Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:27][CH2:28][F:29].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOCC>[F:29][CH2:28][CH2:27][O:1][C:2]1[C:3]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1cc(-c2ccccc2)c2ccc(OC3CCCCO3)c(O)c2o1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: O=c1cc(-c2ccccc2)c2ccc(OC3CCCCO3)c(OCCF)c2o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
To 8-hydroxy-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one (40 mg, 0.12 mmol) and 1-bromo-2-fluoroethane (22 mg, 0.17 mmol) in 0.4 mL NMP was added Cs2CO3 (46 mg, 0.14 mmol). The mixture was stirred at rt for 5 h under Ar atmosphere and diluted with ether (40 mL). It was washed with water (3×30 mL) and dried over MgSO4 and concentrated. The crude product was purified with chromatography (hexane/EtOAc) to afford 8-(2-fluoroethoxy)-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one as a white solid (34 mg, 73%). MS (ESI) m/z 385 (M+H+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]([CH2:11][C@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C(C)(C)C)=[O:25])=[C:20]([F:31])[CH:19]=2)[CH2:13]1)=[N+:9]=[N-:10]>C(Cl)Cl>[N:8]([CH2:11][C@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[C:20]([F:31])[CH:19]=2)[CH2:13]1)=[N+:9]=[N-:10]
Reactant: CC(C)(C)OC(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
TFA (30 mL) was added to a solution of 5-(S)-azidomethyl-3-[4′-(tert-butoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one (6.72 g, 20 mmol) in DCM (20 mL), and the solution was kept at r.t. for 1 h. Solvents were removed under vacuum to afford 5-(S)-azidomethyl-3-(4′-carboxy-3′-fluorophenyl)oxazolidine-2-one. THF (75 mL) was added, followed by t-butanol (9.5 mL, 100 mmol), triethylamine (3.6 mL, 26 mmol), and diphenylphosphoryl azide (5.6 mL, 26 mmol). The mixture was stirred at r.t. under nitrogen atmosphere for 2 h, and then at 70° C. overnight. Solvent was removed under vacuum, and the residue distributed between ethyl acetate (150 mL) and aq. saturated sodium bicarbonate (100 mL). Aq. phase was washed with ethyl acetate (2×50 mL). Combined organic layers were washed with aq. saturated sodium bicarbonate, water, brine, and dried (MgSO4). Solvent was removed under vacuum, and the product purified by silica gel column chromatography (eluent: DCM). Yield 4.1 g (58%). MS (m/z): [M+H]+=352.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:7][C:6]=12.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][NH2:34])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][NH:34][C:10]1[N:5]2[N:4]=[CH:3][C:2]([Br:1])=[C:6]2[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:9]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCN
Reactant: Clc1ccccc1-c1cc(Cl)n2ncc(Br)c2n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1CCNc1cc(-c2ccccc2Cl)nc2c(Br)cnn12
Temperature: 75 °C
Yield: 78.7 %

Procedure:
3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (400 mg, 1.166 mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (5.7 mL). 2-Aminoethylpiperidine-1-carboxylic acid tert-butyl ester (266 mg, 1.166 mmoles) and diisopropyl ethylamine (0.409 mL, 2.33 mmoles) were added and the mixture was heated at 75° C. for 48 h. Additional diisopropyl ethylamine (0.204 mL, 1.166 mmoles) was added and the heating was continued for a total of 58 h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column (15×5 cm) using dichloromethane followed by 0.3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 2-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]ethyl}piperidine-1-carboxylic acid tert-butyl ester (491.1 mg, 79%): FABMS: m/z 534.1 (MH+); HRESIMS: m/z 534.12797 (MH+). Calcd. for C24H30N5O2BrCl: m/z 534.12714; δH (CDCl3) 1.50 (1H, m, CH2), 1.51 (9H, s, COOC(CH3)3), 1.57 (2H, m, CH2), 1.68 (2H, m, CH2), 1.76 (2H, m, CH2), 2.24 (1H, bm, CH2), 2.82/3.40/3.54/4.08/4.51 (5H, m, CH/CH2), 6.34 (1H, s, H6), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.08 ppm (1H, s, H2); δC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 19.2, 25.5, 29.2, 29.2, 39.2, 67.1; CH: ˜47.4, 87.1, 127.1, 130.1, 130.1, 131.6, 143.9; C: 80.0, 83.0, 132.1, 138.9, 145.7, 146.2, 158.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)CC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][NH2:11])=[N:3][CH:4]=1
Reactant: NN
Reactant: Fc1ccc(Cl)nc1
Solvent: O
Solvent: CCCO
Product: NNc1ccc(F)cn1
Temperature: 200 °C
Yield: 122.1 %

Procedure:
A mixture of 2-chloro-5-fluropyridine (5 g, 0.038 mol) and hydrazine monohydrate (15 ml, 0.32 mol) in n-propanol (40 ml) in a teflon container was purged with argon and heated in a stainless steel bomb at 200° C. for 19 h (magnetic stirring). Evaporation of solvent and excess hydrazine monohydrate in vacuo gave a solid residue (5.9 g) which was dissolved in sodium bicarbonate solution (5%) and extracted with 6×50 ml ethyl acetate. The combined extracts were dried over anhydrous Na2SO4, filtered and evaporated to give an oil (2.9 g) which proved difficult to purify and was therefore used as such in the next step. The crude product consisted of a ternary mixture of the desired product, 2-chloro-5-hydrazinopyridine, and 5-hydrazinopyridine.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH:20]=[CH2:21].F[C:23](F)(F)S(OC1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(C)C=C2)(=O)=O>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[C:3]([CH:20]=[CH2:21])=[C:2]([CH3:23])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([CH3:12])=[N:9]3)=[CH:14][CH:15]=1
Reactant: C=Cc1c(Cl)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(C)cc2n1
Product: C=Cc1c(C)cc2nc(C)ccc2c1-c1ccc(Cl)cc1

Procedure:
Compound 2F was prepared following the procedure used to prepare compound 1G of Example 1, except that 5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl trifluoromethanesulfonate (2E) was used instead of compound 1F. LCMS-ESI+ (m/z): 294.3, 296.3 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:18]1[C:19]([CH3:24])=[N:20][O:21][C:22]=1[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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>[CH3:24][C:19]1[C:18]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: Cc1noc(C)c1Br
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)noc3C)c(C)nc12
Yield: 23.1 %

Procedure:
Using the procedure analogous to Example 242, from 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (200 mg, 0.90 mmol), 4-bromo-3,5-dimethyl isoxazole (Alfa, 320 mg, 1.8 mmol), cesium carbonate (880 mg, 2.70 mmol) and PdCl2(PPh3)2 (25 mg) in DMF (5 ml), heated at 130 for 4 hrs, then overnight at ambient temperature gives the title compound (65 mg, 23% yield). ES-MS (m/z): calc'd for C18H24N4O: 312.4; found 313.2 (M+H)+. 1H NMR (400 mHz, CDCl3): δ 6.68 (s, 1H), 3.32 (m, 1H), 2.50 (s, 3H), 2.39 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H), 1.82 (m, 4H), 0.87 (m, 6H).
Reaction SMILES: [N:1]([CH:4]([CH:12]([OH:26])[CH:13]([OH:25])[CH:14]([N:22]=[N+]=[N-])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH:4]([CH:12]([OH:26])[CH:13]([OH:25])[CH:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=NC(Cc1ccccc1)C(O)C(O)C(Cc1ccccc1)N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(Cc1ccccc1)C(O)C(O)C(N)Cc1ccccc1
Yield: 78.8 %

Procedure:
A solution of 67 mg (0.19 mmol) of 6 in 4 mL of methanol was stirred with 30 mg of 10% palladium on carbon under 1 atmospheric hydrogen pressure for 18 hours at room temperature. The mixture was filtered through a 0.45 micron Millipore filter and the residue washed with methanol. The filtrate and the washings were concentrated to provide 45 mg (79% yield) of 7. This material showed NMR (CDCl3): d 2.64 (m, 8H), 7.283 (m, 10H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]([NH2:13])([CH2:11][CH3:12])[CH3:10].C(#N)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:13][CH:9]([CH2:11][CH3:12])[CH3:10])=[N:6][CH:7]=1
Reactant: CCC(C)N
Reactant: Clc1ncc(Br)cn1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC(C)Nc1ncc(Br)cn1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
In a sealed tube 2.00 g (10.3 mmol) 5-bromo-2-chloropyrimidine and 3.13 mL (31.0 mmol) sec-butylamin are added to 12 mL ACN. The reaction mixture is stirred at 120° C. for 2 h, then diluted with EtOAc and washed with water (2×). The org. phase is dried with MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:21])[CH2:4][C:5]([O:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[N:22]([O-])=[O:23].[Na+].[Cl-].[Na+]>C(O)(=O)C.O>[Br:1][CH2:2][C:3](=[O:21])[C:4](=[N:22][OH:23])[C:5]([O:7][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:6]
Reactant: O=N[O-]
Reactant: O=C(CBr)CC(=O)OC(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(CBr)C(=NO)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
In 30 ml of acetic acid there were dissolved 6.94 g of benzhydryl 4-bromo-3-oxobutyrate and, under ice-cooling and stirring, a solution of 1.588 g of sodium nitrite in 6 ml of water was added dropwise. The mixture was further stirred at that temperature for 20 minutes and, following addition of 60 ml of a saturated aqueous solution of sodium chloride, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed under reduced pressure to recover 7.56 g of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=[O:8])=O.[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CC(C)=O>[C:15]([C:14]1[CH:18]=[CH:19][C:11]([N:10]2[C:4](=[O:6])[C:3]([CH3:9])=[C:2]([CH3:1])[C:7]2=[O:8])=[CH:12][CH:13]=1)([OH:17])=[O:16]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC1=C(C)C(=O)OC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CC1=C(C)C(=O)N(c2ccc(C(=O)O)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
37.8 g (0.3 mol) of dimethylmaleic anhydride was slowly added to a solution of 41.1 g (0.3 mol) of p-aminobenzoic acid and 300 ml of acetone in a 250 ml flask at 10° C. The mixture was stirred for 2 hours to obtain a yellow precipitate. Thereafter, the precipitate was collected by filtration under reduced pressure and recrystallized from a solution of DMF/water (50:50 (w/w)) to give an intermediate. The intermediate was treated with sodium acetate and acetic anhydride at 85° C. for 4 hours, cooled to room temperature, and placed in an ice bath to obtain a precipitate. The precipitate was collected by filtration under reduced pressure and recrystallized from a solution of ethanol/water (50:50 (w/w)) to give N-(p-carboxyphenyl)dimethylmaleimide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]([C:18]#[N:19])=[CH:10][C:9]=2[CH:20]([OH:22])[CH3:21])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:22][CH:20]([C:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[C:11]([C:18]#[N:19])[CH:10]=1)[CH3:21])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3-fluorophenyl)-7-(1-hydroxyethyl)quinoline-5-carbonitrile (20 mg, 0.07 mmol) in methylene chloride (1 mL) was added triethylamine (0.28 mL, 2.0 mmol) followed by methanesulfonyl chloride (0.12 mL, 1.5 mmol). The reaction was stirred at room temperature for 30 minutes, quenched with water and then extracted with dichloromethane. The combined organic layers were washed with brine and dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was used directly in the next step (28 mg, 100%). LCMS calculated for C19H16FN2O3S (M+H)+: m/z=371.1; Found: 371.1.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)=[O:11])[CH3:8]>C1C=CC=CC=1.CN(C)C=O>[CH2:7]([O:9][C:10]([C:12]1([C:15]([Cl:4])=[O:17])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C(=O)Cl)CC1

Procedure:
Oxalyl chloride (6.0 g. 47 mmol) was added to a stirred mixture of 1-ethoxycarbonylcyclopropane carboxylic acid (1a) (6 g, 38 mmol) in benzene (25 ml) plus two drops of dimethylformamide. After the gas evolution ceased, the stirring was continued at room temperature for another hour. The reaction mixture was concentrated. The residue was purified by distillation. A fraction collected at 91°-2° C./15 mm was redistilled to give the desired product.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:16][C:17]([CH3:21])=[N:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[ClH:2].[CH3:21][C:17]1[CH:16]=[C:15]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:14]2[C:19](=[CH:20][C:11]([O:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:4][CH:5]=3)=[CH:12][CH:13]=2)[N:18]=1
Reactant: C1COCCN1
Reactant: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(Cl)nc3)cc2n1
Agent: Cl
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(N4CCOCC4)nc3)cc2n1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
A suspension of 98.5 mg (0.25 mmol) of 7-(6-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride, product of example 56, in 0.44 ml (5 mmol) of morpholine was heated under nitrogen at 60° C. (oil bath temperature) for 23 h and further 72 h at 100° C. The mixture was cooled to RT and partitioned between EtOAc and water. The organic layer was separated, washed with water, dried over magnesium acetate and concentrated in vacuo. The residue was taken up in ether (20 ml), insoluble material was removed by filtration and the filtrate treated with 0.1 ml of 3 N HCl in MeOH. The solid that precipitated was collected, triturated with ether (5 ml), filtered off by suction, dried in a high vacuum and then applied to a to silica gel column with CH2Cl2/MeOH/NH4OH (19:1:0.05) as eluent. The purified fractions were combined and concentrated in vacuo to a small volume then acidified by adding a few drops of 3 N HCl in MeOH. The solvent was taken off in vacuo to give 23 mg (18%) of the desired 2-methyl-7-(6-morpholin-4-yl-pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinoline hydrochloride as a light yellow solid. ISP mass spectrum, m/e: 405.5 (M+1 calculated for C24H28N4O2: 405).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C@H:10]([C:22]([OH:24])=O)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>CN(C=O)C>[C:12]([NH:11][C@H:10]1[C:22](=[O:24])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9]1)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: Nc1ccccc1SC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1CSc2ccccc2NC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
A mixture of 13.10 g (37.9 mmol) of S-(o-aminophenyl)-N-carbobenzyloxy-D-cysteine and 7.27 g (37.9 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 82 mL of DMF was stirred at room temperature for 2 hours. To this solution was added 330 mL of ethyl acetate. The mixture was extracted 4 times with 200 mL of 1N NaOH. The ethyl acetate solution was dried with magnesium sulfate (MgSO4) and evaporated to a white amorphous residue. The residue was triturated with ether, and the resulting white crystals were filtered to yield 6.70 g (54%) of 3(S)-[(Carbobenzyloxy)amino]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one as a white solid.
Reaction SMILES: O[C:2]([CH3:30])([CH3:29])[CH2:3][C@@:4]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.O.[C:32]1(C)C=CC(S(O)(=O)=O)=C[CH:33]=1.COC(OC)(OC)C>C(OCC)(=O)C>[CH3:29][C:2](=[CH2:30])[CH2:3][C@:4]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]3[O:18][C:32]([CH3:33])=[N:20][N:19]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(C(=O)NN)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(C)(OC)OC
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)C[C@@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3nnc(C)o3)cc2)C(=O)O1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazin-an-3-yl]-ethyl}-benzoic acid hydrazide (90 mg), toluene-4-sulfonic acid monohydrate (10 mg), and 1,1,1-trimethoxy-ethane (1 ml) was stirred at room temperature for 1 h, at 80° C. for 2 h, and finally at reflux temperature for 1.5 h. After cooling to ambient temperature, ethyl acetate was added and the resulting mixture was washed with aqueous NaHCO3 solution and brine. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 99:1→95:5) to afford the title compound as a colorless resin-like solid.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH:14]([C@@H:16]1[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][C@@H:17]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:15].[NH4+].[Cl-]>C1COCC1>[OH:15][C@@H:14]([C@@H:16]1[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][C@@H:17]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Reactant: C#Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)C#Cc1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To a −20° C. solution of phenylacetylene (0.29 mL, 2.69 mmol) in anhyd. THF (1 mL) was added a solution of n-BuLi (1.6M in hexane, 1.56 mL, 2.50 mmol). The reaction mixture was stirred for 2 h at −20° C., then was cooled to −78° C. A solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 389 mg, 1.92 mmol) in THF (2 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature, stirred for 18 h, then treated with a saturated NH4Cl solution and extracted with CH2Cl2. The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (90% EtOAc/hex) to give (±)-(4R*,5R*)-5-((1R*)-1-hydroxy-3-phenylprop-2-ynyl)-1-methyl-4-phenyl-pyrrolidin-2-one (230 mg, 40%) as a white solid: mp 152-153° C.; 1H NMR (CDCl3) δ 2.78-3.09 (m, 5H), 4.02 (q, J=9.0 Hz, 1H), 4.38 (dd, J=9.0 Hz, 2.0 Hz, 1H), 7.22-7.40 (m, 10H), 9.18 (d,J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]#N)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[NH:27][C:28]1C2C(=CC=CC=2)C(C=O)=CC=1)(C)(C)C.C1(C)C(S([N+]#[C-])(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[O:25][CH:26]=[N:27][CH:28]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)c2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [C-]#[N+]S(=O)(=O)c1ccccc1C
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnco2)c2ccccc12
Yield: 44 %

Procedure:
The above mixture of compounds 503A & 503B (3.37 g, 10.0 mmol; corrected for presence of compound 503A), toluene-sulfonylisocyanide (2.15 g, 11.0 mmol) and potassium carbonate (1.66 g, 12.0 mmol) in 50 mL of methanol was refluxed for 4 h. The reaction mixture was partitioned between water (200 mL) and chloroform (200 mL). After extracting the aqueous layer with chloroform (100 mL), the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel eluting with a gradient of 10-40% ethyl acetate in hexane to give 1.35 g (44%) of compound 503C as a white solid. 1HNMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 8.57 (s, 1H), 8.20 (m, 2H), 7.76 (m, 2H), 7.64 (s, 1H), 7.62 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[CH:21]([NH:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:20][CH2:19]4)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:29]2[CH2:30][CH2:31][CH:26]([NH:25][CH:21]3[C:22]4[C:18](=[CH:17][C:16]([O:15][CH:12]5[CH2:13][CH2:14][N:9]([C:6]6[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:32])[F:33])=[CH:4][CH:5]=6)[CH2:10][CH2:11]5)=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)[CH2:27][CH2:28]2)=[CH:37][CH:38]=1
Reactant: FC(F)(F)c1ccc(N2CCC(Oc3ccc4c(c3)CCC4NC3CCNCC3)CC2)cc1
Reactant: Fc1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(CN2CCC(NC3CCc4cc(OC5CCN(c6ccc(C(F)(F)F)cc6)CC5)ccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred mixture of N-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-yl)piperidin-4-amine.3HCl (0.06 g, 0.1 mmol) in anhydrous dimethylformamide (0.5 mL) at room temperature was added 1-bromomethyl-4-fluorobenzene (0.02 g, 0.1 mmol) and N,N-diisopropylethylamine (0.07 g, 0.5 mmol). The resulting mixture was stirred at room temperature overnight. After this time the mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, methylene chloride/methanol/30% ammonium hydroxide=20/1/0.05) to afford the title compound as a off-white solid (0.05 g, 88%). 1H NMR (CDCl3, 300 MHz) 7.46 (m, 2H), 7.25 (m, 3H), 6.96 (m, 4H), 6.75 (m, 2H), 4.47 (m, 1H), 4.29 (m, 1H), 3.58 (m, 2H), 3.48 (s, 2H), 3.06-2.54 (m, 6H), 2.38 (m, 1H), 2.14-1.74 (m, 9H), 1.49 (m, 2H) ppm; MS (ES) 568.6 (M+H).