Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[C:30]([F:33])([F:32])[F:31])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[NH3:41]>CO>[Cl:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH:29]([O:28][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([NH2:41])=[O:26])[C:30]([F:32])([F:31])[F:33]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(c1ccccc1Cl)C(F)(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnc(CO)cc32)cc1OC(c1ccccc1Cl)C(F)(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 470 mg of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[1-(2-chlorophenyl)-2,2,2-trifluoroethoxy]thiophene-2-carboxylate and 40 ml of a saturated solution of ammonia in methanol is stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture is concentrated to dryness and the resulting residue is purified by flash chromatography (ethyl acetate/methanol, 90/10 (v/v)) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(O[CH:30]1[O:47][C@@H:46]([CH2:48][O:49][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:36]([O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:31]1[O:32][C:33](=[O:35])[CH3:34])(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCCl.C(Cl)(Cl)Cl.C(Cl)Cl.CO>[C:33]([O:32][C@H:31]1[C@H:36]([O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:46]([CH2:48][O:49][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:47][C@@H:30]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:35])[CH3:34]
Reactant: CC(=O)OC1O[C@@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(C)=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H]1[C@H](OC(=O)c2ccccc2)[C@H](COC(=O)c2ccccc2)O[C@@H]1n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.9 %

Procedure:
A suspension of 5-fluorouracil (5.0 g, 38.4 mmol) was treated with hexamethyldisilazane (HMDS, 260 mL) and a catalytic amount of ammonium sulfate during 18 h under reflux. After cooling to room temperature, the mixture was evaporated under reduced pressure, and the residue obtained as a colorless oil was diluted with anhydrous 1,2-dichloroethane (260 mL). To the resulting solution was added 1,2-di-O-acetyl-3,5-di-O-benzoyl-L-xylofuranose 1 (11.3 g, 25.6 mmol) [Ref.: Gosselin, G.; Bergogne, M. -C.; Imbach, J.-L., “Synthesis and Antiviral Evaluation of β-L-Xylofuranosyl Nucleosides of the Five Naturally Occurring Nucleic Acid Bases”, Journal of Heterocyclic Chemistry, 1993, 30 (October-November), 1229-1233] in anhydrous 1,2-dichloroethane (130 mL), followed by addition of trimethylsilyl trifluoromethanesulfonate (TMSTf, 9.3 mL, 51.15 mmol). The solution was stirred for 6 h at room temperature under argon atmosphere, then diluted with chloroform (1 L), washed with the same volume of a saturated aqueous sodium hydrogen carbonate solution and finally with water (2×800 mL). The organic phase was dried over sodium sulphate, then evaporated under reduced pressure. The resulting crude material was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-4%) in methylene chloride] to give 2 (11.0 g, 84% yield) as a white foam; mp=96-98° C.; UV (ethanol): λmax=228 nm (ε=25900) 266 nm (ε=9000), λmin=250 nm (ε=7200); 1H-NMR (DMSO-d6): δ 11.1 (br s, 1H, NH), 8.05 (1H, H-6, J6-F5=6.8 Hz), 7.9-7.4 (m, 10H, 2 C6H5CO), 5.99 (d, 1H, H-1′, J1′-2′=3.1 Hz), 5.74 (dd, 1H, H-3′, J3′-2′=4.2 Hz and J3′-4′=2.3 Hz), 5.54 (t, 1H, H-2′, J2′-1′=J2′-3′=2,9 Hz), 4.8-4.6 (m, 3H, H-4′, H-5′ and H-5″); MS: FAB>0 (matrix GT) m/z 513 (M+H)+, 383 (S)+, 105 (C6H5CO)+; FAB<0 (matrix GT) m/z 511 (M−H)−, 469 (M−CH3CO)−, 129 (B)−, 121 (C6H5CO2)−; [α]D20=−91 (c, 0.88 DMSO); Anal C25H21FN2O9 (C,H, N, F).
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:18]#[N:19])([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:20])(OC)=O.C(C1CC(C2C=CC(Cl)=CC=2)(C#N)CCC1=O)(OC)=O.S(=O)(=O)(O)O>C(O)(=O)C>[C:18]([C:9]1([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH2:10][CH2:5][C:6](=[O:20])[CH2:7][CH2:8]1)#[N:19]
Reactant: COC(=O)C1CC(C#N)(c2ccc(C)cc2)CCC1=O
Agent: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccc(C2(C#N)CCC(=O)CC2)cc1
Yield: 74 %

Procedure:
Following the procedure of Example 1, Part C, but substituting 39.3 gm. (0.145 mole) of 2-carbomethoxy-4-cyano-4-(p-tolyl)cyclohexanone (prepared in Part B, above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone and using 960 ml. glacial acetic acid and 480 ml. of 10 percent aqueous sulfuric acid instead of the 660 ml. and 330 ml., respectively, there is obtained after recrystallization from a mixture of diethyl ether and petroleum ether 22.84 gm. (74% yield) of 4-cyano-4-(p-tolyl)cyclohexanone having a melting range at 79° to 82° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:14](=O)([O-])[O-:15].[K+].[K+]>CO.O>[CH3:14][O:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(I)cc(CBr)c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCc1cc(I)cc(C(=O)OC)c1
Temperature: 55 °C
Yield: 96.5 %

Procedure:
A mixture of methyl 3-(bromomethyl)-5-iodobenzoate (400 mg, 1.1 mmol) and potassium carbonate (311 mg, 2.3 mmol) in methanol/tetrathydrofuran (5 mL/5 mL) was heated at 55° C. for 1 hour. After cooling, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. After drying in vacuo, 325 mg (94%) of methyl 3-(methoxymethyl)-5-iodobenzoate was isolated as a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:14][C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)CC[C@H]1F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
A mixture of tert-butyl trans-1-benzyl-4-fluoropiperidin-3-ylcarbamate (0.28 g, 0.91 mmol) and 10% Pd/C (0.097 g, 0.091 mmol) in MeOH (10 mL) was charged 1 atmosphere of hydrogen and stirred at room temperature for 4 hours. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give tert-butyl trans-4-fluoropiperidin-3-ylcarbamate (0.19 g, 96%) as oil.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]2=[N:5][C:4]([O:12][CH2:13][N:14]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([O:29][CH2:30][CH2:31][OH:32])=[CH:21][C:22]=3[CH:26]([CH3:28])[CH3:27])[S:15]2(=[O:17])=[O:16])=[CH:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:48][N:49]([CH3:54])[CH2:50][C:51](O)=[O:52]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]2=[N:5][C:4]([O:12][CH2:13][N:14]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([O:29][CH2:30][CH2:31][O:32][C:51]([CH2:50][N:49]([CH3:54])[CH3:48])=[O:52])=[CH:21][C:22]=3[CH:26]([CH3:27])[CH3:28])[S:15]2(=[O:17])=[O:16])=[CH:3]1
Reactant: CN(C)CC(=O)O
Reactant: CC(C)c1cc(OCCO)cc2c1C(=O)N(COc1cc(=O)n3c(n1)CCCC3)S2(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)c1cc(OCCOC(=O)CN(C)C)cc2c1C(=O)N(COc1cc(=O)n3c(n1)CCCC3)S2(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of the compound of Example 12 (0.8 g, 1.72 mmol) in CH2Cl2 (25 mL) containing 1,3-dicyclohexylcarbodiimide (1.06 g, 5.14 mmol) was added dimethyl glycine (0.19 g, 1.9 mmol), followed by 4-dimethylaminopyridine (0.21 g, 1.72 mmol). The mixture was stirred at room temperature for 2 hours, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica eluting with 10% methanol/ethyl acetate to afford 0.64 g (68%) of 2-[4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-2-yl]oxymethyl-4-isopropyl-6-[2-(dimethylaminomethylcarbonyloxy)ethoxy]saccharin as a white foam.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:31]=[CH:30][CH:29]=[C:7]2[C:8]([N:10]([CH:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)[CH2:14][C:15]([OH:17])=O)[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46]>O1CCCC1>[C:1]([NH:4][C:5]1[CH:31]=[CH:30][CH:29]=[C:7]2[C:8]([N:10]([CH:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)[CH2:14][C:15]([NH:45][OH:46])=[O:17])[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 48.2 %

Procedure:
3-(3-Acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(3-acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (2.0 g, 4.7 mmol), carbonyldiimidazole (1.14 g, 7.03 mmol) and hydroxylamine hydrochloride (651 mg, 9.37 mmol) in tetrahydrofuran (10 mL) to afford 3-(3-acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide as a white solid (1.0 g, 48% yield): mp, 117.0-119.0° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 2.19 (s, 3H, CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.98 (q, J=7.0 Hz, 2H, CH2), 5.65 (t, J=7.8 Hz, 1H, NCH), 6.87-6.95 (m, 2H, Ar), 6.99 (br s, 1H, Ar), 7.54 (d, J=6.9 Hz, 1H, Ar), 7.77 (t, J=7.45 Hz, 1H, Ar), 8.41-8.47 (m, 1H, Ar), 8.80 (br s, 1H, OH), 9.71 (s, 1H, NH), 10.59 (br s, 1H, NH); 13C NMR (DMSO-d6) δ24.69, 34.20, 44.09, 60.04, 65.48, 73.79, 121.78, 122.43, 126.69, 127.97, 129.64, 135.83, 141.00, 141.44, 145.75, 146.38, 157.70, 158.59, 175.97, 177.13, 178.19, 179.22; Anal Calcd for C22H23N3O7+0.3H2O: C, 59.14; H, 5.32; N, 9.40. Found: C, 59.32; H, 5.33; N, 9.02.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][S:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)(=[O:32])=[O:31].O>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:40][CH:39]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1c(Br)cn2c(=O)[nH]nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)cn2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
To a solution of 6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (Int. 15, 55 mg, 0.148 mmol) in DMF (3 mL) was added cesium carbonate (58 mg, 0.177 mmol) followed by 4-(methylsulfonyl)benzyl bromide (40 mg, 0.163 mmol) and the mixture was stirred at RT for 20 hrs. Further amounts of cesium carbonate (25 mg) and 4-(methylsulfonyl)benzyl bromide (20 mg) were added and stirring was continued for 2 hrs. Water was added and the mixture was extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound as a yellow solid (49 mg).
Reaction SMILES: [OH:1][CH:2]([C:20]1[N:21]=[CH:22][N:23](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:24]=1[CH3:25])[CH:3]1[C:18](=[O:19])[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][CH3:17])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3>C(O)(=O)C.O>[OH:1][CH:2]([C:20]1[N:21]=[CH:22][NH:23][C:24]=1[CH3:25])[CH:3]1[C:18](=[O:19])[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][CH3:17])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CCCc1c2n(c3ccccc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: O
Solvent: CC(=O)O
Product: CCCc1c2n(c3ccccc13)C(=O)C(C(O)c1nc[nH]c1C)CC2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
a solution of 8,9-dihydro-7-[(hydroxy) (5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-propylpyrido[1,2-a]-indol-6(7H)-one (1.65 g) in a mixture of acetic acid and water (4:1, 90 ml) was stirred at 60° C. for 4 hours. After evaporation of the solvent, the residue was diluted with as aqueous sodium bicarbonate solution and extracted three times with methylene chloride. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The crystalline residue was suspended in a mixture of methanol and chloroform and filtered to give one isomer of 8,9-dihydro-7-[(hydroxy) (5-methyl-1H-imidazol-4-yl)methyl]-10-propylpyrido[1,2-a]indol-6(7H)-one with an upper Rf value in silica gel thin layer chromatography (TLC) (6% methanol-chloroform) (0.27 g), which was designated as the isomer A. The filtrate was evaporated and purified by silica gel column chromatography (6% methanol-methylene chloride). The fractions eluted first contained the isomer A and the fractions eluted later contained another isomer of 8,9-dihydro-7-[(hydroxy) (5methyl-1H-imidazol-4-yl)methyl]-10-propylpyrido[1,2-a]indol-6(7H)-one with a lower Rf value in TLC, which was designated as the isomer B.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][C@H:15]1[CH2:18][C@H:17]([O:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[N+:27]([O-:29])=[O:28])[CH2:16]1)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:26][C:24]1[CH:23]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([CH:25]=1)[O:19][C@H:17]1[CH2:16][C@H:15]([NH2:14])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Reaction time: 2 h

Procedure:
14 ml trifluoroacetic acid were added to a mixture of 2.8 g [trans-3-(5-fluoro-2-nitrophenoxy)-cyclobutyl]-carbamic acid tert-butyl ester in 100 ml methylene chloride at 0° C. The mixture was stirred then for 2 hours at rt and afterwards concentrated. The residue was stirred with diisopropylether and filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH:33]([CH3:35])[CH3:34])[C:10]3[N:15]=[C:14]([C:16]4[CH:30]=[C:29]([CH3:31])[C:19]([O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[C:18]([CH3:32])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH:33]([CH3:34])[CH3:35])[C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[C:18]([CH3:32])[C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:29]([CH3:31])[CH:30]=4)[O:13][C:11]=3[N:12]=2)=[CH:36][CH:37]=1
Reactant: Cc1cc(-c2nc3c(C(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nc3c(C(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc(C)c1OCC(=O)O
Yield: 123.7 %

Procedure:
Analogously to example 1 (j), the reaction of 67 mg of tert-butyl {4-[5-(4-chlorobenzyl)-7-isopropyloxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetate with trifluoroacetic acid gave 74 mg (100%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([CH3:11])[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:3]1[C:2](=[O:1])[C:7]([C:8]([OH:10])=[O:9])=[CH:6][NH:5][C:4]=1[CH3:11]
Reactant: Cc1cc(O)c(C(=O)O)cn1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1[nH]cc(C(=O)O)c(=O)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-hydroxy-6-methyl-nicotinic acid (10.00 g, 65.3 mmol) in glacial acetic acid (35 mL) is added bromine (4.00 mL, 78.1 mmol). After stirring for 18 h at room temperature, additional bromine (0.5 mL) is added and the reaction mixture is stirred for an additional 24 h. The reaction mixture is evaporated under reduced pressure and the remaining residue is co-evaporated with toluene. The remaining residue is treated with a small amount of MeOH and then triturated with water. The precipitate is filtered off and dried. Yield: 13.8 g (92% of theory); ESI mass spectrum: [M+H]+=232 (bromine isotope pattern); Retention time HPLC: 0.61 min (Z002—002).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:10]=1)=[O:4].O[Li].O>C1COCC1.O>[CH3:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(-c2nccs2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3nccs3)c2)cc1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a solution of 4′-methyl-5-thiazol-2-yl-biphenyl-3-carboxylic acid methyl ester (0.310 g, 1 mmol) in THF (10 mL) was added a solution of LiOH—H2O (1.2 mmol) in H2O (15 mL) at 0° C. The reaction was allowed to warm to room temperature and was stirred until the disappearance of the ester was confirmed by TLC. Solvent was removed under reduced pressure and the aqueous solution was acidified to pH=2 by dropwise addition of 10% aqueous HCl. The resulting solid was collected by filtration and dried to yield 4′-Methyl-5-thiazol-2-yl-biphenyl-3-carboxylic acid (0.22 g, 75%). MS (M+H)=296.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([N:26]([CH2:34][C@H:35]1[C@@H:39]([F:40])[CH2:38][N:37](C(OCC2C=CC=CC=2)=O)[CH2:36]1)[C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][O:30]1)=[O:28])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([N:26]([CH2:34][C@H:35]1[C@@H:39]([F:40])[CH2:38][NH:37][CH2:36]1)[C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][O:30]1)=[O:28])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)C(=O)[C@@H]1CCCO1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[C@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)N(C[C@@H]1CNC[C@@H]1F)C(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ((3R,4R)-benzyl 3-(((S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)tetrahydrofuran-2-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (30 mg, 0.043 mmol) in degassed ethanol (0.5 mL, 0.1 M solution) was added Pd/C (3 mg, 10 wt %) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for 2 h. The reaction mixture was filtered through Celite® pad that was washed with EtOAc. The volatile organic filtrate was removed in vacuo to give the crude amine. The crude product was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The dried product was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h The white powdery (S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)tetrahydrofuran-2-carboxamide was obtained in 14% (5.4 mg) as the free amine. LC/MS (uplc): MH+ 572.0, 1.04 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)=O>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)[N:12]=3)[CH:11]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(OCC2CC2)cn1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CCO
Product: Oc1ccc(-c2cn3cc(OCC4CC4)ccc3n2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
A mixture of 5-(cyclopropylmethoxy)pyridin-2-amine (328 mg), 2-bromo-1-(4-hydroxyphenyl)ethanone (430 mg) and ethanol (10 mL) was stirred at 80° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The obtained crystals were dissolved in saturated aqueous sodium hydrogen carbonate solution and THF, and the solution was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a brown solid (561 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1>COC(C)(C)C.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: OCc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: COC(C)(C)C
Product: O=Cc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
1-(4′-Fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (299.3 g) and manganese dioxide (2.25 kg, type HMH, manufactured by Toso) were dispersed in t-butyl methyl ether (3.4 L) and the mixture was stirred at 10-30° C. for 6 hr. The reaction mixture was filtered and washed with t-butyl methyl ether (0.9 L). The solvent was evaporated under reduced pressure to give nearly pure 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde (258.2 g, 87%) as pale-yellow white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]2[CH2:14][C@@H:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)=O)(C)(C)C.[ClH:21]>>[ClH:21].[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[N:11]1[CH2:10][C@H:9]2[CH2:14][C@@H:12]1[CH2:13][NH:8]2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1CN2c1cnccn1
Agent: Cl
Product: c1cnc(N2C[C@H]3C[C@@H]2CN3)cn1

Procedure:
A solution of 3.2 g of product from Example 3 and 58 ml of 1N methanolic hydrogen chloride is stirred at room temperature overnight. The reaction is concentrated in vacuo to dryness, diluted with isopropyl alcohol and reconcentrated in vacuo to dryness. The residue is recrystallized from a mixture of isopropanol/diethyl ether to give 2.1 g of the desired product as pale yellow crystals:
Reaction SMILES: C(OC(=O)NC1CCNC([CH2:14][N:15]2[C:24]([C:25]#[N:26])=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:33][CH3:34])[CH:21]=3)[C:16]2=[O:35])C1)(C)(C)C.[ClH:37]>C(OCC)(=O)C>[ClH:37].[C:25]([C:24]1[N:15]([CH2:14][CH:22]2[CH2:23][CH2:24][NH:15][CH2:16][CH2:17]2)[C:16](=[O:35])[C:17]2[C:22]([C:23]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:21][C:20]([O:33][CH3:34])=[CH:19][CH:18]=2)#[N:26]
Reactant: COc1ccc2c(=O)n(CC3CC(NC(=O)OC(C)(C)C)CCN3)c(C#N)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(=O)n(CC3CCNCC3)c(C#N)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 57 (200 mg, 0.423 mmol) in ethyl acetate (100 mL) was cooled in an ice bath and treated with hydrogen chloride gas for 10 min. The resulting solution was stirred 1.5 h and then warmed to room temperature. Evaporation of the solvent in vacuo gave 58 as a white solid.