Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:23](O)[CH3:24]>>[CH2:23]([O:17][C:16](=[O:18])[C@@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH3:24]
Reactant: CC(C)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](NS(=O)(=O)c1ccc(F)cc1)C(C)C
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a solution of 15.0 g (54 mmol) of N-[(4-fluorophenyl)sulfonyl]-D-valine from Example 1a in 55 mL of anhydrous ethanol cooled in an ice bath, was slowly added 5.0 mL (8.1 g, 68 mmol) of thionyl chloride over 5 minutes. The reaction mixture was then stirred at room temperature for 28 hours, the solvents removed under reduced pressure and the residue dissolved in ethyl acetate. This was then washed with saturated sodium bicarbonate, 5% potassium hydrogen sulfate and brine, dried over sodium sulfate, filtered and concentrated to afford crude product, which was chromatographed on silica gel using 10-20% ethyl acetate/hexane to yield 12.8 g of pure N-[(4-fluorophenyl)sulfonyl]-D-valine ethyl ester, m/e=304 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:24]=[CH:25][S:26][CH:27]=2)[CH3:12])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[NH3:32]>O1CCOCC1>[NH2:32][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:24]=[CH:25][S:26][CH:27]=2)[CH3:12])[N:5]=1
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1cscn1
Reactant: N
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1cscn1
Temperature: 60 °C
Yield: 70 %

Procedure:
To a sealed tube were added (S)-4-amino-6-((1-(1-methyl-6-(thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (20 mg, 0.044 mmol) in dioxane (5 mL) along with 0.5M ammonia in dioxane (0.440 mL, 0.220 mmol). The reaction mixture was heated at 60° C. overnight and then concentrated. The crude product was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 30-40% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as an off-white solid (12 mg, 70%). 1H NMR (500 MHz, CD3OD) δ ppm 1.42 (d, J=6.83 Hz, 3 H), 3.87 (s, 3 H), 5.76 (d, J=6.83 Hz, 1 H), 6.60-6.67 (m, 1 H), 7.56 (s, 1 H), 7.76 (s, 1 H), 7.91 (d, J=0.98 Hz, 1 H), 9.16 (d, J=1.95 Hz, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H17N9S, 392; found 392.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(O)CO>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CN1CCNCC1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Yield: 58.9 %

Procedure:
To a solution of p-nitrobenzyl chloride (5.2 g, 10mM) and 3.2 g of triethylamine in 30 ml of ethylene glycol is added a solution of N-methylpiperazine (3 g, 30 mM) in 20 ml of ethylene glycol. After complete addition, the resulting solution is heated to 80° C. under nitrogen for 30 minutes. The reaction mixture is quenched into aqueous 10% sodium carbonate solution and extracted with methylene chloride. The methylene chloride solution is washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 4.15 g (59%) of 1-methyl-4-[(4-nitrophenyl)methyl]piperazine.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Ni]>[F:15][C:12]([F:13])([F:14])[CH:11]([O:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH3:16]
Reactant: CC(Oc1ncccc1[N+](=O)[O-])C(F)(F)F
Agent: [Ni]
Solvent: CO
Product: CC(Oc1ncccc1N)C(F)(F)F

Procedure:
3-Nitro-2-(1,1,1-trifluoropropan-2-yloxy)pyridine (6.2 g) was dissolved in methanol (500 ml) and Raney nickel (1.0 g) was added. The reaction mixture was hydrogenated at room temperature and 5 bar. The catalyst was filtered off and the filtrate was concentrated in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:10]([C:11]=1[CH:12](O)[C:13]([NH2:15])=[O:14])=[C:9]([O:17][CH3:18])[CH:8]=[CH:7][CH:6]=2)[CH3:2].C([SiH](CC)CC)C.C(OCC)(=O)C>FC(F)(F)C(O)=O>[CH2:1]([C:3]1[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([O:17][CH3:18])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1c(C(O)C(N)=O)c2c(OC)cccc2n1Cc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(CC(N)=O)c2c(OC)cccc2n1Cc1ccccc1
Yield: 62.2 %

Procedure:
A solution of 875 mg (2.6 mmol) of 2-ethyl-4-methoxy-alpha-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide and 0.51 mL (3.23 mmol) of triethylsilane in 10 mL of trifluoroacetic acid was stirred for 16 hours and concentrated at reduced pressure. The residue was taken up in ethyl acetate and water, the ethyl acetate separated, washed with brine and dried (MgSO4). The residue was chromatographed on silica gel and eluted first with 50% ethyl acetate/hexane and then ethyl acetate to give 521 mg (62% yield) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 152-154° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:18]([OH:20])=O)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:10]=1)[CH3:3].Cl.Cl.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:18]([NH:32][C@@H:30]([C:27]2[CH:28]=[N:29][C:24]([CH3:23])=[CH:25][CH:26]=2)[CH3:31])=[O:20])[CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH:10]=1)[CH3:1]
Reactant: Cc1ccc(-c2cc(CN(C)C)cc(C(=O)O)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(CN(C)C)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-((dimethylamino)methyl)-4′-methylbiphenyl-3-carboxylic acid (20 mg, 0.074 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (40 mg, 0.19 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (60 mg, 0.16 mmol), and N,N-diisopropylethylamine (200 μL, 1.15 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]1)(=O)=O.[C-:21]#[N:22].[Na+]>CS(C)=O>[C:21]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][CH2:8]1)#[N:22]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC#N)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of {trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}methyl methanesulfonate (1.48 g, 4.81 mmol) and sodium cyanide (0.46 g, 9.4 mmol) in dimethyl sulfoxide (20 mL) was stirred at 90° C. for 4 h. After cooling, the mixture was partitioned between EtOAc and brine. The organic layer was washed with water, concentrated and purified on silica gel (eluting with 50% EtOAc in hexanes) to give tert-butyl [trans-4-(cyanomethyl)cyclohexyl]carbamate. LCMS calculated for C13H22N2O2Na (M+Na)+: m/z=261.2. Found: 261.1. A solution of the Boc-protected intermediate in methylene chloride (20 mL) was treated with trifluoroacetic acid (3 mL, 40 mmol) and the resulting mixture was stirred at room temperature for 2 h, then concentrated to give the desired product as TFA salt. LCMS calculated for C8H15N2 (M+H)+: m/z=139.1. Found: 139.1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[C:4]([O:13][CH3:14])[C:3]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.C([Mg]Cl)(C)C.CON(C)[C:34]([C:36]1[N:40]([CH3:41])[N:39]=[N:38][CH:37]=1)=[O:35].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:34]([C:36]3[N:40]([CH3:41])[N:39]=[N:38][CH:37]=3)=[O:35])[CH:10]=2)[N:5]=[C:4]([O:13][CH3:14])[C:3]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)c1cnnn1C
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc2ccc(C(=O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-chloro-6-iodo-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (41.39 g, 86.6 mL, Intermediate 62: step c) in THF (800 mL) was cooled to 4° C., and isopropylmagnesium chloride (44.2 mL, 88.4 mmol, 2 M in THF) was added over 10 min. The mixture was stirred for 20 min and then N-methoxy-N,1-dimethyl-1H-1,2,3-triazole-5-carboxamide (14.74 g, 86.6 mmol, Intermediate 61) in THF (150 mL) was added. After warming to room temperature and stirring for 15 h, a solution of aqueous ammonium chloride (900 mL, 13 wt %) was added. The resulting biphasic mixture was stirred for 15 min. The layers were then separated, and the organic layer was washed with brine (450 mL). The organic layer was diluted with heptane (500 mL) and stirred for 1 h. The resulting suspension was filtered, washed with heptane (100 mL), and dried in a 60° C. vacuum oven to afford the title compound as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH3:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].OS([O-])(=O)=O.[K+]>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(C)O)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
p-Hydroxyxstyrene was converted to 1-(p-acetoxyphenyl)ethanol and then dehydrated using liquid phase dehydration in the presence of potassium acid sulfate to produce p-acetoxystyrene, according to the method of Corson et al (J. Org. Chem. 1958 23 544). p-Acetoxystyrene (1.6 g) was added to a stirred solution of potassium hydroxide (1.4 g) in water (14 ml) at 5 degrees Centigrade. Stirring was continued at 0-5 degrees Centigrade for 2 h. The mixture was then washed with ether, and the aqueous phase neutralised with saturated sodium hydrogen carbonate solution. The product was extracted into dichloromethane, the solution was dried over anydrous calcium chloride and the solvent removed, to yield a cloudy oil (0.7 g) which solidified on standing to a waxy solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:25][CH2:24][C:12]3([N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:14][CH2:13]3)[CH2:11]2)=[CH:6][C:5]=1[O:26][CH:27]([CH3:29])[CH3:28])([O-])=O.O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:25][CH2:24][C:12]3([N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:14][CH2:13]3)[CH2:11]2)=[CH:6][C:5]=1[O:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Oc1cc(N2CCC3(CCCN3C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cc(N2CCC3(CCCN3C(=O)OC(C)(C)C)C2)ccc1N
Yield: 98.5 %

Procedure:
A mixture of 400 mg of 2-methylpropan-2-yl 7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylate, 592 mg of hydrazine hydrate and 52.5 mg of 10% palladium-on-carbon in 10 ml of ethanol is refluxed for 1 h. The mixture is filtered and the filtrate is concentrated under reduced pressure, so as to obtain 365 mg of 2-methylpropan-2-yl 7-[4-amino-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylate in the form of a mauve gum.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=4[CH3:25])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1.[NH4+].O[N:33]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([NH2:33])=[O:21])=[CH:18][C:17]=4[CH3:25])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(C(=O)O)cc1C
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a solution of 4-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-3-methylbenzoic acid (330 mg, 0.775 mmol) in N,N-dimethylformamide (4.0 mL) were added 1-hydroxy-1H-benzotriazole ammonium salt (172 mg, 1.01 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg, 0.853 mmol). The mixture was stirred at room temperature for 11 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 80-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture contained an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethanol/diisopropyl ether to give the title compound as a colorless crystal (58.5 mg, 0.138 mmol, 18%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:26][NH:27][CH3:28]>O>[CH3:26][N:27]([CH2:20][C:11]1[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)[CH:10]=1)[CH3:28]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Reactant: CNC
Solvent: O
Product: Cc1ccc(-c2cc(CN(C)C)c(=O)n(CC(C)C)n2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To 6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one (100 mg, 0.27 mmol) was added a 40% aqueous dimethylamine (1 mL), and the mixture was stirred at 80° C. for 2 hours. The temperature of the reaction mixture was allowed to drop back to room temperature, and then, water was added. The mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel [chloroform/methanol (40/1)] to yield the title compound as a yellow oil (69.7 mg, 80.9%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9](I)([CH3:11])[CH3:10]>>[CH:9]([S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([CH3:11])[CH3:10]
Reactant: Oc1ccccc1S
Reactant: CC(C)I
Product: CC(C)Sc1ccccc1O
Yield: 51 %

Procedure:
This compound was prepared in 51% yield from 2-mercaptophenol and isopropyl iodide according to the procedure for 1p in Example VIII. Colorless Oil; 1H NMR (CDCl3): δ 1.25 (d, J=6.85 Hz, 6H), 3.09 (s-7, J=6.66 Hz, 1H), 6.85 (s, 1H), 6.87 (dd, J=1.10 Hz, J=7.45 Hz, 1H), 6.99 (dd, J=1.10 Hz, J=7.95 Hz, 1H), 7.27 (dd, J=1.65 Hz, J=7.95 Hz, 1H), 7.44 (dd, J=1.65 Hz, J=7.70 Hz, 1H);); 13C NMR (CDCl3): δ 23.36, 40.66, 114.71, 118.02, 120.61, 131.44, 137.00, 157.56; HRMS (FAB): 169.06872 calcd for C9H12OS [M+1]+. found 169.06956 (3.1 ppm, 0.5 mmu).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:25]([CH:22]3[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20][CH2:21]3)=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NCc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.3 %

Procedure:
To a solution of 1-(1H-indazol-5-yl)methanamine (291 mg) in N,N-dimethylformamide (8 ml) were added 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (507 mg, 2.21 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (578 mg, 3.02 mmol) and hydroxybenzotriazole (229 mg, 2.21 mmol), and the resulting mixture was stirred at room temperature for 14 hours. Subsequently, a saturated aqueous sodium hydrogencarbonate solution and then water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=40/1). To a solution of the resulting solid in a mixture of methanol (1 ml) and tetrahydrofuran (1 ml) was added a 2N-aqueous lithium hydroxide solution (0.68 ml), and the resulting mixture was stirred at room temperature for 30 minutes. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=30/1) to obtain tert-butyl 4{[(1H-indazol-5-ylmethyl)amino]carbonyl}-1-piperidinecarboxylate (179 mg).
Reaction SMILES: I[CH2:2][C@:3]1([O:14][CH2:13][C@@H:10]([O:11][CH3:12])[C@@H:7]([O:8][CH3:9])[C@@:5]1([C:15]([CH3:17])=[CH2:16])[OH:6])[OH:4]>O1CCOCC1.[Ag-]=O>[C:15]([C@:5]1([OH:6])[C@:3]2([O:4][CH2:2]2)[O:14][CH2:13][C@@H:10]([O:11][CH3:12])[C@H:7]1[O:8][CH3:9])([CH3:17])=[CH2:16]
Reactant: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC)CO[C@]1(O)CI
Agent: O=[Ag-]
Solvent: C1COCCO1
Product: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC)CO[C@]12CO2
Yield: 95.9 %

Procedure:
2.20 g (9.49 mmol) of silver(I) oxide are added in portions, over a period of 48 hours, to a solution of the compound obtained in Example 31 (0.52 g; 1.45 mmol) in 5 ml of dioxane. The reaction mixture is then filtered and the filtrate is evaporated to give 0.32 g (1.39 mmol) of the desired product in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N+:14]([O-:16])=[O:15])=[C:7]([C:11]([OH:13])=O)[NH:8]2)=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N+:14]([O-:16])=[O:15])=[C:7]([C:11]([N:19]([O:20][CH3:21])[CH3:18])=[O:13])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1[nH]c2cc(Cl)ccc2c1[N+](=O)[O-]
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON(C)C(=O)c1[nH]c2cc(Cl)ccc2c1[N+](=O)[O-]
Reaction time: 4 h
Yield: 55.9 %

Procedure:
To a mixture of 6-chloro-3-nitroindole-2-carboxylic acid (step 1, 2.35 g, 9.77 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.81 g, 39.1 mmol) in DMF (50 ml) was added dropwise a dimethylformamide (15 ml) solution of WSC (5.61 g, 29.3 mmol) over 10 min. After stirring for 4 h the mixture was diluted with diethyl ether (200 ml) and washed with water (100 ml×4). The organic extract was dried (MgSO4) and solvent removed by evaporation. The crude product was recystallized from ethyl acetate to afford 1.55 g (56%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([NH2:16])=[N:14][CH:15]=1)=[O:8].C(N(CC)CC)C.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>C(Cl)(Cl)Cl>[NH2:16][C:13]1[N:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([NH:1][S:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:38])[F:39])[CH:29]=3)(=[O:36])=[O:35])[CH:3]=[CH:4][C:5]=2[CH3:18])=[CH:15][N:14]=1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cnc(N)nc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cnc(N)nc1
Temperature: 25 °C

Procedure:
To a solution of 5-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 28 (85 mg, 0.349 mmol) in CHCl3 (2 mL) was added triethylamine (0.453 mmol) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.064 mL, 0.401 mmol). The reaction mixture was heated to reflux for 12 h, cooled to rt and concentrated in vacuo. The crude residue was adsorbed on SiO2 and purified by flash chromatography (CH2Cl2/MeOH 99:1) on SiO2 to afford N-(2-aminopyrimidin-5-yl)-2-methyl-5-(3-(trifluoromethyl)phenylsulfonamido)benzamide 29. MS m/z found 452 [MH+]; calc. for C19H16F3N5O3S=451.09.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.P(Cl)(Cl)(Cl)=O.[CH3:18][S:19](C)=O>Cl(O)(=O)(=O)=O>[CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[C:8]([S:19][CH3:18])[CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: CS(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1cc(O)c2c(c1)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a mixture of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (16.4 g), 20 ml of 70% perchloric acid and 16 ml of phosphorus oxychloride, dimethyl sulfoxide (7.8 g, 0.1 mol) was gradually added at a temperature of not higher than 5° C. The reaction solution was stirred at room temperature for further one hour, then poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, concentrated and then heated and refluxed, together with 200 ml of pyridine, for 4 hours. Pyridine was concentrated under reduced pressure, and the residue was washed with ether. The ether layer was washed with 1N hydrocloric acid and water successibly, then dried over anhydrous sodium sulfate and concentrated. The solid substance thereby obtained was recrystallized from ether-hexane, whereby 9.7 g of 2,3-dihydro-2,2-dimethyl-5-methylthio-7-benzofuranol was obtained. The melting of this product was 57°-59° C. The structure was confirmed by 1H-NMR spectrum and IR spectrum. Then, this phenol derivative was reacted with O-ethyl-ethylthionophosphonic acid chloride in the same manner as in Example 1, whereby the compound (No. 49) identified in Table 1 was obtained.