Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:28][O:29][CH2:30][O:31][CH3:32])[CH2:17][O:18][C:19]2[CH:26]=[CH:25][CH:24]=[C:23](F)[C:20]=2[C:21]#[N:22])=[CH:12][CH:11]=1>CC(N(C)C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH2:28][O:29][CH2:30][O:31][CH3:32])[CH2:17][O:18][C:19]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:20]=2[C:21]([NH2:22])=[N:7][C:6]([NH2:8])=[N:5]3)=[CH:14][CH:15]=1
Reactant: COCOCC(COc1cccc(F)c1C#N)c1ccc(Cl)cc1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: COCOCC(COc1cccc2nc(N)nc(N)c12)c1ccc(Cl)cc1
Temperature: 135 °C
Reaction time: 24 h
Yield: 24.4 %

Procedure:
Guanidine carbonate (792 mg; 4.4 mmol) is suspended in a solution of 2-[2-(4-Chlorophenyl)-3-methoxymethoxypropoxy]-6-fluorobenzonitrile (769 mg; 2.20 mmol) in DMA, and heated to 135° C. for 8 hours. The solution is cooled to RT overnight and placed in a freezer at 4° C. for 24 hours. The resulting black solids are removed by filtration through paper. The filtrate is concentrated under vacuum, and purified by column chromatography (10% MeOH/EtOAc). The collected fractions are dried to give 209 milligrams of 5-[2-(4-chlorophenyl)-3-methoxymethoxy-propoxy]-quinazoline-2,4-diamine.
Reaction SMILES: [CH3:1][C:2]1([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[O:3]1.CO>[Pd].C1C=CC=CC=1>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:2]2([CH3:1])[CH2:11][C:10](=[O:12])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=3)[O:3]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)C(=O)CC(C)(COc1ccc(N)cc1)O2
Yield: 79.4 %

Procedure:
Following a procedure similar to that described in Preparation 4, 10 g of methyl 2-methyl-2-(4-nitrophenoxymethyl)-4-oxochroman-6-carboxylate (prepared as described in Preparation 43) were hydrogenated, using 2 g of 10% w/w palladium-on-carbon, 100 ml of methanol and 200 ml of benzene, to afford 7.3 g of the title compound as a pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)=[O:15])[C:9](=[O:27])[CH2:8]2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:32](O)[CH3:33]>>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([O:24][CH2:32][CH3:33])=[O:23])=[CH:18][CH:17]=3)=[O:15])[C:9](=[O:27])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C(O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2=O)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2=O)cc1

Procedure:
A crude sample of the product of Example 62 (3.4 g) was treated with a solution, at 0° C., made by adding thionyl chloride (2.25 g) dropwise to ethanol (45 ml) with stirring at below 0° C. The mixture was stirred at room temperature for 2 hours, heated at gentle reflux for 21/2 hours, and evaporated. The residue was treated with water and adjusted to pH6 with aqueous sodium bicarbonate solution. The gum which precipitated was separated and the aqueous solution was adjusted to pH8 and extracted with dichloromethane (2×50 ml). The combined extracts were washed with brine, dried and evaporated. The residue was purified by chromatography using a 10 g. Mega Bond Elut silica gel column, eluting with 5% methanol/dichloromethane/0.5% triethylamine to give the title product as a solid (0.2 g); m.p. 163°-165° C.; NMR(CDCl3) δ 8.34(2H,m), 7.97(2H,m), 6.98(2H,m), 6.63(2H,m), 4.89(2H,s), 4.7(2H,s), 4.29(2H,q), 4.1(2H,s), 3.7(2H,m), 3.6(2H,m), 1.31(3H,t); m/e 398(M+H)+ ; calculated for C21H23N3 O5 : C, 63.5; M, 5.83; N, 10.6. Found: C, 61.5; H, 5.9; N, 10.5%.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: ClCCN1CCOCC1
Reactant: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1O
Product: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OCCN1CCOCC1

Procedure:
Similar procedure as described in example 329 was used, starting from 1-Isopropoxy-7-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol and N-(2-chloroethyl)-morpholine to give [1-Isopropoxy-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 442(MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:8]=1)#[CH:2].[N:17]([Si](C)(C)C)=[N+:18]=[N-:19].CN(C)C=O.CO>ClCCl>[NH:17]1[CH:2]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=3)[CH:8]=2)[N:19]=[N:18]1
Reactant: C#Cc1ccc2nc(C(=O)OCC)cn2c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2cc(-c3c[nH]nn3)ccc2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 220 mg of ethyl 6-ethynylimidazo[1,2-a]pyridine-2-carboxylate and 0.21 mL of azidotrimethylsilane in 4 mL of a mixture (9/1) of N,N-dimethylformamide and methanol are added 9.8 mg of cuprous iodide. The reaction mixture is stirred for 2 hours at 100° C. and then cooled, diluted with 4 mL of dichloromethane, filtered through alumina and concentrated to dryness. The residue is chromatographed on silica, eluting with a mixture of dichloromethane and ethanol (97/3). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 125 mg of ethyl 6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate in the form of an off-white solid.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[F:20][C:21]([F:27])([F:26])[CH2:22][CH2:23][CH:24]=[O:25]>O1CCCC1>[F:20][C:21]([F:27])([F:26])[CH2:22][CH2:23][CH:24]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)[OH:25]
Reactant: O=CCCC(F)(F)F
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)CCC(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of the ethyl 4-iodobenzoate (1.21 ml, 7.24 mmol) in tetrahydrofuran (12 ml) at −40° C. was added isopropylmagnesium chloride lithium chloride complex (6.13 ml, 7.97 mmol, 1.3 M in tetrahydrofuran) dropwise. The mixture was stirred for approximately 1 hour whereupon 4,4,4-trifluorobutanal (0.761 ml, 0.724 mmol) was added dropwise. The mixture was stirred at −40° C. for 15 minutes and slowly warmed to ambient temperature over 12 hours. The reaction was quenched with aqueous 1.0 M hydrochloric acid, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give ethyl(+/−)-4-(4,4,4-trifluoro-1-hydroxybutyl)benzoate, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[CH2:11])[CH:5]=[C:4]([CH:12](O)[CH3:13])[N:3]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[CH2:11])[CH:5]=[C:4]([CH:12]([Cl:17])[CH3:13])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: C=Cc1cc(C(C)O)nc(Cl)c1OC
Solvent: ClCCl
Product: C=Cc1cc(C(C)Cl)nc(Cl)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A solution of 2-chloro-3-methoxy-4-vinyl-6-(1-hydroxyethyl)-pyridine (446 mg, 2.09 mmol) in 10 mL of methylene chloride at 0° C. is treated with thionyl chloride (0.227 mL, 3.13 mmol) and stirred at room temperature for 1 h. The reaction is quenched with 15 mL of saturated sodium bicarbonate. The aqueous layer is extracted with 3×10 mL of methylene chloride. The combined organics are dried over potassium carbonate and concentrated in vacuo to provide 447 mg (92%) of 2-chloro-3-methoxy-4-vinyl-6-(1-chloroethyl)-pyridine.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([OH:10])=[CH:6][N:5]=2)[CH2:3][CH2:2]1.F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([O:10][C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cnc(C2CC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cnc(C3CC3)nc2)cc1
Yield: 99.5 %

Procedure:
2-Cyclopropylpyrimidin-5-ol (0.272 g, 2.0 mmol), 4-fluorobenzaldehyde (0.22 mL, 2.1 mmol) and potassium carbonate (0.414 g, 3.0 mmol) in dry DMF (2.0 mL) were heated to 120° C. in a sealed tube for 3 hours. The slurry was diluted with water and extracted twice with EtOAc. The combined organic phases were washed three times with water and brine, dried, filtered and concentrated to give a yellow oil. Purification by column chromatography using 20 g silica and a gradient of 0% to 50% EtOAc-heptanes as eluent gave 0.478 g (99% yield) of the subtitle compound as a colourless oil.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8](F)[C:7]([F:13])=[CH:6][C:3]=1[C:4]#[N:5].[OH:14][C:15]([C@H:18]1[CH2:22][CH2:21][NH:20][C@H:19]1[CH3:23])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Li+].[Li+]>>[F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([N:20]2[CH2:21][CH2:22][C@H:18]([C:15]([OH:14])([CH3:17])[CH3:16])[C@@H:19]2[CH3:23])[C:7]([F:13])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: COc1c(F)c(F)cc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: COc1c(F)c(C#N)cc(F)c1N1CC[C@H](C(C)(C)O)[C@@H]1C

Procedure:
Using 2,4,5-trifluoro-3-methoxybenzonitrile (347 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (409 mg) and lithium carbonate (328 mg), the title compound was obtained as a pale-yellow oil (yield: 175 mg) by an operation similar to that in Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10](Cl)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:5][CH:4]=1.[C:21]([NH:25][NH2:26])(=O)[CH2:22][CH3:23]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:22]([C:21]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:26][N:25]=1)[CH3:23]
Reactant: COc1ccc(N=C(Cl)c2cccc([N+](=O)[O-])c2)cc1
Reactant: CCC(=O)NN
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1nnc(-c2cccc([N+](=O)[O-])c2)n1-c1ccc(OC)cc1
Yield: 56.8 %

Procedure:
Using the procedure of Step B of Example 4, 15 g of the product of Step A and 8.8 g of propionic acid hydrazide in 200 ml of toluene and 14 ml of triethylamine were reacted to obtain 9.5 g of 3-ethyl-4-(4-methoxyphenyl)-5-(3-nitrophenyl)-4H-1,2,4-triazole melting at 126° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:4][CH2:3]1.C([Li])(C)(C)C.CO[NH2:28].O>CCCCCC.CCCCC>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([NH2:28])[C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CC1)c1ccccc1Oc1ccccc12
Reactant: CON
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCCCCC
Solvent: O
Product: CN1CCC2(CC1)c1ccccc1Oc1c(N)cccc12
Temperature: 25 °C

Procedure:
To a solution of 1'-methylxanthene-9-spiro-4'-piperidine (1.3 g.) in hexane (25 ml.) in an argon atmosphere is added a 1.6 molar solution of t-butyl lithium in pentane (3.5 ml.) with stirring at room temperature. The mixture is stirred for 1 hour at room temperature. Hydroxylamine methyl ether (0.4 g.) in hexane (5 ml.) is added dropwise during 5 minutes. Water is added and the organic layer separated, washed with water and dried with MgSO4. The solvent is evaporated to give a solid residue, which is recrystallised from hexane to give 1'-methyl-4-aminoxanthene-9-spiro-4'-piperidine, m.p. 173°-174° C. The above process is repeated using an equivalent amount of sulphur and paraformaldehyde as starting material in place of hydroxylamine methyl ether. The following compounds are thus prepared:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](I)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1COCC1.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:1][C:2]1[CH:9]=[C:8]([C:22]2[N:18]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:19]=[CH:20][CH:21]=2)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cc(I)cc1Cl
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(F)cc(-c2ccnn2C2CCCCO2)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of 2-chloro-6-fluoro-4-iodobenzonitrile (5.75 g, 20.4 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.39 g, 26.6 mmol) in THF (60 ml) was added bis(triphenylphosphine)-palladium(II) chloride (0.717 g, 1.02 mmol), sodium carbonate (5.20 g, 49.0 mmol) and water (20 ml). Reaction mixture was heated at 60° C. for 2 h, concentrated to ¼ of the volume, diluted with water (40 ml) and stirred at RT for 1 h. Thus resulting solid was filtered and suspended in EtOH (30 ml). Suspension was stirred at −10° C. for 1 h, precipitate was filtered and washed with EtOH to yield 2.90 g (46%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.49-1.72 (m, 3H), 1.78-2.03 (m, 2H), 2.29-2.44 (m, 1H), 3.56-3.68 (m, 1H), 3.93-4.03 (m, 1H), 5.36 (dd, 1H), 6.78 (d, 1H), 7.66 (d, 1H), 7.73 (dd, 1H), 7.81 (m, 1H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68][NH2:69]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18](=[O:19])[NH:69][CH2:68][CH2:67][N:66]([CH3:70])[CH3:65])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24](=[O:25])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cc3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 31)(4.88 g, 11.50 mmol) and HATU (5.25 g, 13.80 mmol) was added DMF (2 mL). The resulting mixture was treated with DIPEA (6.02 mL, 34.5 mmol) then after 5 min with N1,N1-dimethylethane-1,2-diamine (1.317 g, 14.95 mmol). After 0.5 h most of the DMF was removed in vacuo. The residue was treated with EtOAc and saturated NaHCO3. Insoluble solid appeared which was isolated by filtration and dried under vacuum at 60° C. for 3 h to give tert-butyl ((2S,4R)-1-acetyl-6-(4-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate as white solid (8.5 g), which was used without further purification in the subsequent reaction. The phases of the filtrate were separated, and the aqueous extracted with EtOAc (×2). The combined organic phases were washed with saturated NaHCO3(×3), dried over MgSO4 and concentrated in vacuo to give a liquid (2.1 g). This liquid was loaded onto a SCX cartridge (50 g, pre-conditioned with MeOH) the cartridge washed with MeOH (200 ml) and eluted with ammonia in MeOH (2M, 200 ml). The methanolic ammonia fractions were combined and concentrated in vacuo to give a further portion of tert-butyl ((2S,4R)-1-acetyl-6-(4-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (0.3 g, 0.6 mmol, 5% yield) as an orange solid. LCMS (Formate, 2 min), Rt=0.94 min, MH+=495.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[C:8]2[CH3:14].[C:32](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:12]=1[N:11]([CH3:32])[C:10](=[O:13])[CH:9]=[C:8]2[CH3:14]
Reactant: COc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)cc2c(C)cc(=O)[nH]c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)cc2c(C)cc(=O)n(C)c12

Procedure:
To a solution of 8-methoxy-4-methyl-6-[2,2,2-trifluoro-1-benzyloxy-1-(trifluoromethyl)ethyl]-2(1H)-quinolinone in dimethylformamide is added potassium carbonate and methyl iodide. The solution is stirred and heated until analysis by thin layer chromatography indicates the reaction is complete. The solution is cooled and added to water. The aqueous mixture is extracted with ether. The etheral solution is dried with anhydrous magnesium sulfate, filtered and evaporated at reduced pressure. The residual material is purified by chromatography on silicic acid to give 8-methoxy-1,4-dimethyl-6-[2,2,2-trifluoro-1-benzyloxy-1-(trifluoromethyl)ethyl]-2(1H)-quinolinone.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CN1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(CNC2CCN(C)CC2)cc1
Yield: 93 %

Procedure:
1-Methyl-4-piperidone (1.13 g, 10 mmol) was dissolved in 20 ml of methanol and added to a 100 ml flask. 4-Methylbenzylamine (1.21 g, 10 mmol) in 10 ml of methanol was added. Acetic acid (˜1.5 ml) was added until pH˜5. NaCNBH3 (1.26 g, 20 mmol) was slowly added. After 20 hrs magnetic stirring methanol was partly removed on Rotavapor (40° C.). Dichloromethane, water and 2M NaOH were added until pH˜10. The phases were separated and aq. phase was extracted twice with dichloromethane. The combined organic phases were washed with brine and dried over MgSO4. Concentration on Rotavapor (40° C.) yielded 2.06 g crude (93%) 47AKU-5. TLC (20% methanol in dichloromethane): Rf=0.3. HPLC-MS (Method A): M+=219.1 (UV/MS(%)=89/98).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([OH:35])[C:18]([Cl:36])=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:36].[ClH:37].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([OH:35])[C:18]([Cl:36])=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2c1cc(Cl)c(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.016 g, 0.031 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 1 hour. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in methylene chloride and thereby washed to obtain (Z)-2-[(1H-indol-3-yl)methylene]-5-chloro-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.011 g, 73%).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH:29]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:28][CH2:27][CH2:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:29]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)NCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(c1ccccc1)N(CCCCCCCC(=O)NOCc1ccccc1)CC2

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.3 g, 1.1 mmol) was reacted with 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.32 g, 1 mmol) in the presence of potassium carbonate (0.14 g, 1 mmol) and DMF as solvent to give 8-(6,7-dimethoxy-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-octanoic acid benzyloxyamide as an amorphous solid (yield 0.12 g, 23%; purified by column chromatography using silica gel and ethyl acetate: heptane=1:1 as an eluent). MS (M+H+)=517.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])/[CH:10]=[C:11](/[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][C:15]=1I)\[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CCC)CCC)CC>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][OH:22])[CH:18]=2)[NH:13][C:11]=1[CH3:12])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C(=C\C(=O)OCc1ccccc1)Nc1ccc(CCO)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCN(CCC)CCC
Solvent: CN(C)C=O
Product: Cc1[nH]c2ccc(CCO)cc2c1C(=O)OCc1ccccc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 25.5 %

Procedure:
To a mixture of (E)-3-[4-(2-hydroxy-ethyl)-2-iodo-phenylamino}-but-2-enoic acid benzyl ester (16.6 g, 38 mmol) and tripropylamine (7.2 mL, 38 mmol) in DMF (30 mL) was added palladium acetate (170 mg, 0.76 mmol). The mixture was stirred at 120° C. for 1 hour and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by chromatography (10%-30% ethyl acetate in hexanes) to give 3.0 g (26%) of the desired product as a white solid: mp 170-172° C.; MS(APCI+): m/z 310.4 (MH+); Anal. Calcd for C19H19N1O3.0.1H2O: C, 73.34; H, 6.22; N, 4.50. Found: C, 73.32; H, 6.37; N, 4.39.
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>N1C=CC=CC=1>[C:8]([N:6]1[CH:3]([S:2][CH3:1])[CH2:4][C:5]1=[O:7])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CSC1CC(=O)N1
Solvent: c1ccncc1
Product: CSC1CC(=O)N1C(C)=O
Reaction time: 24 h
Yield: 78 %

Procedure:
A mixture of 300 mg (2.6 mM) 4-methylthioazetidin-2-one, 10 ml acetic anhydride and 10 ml pyridine was stirred at 100° in a sealed tube 24 hours. After concentrating in vacuo, the residue was chromatographed on silica gel in hexane/ethyl acetate to yield 324 mg (78%) of 1-acetyl-4-methylthioazetidine-2-one.