Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1.[CH2:17](Br)[C:18]#[CH:19].Cl>CO.CN(C=O)C.O>[CH2:19]([O:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)[C:18]#[CH:17]
Reactant: C#CCBr
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: C#CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Reaction time: 2.5 h
Yield: 28.3 %

Procedure:
To a stirring solution of NaOH in MeOH (2.5 M, 18.8 mL) and DMF (60 mL) was added 1 (4.33 g, 18.8 mmol). The mixture was allowed to stir for 45 min at 23° C. before propargyl bromide (80% in PhMe, 3.36 mL, 22.56 mmol) was added slowly over 10 min. After 2.5 h, an aqueous solution of 1 M HCl was added to achieve pH=6, where upon a white precipitate forms. Water was then added and the organic layer was extracted 3×EtOAc and the combined organic extracts washed 1×H2O, 1× brine, and then dried over MgSO4. The solvents were removed in vacuo and the crude residue purified by flash chromatography using Hexanes:EtOAc on a Biotage purification system to yield 3 as a pale yellow solid (1.43 g, 29%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[CH:5][CH:4]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CN5CCOCC5)cc4)sc23)c(F)c1
Temperature: 60 °C
Yield: 94.4 %

Procedure:
To a suspension of 52 (823 mg, 1.82 mmol) in DMF (10 ml) was added morpholine (317 mg, 3.65 mmol) and the reaction mixture was heated for 4 hours at 60° C., the solvent was removed under reduced pressure and the residual solid was triturated with EtOAc and collected by filtration. It was further washed with EtOAc until no color was observed in the filtrate, to form the title compound 53 (800 mg, 94% yield), which was used without additional purification. 1HNMR (DMSO) δ (ppm): 8.57 (d, J=4.7 Hz, 1H), 8.46 (dd, J=2.7 and 10.4 Hz, 1H), 8.18 (m, 1H), 8.07 (s, 1H), 7.83 (d, J=12.2 Hz, 1H), 7.71 (t, J=8.02 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 6.91 (d, J=5.3 Hz, 1H), 3.56 (m, 4H), 3.51 (m, 2H), 3.33 (m, 2H), 2.50 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:21][OH:22])[NH2:20])[C:3]=1[S:23][CH3:24].O.[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:37](OC)(OC)[O:38][CH3:39]>>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([N:1]=[CH:37][O:38][CH3:39])=[C:3]([S:23][CH3:24])[C:4]([C:19]2[N:20]=[CH:26][O:22][N:21]=2)=[N:5]1
Reactant: COC(OC)OC
Reactant: CSc1c(C(N)=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC=Nc1c(SC)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 74 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylthio-3-pyrazolecarboxamide oxime (1.77 g, 4.4 mmol) was dissolved in 25 ml of trimethyl orthoformate, and then p-toluenesulfonic acid monohydrate (130 mg) was added at room temperature. The mixture was heated. under reflux for 2 hours. The trimethyl orthoformate was distilled off under reduced pressure and the residue was dissolved in 60 ml of ethyl acetate. After the solution was washed with 120 ml of an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain a yellow crystal which was washed with n-hexane to yield 1.47 g (3.3 mmol) of the title compound as a pale yellow crystal. Yield 74%.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH2:29][CH3:30])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH2:29][CH3:30])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2CC)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Yield: 49 %

Procedure:
Prepared analogously to Example 26 from 1-ethyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 2N sodium hydroxide solution. Yield: 49% of theory, C26H27N7O3 (485.6) ##EQU56##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].[NH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=O>>[O:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=[C:12]1[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[NH2:9]
Reactant: Nc1cnccc1O
Reactant: Nc1ccccc1C(=O)O
Product: Nc1ccccc1-c1nc2cnccc2o1
Yield: 39.3 %

Procedure:
3-Amino-4-hydroxypyridine (2.225 g, 20.0 mmol) and 2-aminobenzoic acid (2.740 g, 20.0 mmol) were stirred in polyphosphoric acid (40 mL) at 140° C. for 6 hrs. The reaction mixture was poured into distilled water and sodium hydroxide was added until pH=8. The precipitate was collected by filtration and the crude product was purified by chromatography on silica gel eluting with petroleum ether:ethyl acetate:Et3N (160:40:1) to give 2-(oxazolo[4,5-c]pyridin-2-yl)benzenamine (1.659 g, Yield: 39%). 1H NMR (400 MHz, DMSO-d6) δ: 6.68 (1H, t, J=7.6 Hz), 6.93 (1H, d, J=8.0 Hz), 7.17 (2H, s), 7.30 (1H, t, J=7.6 Hz), 7.83 (1H, d, J=5.6 Hz), 7.90 (1H, d, J=8.0 Hz), 8.55 (1H, d, J=5.6 Hz), 9.05 (1H, s); MS (ESI) calcd. for C12H9N3O (m/z): 211, found: 212 [M+1]+.
Reaction SMILES: C(O)(=[O:3])C.[CH2:5]([O:12][CH2:13][C:14](=O)[CH:15]([CH2:18][CH3:19])[CH:16]=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21](#[N:25])[CH2:22][C:23]#[N:24].N1CCCCC1>C(O)C>[C:23]([C:22]1[C:21](=[O:3])[NH:25][C:14]([CH2:13][O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:15]([CH2:18][CH3:19])[CH:16]=1)#[N:24]
Reactant: CC(=O)O
Reactant: CCC(C=O)C(=O)COCc1ccccc1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: CCc1cc(C#N)c(=O)[nH]c1COCc1ccccc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
Acetic acid (2.0 mL, 35 mmol) was added to a solution of crude 4-benzyloxy-3-oxo-2-ethylbutanal (6.4 g, ~24 mmol) and malononitrile (2.22 g, 33 mmol) in ethanol (30 mL) followed by dropwise addition of piperidine (2.37 mL, 24 mmol) to give a dark reddish brown solution. After stirring for 14 hours, a copious precipitate formed. This mixture was warmed at 70° C. for 15 hours and then allowed to cool to room temperature. This blackish mixture was diluted with ethanol and the precipitated product was filtered, rinsed with ethanol and diethyl ether to give off-white product with m.p. of 141°-143° C. Additional material was obtained by evaporation of the filtrate. The residue was extracted into chloroform, and after washing the extract with saturated aqueous NaHCO3, filtered through a pad of charcoal. This amber solution was evaporated and the residue triturated with diethyl ether to give additional product.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:22][C:21]2[NH:20][CH:19]=[CH:18][C:17](=O)[C:16]=2[C:15](=[O:24])[CH2:14]1>>[Cl:3][C:17]1[C:16]2[C:15](=[O:24])[CH2:14][CH:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[Cl:6])[CH2:22][C:21]=2[N:20]=[CH:19][CH:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(c2ccccc2Cl)Cc2[nH]ccc(=O)c21
Product: O=C1CC(c2ccccc2Cl)Cc2nccc(Cl)c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
Under ice-cooling, to phosphorus oxychloride (5.4 g) was added 7-(2-chlorophenyl)-1,4,5,6,7,8-hexahydroquinoline-4,5-dione (0.60 g), and the mixture was stirred at 100° C. for 2 hours and cooled. Under reduced pressure, phosphorus oxychloride was evaporated, and to the residue was added 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give colorless crystals of 4-chloro-7-(2-chlorophenyl)-5,6,7,8-tetrahydroquinolin-5-one (0.55 g).
Reaction SMILES: C([O:3][C:4](=[O:17])[C@H:5]([CH2:13][C:14]([OH:16])=O)[NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])C.O=S(Cl)[Cl:20].[C:22]1([CH3:28])C=CC=CC=1>>[CH2:22]([N:6]([C:7](=[O:12])[C:8]([F:9])([F:10])[F:11])[C@H:5]([C:4]([OH:3])=[O:17])[CH2:13][C:14]([Cl:20])=[O:16])[CH3:28]
Reactant: CCOC(=O)[C@H](CC(=O)O)NC(=O)C(F)(F)F
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1
Product: CCN(C(=O)C(F)(F)F)[C@@H](CC(=O)Cl)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of N-(trifluoroacetyl)-L-aspartic acid α-ethyl ester (3 g, 11.7 mmol) in dry toluene (15 mL) was added SOCl2 (3 mL). After stirring at reflux for 1 h, the solution was cooled to rt. The mixture was filtered and the solid was washed with cold toluene. The solid was dried to afford the title compound. 1H NMR (400 MHz, CDCl3): δ4.71-4.75 (m, 1H), 4.28-2.36 (m, 2H), 3.64-3.70 (m, 1H), 3.56-3.61 (m, 1H), 1.31 (t, J=6 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[CH3:9][S:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH3:22])[C:14]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:12])=[O:11].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[C:14]([C:23]([O:25][CH3:26])=[O:24])[C:15]=2[CH3:22])[CH:5]=[N:4]1)[CH3:2]
Reactant: COC(=O)c1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)c1O
Yield: 61.7 %

Procedure:
1.12 g (0.01 mol) of 1-ethyl-5-hydroxypyrazole was dissolved in 30 ml of t-amyl alcohol, and 2.72 g (0.01 mol) of 4-methanesulfonyl-3-methoxycarbonyl-2-methylbenzoic acid, 2.27 g (0.011 mol) of N,N'-dicyclohexylcarbodiimide and 0.76 g (0.0055 mol) of anhydrous potassium carbonate were sequentially added thereto. The mixture was reacted at 80° C. for 6 hours under stirring. After completion of the reaction, t-amyl alcohol was distilled off under reduced pressure, and then water was added to the residue to dissolve the soluble component. The mixture was subjected to filtration to separate out the insolubles. The aqueous solution thus obtained was washed twice with chloroform, and then concentrated hydrochloric acid was added to adjust pH<1. The precipitated oil component was extracted with chloroform. The chloroform layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate Then, the solvent was distilled off under reduced pressure, and the residue thus obtained was recrystallized from water/ethanol to obtain 2.26 g of the desired product. (Yield: 62%, melting point: 150°-152° C.)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=[CH:4][N:3]=1.[OH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(O)C>[ClH:1].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:7]2[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([OH:17])=[CH:19][CH:20]=3)=[N:3][CH:4]=[N:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ccc(C#Cc2cncnc2Cl)cc1
Solvent: CCO
Product: Cl
Product: Oc1ccc(Nc2ncncc2C#Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.8 %

Procedure:
A mixture of 0.28 g of 4-chloro-5-(4-Chlorophenylethynyl)pyrimidine, 10 mL of ethanol and 0.14 g of 4-hydroxyaniline was stirred at room temperature for 18 hours. The black mixture was evaporated in vacuo and the residue was triturated with dichloromethane, ethylacetate and acetonitrile. The combined organic extracts were absorbed on silica gel and evaporated in vacuo. The powder was added to a column of silica gel equilibrated in dichloromethane and eluted with the same solvent. The column was eluted with ethyl acetate and then 10% methanol in dichloromethane. These eluates on evaporation produced 100 mg of the 5-(4-chlorophenylethynyl)-4-(4-hydroxyanilino)pyrimidine hydrochloride as a muddy yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>N1C=CC=CC=1.O>[CH2:13]([O:12][C:10](=[O:11])[C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH3:14]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.1 %

Procedure:
Aniline (3.4 g, 37 mmol) was dissolved in pyridine (50 mL), then ethyl chloroxoacetate (5.0 g, 37 mmol) was added to the resulting solution dropwise. The resulting mixture was stirred at room temperature for 48 hours, then diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with 1N HCl, water, brine, then dried (Na2SO4) and concentrated to provide 5.8 g (81%) of an oil that crystallized on standing. 1H-NMR (DMSO-d6) δ: 1.3 (t, J=7 Hz, 3H), 4.3 (q, J=7 Hz, 2H), 7.1–7.8 (m, 5H), 10.7 (s, 1H); MS ES+m/e 194.2 (p+1), ES−m/e 192.3 (p−1).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([C:17](OC)=[O:18])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:3])[CH3:2].[BH4-].[Li+]>C1COCC1.CCOCC>[OH:18][CH2:17][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:8]=1
Reactant: COC(=O)c1cc(CCNC(C)=O)cc2ccccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)NCCc1cc(CO)c2ccccc2c1

Procedure:
Methyl 3-[2-(acetylamino)ethyl]-naphthalenecarboxylate (1 eq.) from the previous step was taken up in THF (0.18 M). To this solution was then added lithium borohydride (12 eq.) and the resulting solution was vigorously stirred at 50° C. for 5 h. The reaction mixture thus obtained was diluted further with ether and carefully quenched with 1 N aq. HCl. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: BrC1C=C2C(=CC=1)N=C(C1C=CC=CC=1O)N=C2N[C@H]1CCN(C(OC(C)(C)C)=O)C1.[CH3:32][C:33]([OH:37])([CH3:36])[C:34]#[CH:35].Br[C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[N:45]=[C:44]([C:49]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:50]=1[OH:56])[N:43]=[C:42]2[NH:57][C@H:58]1[CH2:62][CH2:61][N:60](C(OC(C)(C)C)=O)[CH2:59]1.OC1C=CC=CC=1C1N=C(N[C@H]2CCN(C(OC(C)(C)C)=O)C2)C2C(=CC=C(C#CCO)C=2)N=1>>[F:55][C:53]1[CH:52]=[CH:51][C:50]([OH:56])=[C:49]([C:44]2[N:43]=[C:42]([NH:57][C@H:58]3[CH2:62][CH2:61][NH:60][CH2:59]3)[C:41]3[C:46](=[CH:47][CH:48]=[C:39]([CH2:35][CH2:34][C:33]([OH:37])([CH3:36])[CH3:32])[CH:40]=3)[N:45]=2)[CH:54]=1
Reactant: C#CC(C)(C)O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3cc(F)ccc3O)nc3ccc(Br)cc23)C1
Agent: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(Br)cc23)C1
Agent: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Product: CC(C)(O)CCc1ccc2nc(-c3cc(F)ccc3O)nc(N[C@H]3CCNC3)c2c1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 59 and 60, replacing propargyl alcohol and (S)-tert-butyl 3-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate with dimethyl propargyl alcohol and (S)-tert-butyl 3-(6-bromo-2-(5-fluoro-2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate in Synthesis 59-A.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[O:7])=[CH:33][CH:34]=1)(=[O:37])[CH3:36]
Reactant: Cc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccc(C)c2)cc1
Yield: 100.3 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methylphenyl)benzamide (285.0 mg, 0.62 mmol) and acetic anhydride (0.071 ml, 0.74 mmol), the procedure of Inventive Example 94 was repeated to obtain 311.8 mg (99.9%) of the title compound in a colorless amorphous form.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(=O)([O-])O.[Na+].[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>O.C(OCC)(=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][NH:13][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)NCCc1ccc([N+](=O)[O-])cc1

Procedure:
2-(4-Nitrophenyl)ethylamine hydrochloride (1.72 g) and sodium hydrogencarbonate (5.00 g) were dissolved in water (25 mL), to which ethyl acetate (25 mL) was added, followed by being stirred in an ice bath. Methacryloyl chloride (1.79 g) was added dropwise thereto. After stirring for 10 minutes, the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The recrystallization was performed by using a mixture solvent of hexane and ethyl acetate. N-[2-(4-Nitrophenyl)ethyl]methacrylamide was obtained as pale yellowish crystals. The yield was 1.25 g (63%). Spectrum data of 1H-NMR (400 MHz, CDCl3) is shown for the obtained compound.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]1([CH2:26][Br:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[Br-:27].[CH:20]1([CH2:26][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCC1CCCCC1
Solvent: Cc1ccccc1
Product: [Br-]
Product: c1ccc([P+](CC2CCCCC2)(c2ccccc2)c2ccccc2)cc1
Yield: 72.3 %

Procedure:
A solution of 5.80 g (21.9 mmol) of triphenylphosphine and 8.00 g (43.8 mmol) of cyclohexylmethyl bromide in 30 ml of toluene was heated at reflux for 4 days. After removal of solvent in vacuo, the residue was taken up in tetrahydrofuran and filtered to give 6.96 g (37%) of the desired compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19](OCC)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C:25]([NH:28][CH2:29][CH2:30][NH2:31])([CH3:27])[CH3:26]>C[O-].[Na+]>[CH3:24][C:25]([NH:28][CH2:29][CH2:30][NH:31][C:19](=[O:20])[CH2:18][N:10]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]1)([CH3:27])[CH3:26]
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Reactant: CC(C)(C)NCCN
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)NCCNC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Yield: 66.8 %

Procedure:
A solution of 10.7 g (0.035 mol) of ethyl 4,5-diphenylpyrazole-1-acetate of example 1 in 10.9 g (0.094 mol) of 2-[(1,1-dimethylethyl)amino]ethanamine was heated with about 50 mg of sodium methoxide at about 150° for two hours. The excess amine was stripped off under vacuum and the residue was triturated in acetonitrile. The solid product was filtered off and recrystallized from isopropyl acetate to yield 8.8 g of white crystals, mp 115°-116° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32]>>[OH:33][C:31]([CH3:34])([CH3:32])[CH2:30][NH:29][C:15]([C:14]1[CH:18]=[CH:19][N:20]=[CH:21][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=1)=[O:11])=[O:17]
Reactant: CC(C)(O)CN
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Product: CC(C)(O)CNC(=O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Yield: 74 %

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with 1-amino-2-methylpropan-2-ol, providing the title compound as yellow solid (74%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][C:18]1=[O:23]>CN(C)C=O.C(Cl)(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:21][CH2:22][NH:17][C:18](=[O:23])[CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2)CCN1
Temperature: 140 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 1.275 g (9.04 mmol) of 4-fluoronitrobenzene in 30 mL of N,N-dimethylformamide were added 1.879 (13.56 mmol) of potassium carbonate and 905 mg (9.04 mmol) of piperazine-2-one, and the mixture was stirred for 1 hour at 130° C. and for 1 hour at 140° C. The reaction mixture was cooled to room temperature and diluted with chloroform, then, insoluble substances were removed off by filtration. The filtrate was condensed under reduced pressure and the resulting solid was washed with ethanol to give 859 mg (43%) of the title compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]#[CH:21])[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CI.[CH3:26]COCC>C1COCC1>[C:1]([N:8]([C@H:9]([C:20]#[CH:21])[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH3:11])[CH3:26])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CCOCC
Reactant: C#C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C#C[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(2R,3R)-3-(N-Boc-N-methylamino)-2-(-tert-butyldimethylsilyloxy)-pent-4-yne was synthesized according to Method Y above by the treatment of (2R,3R)-N-Boc-3-amino-2-(-tert-butyldimethylsilyloxy)-pent-4-yne (400 mg, 1.27 mmol) (Example 117B) with NaH (36 mg, 1.52 mmol) and MeI (360 mg, 2.54 mmol) in THF (30 mL). The product was obtained after silica gel column chromatography with a 0-10% Et2O in hexanes gradient. (Yield 370 mg, 89%).
Reaction SMILES: [C:1](=[O:7])([O:3][CH2:4][CH2:5][CH3:6])[NH2:2].C(Cl)(=O)[C:9](Cl)=[O:10]>>[CH2:4]([O:3][C:1]([N:2]=[C:9]=[O:10])=[O:7])[CH2:5][CH3:6]
Reactant: CCCOC(N)=O
Reactant: O=C(Cl)C(=O)Cl
Product: CCCOC(=O)N=C=O

Procedure:
When propyl carbamate is reacted with oxalyl chloride as described in the procedure of Example 13, propoxycarbonyl isocyanate is obtained.