Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:18]1[O:19][C:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][C:2]([C:18]2[O:19][C:20]([C:23]3[N:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)=[O:1])=[CH:10][CH:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(O)CCc3ccc(Oc4ccccc4)cc3)o2)nc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cnc(C(=O)CCc3ccc(Oc4ccccc4)cc3)o2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
Methyl 6-(2-(1-Hydroxy-3-(4-phenoxyphenyl)propyl)oxazol-5-yl)pyridine-3-carboxylate (77 mg, 0.18 mmol) was dissolved in anhydrous CH2Cl2 (2.5 mL) and Dess-Martin periodinane (113 mg, 0.268 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 90 min. The addition of saturated aqueous NaHCO3 quenched the reaction and the organic layer was washed with saturated aqueous Na2S2O3 then saturated aqueous NaCl. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 0-50% EtOAc/hexanes) to provide methyl 6-(2-(3-(4-phenoxyphenyl)propanoyl)oxazol-5-yl)pyridine-3-carboxylate as a white solid (63 mg, 82%): 1H NMR (CDCl3, 500 MHz) δ 9.22 (d, 1H, J=1.0 Hz), 8.39 (dd, 1H, J=8.0, 2.0 Hz), 7.97 (s, 1H), 7.91 (d, 1H, J=8.0 Hz), 7.30 (t, 2H, J=7.5 Hz), 7.22 (d, 2H, J=8.5 Hz), 6.93 (d, 2H, J=8.5 Hz), 3.97 (s, 3H), 3.46 (t, 2H, J=7.0 Hz), 3.09 (t, 2H, J=7.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 187.2, 165.0, 157.6, 157.4, 155.5, 152.5, 151.2, 149.2, 138.2, 135.1, 129.7, 129.6, 128.7, 125.8, 123.0, 119.6, 119.1, 118.6, 52.6, 40.8, 28.9; HR ESI-TOF m/z 429.1440 (M+H+, C25H20N2O5, requires 429.1445).
Reaction SMILES: [CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][C:2]=1[C:14]([O:16]C)=[O:15].[OH-].[Na+].Cl>CO.O>[CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][C:2]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1cn2c(n1)COc1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn2c(n1)COc1ccccc1-2
Yield: 90.4 %

Procedure:
10.0 g (0.0435 mole) of methyl 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate were suspended in a mixture of 100 ml of methanol and 50 ml of water and 2N NaOH solution was added to the mixture thus obtained until the pH was 11. The mixture was warmed until the starting material had completely dissolved and thin layer chromatography indicated that no starting material remained. The solution was subsequently acidified to a pH of 2-3 with concentrated hydrochloric acid and the desired product precipitated out. After cooling, the mixture was filtered and the solid product was washed well with water. The white product was dried over P2O5 to obtain 8.5 g (91% yield) of 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylic acid with a melting point of 256°-8° C. (decarboxylates).
Reaction SMILES: O[C:2]([C:5]1[S:9][C:8]([NH:10]C(=O)OC(C)(C)C)=[N:7][C:6]=1[CH2:18][CH2:19][O:20]C1CCCCO1)([CH3:4])[CH3:3].Cl.[OH-].[Na+]>C1COCC1>[CH3:4][C:2]1([CH3:3])[C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH2:18][CH2:19][O:20]1
Reactant: CC(C)(C)OC(=O)Nc1nc(CCOC2CCCCO2)c(C(C)(C)O)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)OCCc2nc(N)sc21
Yield: 51.3 %

Procedure:
To a solution of Example 89D (4.6 g, 11 mmol) in THF (90 mL) was added conc. HCl (6.9 mL). The reaction mixture was refluxed for overnight and then cooled. The mixture was basified with 5N NaOH ((17 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-10% methanol in dichloromethane) to afford 1.04 g (51%) of the title compound. MS (ESI+) m/z 185 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:12])=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[F:12][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([O:14][CH3:13])=[N:3]2)=[CH:8][CH:7]=1
Reactant: C[O-]
Reactant: Fc1ccc2ncc(Cl)nc2c1
Agent: [Na+]
Solvent: CO
Product: COc1cnc2ccc(F)cc2n1
Yield: 93.5 %

Procedure:
To a solution of 2-chloro-7-fluoroquinoxaline (0.1 g, 0.54 mmol) in methanol (15 ml) was added sodium methoxide (0.29 g, 0.54 mmol) at room temperature under nitrogen atmosphere. The reaction mass was heated at reflux for 3 h. The solvent was evaporated under reduced pressure and the residue was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound 7-fluoro-2-methoxyquinoxaline (0.09 g, 88% yield) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.41 (s, 1H), 8.01-7.98 (d, J=12 Hz, 1H), 7.49-7.46 (d, J=12 Hz, 2H), 7.34-7.3 (m, 1H), 4.09-4 (s, 3H); 19F NMR: δ ppm −108.99 (1F).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH3:25]>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:22]([CH2:21][CH2:20][O:19][CH3:18])[CH2:23][CH2:24][CH3:25])=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCCNCCOC
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: CCCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
300 mg (1.16 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using N-(2-methoxyethyl)propan-1-amine to give after working up and purification 293 mg (71%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]([CH3:13])[CH3:12].I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>[Cu]Br.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:6]=[C:5]2[CH:11]([CH3:13])[CH3:12]
Reactant: Ic1ccccc1
Reactant: CC(C)c1c[nH]c2ccc(Br)cc12
Agent: [Cu+2]
Agent: [Cu]Br
Agent: CC(=O)[O-]
Product: CC(C)c1cn(-c2ccccc2)c2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
Copper(I) bromide (66 mg, 0.462 mmol) was added to a solution of 94A (1.1 g, 4.62 mmol) in iodo benzene (3.77 g, 18.48 mmol) followed by potassium carbonate (2.55 g, 18.48 mmol), and the mixture was stirred at 100° C. for 10 min. NaOH (150 mg, 3.75 mmol) and copper(II) acetate (10 mg, 0.055 mmol) was added at 140° C., and the mixture was stirred for 9 h. Insoluble solids were filtered, the filtrate was concentrated and partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography using 8% ethyl acetate in hexane to afford title compound (1.0 g, 68.9%) as an oil. 1H NMR (300 MHz, CDCl3): δ 7.80 (d, J=2.1 Hz, 1H), 7.54-7.42 (m, 5H), 7.4-7.28 (m, 2H), 7.21-7.08 (m, 2H), 3.19 (m, 1H), 1.38 (d, J=6.9 Hz, 6H).
Reaction SMILES: C1(C)C=CC=CC=1.Cl.[NH2:9][CH2:10][CH2:11][SH:12].C(N(CC)CC)C.[CH3:20][C:21](=[N:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](=[N:43][O:44][CH3:45])[CH:41]=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>[Cl-].[Na+].O.C(O)CCC>[CH3:45][O:44][N:43]=[C:40]([CH:41]1[NH:9][CH2:10][CH2:11][S:12]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[O:33][N:32]=[C:21]([CH3:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1
Reactant: NCCS
Reactant: CON=C(C=O)c1ccccc1ON=C(C)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCO
Product: CON=C(c1ccccc1ON=C(C)c1cccc(C(F)(F)F)c1)C1NCCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Toluene (2.5 ml), butanol (2.5 ml), cysteamine hydrochloride (0.29 g, 2.54 mmol) and triethylamine (0.26 g, 2.54 mmol) were added to 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxy]-α-methoxyiminophenylacetaldehyde (0.48 g, 1.27 mmol), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, half-saturated brine (100 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxy]phenyl thiazolidin-2-yl ketone O-methyloxime (0.52 g, yield 93.6%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13]O2.[CH3:30][NH2:31]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:31]([CH3:30])[CH:13]=[CH:14][N:15]2[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([OH:29])([CH3:27])[CH3:28])=[N:24][N:25]=2)[N:22]=1
Reactant: CN
Reactant: CC(C)(O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Solvent: O
Solvent: C1COCCO1
Product: Cn1ccn2c(-c3ccc4nnc(C(C)(C)O)n4n3)c(-c3ccc(F)cc3F)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
The 2-(6-(6-(2,4-difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)propan-2-ol (0.200 g, 0.505 mmol, Example #35) in 1,4-dioxane (1 mL) and 40% methylamine in water (1.5 mL, 17 mmol) was heated in a CEM microwave at about 120° C. for about 55 minutes, (100 psi maximum pressure, 5 min ramp, 300 max watts). The mixture was evaporated and then dissolved in HOAc (2 mL). The solution was stirred at room temperature for about 1 hour then the material was purified by RP-HPLC (Table 1, Method f). The combined fractions were concentrated under reduced pressure to remove the acetonitrile then the solution was basified with saturated aqueous NaHCO3 solution gave an oil. The mixture was extracted with 20% EtOAc in DCM (25 mL) then EtOAc (approx. 15 mL). The combined organics solutions were dried over MgSO4 then filtered and evaporated. The solid was triturated with about 10 mL water then collected by filtration. The material was dissolved in hot acetonitrile (1 mL) then added dropwise to about 10 mL water. The solution was allowed to stand at ambient temperature until a solid formed then the mixture was diluted with water (5 mL). The solid was collected by filtration then dried under vacuum at about 80° C. to give the title compound (0.040 g, 20%); 1H NMR (DMSO-d6) δ 8.15 (d, 1H), 8.10 (d, 1H), 7.76-7.67 (m, 1H), 7.46 (m, 2H), 7.31-7.23 (m, 1H), 6.85-6.80 (m, 1H), 5.66 (s, 1H), 3.72 (s, 3H), 1.78 (s, 6H); LC/MS (Table 1, Method g) Rt=1.65 min; MS m/z: 410.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])/[C:5](/[O:31][CH2:32][CH3:33])=[CH:6]/[C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([O:31][CH2:32][CH3:33])[CH2:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:22][C:23]=2[CH3:24])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2c1CCC2)OCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2c1CCC2)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
250 mg of Pd/C were added under argon to 850 mg of 2Z-ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-acrylic acid ethyl ester (1.84 mmol) dissolved in 10 ml of tetrahydrofuran. The atmosphere was then replaced with H2, and the suspension was rapidly stirred at room temperature under the atmosphere of H2 for four hours. Filtration over dicalite and evaporation of the solvents left 850 mg (99.6%) of [rac]-2-ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-propionic acid ethyl ester as brown oil.
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH:4]=1.[NH2:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([NH:39][OH:40])=[NH:38])=[CH:35][N:34]=1>>[F:31][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:40][N:39]=[C:37]([C:36]4[CH:41]=[CH:42][C:33]([NH2:32])=[N:34][CH:35]=4)[N:38]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH:4]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)c(OCC(F)(F)F)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.14) (228 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (125 mg, 44%). MS (ISP) 572.1 [(M+H)+]; mp 285° C.
Reaction SMILES: CO[C:3](=[O:25])[C:4]([OH:24])=[CH:5][C:6](=[O:23])[N:7]([O:16][CH2:17][C:18](=[O:22])[N:19]([CH3:21])[CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:34][N:35](C)[C:36](C1CN(C)C(=O)C=1O)=O>>[CH3:21][N:19]([CH3:20])[C:18]([CH2:17][O:16][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[C:6]([C:5]1[CH2:34][N:35]([CH3:36])[C:3](=[O:25])[C:4]=1[OH:24])=[O:23])=[O:22]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)OCC(=O)N(C)C
Agent: C=O
Agent: CN
Product: CN(C)C(=O)CON(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 25 %

Procedure:
3-[Dimethylcarbamoylmethoxy-(4-fluorobenzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 72-B) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (25% yield); mp 147–149° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.79 (3H, s, NCH3), 2.96 (3H, s, NCH3), 3.11 (3H, s, NCH3), 4.25 (2H, s, CH2), 4.51 (2H, s, CH2), 4.96 (2H, s, CH2), 7.06 (2H, m, aromatics), 7.38 (2H, m, aromatics), 11.54 (1H, broad s, OH). HRMS (ES+) calculated for C17H21FN3O5, [M+H]+: 366.146524. found: 366.146176.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].C(C1C=C(C=C(OC(C)C)C=1)C(O)=O)#N>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Agent: CC(C)Oc1cc(C#N)cc(C(=O)O)c1
Product: CC(C)Oc1ccc(C(=O)O)cc1Cl

Procedure:
Prepared from methyl 3-chloro-4-isopropoxybenzoate according to the procedure for 3-cyano-5-isopropoxybenzoic acid. LCMS-ESI (m/z) calculated for C10H11ClO3: 214.7; found 215.0 [M+H]+, tR=3.22 min. 1H NMR (400 MHz, CDCl3) δ 12.94 (s, 1H), 7.98-7.74 (m, 2H), 7.26 (d, J=8.9 Hz, 1H), 4.80 (dt, J=12.1, 6.0 Hz, 1H), 1.33 (t, J=5.6 Hz, 6H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C@@H:10]2[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]2[O:12]C(=O)C)[N:6]=1)=O.[NH3:28]>CO>[C@@H:10]1([N:7]2[CH:8]=[N:9][C:5]([C:3]([NH2:28])=[O:2])=[N:6]2)[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@H:11]1[OH:12]
Reactant: N
Reactant: COC(=O)c1ncn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)n1
Solvent: CO
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Yield: 90 %

Procedure:
A solution of 1-(2,3,5-tri-O-acetyl-β -D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester (10.0 g., 26.0 mmole) in methanol (70 ml.) saturated at 0° with anhydrous ammonia was kept in a sealed pressure flask at 25° for 18 hrs. The product was crystallized from ethanol to give 1-(β -D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (5.70 g., 90.0%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.C([Li])CCC>C1COCC1>[CH2:12]([O:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([B:20]([OH:21])[OH:19])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)COS(=O)(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)COS(=O)(=O)c1ccc(B(O)O)cc1
Temperature: 20 °C
Yield: 92 %

Procedure:
To a solution of isobutyl 4-bromobenzenesulfonate (56 g, 200 mmol) in 280 ml of THF was added triisopropylborate (84 ml, 1.82 eq) and the reaction mixture was cooled to less than −65° C. To the cooled solution, n-butyllithium (144 ml, 0.9 eq, 1.07 M in hexanes) was slowly added while maintaining the temperature below −65° C. The reaction mixture was stirred for at least 0.5 hours and then was quenched with 1M sulfuric acid (200 ml). The reaction mixture was allowed to warm to ca. 20° C. The layers were separated and the rich organic layer containing 35 g (92% yield) of 4-(isobutoxysulfonyl)phenylboronic acid was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][NH:6]3.[CH2:22]=[O:23]>C(O)(=O)C>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][OH:23]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2
Reactant: C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2CO

Procedure:
100 mg of the compound (5) obtained in Example 1 was dissolved in 3 ml of acetic acid, and while stirring, 1.5 ml of formalin was added to the solution. The solution was stirred for 30 minutes, and the deposited solid matter was filtered off and washed with ether to obtain 64 mg of the subject compound (177).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:11]([N:9]1[C:8](=[O:15])[N:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)=[C:3]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:4]2=[N:10]1)[CH:12]([CH3:14])[CH3:13]
Reactant: Cc1ccc(-c2c(Br)ccn3c(=O)n(CC(C)C)nc23)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(C)cc2)cn1
Temperature: 150 °C
Yield: 32.2 %

Procedure:
To a stirring, degassed mixture of 7-bromo-2-isobutyl-8-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.015 g, 0.04 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.04 g, 0.17 mmol), and tetrakis(triphenylphosphine)palladium (2.5 mg, 0.002 mmol) in dioxane (0.3 mL) at 20° C. was added K2CO3 (0.024 g, 0.17 mmol) in water (0.11 mL). The resulting reaction mixture was heated in a microwave reactor at 150° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 5 mg of the title compound as a white solid. MS: [M+H]+=388.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:33][CH3:34].[N:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42](=O)[O:43]C2C=CC=CC=2)=[CH:37][CH:36]=1>O1CCOCC1>[F:30][C:28]([F:31])([F:29])[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:42]([NH:41][C:38]4[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=4)=[O:43])=[C:3]([O:33][CH3:34])[CH:4]=3)=[O:9])[CH2:15][CH2:14]2)=[CH:18][CH:19]=1)([OH:32])[C:24]([F:25])([F:26])[F:27]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: COc1cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)ccc1N
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)ccc1NC(=O)Nc1ccncc1
Temperature: 80 °C
Yield: 4.9 %

Procedure:
(4-Amino-3-methoxyphenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.407 mmol, 200 mg) and phenyl pyridin-4-ylcarbamate (0.610 mmol, 131 mg) were combined in dioxane (2 mL) and heated to 80° C. overnight in a reactivial. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (dichloromethane—4% methanol/dichloromethane) to afford title compound (12.2 mg). MS (ESI) m/z 612.3 [M+H]+
Reaction SMILES: [C:1]([CH2:6][S:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH:13]1OCC[O:14]1)([O:3][CH2:4][CH3:5])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:1]([CH2:6][S:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH:13]=[O:14])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CSc1sccc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCOC(=O)CSc1sccc1C=O

Procedure:
To a solution of 2-(carboethoxymethylthio)3-(1,3-dioxolan-2-yl)thiophene (from step b) in acetone (200 mL) was added p-toluenesulfonic acid (761 mg, 4.0 mmole) at RT. After 18 hr the mixture-was concentrated. The residue was taken up in Et2O, washed with saturated NaHCO3, H2O (2×), dried (MgSO4), and concentrated under reduced pressure to give the tide compound as an oil which was sufficiently pure for use in the next step.
Reaction SMILES: [CH2:1]([C@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:26])[NH:5]1)[CH:2]=[CH2:3].[OH-:34].[Na+].OO>C1COCC1>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]([N:7]2[CH2:8][CH2:9][C@@:4]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([CH2:1][CH2:2][CH2:3][OH:34])[NH:5][C:6]2=[O:26])[CH3:11])=[CH:17][CH:16]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)N1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)NC1=O
Reaction time: 2 h
Yield: 18.6 %

Procedure:
To a solution of (R)-4-allyl-1-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (42 mg, 0.092 mmol) in THF (10 mL) was added 1M BH3 in THF (1.5 mL, 1.5 mmol) at 0° C. under nitrogen. The mixture was stirred for 2 h. The reaction was quenched by water. 3 M aq NaOH (0.3 mL, 3 mmol) and H2O2 (3 mL) were added. The resulting mixture was stirred for 1.5 h. The mixture was extracted with EtOAc and the combined organic phase was concentrated to give the crude product, which was purified by preparative HPLC to give (R)-1-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)tetrahydropyrimidin-2(1H)-one (8 mg, 19%). LC-MS Method 1 tR=1.413 min, m/z=469.2; 1H NMR (CDCl3): δ=1.36 (m, 2H), 1.45 (m, 3H), 1.91-2.01 (m, 5H), 2.18 (m, 1H), 2.83 (m, 1H), 3.52 (m, 2H), 5.76 (m, 2H), 6.09 (m, 1H), 6.38-6.98 (m, 4H), 7.16 (m, 2H), 7.22 (m, 1H), 7.25 (m, 1H), 7.28 (m, 3H).