Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1N[N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>CC1C=CC=CC=1C>[Br:12][C:13]1[CH:14]=[C:15]([C:16]2[O:17][C:5]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)=[N:4][N:3]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: c1cncc(-c2nn[nH]n2)c1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: Cc1ccccc1C
Product: Brc1cccc(-c2nnc(-c3cccnc3)o2)c1

Procedure:
16.8 g (114 mmol) of 3-(2H-tetrazol-5-yl)pyridine) according to Synthesis Example 7 and 25 g (114 mmol) of 3-bromobenzoylchloride were dissolved in 180 mL of o-xylene. The solution was reacted at 150° C. for 8 hours. The acquired reactant was purified under reduced pressure and washed with methanol, obtaining 30 g (Y=87%) of a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:36])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:36][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:40]([CH:37]2[CH2:39][CH2:38]2)=[O:41])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 31 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide (Intermediate-26, 0.060 g, 0.11 mmol), cyclopropylcarbonyl chloride (0.019 g, 0.17 mmol), DIPEA (1 mL) and THF (5 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.06 (m, 2H), 1.22 (m, 2H), 3.17 (m, 1H), 3.95 (s, 3H), 4.34 (d, J=6.0 Hz, 2H), 7.44-7.84 (m, 8H), 7.95 (d, J=9.0 Hz, 1H), 8.25 (s, 1H), 8.70 (m, 1H), 10.43 (m, 1H), 12.05 (m, 1H); MS (m/z): 584.35 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].Cl.[OH2:16]>>[OH:16][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O
Agent: Cl
Product: COc1cc(C(=O)O)ccc1CO
Temperature: 25 °C
Yield: 35 %

Procedure:
methyl 4-(bromomethyl)-3-(methyloxy)benzoate (300 mg, 1.15 mmol) was suspended in water (3 ml) and concentrated aqueous hydrochloric acid (380 μl) was added. The reaction mixture was refluxed for 16 h, then cooled to room temperature and partitioned with ethyl acetate (10 ml). The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (dichloromethane:methanol 95:5) to provide 4-(hydroxymethyl)-3-(methyloxy)benzoic acid (74 mg, 35% yield). MS (EI) for C9H10O4: 181(M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[CH:13][CH:12]=3)[O:8][C:7](=[O:23])[C:6]=2[CH:24]=1.O.[NH2:27][NH2:28].O1CCCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[O:8])=[C:6]([C:7]([NH:27][NH2:28])=[O:23])[CH:24]=1
Reactant: NN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3ccnn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1ccnn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 0.50 g of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.13 ml of hydrazine monohydrate and 20 ml of tetrahydrofuran was stirred at room temperature for 4 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of ethyl acetate and hexane to obtain 0.44 g of N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [C:1]([CH:5]([C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)[O:6][C:7]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:10]([CH2:11]O)=[CH:9][C:8]=1[CH2:18][CH2:19][CH3:20])([O:3][CH3:4])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:50].CC#N>C1COCC1>[C:1]([CH:5]([C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)[O:6][C:7]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:10]([CH2:11][Br:50])=[CH:9][C:8]=1[CH2:18][CH2:19][CH3:20])([O:3][CH3:4])=[O:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCCc1cc(CO)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.1 %

Procedure:
To a solution of the product of Step B (0.53 g, 1.38 mMol) in dry THF (10 mL) were added Ph3P (0.49 g, 2.06 mMol), CBr4 (0.69 g, 2.06 mMol) and CH3CN (2 mL), and the mixture was stirred at room temperature for 14 h. At the end of this period, the reaction mixture was concentrated in vacuo to provide an oil, which was then purified by flash chromatography on silica-gel using ethyl acetate-hexane (1:9) to provide the titled product as a thick colorless oil (0.57 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[Br:12][C:13]1[C:22]2[CH:21]=[N:20][CH:19]=[CH:18][C:17]=2[C:16]([NH2:23])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:23][C:10]([NH:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:11])=[C:17]2[C:22]=1[CH:21]=[N:20][CH:19]=[CH:18]2
Reactant: O=C=NCc1ccc(F)cc1
Reactant: Nc1ccc(Br)c2cnccc12
Product: O=C(NCc1ccc(F)cc1)Nc1ccc(Br)c2cnccc12

Procedure:
The title compound was prepared using 1-fluoro-4-(isocyanatomethyl)benzene, the product of Example 73A and the procedure described in Example 73B (white solid, 108 mg, 65%). MS (ESI+) m/z 376 (M+H)+; MS (ESI−) m/z 374 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.35 (d, 5.8, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 7.99 (d, J 6.1, 1H), 8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.88 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H13BrFN3O: C, 54.56; H, 3.50; N, 11.23. Found: C, 54.61; H, 3.35; N, 11.14.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH3:16][NH2:17]>O1CCCC1.O>[CH3:16][NH:17][C:10]([N:8]1[CH2:9][CH:6]([O:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([CH3:1])[CH:3]=2)[CH2:7]1)=[O:11]
Reactant: CN
Reactant: Cc1cccc(OC2CN(C(=O)Cl)C2)c1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2cccc(C)c2)C1
Temperature: -78 °C
Reaction time: 17 h
Yield: 18.2 %

Procedure:
A stirred solution of 3.92 g (0.01 mole) of 3-(3-methylphenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated with 2.4 g (0.03 mole) of 40% aqueous monomethylamine and stirring continued for 17 hr. The reaction mixture was diluted with 200 ml of water. The reddish oil residue was cooled to -78° C. whereupon it crystallized (4.28 g). Recrystallization from benzene-ligroin gave 400 mg of fine white crystals, m.p. 143°-144° C. Addition of more ligroin yielded an additional 800 mg of "cream" colored crystalline product, m.p. 138°-142° C. The two fractions were combined and recrystallized from ethanol-isopropyl ether, yielding 600 mg (27.3%) of fine white crystals, m.p. 143°-144° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40]>ClCCl>[C:20]1(=[O:21])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([O:1][S:39]([C:35]4[S:34][CH:38]=[CH:37][CH:36]=4)(=[O:41])=[O:40])=[CH:3][CH:4]=3)[CH2:9]2)[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccc(O)cc2C1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccc(OS(=O)(=O)c3cccs3)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
A stirred mixture of 7-hydroxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (2.94 g, 8.4 mmol) and triethylamine (1.4 ml, 10 mmol) in dichloromethane (75 ml) was treated with 2-thiophenesulfonyl chloride (1.69 g, 9.2 mmol). After stirring at room temperature for 18 h the mixture was washed with saturated aqueous sodium bicarbonate (100 ml). The aqueous layer was separated and extracted with dichloromethane (2×50 ml). The combined extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica using 30-100% ethyl acetate-pentane gradient elution to afford the title compound as a pale yellow oil (3.45 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH:11]1[NH:15][CH2:14][CH2:13][S:12]1.[C:16]([CH2:19][C:20](Cl)=[S:21])(=[O:18])[CH3:17]>N1C=CC=CC=1.OS(O)(=O)=O>[C:16]([CH2:19][C:20]([N:15]1[CH2:14][CH2:13][S:12][CH:11]1[CH2:10][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:21])(=[O:18])[CH3:17]
Reactant: COc1ccccc1SCC1NCCS1
Reactant: CC(=O)CC(=S)Cl
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: COc1ccccc1SCC1SCCN1C(=S)CC(C)=O

Procedure:
A solution of 2-(o-methoxyphenylthio)methyl-thiazolidine (5 g) in pyridine (25 ml) is reacted with acetylthioacetylchloride (2.93 g) for a night at room temperature, the reaction mixture is diluted with 2N H2SO4, extracted with ethylether to give after the usual work-up 3α-acetylthioacetyl-2-(o-methoxyphenylthio)methyl-thiazolidine, m.p. 62°-64° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:21]2)[CH:12]=[CH:11]1>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:24][CH2:25]3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4cc[nH]c34)CC2)c1
Reactant: COc1cccc(I)c1
Product: COc1cccc(-n2ccc3cccc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)c32)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-methoxybenzene and N-{3-[1-(1H-indol-7-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 482.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[CH:4]=1.[OH:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][O:8][C:5]1[CH:4]=[C:3]([CH2:2][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=2)[O:7][N:6]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)on1
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCc2cc(OCc3nc(-c4ccccc4)oc3C)no2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A mixture of 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (457 mg), methyl 2-(3-hydroxyphenyl)acetate (249 mg), anhydrous potassium carbonate (415 mg) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]phenyl]acetate as a colorless oil (604 mg, 93%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][NH:28][C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:27]
Reactant: NCc1ccccn1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)NCc2ccccn2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and 2-aminomethylpyridine. The crude product was used without further purification (57%, oil). HPLC-MS: m/z=362.2 (M+1); Rt: 2.43 min.
Reaction SMILES: [CH:1]1([N:4]([CH:32]2[CH2:34][CH2:33]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:24]=[C:23]([CH:25]=[O:26])[N:22]([CH2:27][CH3:28])[N:21]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[OH:35]OS([O-])=O.[K+].O>CN(C=O)C>[CH:32]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:24]=[C:23]([C:25]([OH:35])=[O:26])[N:22]([CH2:27][CH3:28])[N:21]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:33][CH2:34]1
Reactant: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1C=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.1 %

Procedure:
A mixture of N,N-dicyclopropyl-6-ethyl-4-(1-ethyl-5-formyl-1H-pyrazol-3-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 101C, 27 mg, 0.059 mmol) and OXONE (79 mg, 0.129 mmol) in DMF was stirred at room temperature for 20 hrs. Water was added and the mixture was extracted with dichloromethane 3 times. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified with preparative HPLC to give 3-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-1-ethyl-1H-pyrazole-5-carboxylic acid (20 mg, 98% yield)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]3[O:43][CH2:42][C:41](=[O:44])[NH:40][C:39]=3[CH:45]=2)O1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[CH:37][C:38]5[O:43][CH2:42][C:41](=[O:44])[NH:40][C:39]=5[CH:45]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)CO3)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccc4c(c3)NC(=O)CO4)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 129, Step 4 starting from 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.0209 g, 0.0500 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one. LCMS (M+H)+: m/z=486.2.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10]([CH3:11])=[CH:9][N:8]=[C:7]([NH:12][NH2:13])[C:6]1=[O:14])([OH:3])=[O:2].C([O-])(O)=O.[Na+].[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.O1CCOCC1>[CH2:20]([O:27][C:28]([NH:13][NH:12][C:7]1[C:6](=[O:14])[N:5]([CH2:4][C:1]([OH:3])=[O:2])[C:10]([CH3:11])=[CH:9][N:8]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cnc(NN)c(=O)n1CC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(NNC(=O)OCc2ccccc2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
To a solution of the compound of Example 5 (Step G) (5.0 g, 0.025 mol) and NaHCO3 (9.4 g, 0.112 mol) in water (180 mL), was added drop-wise a solution of benzylchloroformate (6.0 mL, 0.042 mol) in dioxane (300 mL). The resulting mixture was stirred at room temperature for 4 hours, diluted with water (200 mL), and washed with ether (200 mL). The aqueous phase was acidified with aqueous 2M KHSO4 and extracted with EtOAc (3×300 mL). The combined organic phases were washed with brine (400 mL), dried (Na2SO4), and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel to afford the title compound (7.35 g, 90%) as a pale brown solid. 1H NMR (DMSO-d4) δ 2.15 (s, 3H), 4.3 (br s, 1H), 4.73 (s, 2H), 5.12 (s, 2H), 6.76 (s, 1H), 7.20-7.50 (m, 5H), 9.7 (br s, 1H), 10.0 (br s, 1H). HPLC Rt 8.10 minutes (water/ACN/TFA, 5 to 75%, 0.1% TFA, 20 minutes).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4]=[C:5]([O:21][C:22](=[O:36])[N:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:6]2[N:7]=[CH:8][N:9]([C:19]=2[N:20]=1)[C@@H:10]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:11]1[OH:12].[CH3:37][O:38][C:39]1[CH:60]=[CH:59][C:42]([C:43](Cl)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)=[CH:41][CH:40]=1.C1(C)C=CC=CC=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([C:43]([O:17][CH2:16][C@H:15]2[O:18][C@@H:10]([N:9]3[C:19]4[N:20]=[C:3]([NH:2][CH3:1])[N:4]=[C:5]([O:21][C:22](=[O:36])[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:6]=4[N:7]=[CH:8]3)[C@H:11]([OH:12])[C@@H:13]2[OH:14])([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:42]2[CH:59]=[CH:60][C:39]([O:38][CH3:37])=[CH:40][CH:41]=2)=[CH:49][CH:48]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CNc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CNc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
Compound 5 (0.51 g, 1.05 mmol, 1.0 eq) and 4,4′-dimethoxytritylchloride (0.39 g, 1.14 mmol, 1.09 eq) were azeotroped three times with toluene for ˜15 h. To the dried compound 5, anhydrous pyridine (5 mL) was added. The mixture was stirred at room temperature under Ar atmosphere for 4 h. 4-Dimethylaminopyridine (0.09 g, 0.7 mmol, 0.7 eq) was subsequently added and stirring was continued for 17 h. The reaction was quenched with methanol (1 mL) and evaporated to dryness. The crude residue was dissolved in 50 mL of dichloromethane and washed with 5% sodium bicarbonate followed by saturated sodium chloride. The organic layer was dried over sodium sulfate and filtered. The product was then purified via silica gel chromatography using a solvent mixture of 90% dichloromethane, 9% methanol, 1% triethylamine to give 11 as a light yellow crystalline solid (0.56 g, 67%). TLC (CH2Cl2:MeOH, 9:1 v/v): Rf=0.4; 1H NMR (CD3OD, 400 MHz) 2.71 (br.s, 1H), 2.98-3.03 (q, 1H), 3.21 (d, J=3.2 Hz, 3H), 3.25-3.27 (m, 1H), 3.29-3.32 (m, 1H), 3.60 (d, J=4.8 Hz, 6H), 3.66 (m, 1H), 4.07-4.10 (m, 1H), 4.45 (m, 1H), 4.83 (m, 1H), 5.87 (d, J=4.8 Hz, 1H), 6.64-6.69 (m, 5H), 7.05-7.38 (m, 18H), 8.0 (s, 1H); 13C NMR ((CD3)2SO, 500 MHz) 28.8, 55.6, 72.2, 74.9, 82.3, 85.3, 87.7, 113.8, 114.0, 126.3, 127.8, 128.5, 128.7, 129.1, 129.2, 129.3, 129.9, 130.2, 130.4, 131.2, 141.2, 149.2, 159.9; ESI-MS (ES+) calculated for C45H42N6O8 794.3064, found 795.7 (M+H+), 303.4 ([(MeO)2Tr]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1.C(N(CC)CC)C.[C:52](Cl)(=[O:54])[CH3:53]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:52](=[O:54])[CH3:53])[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1
Reactant: CCc1cc(NC(CC)CCCCCCN)nc(Cl)n1
Reactant: CC(=O)Cl
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cc(NC(CC)CCCCCCNC(C)=O)nc(Cl)n1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
In 10 ml of chloroform were dissolved 0.55 g of dl-5-chloro-6-ethyl-4-(1-ethyl-7-aminoheptyl)aminopyrimidine and 0.25 g of triethylamine, and under ice cooling, 0.18 g of acetyl chloride was added to the solution and the mixture was stirred for one hour. After completion of the reaction, the reaction mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; ethyl acetate) to give 0.20 g of the title compound as pale yellow oily product. nD22.4 1.5296.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][CH:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1>C(O)CCC>[CH3:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])[CH2:20]1
Reactant: CC1CCCNC1
Reactant: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])c1Cl
Solvent: CCCCO
Product: CC1CCCN(c2c([N+](=O)[O-])cnn2COCC[Si](C)(C)C)C1
Yield: 113.9 %

Procedure:
To a solution of 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (348.3 mg, 1.254 mmol) in 1 mL n-butanol was added 3-methyl-piperidine (0.20 mL, 1.7 mmol). The reaction mixture was subjected to microwave irradiation at a temperature of 120° C. for 30 minutes. The solvent was evaporated in vacuo and the crude product purified via flash chromatography on silica gel (0 to 40% ethyl acetate in heptanes) to yield 486.5 mg of 3-methyl-1-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidine. LCMS (ESI) m+H=341.4; 1H NMR (400 MHz, DMSO-d6) δ: 8.04 (s, 1H), 5.36 (s, 2H), 3.71-3.62 (m, 2H), 3.20 (m, 3H), 2.96-2.85 (m, 1H), 1.84-1.76 (m, 4H), 1.15 (m, 1H), 0.97-0.87 (m, 5H), 0.00 (s, 9H).