Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C:5]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:25]([O:29][C:30]([N:32]1[CH:37]2[CH2:38][CH2:39][CH:33]1[CH2:34][N:35]([C:40]([C:42]1[CH:43]=[N:44][C:45]([NH2:48])=[CH:46][CH:47]=1)=[O:41])[CH2:36]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH:33]2[CH2:39][CH2:38][CH:37]1[CH2:36][N:35]([C:40]([C:42]1[CH:43]=[N:44][C:45]([NH:48][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:24])[CH3:1])[N:14]([CH:15]5[CH2:20][CH2:19][N:18]([CH:21]6[CH2:23][CH2:22]6)[CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:46][CH:47]=1)=[O:41])[CH2:34]2)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCN(C2CC2)CC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCN(C2CC2)CC1
Yield: 74.5 %

Procedure:
Using General Buchwald method 1, 2-Chloro-7-(1-cyclopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (95 mg, 0.273 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.300 mmol, 1.1 eq) to give 3-{6-[7-(1-Cyclopropyl-piperidin-4-yl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (131 mg, 71% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.46 (br. s., 2H) 0.54 (br. s., 2H) 1.52 (s, 10H) 1.61 (br. s., 2H) 1.71 (br. s., 2H) 1.88 (d, J=10.11 Hz, 3H) 1.96 (d, J=6.06 Hz, 2H) 2.37 (t, J=11.62 Hz, 2H) 2.79-3.01 (m, 2H) 3.20 (s, 10H) 3.63 (br. s., 2H) 4.27 (br. s., 2H) 4.41 (br. s., 2H) 6.50 (s, 1H) 7.69 (br. s., 1H) 8.22 (s, 1H) 8.41 (s, 1H) 8.63 (d, J=8.59 Hz, 1H) 8.77 (s, 1H); MS m/z 644.6 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:32]>>[ClH:32].[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2ccc(OC3CCNCC3)cc2=O)cc1
Reaction time: 0.33 h

Procedure:
A mixture of tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (5.279 g, 11.77 mmol) and hydrogen chloride (37% in H2O, 40 mL, EMD) was stirred for 20 min and then concentrated in vacuo. The obtained solid was dissolved in methanol (80 mL) and diethyl ether (300 mL) was added. The resulting solid was filtered to give 4.52 g of the desired product as an off-white solid. MS (ESI) 349 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:46])(=[O:45])[CH2:41][C:42]([OH:44])=[O:43]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:46])(=[O:45])[CH2:41][C:42]([O-:44])=[O:43]
Reactant: O=C(O)CC(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: O=C([O-])CC(=O)[O-]
Temperature: 68 °C
Reaction time: 5 h

Procedure:
Nilotinib base Form A (3.00 g, 5.67 mmol) was dissolved in TFE (29 mL, 9.7V) at room temperature with stirring. Separately, malonic acid (0.62 g, 5.95 mmol, 1.05 mol eq), was mixed with TFE (3 mL) and heated to 68° C. to afford dissolution. The malonic acid solution was added to the solution of Nilotinib base in TFE at 68° C. and stirring was continued at the same temperature for 5 h. The heating source was removed and the mixture was allowed to cool to ambient temperature over a period of 30 min. Then, the mixture was transferred to the refrigerator and kept at 5° C. for 16 h. Methyl tert-butyl ether (“MTBE”) (30 mL) was then added and the resulting mixture was stirred at room temperature for about 20 min leading to the formation of a white precipitate. The precipitate was filtered and dried overnight in a vacuum oven (60° C.) to give Nilotinib malonate form I.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=[C:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1.[CH3:32][C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][N:8]1[C:7]([CH:12]=[C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:34]1[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=[C:33]1[CH3:32])=[N:3][C:4]=2[N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: Cn1c(C=C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Temperature: 140 °C
Yield: 85.8 %

Procedure:
A mixture of tert-butyl 4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methylene)piperidine-1-carboxylate (0.375 g, 0.835 mmol), 2-methylbenzimidazole (0.132 g, 1.0 mmol), Xphos (0.040 g, 0.084 mmol), Pd2(dba)3 (0.040 g, 0.042 mmol) and cesium carbonate (0.54 g, 1.67 mmol) in DMF (3 5 mL) was heated in a Biotage microwave at 140° C. for 30 minutes. The reaction mixture was then filtered through paper and then partitioned between brine and EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (0-10% MeOH in DCM) to give the title compound (0.39 g, 87%). LCMS m/z: 545.3 (MH+).
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:47][O:48][C:49]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[C:52]([O:58][CH3:59])[C:50]=1[NH2:51].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH:51][C:50]2[C:52]([O:58][CH3:59])=[CH:53][C:54]([O:56][CH3:57])=[CH:55][C:49]=2[O:48][CH3:47])=[O:21])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn(C(C(=O)O)c2ccccc2)n1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of (±)-5-dodecyl-α-phenyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-trimethoxyaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 141°-145° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[O:6][C:7]([C:10](=O)[CH2:11]Br)=[CH:8][CH:9]=1)=[O:4].[C:15]([NH:18][C:19]([NH2:21])=[S:20])(=[NH:17])[NH2:16].[OH-].[Na+]>CC(C)=O>[NH:18]([C:19]1[S:20][CH:11]=[C:10]([C:7]2[O:6][C:5]([C:3](=[O:4])[N:2]([CH3:14])[CH3:1])=[CH:9][CH:8]=2)[N:21]=1)[C:15]([NH2:17])=[NH:16]
Reactant: N=C(N)NC(N)=S
Reactant: CN(C)C(=O)c1ccc(C(=O)CBr)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(C)C(=O)c1ccc(-c2csc(NC(=N)N)n2)o1
Reaction time: 72 h
Yield: 17.9 %

Procedure:
A mixture of 2.6 g. (0.01 mole) of N,N-dimethyl5-(2-bromoacetyl)furan-2-carboxamide, 1.18 g. (0.01 mole) of guanylthiourea and 100 ml. of acetone was stirred at room temperature for 4 hours. An additional 354 mg. of guanylthiourea was added and stirring was continued for 3 days. The reaction mixture was filtered, and the residue was washed with acetone and then dissolved in water. The solution thus obtained was made alkaline using 10% sodium hydroxide solution and extracted with ethyl acetate. The extracts were dried (MgSO4) and concentrated in vacuo to give a first crop of the title compound (500 mg.). The aqueous phase from the extraction was further basified (to pH 14) and extracted with n-butanol. Evaporation of the n-butanol gave a second crop of the title compound (900 mg.). The two crops of the title compound were combined and recrystallized from aqueous ethanol, giving 550 mg. of a brown solid, mp. 252°-253.5° C. (dec). Two additional samples of the title compound were obtained from the recrystallization mother liquors: 190 mg. mp 249°-252° C.; 91 mg., mp 248°-251° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([NH:32][CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=[N:8][C:9]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=3[N:20]=[C:19]2[CH:29]([F:31])[F:30])=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CC(O)=O.O.O>[F:31][CH:29]([F:30])[C:19]1[N:18]([C:9]2[N:10]=[C:11]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:6]3[N:5]=[N:1][N:32]([CH:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)[C:7]=3[N:8]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=2[N:20]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c(N2CCOCC2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2nnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Aqueous NaNO2 solution (0.5 M, 1.7 mL) was added dropwise to a stirred suspension of tert-butyl 4-{[5-amino-2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]amino}-1-piperidinecarboxylate (Example 96) (250 mg, 0.435 mmol) in HOAc/H2O (2:1, 12 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 hrs and then diluted with H2O. The resulting precipitate was collected by filtration, washed sequentially with H2O and aqueous NH3, and dried to give tert-butyl 4-[5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-7-(4-morpholinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-1-piperidinecarboxylate (192 mg, 75%): mp (CH2Cl2/hexanes) 220-222° C.; 1H NMR (CDCl3) δ 7.81 (dd, J=8.4, 0.6 Hz, 1H), 7.42 (t, JHF=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.71 Hz, 1H), 4.92 (tt, J=11.3, 4.1 Hz, 1H), 4.79 (br s, 2H), 4.33 (m, 2H), 4.15 (br s, 2H), 3.92 (dd, J=13.4, 3.0 Hz, 4H), 3.05 (t, J=12.0 Hz, 2H), 2.40 (dq, J=12.0, 4.4 Hz, 2H), 2.18 (dd, J=12.9, 2.5 Hz, 2H), 1.50 (s, 9H); Anal. Calcd. for C27H33F2N9O4: C, 55.4; H, 5.7; N, 21.5. Found: C, 55.5; H, 5.7; N, 21.3%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(N3CCOCC3)cc21
Product: CC1c2cc(N3CCOCC3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Na].Cl.[CH3:3][O:4][CH2:5][C:6]([NH2:8])=[NH:7].[CH:9]([CH:11]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12](OCC)=O)=[O:10]>C(O)C>[CH3:3][O:4][CH2:5][C:6]1[N:8]=[C:9]([OH:10])[C:11]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:7]=1
Reactant: CCOC(=O)CC(C=O)C(=O)OCC
Reactant: COCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cc1cnc(COC)nc1O
Temperature: 25 °C
Yield: 43 %

Procedure:
Sodium metal (0.754 mol) was dissolved in absolute ethanol (100 ml) and the resulting solution was added dropwise to a solution of methoxyacetamidine hydrochloride (0.703 mol) in ethanol (100 ml). After 15 minutes the reaction mixture was filtered and the filtrate was added to a solution of diethyl formylsuccinate (0.703 mol), which was prepared according to H. Nakao et al. Ann. Sankyo Res. Lab., 18, 33-37 (1966). The reaction was refluxed for 15 hours, cooled to room temperature and was then concentrated to obtain a crude solid. This solid was crystallized from isopropanol to obtain the title compound (43% yield), m.p. 142°-143° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(F)cc1
Yield: 90 %

Procedure:
A mixture of 3-[5-(4-fluorophenyl)-4-isoxazolyl]propionic acid (3.68 g), conc. sulfuric acid (0.05 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-fluorophenyl)-4-isoxazolyl]propionate (3.50 g, yield 90%) was obtained as a pale yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). NMR (CDCl3) δ: 2.65 (2H, t, J=7.4 Hz), 2.98 (2H, t, J=7.4 Hz), 3.69 (3H, s), 7.12–7.28 (2H, m), 7.64–7.78 (2H, m), 8.22 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].C(B(CC)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:7]=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2]
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCB(CC)c1cccnc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 73.7 %

Procedure:
2-Nitro-4-bromotoluene (8.74 g, 40.46 mmol) was dissolved in 75 mL dioxane and 25 mL water to which was added diethyl-(3-pyridyl)borane (5.95 g, 40.46 mmol), sodium carbonate (8.58 g, 80.91 mmol) and tetrakis(triphenylphosphine palladium(0) (0.94 g, 0.81 mmol). The mixture was heated at reflux for 18 h then cooled to ambient temperature. The mixture was diluted with 600 mL water and extracted with diethyl ether (2×300 mL). The organic phases were combined and extracted with 0.3 N HCl (3×200 mL). The acidic extractions were combined and made basic with 5N aqueous sodium hydroxide. This basic layer was extracted with diethyl ether (2×300 mL) and the extracts were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 6.39 g (74%) of 2-nitro-4-(3-pyridyl)toluene as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[N:36][CH:37]=2)O1>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:32]5[CH:37]=[N:36][C:35]([N:38]6[CH2:39][CH2:40][O:41][CH2:42][CH2:43]6)=[CH:34][CH:33]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc(N4CCOCC4)nc3)cc1-2
Yield: 58 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine were reacted to give 325 (0.106 g, 58%). 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J=2.1, 1H), 8.49 (d, J=1.8, 1H), 7.93 (s, 1H), 7.76 (dd, J=8.7, 2.4, 1H), 7.42 (dd, J=8.4, 2.2, 1H), 7.14 (d, J=8.3, 1H), 6.73 (d, J=8.8, 1H), 5.88 (dt, J=13.3, 6.6, 1H), 4.45 (t, J=5.0, 2H), 3.95-3.76 (m, 4H), 3.68-3.52 (m, 4H), 3.45 (t, J=5.0, 2H), 1.65 (d, J=6.6, 6H). MS (ESI(+)): m/z 475.2 (M+H)
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:30]=1[CH:31]=[CH:32][C:33](O)=[O:34]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:33](=[O:34])[CH:32]=[CH:31][C:30]1[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:29]=1[O:28][CH3:27])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Product: COc1ccc(OC)c(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 69 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 2,5-dimethoxycinnamic acid under the conditions described in example 86 to yield 69% of the desired product.
Reaction SMILES: [C:1](=O)([O:43]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32]([O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)=[O:33])[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][CH:4]=1.[CH3:54][NH:55][CH3:56].O1CCCC1.C(OCC)(=O)C>O1CCCC1>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][C@@H:11]([OH:30])[C@@H:10]([NH:31][C:32](=[O:33])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][C:1]([N:55]([CH3:56])[CH3:54])=[O:43])=[CH:4][CH:5]=3)(=[O:20])=[O:19])=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)N(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenyl 4-nitrophenyl carbonate (60 mg) in tetrahydrofuran (0.5 mL) was added 2M dimethylamine/tetrahydrofuran (0.5 mL) and the mixture was stirred at ambient temperature for 30 min. Ethyl acetate was added and the mixture was washed with saturated sodium bicarbonate/water (4×), dried (sodium sulfate), evaporated, and purified by chromatography (silica gel, hexanes/ethyl acetate, 3:7) to provide the title compound as a solid foam. 1H NMR (DMSO-d6): δ 0.76 (3H, d), 0.82 (3H, d), 1.1-1.2 (1H, m), 1.2 (1H, br quintuplet), 1.9-2.0 (1H, m), 2.2 (1H, t), 2.6-2.8 (3H, m), 2.81 (3H, s), 2.9 (3H, s), 3.0 (1H, br s), 3.2-3.3 (2H, m), 3.4-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dt), 5.0 (1H, br s), 5.5 (1H, d), 6.1 (2H, s), 6.9 (2H, d), 7.0 (1H, d), 7.15 (2H, d), 7.19 (1H, s), 7.22 (2H, br d); MS: 664 (MH+); C31H41N3O11S.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21]([S:24]([C:27]3[C:28]4[C:29]([Cl:37])=[CH:30][N:31]=[CH:32][C:33]=4[CH:34]=[CH:35][CH:36]=3)(=[O:26])=[O:25])[CH2:20]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OC(N1CCN(CCC(O)=O)CC1)=O)(C)(C)C.COCC(O)=O>>[N:11]1([CH2:14][CH2:15][C:16]([NH:18][C@@H:19]2[CH2:23][CH2:22][N:21]([S:24]([C:27]3[C:28]4[C:29]([Cl:37])=[CH:30][N:31]=[CH:32][C:33]=4[CH:34]=[CH:35][CH:36]=3)(=[O:26])=[O:25])[CH2:20]2)=[O:17])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCC(=O)N[C@H]2CCN(S(=O)(=O)c3cccc4cncc(Cl)c34)C2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(CCC(=O)O)CC1
Agent: COCC(=O)O
Agent: Cl
Product: O=C(CCN1CCNCC1)N[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1

Procedure:
(S)-3-[3-[1-(tert-Butoxycarbonyl)piperazin-4-yl]propionyl]amino-1-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine can be prepared from hydrochloride of the compound prepared in Example 19-2 by using 3-[1-(tert-butoxycarbonyl)piperazin-4-yl]propionic acid in the method of Example 56-1 instead of 2-methoxyacetic acid, and the protective group of the obtained compound can be removed according to the method described in Example 1-1, Step B to obtain the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:48])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=4[O:30][C@H:31]([CH2:33][CH:34]=[CH2:35])[CH3:32])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:36])[C:12]=2[C@H:37]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:7][CH2:6]1)C=C>ClCCCl.C1(C)C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru](Cl)(Cl)=CC1C=CC=CC=1OC(C)C.[Cu]I>[C:44]([O:43][C@@H:37]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:48])([O:4][CH2:1][CH:35]=[CH:34][CH2:33][C@H:31]([CH3:32])[O:30][C:24]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=2[CH2:22][O:21][CH2:20]3)[CH2:6][CH2:7]1)[C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH3:46])([CH3:47])[CH3:45]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4cc(F)ccc4O[C@@H](C)CC=C)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Cu]I
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1ccc(F)cc1COC3
Solvent: ClCCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1ccc(F)cc1COC3
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((5-fluoro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.1481 g, 0.222 mmol) in DCE (500 mL) were added (1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI) chloride (0.035 g, 0.056 mmol) and copper(I) iodide (0.042 g, 0.222 mmol) and the resulting solution was stirred at 90° C. for 3 h. The mixture was cooled to rt and concentrated. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give ethyl (2S)-2-(tert-butoxy)-2-[(20S,22Z)-15-fluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16,22-octaen-3-yl]acetate: (0.0461 g, 0.072 mmol, 32.5% yield) as a pale brown foam. LCMS (M+H) calcd for C35H48FN4O6: 639.35. found: 639.5.