Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:4]=1[O:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[OH:8]>CO.[Pt]=O>[ClH:1].[CH3:2][C:3]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:4]=1[O:5][CH2:6][CH:7]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)[OH:8]
Reactant: Cc1cccc(C)c1OCC(O)c1ccccn1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: Cc1cccc(C)c1OCC(O)C1CCCCN1
Yield: 68.3 %

Procedure:
A solution of α-[(2,6-dimethylphenoxy)methyl]pyridine-2-methanol hydrochloride (11.20 g, 0.04 mole) in 200 ml of methanol was hydrogenated at room temperature with 1.4 g of platinum oxide for 45 minutes. The solution was filtered and the methanol removed by rotary evaporator. Trituration with ethyl ether gave a white solid which was recrystallized from methanol-ethyl ether (and dried at 100° C. overnight) to give 7.81 g (67.5%) of white crystalline product, m.p. 178°-179° C. with decomposition.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[C:1]([N:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[CH:13]=[CH:14][C:15]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C1=Cc2ccccc2Nc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(=O)N1c2ccccc2C=Cc2ccccc21
Yield: 94 %

Procedure:
Acetyl chloride (11.0 ml) was added to a chloroform (250 ml) solution of 5H-dibenzo[b,f]azepine (25.0 g) under ice-cooling. The solution was heated under reflux for 30 minutes, then allowed to cool. The organic phase was washed with a saturated sodium bicarbonate aqueous solution, water, and saturated brine; dried over anhydrous sodium sulfate; and filtered. The filtrate was concentrated, and the resulting residue was recrystallized from ethyl acetate-hexane to obtain N-acetyl-5H-dibenzo[b,f]azepine (28.6 g; yield, 94%) as a white solid.
Reaction SMILES: C(O[C:5]1([CH3:14])[CH:9]=[CH:8][C:7](=[O:10])[CH:6]1[CH2:11][CH:12]=[CH2:13])(=O)C.[Cl-].[Na+].S(=O)(=O)(O)[OH:18]>>[CH2:11]([C:6]1[C:7](=[O:10])[CH2:8][CH:9]([OH:18])[C:5]=1[CH3:14])[CH:12]=[CH2:13]
Reactant: O=S(=O)(O)O
Reactant: C=CCC1C(=O)C=CC1(C)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Product: C=CCC1=C(C)C(O)CC1=O
Reaction time: 1 h

Procedure:
Into a four-necked flask equipped with a stirrer and a thermometer, 5% sulfuric acid (10 ml) was charged, and dl-3-acetoxy-2-allyl-3-methyl-4-cyclopentenone (2 g) was dropwise added thereto in 1 hour while keeping the inner temperature at 30° to 50° C. After completion of the dropwise addition, the resultant mixture was kept at the same temperature as above for 3 hours. Thereafter, sodium chloride (3 g) was added to the reaction mixture, which was extracted with methyl isobutyl ketone (20 ml) three times. The organic layer was washed with a saturated aqueous sodium chloride solution, and methyl isobutyl ketone was removed by distillation. The residue was purified by column chromatography to give 1.27 g of 2-allyl-4-hydroxy-3-methyl-2-cyclopentenone. Yield, 84%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=1
Reactant: BrCCBr
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(OCCBr)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 15.3 %

Procedure:
4-(Hydroxyethyl)phenol (2.7 g, 20.0 mmol) was dissolved in N,N-dimethylformamide (50 mL) and thereto were added potassium carbonate (6.90 g, 50.0 mmol) and 1,2-dibromoethane (15.03 g, 80.0 mmol). After stirring at 80° C. for 6 hours, the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 2-[4-(2-bromoethoxy)phenyl]-1-ethanol (750.0 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:35]2=[O:50].O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:50])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:8](=[O:10])[C:7]4[CH:11]=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=4)[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCOc1ccc(C(=O)O)cn1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A stirred mixture of 6-ethoxy-nicotinic acid (0.50 g, 3.00 mmol) and CDI (0.54 g, 3.30 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (1.15 g, 3.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solvent was removed in vacuo and the crude product was purified by column chromatography (EtOAc hexanes). The product fractions were combined, concentrated and the residue was triturated in Et2O (20 mL) for 18 h. The product was isolated by filtration and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-6-ethoxy-nicotinamide as a white solid (1.11 g, 85% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.04 min (98.73%); mp: 243-245° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=7.1 Hz, 3H, CH3), 1.96-2.16 (m, 1H, CHH), 2.41-2.69 (m, 2H, CHH, CHH), 2.79-3.00 (m, 1H, CHH), 4.37 (q, J=7.1 Hz, 2H, CH2), 4.65 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.7 Hz, 1H, CH), 6.88 (dd, J=0.7, 8.8 Hz, 1H, Ar), 7.77-7.94 (m, 3H, Ar), 8.16 (dd, J=2.6, 8.7 Hz, 1H, Ar), 8.71 (dd, J=0.8, 2.5 Hz, 1H, Ar), 9.21 (t, J=5.9 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.41, 21.99, 30.93, 42.51, 49.01, 61.84, 110.27, 121.99, 123.04, 123.55, 129.82, 131.62, 133.44, 138.18, 147.13, 147.48, 164.79, 165.00, 166.97, 167.12, 169.80, 172.72; LCMS: MH=437; Anal Calcd for C22H20N4O6+0.1H2O: C, 60.30; H, 4.65; N, 12.78. Found: C, 60.08; H, 4.62; N, 12.77.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:14]([O:16][CH2:17][CH3:18])=[CH2:15])CCC.[F-].[K+]>CN(C=O)C.CCOCC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:14]([O:16][CH2:17][CH3:18])=[CH2:15])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(OCC)c1cnc(Cl)nc1
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (12.5 g, 64.62 mmol) in dry DMF (175 mL) under N2 was added tributyl(1-ethoxyvinyl)tin (21.8 mL, 64.62 mmol) and dichlorobis(triphenylphosphine)palladium (II) (2.27 g, 3.23 mmol). The mixture was heated at 100° C. for 3 h before being allowed to stir at room temperature for 16 Hr. The mixture was then diluted with ether (200 mL) and treated with aqueous KF soln (55 g of potassium fluoride in 33 mL of water). The two phase mixture was stirred vigorously for 1 h at room temperature before being filtered through diatomaceous earth (Celite®). The Titrate was washed with sat'd NaHCO3 soln and brine prior to drying (Na2SO4). The original aqueous phase was extracted with ether (2×) and the organic phase was treated as above. Repetition on 13.5 g of 5-bromo-2-chloropyrimidine and combined purification by Biotage™ flash chromatography on silica gel (gradient elution on a 65M column using 3% ethyl acetate in hexanes to 25% ethyl acetate in hexanes with 3.0 L) afforded the title compound as a white, crystalline solid (18.2 g, 73%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][CH:6]=1.[F:16][C:17]([F:30])([F:29])[C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([CH2:27][NH2:28])=[CH:22][CH:21]=2.FC(F)(F)C1NC2C(C=1)=CC(CNC(C1C=NC(C(F)(F)F)=CC=1)=O)=CC=2>>[F:30][C:17]([F:16])([F:29])[C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([CH2:27][NH:28][C:11]([C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:14])=[CH:6][CH:7]=1)=[O:13])=[CH:22][CH:21]=2
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(OCC(F)(F)F)nc1

Procedure:
Prepared from 6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid (Apollo Scientific) and [(2-trifluoromethyl-1H-indol-5-yl)methyl]amine (Intermediate 4) according to the method as described of Compound 1; m/z (ES+) 418 (M+1); 1H NMR (400 MHz, d6-DMSO): δ 12.21 (1H, s), 9.16 (1H, t), 8.74 (1H, s), 8.27 (1H, dd), 7.62 (1H, s), 7.44 (1H, d), 7.30 (1H, dd), 7.08 (1H, dd), 7.00 (1H, s), 5.06 (2H, m), 4.57 (2H, d).
Reaction SMILES: Cl[CH:2]([CH3:27])[C:3]([NH:5][C:6]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:4].[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[CH:28]([NH:31][CH:2]([CH3:27])[C:3]([NH:5][C:6]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:4])([CH3:30])[CH3:29]
Reactant: COc1ccc(Cc2nccc3ccccc23)c(NC(=O)C(C)Cl)c1OC
Reactant: CC(C)N
Product: COc1ccc(Cc2nccc3ccccc23)c(NC(=O)C(C)NC(C)C)c1OC

Procedure:
Following the procedure of Example 1, but reacting 1-(2-[2-chloro-propionyl] amino-3,4-dimethoxybenzyl) isoquinoline with isopropylamine, there is obtained 1-(2[2-isopropylamino-propionyl] amino-3,4-dimethoxybenzyl) isoquinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15]S(C(F)(F)F)(=O)=O)[CH:12]=[C:11](OCC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1>>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:35]2[CH:36]=[C:37]([C:39]([F:41])([F:40])[F:42])[CH:38]=[C:33]([F:32])[CH:34]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 15, step (d)) under the conditions described in Example 15, step (e-f) using 3-fluoro-5-trifluoromethylphenylboronic acid in step (e).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([N:40]1[CH:44]=[C:43](B(O)O)[CH:42]=[N:41]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.CCO>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12]([C:43]3[CH:42]=[N:41][N:40]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:44]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Br)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(Br)cnc21
Yield: 57.2 %

Procedure:
A mixture of 46 (1 g, 2.16 mmol), EtOH (14 mL), toluene (14 mL), 1-trityl-1H-pyrazole-4-boronic acid (767 mg, 2.16 mmol), 1M aq. Na2CO3 (5.4 mL, 5.4 mmol), LiCl (275 mg, 6.5 mmol) and PdCl2(PPh3)2 (75 mg, 0.108 mmol) was refluxed for 1 h 45 min. The reaction mixture was concentrated to afford a pale yellow solid. The solid was purified by silicagel chromatography (Si 50 g column) using 30% ethyl acetate in hexane as eluent (gradient elution) to give the product 47 (798 mg, 57%) as a pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.18-7.23 (m, 6H), 7.33-7.37 (m, 9H), 7.47 (t, J=15.6, 7.4 Hz, 2H), 7.57-7.60 (m, 2H), 7.74 (s, 1H), 7.91 (s, 1H), 7.95 (d, J=2.1 Hz, 1H), 8.15-8.18 (m, 2H), 8.46 (d, J=2.2 Hz, 1H).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH:16][CH2:17][CH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][C:22](=[O:28])[NH:23]2>O1CCCC1.CN(C)C=O.N1C=CC=CC=1>[O:28]=[C:22]1[CH2:21][C:20]2[C:24](=[CH:25][CH:26]=[CH:27][C:19]=2[CH2:18][CH2:17][O:16][C:8](=[O:9])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:23]1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=C=Nc1ccccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C1Cc2c(CCOC(=O)Nc3ccccc3-c3ccccc3)cccc2N1
Temperature: 80 °C
Yield: 79.7 %

Procedure:
2-Biphenylyl isocyanate (1.15 mL, 6.7 mmol) was added dropwise to a stirred mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (709 mg, 4 mmol) in tetrahydrofuran (8 mL), dimethylforamide (2 mL) and pyridine (3 drops) under nitrogen atmosphere. The mixture was heated at 80° C. for 15 hours. The reaction was cooled, quenched with 1 N sodium hydroxide solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate:hexane 3:2 to give 1.188 g (80%) of biphenyl-2-yl-carbamic acid 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl ester as a white fluffy solid.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH:8]1([CH2:11][C@H:12]([NH:18]C(=O)OC(C)(C)C)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:10][CH2:9]1>C(O)C>[ClH:1].[NH2:18][C@@H:12]([CH2:11][CH:8]1[CH2:10][CH2:9]1)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14]
Reactant: CN(C)C(=O)[C@H](CC1CC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@@H](N)CC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A 4M solution of HCl in dioxane (4.68 mL, 18.7 mmol) was added to a solution of (S)-tert-butyl 3-cyclopropyl-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (1.2 g, 4.68 mmol) in ethanol (10 mL). After 16 h stirring at ambient temperature the solvent was removed under reduced pressure. The remaining solid was digerated with diethyl ether (10 mL), filtered off, washed with diethyl ether (3×5 mL) and dried for 3 h in vacuo at 40° C. to give the title compound as off-white solid (820 mg, 91%). MS (EI): m/e=157.1 [M+H]+.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25](=[O:27])[CH3:26])[C:5]1=[O:30])[CH:2]=[CH2:3].[CH3:32][Mg]Br.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25]([OH:27])([CH3:32])[CH3:26])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)=O)C1=O
Reactant: C[Mg]Br
Agent: C[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)(C)O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-one (0.100 g, 0.218 mmol; Example 149, Step B) in THF (4 mL) was added a solution of methylmagnesium bromide, 1.4M in toluene (0.104 g, 0.873 mmol) at 0° C. The reaction was allowed to warm to room temperature. After being stirred at room temperature for 4 h, another 1 eq. of MeMgBr was added and stirred for another 2 h. The reaction was quenched w/sat NH4Cl solution, and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography on silica gel, eluting with 40% EtOAc/hexanes, to provide the title compound as a light-yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[N-:16]=[N+:17]=[N-:18].[Na+].[Al]>O>[N:16]([CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15])=[N+:17]=[N-:18]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Al]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCCCN1C(=O)c2ccccc2C1=O
Yield: 72.4 %

Procedure:
A heavy-walled Pyrex tube was charged with a suspension of N-(3-bromopropyl)phthalimide (1.00 g, 3.72 mmol) and sodium azide (0.32 g, 4.84 mmol) in H2O (2 mL). The tube containing the resulting mixture was sealed with an aluminum crimp cap fitted with a silicon septum and then it was exposed to microwave irradiation for 30 min at a temperature of 120° C. After the irradiation, the reaction tube was cooled with high-pressure air until the temperature had fallen below 40° C. The product was extracted with ethyl acetate. The combined organic layers were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude material (0.62 g, 72% yield) was used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ 7.86-7.83 (m, 2H), 7.73-7.70 (m, 2H), 3.77 (t, J=6.4 Hz, 2H), 3.36 (t, J=8.0 Hz, 2H), 1.94 (m, 2H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[N:29]=[C:28]([CH2:30][OH:31])[C:27]([O:32][CH2:33][CH3:34])=[C:26]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:25]=1>C(Cl)Cl>[Cl:23][C:24]1[N:29]=[C:28]([CH:30]=[O:31])[C:27]([O:32][CH2:33][CH3:34])=[C:26]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:25]=1
Reactant: CCOc1c(CO)nc(Cl)nc1N1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOc1c(C=O)nc(Cl)nc1N1CCOCC1
Yield: 96.3 %

Procedure:
To a suspension of Dess-Martin periodinane in CH2Cl2 (15%, 11.2 ml, 1.1 eq) was added to a stirred solution of (2-chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-4-yl)-methanol (1.13 g, 1 eq.) in CH2Cl2 (20 ml) and the mixture was reacted at r.t. for 2 h. The mixture was quenched with NaHCO3(sat), extracted with EA, and washed with brine. The crude was purified by chromatography to give a product (1.08 g, 80.8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1Br.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH:12]=1)=[O:33]
Reactant: COC(=O)c1ccncc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccncc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 14 h
Yield: 85.8 %

Procedure:
PdCl2(PPh3)2 (0.7 g, 1.03 mmol, 0.05 eq.) was added to a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (6.3 g, 20.5 mmol, 1.0 eq.) in THF (120 mL) under nitrogen. To this was added 3-bromoisonicotinic acid methyl ester (4.4 g, 20.5 mmol, 1.0 eq.). This was followed by the addition of a solution of Na2CO3 (8.7 g, 82.1 mmol, 4.0 eq.) in water (41 mL). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The resulting solution was diluted with EtOAc (100 mL), and washed with saturated aqueous NaCl (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:10) to yield 3′,6′-dihydro-2′H-[3,4′]bipyridinyl-4,1′-dicarboxylic acid 1′-t-butyl ester 4-methyl ester (5.6 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13](O)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>FC(F)(F)C(O)=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([N:24]=[N+:25]=[N-:26])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1CCCC(O)(c2ccccc2)C1
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
g (3.212 mmol) 3-Hydroxy-3-phenyl-piperidine-1-carboxylic acid benzyl ester was dissolved in a cold mixture (10° C.) of trifluoroacetic acid (12.3 ml) and water (2.0 ml). The solution was cooled to 0° C. and 1.46 g (22.48 mmol) sodium azide were added portionwise. The temperature rose to 10° C. The ice bath was removed and the mixture was stirred at room temperature for 3 hours. The mixture was cooled in an ice bath and basified by dropwise addition of a 25% ammonium hydroxide solution (13.0 ml) maintaining the temperature below 20° C. The mixture was diluted with water (45 ml) and extracted 3 times with dichloromethane. The combined extracts were washed once with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a light yellow oil which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C[N:13](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].[OH-].[NH4+]>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([NH2:13])=[O:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Br)ccc1I
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cc(Br)ccc1I
Reaction time: 0.03 h
Yield: 72.2 %

Procedure:
To 5-bromo-2-iodobenzoic acid (20 g, 61.2 mmol) in 1:1 mixture of dichloromethane and dimethylformamide (200 mL) was added HATU (25 g, 65.8 mmol), and the solution stirred 2 min. Excess ammonium chloride (20 g) was added, and the heterogeneous mixture was stirred 1 h. Ammonium hydroxide (20 mL) was added causing a white precipitate. The precipitate was filtered and washed with ethyl acetate. The solution was diluted with ethyl acetate, washed with water, 1 N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride, dried (magnesium sulfate), filtered, and concentrated under reduced pressure resulting in the formation of a white precipitate. The solid was filtered to provide the title compound (14.4 g). ESI MS m/z 327.0 [M+H]+.