Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[O:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=2)[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][CH2:29][NH:30][CH3:31].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:12]1[CH2:13][CH2:14][CH2:15][O:16][CH:11]1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=[C:2]2[N:30]([CH2:29][CH2:28][CH2:27][O:26][CH3:25])[CH3:31]
Reactant: CNCCCOC
Reactant: C[Si](C)(C)CCOCn1nc(Cl)c2cc(C3OCCCO3)ccc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: COCCCN(C)c1nn(COCC[Si](C)(C)C)c2ccc(C3OCCCO3)cc12
Temperature: 25 °C
Yield: 39.7 %

Procedure:
To a degassed solution of 400 mg (1.08 mmol) 3-chloro-5-(1,3-dioxan-2-yl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-indazole (Example 45A) and 135 mg (1.52 mmol) 3-methoxy-N-methyl-propanamine in anhydrous THF (11 ml) were added under inert gas atmosphere 103 mg (0.22 mmol) 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (XPhos), 50 mg (0.054 mmol) tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) and 5.42 ml (5.42 mmol) lithium hexamethyldisilazide solution (1 M in THF). The resulting mixture was stirred under reflux for 12 h. After cooling to room temperature and concentration under reduced pressure, the remaining solid was dissolved in ethyl acetate (20 ml). The solution was washed with water and with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient, final mixture 90:10 v/v) to yield the title compound as a white solid (187 mg, 24% of th.).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([CH2:29][CH2:30][CH2:31][OH:32])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(O)(C(F)(F)F)=O.CO>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([NH:20][C:18]3[C:17]([CH2:29][CH2:30][CH2:31][OH:32])=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:19]=3)[CH:25]=2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(CCCO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NS(=O)(=O)c1ccc(-c2ncc(CCCO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(3-hydroxypropyl)pyrimidin-2-yl)thiophene-2-sulfonamide (10 mg, 0.02 mmol) in TFA (1 mL) was heated to reflux for 0.5 h. The reaction was removed in vacuo, to which K2CO3 (43 mg, 0.31 mmol) in MeOH (5 mL) was added. After stirring at room temperature for 1 h the reaction mixture was filtered, the filtrate was concentrated and purified by HPLC-prepare to afford the desired compound 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(3-hydroxy propyl)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 311) (6 mg, 66.7%, two step). LC-MS (m/z)=421 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ: 0.75-0.79 (m, 2H), 0.99-1.03 (m, 2H), 1.71 (q, J=6.4 Hz, 2H), 1.94-1.99 (m, 1H), 2.71 (t, J=6.4 Hz, 2H), 3.47 (t, J=6.4 Hz, 2H), 6.45 (s, 1H), 7.64 (d, J=4.0 Hz, 1H), 7.80 (s, 2H), 8.05 (d, J=3.2 Hz, 1H), 8.22 (s, 1H), 10.06 (bs, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4[CH2:27][C:28]3([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30][CH2:29]3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2]>ClCCCl.C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH2:27][C:28]3([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:42])[CH3:41])[CH2:29][O:30][C:31]([CH3:34])([CH3:35])[O:32][CH2:33]3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Agent: O=[Mn]=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOc1ccc(-c2nc(-c3cccc4c3ccn4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Temperature: 50 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A suspension of the product of Example 34, Step D (0.07 g; 0.118 mmol), MnO2 (0.58 g; 6.67 mmol) and anhydrous MgSO4 (0.5 g; 4.2 mmol) in 1,2-dichloroethane (2.5 ml) was vigorously stirred for 2 h at ˜50° C., then overnight at room temperature. This was diluted to 20 ml with CH2Cl2 and filtered through Celite pad, washed with fresh CH2Cl2 (10 ml). The combined organic phase was evaporated under reduced pressure and the residue was purified by FCC (SiO2, CH2Cl2/EtOAc 9:1) to give the title compound (0.02 g; 28%), as creamy solid. 1H-NMR (CDCl3) 1.43-1.53 (m, 21H+H2O); 3.78 (d, 2H, J=11.9 Hz); 3.90 (d, 2H, J=11.9 Hz); 4.13-4.38 (m, 5H); 4.76 (s, 1H); 6.98 (d, 1H, J=8.5 Hz); 7.15 (s, 1H); 7.28-7.34 (m, 2H); 7.68 (d, 1H, J=8.4 Hz); 7.73 (d, 1H, J=1.9 Hz); 7.83 (dd, 1H, J=1.9, 8.4 Hz); 8.03 (d, 1H, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:25][CH3:26])[CH:9]=[C:10]([CH2:13][C:14](=[CH:17]NC3C=CC=CC=3)[C:15]#[N:16])[CH:11]=2)[N:6]=[C:5]([CH3:27])[CH:4]=1.N(C(C)C#N)C1C=CC=CC=1.C[O-].[Na+].Cl.[NH2:43][C:44]([NH2:46])=[NH:45]>CS(C)=O.C(O)C>[NH2:45][C:44]1[N:46]=[C:15]([NH2:16])[C:14]([CH2:13][C:10]2[CH:11]=[C:12]3[C:7](=[C:8]([O:25][CH3:26])[CH:9]=2)[N:6]=[C:5]([CH3:27])[CH:4]=[C:3]3[O:2][CH3:1])=[CH:17][N:43]=1
Reactant: COc1cc(C)nc2c(OC)cc(CC(C#N)=CNc3ccccc3)cc12
Reactant: N=C(N)N
Agent: CC(C#N)Nc1ccccc1
Agent: C[O-]
Agent: Cl
Solvent: CCO
Solvent: CS(C)=O
Product: COc1cc(C)nc2c(OC)cc(Cc3cnc(N)nc3N)cc12

Procedure:
The aldehyde from above was converted to 2-(4,8dimethoxy-2-methyl-6-quinolylmethyl)-3-anilinoacrylonitrile with anilinopropionitrile and sodium methylate in dimethyl sulfoxide on a 1.4 mmol scale in the same manner as in Example 5-A. The crude product from this reaction was condensed with guanidine hydrochloride and sodium methylate in ethanol as in Example 5-B to give the crude product.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:7]([NH:9][C:10]1[CH:11]=[C:12]([C:23]([CH3:30])([CH3:29])[CH2:24][O:25]C(=O)C)[CH:13]=[C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:15]=1[O:16][CH3:17])=[O:8])=[N+:2]=[N-:3].[OH-].[Na+].[CH:37]1([C:40]2[N:41]([CH3:47])[C:42]([C:45]#[CH:46])=[CH:43][N:44]=2)[CH2:39][CH2:38]1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CCO.O.[NH4+].[Cl-].[O-]S([O-])(=O)=O.[Cu+2]>[CH:37]1([C:40]2[N:41]([CH3:47])[C:42]([C:45]3[N:3]=[N:2][N:1]([C:4]4[CH:5]=[C:6]([CH:31]=[CH:32][C:33]=4[CH3:34])[C:7]([NH:9][C:10]4[CH:11]=[C:12]([C:23]([CH3:30])([CH3:29])[CH2:24][OH:25])[CH:13]=[C:14]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:15]=4[O:16][CH3:17])=[O:8])[CH:46]=3)=[CH:43][N:44]=2)[CH2:39][CH2:38]1
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)COC(C)=O)cc1NS(C)(=O)=O
Reactant: C#Cc1cnc(C2CC2)n1C
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C5CC5)n4C)nn3)c2)cc(C(C)(C)CO)cc1NS(C)(=O)=O

Procedure:
To a stirring suspension of 49 mg (0.10 mmol) of acetic acid 2-[3-(3-azido-4-methyl-benzoylamino)-5-methanesulfonylamino-4-methoxy-phenyl]-2-methyl-propyl ester in 1 mL of EtOH was added 4N NaOH dropwise until the solids dissolved. 2-Cyclopropyl-5-ethynyl-1-methyl-1H-imidazole (125 mg, 0.855 mmol) was added followed by 20 mg (0.1 mmol) of sodium ascorbate in water. The mixture was stirred under N2 and CuSO4 (0.1 M; 0.1 mL, 0.010 mmol) was added. The suspension was stirred overnight, then was was diluted with half-saturated NH4Cl, and extracted with EtOAc. The extract was washed with brine, and the washes were extract once more wtih EtOAc. The extracts were combined, dried with Na2SO4, filtered, and concentrated. Chromatography (0–4% MeOH (0.5% NH4OH) in CH2Cl2) provided the desired product with a slight blue-green color. The product was then redissolved in EtOAc and washed again with NH4Cl with a few drops of NH4OH added. The aqueous layer became blue, and the organic layer was washed once more with NH4Cl/NH4OH, and once with brine. The organic layer was then dried with Na2SO4, filtered, and concentrated to provide Example 133 (83 mg). ESI MS m/z 594 [C29H35N7O5S+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([C@@H:12]([CH3:17])[C:13]([O:15]C)=[O:14])[CH:7]=[N:6][C:5]=2[N:4]([CH3:18])[C:3]1=[O:19].Cl.OP([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([C@@H:12]([CH3:17])[C:13]([OH:15])=[O:14])[CH:7]=[N:6][C:5]=2[N:4]([CH3:18])[C:3]1=[O:19]
Reactant: COC(=O)[C@H](C)n1cnc2c1c(=O)n(C)c(=O)n2C
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@@H](C(=O)O)n1cnc2c1c(=O)n(C)c(=O)n2C
Reaction time: 0.5 h

Procedure:
To a solution of methyl(S)-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propanoate (Intermediate 7, 39 g, 146 mmol) in 1,4-dioxane (400 mL) was added 6N HCl (200 mL). The resulting mixture was refluxed for 3 h, then cooled and concentrated under vacuum (water bath temp: 40-45° C.). Water (35 mL) was added to the residue, and the resulting mixture was then stirred for 0.5 h. The precipitate was collected by filtration, washed with cooled water and ethyl acetate to give the (S)-acid (17.3 g, ee: 99%). The filtrate was carefully neutralized with K2HPO4 solution (aq) to pH 4, extracted with (9:1) CH2Cl2:MeOH mixture (2×), dried over MgSO4, filtered, and concentrated. The residue was purified using silica gel chromatography eluting with CH2Cl2:MeOH (9:1) to give additional (S)-acid (3.2 g, ee: 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[C:28](=[O:33])[C:29](=[O:32])[C:30]=5[NH2:31])[CH:25]=4)[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1>C(#N)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[C:28](=[O:33])[C:29](=[O:32])[C:30]=5[NH2:31])[CH:25]=4)[NH:20][CH:19]=3)[CH2:13][CH2:14]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: COc1cncnc1N1CCN(CCCc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ccc(-c4c(N)c(=O)c4=O)cc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(-c4c(N)c(=O)c4=O)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-(1,2-dioxo-4-amino-3-cyclobuten-3-yl)-1-triisopropylsilylindole (0.280 g, 0.465 mmol) in 10 mL of acetonitrile was added 48% HF (34 μL, 0.94 mmol) and the mixture was stirred at room temperature for 2 h. The resulting suspension was filtered and the residue was washed with acetonitrile and ether, and then it was air-dried to give a pale yellow solid. The solid was suspended in saturated aqueous NaHCO3 with vigorous stirring and the suspension was then filtered and the residue was washed with water, a little ethanol and finally with ether. This material was dried in vacuo to give the title compound (0.194 g, 94%) as a yellow solid. Crystallization from ethanol afforded the analytical sample (0.141 g, 68%) as a beige solid, mp 233° C. (dec): IR (KBr) 3330, 3195, 1772, 1700, 1660, 1577 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) d 11.15 (br s, 1H), 8.93 (br s, 1H), 8.83 (br s, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.24 (s, 1H), 3.81 (s, 3H), 3.67 (br s, 4H), 2.81-2.73 (m, 2H), 2.49-2.35 (m, 6H), 1.88-1.81 (m, 2H). Anal. Calcd for C24H26N6O3. 0.5 H2O. 0.25 C2H6O: C, 63.06; H, 6.12; N, 18.08. Found: C, 63.32; H, 5.83; N, 17.73.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C([O-])(C)C.[K+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[N+:29]([O-:31])=[O:30])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CS(C)=O>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[CH2:7][C@@H:28]2[N+:29]([O-:31])=[O:30])=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])[C@H]1C[C@@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions to a solution of t-BuOK (0.32 g, 2.82 mmol) in dry DMSO (5 mL). After 10 min a solution of 1-(benzyloxy)-4-[(E)-2-nitrovinyl]benzene (0.60 g, 2.35 mmol) in DMSO (5 mL) was transferred via canula and the mixture was stirred at room temperature for 6 h. The reaction was poured over water (10 mL) and extracted with Et2O (3×10 mL); the organic layers were washed with brine (2×15 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual orange oil was purified by column chromatography on silica gel (5% EtOAc/hexanes) affording 0.16 g of 1-(benzyloxy)-4-[(1R,2S)-2-nitrocyclopropyl]benzene [Rf=0.5 (20% EtOAc/hexanes), white solid, 26% yield].
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[OH:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][NH:36][CH2:35][CH2:34][NH:33]2)=[CH:28][CH:27]=1.O>CS(C)=O>[F:1][C:2]1[C:20]([N:36]2[CH2:35][CH2:34][NH:33][CH:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][OH:22])=[CH:31][CH:30]=3)[CH2:37]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: OCCOc1ccc(C2CNCCN2)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccc(OCCO)cc5)C4)cc3nc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A suspension of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.015 g) and (RS)-2-[4-(2-hydroxyethoxy)phenyl]-piperazine (1.7 g) in dimethyl sulphoxide (15 cc) is heated with stirring to a temperature in the region of 100° C. for 2 hours and a half. After cooling to approximately 20° C., the suspension is treated with water (30 cc), drained and washed with water (3×10 cc). After one recrystallization in dimethylformamide (15 cc), (RS)-7-fluoro-8-{3-[4-(2-hydroxyethoxy)phenyl]-1-piperazinyl}-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.2 g)is obtained in the form of a yellow solid, m.p. 276° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>CC(C)=O>[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N:8]([CH2:7][C:6]2[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)(=[O:11])=[O:10])=[CH:33][CH:32]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) (4.3 g, 12.8 mmol) was dissolved in acetone (70 mL). Cesium carbonate (8.57 g, 25.6 mmol) and (4-fluorobenzyl bromide (1.76 mL, 14.08 mmol) were added and the mixture was stirred at room temperature overnight. The inorganic salts were filtered off and acetone was removed in vacuo. The residue was re-dissolved in ethyl acetate, washed with water and brine, then the organic layer was dried over magnesium sulfate and concentrated. The crude product was purified by re-crystallization with ethyl acetate/hexanes to afford pure Methyl 4-(N-(4-fluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate (3.7 g, 65%) as a white solid. 1H NMR (400 MHz, CDCl3): δ, ppm: 3.77 (s, 3H), 3.98 (s, 3H), 4.27 (s, 2H), 4.28 (s, 2H), 6.74 (d, 2H, J=8 Hz), 6.92 (m, 4H), 7.03 (m, 2H), 7.88 (d, 2H J=8 Hz), 8.16 (d, 2H, J=8 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([NH:33]C(=O)OCC3C=CC=CC=3)(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:45])(=[O:44])[N:20]=1>CO.[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([NH2:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:44])(=[O:45])[N:20]=1
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(N)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
A solution of Example 85 (56 mg, 0.086 mmol) in 7 mL of methanol was treated with 10% palladium on carbon (28 mg, 50 wt %) and placed under an atmosphere of hydrogen. The mixture was stirred at room temp for 5 h, filtered through a 0.45 □M syringe filter, and concentrated in vacuo to afford the desired product (35 mg, 79% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.56 (m, 2H) 0.67 (m, 6H) 0.87 (m, 2H) 1.96 (m, J=11.40, 11.40 Hz, 2H) 2.16 (m, 2H) 7.37 (s, 2H) 7.59 (m, 6H) 8.15 (d, J=7.72 Hz, 1H) 9.99 (s, 1H) 13.94 (s, 1H); (ESI+) m/z 519 (M+H)+ (ESI+) m/z 536 (M+NH4)+ (ESI+) m/z 541 (M+Na)+ (ESI+) m/z 1054 (2M+NH4)+ (ESI−) m/z 517 (M−H)− (ESI−) m/z 1035 (2M−H)−
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=4[N:15]=3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:25]1([C:2]2[C:3]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[NH:18][C:17]5[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=5[N:15]=4)[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1ccc2[nH]c(C3CCN(c4nccnc4Cl)CC3)nc2c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc2[nH]c(C3CCN(c4nccnc4-c4ccccc4)CC3)nc2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 16.1 %

Procedure:
The mixture of 2-[1-(3-chloro-pyrazin-2-yl)-piperidin-4-yl]-1H-benzoimidazole-5-carbonitrile (160 mg, 0.47 mol), phenylboronic acid (69.3 mg, 0.57 mmol), K2CO3 (131 mg, 0.95 mmol) and Pd(dppf)Cl2 (34 mg, 0.047 mmol) in toluene (10 mL) and H2O (3 mL) was stirred at 90° C. under N2 for 12 h. Then it was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column (ethyl acetate:petroleum ether=1:2) to give the compound 2-[1-(3-phenyl-pyrazin-2-yl)-piperidin-4-yl]-1H-benzoimidazole-5-carbonitrile (35 mg, yield 19.1%) as white solid. [M+1] 381. IC50 (uM) 0.272.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1[NH2:75])[CH3:66]>C(Cl)Cl>[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1[NH:75][C:28]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]1)=[O:30])[CH3:66]
Reactant: CCOC(=O)c1ccccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 2-amino benzoic acid ethyl ester (Aldrich, 43 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 13 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Br)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>CO.C(OCC)(=O)C.O.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Br)ncc3O2)CC1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-n4ccnc4)ncc3O2)CC1
Temperature: 130 °C

Procedure:
A mixture of 4-(5-bromo-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (115 mg), imidazole (41 mg), cesium carbonate (215 mg), 1,10-phenanthroline (11 mg), and copper iodide (6 mg) in methanol (2 mL) is heated in a microwave oven to 130° C. for 45 min under an argon atmosphere. After cooling to room temperature the reaction mixture is diluted with ethyl acetate and water. The organic phase is separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by HPLC to give the title compound. LC (method 7): tR=1.16 min; Mass spectrum (ESI+): m/z=371 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[Cr+6].[O-2].[O-2]>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[CH:5][C:6]=1[O:11][CH:12]([CH3:17])[C:13]([F:15])([F:14])[F:16])[C:1]([OH:20])=[O:2])#[N:9]
Reactant: CC(Oc1ccc(C=O)cc1C#N)C(F)(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(Oc1ccc(C(=O)O)cc1C#N)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 440 mg (1.81 mmol) of 5-formyl-2-(2,2,2-trifluoro-1-methylethoxy)benzonitrile (from Step A) in 20 mL of acetone at 0° C. was added dropwise a solution of Jones reagent, which was prepared by dissolving 0.27 g (2.71 mmol) of chromium (VI) oxide in 0.25 mL of concentrated sulfuric acid and diluted with 2 mL of water at 0° C. The reaction mixture was gradually warmed up to rt, stirred overnight, and concentrated. The residue was diluted with 20 mL of EtOAc and washed with brine (10 mL), H2O (3×10 mL), and brine (10 mL). The organic layer was dried over MgSO4 and concentrated to give 0.44 g of the title compound: 1H NMR (500 Mhz, CDCl3) δ 1.69 (d, J=6.4, 3H), 4.94 (m, 1H), 7.16 (d, J=9.1, 1H), 8.34 (dd, J=2.0, 6.9, 1H), 8.42 (d, J=2.1, 1H).