Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:15](=[O:27])[O:14][N:13]=2)=[N:9][O:10][N:11]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[O:27]=[C:15]1[O:14][N:13]=[C:12]([C:8]2[C:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][S:36]([CH3:35])(=[O:38])=[O:37])=[N:11][O:10][N:9]=2)[N:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1
Reactant: NCCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-{4-[(3-aminopropyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one hydroiodide (from Example 15, Step F; 25 mg, 50 μmol) in dichloromethane (1 mL) was treated with triethylamine (17 μL, 0.12 mmol) and methanesulfonyl chloride (6 μL, 70 μmol) and stirred at 25° C. for 2 h. The reaction mixture was concentrated to give the intermediate, N-{3-[(4-{5-oxo-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2,4-oxadiazol-3-yl}-1,2,5-oxadiazol-3-yl)amino]propyl}methanesulfonamide, as a crude residue which was used without further purification. A solution of the crude intermediate in methanol (1 mL) was treated with 2 N NaOH (0.25 mL, 0.5 mmol) and stirred at 25° C. for 30 min. The reaction mixture was treated with acetic acid (50 μL, 0.9 mmol), filtered and purified by preparative LCMS to give the desired product (13 mg, 65%) as a solid. LCMS for C14H18F3N6O4S (M+H)+: m/z=423.1. 1H NMR (400 MHz, DMSO-d6): δ 11.6 (s, 1 H), 9.11 (s, 1 H), 7.37 (dd, J=8.0, 8.0 Hz, 1 H), 7.20 (d, J=7.8 Hz, 1 H), 7.07-7.01 (m, 2 H), 6.96 (d, J=8.0 Hz, 1 H), 6.20 (t, J=5.9 Hz, 1 H), 3.27-3.22 (m, 2 H), 2.99-2.94 (m, 2 H), 2.87 (s, 3 H), 1.78-1.71 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][CH:3]=1.[Br-:21].[Br-:22].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO.O.CCOC(C)=O>[Br:21][C:16]1[CH:15]=[C:14]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([Br:22])[CH:4]=2)[N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: [Br-]
Reactant: Oc1ccc(C(c2ccc(O)cc2)n2cncn2)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1ccc(C(c2ccc(O)c(Br)c2)n2cncn2)cc1Br
Reaction time: 7 h

Procedure:
To a stirred solution of 1-[Bis-(4-hydroxyphenyl)methyl]-1H-[1,2,4]triazole (STX267, 500 mg, 1.87 mmol) in CH2Cl2/MeOH 1:1 (40 ml) at −78° C. under nitrogen, a solution of benzyltrimethylammonium tribromide (1.49 g, 3.74 mmol) in CH2Cl2/MeOH 1:1 (10 ml) was added dropwise over 45 min. The orange mixture was kept at 0° C. for 7 h and then at room temperature overnight, at which time the solution had become colorless. The reaction mixture was evaporated and the residue that obtained was dissolved in a mixture water (100 mL) and EtOAc (100 mL). The aqueous layer was separated and was further extracted with EtOAc (2×50 mL). The organic extracts were combined and washed with brine, dried (Na2SO4) and evaporated. The crude product was fractionated by flash chromatography (hexane/ethyl acetate, 1:3) and the second fraction that collected gave JRL01105 (STX356) (485 mg) as white solid at about 97% purity; δH (400 MHz, DMSO-d6) 6.90 (1H, s, CH), 6.93 (2H, d, J 8.6 Hz), 7.03 (2H, dd, J 2.1 and 8.6 Hz), 7.30 (2H, d, J 2.1 Hz), 8.06 (1H, s), 8.56 (1H, s) and 10.45 (2H, br s, exchanged with D2O, 2×OH). The main impurity was the mono-brominated derivative of STX356. A small quantity of this fraction was further purified by semi-preparative HPLC (Waters PrepLC RP18, 25×10 mm, flow rate: 10 mL/min, mobile phase: MeOH/H2O, 60:40). The fraction with a retention time of 5.5 nm in was collected and upon evaporation gave a white solid; m.p. 198-205° C. (dec.). Found: C, 42.2; H, 2.65; N, 9.79; C15H11Br2N3O2 requires C, 42.38, H, 2.61, N, 9.89.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:44])([CH:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)[C:9]2[CH:10]=[C:11]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=3)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16](COCC[Si](C)(C)C)[N:15]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+].CCOC(C)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:44])([CH:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)[C:9]2[CH:10]=[C:11]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=3)[S:12][C:13]=2[C:14]2[NH:18][CH:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(-c2cc(C(O)(c3ccc(Cl)cc3)C3CCN(C)CC3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2cc(C(O)(c3ccc(Cl)cc3)C3CCN(C)CC3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 80 °C
Yield: 25 %

Procedure:
A 5 mL microwave tube was charged with N-(4-{4-[(4-chlorophenyl)(hydroxy)(1-methylpiperidin-4-yl)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl}pyridin-2-yl)acetamide (10.0 mg, 0.0153 mmol) and tetrahydrofuran (0.500 mL, 6.16 mmol). To the solution was added 1.00 M of tetra-n-butylammonium fluoride in tetrahydrofuran (61.2 uL). The tube was sealed and heated to 80° C. in an oil bath for 4 hrs. The resulting mixture was cooled to rt and distributed between NaHCO3(aq) saturated solution and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined org layer was dried and concentrated. Purification on HPLC (reverse phase, AA) provided N-(4-{4-[(4-chlorophenyl)(hydroxy)(1-methylpiperidin-4-yl)methyl]-5-(4H-1,2,4-triazol-3-yl)-2-thienyl}pyridin-2-yl)acetamide as a white solid. (2.0 mg, 25% yield) LCMS (AA) ES+ 523, 525; 1H NMR (400 MHz, MeOD) δ 8.50-8.42 (s, 1H), 8.41-8.36 (s, 1H), 8.36-8.29 (d, J=5.3 Hz, 1H), 7.92-7.83 (s, 1H), 7.50-7.43 (m, 1H), 7.43-7.34 (d, J=8.6 Hz, 2H), 7.25-7.14 (d, J=8.6 Hz, 2H), 2.91-2.76 (m, 1H), 2.65-2.55 (m, 4H), 2.26-2.15 (s, 3H), 2.11-2.01 (m, 2H), 1.88-1.72 (m, 2H), 1.70-1.57 (s, 1H), 1.47-1.35 (dd, J=15.0, 7.4 Hz, 1H), 1.31-1.20 (m, 2H).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18]CC)=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[CH2:28][CH3:29].O.[OH-].[Li+]>O.C(O)C.CCOC(C)=O.CN(C=O)C>[CH2:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:16]([OH:18])=[O:17])[CH:8]([C:12]([F:14])([F:13])[F:15])[O:9]3)=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)[CH2:28][CH3:29]
Reactant: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Reactant: CCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1ccc(Oc2ccc3c(c2)OC(C(F)(F)F)C(C(=O)O)=C3)cc1
Temperature: 110 °C

Procedure:
To the mixture of ethyl 7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.29 g, 1.0 mmol) and potassium carbonate (0.21g, 1.4 mmol) was added 4-propylphenol (0.153 mL, 1.1 mmol) and 3 mL of dry DMF. The resulting mixture was heated at 110° C. for 15 hrs. LC-MS indicated that the reaction was done. To the reaction was added 15 mL of EtOAc. The resulting organic phase was washed with brine, and the volatiles were removed. To the residue was added 3 mL of THF, and a solution of lithium hydroxide hydrate (105 mg, 2.5 mmol) in 3 mL of water. Then to the resulting mixture was added 3 mL of ethanol. The resulting solution was heated at 80° C. for 5 hrs. LC-MS indicated that the reaction was completed. The volatiles were removed, the residue was diluted with water, and acidified at 0° C. with dilute HCl to pH=1.0, the product was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After removing the volatiles, it gave a light yellow oil. The residue was purified on reverse phase HPLC. The product was obtained as a light yellow solid, 80 mg (21%). M.P.=143.5-146.5° C. 1H(CDCl3/300 Mhz) 7.80(s, 1H), 7.18-7.13(m, 3H), 6.96(d, J=8.4 Hz, 2H), 6.59-6.52(m, 2H), 5.62(q, 1H, J=6.9 Hz), 2.57(t, 2H, J=6.9 Hz,), 1.67-1.57(m, 2H), 0.93(t, J=7.2 Hz, 3H). 13C NMR(CDCl3/300 MHz)169.5, 163.6, 155.5, 153.0, 139.7(d, J=13.0 Hz), 131.4, 130.2(d, J=5.3 Hz), 123.7(q, J=287.6 Hz), 120.6, 119.8, 113.7, 112.8, 112.0, 105.0, 70.7(q, J=33.5 Hz), 73.6, 24.9, 14.1. 19F(CDCl3/300 MHz) −78.96(d, J=6.9 Hz). LC-MS(EI+) 379.1 (M+1, 100). HRMS (EI+) m/z calcd for (C20H17F3O4) 378.1079(M+), found 378.1061.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:21]=[CH:22][C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:32])(C)(C)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:15][C:14]1[CH:13]=[C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:21]=[CH:22][C:23]=3[N:24]=2)[CH:11]=[C:10]([CH3:32])[C:9]=1[O:8][CH2:7][C:6]([OH:33])=[O:5]
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4)nc3o2)cc(C)c1OCC(=O)O

Procedure:
A solution of 77 mg of [2,6-dimethyl-4-(5-phenoxy-oxazolo[5,4-d]pyrimidin-2-yl)-phenoxy]-acetic acid tert-butyl ester in 0.7 ml of trifluoroacetic acid was stirred at room temperature for 2 h. Then 5 ml of toluene were added and the solvents were distilled off in vacuo. The residue was triturated with 2 ml of acetonitrile, and the title compound was isolated by filtration. Yield: 26 mg of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[C:35]([C:36]([F:37])([F:38])[F:39])[C:29]=3[F:28])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1cccc(C(F)(F)F)c1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cccc(C(F)(F)F)c3F)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 36.4 %

Procedure:
The title compound was prepared following the procedure described for Example-137 using methyl 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-15, 0.100 g, 0.256 mmol), 2-fluoro-3-(trifluoromethyl)aniline (0.068 g, 0.379 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.050 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 3.13 (s, 2H), 7.32 (m, 2H), 7.42-7.45 (m, 4H), 8.76 (m, 1H), 10.20 (s, 1H), 11.20 (s, 2H); MS [M+H]+: 537.19.
Reaction SMILES: [CH2:1]([C@@:4]1([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].C[NH:39][S:40]([CH:43]1[CH2:45][CH2:44]1)(=[O:42])=[O:41]>>[CH2:1]([C@@:4]1([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:39][S:40]([CH:43]2[CH2:45][CH2:44]2)(=[O:42])=[O:41])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Reactant: CNS(=O)(=O)C1CC1
Product: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CC2)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one (Example 414, Step B) and N-methylcyclopropanesulfonamide by a procedure similar to the one described in Example 201, Step A. The product was purified by chromatography through a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[OH:9].N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:17][S:18]([O:9][CH:3]1[C:4]([CH3:8])([CH3:7])[CH2:5][CH2:6][C:2]1([CH3:10])[CH3:1])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CCC(C)(C)C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)C1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.6 %

Procedure:
2.84 g of 2,2,5,5-tetramethylcyclopentanol and 3.2 ml of pyridine were dissolved in 20 ml of methylene chloride, and 4.5 g of methanesulfonyl chloride was added thereto. The mixture was stirred at room temperature for 12 hours, and then 50 ml of aqueous saturated sodium hydrogen carbonate solution was added thereto. The mixture was extracted with 50 ml of ethyl acetate, and the organic layer was washed with aqueous 10% copper sulfate solution, and concentrated under reduced pressure. The resulting residue was recrystallized from n-hexane, whereby 1.26 g of 1-methanesulfonyloxy-2,2,5,5-tetramethylcyclopentane was obtained (m.p 46° C.).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][N:9]([NH2:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:22])([CH3:21])[CH3:20])[N:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[OH:22][C:19]([C:15]1[N:14]=[C:13]([CH2:12][N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=4)[C:3]=3[NH:10][N:9]2[NH2:11])[CH:18]=[CH:17][CH:16]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1cccc(CN2c3ncnc(Cl)c3NN2N)n1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ncnc3c2NN(N)N3Cc2cccc(C(C)(C)O)n2)c1
Yield: 37 %

Procedure:
Prepared as described in Example 20 from 7-chloro-3-(6-[1-hydroxy-1-methylethyl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine and 3-methoxyphenylboronic acid (0.08 g, 0.56 mmol) to give the title compound (68 mg, 37%) as a yellow solid.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=1>>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:31][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])[C:6]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:5][N:4]=2)[CH:25]=1
Reactant: OCc1cccnc1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Clc1ccc(-c2cnc(OCc3cccnc3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with 3-pyridinemethanol according to the procedure described in Example 59 to afford 2-(3-pyridylmethoxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=442 (M++1); Rt=3.01 min; 1H-NMR 500 MHz (CDCl3): δ 5.61 (s, 2H), 7.05 (d, J=9 Hz, 2H), 7.15-7.22 (m, 1H), 7.24-7.32 (m, 4H), 7.50-7.58 (m, 1H), 7.60 (m, 1H), 7.62-7.63 (m, 1H), 8.45 (m, 1H), 8.83 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.[N:22]1[C:23]([CH2:31]Cl)=[CH:24][N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12.C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4]([N:16]2[CH2:17][CH2:18][N:19]([CH2:31][C:23]3[N:22]=[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]4[CH:24]=3)[CH2:20][CH2:21]2)[N:3]=1
Reactant: ClCc1cn2ccccc2n1
Reactant: Nc1nc(N2CCNCC2)cc2nc(-c3ccco3)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCN(Cc3cn4ccccc4n3)CC2)cc2nc(-c3ccco3)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
In 7.5 mL of DMF, 500 mg (1.75 mmol) of Compound F and 582 mg (3.51 mmol) of imidazo[1,2-a]pyridin-2-ylmethyl chloride were dissolved. The solution was cooled to 0° C. in an ice bath, and then 1.6 mL of triethylamine was added thereto, followed by stirring at room temperature overnight. After completion of the reaction, water was added to the reaction mixture and a 1.0 mol/L sodium hydroxide solution was further added thereto to adjust the solution to be basic. Then, the mixture was extracted by adding chloroform, and the organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography (2% methanol-chloroform) and then recrystallized from ethanol to obtain 374 mg of Compound 15 as white powder (yield: 51%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][N:11]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(OCc1ccccc1)N(Cc1ccccc1)C[C@H]1CCNC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC[C@H](CN(Cc2ccccc2)C(=O)OCc2ccccc2)C1
Yield: 63 %

Procedure:
Acetyl chloride (2.86 g) was added to a stirred solution of benzyl N—((S)-pyrrolidin-3-ylmethyl)-N-benzylcarbamate (Intermediate 166, 5.9 g) and triethylamine (3.68 g) in DCM (80 mL) with ice cooling. The resultant mixture was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with ethyl acetate to give benzyl N—((S)-1-acetylpyrrolidin-3-ylmethyl)-N-benzylcarbamate (4.2 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]2[S:14][C:13]([NH2:16])=[N:12][C:11]=2[NH:10][N:9]=1.[C:17]([O:20][C@@H:21]([CH3:25])[C:22](Cl)=[O:23])(=[O:19])[CH3:18].C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]2[S:14][C:13]([NH:16][C:22]([C@@H:21]([O:20][C:17](=[O:19])[CH3:18])[CH3:25])=[O:23])=[N:12][C:11]=2[NH:10][N:9]=1
Reactant: Nc1nc2[nH]nc(-c3ccccc3Cl)c2s1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: CC(=O)O[C@@H](C)C(=O)Nc1nc2[nH]nc(-c3ccccc3Cl)c2s1
Temperature: 70 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a vial charged with 3-(2-chloro-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine (30 mg, 0.12 mmol) and PS-DMAP (Argonaut resin, 450 mg, 5 equiv.) were added THF (0.8 mL) and (S)-(−)-2-acetoxypropionyl chloride (126 mg, 0.84 mmol). The reaction mixture was shaken at 70° C. overnight, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 1.03 g, 30 equiv.) at 50° C. for 4 hours. The resin was filtered, washed with DMF and the solvent was evaporated. Purification by reverse-phase preparative HPLC provided 21 mg (48% yield) of the title compound. 1H-NMR (d6-DMSO) δ: 7.78 (broad m, 1H), 7.61 (broad m, 1H), 7.47 (broad m, 2H), 5.13 (q, 1H), 2.09 (s, 3H), 1.44 (d, 3H); HPLC/MS m/z: 365.0 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][C:18](=[O:23])[CH2:17]3)=[N:13][CH:12]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:73]1[N:78]=[C:77]([C:79]([F:82])([F:81])[F:80])[CH:76]=[CH:75][N:74]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[N+:8]([C:6]1[CH:5]=[C:4]([C:11]2[S:15][C:14]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][C:18](=[O:23])[CH2:17]3)=[N:13][CH:12]=2)[CH:3]=[C:2]([NH:1][C:73]2[N:78]=[C:77]([C:79]([F:82])([F:81])[F:80])[CH:76]=[CH:75][N:74]=2)[CH:7]=1)([O-:10])=[O:9]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Nc1cc(-c2cnc(N3CCCNC(=O)C3)s2)cc([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C1CN(c2ncc(-c3cc(Nc4nccc(C(F)(F)F)n4)cc([N+](=O)[O-])c3)s2)CCCN1
Temperature: 125 °C
Reaction time: 5 h

Procedure:
4-[5-(3-Amino-5-nitrophenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (482 mg, 1.446 mmol), XantPhos (251 mg, 0.434 mmol), cesium carbonate (942 mg, 2.89 mmol), palladium(II) acetate (64.9 mg, 0.289 mmol), dioxane (10 mL) and 2-chloro-4-(trifluoromethyl)pyrimidine (0.174 mL, 1.446 mmol) were successively added in a sealable reaction tube under nitrogen. The tube was sealed and the mixture was stirred at 125° C. for 5 hours. The reaction mixture was cooled to room temperature, partitioned between 25% aqueous ammonium acetate and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and three times with 2-methyltetrahydrofuran. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification via CombiFlash (ethanol/dichloromethane) afforded 4-[5-(3-nitro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one as an amber gum. MS APCI: [M+H]+ m/z 480.1.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[N:13]([C:24](=[O:28])[NH:25][CH2:26][CH3:27])[N:12]=2)=[CH:7][CH:6]=1)(=O)C>CO.[OH-].[Na+].O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[N:13]([C:24](=[O:28])[NH:25][CH2:26][CH3:27])[N:12]=2)=[CH:7][CH:6]=1
Reactant: CCNC(=O)N1N=C(c2ccc(NC(C)=O)cc2)c2cc(SC)ccc2C1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCNC(=O)N1N=C(c2ccc(N)cc2)c2cc(SC)ccc2C1C
Yield: 87 %

Procedure:
The solution of acetyl amide 9 in methanol and NaOH (2 N) was refluxing until there is no more starting material left monitored by TLC. The solution was diluted with water, and extracted with DCM three times. Removal of the solvent afforded the crude product, which was purified by using a silica gel column, gave the desired products 12 (Yield: 87%). 1HNMR (CDCl3): 7.45 (d, J=8.6 Hz, 2H), 7.35−7.25 (m, 4H), 6.78 (d, J=8.6 Hz, 2H), 6.53 (br, 1H), 5.60 (q, J=13.2 Hz, 1H), 3.42 (m, 2H), 2.40 (s, 3H), 1.22 (m, 6H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][CH2:13]1)C>C1COCC1>[N:20]1[CH:21]=[CH:22][CH:23]=[N:24][C:19]=1[NH:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([CH2:11][CH2:10][OH:9])[CH2:17][CH2:16]1
Reactant: CCOC(=O)C[C@H]1CC[C@H](Nc2ncccn2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC[C@H]1CC[C@H](Nc2ncccn2)CC1
Reaction time: 0.08 h

Procedure:
A suspension of lithium aluminum hydride (0.45 g, 11.85 mmol) is cooled in an ice water bath and treated with a solution of trans-[4-(pyrimidin-2-ylamino)-cyclohexyl]-acetic acid ethyl ester (2.09 g, 7.9 mmol) in THF (15 mL) over 20 minutes. After stirring for 5 minutes, the ice bath is removed, and the reaction is stirred for an additional 40 minutes. The reaction is quenched with water, and sodium hydroxide is added. The mixture is stirred for 1 hour and is filtered through Celite and the filtrate evaporated to give trans-2-[4-(pyrimidin-2-ylamino)-cyclohexyl]-ethanol which is used without further purification.