Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:6])[CH:4]=[CH2:5].C(N(CC)CC)C.[F:14][C:15]([F:29])([F:28])[C:16]1[N:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[OH-].[Li+:31]>O.C(#N)C.O1CCCC1>[Li+:31].[F:29][C:15]([F:14])([F:28])[C:16]1[N:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH2:5][CH2:4][C:3]([O-:2])=[O:6])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cn1
Reactant: C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C([O-])CCN1CCN(c2ccc(C(F)(F)F)nc2)CC1
Yield: 65.9 %

Procedure:
Acrylic acid methyl ester (189 mg; 2.20 mmol) and triethylamin (0.2 mL) are added to 1-(6-trifluoromethyl-pyridin-3-yl)-piperazine (420 mg; 1.82 mmol) in a 1 to 1 mixture of water and tetrahydrofuran (1.6 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 30 minutes at 120° C. Lithium hydroxide (92 mg; 3.84 mmol) in water (5 mL) is then added and the reaction mixture is again irradiated in a mono-mode microwave oven for 30 minutes at 100° C. The mixture is then diluted with acetonitrile and the precipitate formed is filtered, collected and dried under high vacuum to afford the desired product (363 mg; 1.20 mmol).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:16]1([CH2:22][CH2:23]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[CH2:23]([S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1)[CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCc1ccccc1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Solvent: CCO
Product: c1ccc(CCSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol), phenylethylbromide (0.206 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [OH-].[Na+].C([O:11][CH2:12][CH:13]([CH2:32][CH:33]([O:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:34])[CH2:14][S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=O)C1C=CC=CC=1>CO>[C:36]([O:35][CH:33]([CH3:34])[CH2:32][CH:13]([CH2:14][S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:12][OH:11])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCCCCCCCCCCCCCCCSCC(COC(=O)c1ccccc1)CC(C)OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCSCC(CO)CC(C)OC(=O)c1ccccc1
Yield: 62.8 %

Procedure:
Using 6.89 ml (13.78 mM) of 2N aqueous sodium hydroxide, 4.017 g (6.89 mM) of 2-(2-benzoyloxypropan-1-yl)-3-hexadecylthiopropyl benzoate m11 in 38 ml of methanol and 43 ml of tetrahydrofuan is converted to 2.071 g (62.8% yield) of the titled compound m12 by the same procedure as described in (125).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.FC(F)(F)S(O)(=O)=O.[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:17]([C:5]1[C:6]([OH:7])=[C:1]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[C:3]([CH3:8])[CH:4]=1)=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=Cc1ccccc1
Reactant: Cc1ccc(O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1cc(C=Cc2ccccc2)c(O)c(C=Cc2ccccc2)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a one liter round-bottomed flask equipped with a stirrer, thermometer, and addition funnel was charged 151.3 grams (1.4 moles) of p-cresol. The mixture was heated to 70° C., followed by the addition of 5 μL of trifluoromethane sulfonic acid via a 100 μL syringe. Under a nitrogen blanket, 284.5 grams (2.73 moles) of styrene was placed into the funnel and then added dropwise, with stirring, over a period of three hours. During styrene addition, the pot temperature did not exceed 80° C. Stirring was continued at a pot temperature of 70° C. for a period of 1.5 hours after all the styrene had been added. The resultant styrenated p-cresol composition analyzed as follows:
Reaction SMILES: C(N(CC)CC)C.Cl.[OH:9][C@H:10]1[CH2:14][N:13]([CH3:15])[C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1.[S:20](Cl)([CH3:23])(=[O:22])=[O:21].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:23][S:20]([O:9][C@H:10]1[CH2:14][N:13]([CH3:15])[C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1)(=[O:22])=[O:21]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C
Temperature: 40 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Triethylamine (1.53 mL) was added to a suspension of methyl (2S, 4R)-4-hydroxy-1-methyl-2-pyrrolidinecarboxylate hydrochloride (1 g) obtained from Reference example 1 or 3 in tetrahydrofuran (10 mL) and the mixture was stirred at 40° C. for 3 hours. Mesyl chloride was added to the mixture under ice cooling and the mixture was stirred for 2 hours. Ethyl acetate (20 mL) and 5% aqueous sodium hydrogencarbonate solution (10 mL) were added to the reaction mixture, which was then extracted. The organic layer was separated from the aqueous layer and the solvent of the organic layer was removed by distillation under reduced pressure to give the title compound (1.0 g, yield 83%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:8](/[CH:26]=[C:27]2\[C:28](=[O:32])[O:29][CH2:30][CH2:31]\2)[CH:7]=1)=[O:4]>CO.[Pd]>[F:34][C:2]([F:1])([F:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:8]([CH2:26][CH:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH:7]=1)=[O:4]
Reactant: O=C1OCC/C1=C/c1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: [Pd]
Solvent: CO
Product: O=C1OCCC1Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2

Procedure:
(Z)-2,2,2-Trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3-((2-oxodihydrofuran-3(2H)-ylidene)methyl)phenyl)acetamide (200 mg) was hydrogenated with Pd/C (10%, 50 mg) in MeOH (20 ml) at 30 psi for 2 hrs. The reaction mixture was filtered, concentrated in reduced pressure to dryness. The crude product was treated with DCM to give 2,2,2-trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3-((2-oxotetrahydrofuran-3-yl)methyl)phenyl)acetamide as a solid. 1H NMR (400 MHz, CD3OD) δ (ppm): 7.92 (d, J=8.6 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.64 (dd, J=8.2, 2.4 Hz, 1H), 7.28 (s, 1H), 7.22 (d, J=8.2 Hz, 1H), 7.17 (dd, J=8.2, 2.0 Hz, 1H), 4.95 (s, 2H), 4.36 (dt, J=8.8, 2.8 Hz, 1H), 4.19 (m, 1H), 3.53 (m, 1H), 3.06 (m, 2H), 2.22 (m, 1H), 2.04 (m, 1H). MS (ESI) m/z=497 (M−1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:11][O:12][CH3:13])[CH:10]=1)[C:6]#[N:7])=[O:2].CC(=CC)C.Cl([O-])=[O:20].[Na+]>C(O)(C)(C)C.O>[C:6]([C:5]1[CH:4]=[C:3]([CH:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=1)[C:1]([OH:20])=[O:2])#[N:7]
Reactant: [O-][Cl+][O-]
Reactant: COCc1cc(C#N)cc(C=O)c1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COCc1cc(C#N)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
To a reaction mixture of 3-formyl-5-methoxymethyl-benzonitrile (128 mg, 0.73 mmol) in tert-butyl alcohol (3 mL) and water (1.5 mL) were added 2-methyl-2-butene (1.5 mL) and sodium chlorite (198 mg, 80% technical grade, dissolved in 1.5 mL of water), respectively. The resulting mixture was stirred at room temperature for 5 h then partitioned between water and methylene chloride. The aqueous layer was extracted with methylene chloride. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to dryness to afford 3-cyano-5-methoxymethyl-benzoic acid (90 mg, 64%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[K+].O>C(O)C>[O:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[CH:12][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)N1CCN(Cc2ccc(Oc3ccccc3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(Oc2ccc(CN3CCNCC3)cc2)cc1
Yield: 97.7 %

Procedure:
1-acetyl-4-((4-phenoxyphenyl)methyl)piperazine (316 mg) was dissolved in ethanol (20 ml), and aqueous potassium hydroxide solution (3 ml, potassium hydroxide 1 g) was added, followed by heating the mixture to reflux for 4 hours. Water was added to the reaction mixture and the mixture was extracted 3 times with chloroform. Organic layers were combined and dried over anhydrous sodium sulfate, followed by removal of chloroform to obtain 267 mg of 1-((4-phenoxyphenyl)methyl)piperazine. Yield: 98%.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)[CH3:2].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=O)cc1
Reactant: CC(=O)c1ccccc1
Product: CCc1ccc(C=CC(=O)c2ccccc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-ethylbenzaldehyde and acetophenone, 3-(4-ethylphenyl)-1-phenylprop-2-en-1-one was obtained as yellow oil.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([C:19](=O)[CH3:20])[CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[C:17]([CH:19]([NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH3:20])[CH:16]=[CH:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: CC(=O)c1ccnc(-c2ccc(F)cc2)c1
Reactant: NC1CCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: CO
Product: CC(NC1CCC1)c1ccnc(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
Titanium(IV) isopropoxide (1.85 g) was added to a solution of cyclobutylamine (930 mg) in methanol (10 mL), and the mixture was stirred at room temperature for 10 min. A solution of 1-[2-(4-fluorophenyl)pyridin-4-yl]ethanone (350 mg) in methanol (5 mL) was added thereto and the mixture was stirred at room temperature overnight. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, which was then filtered through Celite, and the solvent was distilled off under reduced pressure. After extracting with chloroform, the organic phase was separated out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=98:2-80:20) to afford the title compound (430 mg).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[CH:8]1([N:14]([CH2:33][C:34]2C=N[C:37]([N:40]3[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[N:41]3)=[CH:38][CH:39]=2)[C:15]2[N:32]=[CH:31][CH:30]=[CH:29][C:16]=2[C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[CH:8]1([N:14]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH:44]=[C:43]([C:45]([F:48])([F:46])[F:47])[CH:42]=[N:41]3)=[CH:3][CH:2]=2)[C:15]2[N:32]=[CH:31][CH:30]=[CH:29][C:16]=2[C:17]([NH:19][CH:20]=[CH:21][C:22]([OH:24])=[O:23])=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1cccnc1N(Cc1ccc(-n2cc(C(F)(F)F)cn2)nc1)C1CCCCC1
Solvent: ClCCl
Product: O=C(O)C=CNC(=O)c1cccnc1N(Cc1ccc(-n2cc(C(F)(F)F)cn2)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.30 mL) was added to a solution of tert-butyl 3-(2-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-yl)methylamino)nicotinamido)propanoate (30 mg, 0.052 mmol) in dichloromethane (0.4 mL). The mixture was stirred at room temperature for 2 hours. The reaction was concentrated and the residue was co-evaporated with dichloromethane, ethyl acetate and toluene several times, to give (+/−)-3-(2-(cyclohexyl(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinamido)propenoic acid, as a solid. 1H NMR (400 MHz, CDCl3, δ): 9.81 (br. s, 1H), 8.94 (hr. s, 1H), 8.31-8.21 (m, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.66 (d, J=8.58 Hz, 2H), 7.61-7.51 (m, 1H), 7.39 (d, J=8.39 Hz, 2H), 6.70-6.58 (m, 1H), 4.29-4.17 (m, 1H), 3.69-3.53 (m, 2H), 2.76-2.65 (m, 2H), 2.00-0.91 (m, 11H). MS (M+1): 516.2.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[N:15]=[CH:14][C:13]3[NH:16]/[C:17](=[N:25]\[C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)/[N:18]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:12]=3[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>CN(C=O)C.O.C(Cl)Cl>[CH2:34]([S:36]([N:22]1[CH2:21][CH2:20][CH:19]([N:18]2[C:12]3[CH:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[N:15]=[CH:14][C:13]=3[NH:16]/[C:17]/2=[N:25]\[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23]1)(=[O:38])=[O:37])[CH3:35]
Reactant: CCS(=O)(=O)Cl
Reactant: O=C(/N=c1\[nH]c2cnc(OCCN3CCCCC3)cc2n1C1CCNCC1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(n2/c(=N/C(=O)c3ccccc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
A suspension of (E)-N-(6-(2-(piperidin-1-yl)ethoxy)-1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (0.10 g, 0.223 mmol) in DMF (1.12 mL) was cooled to 0° C. under nitrogen atmosphere. To this mixture was added TEA (0.045 g, 0.446 mmol) followed by ethanesulfonyl chloride (0.043 g, 0.334 mmol). The resulting mixture was stirred for 30 minutes and diluted with water (10 mL) and DCM (20 mL). The organic layer was collected and concentrated to yield a brown residue. The residue was purified by HPLC (10-70% ACN/H2O; 0.1% TFA) to afford (E)-N-(1-(1-(ethylsulfonyl)piperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide as an off-white solid (15 mg, 12.4%). MS m/z=541.2 [M+H]. Calc'd for C27H36N6O4S: 540.3.
Reaction SMILES: C[O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:22](=[CH:23][CH:24]=1)[O:21][C:11]1([CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:25].[OH-].[Na+]>>[CH3:20][S:17]([N:14]1[CH2:13][CH2:12][C:11]2([CH2:10][C:9](=[O:25])[C:8]3[C:22](=[CH:23][CH:24]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:26])=[O:2])[CH:7]=3)[O:21]2)[CH2:16][CH2:15]1)(=[O:18])=[O:19]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(S(C)(=O)=O)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Yield: 95.8 %

Procedure:
(E)-3-{1′-Methanesulfonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (162 mg, 0.42 mmol) was hydrolyzed with NaOH following the procedure described in Example 1, Step A, giving (E)-3-{1′-methanesulfonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid as a white solid (147 mg, 96%). The resulting product was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1′-methanesulfonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Finally, the removal of the THP protecting group following the procedure described in Example 2 Step D, gave the crude product, which was purified by preparative LC-MS giving 35 mg of (E)-3-{1′-methanesulfonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]2[N:19]=[C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:17]3=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:29]=[CH:30][N:16]3[N:15]=2)[N:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[C:31]1([C:28]2[CH:29]=[CH:30][N:16]3[C:17]=2[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:19][C:14]([C:12]2[N:13]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[S:10][CH:11]=2)=[N:15]3)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)NS(=O)(=O)c1nc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)cs1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1nc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)cs1
Yield: 25.2 %

Procedure:
N-(tert-Butyl)-4-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thiazole-2-sulfonamide (40.0 mg, 0.0770 mmol) and TFA (3 mL) were stirred at ambient temperature for 14 h. The excess TFA was evaporated under reduced pressure and the residue purified by preparative HPLC (Condition B-33 as described in general methods) to obtain 4-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thiazole-2-sulfonamide (9.00 mg, 26.0%). LCMS Condition B-13: retention time 1.94 min, [M+1]=464.0. HPLC Condition B-32: retention time 7.06 min, Purity 97.62%. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.91 (d, J=4.4 Hz, 2H), 6.82 (d, J=2.8 Hz, 1H), 7.27-7.31 (m, 2H), 7.43-7.61 (m, 6H), 7.79 (dt, J=2.0 Hz, J=8.0 Hz, 1H), 7.90 (d, J=2.8 Hz, 1H), 8.24 (s, 2H), 8.39-8.40 (m, 1H), 8.63 (s, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: OB(O)c1ccc(C(F)(F)F)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: Cc1ccccc1
Product: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)s1
Yield: 35.7 %

Procedure:
To a solution of ethyl 2-bromothiazole-5-carboxylate (39 μl, 0.26 mmol) in toluene (2 mL) were added 4-(trifluoromethyl)phenylboronic acid (60 mg, 0.32 mmol), 2M Na2CO3(390 μl, 0.78 mmol), and catalytic amounts of Pd(PPh3)4 (61 mg, 0.05 mmol). The reaction mixture was refluxed for 6 hrs, diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (EtOAc/n-Hex=1:5) to give title compound (28 mg, 30%).
Reaction SMILES: CCN=C=NCCCN(C)C.[NH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([C:18]([OH:20])=O)[CH2:14][CH:15]([CH3:17])[CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1.[CH:39]1[CH:44]=[CH:43][C:42]([CH2:45][O:46][C:47]([CH2:49][NH2:50])=[O:48])=[CH:41][CH:40]=1>ClCCl.CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[NH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([C:18]([NH:50][CH2:49][C:47]([O:46][CH2:45][C:42]1[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=1)=[O:48])=[O:20])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
A solution of WSC (34 g.) in dichloromethane (50 ml.) was added dropwise to a suspension of BOC-Leu-OH (46.2 g.), HOBT (1 g.) and H-Gly-OBzl.TosOH (74 g.) in DMF (100 ml.) and dichloromethane (200 ml.) with stirring at -5° C. for 1 hour. After 1 hour, the solution was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to remove dichloromethane. To the DMF layer was added water and the mixture was extracted with ethyl acetate (1 l.), and again with the same solvent (500 ml.). The ethyl acetate layer was washed with 1 N HCl, water, 5% sodium bicarbonate and water, in this order and dehydrated with sodium sulfate (anhydrous), then concentrated in vacuo to obtain oily BOC-Leu-Gly-OBzl (82 g.) Rf = 0.68.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38]([CH:41]=O)[CH:39]=[CH:40][C:34]=2[S:33][CH2:32]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:41][C:38]2[CH:39]=[CH:40][C:34]3[S:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=3[CH:37]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc2nccc(-c3ccc(CCN)cc3)c2n1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2nccc(-c3ccc(CCNCc4ccc5c(c4)NC(=O)CS5)cc3)c2n1
Reaction time: 24 h
Yield: 68.4 %

Procedure:
To a stirred solution of 2-[4-(6-Methoxy-[1,5]naphthyridin-4-yl)phenyl]ethylamine hydrochloride salt (1.76 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added triethylamine (0.74 mL, 5.28 mmole) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde (0.34 g, 1.76 mmole). After 24 h, the reaction contents were concentrated and dried under high vacuum. To a stirred solution of the crude imine in dry EtOH (25 mL) at RT was added NaBH4 (0.66 g, 1.76 mmole). After 24 h, the reaction solution was concentrated under vacuum and to the residue was added 1M HCl (5 mL) and EtOAc (50 mL): After stirring for 1 h, 6M NaOH (1 mL) was added and the organic layer was separated, dried (Na2SO4) and concentrated. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.55 g, 69%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 9.11 (d, J=4.5 Hz, 1H), 8.57 (d, J=9.1 Hz, 1H), 8.27 (d, J=4.5 Hz, 1H), 8.14 (m, 2H), 7.90 (s, 2H), 7.61 (m, 3H), 7.46 (d, J=7.1 Hz, 1H), 7.22 (m, 2H), 5.52 (m, 2H), 4.23 (s, 2H), 4.08 (s, 3H), 3.68 (s, 2H), 3.19 (m, 2H). LC-MS (ES) m/e 457 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Li]CCCC.CCCCCC.[CH3:23][N:24]([CH3:35])[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:30](=O)[O:29][CH2:28]2.Cl.[OH-].[Na+]>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:30]1[C:32]2[C:27](=[CH:26][C:25]([N:24]([CH3:35])[CH3:23])=[CH:34][CH:33]=2)[CH2:28][O:29]1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CN(C)c1ccc2c(c1)COC2=O
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CN(C)c1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.8 %

Procedure:
A solution of 5-chlorooxindole (1.18 mg, 7.05 mmol) in 20 mL of DME was cooled to 0° C., and treated with 6.2 mL of 2.5M n-BuLi/hexane solution (15.5 mmol) dropwise under nitrogen. The mixture was stirred at 0° C. for 10 minutes. 5-dimethylaminophthalide (1.0 g, 5.64 mmol) was added as one portion. The mixture was allowed to warm to room temperature under nitrogen and stirring was continued for 3 hours. The cloudy mixture was then slowly added into 0.5M aqueous HCl solution (0° C.) with vigorous stirring. The resulting mixture was neutralized with 1M NaOH solution until pH=9. The yellow precipitate which formed was collected by filtration, washed with water, dried under vacuum. The solid obtained was triturated with hot MeOH (20 mL) followed by ethyl acetate (10 mL), collected by filtration and dried to give title compound (900 mg, 49%) as a bright yellow powder.