Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][N:6]([C:8]1[CH:15]=[CH:14]C=[CH:12][C:9]=1C=O)[CH3:7].[S:17]([O:22]C)(O[CH3:21])(=[O:19])=[O:18].[C:24]([O:27][CH2:28][CH3:29])(=O)C>ClCCl>[CH3:24][S:17]([O-:22])(=[O:19])=[O:18].[CH:28]([C:29]1[CH:12]=[CH:9][C:8]([N:6]([CH3:7])[CH2:5][CH2:4][CH2:3][N+:2]([CH3:1])([CH3:16])[CH3:21])=[CH:15][CH:14]=1)=[O:27]
Reactant: CCOC(C)=O
Reactant: CN(C)CCCN(C)c1ccccc1C=O
Reactant: COS(=O)(=O)OC
Solvent: ClCCl
Product: CN(CCC[N+](C)(C)C)c1ccc(C=O)cc1
Product: CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
5 g of [[3-(dimethylamino)propyl](methyl)amino]benzaldehyde are diluted in 15 ml of dichloromethane. 2.36 ml of dimethyl sulphate diluted in 10 ml of dichloromethane are gradually added. The mixture is refluxed for 4 h and then cooled to ambient temperature and poured into 100 ml of ethyl acetate. The brown oil formed is separated by settling out, washed with 100 ml of EtOAc, taken up in 200 ml of methanol and concentrated under vacuum. It is subsequently dissolved in a saturated solution of sodium bicarbonate and of sodium chloride and extracted with butanol. The butanol phase is concentrated under vacuum and dried under vacuum in the presence of P2O5, and the product is then used for the subsequent step.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Br.[H-].[Na+]>C(#N)C.O>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][N:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:22][CH:21]=1)[C:24](=[O:32])[CH2:25][N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: O=C(CN1CCOCC1)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(CN1CCOCC1)N(Cc1ccccc1Cl)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 126.9 %

Procedure:
A mixture of 0.11 g of N-[4-(5H-pyrrolo[-2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-4-morpholineacetamide, 56 mg of 0-chlorobenzyl bromide and 0.41 g of K2 CO3 in 5 ml of acetonitrile is heated at reflux for 18 hours. An additional 30 mg of O-chlorobenzyl bromide and 0.4 mmol of sodium hydride is added followed by heating for 24 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried with Na2SO4 and evaporated to give 0.18 g of a residue which is purified by chromatography on silica gel with 1:1 ethyl acetate-methylene chloride to give 80 mg of off white solid. MS(CI): 555(M+H).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19]CC)=O.Cl.[NH2:23][OH:24].[OH-].[K+].C(O)(=O)C>CO>[OH:24][NH:23][C:17]([C:2]1[S:1][C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=1)=[O:19]
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2sc(C(=O)NO)cc2C1
Temperature: 75 °C
Yield: 50.1 %

Procedure:
A mixture of 5-tert-butyl 2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (0.056 g, 0.18 mmol; prepared as described in J. Med. Chem. 2006, 49(15): 4623), hydroxylamine hydrochloride (0.037 mg, 0.54 mmol) and potassium hydroxide (0.1 mg, 1.8 mmol) in methanol (2 mL) was heated at 75° C. for 1 hour. Upon cooling to room temperature the reaction was quenched by the addition of acetic acid (100 μL, 1.8 mmol) and the solvent was evaporated to dryness. The residue was dissolved in DMSO (1 mL) and purified using a Gilson prep to afford a white solid (26.9 mg, 50%). LCMS (FA) ES+ 299; 1H NMR (400 MHz, MeOD) δ 7.27 (s, 1H), 4.46 (s, 2H), 3.71 (t, J=5.4 Hz, 2H), 2.84 (t, J=5.7 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.Cl[P:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-:39].[Na+].O>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:27]1([P:26]([CH2:14][C:13]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=2[CH:16]([CH3:18])[CH3:17])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CP(=O)(c1ccccc1)c1ccccc1
Temperature: 111 °C
Reaction time: 3.5 h

Procedure:
2.02 g (5.69 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 13.1 g of toluene and, with ice-bath cooling, admixed with 1.71 g (7.69 mmol) of chlorodiphenylphosphine in 1.9 g of toluene. The mixture was heated at 111° C. for 2.5 h. After cooling to room temperature, 1.17 g (8.78 mmol) of 30 percent strength sodium hydroxide solution and 182 mg (0.597 mmol) of tetrabutylammonium chloride were added, and the mixture was stirred vigorously at 60° C. for 3.5 h. 30 ml of water was added to the warm reaction mixture. The mixture was briefly stirred at 60° C. and slowly cooled to 4° C., and the precipitated solid was filtered off. The product was washed with cold water (10 ml) and cold toluene (10 ml) and dried under reduced pressure at 40° C. 2.18 g (71.3 percent; content: 97.3 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide were isolated in the form of a colorless solid. The melting point of the product was 184° to 185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:16]O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[N:11]([CH:12]=[N:13][CH:14]=[CH:15]3)[N:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON=C(Cc1ccncn1)c1cccc(Cl)c1
Agent: Cl[Fe]Cl
Solvent: COCCOC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: Clc1cccc(-c2cc3ccncn3n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
To a cold (0° C.) solution of 1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethanone oxime (5.0 g, 20.2 mmol) in ethylene glycol dimethyl ether (50 mL) was added trifluoroacetic anhydride (2.85 ml, 20.2 mmol) dropwise). The reaction mixture was warmed to room temperature and stirred 10 minutes then recooled to 0° C. A solution of triethylamine (5.63 mL, 40.4 mmol) in ethylene glycol dimethyl ether was added and the resultant solution was stirred at room temperature 1.5 hours. Iron (II) chloride (25 mg, 0.20 mmol) was added and the reaction mixture was refluxed 3 hours. The reaction mixture was cooled to room temperature and the excess ethylene glycol dimethyl ether was removed in vacuo. The resultant oil was chromatographed (9:1 to 4:1 hexanes:ethyl acetate) to provide 2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidine (3.2 g, 69%) as a pale yellow solid. Rf 0.27 (4:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 9.25 (s, 1H), 8.00 (s, 1H), 7.88–7.81 (m, 2H), 7.46–7.39 (m, 3H), 6.81 (s, 1H); MS m/z 230 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30]C(=O)OC(C)(C)C)=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:44][CH:43]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(N)nc3)n2)cc1
Yield: 94.1 %

Procedure:
A solution of tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-ylcarbamate (0.827 g, 1.24 mmol) and TFA (5.0 mL, 64.9 mmol) in DCM (10 mL) was stirred at rt for 1.5 h. Toluene (3 mL) was added and the mixture was concentrated in vacuo. Saturated aqueous sodium bicarbonate (50 mL) was added carefully. The aqueous phase was extracted with 25% iPrOH in CHCl3+1% NH4OH (2×50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-yl)pyridine-2,5-diamine (0.664 g, 94% yield) as a bright orange solid. 1H NMR (300 MHz, CDCl3) δ 11.46 (s, 1H); 8.72 (d, J=2.48 Hz, 1H); 8.17 (d, J=2.34 Hz, 1H); 8.06-8.13 (m, 1H); 7.64-7.75 (m, 1H); 7.18 (dd, J=12.57, 8.48 Hz, 4H); 6.86 (t, J=7.89 Hz, 4H); 6.49 (d, J=8.77 Hz, 1H); 4.83 (d, J=15.05 Hz, 4H); 4.31 (br. s., 2H); 3.80 (d, J=5.85 Hz, 6H); 2.56 (s, 3H). m/z (ESI, +ve ion) 569.2 (M+H)+.
Reaction SMILES: C([N:11]1[CH2:34][CH2:33][CH2:32][C@H:12]1[C:13]([NH:15][CH2:16][CH:17]1[O:31][C:20]2=[C:21]3[C:26](=[C:27]([CH3:29])[CH:28]=[C:19]2[CH2:18]1)[NH:25][C:24](=[O:30])[CH:23]=[CH:22]3)=[O:14])(OCC1C=CC=CC=1)=O.[H][H].CCOCC>CN(C)C=O.CO.[Pd]>[CH3:29][C:27]1[CH:28]=[C:19]2[CH2:18][CH:17]([CH2:16][NH:15][C:13](=[O:14])[C@@H:12]3[CH2:32][CH2:33][CH2:34][NH:11]3)[O:31][C:20]2=[C:21]2[C:26]=1[NH:25][C:24](=[O:30])[CH:23]=[CH:22]2
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOCC
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@@H]1CCCN1)C2
Yield: 109.6 %

Procedure:
2-(Carbobenzyloxy-L-prolyl)aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1.04 g, 2.25 mmol) was dissolved in dimethylformamide (130 ml). To the obtained solution, 10% palladium-on-carbon (1.04 g) was added, followed by stirring at room temperature for 4 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was dissolved in methanol (65 ml), to which 1.37 N-HCl--methanol (1.81 ml) was added. The mixture was condensed under reduced pressure. The resultant residue was submitted to a recrystallizing procedure using methanol--ether to obtain 807 mg of the title compound as pale yellow powdery crystals (98.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][NH:14][CH3:15])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:32])([F:31])[CH2:27][C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][N:14]([CH3:15])[C:28](=[O:29])[CH2:27][C:26]([F:32])([F:31])[F:25])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCC(CNC)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Reactant: O=C(O)CC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(CN(C)C(=O)CC(F)(F)F)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
tert-Butyl[1-(3,4-dichlorophenyl)-1-methylaminomethyl-3-butenyl]methylcarbamate (5.0 g) was dissolved in N,N-dimethylformamide (50 mL), and, at room temperature, 3,3,3-trifluoropropionic acid (1.3 mL), [2-(1H)-benzotriazole-1-yl]-1,1,3,3-tetramethyluronium hexafluorophosphate (5.6 g), 1-hydroxybenzotriazole monohydrate (2.0 g), and N,N-diisopropylethylamine (3.5 mL) were added thereto, followed by stirring for 2 hours at room temperature. 3,3,3-Trifluoropropionic acid (0.6 mL), [2-(1H)-benzotriazole-1-yl]-1,1,3,3-tetramethyluronium hexafluorophosphate (2.5 g), 1-hydroxybenzotriazole monohydrate (1.0 g), and N,N-diisopropylethylamine (1.75 mL) were added to the reaction mixture, and the resultant mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby give the title compound (3.38 g, 52%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([S:18][C:19]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:22]=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([OH:32])=[O:31])=[C:15]([S:18][C:19]4[N:23]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:22]=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccnn3-c3ccccc3)CS[C@H]12
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Sc3ccnn3-c3ccccc3)CS[C@H]12
Reaction time: 2 h
Yield: 83 %

Procedure:
To a stirring solution of (7R)-7-[(phenylacetyl)amino]-3-(1-phenylpyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (80 mg, 0.12 mmol) and anisole (0.02 mL) in dichloromethane (2 mL) at 0° C. was added trifluoroacetic acid (0.5 mL). After 2 h at 0° C., the solvent was removed with a rotary evaporator, and the residue was subjected to chromatography on silica gel (3% acetic acid/ethyl acetate), affording 49 mg (83%) of the title compound. 1H NMR (acetone-d6) δ 3.21 (s, 2), 3.60 (d, 1, J=16), 3.65 (d, 1, J=16), 4.96 (d, 1, J=4), 5.71 (dd, 1, J=4, 9), 6.83 (d, 1, J=2), 7.2-7.6 (m, 10), 7.80 (d, 1, J=2), 8.05 (d, 1, J=9).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[OH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[C:24]2[C:28](=O)[C:29](OC)=[O:30].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[OH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[C:24]2[C:28]1[C:29](=[O:30])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2c(CCCO)cccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5c(CCCO)cccc45)C(=O)NC3=O)c21
Temperature: 60 °C
Reaction time: 12 h
Yield: 89.2 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (105 mg, 0.55 mmol) and methyl 2-(7-hydroxypropyl-1H-indol-3-yl)oxoacetate (146 mg, 0.56 mmol) in DMF (2.0 mL) at 4° C. under N2, was added a 1.0 M solution of potassium tert-butoxide in THF (1.7 mL, 1.7 mmol) dropwise over 25 min. The reaction was heated to 60° C. and stirred for 12 h. The reaction mixture was then cooled to room temperature and quenched with 1.0 N hydrochloric acid (5.0 mL). The mixture was extracted with EtOAc (2×15 mL), washed with saturated NaHCO3 (30 mL), saturated NaCl (30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 3:47:50 MeOH/EtOAc/CH2Cl2) gave the title compound (196 mg, 87%) as a red solid, mp 183–185° C. 1H NMR (300 MHz, DMSO-d6) 11.81 (s, 1H), 11.12 (s, 1H), 7.87 (m, 1H), 7.61 (m, 1H), 7.28 (m, 1H), 6.98 (m, 3H), 6.50 (m, 2H), 6.29 (m, 1H), 3.68 (s, 3H), 3.41 (m, 2H), 2.78 (m, 2H), 1.76 (m, 2H). MS (electrospray, m/z) 398 [C24H21N3O3−H]−
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:38])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][S:28][CH:29]4[NH:34][C:33](=[O:35])[C:32](=[O:36])[NH:31][N:30]4[CH3:37])[O:24][CH2:23]2)[CH:17]([CH:39]([OH:41])[CH3:40])[C:16]3=[O:42])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:47].O>[Pd].O1CCOCC1>[Na+:47].[CH3:37][N:30]1[CH:29]([S:28][CH2:27][CH:25]2[O:24][CH2:23][CH:22]([S:21][C:20]3[CH:19]([CH3:38])[CH:18]4[N:15]([C:16](=[O:42])[CH:17]4[CH:39]([OH:41])[CH3:40])[C:14]=3[C:12]([O-:13])=[O:11])[CH2:26]2)[NH:34][C:33](=[O:35])[C:32](=[O:36])[NH:31]1
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CSC4NC(=O)C(=O)NN4C)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(CSC4NC(=O)C(=O)NN4C)C3)C(C)C12
Yield: 46.5 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.10 g of product from Example 86, 0.0135 g of sodium bicarbonate, 2 ml of water, 10 ml of dioxane, and 0.030 g of 10% palladium/carbon to give 0.038 g of the desired product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][NH2:16])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=O)[CH3:27])[CH:21]=1>CO.C(O)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15]/[N:16]=[C:26](/[C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)\[CH3:27])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cccnc1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cccnc1
Temperature: 120 °C
Yield: 27.6 %

Procedure:
3-(Morpholinosulfonyl)benzohydrazide (40 mg, 0.140 mmol) and 1-(pyridin-3-yl)ethanone (16.98 mg, 0.140 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (15 mg). 1H NMR (400 MHz, CDCl3): δ 9.53 (bs, 1H), 8.87 (s, 1H), 8.59 (m, 1H), 8.39 (m, 1H), 8.17 (m, 1H), 7.98 (m, 1H), 7.89 (d, 1H, J=8.0 Hz), 7.67 (t, 1H, J=8.0 Hz), 7.32 (m, 1H), 3.70 (m, 4H), 3.00 (m, 4H), 2.39 (s, 3H). ESI-MS: 389.0 [M+H]+.
Reaction SMILES: [OH-].[Na+:2].O.CO.[CH3:6][N:7]1[C:11]([C:12]([O:14]C)=[O:13])=[C:10]([C:16]2[S:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=2)[CH:9]=[N:8]1>C1(C)C=CC=CC=1>[CH3:6][N:7]1[C:11]([C:12]([O-:14])=[O:13])=[C:10]([C:16]2[S:17][CH:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[N:20]=2)[CH:9]=[N:8]1.[Na+:2]
Reactant: COC(=O)c1c(-c2nc(C(F)(F)F)cs2)cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1ncc(-c2nc(C(F)(F)F)cs2)c1C(=O)[O-]
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 149.8 %

Procedure:
Sodium hydroxide (3.5 mg) was added to a mixed solution of water (1 ml) and methanol (1 ml) containing the methyl 1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate (13 mg) obtained in (Example 1.5) <Step 1>, and the obtained mixture was then stirred at 70° C. for 30 minutes. Thereafter, the reaction solution was subjected to azeotropy with toluene, so as to obtain the title compound (20 mg) in the form of a colorless solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:38]=[CH:37][C:9]2[N:10]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:30])[NH:24][CH:25]([C:27](=[O:29])[NH2:28])[CH3:26])[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.N[C@H](C(N)=O)C[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(C(NC(C1C=CC2C(=CC=C(C3N(C4CCCCC4)C4C=CC(C(O)=O)=CC=4N=3)C=2)N=1)=O)C)(=O)N>>[C:27]([CH:25]([NH:24][C:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]3[N:10]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:9]4[CH:37]=[CH:38][C:6]([C:4]([OH:3])=[O:5])=[CH:7][C:8]=4[N:12]=3)[CH:14]=2)[N:19]=1)=[O:30])[CH2:26][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:29])[NH2:28]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NC(C)C(N)=O)ccc3c1)n2C1CCCCC1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(NC(=O)c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1)C(N)=O
Product: NC(=O)C(Cc1ccccc1)NC(=O)c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1

Procedure:
The title compound (5 mg yield) was prepared as described for Compound 497a using L-phenylalaninamide in place of L-alaninamide and hydrolyzed as described for Compound 497.
Reaction SMILES: [H-].[Na+].[CH:3](OC)=[O:4].[CH3:7][C:8]([C:10]1([CH3:16])[CH2:13][CH:12]([CH2:14][CH3:15])[CH2:11]1)=[O:9].CO>CCCCCC.CCOCC>[OH:4][CH:3]=[CH:7][C:8]([C:10]1([CH3:16])[CH2:13][CH:12]([CH2:14][CH3:15])[CH2:11]1)=[O:9]
Reactant: COC=O
Reactant: CCC1CC(C)(C(C)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOCC
Product: CCC1CC(C)(C(=O)C=CO)C1

Procedure:
Sodium hydride (1.25 g of 50% mineral oil dispersion, 50 mmol) was washed with dry hexane and then stirred under an argon atmosphere with 12.5 ml of dry ether. A solution of 5 ml of methyl formate and 2.4 g of (1-methyl-3-ethylcyclobutyl) methyl ketone (prepared in Example 3A) in 5 ml of ether was then added to the reaction mixture along with about 0.5 ml of methanol. As a voluminous precipitate formed, sufficient ether was added to make the reaction mixture more easily stirred. The resultant mixture was stirred for 1 hr and then quenched by the addition of water. The ether phase was separated and extracted three times with 1 M sodium hydroxide. The combined aqueous extraction phases were acidified with concentrated hydrochloric acid and extracted three times with ether. The combined ether extract was evaporated in vacuo. Traces of water were removed by twice addition of benzene which was removed by evaporation in vacuo. The title compound had the following physical characteristics:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[C:18]([C:22]1[N:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30](O)=[O:31])=[C:24]([C:33]([F:36])([F:35])[F:34])[CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CN1C(=O)CCC1>C1COCC1>[C:18]([C:22]1[N:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:31])=[C:24]([C:33]([F:36])([F:34])[F:35])[CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc(C(F)(F)F)c(C=CC(=O)O)cn1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C#Cc1cc(CNC(=O)C=Cc2cnc(C(C)(C)C)cc2C(F)(F)F)cc(F)c1NS(C)(=O)=O
Yield: 30.2 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (11.2 mg, 0.04 mmol) was reacted with 3-(6-tert-butyl-4-trifluoromethyl-pyridin-3-yl)-acrylic acid (1.0 eq, 11.0 mg) DMTMM (1.0 eq, 11.1 mg) and NMP (1.2 eq, 6 μl) in THF to give the title compound (6 mg, 30.2%) after purification by column chromatography (Hex/EtOAc=3/2).