Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:12]2[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)[C:6]([CH3:11])=[N:7][C:8]=1[O:9]C)[CH3:2].[I-].[K+].Cl[Si](C)(C)C>C(#N)C>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:11])=[C:5]([C:12]2[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(C=O)s2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(-c2ccc(C=O)s2)c(C)[nH]c1=O
Temperature: 60 °C
Yield: 167.3 %

Procedure:
To a mixture of 5-(5-ethyl-6-methoxy-2-methylpyridin-3-yl)thiophene-2-carbaldehyde (0.7 g, 2.9 mmol) prepared in accordance with the procedures of Step 2 as described above, potassium iodide (1.43 g, 8.6 mmol) and acetonitrile (15 mL) is added chlorotrimethylsilane (1.1 mL, 8.6 mmol) at room temperature then the reaction is heated at 60° C. for 0.5 hr. Solid product begins to form so more solvent is added to facilitate stirring. The solids are collected by filtration, washed with water, with ether and dried to afford 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-carbaldehyde (1.2 g, 61% yield). MS: m/e=248 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[N:4][CH:3]=1.[CH:18]1([CH2:21][NH2:22])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(OC(O)C)C>[CH:18]1([CH2:21][NH:22][C:2]2[N:7]=[C:6]([N:8]3[C:12]4[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[N:4][CH:3]=2)[CH2:20][CH2:19]1
Reactant: Nc1ccc2ncn(-c3cncc(Cl)n3)c2c1
Reactant: NCC1CC1
Agent: CCOC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc2ncn(-c3cncc(NCC4CC4)n3)c2c1

Procedure:
A solution of 1-(6-chloropyrazin-2-yl)-1H-benzimidazol-6-amine (100 mg, 0.41 mmol) and cyclopropylmethylamine (424 μL, 4.1 mmol) in ethoxyethanol (2 mL) containing DIPEA (140 μL) was heated at reflux overnight under N2. The solution was concentrated under reduced pressure and the residue dissolved in EtOAc (20 mL) and washed successively with H2O (20 mL), 1M HCl (2×20 mL), H2O (20 mL) and brine (20 mL). After drying (Na2SO4) the solvent was removed under reduced pressure and the residue chromatographed eluting with dichloromethane-methanol (9:1-94:6) to separate pure product from the lower fractions (98 mg)
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:39][CH3:40])[C:7]([NH:28][CH:29]2[CH2:34][CH2:33][CH:32]([C:35]([O:37]C)=[O:36])[CH2:31][CH2:30]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[C:13]([C:24]([F:27])([F:26])[F:25])[CH:12]=1)(=[O:3])[NH2:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([C:4]1[N:5]=[C:6]([CH2:39][CH3:40])[C:7]([NH:28][CH:29]2[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[C:13]([C:24]([F:25])([F:27])[F:26])[CH:12]=1)(=[O:3])[NH2:2]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)c(C(F)(F)F)c2)nc1NC1CCC(C(=O)OC)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)c(C(F)(F)F)c2)nc1NC1CCC(C(=O)O)CC1
Yield: 38.3 %

Procedure:
To a mixture of methyl 4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylate (Example 435) (126 mg), THF (2 mL) and methanol (2 mL), 10% aqueous sodium hydroxide (1 mL) was added and heated under reflux for 2 hours. To the reaction liquid, 10% hydrochloric acid was added to give a pH of about 7, and the resulting solid was collected by filtration. This solid was purified by silica gel column chromatography (eluent; chloroform:methanol) to give 4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (Example 436) (47 mg), which was a low-polarity product, as a light yellow white powder and 4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (Example 437) (59 mg), which was a high-polarity product, as a light yellow powder.
Reaction SMILES: C([O:8][CH2:9][C:10]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][O:11]1)C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][C:10]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][O:11]1
Reactant: COC(=O)C1(COCc2ccccc2)CCCO1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(CO)CCCO1
Yield: 178.3 %

Procedure:
10% Pd—C (80 mg, 0.753 mmol) was added under nitrogen to a solution of methyl 2-((benzyloxy)methyl)tetrahydrofuran-2-carboxylate (377 mg, 1.506 mmol) in MeOH (20 mL) in a Parr shaker bottle and hydrogenated at 30 psi overnight. The suspension was filtered and the filtrate was evaporated to dryness to afford methyl 2-(hydroxymethyl)tetrahydrofuran-2-carboxylate as a clear oil (0.43 g, 97.5%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 4.10-3.98 (m, 2H), 3.85 (d, J=11.4 Hz, 1H), 3.78 (s, 3H), 3.69 (d, J=11.4 Hz, 1H), 2.19-2.12 (m, 1H), 2.09-2.02 (m, 1H), 2.01-1.93 (m, 2H).
Reaction SMILES: C(C1C=CC(C2C=CC=CC=2F)=CC=1)#C.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)#[CH:17].S(=O)(=O)(O)O.[H][H]>>[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:17]
Reactant: [H][H]
Reactant: C#Cc1ccc(-c2ccc(F)cc2)cc1
Agent: C#Cc1ccc(-c2ccccc2F)cc1
Agent: O=S(=O)(O)O
Product: CCc1ccc(-c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
The procedure of Example 1 was repeated, except that the 1-ethynyl-4-(2-fluorophenyl)benzene was replaced with 1.5 g of 1-ethynyl-4-(4-fluorophenyl)benzene, the amount of catalyst was reduced to 0.5 g, the sulfuric acid was omitted, initial hydrogen pressure was 48 psig, and the reduction was allowed to proceed overnight. Evaporation of the benzene left a solid which was recrystallized from hexane to give 1-ethyl-4-(4-fluorophenyl)benzene, mp 60°-63°. The following elemental analysis was obtained:
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2I)[CH2:3][CH2:2]1.C([SnH](CCCC)CCCC)CCC.[C]=O.C[CH2:33][O:34]CC>C1(C)C=CC=CC=1.[F-].[K+].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>[CH:1]1([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2[CH:33]=[O:34])[CH2:3][CH2:2]1
Reactant: FC(F)(F)Oc1ccc(OC2CC2)c(I)c1
Reactant: CCOCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: [C]=O
Solvent: Cc1ccccc1
Product: O=Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 2-cyclopropoxy-5-(trifluoromethoxy)iodobenzene (Description 8, 0.344 g, 1 mmol) in toluene (2.5 mL) was degassed with bubbling nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (15 mg) was added, the mixture was degassed with bubbling nitrogen for a further 5 min., then carbon monoxide was bubbled through the mixture for 10 min. The mixture was warmed to 50° C. and a solution of tributyl tin hydride (0.3 mL, 1.1 mmol) in toluene (5 mL) was added at a rate of 2 mL/h. via a syringe pump, maintaining carbon monoxide bubbling throughout. The mixture was cooled, diluted with ether (20 mL) and aqueous potassium fluoride solution (50%) was added. The mixture was stirred at room temperature overnight, filtered and the layers were separated. The organic layer was dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2O (80:20), to give the title compound as a colourless oil. 1H NMR (360 MHz, CDCl3) δ 0.86 (4H, m), 3.82-3.9 (1H, m), 7.42 (2H, m), 7.62 (1H, d, J=2.5 Hz), and 10.36 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]([C:16]1[NH:17][C:18]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([Cl:28])=[C:25]([OH:27])[CH:26]=2)[N:20]=1)([CH3:15])[CH3:14]>ClCCl.CO>[Cl:28][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:16]([C:13]([CH3:14])([CH3:15])[CH2:12][NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:10])[NH:17][C:18]=2[C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)=[CH:26][C:25]=1[OH:27]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CNC(=O)Nc1ccc(Cl)cc1)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
A solution of 4-chlorophenylisocyanate (46 mg, 0.3 mmol) in dichloromethane (5 ml) was treated with a solution of Example 3 (103 mg, 0.3 mmol) in methanol (1 ml). After stirring at room temperature for 30 min the solution was concentrated under reduced pressure and the residue chromatographed on silica gel eluting with dichloromethane/methanol (10:1) to the give the title compound (72 mg, 48%) as a pale yellow solid; MS(ES+) m/e 496/498/500 [M+H]+.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH:38][C:39](=[O:50])[CH2:40][CH2:41][NH:42]C(OC(C)(C)C)=O)=[CH:27][CH:26]=4)=[O:24])(=[O:21])=[O:20])=[CH:15][C:14]=3[N+:51]([O-:53])=[O:52])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl>ClCCl.O1CCOCC1>[C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:26]=[CH:27][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH:38][C:39](=[O:50])[CH2:40][CH2:41][NH2:42])=[CH:29][CH:30]=4)=[O:24])(=[O:20])=[O:21])=[CH:15][C:14]=3[N+:51]([O-:53])=[O:52])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCC(=O)Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1
Reaction time: 4 h

Procedure:
A room temperature solution of Example 49A (19 mg, 0.03 mmol) in dichloromethane (1 mL) was treated with 4M HCl in dioxane, stirred for 4 hours, and concentrated to provide the desired product. MS (ESI(+)) m/e 650 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ9.12 (br s, 1H), 8.65 (d, 1H), 8.56 (t, 1H), 7.95 (dd, 1H), 7.94 (m, 3H), 7.65 (br s, 3H), 7.50-7.35 (m, 4H), 7.15 (dt, 1H), 3.18 (d, 2H), 2.75 (s, 6H), 1.98 (m, 3H), 1.72-1.55 (m, 12H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[S:15])([CH3:4])([CH3:3])[CH3:2].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]=[CH:20][N:21]([CH3:23])[CH3:22])=[S:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCCNC(N)=S
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=S)NCCCCCNC(=O)OC(C)(C)C
Yield: 54 %

Procedure:
The title compound was synthesized from (5-Thioureido-pentyl)-carbamic acid tert-butyl ester and Dimethylformamide dimethyl acetal according to the procedure described for Example C in 54% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:29])[C:14]([CH2:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:41]([O:45][C:46](=[O:52])[CH2:47][S:48](Cl)(=[O:50])=[O:49])([CH3:44])([CH3:43])[CH3:42]>ClCCl>[CH:26]1([CH2:25][CH2:24][C:14]2([CH3:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]([OH:22])=[C:12]([C:7]3[NH:6][C:5]4[CH:30]=[CH:31][C:2]([NH:1][S:48]([CH2:47][C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:52])(=[O:50])=[O:49])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)[C:13]2=[O:29])[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)CS(=O)(=O)Cl
Reactant: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC3CC3)C1=O)N2
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a stirring solution of Example 158 (0.070 g, 0.160 mmol) in dichloromethane containing N,N-diisopropylethylamine (0.036 mL, 0.208 mmol) was added chlorosulfonyl-acetic acid tert-butyl ester (0.041 g, 0.192 mmol). The reaction mixture was stirred overnight and then partitioned between ethyl acetate and water. The organic layer was washed sequentially with 10% 1N HCl in water, bicarb, and brine. The product was purified by flash chromatography on SiO2 eluting with 0-50% ethyl acetate/hexanes yielding the title compound (0.030 g, 30.5% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm −0.23 (dd, J=9.01, 4.23 Hz, 2 H) 0.25 (d, J=6.62 Hz, 2 H) 0.45 (m, 2 H) 0.85 (m, 1 H) 1.25 (m, 1 H) 1.39 (s, 9 H) 1.57 (m, 3 H) 2.34 (m, 1 H) 4.22 (m, 2 H) 7.55 (m, 2 H) 7.62 (dd, J=10.29, 2.21 Hz, 2 H) 7.75 (m, 3 H) 8.15 (d, J=7.72 Hz, 1 H) 10.61 (s, 1 H) 13.73 (m, 1 H). MS (ESI+) m/z=516 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([I:13])[C:4]=1[OH:14].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1>[CH3:12][C:9]([C:7]1[CH:6]=[C:5]([I:13])[C:4]2[O:14][C:15]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[NH:1][CH2:2][C:3]=2[CH:8]=1)([CH3:11])[CH3:10]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)c1cc(I)c(O)c(CN)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(I)c2c(c1)CNC1(CCCCC1)O2
Reaction time: 16 h
Yield: 72.7 %

Procedure:
A mixture of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol (1.5 g., 0.005 mole), cyclohexanone (0.5 g., 0.005 mole), and magnesium sulfate (0.5 g.) in tetrahydrofurane (50 ml.) is kept under nitrogen at 20°-25° C., for 16 hours. The magnesium sulfate is removed and the filtrate evaporated to dryness. The residue is crystallized from ethanol to obtain 3,4-dihydro-6-(1,1-dimethylethyl)-8-iodospiro[2H-1,3-benzoxazine-2,1'-cyclohexane] (1.4 g.), m.p. 112-114° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][N:9]1[N:13]=[N:12][C:11]([C:14]2[CH:40]=[CH:39][C:17]([O:18][C:19]3[C:33]([CH:34]4[CH2:38][CH2:37][CH2:36][NH:35]4)=[CH:32][C:22]4[NH:23][C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)=[N:25][C:21]=4[CH:20]=3)=[CH:16][CH:15]=2)=[N:10]1>C(Cl)(Cl)Cl>[C:1]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[C:33]1[C:19]([O:18][C:17]2[CH:16]=[CH:15][C:14]([C:11]3[N:12]=[N:13][N:9]([CH3:8])[N:10]=3)=[CH:40][CH:39]=2)=[CH:20][C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[NH:23][C:22]=2[CH:32]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nnc(-c2ccc(Oc3cc4nc(-c5ccccn5)[nH]c4cc3C3CCCN3)cc2)n1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-c2nnn(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.006 ml of acetic anhydride was added to a chloroform (1 ml) solution of 24.7 mg of 5-(4-(2-methyl-2H-tetrazol-5-yl)phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole enantiomer A obtained in Example 542, and the reaction liquid was stirred at room temperature for 10 minutes. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain one chiral form of the entitled compound as a white solid.
Reaction SMILES: C([Li])CCC.[CH:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]>>[F:14][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[CH:19][C:20]=1[CH:6]([OH:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC=O
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Product: CCCCCCC(O)c1cccc(F)c1F

Procedure:
Quantities: n-butyllithium (50 cm3, 10.0M in hexanes, 0.5 mol), heptanal (57 g, 0.5 mol) and 1,2-difluorobenzene (57 g, 0.5 mol). The experimental procedure was as described in Example 16.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:14]2[CH:15]=[CH:16][C:12]([NH2:11])=[N:13]2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Nc1cc[nH]n1
Reactant: COc1cc(I)ccc1Br
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc(N)n2)ccc1Br
Temperature: 95 °C
Yield: 37.3 %

Procedure:
A mixture of 1-bromo-4-iodo-2-methoxybenzene (2.5 g, 7.99 mmol), 3-aminopyrazole (0.797 g, 9.59 mmol), salicylaldoxime (0.219 g, 1.598 mmol), Cu2O (91 mg, 0.479 mmol), and Cs2CO3 (3.9 g, 11.98 mmol) in DMF (8 mL) was degassed with N2 and heated at 95° C. overnight. After cooling to RT, the mixture was filtered through celite and rinsed with EtOAc. The filtrate was washed with water and brine. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10%-60% EtOAc in Heptane) to give 1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-amine (800 mg, MS: 270.3 [M+H+]).
Reaction SMILES: [C:1]1([C:7](=[O:18])[C:8]#[C:9][CH2:10][O:11]C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CCO>[OH:11][CH2:10][C:9]#[C:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18]
Reactant: O=C(C#CCOC1CCCCO1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: O=C(C#CCO)c1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of (1-phenyl-4-(tetrahydro-2H-pyran-2-yloxy)but-2-yn-1-one (3.0 g, 12.3 mmol) in EtOH (20 mL) was added pyridinium p-toluenesulfonate (0.62 g, 2.5 mmol). The resulting solution was stirred for 1 h at 50° C. and then the reaction mixture was poured into water (150 mL), extracted with Et2O (3×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4-hydroxy-1-phenylbut-2-yn-1-one as a dark red oil (3.2 g, crude).
Reaction SMILES: CC(O[C:6]([NH:8][C@H:9]([C:20]([OH:22])=[O:21])CC1NC2C=CC=CC=2C=1)=[O:7])(C)C.[NH:23](C(OC(C)(C)C)=O)[C@H:24](C(O)=O)CC1N=CNC=1.N[C@H](C(O)=O)CCC(=O)O>>[CH2:24]([NH2:23])[C:6]([NH:8][CH2:9][C:20]([OH:22])=[O:21])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc2ccccc2[nH]1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Product: NCC(=O)NCC(=O)O

Procedure:
The synthesis of the peptide resin 15 was done according to the method described in Example 6 by building on Boc glycine resin (2.0 g, 0.3 mmol Gly/g) or by using resin 14a and adding Boc-Trp, Boc-His (Bzl) and Pyro-Glu. Amino acid analysis gave Gly2.0 Ser0.96 Pro1.05 Glu1.05 Leu1.06 Tyr1.13 Arg1.10 BzlHis0.86. A suspension of 1.1 g of 13 in absolute ethanol was photolyzed and purified as described in Example 7. The purified protected decapeptide 15 was obtained in 64% yield (0.257 g): m.p. 155°-159°; tlc Rf1 0.80, Rf2 0.11, Rf3 0.75, Rf4 0.04; UV max (MeOH) 262 mμ (t = 6000); the nmr was consistent with the structure; [α]27D - 22 (c 1 (CH3CO2H); the amino acid composition was Gly1.90 Ser0.92 Pro1.0 Leu1.0 Tyr0.92 Arg1.02 Glu1.02.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:10]=[C:11]3[C:16](O)=[N:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:38]>ClCCCl>[Cl:38][C:16]1[C:11]2[C:12](=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:10]=2)[N:13]=[CH:14][N:15]=1
Reactant: Oc1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: ClCCCl
Product: Clc1ccc(-c2c3ncnc(Cl)c3nn2-c2ccccc2Cl)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
To a suspension of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol I-2A-1 b (17.55 g, 49.1 mmol) in 1,2-dichloroethane (109 ml) was added N,N-diethylaniline (32.8 ml, 206.22 mmol) followed by POCl3 (70 ml, 0.7 M). The reaction mixture was heated to reflux under nitrogen for 3 hours, and cooled to room temperature. The solvent was removed under reduced pressure. Excess POCl3 was removed by co-evaporation with toluene three times. The residue was dissolved in methylene chloride and slowly poured into vigorously stirred 1:1 CH2Cl2/saturated aqueous NaHCO3 (500 ml). Additional saturated aqueous NaHCO3 was added until the pH of the mixture was adjusted to neutral. The organic layer was separated and the aqueous layer was extracted with 200 ml methylene chloride three times. The organic layers were combined, dried (MgSO4), and concentrated. The residue was purified by SiO2-gel chromatography using 100% CH2Cl2 as the eluant to give 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine I-2A-1c (18.4 g, 76%): MS: 375.0 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NC(C)(C)C
Reaction time: 0.5 h

Procedure:
55.8 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.2 mol.) are dissolved in 300 ml. of alcohol and 25 g. of triethylamine. At reflux temperature, 14.6 g. of tert. butylamine are slowly added dropwise and the mixture is heated with stirring for an additional 30 minutes. The solvent is distilled off in vacuo and the residue is dissolved in benzene. The precipitated triethylamine hydrochloride is filtered off and the benzene layer is evaporated to dryness. The remaining oil, 6-chloro-4-[(1,1-dimethylethyl)amino]-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester crystallizes with methanol, yield 38.4 g. (61%), m.p. 40°-43°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([S:38](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH:31]=[CH:30][N:29]=1>C1COCC1>[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([S:38]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][N:10]=3)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH:31]=[CH:30][N:29]=1
Reactant: COc1ccc(CNc2ccncn2)cc1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.7 %

Procedure:
A 100-mL round-bottom flask was charged with N-(4-methoxybenzyl)pyrimidin-4-amine (Intermediate OO; 0.796 g, 3.70 mmol) and THF (16.08 ml). The flask was cooled in a dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (3.70 ml, 3.70 mmol) was added drop wise. The flask was removed from the cooling bath for 5 min, then recooled for 5 min. A solution of perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see EXAMPLE 73, STEP 1, 1.515 g, 3.70 mmol) in THF (4 mL with a 1-mL flask wash) was added drop wise. After 20 min, the flask was switched to an ice-water bath. The mixture was stirred for 20 min, then an additional portion of LHMDS solution (1 mL) was added drop wise. The mixture was warmed to room temperature and quenched by the addition of saturated aq. ammonium chloride. The mixture was extracted with EtOAc (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g silica gel loading column, 0-50% EtOAc/Heptante) to give 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (648 mg, 1.470 mmol, 39.7% yield) as a tan foam. m/z (ESI) 441.2 (M+H)+.