Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:22])=[C:7]([C@:9]2([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]2)[CH:8]=1)#[CH:2].Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=1.C(N(CC)CC)C>C1COCC1.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.[Cu]I>[NH2:19][C:11]1[O:12][C@H:13]([C:15]([F:16])([F:17])[F:18])[CH2:14][C@:9]([C:7]2[CH:8]=[C:3]([C:1]#[C:2][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=3)[CH:4]=[CH:5][C:6]=2[F:22])([CH2:20][F:21])[N:10]=1
Reactant: C#Cc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Reactant: N#Cc1ccc(Br)nc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C#Cc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)nc1
Temperature: 80 °C
Yield: 53 %

Procedure:
A mixture of (4S,6S)-4-(5-ethynyl-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (70 mg, 0.220 mmol), 6-bromonicotinonitrile (60.4 mg, 0.330 mmol), triethylamine (92 μl, 0.660 mmol), tetrakis (25.4 mg, 0.022 mmol), and copper(I) iodide (8.38 mg, 0.044 mmol) in 2 mL of THF in a microwave vial was heated at 80° C. for 20 min. The reaction mixture was filtered and purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 16 min. The desired fractions were combined, neutralized with 1N NaOH, extracted with 3×25 mL of DCM, dried over Na2SO4 and concentrated to afford the title compound as a white solid: 49 mg, 53% yield. MS m/z=421.0 [M+H]+. Calculated for C20H13F5N4O: 420.1.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16](I)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.CO[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1.[NH4+].[Cl-]>C1COCC1>[Si:5]([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH:17]=[C:16]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19]
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(I)cn2)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Temperature: 0 °C

Procedure:
To a stirred THF (30.00 mL) solution of 1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-4-iodo-1H-pyrazole (Compound 137B, 1.1400 g, 2.8053 mmol) was added 2.00 M of isopropylmagnesium chloride in THF (2.31 mL, 4.63 mmol) dropwise under an atmosphere of Nitrogen in 5 min at 0° C. The reaction mixture was stirred at 0° C. for another hour. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.9577 mL, 5.610 mmol) was added at 0° C. and then the mixture was stirred at room temperature for another hour. The mixture was treated with saturated NH4Cl (10 ml), extracted with EtOAc (20 ml×3). The extracts were washed with water (10 ml), brine (15 ml), dried over Na2SO4. Solvent was removed under reduced pressure to give a residue which was purified by flash chromatography (10% EtOAc/hexane). MS (ES+): m/z=407.18 [MH+]. HPLC: tR=3.21 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:20])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: CI
Reactant: Cc1cc(Nc2cc(Cl)nn(C)c2=O)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(Cl)nn(C)c2=O)nn1C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
To a mixture of 127a (480 mg, 2.0 mmol) in anhydrous DMF (10 mL) was added NaH (purity 60%) (64 mg, 1.6 mmol) at 0° C. and the resulting mixture was stirred for 0.5 h. To the mixture was added iodomethane (227 mg, 1.6 mmol) in DMF (5 mL) dropwise at 0° C. The reaction mixture was stirred for additional 1.5 h and quenched with water (20 mL). It was then extracted with dichloromethane (3×20 mL) and the combined organic layer was evaporated under reduced pressure. The residue was purified by reverse-phase Combiflush (A: 2% aqueous NH4HCO3, B: acetonitrile) to afford 127b (120 mg, 24%) as a light yellow solid. MS-ESI: [M+H]+ 254.3
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([CH3:12])[N:9]=[C:10]([Cl:11])[C:5]=2[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:3]=1[CH3:21].C([Li])CCC.CN([CH:30]=[O:31])C>O1CCCC1>[Cl:11][C:10]1[C:5]2[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:3]([CH3:21])=[C:2]([CH:30]=[O:31])[C:6]=2[N:7]=[C:8]([CH3:12])[N:9]=1
Reactant: Cc1nc(Cl)c2c(n1)c(Br)c(C)n2COCC[Si](C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(Cl)c2c(n1)c(C=O)c(C)n2COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-Bromo-4-chloro-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine from example A9 (12.41 g; 31.76 mmol) is dissolved in dry tetrahydrofurane (100 mL). At −78° C. n-butyllithium (12.7 mL; 31.76 mmol; 2.5M solution in n-hexane) is syringed into the stirred reaction mixture. After 30 min DMF (12.4 mL; 158.80 mmol) is added via syringe and the mixture is stirred for additional 2 hours at −78° C. and for 30 minutes at 0° C. The reaction is quenched by addition of 1M citric acid (32 mL) and brine (32 mL). After diluting with tert-butylmethylether the aqueous layer is separated and extracted with tert-butylmethylether (3×50 mL). The combined organic layers are dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel (cyclohexane:ethylacetate/7:3) affording the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[C:26](F)=[N:27][CH:28]=[CH:29][CH:30]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][OH:39])=[CH:36][CH:35]=1.CC(C)([O-])C.[K+].CC(O)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[C:26]([O:39][CH2:38][C:37]4[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[N:27][CH:28]=[CH:29][CH:30]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: COc1ccc(CO)cc1
Reactant: O=C(c1ccc(Oc2nccnc2-c2cccnc2F)cc1)c1nc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COc1ccc(COc2ncccc2-c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
To a mixture of (1H-benzo[d]imidazol-2-yl)(4-(3-(2-fluoropyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone (200 mg, 0.486 mmol) and 4-methoxybenzyl alcohol (0.905 mL, 7.29 mmol) in toluene in a 6 mL tube was added potassium tert-butoxide, 1.0 m solution in 2-methyl-2-propanol (2.431 mL, 2.431 mmol). The reaction was heated to 80° C. After 7 min a mixture of products was observed by LC/MS. The mixture was diluted with DCM (30 mL), and washed with water (3×25 mL) and brine (30 mL). It was dried over magnesium sulfate, concentrated and dried in vacuo. It was purified by flash chromatography (40 g SiliaSep pre-packed silica gel column, eluent: 0-40% EtOAc in hexane) to give (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(4-methoxybenzyloxy)pyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 532.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[CH3:17][O:18][C:19](=[O:26])[C@H:20]([CH2:22][CH2:23][S:24][CH3:25])[NH2:21]>>[CH3:17][O:18][C:19](=[O:26])[C@H:20]([CH2:22][CH2:23][S:24][CH3:25])[NH:21][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)c1ccc(F)cc1-c1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(F)cc1-c1ccccc1

Procedure:
The resultant product from Example 13B is coupled to methionine methyl ester according to the procedure of Example 1C to give the tide compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:25][O:26][C:27]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:28]=1[NH2:29].C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([O:26][CH3:25])[CH:33]=3)[C:3]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1N
Temperature: 85 °C
Yield: 91.1 %

Procedure:
A mixture of tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.50 g, 11.26 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.10 g, 12.39 mmol), sodium carbonate (2.90 g, 27.0 mmol) and tetrakis(triphenylphosphine)palladium (0.78 g, 0.67 mmol) in ethylene glycol dimethyl ether (90 mL) and water (45 mL) was heated at 85° C. for 18 hours. The mixture was cooled and evaporated under reduced pressure then partitioned between water (50 mL) and dichloromethane (50 mL). The aqueous layer was extracted further with dichloromethane (2×50 mL) then the combined organic solutions were dried over magnesium sulfate and then filtered. The filtrate was concentrated and purified by flash chromatography on silica gel using dichloromethane/methanol (96:4) as an eluent to provide the title compound (4.51 g, 91%) as a tan solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (s, 1H), 7.04 (s, 1H), 6.98 (d, 1H), 6.76 (d, 1H), 5.06 (bs, 1H), 4.86 (m, 1H), 4.08 (m, 2H), 3.83 (s, 3H), 2.90 (m, 2H), 2.03 (m, 2H), 1.90 (m, 2H), 1.43 (s, 9H); RP-HPLC (Hypersil HS C18 Hypersil HS C18, 5 μm 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05 M ammonium acetate over 10 min, 1 mL/min) tr 9.70 min.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=1[CH3:33].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CO>[CH3:1][C:2]1[N:3]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[C:24]=2[CH3:33])[C:4]2[CH:10]=[C:9]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[N:6]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
A solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate prepared as described in Example 26, step d (500 mg, 1.8 mmol), 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (483 mg, 1.9 mmol) and K2CO3 (497 mg, 3.6 mmol) in DMF (50 mL) was stirred at 80° C. for 3 h. The reaction mixture was cooled to rt and poured into water (50 mL), extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel chromatography eluted with DCM:MeOH=50:1 to give the crude product (230 mg, yield 29%), as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.39 (s, 3H), 2.54 (s, 3H), 3.08 (t, 4H, J=4.8 Hz), 3.72 (t, 4H, J=4.8 Hz), 3.89 (s, 3H), 5.57 (s, 2H), 6.27 (d, 1H, J=7.5 Hz), 7.22 (t, 1H, J=7.5 Hz), 7.27 (d, 1H, J=2.4 Hz), 7.38 (d, 1H, J=2.4 Hz) 7.60 (d, 1H, J=7.5 Hz); LC-MS: m/e=448 [M+1]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:27]5[CH2:31][CH2:30][N:29]([CH3:32])[C:28]5=[O:33])=[O:26])=[CH:20][C:19]=4[F:34])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:38][NH:39][C:40]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)=[O:41].C([O-])([O-])=O.[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[F:34][C:19]1[CH:20]=[C:21]([NH:24][C:25]([CH:27]2[CH2:31][CH2:30][N:29]([CH3:32])[C:28]2=[O:33])=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:36]=[CH:37][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([C:45]3[CH:46]=[CH:47][C:42]([C:40](=[O:41])[NH:39][CH3:38])=[CH:43][CH:44]=3)[C:11]=12
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)C5CCN(C)C5=O)cc4F)ccnc32)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)c1ccc(-c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)C5CCN(C)C5=O)cc4F)c23)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 53.4 %

Procedure:
A 50 mL round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide (20.0 mg, 0.0325 mmol), 4-(methylcarbamoyl)phenylboronic acid (17.5 mg, 0.0975 mmol), tetrakis(triphenylphosphine) palladium (7.51 mg, 0.00650 mmol), Na2CO3 (0.0812 ml, 0.162 mmol) and DME (10 mL). The reaction mixture was stirred at 60° C. for 4 hours, and then partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (10.8 mg, 53.4%). LRMS (APCI pos) m/e 623 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:34]([F:37])([F:36])[F:35])/[CH:11]=[CH:12]/[C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][CH2:20][C:21](=[O:28])[NH:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[O:18])=[C:15]([N+:31]([O-])=O)[CH:14]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].Cl.NCC(NCC(F)(F)F)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ClC1C=C(C(C(F)(F)F)/C=C/C2C=CC(C(O)=O)=C([N+]([O-])=O)C=2)C=C(Cl)C=1F>C(Cl)Cl.O>[NH2:31][C:15]1[CH:14]=[C:13](/[CH:12]=[CH:11]/[CH:10]([C:4]2[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[C:34]([F:35])([F:36])[F:37])[CH:30]=[CH:29][C:16]=1[C:17]([NH:19][CH2:20][C:21](=[O:28])[NH:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[O:18]
Reactant: O=C(CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)cc1[N+](=O)[O-])NCC(F)(F)F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC(=O)NCC(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-nitro-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)benzamide: 2-Amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (96 mg, 0.35 mmol), PyBOP (165 mg, 0.32 mmol) and DIPEA (0.1 mL, 0.57 mmol) were added to a stirred solution of (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-nitrobenzoic acid (130 mg, 0.29 mmol) in CH2Cl2 (3 mL) and the reaction mixture was stirred at ambient temperature for 8 h. Water was added to reaction mixture and extracted with CH2Cl2. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 30% EtOAc in petroleum ether to afford the title compound as a yellow solid (120 mg, 74%): 1H NMR (300 MHz, DMSO-d6) δ 9.04 (t, J=5.7 Hz, 1H), 8.60 (t, J=6.0 Hz, 1H), 8.25 (s, 1H), 7.97-7.94 (m, 1H), 7.87 (d, J=6.3 Hz, 2H), 7.69 (d, J=7.5 Hz, 1H), 7.15 (dd, J=15.9, 9.3 Hz, 1H), 6.89 (d, J=15.9 Hz, 1H), 4.88-4.83 (m, 1H), 3.98-3.89 (m, 4H); ESIMS m/z 575.87 ([M+H]+); IR (KBr) 3430, 2925, 1663, 1168, 832 cm−1.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=3[CH3:19])=[CH:13][CH:14]=2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Product: CCOc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1

Procedure:
Compound (98) was prepared from compound (20) and (4-ethoxyphenyl)-boronic acid by an adapting the procedure of Example 24A. LC/MS System B; Rt=1.86 mins, m/z (ES−)=351 (M−H for C21H20O5).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4]>O.[Pd]>[CH2:11]([OH:12])[C@H:9]([OH:10])[C@H:7]1[O:8][C:2](=[O:1])[C@@H:3]([OH:4])[C@H:5]1[OH:6]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Pd]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)[C@H](O)[C@@H]1O
Reaction time: 62 h
Yield: 95.3 %

Procedure:
To a solution of L-ascorbic acid (83.9 g, 0.477 mole) in water (600 mL) was added Pd/C (10%, 8.3 g). The mixture was subjected to hydrogenation in a Parr hydrogenator at 48 psi, 18° C. for 62 hrs. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford L-gulonic γ-lactone (81.0 g, 96%) as an off-white solid, after drying at 50° C. in a vacuum oven for 18 hrs: m.p. 182-184° C.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[S:33]>>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1)=[S:33]
Reactant: FC(F)(F)c1ccccc1N=C=S
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccccc4C(F)(F)F)CC3)nc21

Procedure:
Pipemidic acid (48 mg, 0.159 mmol) and 2-(trifluoromethyl)phenyl isothiocyanate (20 μL, 0.132 mmol) were used. Purification on silica yielded compound 12 in Table 1, below (55 mg, 82%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.69 (s, 1H), 7.74-7.64 (m, 1H), 7.63-7.51 (m, 2H), 7.43-7.33 (m, 1H), 4.47-3.90 (m, 10H), 1.50 (t, J=6.86 Hz, 3H) ppm.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.C(N(C(C)C)CC)(C)C.[C:25]1([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[Cl:13][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([N:31]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=[C:4]([S:14][CH3:15])[N:5]=1
Reactant: CCOC(=O)CCNc1ccccc1
Reactant: CCOC(=O)c1c(Cl)nc(SC)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN(c1ccccc1)c1nc(SC)nc(Cl)c1C(=O)OCC
Temperature: 100 °C
Reaction time: 7 h
Yield: 80.9 %

Procedure:
To a solution of ethyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (47.0 g, 175.94 mmol) in DMF (470 mL) and diisopropylethylamine (100.43 mL, 582.7 mmol) was added ethyl 3-(phenylamino)propanoate (31.0 g, 160.4 mmol). The reaction mixture was heated to 100° C. and stirred for 7 h. Upon completion of the reaction (monitored by TLC), DMF was evaporated under reduced pressure and water (250 mL) was then added. The reaction mixture was extracted using EtOAc (200 mL×3). The combined organic layer was washed with water (500 mL×2), brine (500 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (using 0-20% Ethyl acetate in hexane) to afford ethyl 4-chloro-6-((3-ethoxy-3-oxopropyl)(phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (55 g, 80.8% yield). 1H NMR (400 MHz, CDCl3): δ 7.38 (t, J=8.0 Hz, 2H), 7.31 (d, J=7.6 Hz, 1H), 7.18 (d, J=7/2 Hz, 2H), 4.26 (t, J=7.6 Hz, 2H), 4.05 (q, J=7.2 Hz, 2H), 3.47 (q, J=7.2 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 2.54 (s, 3H), 1.19 (t, J=7.2 Hz, 3H), 1.08 (t, J=7.2 Hz, 3H). LCMS [M+H]; 424
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)NCCn2ccnn2)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.1 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (61 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([C:14](=[O:19])C(F)(F)F)=[C:5]2[S:4][CH:3]=1.[OH-:20].[Na+]>C(O)C>[CH3:1][C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([C:14]([OH:19])=[O:20])=[C:5]2[S:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1csc2c(C(=O)C(F)(F)F)c3ccccc3n12
Agent: [Na+]
Solvent: CCO
Product: Cc1csc2c(C(=O)O)c3ccccc3n12
Yield: 100 %

Procedure:
3-Methyl-9-trifluoroacetylthiazolo[3,2-a]indole (370 mg, 0.0013 mole) was treated with 20% NaOH solution (15 ml) and ethanol (15 ml) and heated under reflux for 6 h. The mixture was concentrated in vacuo to half its volume and the residue acidified with 2M HCl acid and then extracted with ethyl acetate (2×30 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the title compound (D13) as a brown solid (300 mg, 100%).