Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.CN(C(O[N:47]1N=[N:54][C:49]2C=CC=N[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:48]([CH2:49][NH:54][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)#[N:47]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N#CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 46.9 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 35 mg, 0.081 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.054 mL, 0.487 mmol), 2-aminoacetonitrile, HCl (15.02 mg, 0.162 mmol), and HATU (61.7 mg, 0.162 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=33.2 min) to give single enantiomer N-(cyanomethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (18.3 mg, 0.038 mmol, 46.6% yield): LCMS=470.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15-8.23 (2 H, m), 7.65-7.76 (4 H, m), 7.53-7.64 (3 H, m), 5.21 (1 H, s), 4.19 (2 H, d, J=2.86 Hz). HPLC Peak RT=9.5 min (Analytical Method A).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[CH:11][C:12]([NH:21][CH3:22])=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:23]([O:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH2:34][C:35]([CH2:41]Cl)=[CH:36]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH2:34][C:35]([CH2:41][N:21]([C:12]1[CH:11]=[N:10][C:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=1)[CH3:22])=[CH:36]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: ClCC1=Cc2cccc(OCc3ccccc3)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC1=Cc2cccc(OCc3ccccc3)c2CC1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
Under an argon atmospshere, 0.97 g of 60% sodium hydride was suspended in anhydrous N,N-dimethylformamide and 0.97 g of 5,6-diphenyl-2-(methylamino)-pyrazine was added in three portions. After stirring at 80° C. for 30 minutes, the reaction solution was ice-cooled and a solution of 0.97 g of 5-(benzyloxy)-2-(chloromethyl)-3,4-dihydronaphthalene in 5 ml of anhydrous N,N-dimethylformamide was added dropwise. After stirring for 30 minutes, the reaction solution was diluted with ice water and then extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.81 g of the desired compound as a pale yellow amorphous.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[C:5]2[C:8]([CH3:16])=[C:9]([N+:13]([O-])=O)[CH:10]=[C:11]([CH3:12])[C:4]=2[O:3]1>C(OCC)(=O)C.CCCCCC>[NH2:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:4]2[O:3][C:2]([CH3:1])([CH3:17])[C:6](=[O:7])[C:5]=2[C:8]=1[CH3:16]
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c1OC(C)(C)C2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(N)c(C)c2c1OC(C)(C)C2=O
Yield: 97 %

Procedure:
Using 2,2,4,7-tetramethyl-5-nitro-1-benzofuran-3(2H)-one obtained in Reference Example 47, the title compound was synthesized in the same manner as in Reference Example 54. Yield 97%. Melting point: 124-126° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]([CH:16]([CH3:18])[CH3:17])=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1COCC1.C([Li])CCC.Cl[P:30]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O>[C:4]1([C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([P:30]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:16]([CH3:18])[CH3:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: CC(C)C(Br)=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Temperature: -70 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
Into a reactor were introduced 1.20 g (4.00 mmol) of the 2-bromo-1,1-diphenyl-3-methylbutene and 12 mL of THF under a nitrogen atmosphere. The contents were cooled to −70° C., and 2.8 mL (4.4 mmol; 1.6 M hexane solution) of butyllithium was gradually added dropwise thereto. The resultant mixture was stirred at that temperature for 30 minutes. Thereafter, 1.1 mL (4.8 mmol) of chlorodicyclohexylphosphine was added thereto, and this mixture was stirred at that temperature for 3 hours and then heated to room temperature over 13 hours. Water was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol and toluene to obtain 0.72 g (43%) of the target compound as white crystals.
Reaction SMILES: Cl[C:2]([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=[O:3].CCN(C(C)C)C(C)C.[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH2:56]>ClCCCl.CN(C1C=CN=CC=1)C>[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH:56][C:2]([C@:4]12[CH2:39][CH2:38][C@@H:37]([CH:40]([CH3:42])[CH3:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C@@H:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)=[O:3]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)Cl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)CCN
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)NCCN(C)C)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a flask containing methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(chlorocarbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (77 mg, 0.13 mmol) in DCE (2 mL) was added Hunig's base (0.068 mL, 0.390 mmol), DMAP (1 mg, 8.19 mmol), and N,N-dimethylethylenediamine (0.029 mL, 0.260 mmol). The mixture was stirred for two hours at rt. The reaction was quenched with 5 mL of water and was extracted with dichloromethane (3×5 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure and was purified by Biotage flash chromatography using a 0-10% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)ethylcarbamoyl)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a white foam (37 mg, 44% yield). LCMS: m/e 647.7 (M+H)+, 3.09 min (method 3).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[Br:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH2:34]>ClCCl>[Br:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH:34][C:10]([C@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12]
Reactant: Nc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
In a 500 mL flask, N-Boc-D-Proline (300 mg, 1.39 mmol) was dissolved in dichloromethane (35 mL) and cooled to 0° C. under nitrogen. N-Methylmorpholine (153 μL, 1.39 mmol) was added followed by dropwise addition of iso-butyl chloroformate (180 μL, 1.39 mmol) and the reaction mixture stirred at 0° C. for 1 h. 2-Bromoaniline (1.31 mL, 1.39 mmol) was dissolved in dichloromethane (5 mL) then added quickly to the activated acid at 0° C. The mixture was stirred overnight from 0° C. to room temperature. The reaction mixture was diluted with dichloromethane, washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified on column chromatography (eluent: Pentane/EtOAc, 50/50 to 0/100 then EtOAc/MeOH 80/20) to give the product (394 mg, 77%) as a yellow oil. This product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Br:9][C:5]1[N:6]=[C:7]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ncc(Br)nc1Br
Product: Nc1ncc(Br)nc1-c1ccc(F)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 19a using 2-amino-3,5-dibromopyrazine, and 4-fluorophenylboronic acid (commercially available) as starting materials to give the title compound as a white solid, MS (ISP) 268.1, 270.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][C:3]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23](N(OC)C)=[O:24])=[N:15]1.[CH3:29][Mg+].[Br-]>C1COCC1>[C:23]([C:16]1[C:17](=[O:22])[C:18]([O:20][CH3:21])=[CH:19][N:14]([C:3]2[CH:4]=[C:5]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[CH:6]=[CH:7][C:2]=2[F:1])[N:15]=1)(=[O:24])[CH3:29]
Reactant: COc1cn(-c2cc(-c3cnn(C)c3)ccc2F)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cc(-c3cnn(C)c3)ccc2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a mixture of 1-[2-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (267 mg, 0.687 mmol) in THF (80 mL) was added MeMgBr (1.0 M in THF, 2.06 mL, 2.06 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 2 h. To the mixture was added MeMgBr (1.0 M in THF, 0.687 mL, 0.687 mmol) at −78° C. The mixture was stirred at −78° C. for 1 h. To the mixture was added MeMgBr (1.0 M in THF, 1.37 mL, 1.37 mmol) at −78° C. The mixture was stirred at −78° C. for 3 h. The reaction was quenched with saturated NH4Cl aqueous solution at −78° C. The mixture was diluted with saturated NaHCO3 aqueous solution, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (EtOAc/MeOH=100/0 to 70/30) to yield the title compound (201 mg, 85% yield) as a yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.52 (3H, s), 3.82 (3H, s), 3.87 (3H, s), 7.53 (1H, dd, J=10.6, 8.7 Hz), 7.78 (1H, ddd, J=8.7, 4.5, 2.3 Hz), 7.92-8.00 (2H, m), 8.23 (1H, s), 8.56 (1H, d, J=1.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[O:21]3)=[CH:16][CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:26][N:27]([CH3:32])[S:28](=[O:31])(=[O:30])[NH2:29].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.Cl>[Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[O:21]3)=[CH:16][CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:29][S:28](=[O:31])(=[O:30])[N:27]([CH3:32])[CH3:26])=[O:8]
Reactant: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2O1
Reactant: CN(C)S(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(COc2ccc3c(c2)OC(C)(C)CC3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
A mixture of 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid (50 mg, 0.14 mmol), dimethyl(sulfamoyl)amine (26 mg, 0.21 mmol), N,N-Diisopropylethylamine (54 mg, 0.42 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) in DMF (2.5 mL) was stirred at room temperature for 16 hrs. The mixture was diluted with HCl (2.0 N, 20 mL) and extracted with EtOAc (50×3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase combiflash (15%-25% MeCN in 0.5% NH4HCO3) to give target product (11.8 mg, 18%) as a white solid. LCMS (ESI) Method A: RT=5.57 min, m/z: 471.2 [M+H]; 1H-NMR (500 MHz, MeOH-d4,): δ 7.62 (d, J=6.0 Hz, 1H), 7.31 (d, J=10.5 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.40 (dd, J=8.0, 2.5 Hz, 1H), 6.24 (d, J=2.5 Hz, 1H), 5.02 (s, 2H), 2.86 (s, 6H), 2.61 (t, J=7.0 Hz, 2H), 1.68 (t, J=7.0 Hz, 2H), 1.20 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)c1ccc(OCc2ccccn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-Butyl 4-(4-((2-pyridinyl)-methoxy)phenyl)-4-oxobutyrate (Step C, 1.27 g, 4.2 mmol) in dichloromethane (25 ml) was treated with trifluoroacetic acid (5 ml). The mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to provide the title compound as a white solid.
Reaction SMILES: C(N1CC(=C([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Br:34])[CH:24]=2)S(C)(=O)=O)C1)(C1C=CC=CC=1)C1C=CC=CC=1.BrCCCCBr.C(=O)([O-])[O-].[K+].[K+].[CH:47]([N:60]1[CH2:63][C:62](=[C:64](C2C=CC=C(O)C=2)[S:65]([CH3:68])(=[O:67])=[O:66])[CH2:61]1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CC(CC)=O>[CH:47]([N:60]1[CH2:61][C:62](=[CH:64][S:65]([CH2:68][C:27]2[CH:28]=[CH:23][CH:24]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Br:34])[CH:26]=2)(=[O:67])=[O:66])[CH2:63]1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc(OCCCCBr)c1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: BrCCCCBr
Solvent: CCC(C)=O
Product: O=S(=O)(C=C1CN(C(c2ccccc2)c2ccccc2)C1)Cc1cccc(OCCCCBr)c1

Procedure:
1-Benzhydryl-3-{[3-(4-bromobutoxy)phenyl]-methanesulfonylmethylene}azetidine may be prepared in the following manner: 0.586 cm3 of 1,4-dibromobutane and 255 mg of potassium carbonate are successively added at a temperature close to 20° C., under an inert atmosphere of argon, to a solution of 500 mg of 1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine in 10 cm3 of methylethyl ketone. The reaction mixture is heated at the reflux temperature of the solvent, under an inert atomosphere of argon, for 7 hours and then left at a temperature close to 20° C. for about 4 days. The reaction mixtue is filtered on sintered glass covered with celite. The solid residue is rinsed with ethyl acetate and then the filtrate is concentrated to dryness under reduced pressure (10 kPa) at a temperature close to 40° C. The brown oil obtained is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.200 mm) contained in a column 3 cm in diameter, eluting with a methanol-dichloromethane mixture (0.5-99.5 by volume). The fractions (10 cm3) containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40° C. for 2 hours, 408.4 mg of 1-benzhydryl-3-{[3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidine are thus obtained in the form of a brown foam.
Reaction SMILES: [C:1]([SiH:5]([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:15]([O:18][CH2:19][C:20]1[O:25][CH2:24][N:23]([C:26]([CH3:38])([CH3:37])[C:27]([O:29]CC2C=CC=CC=2)=[O:28])[C:22](=[O:39])[C:21]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:17])[CH3:16]>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:15]([O:18][CH2:19][C:20]1[O:25][CH2:24][N:23]([C:26]([CH3:38])([CH3:37])[C:27]([O:29][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[O:28])[C:22](=[O:39])[C:21]=1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)(=[O:17])[CH3:16]
Reactant: C[SiH](C)C(C)(C)C
Reactant: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)OCc2ccccc2)CO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O[Si](C)(C)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of palladium (II) acetate (25 mg), tert butyl-dimethylsilane (1.25 ml) and triethylamine (0.05 ml) in dichloromethane was stirred at room temperature under an inert atmosphere for 0.25 hour. A solution of benzyl 2-(6-acetoxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (1.0 g) was added and stirring continued for 18 hours. The mixture was filtered (hyflo) and evaporated to give tert butyldimethylsilyl 2-(6-acetoxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (0.92 g) as a yellow oil, NMR (CDCl3)δ 0.25(s,9H), 1.5(s,6H), 2.0(s,3H), 4.5(s,2H), 5.2(s,2H), 7.0-7.3(m,5H).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([C:6]1[C:11]([N:12]([CH2:27][O:28][CH3:29])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5].[CH3:35][S:36](Cl)(=[O:38])=[O:37].Cl.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>N1C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:12]([C:11]2[C:6]([C:4](=[O:5])[C:3]3[CH:31]=[CH:32][CH:33]=[CH:34][C:2]=3[NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[N:7][CH:8]=[C:9]([Cl:30])[CH:10]=2)[CH2:27][O:28][CH3:29])(=[O:15])=[O:14])=[CH:17][C:18]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1N)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: c1ccncc1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1NS(C)(=O)=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred suspension of N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide in pyridine (1 mL) was added methanesulfonyl chloride (26 mg, 0.226 mmol). After 2 h the reaction mixture was poured into 1 M HCl and the aqueous portions were subsequently extracted with EtOAc. The combined extracts were dried and concentrated under reduced pressure. The resulting residue was dissolved in THF (5 mL), treated with TBAF (1 M in THF, 200 μL, 0.200 mmol), and then stirred at room temperature for 3-4 h. The reaction mixture was subsequently poured into 1 M HCl and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide 4-chloro-N-[5-chloro-2-(2-methanesulfonylamino-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. MS m/z: 634.0 (M+Na).
Reaction SMILES: [CH:1]1([C@H:4]([N:7]2[CH:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[C:8]2=[O:15])[CH2:5][CH3:6])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[N:22]([C:9]1[C:8](=[O:15])[N:7]([C@@H:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][CH3:6])[CH:12]=[C:11]([Cl:13])[N:10]=1)[CH2:21][CH2:20]2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Br)cc2c1NCC2
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 1-[(1R)-1-cyclopropylpropyl]-3,5-dichloro-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 154–156° C.; 1H NMR (300 MHz, CDCl3) δ 7.31 (d, J=1.9 Hz, 1 H), 7.24 (d, J=1.8 Hz, 1 H), 7.01 (s, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 4.05 (app. q, J=8.2 Hz, 1 H), 3.14 (t, J=7.9 Hz, 2 H), 1.96–1.83 (m, 2 H), 1.07–1.00 (m, 1 H), 0.94 (t, J=7.3 Hz, 3 H), 0.81–0.75 (m, 1 H), 0.55–0.48 (m, 2 H), 0.35–0.28 (m, 1 H); HRMS (ESI) calcd for C18H19N3OBrCl2 (M+H)+: 442.0089; Found m/z 442.0102.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10]Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[Mg].[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>CCOCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Clc1ccc(CCBr)cc1Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)CCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 12.9 %

Procedure:
2-(3,4-Dichlorophenyl)ethyl bromide (5 g, 19.7 mmol) was added slowly to a suspension of magnesium turnings (0.48 g, 19.7 mmol) in ether (30 ml). After spontaneous reflux had finished the mixture was stirred under reflux for 15 minutes and allowed to cool to room temperature. The mixture was added dropwise via cannula to a stirred, cooled (-25° C.) solution of diethyl oxalate (3 g, 20.7 mmol) in THF (15 ml). The mixture was stirred at -10° C. for 30 minutes and allowed to warm to room temperature. Hydrochloric acid (2M, 15 ml) was added and the mixture was extracted with ether (2×20 ml). The combined organic fractions were washed with water, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexane (10:90) to give the title compound (0.7 g).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].NC1OC(C2C=CC(C3CCCCC3)=CC=2)=CC=1C(OC)=O>CO.C(OCC)(=O)C.[C].[Pd]>[CH:17]1([C:14]2[CH:15]=[CH:16][C:11]([C:4]3[NH:3][CH:2]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=3)=[CH:12][CH:13]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)c1cc(-c2ccc(C3CCCCC3)cc2)[nH]c1Cl
Agent: [Pd]
Agent: COC(=O)c1cc(-c2ccc(C3CCCCC3)cc2)oc1N
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Temperature: 50 °C
Reaction time: 14 h
Yield: 41.1 %

Procedure:
To a solution of a nearly 1:1 mixture (3.41 g) of methyl 2-chloro-5-(4-cyclohexylphenyl)-1H-pyrrole-3-carboxylate and methyl 2-amino-5-(4-cyclohexylphenyl)-3-furoate in methanol (30 mL) and ethyl acetate (10 mL) was added 10% palladium carbon (50% containing water, 0.34 g), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 14 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=3:1→2:1) to give the title compound as crystals (yield 1.25 g, 41%).