Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH:14]1([C:20]2([C:23](O)=[O:24])[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([C:20]2([C:23]([NH:12][C:8]3[C:7]([Cl:13])=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([Cl:1])=[N:3]4)=[O:24])[CH2:21][CH2:22]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=C(O)C1(C2CCCCC2)CC1
Reactant: Nc1c(Cl)ccc2nc(Cl)ccc12
Product: O=C(Nc1c(Cl)ccc2nc(Cl)ccc12)C1(C2CCCCC2)CC1
Yield: 50.8 %

Procedure:
Prepared according to the method of example 1(a), using 2,6-dichloro-5-quinolinamine (prepared as described in Example 1(d)) (0.3 g) and 1-cyclohexyl cyclopropanecarboxylic acid (Example 26(a)) (0.28 g) at 100° C. for 15 hours. Purification by chromatography (SiO2, dichloromethane as eluant) afforded the sub-title compound (0.26 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:21](Cl)(=[O:23])[CH3:22].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:21](=[O:23])[CH3:22])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 29.5 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.78 mmol) and 4-dimethylaminopyridine (0.06 g, 0.51 mmol) in N,N-dimethylacetamide (5 mL) was added acetyl chloride (0.21 g, 2.67 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate. The precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.17 g, yield 29%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([F:13])=[CH:5][C:3]=1[NH2:4].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:36]([O:40][CH2:41][CH3:42])(=[O:39])[CH:37]=[CH2:38]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:4][C:3]1[CH:5]=[C:6]([F:13])[C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1/[CH:38]=[CH:37]/[C:36]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: Nc1cc(F)c(C(F)(F)F)cc1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(C(F)(F)F)c(F)cc1N
Temperature: 85 °C

Procedure:
2-Bromo-5-fluoro-4-(trifluoromethyl)aniline (0.97 mmol) and P(o-tol)3 (0.40 mmol) were dissolved in triethylamine (2.0 mL) in a glass pressure tube and nitrogen gas was bubbled through the solution via a gas dispersion tube for 10 minutes. Ethyl acrylate (1.0 mmol) and palladium acetate (0.20 mmol) were added to the reaction mixture and the tube was sealed and placed into an oil bath pre-heated to 85° C. for 18 h. The resulting solution was concentrated under vacuum and purified via an isco column. Retention time (min)=2.504, method [1], MS (ESI) 278.0 (M+H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.N.[F:15][C:16](I)([F:18])[F:17]>C(OCC)(=O)C>[CH3:12][C:9]1([CH3:11])[CH:8]=[CH:7][C:6]2[CH:13]=[C:2]([S:1][C:16]([F:18])([F:17])[F:15])[CH:3]=[CH:4][C:5]=2[O:10]1
Reactant: FC(F)(F)I
Reactant: CC1(C)C=Cc2cc(S)ccc2O1
Agent: N
Solvent: CCOC(C)=O
Product: CC1(C)C=Cc2cc(SC(F)(F)F)ccc2O1
Reaction time: 2 h
Yield: 59.6 %

Procedure:
1.45 g of 6-mercapto-2,2-dimethyl-2H-1-benzopyran (prepared as described in Preparation 6) was suspended in 30 ml of liquid ammonia, and 8.23 g of trifluoromethyl iodide were then added to the suspension at -60° C. in an atmosphere of nitrogen. The resulting mixture was then irradiated at -65° C. for 2 hours and then at 25° C. for 2 hours, using a low pressure mercury lamp. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with dilute aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic layer was then dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 20:2:1 by volume mixture of cyclohexane, chloroform and ethyl acetate as the eluent, to afford 1.17 g of the title compound as an oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N+:35]([O-:37])=[O:36])[N:5]([CH2:7][C:8]2([CH2:16][O:17][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]2)[CH:6]=1.[CH2:38](C([Sn])=C(CCCC)CCCC)[CH2:39]CC>CN(C)C=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>[O:17]([CH2:16][C:8]1([CH2:7][N:5]2[CH:6]=[C:2]([CH:38]=[CH2:39])[N:3]=[C:4]2[N+:35]([O-:37])=[O:36])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)[Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2cc(Br)nc2[N+](=O)[O-])CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cn(CC2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)COC(C)(C)OC2)c([N+](=O)[O-])n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 62.5 %

Procedure:
280 mg (0.48 mmol equivalents) of 5-{(4-bromo-2-nitro-1H-imidazol-1-yl)methyl}-5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-1,3-dioxane was dissolved in 4.7 mL of dimethylformamide, 278 μL (0.95 mmol equivalents) of tributylvinyltin and 55 mg (0.05 mmol equivalents) of tetrakis(triphenylphosphine)palladium were added thereto, and the mixture was heated to 80° C. in an oil bath and then stirred for 5 hours. After completion of the reaction, the reaction liquid was concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=4/1) to give 163 mg (0.30 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-vinyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:38](Cl)(=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Product: CCCCCCCC(=O)NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(CCCC)nn(-c3ccccc3C(F)(F)F)c2=O)cc1
Yield: 37 %

Procedure:
By the procedure of Example 13, Step C, 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) was reacted with octanoyl chloride. Flash chromatography of the crude product twice on silica gel (gradient elution with 0.3-3% and 0.5-2% MeOH in CH2Cl2) gave a 37% yield of the title compound as a gum, homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 657 (M+1)+. 400 MHz NMR CDCl3) δ0.81 (t, 3H), 0.89 (t, 3H), 1.1-1.3 (m, 8H), 1.39 (m, 4H), 1.66 (m, 2H), 1.88 (t, 2H), 2.55 (t, 2H), 4.92 (s, 2H), 7.26, (d, 2H), 7.35 (d, 2H), 7.5-7.7 (m, 6H), 7.78 (d, 1H), 8.20 (br s, 1H), 8.28 (d, 1H).
Reaction SMILES: O[CH2:2][C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[S:5][C:4]=1[C:23]([OH:25])=[O:24].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:6]2[S:5][C:4]3[C:23](=[O:25])[O:24][CH2:2][C:3]=3[C:7]=2[C:8]2[CH:9]=[CH:10][C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)=[CH:17][CH:18]=1
Reactant: CSc1ccc(-c2c(-c3ccc(F)cc3)sc(C(=O)O)c2CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CSc1ccc(-c2c(-c3ccc(F)cc3)sc3c2COC3=O)cc1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a solution of 120 mg of the product of Step 3 in 10 mL of CH2Cl2 was added 150 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After stirring for 30 min, the reaction mixture was concentrated in vacuo and purified by silica gel chromatography eluted with 6:1 hexane/EtOAc to give 89 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Br:20])[NH2:16]>>[CH3:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[Br:20]
Reactant: Cc1cc(N)ccc1Br
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1cc(Nc2ccccc2CC(=O)O)ccc1Br

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-methyl-4-bromoaniline to yield 2-[(3-methyl-4-bromophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1.[NH2:19][NH2:20]>C(O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N+:19]=[N-:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: NN
Solvent: CCCO
Product: COc1ccc(C(=[N+]=[N-])c2ccc(OC)cc2)cc1

Procedure:
25 grams (0.1 moles) of p,p'-dimethoxybenzophenone, which was purchased from the Aldrich Chemical Company, was dissolved in 50 ml of n-propanol and with solution was treated with 20 grams of hydrazine, which had been freshly distilled over sodium hydroxide pellets. The mixture was then refluxed for a total of 12 hours, after which the solvent (n-propanol) and excess hydrozine were removed at reduced pressure. The residual crude hydrazone was recrystallized from ethanol and had a melting point of 85° C.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])(=[O:5])[CH3:4]>C1COCC1>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Solvent: C1CCOC1
Product: Cc1c(C(=O)CBr)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 40.7 %

Procedure:
Bromine (34 μl, 0.66 mmol) in THF (5 ml) was added to a solution of 5-acetyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (320 mg, 0.63 mmol) in THF (10 ml). After 2 h, the yellow colour had disappeared. The reaction mixture was partitioned between water and ethyl acetate, the organic phase was separated, evaporated, and the residue was chromatographed on silica using ethyl acetate/heptane (1/1, 2/1, 4/1) as eluent. Fractions containing the product were combined and evaporated to give the title compound (150 mg, 41%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:41]=[CH:40][C:12]2[N:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:27]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:32])=[O:31])=[O:28])=[CH:20][CH:19]=3)[C:14]([CH2:16][CH3:17])=[N:15][C:11]=2[CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:16]([C:14]1[N:13]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:27]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])=[O:28])=[CH:20][CH:19]=2)[C:12]2[CH:40]=[CH:41][C:9]([OH:8])=[CH:10][C:11]=2[N:15]=1)[CH3:17]
Reactant: CCc1nc2cc(O[Si](C)(C)C(C)(C)C)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1nc2cc(O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 91.6 %

Procedure:
A solution of 5-{[tert-butyl(dimethyl)silyl]oxy}-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (step 5, 78 mg, 0.13 mmol) in THF (5 mL) was added tetrabutylammonium fluoride (1.0 M solution in THF, 0.16 mL, 0.16 mmol) at 0° C. The mixture was stirred at 0° C. for 2.5 h, then concentrated. The residue was dissolved in water (30 mL) and extracted with dichloromethane (50 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (gradient elution from 20:1 to 10:1) to afford 57 mg (92%) of the title compound as white amorphous: MS (ESI) m/z 479 (M+H)+;
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:43]1[CH2:46][CH2:45][CH2:44]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH:43]1([N:3]2[C:2](=[O:1])[CH2:7][O:6][C:5]3[N:8]=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]5)=[CH:20][CH:19]=4)[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:4]2=3)[CH2:46][CH2:45][CH2:44]1
Reactant: BrC1CCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(C3CCC3)C(=O)CO4)cc2)CCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.106 mmol), potassium carbonate (44 mg, 0.318 mmol) and bromocyclobutane (0.030 mL, 0.318 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give an orange suspension. The reaction mixture was stirred at 80° C. for one hour, then 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with saturated sodium bicarbonate solution (5 mL) and extracted into dichloromethane (3×3 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as an off-white solid (15 mg, 27% yield). 1H-NMR (500 MHz, CDCl3) δ 7.25-7.37 (8H, m), 7.16-7.25 (2H, m), 5.03 (1H, br s), 4.78 (2H, s), 4.53 (1H, quin), 2.30-2.67 (8H, m), 2.02-2.14 (1H, m), 1.76-1.97 (3H, m), 1.10-1.50 (9H, br m). LCMS (Method A) RT=7.76 min, M+H+=526.16.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].[CH:24]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(O)C>[N:19]1([C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:11]([C:7]3[N:8]=[C:9]4[NH:10][C:24]([C:26]5[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=5)[C:29]#[N:30])=[N:3][C:4]4=[CH:5][CH:6]=3)[CH2:12]2)=[O:18])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: N#Cc1cccc(C=O)c1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Reaction time: 20 h
Yield: 66.6 %

Procedure:
To a solution of (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (Intermediate 1, Step 3) (50 mg, 0.15 mmol) and 3-formylbenzonitrile (34 mg, 0.31 mmol) in ethanol (2 mL) were added sodium dithionite (52 mg, 0.4 mmol), and water (0.5 mL). After 20 h at 80° C., the mixture was concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was concentrated under reduced pressure and the resulting residue was purified by preparative TLC to afford (R)-3-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzonitrile as a yellow solid (40 mg, 81%). MS (ES+APCI) (M+H) 401.0; HPLC retention time 4.016 min (Method I).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([N:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([O:22]C(C)(C)C)=[O:21])=[C:8]([CH3:27])[NH:7][C:6]1=[O:28])=[O:4].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:29][N:2]([CH3:1])[C:3]([N:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([OH:22])=[O:21])=[C:8]([CH3:27])[NH:7][C:6]1=[O:28])=[O:4]
Reactant: CC1=C(C(=O)OC(C)(C)C)C(c2cccc([N+](=O)[O-])c2)N(C(=O)N(C)C)C(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)N(C(=O)N(C)C)C(=O)N1
Reaction time: 2.5 h
Yield: 65.2 %

Procedure:
A solution of 3-[(dimethylamino)carbonyl]-1,2,3,4-tetrahydro-6-methyl-4-(3-nitrophenyl)-2-oxo-5-pyrimidinecarboxylic acid, t-butyl ester (230 mg, 0.59 mmol) in chloroform (4.0 ml) was treated with trifluoroacetic acid (1.2 ml) at ambient temperature under argon. Aftr stirring for 2.5 hours, the reaction was evaporated, coevaporated with toluene and crystallized from ethanol/ether to give the title compound as colorless crystals (134 mg), melting point 193°-195° C. TLC (5% methanol/dichloromethane) single spot, Rf =0.21.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH2:17].C([O-])(=O)C.[Na+]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: Clc1ncnc2ccccc12
Reactant: COc1ccc(N)cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(Nc2ncnc3ccccc23)cc1OC

Procedure:
The title compound was prepared from 4-chloro-quinazoline (82.3 mg, 0.5 mmol), 3,4-dimethoxy-aniline (76.6 mg, 0.5 mmol) and sodium acetate (49.2 mg, 0.6 mmol) similar to example 20 to give 138 mg (92.5%) of off white solids. 1H NMR (CDCl3): 8.74 (s, 1H), 7.91 (t, J=8.7 Hz, 2H), 7.57 (t, J=8.1 Hz, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.45 (s, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.16-7.13 (m, 1H), 6.92 (d, J=8.4 Hz, 1H), 3.93-3.91 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21](Cl)(=O)[CH2:22][CH:23]([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH2:22][CH:23]([CH3:25])[CH3:24])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CC(C)CC(=O)Cl
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccc2)=NC1
Product: CC(C)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
Following the procedure of Example 5, 2.5 g of 7-bromo-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and 1.11 ml of isovaleryl chloride is transformed to 1.03 g of title product with melting point 93°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH2:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[C:16]([F:26])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O1CCCC1.CO.[OH-].[Na+].Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH2:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:26])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)c1cc(F)c(COc2cnc(OC(C)C)c(Cl)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(OCc2cc(F)c(C(=O)O)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of ethyl 4-{[(5-chloro-6-isopropoxypyridin-3-yl)oxy]methyl}-2,5-difluorobenzoate (Preparation 14, 400 mg, 1.03 mmol) in a mixture tetrahydrofuran/methanol (1/1 10 mL) was added an aqueous solution of sodium hydroxide (2M, 2.6 mL, 5.15 mmol). The reaction was stirred at room temperature for 2 hours and diluted with ethyl acetate (20 mL). An aqueous solution of hydrochloric acid (2M, 10 mL) was added to pH 1. The organic phase was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo to afford the title compound as a colourless oil (240 mg, 94% over two steps). No further purification undertaken.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[O:17]([C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1)[CH3:16]
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(Oc2cc(Nc3cccc(N)n3)ncn2)c1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
To a solution of N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (200 mg, 0.90 mmol) in dry DMF (2 mL) was added 3-methoxyphenol (112 mg, 0.90 mmol) and anhydrous K2CO3 (186 mg, 1.353 mmol). The reaction mixture was heated at 100° C. for 16 h under N2 atmosphere. It was then cooled and DMF removed under reduced pressure to give a yellowish gummy residue that was taken in EtOAc (10 mL). It was washed with water (5 mL), brine (5 mL), dried over Na2SO4 and then concentrated under reduced pressure to give a crude product. This was further purified by column chromatography (SiO2, 60-120, hexane/EtOAc, 5/5) to give N2-(6-(3-methoxylphenoxy)pyrimidin-4-yl)pyridine-2,6-diamine (110 mg, 40.7%) as a pale yellow solid.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])(=[O:18])=[O:17])[CH:15]=1)C)=O)(C)(C)C.C(OCC)(=O)C.[ClH:40].CO>C(OCC)(=O)C>[ClH:40].[CH3:6][NH:8][CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])(=[O:18])=[O:17])[CH:15]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2C(=O)O)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2C(=O)O)c1
Reaction time: 3 h
Yield: 50 %

Procedure:
2-[(4-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoic acid (256 mg) was dissolved in ethyl acetate (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added at room temperature. After stirring at the same temperature for 3 hr, the reaction mixture was homogenized with methanol, activated carbon was added and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate. The obtained crystal was recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as colorless crystals (yield 110 mg, 50%).