Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:9]([NH2:18])[N:8]=[C:7]([NH2:19])[N:6]=1)=O.Cl.[CH3:21][NH:22][OH:23]>>[CH3:2][C:3]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:9]([NH2:18])[N:8]=[C:7]([NH2:19])[N:6]=1)=[N+:22]([CH3:21])[O-:23]
Reactant: CNO
Reactant: CC(=O)c1nc(N)nc(N)c1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Product: CC(c1nc(N)nc(N)c1-c1ccc(Cl)cc1)=[N+](C)[O-]

Procedure:
To a solution of sodium metal (0.6 g.) in absolute alcohol (20 ml.) was added [2,6-diamino-5-(p-chlorophenyl)-4-pyrimidinyl] methyl ketone (2.0 g.) and N-methyl hydroxylamine hydrochloride (1.2 g.), and the mixture was refluxed together for 5 hours. After removal of ethanol, the residue was filtered and recrystallized from ethanol-chloroform to give α-methyl-α-[2,6-diamino-5-(p-chlorophenyl)-4-pyrimidinyl]-N-methylnitrone as a white solid, m.p. 306°-309° (decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[NH:26][C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])[CH2:17]1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:14][CH3:15])[CH:6]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH2:14]([O:13][C:7]1[CH:6]=[C:5]([C@H:4]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH2:17]2)[CH2:3][CH2:2][NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc([C@@H](CCN)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc([C@@H](CCNS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[3-amino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (0.45 g, 1.1 mmol) and triethylamine (0.3 mL, 2 mmol) in methylene chloride (10 mL) was added methane sulfonyl chloride (0.10 mL, 1.3 mmol) at 0° C. After 3 hrs, the mixture was extracted with methylene chloride (20 mL) and water (20 mL). The organic layer was washed with HCl (1N, 20 mL), sodium hydrogen carbonate (sat 20 mL), brine (20 mL), and dried over MgSO4. The solvent was removed in vacuo to give a solid, which was purified with chromatography (Silca Gel) to give (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonylamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (320 mg, 58% yield): mp, 93-95° C.; 1H NMR (CDCl3) δ 0.89-0.93 (m, 2H, CH2), 1.08-1.10 (m, 2H, CH2), 1.42 (t, J=7 Hz, 3H, CH3), 1.65-1.72 (m, 1H, CH), 2.27-2.32 (m, 2H, CH2), 2.94 (s, 3H, CH3), 2.97-3.06 (m, 1H, CHH), 3.85 (s, 3H, CH3), 3.50 (d, J=17 Hz, 1H, NCHH), 4.04 (q, J=7 Hz, 2H, CH2), 4.18 (d, J=17 Hz, 1H, NCHH), 5.51 (dd, J=6, 9 Hz, 1H, NCH), 5.60-5.62 (m, 1H, NH), 6.83-6.99 (m, 4H, Ar), 7.42 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.47 (s, 1H, NH); 13C NMR (CDCl3) δ 8.35, 14.76, 16.19, 32.26, 40.24, 40.65, 46.05, 51.12, 55.98, 64.63, 111.50, 112.83, 116.86, 116.94, 117.84, 119.64, 130.31, 133.43, 138.02, 141.44, 148.72, 149.41, 170.07, 172.72; Anal Calcd for C25H31N3O6S+0.35H2O: C, 59.12; H, 6.29; N, 8.27, H2O 1.26. Found: C, 59.42; H, 6.16; N, 8.05, H2O 1.24.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([I:14])=[C:12]([Cl:15])[CH:11]=[CH:10][N:9]=1)(C)(C)C.[OH-].[Na+]>Br.C1COCC1>[Cl:15][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[C:13]=1[I:14]
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1I
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nccc(Cl)c1I
Temperature: 100 °C
Yield: 92 %

Procedure:
A suspension of (4-chloro-3-iodo-pyridin-2-yl)-carbamic acid tert-butyl ester (5.6 g, 15.8 mmol) in 48% hydrobromic acid was heated at 100° C. for 10 min to give a clear solution. The mixture was cooled, treated with crushed ice and made basic with 6 M NaOH. The precipitated product was collected by vacuum filtration, washed with H2O and sucked partially on the funnel to give a white solid. The product was dissolved in THF and the solution dried over MgSO4 and concentrated in vacuo to give the title compound (3.7 g, 93%) as a white solid. 1H NMR (DMSO-d6) δ 7.84 (d, 1H, J=5.1 Hz), 6.73 (d, 1H, J=5.6 Hz), 6.51 (br s, 2H); MS (ESI+): m/z 254.97 (M+H)+.
Reaction SMILES: [C:1]1([N:7]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]([CH2:25][CH2:26]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([CH2:25][CH2:26][N:15]1[CH2:14][CH2:13][CH:12]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:11])[CH2:9][CH3:10])[CH2:17][CH2:16]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCCOc1ccccc1
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Product: CCC(=O)N(c1ccccc1)C1CCN(CCOc2ccccc2)CC1
Yield: 98.6 %

Procedure:
By condensing 14.7 g 4-(N'-phenyl-N'-propionylamino)-piperidine and 19.9 g phenoxyethyl chloride, they are obtained after 24 hours reflux 22 g of the title product which after recrystallization from hot cyclohexane gives a first crop weighing 13.5 g. The pure compound melts at 100°-102°. It is soluble in hydrochloric acid. The solution after distillation leads to the recovery of the hydrochloride. The hydrochloride is soluble in water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:36]1([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:44][CH2:43][C:42]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (7.87 mmol) and THF/H20 (3/1, 80 mL) were combined. 4-Phenyl-piperidine-4-carboxylic acid amide hydrochloride (2.8 g, 11.64 mmol, 1.5 eq.) and potassium carbonate (3.3 g, 23.88 mmol, 3 eq.) were added. The mixture was heated to reflux for 72 h. The mixture was concentrated in in vacuo. The aqueous residue was extracted with dichloromethane. The organic phase was extracted with H2O (50 mL). The organic phase was dried over MgSO4, filtered, and concentrated in uacuo to obtain a residue. The residue was purified by chromatography on silica gel (350 g) eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and then 10% methanol in dichloromethane to give the title compound:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:32][C:33]1[C:34]([OH:39])=[N:35][O:36][C:37]=1[CH3:38].O[CH:41]1[CH:46]2[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]2)[CH2:42]1>O1CCCC1>[Cl:32][C:33]1[C:34]([O:39][CH:41]2[CH:46]3[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]3)[CH2:42]2)=[N:35][O:36][C:37]=1[CH3:38]
Reactant: Cc1onc(O)c1Cl
Reactant: OC1CN2CCC1CC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1onc(OC2CN3CCC2CC3)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.9 %

Procedure:
A solution of 7.86 g of triphenylphosphine in 100 ml of tetrahydrofuran was cooled to 5° C., and then 5.22 g of diethyl azodicarboxylate were added dropwise to the cooled solution, followed by 4.00 g of 4-chloro-3-hydroxy-5-methylisoxazole. 3.81 g of 3-hydroxyquinuclidine were then added to the resulting mixture, and the mixture was stirred at room temperature for 24 hours. At the end of this time, the solvent was removed from the mixture by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to afford 4.72 g (yield 64.8%) of the title compound as a colorless powder, melting at 37°-38° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:10])=[N:6][CH:7]=1.C1C(=O)N([Br:28])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(NC(=O)c2ccc3ccccc3c2)cn1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1cnc(CBr)cn1)c1ccc2ccccc2c1

Procedure:
N-(5-methylpyrazin-2-yl)-2-naphthamide (2.63 g, 10.0 mmol) was weighed and dissolved in 30 mL carbon tetrachloride. NBS (1.96 g, 11.0 mmol), BPO (242 mg, 1.0 mmol) were added and heated to reflux and reacted in dark for 12 hours. It was rotate evaporated to dryness to remove the solvent, and was used for the next step directly.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([C:24](=[O:25])[C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[O:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: O=C1c2ccccc2OC12CCNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)Oc3ccccc3C4=O)nn2)n1

Procedure:
The object product (163 mg, 72%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (123 mg) obtained in Example 43(2), 3H-spiro[1-benzofuran-2,4′-piperidin]-3-one hydrochloride (150 mg) and potassium carbonate (173 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.FC(F)(F)C(O)=[O:22].OO>C(O)(=O)C>[F:1][C:2]1[C:3]([S:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:22])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Fc1cc(C(F)(F)F)cnc1Sc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: OO
Solvent: CC(=O)O
Product: O=S(c1ccccc1)c1ncc(C(F)(F)F)cc1F
Temperature: 22 °C

Procedure:
20 g (0.0693 mol) of 95% pure 3-fluoro-2-phenylthio-5-trifluoromethylpyridine were introduced into 100 ml of glacial acetic acid and 20 ml of trifluoroacetic acid and over a period of 5 min, with stirring at 22° C., 5.64 g (0.083 mol) of 50% strength hydrogen peroxide were added. The reaction mixture was stirred at 22° C. for 10 h and then poured into 1 l of ice-water and extracted with methylene chloride. The organic phase was washed with saturated sodium bicarbonate solution and water. After drying, filtration through silica gel and concentration under reduced pressure, 19.1 g (95.4% of theory) of the title compound of 24 n D
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(O)C>[CH3:21][Si:20]([CH3:22])([O:19][CH2:18][CH2:17][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of diethyl malonate (5.14 g, 32.1 mmol) in anhydrous ethyl alcohol (100 mL) was reacted with 96% sodium ethoxide (2.28 g, 32.2 mmol) at 76° C. for 1 h. After the solution cooled to room temperature, (2-bromoethoxy)-tert-butyldimethylsilane (7.68 g, 32.1 mmol) was added. The resulting solution was heated at 76° C. for 15.5 h and then concentrated. The residue was partitioned between dichloromethane and water. The organic layer was dried (Na2SO4) and concentrated to give the title compound as a brown oil (10.22 g, 100%). 1H NMR (CDCl3) δ 4.19-4.11 (m, 4H), 3.62 (t, 2H, J=6.0 Hz), 3.55 (t, 1H, J=7.3 Hz), 2.10-2.06 (m, 2H), 1.23 (t, 6H, J=7.1 Hz), 0.85 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:33][CH2:34][CH2:35][CH3:36])[CH3:32]>>[CH2:31]([N:33]([CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH2:34][CH2:35][CH3:36])[CH3:32]
Reactant: CCCNCC
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Product: CCCN(CC)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and ethyl(propyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.84 (m, 1H), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.82 (s, 1H), 3.32-3.8 (m, 14H), 3.20 (m, 2H), 1.80 (m, 2H), 1.38 (t, J=7.5 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H); MS (DCI) m/z 421 (M+H)+;
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][CH2:23][CH2:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH2:24][CH2:23][O:22][CH3:21])[N:26]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Reactant: COCCn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.37 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 72, 0.054 g, 0.38 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.19 g, 0.44 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) dropwise and the resulting solution stirred at room temperature over night. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium chloride solution (20 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-40 g column, 50-70% ethyl acetate/hexanes) to give (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (94 mg, 65%) as an off white solid: [α]29D=−62.6°, (C=0.31, chloroform); HR-ES(+) m/e calcd for C22H28N4O3 [M+Na]+ 419.2053, observed 419.2055; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-2.09 (m, 7H), 3.18 (s, 4H), 3.61 (t, J=5.28 Hz, 2H), 4.12 (t, J=5.13 Hz, 2H), 4.38-5.23 (m, 4H), 6.37 (d, J=2.11 Hz, 1H), 7.32-7.84 (m, 7H), 10.84 (s, 1H).
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].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>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@@H:25]([OH:27])[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
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)[C@H](C)O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-one (185 mg, 0.40 mmol; Example 149, Step B) in THF (4 mL) under a nitrogen atmosphere at −8° C. (internal temperature) was added L-Selectride® (Aldrich, St. Louis, Mo.) (0.48 mL, 0.48 mmol, 1M solution in THF) dropwise over 2 minutes (internal temperature reached −5° C.). After 10 minutes the reaction was quenched with MeOH (0.1 mL) and treated with Oxone® (2 KHSO5.KHSO4.K2SO4, DuPont, Wilmington, Del.) (992 mg, 1.61 mmol) in water (30 mL) and then it was stirred at rt for 2 hours. After this time the reaction was partitioned between EtOAc (50 mL) and Na2S2O3 (30 mL, saturated aqueous solution). The separated organic layer was washed with brine (20 mL) and then it was dried over MgSO4, filtered and evaporated in vacuo to give the title compound. Mass Spectrum (ESI) m/z=460.0 (M+1).
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[NH:16][S:27]([CH3:26])(=[O:29])=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1Cc2ccccc2[C@H]1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1Cc2ccccc2[C@H]1NS(C)(=O)=O
Reaction time: 2 h

Procedure:
(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-ylamine (1.60 g) is dissolved in 16 mL DCM and combined with triethylamine (2.54 mL). Then methanesulphonyl chloride (0.61 mL in 5 mL DCM) is added dropwise. The reaction mixture is stirred for 2 h and after elimination of the solvent it is purified by normal phase chromatography (cHex/EA). The product-containing fractions are combined and freed from the solvent using the rotary evaporator.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[CH2:14][CH:15]([OH:36])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.CC([O-])(C)C.[K+]>>[C:30]1([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH:15]([OH:36])[CH2:14][O:1][C:2]3[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[N:7]4)[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1ccc(O)c2cccnc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1ccc(OCC(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2cccnc12

Procedure:
Following the same procedure as in Example 23-(c), reaction and treatment were carried out using 360 mg of the above synthesized 5-hydroxy-8-methylquinoline, 1.39 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine and mg of t-BuOK in order to obtain 120 mg of 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-8-methylquinoline.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.N1([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)CCCC1>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(CN2CCCC2)cc1
Reactant: COC[C@@H]1CCCN1
Product: COC[C@@H]1CCCN1Cc1ccc(C(=O)OC)cc1

Procedure:
The title compound was synthesized from (S)-2-(methoxymethyl)pyrrolidine (0.175 g, 1.52 mmol) according to a procedure similar to that used for compound 56. 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 4.17 (d, J=13.6 Hz, 1H), 3.92 (s, 3H), 3.45 (m, 2H), 3.35 (m, 4H), 2.92 (m, 1H), 2.74 (m, 1H), 2.21 (m, 1H), 1.95 (m, 1H), 1.69 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][N:56]([CH3:58])[NH2:57]>CN(C=O)C>[CH3:55][N:56]([CH3:58])[NH:57][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23]
Reactant: CN(C)N
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) in DMF (5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.36 mmol), N,N-diisopropyl ethyl amine (0.27 mL, 8.1 mmol) and N,N-dimethylhydrazine (21 mg, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated and then diluted with water and extracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo. Concentration and purification by chromatography (silica, 0 to 5% methanol in dichloromethane) afforded the title compound (31 mg, 27%) as a white solid. MS: m/e=353.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[H-].[Na+].Br[CH2:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[CH2:1]([N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:10][CH2:11][O:12][CH2:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1)[CH3:2]
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: CCN(CCO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CCOCc1ccc(C(=O)c2ccccc2)cc1)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
2-(N-Ethylanilino)ethanol (3.03 g, 18.4 mmol, 1.2 eq) in THF (20 cm3) was treated with NaH (60% dispersion in oil, 524 mg, 13.1 mmol, 1.4 eq) and stirred at 20° C. for 1 hour. 4-Bromomethylbenzophenone (4.21 g, 15.3 mmol) was then added and stirring continued for 72 hours. Excess solvent was removed in vacuo and the residue diluted with DCM, washed with water and NaHCO3 solution (sat.), dried (MgSO4) and solvent removed under vacuum. The resulting oil was purified by flash chromatography, eluting with petroleum (bp 40–60° C.):EtOAc (9:1), to give the desired product as a yellow oil (4.36 g, 80%), Rf=0.54 (4:1, petrol:EtOAc) (Found: C, 78.34; H, 6.86; N, 5.29. C24H25NO2 requires C, 80.19; H, 7.01; N, 3.90%); vmax (film/cm−1 1658 (s), 1598 (s), 1506 (s); δH (200 MHz; CDCl3) 1.22 (3 H, t, J 7, CH3), 3.49 (2 H, q, J 7, CH2CH3), 3.58–3.79 (4 H, m, OCH2CH2N), 4.66 (2 H, s, ArCH2O), 6.69–6.79 (3 H, m, ArH o- and p- to NR2), 7.28 (2 H, dd, J 7, 7, ARH m- to NR2), 7.46–7.68 (5 H, m, ArH), 7.80–7.88 (4 H, m, ArH o- to C═O); δC (50.3 MHz; CDCl3) 12.2 (CH3),45.5 (NCH2CH3), 50.1 (NCH2CH2O), 68.5 (NCH2CH2O), 72.2 (ArCH2O), 111.8 (ArCH o- to NR2), 115.8 (ArCH p- to NR2), 127.0, 128.3, 129.3, 130.0 and 130.3 (ArCH o- and m- to C═O and ArCH m- to NR2), 132.4 (ArCH p- to C═O), 136.8 and 137.7 (4° ArCC═O), 143.2 (4° ArCCH2O), 147.7 (4° ArCNR2), 196.4 (C═O); m/z (APCl+) 360 ([M+H]+, 30%); HRMS C24H26O2N requires 360.1963; found 360.1963.