 621/623/625 (M−H). Anal. Calcd. for C24H16Br2O8S: C, 46.18; H, 2.58; N, 0.00. Found: C, 46.41; H, 2.64; N, 0.00.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[OH:21][CH:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]1=O.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:23]3[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26][CH:22]3[OH:21])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CC1(C)CC(=O)C(O)C1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CC(C)(C)CC3O)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and rac-2-hydroxy-4,4-dimethyl-cyclopentanone using decaborane yielded a mixture of epimers of the title compound as white solid. MS (ESI): m/z=391.4 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=O.[Cl:12][C:13]1C=C(Cl)[N:16]=[CH:15][N:14]=1.CO>O1CCOCC1>[Cl:12][C:13]1[CH:7]=[C:5]([CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])[N:16]=[CH:15][N:14]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)Cc1cc(Cl)ncn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2.7 g (50 mmol) of sodium hydride (80% dispersion in oil) were placed in 100 ml of dry dioxane, and 11.7 g (90 mmol) of ethyl acetoacetate were added dropwise. The mixture was then stirred at 50° C. for 1 hour. After cooling to room temperature, a solution of 4.5 g (30 mmol) of 4,6-dichloropyrimidine in 50 ml of dioxane was added dropwise. After heating at reflux for 6 hours the mixture was cooled to room temperature, 10 ml of methanol were added dropwise in order to destroy superfluous sodium hydride, and the mixture was concentrated. The residue was taken up in water and brought to a pH of 3 to 4 with conc. hydrochloric acid. After extractive stirring with toluene, the organic phase was dried and concentrated. Chromatography on silica gel left 1.8 g (30% of theory) of a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH3:16])[CH:21]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Reactant: CC(C)COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(OCC(C)C)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 42.7 %

Procedure:
A stirred mixture of 4-isobutoxybenzene-1-sulfonyl chloride (0.060 g, 0.24 mmol), 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.050 g, 0.22 mmol), and 4-(dimethylamino)pyridine (DMAP, 0.025 g, 0.20 mmol) in pyridine (2 mL) was heated at 80° C. for 2 h. After cooling to room temperature, aqueous saturated sodium bicarbonate was added to the reaction mixture and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 2-5% methanol in dichloromethane), followed by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.041 g, 0.094 mmol, 43%). 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J=4.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.48-7.44 (m, 2H), 7.23 (d, J=4.0, Hz, 1H), 7.21 (d, J=4.0, Hz, 1H), 7.15 (dd, J=1.2, 7.2 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.25 (s, 1H), 3.72 (dd, J=2.0, 6.4 Hz, 2H), 2.33 (s, 3H), 2.13 (hept, J=6.4 Hz, 1H), 1.08 (dd, J=2.4, 6.4 Hz, 6H); MS: (ES) m/z calculated for C23H25N4O2S [M+H]+ 437.2. found 437.0.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:21])C(=O)C1>CC#N.C(OCC)(=O)C>[Br:21][C:9]1[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:8]=1
Reactant: Nc1cnc(C2CCOCC2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1ncc(C2CCOCC2)nc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine (2.8 g, 15.6 mmol) in CH3CN (52 mL) was added NBS (2.78 g, 15.62 mmol) in two portions at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with ethyl acetate and was washed with saturated sodium carbonate solution, water, brine, dried and concentrated. The crude 3-bromo-5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine (3.9 g, 97%) was used for the next step without further purification. LCMS (m/z): 258/260 (MH+), 0.52 min; 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (s, 1H), 4.90 (br. s., 2H), 4.14-4.02 (m, 2H), 3.59-3.43 (m, 2H), 2.83 (d, J=5.5 Hz, 1H), 1.91-1.77 (m, 4H).