Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5](=[O:8])[N:6]([CH3:13])[CH:7]=1.[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([O:8][CH3:13])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NS(=O)(=O)c1cc(Br)cnc1O
Solvent: CO
Solvent: ClCCl
Product: COc1ncc(Br)cc1S(N)(=O)=O
Product: Cn1cc(Br)cc(S(N)(=O)=O)c1=O
Yield: 34 %
Yield: 53 %

Procedure:
To a solution of 5-bromo-2-hydroxypyridine-3-sulfonamide (0.5 g, 1.9 mmol) in MeOH/DCM (15 mL, 1:1) at −10° C. was added trimethylsilyldiazomethane solution (2 M, 1.97 mL, 3.9 mmol). Upon completion of addition, the reaction mixture was concentrated and the resulting residue was purified by column chromatography using methanol and CHCl3 to 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-sulfonamide yield 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-sulfonamide (280 mg, 53% yield) and 5-bromo-2-methoxypyridine-3-sulfonamide (180 mg, 34% yield). Data for 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-sulfonamide: 1H NMR (400 MHz, DMSO-d6, δ): 8.42 (d, 1H, J=2.8 Hz); 7.99 (d, 1H, J=2.8 Hz); 7.14 (s, 1H); 3.52 (s, 3H). Data for 5-bromo-2-methoxypyridine-3-sulfonamide: 1H NMR (400 MHz, DMSO-d6, δ): 8.54 (d, 1H, J=2.4 Hz); 8.17 (d, 1H, J=2.4 Hz); 7.51 (s, 1H); 4.00 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](C3CCOCC=3)[CH:17]=2)[C:12]([C:28]([NH2:30])=[O:29])=[CH:11][N:10]=1.[CH3:31][OH:32]>[Pd]>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:2]3[CH2:3][CH2:4][O:32][CH2:31][CH2:7]3)=[CH:20][CH:21]=2)[C:12]([C:28]([NH2:30])=[O:29])=[CH:11][N:10]=1
Reactant: CO
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(C2=CCOCC2)c1
Agent: [Pd]
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(C2CCOCC2)cc1

Procedure:
The title compound was prepared from Example 175 using standard catalysis hydrogenation by treating the solution of Example 175 in methanol with 10% Pd/C under H2 balloon for overnight. MS found for C22H30N6O2 as (M+H)+ 411.4. UV λ=243, 296 nm.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1cncnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cncnc1-c1ccc(F)cc1
Temperature: 100 °C
Yield: 58 %

Procedure:
A mixture of 4-chloropyrimidine-5-carbonitrile (1.0 equiv.), (4-fluorophenyl)boronic acid (1.2 equiv.), 1,1′-bis(diphenylphosphino ferrocene-palladium(ii)dichloride dichloromethane complex (10 mol %) and potassium carbonate (3.0 equiv.) in dioxane/water 3:1 (0.5 M) was purged with nitrogen for 3 min. The pressure reaction vessel was tightly capped and heated at 100° C. for 5 h. Ethyl acetate and water were added and layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give a brown, sticky oil, which was purified by silica gel column chromatography (0-30% ethyl acetate in hexane, 100 g column) to give the title compound (58% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ (ppm) 9.39 (s, 1H), 9.06 (s, 1H), 8.23-8.17 (m, 2H), 7.31-7.27 (m, 2H). MS (ESI) m/z 200.2 [M+1]+.
Reaction SMILES: O[N:2]=[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[ClH:15].O>CO.[Pd]>[ClH:15].[NH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4]
Reactant: COC(=O)c1ccc(C(C)=NO)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(C)N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a degassed solution of methyl 4-(1-(hydroxyimino)ethyl)benzoate (1.1 g, 5.6 mmol) and 12.0 M of hydrochloric acid in water (0.6 mL, 7.3 mmol) in methanol (50 mL) was added 10% palladium on carbon (0.20 g, 0.18 mmol). The reaction mixture was stirred overnight at room temperature. All insolubles were removed via filtration through celite and subsequent evaporation of the filtrate to dryness afforded the title compound as a white solid (1.12 g, 83%). LC-MS: (FA) ES+ 180; 1H NMR (400 MHz, MeO D) δ 8.09 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 4.55 (q, J=6.8 Hz, 1H), 3.91 (s, 3H), 1.65 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][C@H:4]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:28])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH3:39][I:40]>>[I-:40].[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C@@H:4]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:28])=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH2:3][N+:2]([CH3:39])([CH3:1])[CH3:38])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCCCCCCOC(=O)Nc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1
Reactant: CI
Product: CCCCCCCCOC(=O)Nc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)C[N+](C)(C)C)cc1
Product: [I-]

Procedure:
According to the method described in example S72b, (R)-benzyl 4-(dimethylamino)-3-(4-(octyloxycarbonylamino)phenylsulfonamido)butanoate was reacted with methyl iodide to give the title compound as a white solid in quantitative yield. MS ESI 563.3 [M]+, calcd for [C29H44N3O6S+] 562.74
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[OH:20])[C:5]([NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[N:13][NH:14]2)=[CH:10][CH:9]=1)=[O:6].[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])=[C:22]=S.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([NH:7][C:5]([C:4]3[CH:17]=[CH:18][C:19]4[O:20][C:22]([NH:21][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:31])([F:32])[F:33])=[N:1][C:2]=4[CH:3]=3)=[O:6])[CH:16]=2)[CH:12]=[N:13]1
Reactant: FC(F)(F)c1ccccc1N=C=S
Reactant: Nc1cc(C(=O)Nc2ccc3cn[nH]c3c2)ccc1O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2cn[nH]c2c1)c1ccc2oc(Nc3ccccc3C(F)(F)F)nc2c1
Temperature: 25 °C

Procedure:
A solution of the aminophenol (0.5 mmol) from above in DMF (2 mL) was added with 1-isothiocyanato-2-trifluoromethylbenzene (0.6 mmol) and DIEA (1 mmol). The reaction mixture was subjected to microwave irradiation at 120° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo. The crude product was purified on a silica gel column chromatography using MeOH/DCM as eluent to provide 2-(2-trifluoromethylphenylamino)-benzooxazole-5-carboxylic acid (1H-indazol-6-yl)-amide, obtained as a yellow solid. MS: m/z 438 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[C:28]([O:42][CH3:43])=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:42][CH3:43])=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCOc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1OC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-ethoxy-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 92.1.1) to give the title compound as a white solid. (HPLC: tR 2.63 min (Method A); M+H=445 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.11-8.07 (m, 2H), 7.98-7.94 (m, 1H), 7.92-7.90 (m, 1H), 7.54-7.53 (m, 1H), 7.22-7.21 (m, 1H), 4.16-4.09 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H), 1.41 (t, 3H))
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)cnc1N
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: Cc1ccccc1
Product: Cc1cc(-c2ccc(N(C)C)cc2)cnc1N
Temperature: 25 °C

Procedure:
A solution of 5-bromo-3-methylpyridin-2-amine (120a, 1.87 g, 10.0 mmol) in toluene (60 mL) was treated with 4-(dimethylamino)phenylboronic acid (2.48 g, 15.0 mmol), Pd(PPh3)4 (345 mg, 0.30 mmol), and 2M Na2CO3(aq) (10 mL). The reaction mixture was heated to reflux for 18 hours and then cooled to room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 5-(4-(dimethylamino)phenyl)-3-methylpyridin-2-amine (120b).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[N:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[N:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1Cl
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(Cl)cc3NC(=O)OC(C)(C)C)c2)n1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-methyl-phenyl)-carbamic acid tert-butyl ester (Example J21) (257 mg, 1.0 mmol) and 3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K16) (312 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (400 mg, 81%).
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=2)[N:8]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[O:19])[C:7](=[O:27])[NH:6][C:5]=1[CH3:28])(=[O:3])C.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([NH2:48])[CH:43]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].Cl.CN(C)CCCN=C=NCC.C(Cl)Cl.CN([CH:67]=[O:68])C>CN(C)C1C=CN=CC=1.O>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([NH:48][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][NH:20][C:18]([N:8]3[CH:9]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=4)[C:4]([C:1]([O:68][CH3:67])=[O:3])=[C:5]([CH3:28])[NH:6][C:7]3=[O:27])=[O:19])[CH:43]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Reactant: CC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)O)C1c1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)Nc2cccc(C3CCN(C(=O)OC(C)(C)C)CC3)c2)C1c1ccc(F)c(F)c1
Reaction time: 12 h
Yield: 67.8 %

Procedure:
A 50-mL RB-flask was charged with 4-{[(5-acetyl-6-(3,4-difluorophenyl)-4-methyl-2-oxo-3,6-dihydro-1(2H)-pyrimidinyl)carbonyl]amino}butanoic acid (313 mg, 0.854 mmol), tert-butyl-4-[3-(amino)phenyl]-1-piperidinecarboxylate (235 mg, 0.857 mmol), 1-[3-(Dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (7.71 mmol, 265 mg), 4-dimethylaminopyridine (10.4 mg, 0.0854 mmol) in DMF:DCM (0.8:8.0 mL) at room temperature. The reaction mixture was stirred for 12 h and water (20.0 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with CHCl3 (3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed (silica, hexanes:EtOAc 9:1) to afford the desired product (378 mg, 67.8%): 1H NMR (400 MHz, CDCl3) δ 8.03 (m, 2H), 7.57 (s, 1H), 7.36-7.28 (m, 3H), 7.27-7.22 (m, 1H), 6.97-6.89 (m, 3H), 6.72 (s, 1H), 3.72 (s, 3H), 3.47-3.37 (m, 2H), 2.42 (s, 3H), 2.37-2.29 (m, 2H), 1.98-1.91 (m, 2H), 1.86-1.75 (m, 2H), 1.72-1.54 (m, 7H), 1.48 (s, 9H); ESMS m/e: 554.3 (M−100).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([NH2:11])[CH:9]=C.C=O>>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:9]=[CH:8][NH:11]1
Reactant: Oc1ccccc1
Reactant: C=CCN
Agent: C=O
Product: C1=Cc2ccccc2ON1
Yield: 82.1 %

Procedure:
At room temperature, phenol, allyl amine and paraformaldehyde were added according to the molar ratio of phenolic hydroxyl group:amine group:aldehyde group of 1:1:2. After being homogeneously stirred, the mixture was heated to a molten state, reacted for 4 h and placed in a cooling unit to obtain a yellowish, translucent viscous body. The viscous body was washed, purified and dried to obtain a benzoxazine intermediate having the following structural formula, wherein the yield is 82.1%.
Reaction SMILES: [CH2:1]([NH2:3])C.[Li]CCCC.[C:9]([Si:13]([CH2:18][CH3:19])(OC)OC)([CH3:12])([CH3:11])[CH3:10].[CH3:20][NH2:21]>CCCCCC.C1COCC1>[CH3:20][NH:21][Si:13]([NH:3][CH3:1])([C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:18][CH3:19]
Reactant: CN
Reactant: CCN
Reactant: CC[Si](OC)(OC)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[Si](NC)(NC)C(C)(C)C
Temperature: -10 °C

Procedure:
A three-necked flask in which the internal atmosphere was sufficiently replaced with nitrogen gas was charged with 60 ml of a THF solution containing 0.04 mol of ethylamine in a nitrogen stream. 30 ml of a hexane solution containing 0.04 mol of BuLi was slowly added to the ethylamine solution cooled to −10° C. using a dripping funnel. After the addition, the mixture was gradually heated and reacted at 50° C. for two hours. Another container of which the internal atmosphere was purged with nitrogen was charged with 60 ml of a toluene solution containing 0.02 mol of t-butylethyldimethoxysilane and cooled to −10° C. The above slurry of Li salt of methylamine was slowly added dropwise to the cooled solution under nitrogen seal. After the addition, the mixture was reacted at 50° C. for three hours. The reaction mixture was separated into a solid and a solution by centrifugation. The solid was washed with 20 ml of toluene and added to the solution. The solvent was evaporated from the solution under reduced pressure and the residue was distilled under reduced pressure to obtain bis(methylamino)-t-butylethylsilane. The elementary analysis confirmed that the compound consists of C: 55.01% (55.11%), H: 12.57% (12.72%), and N: 16.25% (16.07%), wherein the percentages of the parentheses are theoretical values.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C:6]([C:10](=O)[CH3:11])=[C:7]([CH3:9])[N:8]=1)[CH3:2].Cl[CH:14](C(=O)C)C(=O)C.[N+]([O-])(O)=O.[N+:25]([C:28]1[CH:29]=[C:30]([NH:34][C:35]([NH2:37])=[NH:36])[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[CH2:1]([NH:3][C:4]1[S:5][C:6]([C:10]2[CH:11]=[CH:14][N:37]=[C:35]([NH:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=3)[N:36]=2)=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCNc1nc(C)c(C(C)=O)s1
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Solvent: O=[N+]([O-])O
Product: CCNc1nc(C)c(-c2ccnc(Nc3cccc([N+](=O)[O-])c3)n2)s1

Procedure:
3-Dimethylamino-1-(2-ethylamino-4-methyl-thiazol-5-yl)-propenone was prepared by reaction between 1-(2-ethylamino-4-methyl-thiazol-5-yl)-ethanone and 3-chloro-pentane-2,4-dione. It was then condensed with N-(3-nitro-phenyl)-guanidine nitrate in the usual manner to afford the title compound. Yellow solid; 1H-NMR (DMSO-d6) δ: 1.14 (m, 3H, CH3), 2.47 (s, 3H, CH3), 3.23 (m, 2H, CH2), 6.99 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 7.55 (m, 1H, Ph-H), 7.77 (m, 1H, Ph-H), 8.02 (m, 1H, Ph-H), 8.39 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 8.47 (s, 1H, Ph-H), 9.98 (br. s, 1H, NH).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.[C:34](O)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[N:38]1[CH:39]=[CH:40][C:35]([C:34]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]3[O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:5][CH:4]=2)=[O:41])=[CH:36][CH:37]=1
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(=O)c3ccncc3)cc2)C(OCc2ccc3ccccc3c2)C1
Yield: 20.9 %

Procedure:
A solution of 60 mg (0.13 mmol) of tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, 16 mg (0.13 mmol) of isonicotinic acid, 34 mg (0.26 mmol) of ethyldiisopropylamine and 58 mg (0.13 mmol) of benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) in 5 ml of acetonitrile was stirred at room temperature for 2 hours. Subsequently, the reaction mixture was evaporated under reduced pressure and the residue, without further working-up, was chromatographed on silica gel using a 3:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 15 mg (21% of theory) of (3RS,4RS)-4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzyl pyridine-4-carboxylate as a colourless solid; MS: 552 (M)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:38][C:39]1[CH:75]=[CH:74][CH:73]=[CH:72][C:40]=1[CH2:41][NH:42][C:43]([C@@H:45]1[C:49]([CH3:51])([CH3:50])[S:48][CH2:47][N:46]1[C:52](=[O:71])[C@@H:53]([OH:70])[C@@H:54]([NH:62][C:63](=[O:69])[C@H:64]([CH:66]([CH3:68])[CH3:67])[NH2:65])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:44]>C(OCC)(=O)C>[CH3:38][C:39]1[CH:75]=[CH:74][CH:73]=[CH:72][C:40]=1[CH2:41][NH:42][C:43]([C@@H:45]1[C:49]([CH3:51])([CH3:50])[S:48][CH2:47][N:46]1[C:52](=[O:71])[C@@H:53]([OH:70])[C@@H:54]([NH:62][C:63](=[O:69])[C@H:64]([CH:66]([CH3:68])[CH3:67])[NH:65][C:13](=[O:15])[CH2:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2)[CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:44]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Reactant: O=C(O)COc1cccc2cnccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NC(=O)COc2cccc3cnccc23)C(C)C)CSC1(C)C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
5-isoquinolinyloxyacetic acid (64 mg), HOBt (43 mg), and EDC.HCl (60 mg) were added to H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) obtained in the step 2 and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% NaHCO3 and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was reprecipitated from ethyl acetate/n-hexane to obtain the title compound (168 mg).
Reaction SMILES: C[O:2][C:3](=O)[NH:4][C:5]1[NH:6][C:7]2[CH:13]=[C:12]([O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[CH:10][C:8]=2[N:9]=1.[CH3:31][NH:32]C.N12CCCN=C1CCCC[CH2:35]2>CN(C)C=O>[CH:25]1([NH:24][C:21]2[CH:20]=[CH:19][C:18]([S:15]([O:14][C:12]3[CH:11]=[CH:10][C:8]4[NH:9][C:5]([N:4]([CH3:35])[C:3]([NH:32][CH3:31])=[O:2])=[N:6][C:7]=4[CH:13]=3)(=[O:17])=[O:16])=[CH:23][CH:22]=2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CNC
Reactant: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)cc2[nH]1
Solvent: CN(C)C=O
Product: CNC(=O)N(C)c1nc2cc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)ccc2[nH]1
Temperature: 80 °C

Procedure:
Title compound was obtained by reacting 10 mg of methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) with 50 μl dimethylamine (2.0 M in tetrahydrofuran) and 5 μl 1,8-diazabicyclo[5.4.0]undec-7-ene in 2 ml dimethylformamide in a 24 well Inox plate for high pressure reaction. The reaction mixture was put under a 10 Bars argon pressure and then heated to 80° C. for 4 hours, and then cooled at room temperature. Compounds were put in an assay tube and dimethylformamide was evaporated in a JOUAN RC1010 evaporator. Compound was diluted in 0.5 ml dimethylsulfoxide for LC/MS trigged purification yielding 9 mg of the title compound (LC/MS analysis: retention time=3.35 min., mass spectrum: 444.29, [M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[N:15][CH:14]=CN=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC1[S:22]C=NC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:22][CH:14]=[N:15][CH:16]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Brc1cncs1
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Product: Cc1ccc(-c2cncs2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 5-bromothiazole. ESI-MS (m/z): 220 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:28]([CH3:31])([CH3:30])[CH3:29])=[C:8]2[CH2:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36]C)=[O:35])=[CH:4][CH:3]=1.ClC1C=CC(CN2C3C(=CC(OCC4C=CC5C(=CC=CC=5)N=4)=CC=3)C(SC(C)(C)C)=C2CC(C)(C)C(O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:28]([CH3:31])([CH3:29])[CH3:30])=[C:8]2[CH2:32][C:33]([CH3:39])([CH3:38])[C:34]([OH:36])=[O:35])=[CH:40][CH:41]=1
Reactant: COC(=O)C(C)(C)Cc1c(C(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12
Product: CC(C)(Cc1c(C(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared according to the conditions described in Step B of Example 1, but substituting the ester from Step B for the ester of Example 1. The title compound was recrystallized from EtOAc-EtOH; m.p. 201°-202° C. Anal. Calc. C 73.57; H 6.36; N 5.05 Found C 73.75; H 6.37; N 5.03.