Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=[C:6]2[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.Cl.N1C=CC=CC=1>>[CH3:12][C:10]1[CH:11]=[C:3]([OH:2])[CH:4]=[C:5]2[C:9]=1[N:8]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=[C:6]2[CH:21]1[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1
Reactant: COc1cc(C)c2c(c1)c(C1CCN(C)CC1)cn2CCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)cc2c(C3CCN(C)CC3)cn(CCc3ccccc3)c12

Procedure:
By a method similar to Preparation 8, using 5-methoxy-7-methyl-3-(1-methylpiperdin-4-yl)-1-phenethy-1H-indole (0.288 g) and pyridine hydrochloride (25 g) to afford 0.143 (52%) of the title compound: mass spectrum (ion spray): m/z=349 (M+1); Calculated for C23H28N2O-0.3H2O: C, 78.06; H, 8.15; N, 7.92. Found: C, 78.24; H, 8.18; N, 8.11.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14](Br)[CH:13]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C1(C)C=CC=CC=1>C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@H:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[CH:13]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)N[C@H](C)c2ccccc2)cc1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(C(=O)N[C@H](C)c3ccccc3)ccc2C)cc1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To a mixture of N-((1R)-1-phenylethyl)(3-bromo-4-methylphenyl)carboxamide (1.38 g, 4.32 mmol) and 4-methoxyphenylboronic acid (0.53 g, 4.32 mmol) in 10 mL of 2M Na2CO3 aq. soln and 20 mL of toluene was bubbled through N2 for 5 min. Catalyst Pd(PPh3)4 (0.36 g, 0.314 mmol) was then added and the mixture was heated to 80 C for 19 hours under N2. The reaction mixture was cooled to RT and was diluted with 100 mL of EtOAc and 50 mL of water. The organic layer was separated and washed with 50 mL of brine, and dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (CHCl3 to EtOAc) to provide yellow solid (1.0 g, 2.9 mmol, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[C:19]2[CH:20]=[C:21]3[CH:27]=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[C:19]2[CH:20]=[C:21]3[CH:27]=[CH:26][N:25]([S:38]([C:35]4[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:37][CH:36]=4)(=[O:40])=[O:39])[C:22]3=[N:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: O=c1c2ccccc2nc(-c2cnc3[nH]ccc3c2)n1-c1ccc(Cl)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2ccc3cc(-c4nc5ccccc5c(=O)n4-c4ccc(Cl)cc4)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(4-chlorophenyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-4(3H)-one (0.156 g, 0.42 mmol) and benzyltriethylammonium chloride (0.003 g, 0.013 mmol) were combined in CH2Cl2 (10 mL). NaOH powder (0.052 g, 1.31 mmol) was added and the mixture was cool to 0° C. 4-methoxy-benzenesulfonyl chloride (0.107 g, 0.52 mmol) was added, and the reaction mixture was stirred for 30 minutes at 0° C., and warmed to room temperature. After 18 hours, additional NaOH powder (0.050 gm 1.30 mmol), benzyltriethylammonium chloride (0.010 g, 0.04 mmol), and 4-methoxy-benzenesulfonyl chloride (0.200 g, 0.97 mmol) were added and the reaction was continued at room temperature for an additional 6 hours. After concentration and purification by silica gel chromatography, eluting with 100% CH2Cl2 to 100% ethyl acetate to 50% methanol/ethyl acetate, the title compound was afforded as a white solid (0.137 g, 60%). 1H-NMR (300 MHz, DMSO-6): δ8.37 (d, 1.7 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.07 (d, J=1.7 Hz, 1H), 7.98 (d, J=8.9 Hz, 2H), 7.88-7.93 (m, 2H), 7.76 (d, J=8.0 Hz, 1H), 7.61-7.66 (m, 1H), 7.34-7.45 (m, 4H), 7.11 (d, J=9.0 Hz, 2H), 6.79 (d, J=3.9 Hz, 1H), 3.82 (s, 3H). MS (APCI) m/z: 543 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:10]=1[F:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)c1cc(C(C)(C)C)c(F)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,3,5-tri-tert-butylbenzene (442 mg, 2.0 mmol) in ACN (20 mL) was cooled to 0° C. under N2. Selectfluor (1.06 g, 3.0 mmol) was added, keeping the temperature close to 0° C. The reaction was stirred overnight warming up to rt, poured into aq. Na2CO3 (15 mL) and extracted with Et2O (30 mL). The organic layer was washed with brine, dried with Na2SO4, filtered and evaporated to give compound P31a (430 mg, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13](C)[CH3:14])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(N(C)C)cc1[N+](=O)[O-])C(=O)OCC
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc(NC)cc1[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The cinnamic ester (1) (5.0 g, 14.8 mmol) was dissolved in 100 mL of acetic acid and 7.6 g (17.2 mmol) of lead tetracetate was added. After allowing the mixture to stir for one hour at room temperature, the solvent was removed. Toluene (100 mL) was added and the slurry concentrated, then 100 mL of chloroform (CHCl3) was added, the solid broken up thoroughly, and the solution decanted. Chloroform (100 mL) was added to the solid and the mixture refluxed briefly, filtered, and the filtrate combined with the previous CHCl3 solution. After concentrating the organic solution the residue was chromatographed on 350 g of silica gel eluting with 1:19 (v/v) acetone:CHCl3. Fractions 83-140 (15 mL/fraction) were combined and concentrated to yield the product which was crystallized from CH2Cl2 (3.45 g, 72%), m.p. 113°-114° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[O:8])[CH3:7].[C:9](=O)([O:12]C)[O:10][CH3:11].[H-].[Na+].Cl>C(OCC)(=O)C.O.O1CCCC1>[O:8]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH2:7][C:9]([O:10][CH3:11])=[O:12]
Reactant: CC(=O)c1nccs1
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)c1nccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 50 mL of a tetrahydrofuran solution containing 5.0 g of 1-(1,3-thiazol-2-yl)ethanone, 6.3 mL of dimethyl carbonate and 3.0 g of 60% sodium hydride were added at 10° C. The temperature of the reaction mixture was increased to room temperature, and the mixture was stirred for 16 hours. Thereto was further added 0.75 g of 60% sodium hydride, and the mixture was stirred for 4 hours. Water and ethyl acetate were then added thereto, and the reaction mixture was adjusted to pH 3.0 with 6 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to obtain 2.3 g of a yellow oily substance, methyl 3-oxo-3-(1,3-thiazol-2-yl)propionate.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][C:13]=2F)=O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH-].[Na+].[OH-].[K+]>O.CCO>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]2[C:10]([CH:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)=[N:2][O:3][C:13]=2[CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1F)C1CCCCC1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(COc2ccc3c(C4CCCCC4)noc3c2)cc1
Temperature: 6 °C

Procedure:
A solution of hydroxylamine hydrochloride (11.7 g) in warm water (100 ml) was poured into a mixture of cyclohexyl (4-benzyloxy-2-fluorophenyl)methanone (20.22 g, 64.7 mmol) and EtOH (54 ml). A solution of sodium hydroxide (11.13 g, 0.278 mol) in water (54 ml) was then added as rapidly as the reflux permitted. The reaction mixture was heated for 12 h and then most of the EtOH was removed by distillation. To the residue was added a solution of potassium hydroxide (8.7 g, 0.155 mol) in water (54 ml). The mixture was refluxed for 2 days, then cooled to about 6° C. and stirred vigorously. A white solid was obtained, which was thoroughly washed with water and triturated with diisopropyl ether. The benzisoxazole was obtained as a white powder (12.26 g, 62%) after filtration. mp 110° C.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:14][C:15]([C:17]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:27])=[CH:25][C:20]3=[N:19][CH:18]=2)=[O:16])[N:7]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=2)[N:6]=1)[CH3:4].[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCl.CO>[ClH:1].[ClH:1].[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:14][C:15]([C:17]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]([N:28]4[CH2:29][CH2:30][N:31]([CH3:42])[CH2:32][CH2:33]4)=[O:27])=[CH:25][C:20]3=[N:19][CH:18]=2)=[O:16])[N:7]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=2)[N:6]=1)[CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)N5CCNCC5)ccn34)c12
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)N5CCN(C)CC5)ccn34)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(piperazine-1-carbonyl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (Example 12; 5 mg, 0.0084 mmol) in dichloromethane/methanol (1:1; 1 mL) was added an excess of sodium triacetoxyborohydride and formaldehyde solution. The mixture was stirred at ambient temperature for 2 hours. Further excess sodium triacetoxyborohydride and formaldehyde solution were added and the mixture was stirred an additional 0.5 hours. The mixture was concentrated under a stream of nitrogen and the residue was purified using preparative thin layer chromatography on silica, eluting with 15% methanol and 0.5% ammonium hydroxide in dichloromethane to provide the desired product (free base form). This material was dissolved in methanol and filtered. To the filtrate was added hydrogen chloride (1 mL; 2M in ether) and the solvent was evaporated to a residual film under a stream of nitrogen. The material was dried under high vacuum to give N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(4-methylpiperazine-1-carbonyl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (3.3 mg). MS (APCI), positive scan, m/z=537.3 (M+H).
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.[C:10]([O:13][CH2:14]Br)(=[O:12])[CH3:11].Cl[C:17]1[N:22]=[C:21]([O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[CH:27]3)[CH:20]=[CH:19][N:18]=1>CN(C=O)C.C(Cl)Cl.[NH4+].[Cl-].[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:10]([O:13][CH2:14][C:17]1[N:22]=[C:21]([O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[CH:27]3)[CH:20]=[CH:19][N:18]=1)(=[O:12])[CH3:11]
Reactant: Clc1nccc(Oc2ccc3[nH]ccc3c2)n1
Reactant: CC(=O)OCBr
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Si](C)(C)Cl
Solvent: BrCCBr
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OCc1nccc(Oc2ccc3[nH]ccc3c2)n1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a suspension of nano zinc metallic powder (Strem Chemicals; average particle size 75-125 nm) (1.34 g, 20.52 mmol) in DMF (8 ml) is added 1,2-dibromoethane (0.19 mL, 2.2 mmol). The heterogeneous mixture is heated to 60° C. and then stirred for 10 min. The mixture is cooled to room temperature and charged with chlorotrimethylsilane (0.24 mL, 1.8 mmol). The reaction vessel is then sonicated in a room temperature water bath for 30 min. The suspension is then left standing for ca. 30 min to permit the solid to settle and the supernatant is then removed via syringe. DMF (8 ml) is then added, followed by bromomethyl acetate (1.00 mL, 10.3 mmol). The reaction mixture is then stirred for 2 hr at room temperature. The suspension is then left standing for 1 hour to permit the solid to settle. Next a separate flask is charged with 5-(2-chloropyrimidin-4-yloxy)-1H-indole (450 mg, 1.83 mmol), prepared as described in Example 73-A, DMF (3 mL) is then added to the 5-(2-chloropyrimidin-4-yloxy)-1H-indole followed by Pd(dppf)Cl2.CH2Cl2 (230 mg, 0.28 mmol). To this solution is added a portion of the supernatant (6 mL), from the flask containing the organozincate, via syringe. The reaction is heated at 50° C. for 16 h then cooled to room temperature and diluted with DCM and saturated aqueous NH4Cl. The layers are separated and the aqueous layer is extracted 2 additional times with DCM. The organic layers are combined dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue is purified via FCC (0-60% EtOAc/DCM) to provide the title compound. MS (ESI) m/z 284.0 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8](O)[SiH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>>[CH2:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]([Br:35])[SiH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: BrC(Br)(Br)Br
Reactant: C=CCc1ccc(C(O)[SiH](C)C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1ccc(C(Br)[SiH](C)C)cc1

Procedure:
Reaction of 4-allyldimethylsilylbenzyl alcohol (3 Scheme 1) with triphenylphosphine and carbon tetrabromide gave 4-allyldimethylsilylbenzyl bromide (4 Scheme 13). Subsequent reaction with potassium cyanide gave 4-allyldimethylsilylphenylacetonitrile (6 Scheme 13). Under the usual coupling conditions, this was loaded to the polymer and the loading level of resin (2 Scheme 13, 0.23 mequiv/g) was determined by the mass balance of 4-bromophenylacetonitrile which was obtained from cleavage reaction of the resin with bromine.
Reaction SMILES: [CH:1]([C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)(=[O:9])=[O:8])=[O:5])([CH3:3])[CH3:2]>C(O)C.[Pd].O>[CH:1]([C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)(=[O:9])=[O:8])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(C)C(=O)NS(=O)(=O)c1cccc(N)c1
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To a suspension of 1-(isopropylcarbonylaminosulphonyl)-3-nitrobenzene (5 g, 18.4 mmol) in ethanol (100 ml) was added 10% palladium on carbon (0.5 g, 10% (w/w)) in water (5 ml). The mixture was hydrogenated at 40 psi for 10 min then the catalyst was filtered off and washed with ethanol. The solvents were evaporated in vacuo to give the title compound (3.4 g, 76%) as a yellow solid. mp 110°-112° C. 1H NMR (360 MHz, D6 -DMSO) δ 0.95 (6H, d, J=6.9 Hz), 2.45 (1H, septet, J=6.9 Hz), 5.63 (2H, br s), 6.79 (1H, ddd, J=8.0, 2.3 and 0.8 Hz), 6.96 (1H, ddd, J=7.6, 1.7 and 0.8 Hz), 7.09 (1H, dd, J=2.0 and 2.0 Hz), 7.20 (1 H, dd, J=7.9 and 7.9 Hz), 11.79 (1H, brs).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.[C:36]1([S:42](Cl)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl.C(N(C(C)C)C(C)C)C>[C:36]1([S:42]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]3[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=3)([CH3:12])[CH3:11])=[C:4]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH:3]=2)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(NS(=O)(=O)c2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
To a solution of 100 mg (0.2 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 4 ml dichloromethane and 85 μl N-ethyldiisopropylamine were added 56 μl (0.436 mmol) benzenesulfonyl chloride and the mixture was stirred over night at room temperature. The reaction mixture was washed twice with saturated aqueous sodium hydrogencarbonate solution and dried (magnesium sulfate). Chromatography of the residue afforded 26 mg (28%) of the title compound as a white foam.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][N:12]3[C:16](=[O:17])[CH2:15][S:14][C:13]3=[O:18])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:19](=O)[CH2:20][CH2:21][CH3:22].N1CCCCC1>C(O)C>[CH:19](=[C:15]1[S:14][C:13](=[O:18])[N:12]([CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:16]1=[O:17])[CH2:20][CH2:21][CH3:22]
Reactant: O=C1CSC(=O)N1CCc1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.18 g (4.5 mmol) of 3-[2-(imidazo[1,2-a]pyridin-5-yl)ethyl]thiazolidine-2,4-dione and 0.41 ml (4.5 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/2) to yield 1.15 g (81.0%, light yellow oily substance) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:11](=[O:24])[N:10]2[CH2:25][C:26]([O:28]CC)=[O:27])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+:31].[OH-].Cl>C1COCC1.O>[C:18]([O:17][C:15]([N:13]1[CH2:14][C@@H:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)[N:10]([CH2:25][C:26]([O-:28])=[O:27])[C:11](=[O:24])[C:12]1([CH3:23])[CH3:22])=[O:16])([CH3:21])([CH3:19])[CH3:20].[Li+:31]
Reactant: CCOC(=O)CN1C(=O)C(C)(C)N(C(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)[O-])C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (5R)-5-(3,5-difluorophenyl)-4-(2-ethoxy-2-oxoethyl)-2,2-dimethyl-3-oxopiperazine-1-carboxylate from Step C (1.18 g, 2.77 mmol) in THF (18 mL) and H2O (2 mL) was added 1 N aqueous LiOH (3.04 mL, 3.04 mmol) and the resulting mixture was stirred at ambient temperature for 5 h. The mixture was adjusted to pH 6 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=343 (M−C4H7).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].I[CH2:17][CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)CCc1ccc(O)c(Br)c1
Reactant: CCCCI
Product: CCCCOc1ccc(CCC(=O)OCC)cc1Br

Procedure:
According to the procedure described in the synthesis method of the compound 036 in Example 36 (Preparation Method 5, Step e-1), ethyl 3-(3-bromo-4-hydroxyphenyl)propionate and 1-iodobutane were reacted and treated to obtain ethyl 3-(3-bromo-4-butyloxyphenyl)propionate (400 mg). According to the procedure described in the synthesis method of Compound of Example 001 (Preparation Method 4, Step d-1) with the modifications that the reaction was carried out for 16 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate=8:1), the above product was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (360 mg), 2 M aqueous sodium carbonate (0.9 ml) and (Ph3P)4Pd (110 mg) and treated to obtain the title compound (Intermediate 66, 270 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[Li]CCCC.Cl[Si](C)(C)C.[S:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1.Cl>C1COCC1>[NH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:8]([C:23]2([OH:26])[CH2:24][CH2:25][S:20][CH2:21][CH2:22]2)=[C:7]([F:9])[CH:6]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=C1CCSCC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1cc(F)c(C2(O)CCSCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
3,5-Difluoroaniline (250 g, 1.94 mol) was dissolved in THF (3800 ml) and cooled to −78° C. nBuLi (1.59 M, 2560 ml) was added drop wise over 5 hours keeping the temperature below −70° C. and the resulting white slurry was stirred for 1 hour. Chlorotrimethylsilane (502 ml, 4.07 mol) in THF (2000 ml) was added drop wise over 2.5 hours keeping the temperature below −70° C. and the resulting yellow slurry was allowed to warm to room temperature overnight. The brown solution was recooled to −78° C., nBuLi (1340 ml) was charged drop wise over 1.5 hours keeping the temperature below −70° C. and the reaction mixture was stirred for 5 hours. Tetrahydrothiopyran-4-one (241 g, 2.07 mol) in THF (1500 ml) was added drop wise over 2 hours keeping the temperature below −70° C. during the addition and then the reaction allowed to warm to room temperature overnight. The reaction was acidified to pH<1 using 5M HCl (approx 2000 ml) and it was extracted with diethyl ether (2500 ml). The organic layer was washed with 5M HCl (1000 ml) and the combined aqueous layers were basified using 880 ammonia to pH 11 (1500 ml), then extracted with diethyl ether (2500 ml×2), washed with saturated aqueous sodium chloride (1000 ml), dried over MgSO4 and evaporated. The residue was taken up in dichloromethane (800 ml) evaporated to a low volume, isohexane (1000 ml) was added and it was cooled under ice. The yellow solid was filtered and dried in a vacuum oven at 40° C. overnight to provide 287 g of the title compound.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:1][CH:2]([CH2:16][S:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2
Reactant: Sc1ccccc1
Reactant: O=C1CCc2c(cccc2OCC2CO2)N1
Product: O=C1CCc2c(cccc2OCC(O)CSc2ccccc2)N1

Procedure:
Prepared analogous to Example 59 from 5-(2,3-epoxy-propoxy)-3,4-dihydro-carbostyril and thiophenol.