Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[Br:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[O:32])[C:20](=[O:31])[N:21]2[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O1CCCC1.ClCCl>[Br:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([OH:32])([C:7]1[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=1)[C:20](=[O:31])[N:21]2[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol (12.8 g, 92.9 mmol) in tetrahydrofuran (200 mL) was added isopropylmagnesium chloride solution (50.7 mL, 101 mmol, 2.0 M in ether) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h, upon which time the colorless precipitate was formed. After the solvent was removed under reduced pressure, the residue was dissolved in methylene chloride (100 mL) and added to a solution of 4-bromo-1-pentyl-1H-indole-2,3-dione (25.0 g, 84.5 mmol) in dichloromethane (100 mL) via a canula over 10 min at 0° C. The reaction mixture was stirred at ambient temperature for 16 h, quenched with saturated ammonium chloride solution (100 mL) and the organic layer was separated. The aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate-hexane to give the title compound (34.9 g, 97%) as a brown gummy material: 1H NMR (300 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.29-7.21 (m, 2H), 6.88-6.81 (m, 1H), 6.55, (s, 1H), 6.14 (s, 1H), 5.86 (dd, 2H), 4.24 (s, 1H), 3.70-3.52 (m, 2H), 1.69-1.55 (m, 2H), 1.31-1.24 (m, 4H), 0.83 (t, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.6, 152.6, 149.1, 144.8, 141.2, 131.7, 127.7, 127.6, 121.0, 113.8, 108.3, 106.7, 101.7, 101.4, 80.5 40.5, 28.8, 26.7 22.2, 13.9.
Reaction SMILES: [CH2:1]([OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[O:19]1CCC[CH2:21][CH:20]1OC1CCCCO1.C(Cl)(=O)C>C(O)(=O)C>[C:20]([O:18][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:19])[CH3:21]
Reactant: C1CCC(OC2CCCCO2)OC1
Reactant: CCCCC/C=C\CCCCCCCCCCO
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CCCCC/C=C\CCCCCCCCCCOC(C)=O
Reaction time: 3 h
Yield: 51.6 %

Procedure:
A mixture of 5.7 g (0.026 moles) of (Z)-11-heptadecenol-tetrahydropyranyl ether (Formula III, R=CH3, Y=tetrahydropyranyl), 10 ml of acetic acid and 3 ml of acetyl chloride is boiled on an oil bath of about 80° C. for 3 hours. The mixture is cooled, poured onto 30 g. of ice, and extracted with 100 ml. of hexane. The hexane solution is washed with water, dried over magnesium sulfate, the solvent is evaporated, and the residue is distilled in fine vacuo. 2.6 g. (51.6%) of (Z)-11-heptadecenyl acetate (Formula I, R=CH3) are obtained; b.p.: 122°-126° C./0.05 mmHg.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23](O)=[O:24])[CH3:22])[CH:16]=[CH:17][C:18]=1[Cl:19]>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:6][C:23](=[O:24])[C@H:21]([CH3:22])[NH:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-leucine methyl ester hydrochloride (Sigma) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a solid (mp=120-132° C.). The reaction was monitored by tlc (Rf=0.49 in 1:1 EtOAc:Hexanes) and the product was purified by flash chromatography using 1:1 EtOAc:Hexanes as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=O)[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[NH2:30][OH:31]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=[N:30][OH:31])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)C2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 45, 121.9 mg, 0.29 mmol) and hydroxylamine hydrochloride (30.4 mg, 0.43 mmol) in methanol (0.85 mL) and pyridine (0.85 mL) was heated under reflux for 5 h. The reaction mixture was allowed to cool to 25° C. and was then concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (2×50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 80–100% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-hydroxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (68.8 mg, 55%) as a white solid: mp 205–207° C.; (ES)+-HRMS m/e calcd for C19H21ClN4O4S (M+H)+ 437.1045 found 437.1048.
Reaction SMILES: C([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)#N.C[Mg]Br.Cl.CC[O:29][CH2:30][CH3:31]>>[O:29]=[C:30]([CH3:31])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOCC
Reactant: Cc1c(-c2cccnc2)n(CCCCC#N)c2ccccc12
Agent: C[Mg]Br
Agent: Cl
Product: CC(=O)CCCCn1c(-c2cccnc2)c(C)c2ccccc21

Procedure:
1-(4-cyanobutyl)-3-methyl-2-(3-pyridyl)indole (1.5 g) in 15 ml of ether is added to a solution of 0.0103 mole of methyl magnesium bromide in 15 ml of ether, and this mixture is heated at reflux temperature for 3 hours. After cooling, 10 ml of 6N HCl is added dropwise and this mixture refluxed for several hours. The reaction mixture is washed with ether, and basified to pH 10-11 with 3N NaOH. Ether extraction and evaporation of the solvent yields 1-(5-oxohexyl)-3-methyl-2-(3-pyridyl)- indole; IR 1720 cm-1 ; NMR (CDCl3)δ2.0.
Reaction SMILES: C=O.C(O[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:39])[C@@H:26]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=O)C1C=CC=CC=1>CO.C(OCC)(=O)C>[C:35]([O:34][C:32](=[O:33])[NH:31][C@H:26]([C:25](=[O:39])[C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:11])[CH2:18][CH2:17]2)=[CH:24][CH:23]=1)[C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:36])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1)C(C)(C)C
Agent: C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)cc2)CC1
Reaction time: 18 h

Procedure:
Formaldehyde (37% wt. % solution in H2O, 0.5 mL) was added to a solution of 4-[4-(2(S)-tert-Butoxycarbonylamino-3,3-dimethylbutyryl)-phenyl]-piperazine-1-carboxylic acid benzyl ester in methanol (3 mL) and ethyl acetate (1 mL). The mixture was degassed and 10% palladium on charcoal (20 mg) was added. Hydrogen gas was bubbled through the suspension for 15 minutes when a balloon containing hydrogen was introduced to the reaction. After 18 hours, the catalyst was removed by filtration and the solvents were removed in vacuo to give a yellow oil which was used without further purification (0.15 g, 100% crude).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.O([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)C1C=CC=CC=1.[F-].[Cs+]>COCCOCCOC>[C:2]1([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH2:25][O:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(c1ccc(F)cc1)C(F)(F)F
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOCCOC
Product: Fc1ccc(C(COCc2cccc(-c3ccccc3)c2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under a nitrogen atmosphere, 0.50 g of 2-(4-fluorophenyl)-3,3,3-trifluoropropanol and 0.63 g of 3-phenoxybenzyl bromide was dissolved in 15 ml of dry diethyleneglycol dimethylether. Into the solution, 1.83 g of dry cesium fluoride was added at room temperature, and the reaction solution was stirred at room temperature for 48 hours. Thereafter, the reaction solution was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to preparative thin-layer chromatography on silica gel to obtain αmg of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[CH3:18][S:19]([O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:21])=[O:20]
Reactant: OCCc1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1ccccc1Cl
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of 5.26 mL (40 mMol) 2-(2-chlorophenyl)ethanol and 8.36 mL (60 mMol) triethylamine in 100 mL tetrahydrofuran were added dropwise 3.25 mL (42 mMol) methanesulfonyl chloride with cooling. The reaction mixture was stirred 4 hours at ambient and was then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was separated and washed sequentially with water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give 9.22 gm (98.3%) of the title compound as a yellow oil. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].CCN(C(C)C)C(C)C.Br[CH2:21][CH2:22][O:23][CH2:24][CH2:25]Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: BrCCOCCBr
Reactant: COc1ncc(N)cc1Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(N2CCOCC2)cc1Br
Temperature: 120 °C
Yield: 53 %

Procedure:
To a solution of 5-bromo-6-methoxypyridin-3-amine (1.0 equiv.) in DMF was added DIEA (3.0 equiv.) and 1-bromo-2-(2-bromoethoxy)ethane (1.0 equiv.). The solution was heated to 120° C. for 24 hours. Upon cooling to room temperature, the reaction was partitioned between water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate, the organics were combined, dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography eluting with 0-50% ethyl acetate in heptanes. The pure fractions were concentrated to yield 4-(5-bromo-6-methoxypyridin-3-yl)morpholine in 53% yield as an orange oil. LCMS m/z (M+H)=273/275, Rt=0.61 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 2.93-3.18 (m, 4H) 3.80-4.05 (m, 7H) 7.50 (d, J=2.74 Hz, 1H) 7.74 (d, J=2.74 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([OH:9])[CH2:5][CH2:6][CH:7]=[CH2:8].[F:17][CH:18]([F:31])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([N:28]=[C:29]=[O:30])[CH3:27])=[CH:22][CH:21]=1>>[CH2:5]([C:4]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:9][C:29](=[O:30])[N:28]([C@H:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH:18]([F:17])[F:31])=[CH:21][CH:22]=2)[CH3:27])[CH2:2][CH2:3]1)[CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCC(O)(CCCl)c1ccc(F)cc1
Reactant: C[C@H](N=C=O)c1ccc(OC(F)F)cc1
Product: C=CCCC1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(OC(F)F)cc2)C(=O)O1

Procedure:
6-(but-3-enyl)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one was prepared from 1-chloro-3-(4-fluorophenyl)hept-6-en-3-ol and (S)-1-(difluoromethoxy)-4-(1-isocyanatoethyl)benzene following a procedure analogous to that described in Example 110 Step 2. Two isomers were isolated.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CC(C)([O-])C.[K+].CS(O[CH2:16][CH2:17][CH2:18][C:19]1[CH:34]=[CH:33][C:22]2[O:23][CH2:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=3[C:27](=[O:28])[C:21]=2[CH:20]=1)(=O)=O>C(O)C>[O:28]=[C:27]1[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[CH2:24][O:23][C:22]2[CH:33]=[CH:34][C:19]([CH2:18][CH2:17][CH2:16][N:3]([OH:4])[CH3:2])=[CH:20][C:21]1=2
Reactant: CS(=O)(=O)OCCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CNO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CN(O)CCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To a stirring solution of 13.06 g of N-methylhydroxylamine hydrochloride in 250 ml of absolute ethanol was added 17.48 g of potassium tert-butoxide. To the resulting suspension was added 9.0 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2 -yl)propanol methanesulfonate. The resulting product suspension was allowed to reflux for 24 hours and was then cooled to room temperature. The suspension was filtered to remove potassium chloride, and the mother liquor was then treated with 200 ml of water and concentrated in vacuo to remove ethanol. The resulting mixture was partitioned against a total of 450 ml of methylene chloride and 250 ml of water. The organic phase was washed with 250 ml of saturated sodium chloride solution, dried (Na2SO4), filtered, and concentrated in vacuo to a viscous oil which solidified upon triturating the oil, with 10 ml of ethyl acetate and 3 drops of hexane and refrigerating. Thin layer analysis of the solids indicated a mixture, which was separated via HPLC (silica gel). The purified oil solidified upon standing to give 4.03 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methyl-1-propylamine, m.p. 113-114.5° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>CN(C)C=O.O>[N:20]1([CH2:2][C:3]2[CH:4]=[C:5]([CH:10]=[C:11]([I:13])[CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: COC(=O)c1cc(I)cc(CBr)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)cc(Cn2ccnc2)c1
Temperature: 70 °C
Yield: 50.5 %

Procedure:
A mixture of methyl 3-(bromomethyl)-5-iodobenzoate (500 mg, 1.4 mmol), potassium carbonate (388 mg, 2.8 mmol), and imidazole (96 mg, 1.4 mmol) in N,N-dimethylformamide (4 mL) was heated at 70° C. for 3 hours. After cooling, the reaction mixture was diluted with water and then extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 100% ethyl acetate afforded 242 mg (51%) of methyl 3-(imidazol-1-ylmethyl)-5-iodobenzoate as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[C:39]2[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=2[CH:33]=[CH:32][CH:31]=1)[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[C:39]3[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=3[CH:33]=[CH:32][CH:31]=2)=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1cccc2c1CCCC2
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc3c2CCCC3)=CC1=O
Temperature: 60 °C
Reaction time: 1.3 h
Yield: 15.2 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.38 g, 2.09 mmol) in acetonitrile (4.4 mL) was treated with N,N-diisopropylethylamine (0.33 mL, 2.02 mmol). After addition was complete, the mixture was stirred at 60° C. for 1.3 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.33 mL, 2.02 mmol) and acetonitrile (4.4 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (639 mg, 1.88 mmol) in acetonitrile (4.4 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded impure (S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (102 mg, 15%) as an orange/red oil. The material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]2([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]2([C:19]([O:21][CH3:22])=[O:20])[CH2:14][CH2:15][N:16]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)C1(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)CCNCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-[carbomethoxy]-piperidine (1.0 g, 2.39 mmol) in dimethylformamide (160 mL) is added sodium hydride (287.0 mg, 7.18 mmol, 60% in oil) at 0° C., followed by benzyl bromide (450.0 mg, 2.63 mmol). The reaction mixture is slowly warmed to room temperature and stirred overnight. The mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried (Na2SO4) and the solvent is evaporated to give 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1- [benzyl]-4-[carbomethoxy]-piperidine.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([N:15]1[CH2:20][CH2:19][CH:18](C(OC)=O)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12].ClC1N=C2C(C=CC(=O)[N:33]2C2C(Cl)=CC=CC=2Cl)=C(C2C=CC(F)=CC=2Cl)C=1>C1COCC1>[C:11]([N:15]1[CH2:20][CH2:19][CH:18]([NH2:33])[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=c1ccc2c(-c3ccc(F)cc3Cl)cc(Cl)nc2n1-c1c(Cl)cccc1Cl
Reactant: COC(=O)C1CCN(C(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)N1CCC(N)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of LHMDS (1.0M in THF, 0.2 mL) was added to methyl 1-tert-butylpiperidine-4-carboxylate (31 mg, 0.16 mmol) in 2 mL THF at −78° C. After 20 minutes the solution was warmed to 0° C. and stirred for an additional 10 minutes. 7-Chloro-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1,8-naphthyridin-2(1H)-one (COMPOUND BBB2) (28.5 mg, 0.063 mmol) was added and the reaction mixture stirred at 45° C. for 30 min. The solution was cooled to rt and quenched with saturated NH4Cl. The mixture was then partitioned between water and ethyl acetate. The organic phase was washed with water, brine and dried over magnesium sulfate. The filtered solution was concentrated and the residue purified by preparative silica gel thin layer chromatography using CHCl3/MeOH/NH4OH (87/12/1) as eluent to give the title compound. Mass spectrum (ESI) 616 (M+1). (Methyl 1-tert-butylpiperidine-4-carboxylate was prepared from 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) by a procedure analogous to that described by Street, L. J.; et al J. Med. Chem. 1990, 33, 2690.)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:5]=[C:4]([Cl:18])[N:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1.[F-].[Cs+]>O1CCOCC1.O>[Cl:18][C:4]1[N:3]=[C:2]([C:23]2[CH:24]=[N:25][CH:26]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:22]=2)[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:5]=1
Reactant: OB(O)c1cncc(C(F)(F)F)c1
Reactant: Fc1ccc(CNc2cc(Cl)nc(Cl)n2)c(F)c1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(CNc2cc(Cl)nc(-c3cncc(C(F)(F)F)c3)n2)c(F)c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of (2,6-Dichloro-pyrimidin-4-yl)-(2,4-difluoro-benzyl)-amine (1 g, 0.0034 mol) and 5-trifluoromethylpyridine-3-boronic acid (0.726 g, 0.0038 mol) were taken in dioxane:water (20:5) ml and to this CsF (2.1 g, 0.0138 mol) was added and degassed. Then bis-triphenylphosphine-palladium(II) chloride (0.24 g, 0.00034 mol) was added and degassed. The mixture was stirred at 60° C. for 12 hrs. The reaction was cooled to room temperature diluted with water (50 ml) and ethyl acetate (100 ml). After standard work-up, the residue was purified by column chromatography to get compound as white solid.