Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[CH3:9])(=[O:3])[CH3:2].[Br:10]Br>Br>[CH3:9][C:5]1[N:6]=[CH:7][NH:8][C:4]=1[C:1](=[O:3])[CH2:2][Br:10]
Reactant: CC(=O)c1[nH]cnc1C
Reactant: BrBr
Agent: Br
Product: Cc1nc[nH]c1C(=O)CBr
Reaction time: 1.25 h

Procedure:
A solution of 1.57 g (12.6 mmol) of 5-acetyl-4-methylimidazole in 15 ml of concentrated hydrobromic acid was warmed to 50° and a solution of 2.01 g (12.6 mmol) of bromine in 15 ml of concentrated hydrobromic acid was added over 0.75 hour. The mixture was stirred at 50° for 1.25 hour, then concentrated. The residue was triturated with isopropyl alcohol and the white solid was collected by filtration. This amounted to 2.78 g (78%) of 1-(4-methyl-5-imidazolyl)-2-bromoethanone hydrobromide: nmr (D6DMSO) (δ): 9.40 (s, 1H); 4.87 (s, 2H); 2.65 (s, 3H). This material was converted to its free base by stirring for 15 minutes in 50 ml of saturated sodium bicarbonate solution to give, after collection by filtration and drying, 1-(4-methyl-5-imidazolyl)-2-bromoethanone as a white powder.
Reaction SMILES: [C:1]1([C@@H:7]([NH:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]=O.CO.[C:22]([O-:25])([O-])=O.[K+].[K+]>O>[CH3:18][O:25][CH2:22][N:12]([CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=O
Reactant: COC(=O)[C@H](NC[Si](C)(C)C)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COCN(C[Si](C)(C)C)[C@@H](C(=O)OC)c1ccccc1
Temperature: 0 °C

Procedure:
(R)-methyl 2-phenyl-2-((trimethylsilyl)methylamino)acetate (1.0 g, 3.98 mmol) was added to a mixture of 37% aqueous formaldehyde (784 mg) and methanol (310 mg) while stirring at 0° C. After two hours K2CO3 (1.0 g) was added and the mixture was stirred for an additional hour. Then, water (10 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were dried with Na2SO4. Concentration under vacuum gave the crude (R)-methyl 2-((methoxymethyl)((trimethylsilyl)methyl)amino)-2-phenylacetate as an oil (theor. max. 3.98 mmol). The product was directly used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl[CH2:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:36][C:37]2[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cn1ccnc1CCl
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6nccn6C)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 2-(chloromethyl)-1-methyl-1H-imidazole (39.2 mg) were suspended in dimethylformamide (1.8 mL) and potassium carbonate (62 mg) was added. The reaction mixture was shaken for 24 h at 60° C. Another portion of 2-(chloromethyl)-1-methyl-1H-imidazole (39.2 mg) and potassium carbonate (62 mg) was added and the mixture was shaken again for 24 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 31.5 mg; LC (method 23): tR=1.54 min; Mass spectrum (ESI+): m/z=557 [M+H]+.
Reaction SMILES: CO[N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH:5]1[C:19]([O:21]C)=O.B.C1COCC1.C([O-])([O-])=O.[K+].[K+].[O:35](C(OC(C)(C)C)=O)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=O>C1COCC1.CCOC(C)=O.O>[C:39]([O:38][C:36]([NH:3][C@H:4]1[C@@H:5]([CH2:19][OH:21])[CH2:6][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:8]1)=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CON=C1CN(C(=O)OCc2ccccc2)CC1C(=O)OC
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CO
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 37.9 %

Procedure:
A solution of 1-benzyl 3-methyl 4-(methoxyimino)pyrrolidine-1,3-dicarboxylate (12.6 g, 41.1 mmol) in THF (100 mL) at −78° C. was added borane THF complex (1M in THF, 148 mL, 148 mmol) dropwise and stirred for 1.5 hrs, and then it was warmed to 0° C. and stirred for 2 hrs and further warmed up to RT and stirred for 16 hrs. The reaction was quenched with water at 0° C. until effervescence ceased, and to it was added K2CO3 (5.68 g, 41.1 mmol). The reaction mixture was warmed up to RT and stirred for 1 hr. (BOC)2O (11.46 mL, 49.4 mmol) was added. The reaction mixture was stirred at RT for 16 hrs. The reaction mixture was added 200 mL of water and 500 mL of EtOAc and stirred for 10 minutes. The organic phase was separated and washed with 200 mL of brine, dried over Na2SO4, and then it was filtered, concentrated and purified by silica gel chromatography, eluting with 0-70% ethyl acetate in hexanes, to give the racemic title compound (5.46 g, 38% yield). 1H NMR (400 MHz, chloroform-d) δ 7.41-7.30 (m, 5H), 5.15 (d, J=1.3 Hz, 2H), 4.86-4.72 (m, 1H), 4.30 (br. s., 1H), 3.94-3.85 (m, 1H), 3.66 (dd, J=11.9, 5.1 Hz, 2H), 3.59-3.44 (m, 3H), 2.96 (q, J=11.4 Hz, 1H), 2.57 (br. s., 1H), 1.50-1.44 (m, 9H). MS(ES+) m/z: 351.1 (M+H); HPLC retention time: 2.79 min (analytical HPLC Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]([OH:23])=O)=[N:6][CH:7]=1.[CH3:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:11][C:10]=2[C:21]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:34][CH:33]=2)=[O:23])=[N:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(NC(=O)c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazole-4-carboxylic acid (intermediate A 4.1, 15 mg, 0.043 mmol), 4-(methylsulfonyl)aniline (7.32 mg, 0.043 mmol) and DIPEA (0.015 ml, 0.086 mmol) in 0.6 mL of DMF was added BOP (22.7 mg, 0.051 mmol). The reaction was stirred at room temperature for 1 h and purified by reverse phase HPLC to give 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-N-[4-(methylsulfonyl)phenyl]-1,3-oxazole-4-carboxamide: 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.38 (d, J=2.5 Hz, 1H), 8.08 (m, 2H), 7.94 (s, 4H), 7.61 (dd, J=8.4, 2.5 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.19 (m, 2H), 3.06 (s, 3H); HRMS exact mass calc for C22H15ClFN3O4S2 [M+H]+: 504.0245; observed: 504.0249.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(Cl)Cl>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][CH2:20][OH:21])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: OCCCBr
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(OCCCO)cc2)CC1
Temperature: 60 °C

Procedure:
A mixture of 1-acetyl-4-(4-hydroxyphenyl)piperazine (3.00 g) in N,N-dimethylformamide was treated with 3-bromo-1-propanol (1.60 ml) and potassium carbonate (2.82 g), and the mixture was heated at 60° C. for 8 hours. Then 3-bromo-1-propanol (1.60 ml) was added again, and the mixture was heated at 110° C. for 6 hours. After cooling, water and methylene chloride were added to the reaction mixture, and the organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with a mixed solvent of methylene chloride-methanol (from 0% to 6% gradient elution) to give 1-acetyl-4-[4-(3-hydroxypropyloxy)phenyl]piperazine (3.53 g) as a pale pink solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:10])=[CH:5][CH:4]=1.[CH2:11]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14].C([NH+](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Br-:1].[Br:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N+:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:5]=1
Reactant: CCCCN(CCCC)CCCC
Reactant: BrCc1ccc(CBr)cc1
Agent: CCCC[NH+](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC[N+](CCCC)(CCCC)Cc1ccc(CBr)cc1
Product: [Br-]

Procedure:
To a mixture of α,α'-dibromo-p-xylene (7.0 g, 26.5 mmol) in toluene (200 m L) was added tri-n-butylamine (3.4 3 g, 18.6 mmol) under argon gas. The reaction mixture was stirred for several days at room temperature under argon at which time the tri-n-butylammonium salt had crystallized out of solution. The crystals were filtered and washed with toluene (3×50 mL) and hexanes (3×50 mL) and dried: 1H NMR (CDCl3) δ0.97 (t, 9H), 1.39 (m, 6H), 1.76 (m, 6H), 3.32 (m, 6H), 4.4 7 (s, 2H), 4.96 (s, 2H), 7.4 2-7.59 (dd, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[S:17][C:16]2[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[S:17][C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1cc2c(s1)CCCC2
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1cc2c(s1)CCCC2
Temperature: 25 °C
Yield: 33.1 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (370 mg) and 2-bromoacetyl-4,5,6,7-tetrahydrobenzo[b]thiophene (740 mg) in ethanol (15 ml) was treated with triethylamine (0.6 ml, 4.76 mmol) and then stirred at room temperature. After 1.5 h the mixture was concentrated to ca 5 ml and then diluted with ethyl acetate (50 ml). The resulting solution was washed with water (×3), dried (MgSO4) and evaporated to a pale yellow foam. The foam was subjected to preparative thin-layer chromatography on silica developing with chloroform-ethanol (29:1) (two runs). Elution of the major band with ethyl acetate gave a white solid which was crystallised from ethyl acetate to give the title pyrimidinone (290 mg), m.p. 206°-208° C., λmax (EtOH) 225 nm (ε 10,160), 268.5 nm (ε 9,570), 314 nm (ε 12,260).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:3]=1[CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([O:27]C)=[O:26].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[C:3]=1[CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C(F)(F)F)cc1)CCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C(F)(F)F)cc1)CCC3
Temperature: 25 °C
Yield: 46.4 %

Procedure:
To a solution of methyl [2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclo penta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.087 g; 0.194 mmol) in methanol (4 mL) and ethanol (2 mL) was added a 5% sodium hydroxide solution (5.2 mL; 6.500 mmol). The reaction mixture was heated under reflux for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.039 g (46%) of the title compound as a white powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:24])[CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[CH:18]=[CH:19][N:20]=[C:21]([CH:22]=O)[C:10]2=3)[CH2:3][CH2:2]1.[N:25]1[C:34]2[C@@H:33]([NH2:35])[CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:24])[CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[CH:18]=[CH:19][N:20]=[C:21]([CH2:22][NH:35][C@@H:33]4[C:34]5[N:25]=[CH:26][CH:27]=[CH:28][C:29]=5[CH2:30][CH2:31][CH2:32]4)[C:10]2=3)[CH2:3][CH2:2]1
Reactant: N[C@H]1CCCc2cccnc21
Reactant: O=Cc1nccc2c3ccccc3n(CC(=O)N3CCOCC3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Cn1c2ccccc2c2ccnc(CN[C@H]3CCCc4cccnc43)c21)N1CCOCC1
Yield: 85 %

Procedure:
1.5 mmol of 9-(2-morpholino-2-oxoethyl)-9H-pyrido[3,4-b]indole-1-carbaldehyde, 1.5 mmol of (S)-5,6,7,8-tetrahydroquinolin-8-amine, and 3.00 mmol of sodium triacetoxyborohydride in 20 ml dichloromethane were stirred for 2 hours at room temperature, then reaction was quenched with saturated sodium bicarbonate solution. Organic layer was dried over magnesium sulfate, filtered off, and evaporated. Desired product was purified with column chromatography using dichloromethane:methanol:NH4OH (9:1:0.1) solvent system (85% yield). ESI+ MS: m/z (rel intensity) 456.2 (100, [M+H]+). 1H-NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=4.8 Hz), 8.36 (d, 1H, J=1.6 Hz), 8.12 (d, 1H, J=7.6 Hz), 7.92 (d, 1H, J=5.6 Hz), 7.55 (dt, 1H, J=1.2, 8.0 Hz), 7.37 (d, 1H, J=7.6 Hz), 7.29 (q, 2H, J=4.8 Hz), 7.07 (q, 1H, 4.8 Hz), 6.11 (d, 1H, J=18.0 Hz), 5.74 (d, 1H, J=17.6 Hz), 4.46 (d, 1H, J=12.0 Hz), 4.33 (d, 1H, J=12.0 Hz), 4.00 (t, 1H, J=5.6 Hz), 3.82-3.76 (m, 1H), 3.73-3.60 (m, 6H), 3.55-3.50 (m, 1H), 2.78 (t, 2H, J=6.4 Hz), 2.18-2.08 (m, 1H), 1.96-1.66 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH:29]=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(C)C>C1COCC1.O>[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:29]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=2)[OH:30])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: CCOc1cc(Br)ccc1OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOc1cc(C(O)c2ccc(OC)c(OCc3ccccc3)c2)ccc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (5.25 g, 22.7 mmol) and dry THF (50 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (9.1 mL, 22.7 mmol) and stirred for 20 min. Then a mixture of 3-benzyloxy-4-methoxy-benzaldehyde (5.0 g, 20.6 mmol) in dry THF (20 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (9.4 mL, 248 mmol) and added water (50 mL). The mixture was extracted with EtOAc (3×80 mL). The combined organic phases were washed with water (2×80 mL), dried over MgSO4 and concentrated to oil, which was purified by flash column chromatography (EtOAc/Hexane) to give (3-benzyloxy-4-methoxy-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol as an off-white solid (7.26 g, 89% yield): 1H NMR (CDCl3) 1.43 (t, J=7 Hz, 3H, CH2CH3), 2.09 (d, J=3 Hz, 1H, OH), 3.86 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.00 (q, J=7 Hz, 2H, CH2CH3), 5.10 (s, 2H, CH2), 5.68 (d, J=3 Hz, 1H, CH), 6.80-6.92 (m, 6H, Ar), 7.26-7.41 (m, 5H, Ar). The product was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:35])[C@@H:5]([NH:13][C:14]([C:16]1[S:17][C:18]([CH2:21][CH2:22][CH2:23][C:24]2[NH:34][C:27]3[N:28]=[C:29]([NH2:33])[NH:30][C:31](=[O:32])[C:26]=3[CH:25]=2)=[CH:19][CH:20]=1)=[O:15])[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])C.[OH-].[Na+].CO.C(Cl)(Cl)Cl>CO>[NH2:33][C:29]1[NH:30][C:31](=[O:32])[C:26]2[CH:25]=[C:24]([CH2:23][CH2:22][CH2:21][C:18]3[S:17][C:16]([C:14]([NH:13][C@@H:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:4]([OH:35])=[O:3])=[O:15])=[CH:20][CH:19]=3)[NH:34][C:27]=2[N:28]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCc2cc3c(=O)[nH]c(N)nc3[nH]2)s1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc2[nH]c(CCCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)s3)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 (252 mg, 0.5 mmol) in MeOH (10 mL) was added 1 N NaOH (10 mL) and the mixture was stirred under N2 at room temperature for 16 h. TLC showed the disappearance of the starting material (Rf=0.48) and one major spot at the origin (MeOH/CHCl3 1:5). The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in water (10 mL), the resulting solution was cooled in an ice bath, and the pH was adjusted to 3-4 with dropwise addition of 1 N HCl. The resulting suspension was frozen in a dry ice-acetone bath, thawed to 4-5° C. in the refrigerator, and filtered. The residue was washed with a small amount of cold water and dried in vacuum using P2O5 to afford 212 mg (95%) of AAG154544 as white powder. mp 175-176° C.; 1H NMR (DMSO-d6): δ 1.88-2.10 (m, 4H), 2.31-2.34 (t, J=7.6 Hz, 2H), 2.49-2.54 (t, J=7.2 Hz, 2H), 2.78-2.81 (t, J=7.2 Hz, 2H), 4.30-4.35 (m, 1H), 5.88 (s, 1H), 5.97 (s, 2H), 6.89-6.90 (d, J=3.6 Hz, 1H), 7.68-7.69 (d, J=3.6 Hz, 1H), 8.50-8.52 (d, J=8 Hz, 1H), 10.13 (s, 1H), 10.82 (s, 1H) 12.42 (br, 2H). Anal. (C19H21N5O6S) C, H, N, S. calcd for C19H21N5O6S.1H2O; C, 49.02; H, 4.98; N, 15.05; S, 6.89. Found: C, 49.22; H, 4.80; N, 15.03; S, 6.97.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:19][N:18]=4)[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)[N:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43].CCN(CC)CC.[OH-].[Na+]>CN1C(=O)CCC1>[CH:23]([NH:22][C:20]1[O:21][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[C:4]2[N:3]=[C:2]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[C:38](=[O:43])[CH2:39]3)[CH:7]=[CH:6][N:5]=2)=[N:18][N:19]=1)([CH3:25])[CH3:24]
Reactant: CN1CCNCC1=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(-c4nccc(N5CCN(C)C(=O)C5)n4)c3c2)o1
Temperature: 100 °C
Yield: 43.9 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (80 mg, 0.157 mmol) and 1-methylpiperazin-2-one (17.94 mg, 0.157 mmol) in NMP (1.0 mL), followed by Et3N (65.6 μL, 0.472 mmol, Aldrich). The reaction was stirred and heated in a Initiator microwave reactor at 100° C. for 30 min. Then aq. NaOH (5 M, 0.3 mL) was added and the reaction was heated in microwave at 100° C. for 20 min. The mixture was purified with RP-HPLC (eluent: 10-60% MeCN in water with 0.1% TFA) and the fractions containing the product were combined and concentrated to remove AcCN. The remaining mixture was neutralized with sat. NaHCO3 and extracted with CHCl3/iPrOH (4:1). The combined organic layers were dried, filtered and concentrated to give 4-(2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1H-indol-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-one (30.0 mg, 0.069 mmol, 44.1%) as a light yellow solid. MS (ESI, pos. ion) m/z: 433.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.88 (1H, br. s.), 9.10 (1H, s), 8.30 (1H, d, J=6.1 Hz), 8.23 (1H, d, J=2.7 Hz), 7.60-7.73 (2H, m), 7.56 (1H, d, J=8.4 Hz), 6.69 (1H, d, J=6.1 Hz), 4.40 (2H, br. s.), 3.93 (2H, br. s.), 3.75 (1H, dq, J=13.3, 6.5 Hz), 3.51 (2H, t, J=5.2 Hz), 2.97 (3H, s), 1.25 (6H, d, J=6.8 Hz), 1.24 (3H, s).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[C:23]([C:26](=[O:33])[CH2:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[CH:25][C:19]=4[CH:18]=3)[CH:13]=2)[C:8]=1[Br:34])C.[OH-].[K+].Cl>C1COCC1.O>[Br:34][C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17]3[S:21][C:20]4[CH:22]=[C:23]([C:26](=[O:33])[CH2:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[CH:25][C:19]=4[CH:18]=3)=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)COc1ccc2cc(-c3cc4ccc(C(=O)CCC(C)(C)C)cc4s3)ccc2c1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CCC(=O)c1ccc2cc(-c3ccc4c(Br)c(OCC(=O)O)ccc4c3)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A mixture of {1-bromo-6-[6-(4,4-dimethyl-pentanoyl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetic acid ethyl ester (0.167 g, 0.310 mmol) and potassium hydroxide (0.056 g, 1.0 mmoles) in THF (20 mL) and water (20 mL) was stirred for one hour at ambient temperature. It was then poured in excess water and acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate and washed with water and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered, solvent evaporated dried in vacuo at 65° C. for 13.5 hours to yield {1-bromo-6-[6-(4,4-dimethyl-pentanoyl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetic acid as a light yellow solid (0.119 g, 74.8%): MP: 246–7° C.; mass spectrum (−EI, [M−H]−) m/z 509/511. −H NMR (500 MHz, DMSO-d6): δ8.74 (s, 1H), 8.40(d, 1H, J=1.68 Hz), 8.21 (d, 1H, J=9.00 Hz), 8.11–8.15 (m, 3H), 7.97–7.98 (m, 2H), 7.48 (d, 1H, J=9.16 Hz), 5.01 (s, 2H), 3.01 (s, 2H), 1.05 ppm (s, 9H). Elemental Analysis for C26H23BrNO4S: Calcd: C, 61.06; H, 4.53; N, 0.00; Found: C, 60.94; H, 4.59; N, 0.00.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.Cl.[CH3:10][NH:11][O:12][CH3:13].C(N(CC)CC)C.CCCP(=O)=O>CN(C=O)C>[CH3:13][O:12][N:11]([CH3:10])[C:6]([CH:4]1[CH2:5][C:2](=[CH2:1])[CH2:3]1)=[O:8]
Reactant: C=C1CC(C(=O)O)C1
Reactant: CNOC
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C1CC(C(=O)N(C)OC)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a solution of 3-methylenecyclobutanecarboxylic acid (525 mg, 4.68 mmol, Frontiers Scientific Services) in DMF (5 mL, aldrich) was added a solution of N,O-dimethyl hydroxylamine hydrochloride (0.55 g, 5.62 mmol, Aldrich) and triethylamine (0.78 mL, 5.62 mmol, Aldrich) in DMF (5 mL, Aldrich). The reaction was cooled to 0° C. and propylphosphonic anhydride solution (50 wt. % in DMF; 4.47 mL, 7.02 mmol, Alfa Aesar) was added. The reaction was stirred at RT for 16 h. The reaction was quenched with saturated NaHCO3 (10 mL) and stirred at RT for 5 min. The reaction was extracted with EtOAc (2×30 mL) and the combined organic extracts were washed with saturated ammonium chloride (2×40 mL), dried over MgSO4, and concentrated. The residue was dissolved in diethyl ether (5 mL) and the solution mixture was washed with H2O (2×10 mL), dried over MgSO4, concentrated, and dried in vacuo to give 398 mg of the title compound as a light yellow liquid. MS (ESI, positive ion) m/z: 156.1 (M+H).