Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C@@:6]([NH:41]C(=O)C)([CH2:39][CH3:40])[CH2:7][CH2:8][C:9]1[N:10]([CH3:38])[C:11]([C:14]([O:25]C(=O)CCCC2C=CC(C)=CC=2)=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:12][CH:13]=1)(=O)C.O.[OH-].[Li+].C(Cl)Cl>O1CCCC1.CO.O>[NH2:41][C@:6]([CH2:39][CH3:40])([CH2:7][CH2:8][C:9]1[N:10]([CH3:38])[C:11]([C:14](=[O:25])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: CC[C@@](CCc1ccc(C(=CCCc2ccc(C)cc2)OC(=O)CCCc2ccc(C)cc2)n1C)(COC(C)=O)NC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC[C@](N)(CO)CCc1ccc(C(=O)CCCc2ccc(C)cc2)n1C
Temperature: 50 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
(2R)-1-Acetoxy-2-acetylamino-2-ethyl-4-{1-methyl-5-[4-(4-methylphenyl)-1-(4-(4-methylphenyl)butanoyloxy)but-1-enyl]pyrrol-2-yl}butane (372 mg, 0.620 mmol) obtained in Example 12 (12a) was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (5 mL), and water (5 mL) and lithium hydroxide monohydrate (260 mg, 6.20 mmol) were added thereto, followed by stirring of the mixture at 50° C. for 4 hours. After cooling, water was added to the reaction mixture and methylene chloride was added thereto to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by basic silica gel (NH type) chromatography (methylene chloride:methanol, 100:1) to obtain crude (2R)-2-amino-2-ethyl-4-{1-methyl-5-[4-(4-methylphenyl)butanoyl]pyrrol-2-yl}butan-1-ol (206 mg). A 4N hydrochloric acid-dioxane solution (0.135 mL, 0.54 mmol) was added to a solution of the thus obtained crude product in methanol (5.0 mL) under ice-cooling and the mixture was stirred for 10 minutes. The mixture was concentrated under reduced pressure, ethyl acetate was added thereto and the precipitated crystal was collected by filtration. The crystal was washed with ethyl acetate and dried under reduced pressure to obtain the title compound (212 mg, yield: 88%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][N:67]([CH2:69][C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[CH3:68])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][N:67]([CH2:69][C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[CH3:68])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: CN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1)Cc1ccccc1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: CN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1)Cc1ccccc1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-[2-(benzyl-methyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=597, obsd.=597).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>Cl.O>[N:1]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[N+:16]=[N-:17]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Amino-4-methyl benzoic acid (2.28 g, 15.1 mmol) was suspended in 65 mL of 2N HCl and chilled to 0° C. A chilled solution of 1.25 g (18.1 mmol) of NaNO2 in 5 mL of water was added slowly, and the solution was stirred for 30 min. The mixture was filtered through a plug of diatomaceous earth, and then returned to a 0° C. bath where 1.08 g (16.6 mmol) of NaN3 dissolved in about 5 mL of water was slowly added. Gas evolved immediately, and a precipitate formed. The precipitate was filtered, washed with water, and dried under a stream of air to provide 2.34 g (13.4 mmol; 88%) of Compound 2 as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][N:29]4[CH2:30][CH2:31][CH2:26][CH2:27][CH2:28]4)=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCNCC1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1C(F)(F)F
Product: FC(F)(F)c1cc(N2CCC(CN3CCCC3)CC2)ccc1CN1CCCCC1

Procedure:
Prepared from the product of Example 65 and 4-hydroxypiperidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.[C:60]([O:64][C:65]([N:67]1[CH2:71][CH2:70][C@@H:69]([C:72]2[CH:77]=[CH:76][C:75](Br)=[CH:74][C:73]=2[OH:79])[CH2:68]1)=[O:66])([CH3:63])([CH3:62])[CH3:61].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.[Cl-].[Na+].O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:60]([O:64][C:65]([N:67]1[CH2:71][CH2:70][C@@H:69]([C:72]2[CH:77]=[CH:76][C:75]([S:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:74][C:73]=2[OH:79])[CH2:68]1)=[O:66])([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(Br)cc2O)C1
Reactant: Fc1cccc(S)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(Sc3cccc(F)c3)cc2O)C1
Temperature: 5 °C
Yield: 70.5 %

Procedure:
3-Fluorothiophenol (58 μL, 0.681 mmol), Tris(dibenzylideneacetone) dipalladium(0) (77.4 mg, 0.085 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (97.4 mg, 0.170 mmol) and DIPEA (0.156 mL, 1.71 mmol) were added to a solution of (S)-3-(4-bromo-2-hydroxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (233 mg, 0.681 mmol) in 1,4-dioxane (4.6 mL). The reaction mixture was heated at reflux for 18 hours, then cooled to 5° C. and a solution of 10% KHSO4/Na2SO4 was added, followed by brine. The mixture was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered through a celite pad, and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (hexane/acetone, 9/1) to give 187 mg (70% yield) of (S)-3-[4-(3-fluoro-phenylsulfanyl)-2-hydroxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white foam.
Reaction SMILES: [N:1]1(/[C:10](/[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)=[CH:11]/[C:12]([O:14]CC)=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1>Cl>[N:1]1(/[C:10](/[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)=[CH:11]/[C:12]([OH:14])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)/C=C(\c1ccc(CC)cc1)n1cnc2ccccc21
Agent: Cl
Product: CCc1ccc(/C(=C\C(=O)O)n2cnc3ccccc32)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl (2E)-3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate (46 mg, 143 μmol) in hydrochloric acid (10 mL of a 5N solution) was stirred at room temperature for 72 hours, and then heated at reflux for 6 hours. The solution was cooled to room temperature, and evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=6.62 min, MH+ 294].
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[S:26][C:27]5[CH2:33][CH2:32][CH2:31][CH2:30][C:28]=5[N:29]=4)=[CH:21][C:20]=3[CH2:34][CH2:35][CH3:36])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.O[Li].O>C1COCC1.O>[CH2:34]([C:20]1[CH:21]=[C:22]([C:25]2[S:26][C:27]3[CH2:33][CH2:32][CH2:31][CH2:30][C:28]=3[N:29]=2)[CH:23]=[CH:24][C:19]=1[O:18][CH2:17][CH2:16][CH2:15][O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:37])=[O:2])[CH:6]=[CH:7]2)[CH2:35][CH3:36]
Reactant: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(ccn2CC(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
To a solution of methyl(5-{3-[2-propyl-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)phenoxy]propoxy}-1H-indol-1-yl)acetate (Example 55, 145 mg, 0.28 mmol) in THF (4.8 mL), was added LiOH.H2O (39 mg, 0.84 mmol) in water (1.6 mL), and the mixture was stirred for 12 h at rt. The solvents were evaporated and a small volume of water was added to the residue. The pH of the mixture was adjusted to 3 with 1 N HCl. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried, filtered, and concentrated to give 140 mg (99%) of the product as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.30 (d, 1H), 7.25-7.15 (m, 3H), 7.10 (d, 1H), 6.92 (dd, 1H), 6.45 (d, 1H), 6.20 (d, 1H), 4.85 (s, 2H), 4.40-4.32 (m, 2H), 4.32-4.22 (m, 2H), 2.90-2.80 (br, 2H), 2.80-2.70 (br, 2H), 2.50-2.40 (m, 2H), 2.25-2.05 (m, 2H), 1.95-1.75 (br, 4H), 1.60-1.40 (m, 2H), 0.90 (t, 3H). LC/MS m/z 505.2 (M+H)+, RT 3.88 min.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.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>[Cl:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:2]([CH3:14])[C:3]=1[NH2:4]
Reactant: CB1OB(C)OB(C)O1
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Br
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: O
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)cc(Cl)c1N
Temperature: 90 °C

Procedure:
A mixture of 2-bromo-6-chloro-4-trifluoromethyl aniline (1.00 g, 3.64 mmol), trimethylboroxin (0.66 ml, 0.59 g, 4.47 mmol), potassium carbonate (1.00 g, 7.30 mmol) and catalytic amount (10%) Pd(PPh3)4 in DMF (5 ml) was heated to 90° C. for 14 h. Water (20 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The titled compound was obtained as a colorless oil after a flash column using EtOAc:hexane (1:9) as the elute. 1H NMR (CDCl3, 500 MHz): δ 7.43 (s, 1H), 7.24 (s, 1H), 4.38 (br s, 2H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[S:39][CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:38]2[S:39][CH:40]=[C:36]([F:35])[CH:37]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(F)cs2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc(F)cs2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
To a 30 mL sealed cap glass vessel containing tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.401 mmol) and 2-(4-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137 mg, 0.601 mmol) dissolved in DME and water (4:1) was added tetrakis(triphenylphosphine)palladium(0) (105 mg, 0.401 mmol) and potassium phosphate, tribasic (212 mg, 1 mmol). The cap was sealed, and the reaction mixture was heated at 85° C. for 4 hours and then cooled to room temperature. The mixture was diluted with water and extracted with EtOAc (2×25 mL). The organic layers were combined, dried over sodium sulfate, and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(4-fluorothiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and stirred at room temperature for 2 hours. The mixture was evaporated and purified by preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (112 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.54 (m, 2H), 1.60 (d, J=12.88 Hz, 2H), 1.66-1.81 (m, 2H), 1.83-1.99 (m, 2H), 3.81 (br s, 1H), 4.24 (br s, 1H), 4.45 (d, J=2.27 Hz, 2H), 7.14 (d, J=5.31 Hz, 1H), 7.31 (t, J=1.39 Hz, 1H), 7.79 (br s, 3H), 8.62 (s, 1H), 8.97 (d, J=1.77 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C17H18F2N4OS, 365. found, 365.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)CN
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(NCC(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 2.01 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 62-2 (7.81 mmol, crude form) as starting material, 1.91 g of the title compound (colorless powder) was obtained by a similar method to Step 4-2.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]#[N:16])[CH2:7][CH:6]3[CH2:21][O:22][CH2:23][CH2:24][N:5]3[C:4]=2[N:3]=1.S(=O)(=O)(O)[OH:26]>C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]([NH2:16])=[O:26])[CH2:7][CH:6]3[CH2:21][O:22][CH2:23][CH2:24][N:5]3[C:4]=2[N:3]=1
Reactant: N#Cc1ccccc1CN1CC2COCCN2c2nc(Cl)ncc21
Reactant: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1CN1CC2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2-((2-Chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)benzonitrile (PREPARATION x17, 140 mg, 0.410 mmol) was dissolved in concentrated sulfuric acid (1 mL) and was stirred overnight at room temperature. Following reaction, the mixture was diluted with ethyl acetate and was washed with aqueous saturated NaHCO3 (2×15 mL) and brine (2×5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by LC/MS using a gradient of 20-45% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to afford the title compound as a white solid (147 mg, 99%). 1H NMR (400 MHz, DMSO-d6) δ 2.91-3.05 (m, 2H), 3.10-3.19 (m, 1H), 3.22-3.29 (m, 1H), 3.44-3.49 (m, 1H), 3.63-3.73 (m, 1H), 3.81-3.99 (m, 2H), 4.21-4.29 (m, 1H), 4.36-4.61 (m, 2H), 7.19-7.24 (m, 1H), 7.30-7.50 (m, 5H), 7.78-7.87 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C17H18ClN5O2, 360.11. found 360.2.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:20]([O:22][C:23](=[O:37])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH3:21].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH3:36][O:35][C:28]1[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=1[CH2:26][N:25]([CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:37]
Reactant: CCOC(=O)c1onc(-c2ccc(F)cc2)c1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccc(F)cc2)noc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
Ethyl 4-(bromomethyl)-3-(4-fluorophenyl)isoxazole-5-carboxylate (12.4 g, 37.8 mmol) was dissolved in 80 mL of DMF. N-(2,4-dimethoxybenzyl)glycine ethyl ester (9.56 g, 37.8 mmol) and potassium carbonate (5.75 g, 41.6 mmol) were added, and the mixture was stirred at room temperature for 16 h. EtOAc (200 mL) and brine (200 mL) were added and the aqueous layer was extracted with additional EtOAc. The combined organic layer was washed with water and brine, and dried over MgSO4. After solvent was removed in vacuo, the crude product was purified by flash chromatography (0-40% EtOAc/hexanes) to give 8.7 g of the title compound. 1H NMR (CDCl3, 200 MHz): δ=8.00-8.13 (m, 2H), 7.01-7.18 (m, 3H), 6.38-6.45 (m, 2H), 4.48 (q, 2H, J=7.4 Hz), 4.00-4.20 (m, 4H), 3.82 (s, 5H), 3.65 (s, 3H), 3.30 (s, 2H), 1.47 (t, 3H, J=7.0 Hz), 1.20-1.30 (m, 3H).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:28]5[C:24]([S:25][CH:26]=[CH:27]5)=[N:23][C:22]=4[C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=4)[CH:18]=[CH:17][N:16]=3)[CH2:9]2)[CH2:4][O:3]1.O.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:36][O:35][C:31]1[CH:30]=[C:29]([C:22]2[N:23]=[C:24]3[N:28]([C:21]=2[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C@@H:10]4[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][C@@H:5]([OH:6])[CH2:4][OH:3])[CH2:9]4)[N:20]=2)[CH:27]=[CH:26][S:25]3)[CH:34]=[CH:33][CH:32]=1
Reactant: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C[C@@H]4COC(C)(C)O4)C3)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C[C@@H](O)CO)C3)n2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
The N-((3R)-1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}piperidin-3-yl)-4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (150 mg, 0.288 mmol) was dissolved in MeOH (10 ml) and water (1.2 ml) and treated with trifluoroacetic acid (90 uL). The mixture was stirred at 50° C. overnight (18 hours). The mixture was neutralized with potassium carbonate (160 mg) and the volatiles were removed in vacuo. The product was purified by flash chromatography (6:1 EtOAc/MeOH), affording the title compound as an off-white solid (120 mg, 87%). M.p.=106-108° C. 400 MHz 1H NMR (DMSO-d6) δ: 8.72 (br. s, 1H), 8.08 (d, J=5.5 Hz, 1H), 7.44 (d, J=4.4 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.16-7.10 (m, 2H), 7.06-6.97 (m, 2H), 6.36 (d, J=5.5 Hz, 1H), 4.40-4.15 (m, 1H), 4.02-3.90 (m, 1H), 3.77 (s, 3H), 3.68-3.56 (m, 2H), 3.40-3.28 (m, 2H), 3.05-2.95 (m, 1H), 2.80-2.64 (m, 1H), 2.42 (br. s, 1H), 2.32 (br. s, 1H), 2.14 (br. s, 1H), 1.90-1.80 (m, 1H), 1.75-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.45-1.30 (m, 1H). LCMS: 481 [M+H].
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].O.[NH2:10][NH2:11]>CCO.CCOC(C)=O>[CH:2]([C:3]1[NH:11][N:10]=[C:5]([NH2:6])[CH:4]=1)([CH3:8])[CH3:1]
Reactant: CC(C)C(=O)CC#N
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(N)n[nH]1
Yield: 59.2 %

Procedure:
To a solution of 4-methyl-3-oxopentanenitrile (15 g, 135 mmol) in EtOH (150 mL) was added hydrazine hydrate (7.30 g, 146 mmol) slowly at 0° C. The reaction mixture was heated to reflux for 4 h. Removal of EtOH under reduced pressure gave an oily residue that was dissolved in EtOAc (200 mL) and washed with freshly prepared brine (2×50 mL). The organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc gave 5-isopropyl-1H-pyrazol-3-amine, Compound (ii) (10 g, 59% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 1.22 (d, 6H), 2.80-2.92 (m, 1H), 4.80 (brs, 3H), 5.41 (s, 1H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40](C#N)=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.Cl.[C:46]([O:49][CH2:50][CH3:51])(=[O:48])C>C(O)C.O>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:42]=[CH:41][C:40]([C:46]([O:49][CH2:50][CH3:51])=[O:48])=[CH:39][CH:38]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C#N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cc1

Procedure:
The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene (128 mg) was suspended in ethanol (2 ml) and added thereto was a concentrated hydrochloric acid aqueous solution (1 ml). The mixture was heated reflux for 8.5 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-ethoxycarbonylphenyl)-2-thienylmethyl)benzene (39 mg) as pale yellow foam. APCI-Mass m/Z 536/538 (M+NH4).
Reaction SMILES: [O:1]=[C:2]([CH3:6])[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].O.[C:13](=[O:20])([S:17][CH2:18][CH3:19])[O:14][CH2:15]I>C(Cl)Cl>[C:13](=[O:20])([S:17][CH2:18][CH3:19])[O:14][CH2:15][O:4][C:3](=[O:5])[C:2](=[O:1])[CH3:6]
Reactant: CCSC(=O)OCI
Reactant: CC(=O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCSC(=O)OCOC(=O)C(C)=O

Procedure:
Redistilled 2-oxopropanoic acid (12.6 ml, 0.18 mol) is added to a vigorously stirred mixture of NaHCO3 (30.6 g, 0.36 mol), TBA HSO4 (61.2 g, 0.18 mol), H2O (360 mL), and CH2Cl2 (360 mL) in an open Erlenmeyer flask. Following stirring for 10 min 5b (44.0 g, 0.18 mol) in CH2Cl2 (400 mL) is added during 3 h at 25° C. together with CH2Cl2 (500 mL) in portions to compensate for the evaporation. In this way the formation of sulfurous by-products is minimized. The mixture is extracted with CH2Cl2 (300-200 mL). The combined organic phases are washed with H2O (2×200 mL); dried (MgSO4) and evaporated. The residue is triturated with Et2O (600 mL). After filtration the filtrate is treated with charcoal, evaporated, and the residue crystallized from pentane at -70° C. to yield 6ob, melting below room temperature.