Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:37][CH3:38])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.FC(F)(F)S(O[CH2:56][C:57]([F:60])([F:59])[F:58])(=O)=O>O>[CH3:38][O:37][C:4]1[CH:3]=[C:2]([O:1][CH2:56][C:57]([F:60])([F:59])[F:58])[CH:7]=[CH:6][C:5]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(O)cc4OC)nccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCC(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A vial was charged with 1-(4-hydroxy-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (from EXAMPLE 361, STEP 1; 54 mg, 0.102 mmol), cesium carbonate (100 mg, 0.306 mmol), and DMF (511 μl). 2,2,2-Trifluoroethyl trifluoromethanesulfonate (28.0 μl, 0.204 mmol) was added and the vial was heated to 50° C. for 1 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (1 mL), and the resulting solution was stirred overnight. The mixture was diluted with MeOH and concentrated. The residue was dissolved in EtOAc and washed with saturated aq. sodium bicarbonate solution. The aq. wash was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (3.5% MeOH/DCM) to give 1-(2-methoxy-4-(2,2,2-trifluoroethoxy)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (32.7 mg, 0.067 mmol, 65.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.06 (br. s., 1H), 8.70-8.61 (m, 2H), 8.57 (s, 1H), 8.25 (d, J=5.6 Hz, 1H), 8.06 (d, J=5.8 Hz, 1H), 7.94 (dd, J=1.9, 8.9 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.03 (d, J=5.1 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.82 (dd, J=2.3, 8.4 Hz, 1H), 4.89 (q, J=8.9 Hz, 2H), 3.65 (s, 3H). m/z (ESI) 491.2 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH3:25]>CC#N>[Br-:23].[CH2:24]([N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2)[CH3:25]
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: CCBr
Solvent: CC#N
Product: CC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 54.5 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0581 g, 0.198 mmol) and bromoethane (0.030 mL, 0.402 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0434 g, 54.9%). EI-MS m/z 322(M+) Rt (1.56 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1>>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=3)[CH:5]=[CH:6][CH:7]=2)[CH:15]=1
Reactant: Nc1nc(-c2cccc(Br)c2)c[nH]1
Reactant: OB(O)c1cccnc1
Product: Nc1nc(-c2cccc(-c3cccnc3)c2)c[nH]1

Procedure:
In a similar manner to Example 33, Step 1, the Suzuki coupling reaction of the bromide from Step 1 of Example 37 (126 mg, 0.31 mmol) and pyridin-3-yl-boronic acid (96 mg, 0.78 mmol) afforded 4-(3-pyridin-3-yl-phenyl)-1H-imidazol-2-ylamine, after washing with 1N aqueous sodium hydroxide, as an off-white solid (51 mg, 69% yield). LC/MS (m/z 237.2 (M+H)+); HPLC Rt: 0.81 min.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1C(F)(F)F)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)=[O:7].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:35]=[C:34]([C:2]([F:41])([F:40])[F:1])[CH:33]=3)[C@H:9]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:10]2)=[CH:16][CH:17]=1
Reactant: O=C(c1ccc(C(F)(F)F)c(C(F)(F)F)c1)N1CCN(Cc2ccc([N+](=O)[O-])cc2)C[C@H]1Cc1ccc(Cl)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(Cl)c(Cl)c3)C2)cc1
Yield: 171.9 %

Procedure:
A mixture of (2R)-1-[3,4-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-nitrobenzyl)piperazine (157 mg), ammonium chloride (15.7 mg) and iron powder (157 mg) in a mixture of ethanol (5 ml) and water (1.25 ml) was refluxed for 1.5 hours. After cooling, the precipitates were filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of toluene and ethyl acetate as an eluent to give (2R)-4-(4-aminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine (128.4 mg).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=1.[Br:16][C:17]1[CH:18]=[C:19]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1.Cl.CO>O1CCCC1.CO>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]4[CH2:15][CH2:14]4)[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cccc(F)c1C#N
Reactant: Brc1ccnc(C2CC2)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: NC1=NC(c2cccc(Br)c2)(c2ccnc(C3CC3)c2)c2cccc(F)c21
Temperature: -112.5 °C
Reaction time: 0.75 h
Yield: 38.2 %

Procedure:
Under an atmosphere of argon, tert-butyllithium (0.731 mL, 1.24 mmol) was added drop wise over 3 minutes to tetrahydrofuran (5 mL) in a flask cooled in a liquid nitrogen-pentane bath at an external temperature between −105 to −120° C. To the solution was added drop wise over a period of 6 minutes 4-bromo-2-cyclopropylpyridine (123 mg, 0.62 mmol) dissolved in anhydrous tetrahydrofuran (2 mL). The solution was stirred for 4 minutes before drop wise addition of N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (253 mg, 0.62 mmol) dissolved in anhydrous tetrahydrofuran (2 mL) over a period of 10 minutes. The reaction mixture was stirred at a temperature below −100° C. for 45 minutes. MeOH (5.0 mL) was added at −100° C. and then hydrogen chloride-methanol solution (0.745 mL, 0.93 mmol) was added at −90° C. The reaction was left to stir overnight (17 h) and was allowed to reach ambient temperature. The solvents were evaporated and the residue was partitioned between EtOAc (25 mL) and saturated aqueous NaHCO3 (25 mL). The aqueous layer was extracted with EtOAc (25 mL). The organics were combined, dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography on silica gel and gave 100 mg (38%) of the title compound. MS (ES+) m/z 422, 424 [M+H]+
Reaction SMILES: Cl.N[N:3]=[CH:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][C:17]=2[O:31][CH3:32])=[CH:7][CH:6]=1.C([N:37](CC)CC)C.[CH3:42][N:43]=[C:44]=[O:45]>C(Cl)Cl>[NH2:3][C:4](=[N:37][C:44]([NH:43][CH3:42])=[O:45])[C:5]1[CH:34]=[CH:33][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][C:17]=2[O:31][CH3:32])=[CH:7][CH:6]=1
Reactant: CCN(CC)CC
Reactant: CN=C=O
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(C=NN)cc1
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)N=C(N)c1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)cc2OC)cc1
Reaction time: 0.5 h

Procedure:
A stirred, 0° C. solution of 4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide monohydrochloride (200 mg, 0.41 mmol) in 4.0 mL anhydrous methylene chloride is treated sequentially with triethylamine (0.068 mL, 0.48 mmol) and methyl isocyanate (0.030 mL, 0.49 mmol). The solution is stirred 30 minutes, concentrated in vacuo and the resulting solids are partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated. The resulting material is purified by chromatography on silica gel (15 g) with 70-100% ethyl acetate/hexanes as the eluent to afford 4-[5-[4-[amino(methylaminocarbonylimino)methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide as a colorless foam;
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([N:7]([CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)NCc2ccco2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccco2)cc1
Temperature: 165 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
4-(N-(furan-2-ylmethyl)sulfamoyl)benzoic acid (Example 5-2b) (140 mg, 0.5 mmol) and Cesium Carbonate (325 mg, 1 mmol) were placed in a microwave vial and dissolved in 2 mL DMF. (Bromomethyl)benzene (170 mg, 1 mmol) was added into the reaction mixture. The reaction was placed in a microwave reactor and heated at 165° C. for 5 minutes. The reaction mixture was dissolved in Ethyl Acetate and washed with water. The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude product was dissolved in 4/1 solution of 6N NaOH(aq)/tetrahydrofuran (3 mL) and stirred at ambient temperature for 6 hours. The solution was acidified with 3N HCl (aq) to a pH of ˜3 and the product was extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The residue was taken up in methanol (3 mL) and purified by reverse phased HPLC (5-95% acetonitrile in H2O gradient: 25 minutes). Yield 35%. MS M+H calculated 372.4. Found 372.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:48]([O:50]C)=[O:49])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH2:1]([O:8][C:9]1[C:10]([C:48]([OH:50])=[O:49])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH2:38][NH:39][C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(N2CCN(C(=O)CCCCOc3cc(F)ccc3CNC(=O)OC(C)(C)C)CC2)c2cccnc2c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(F)cc1OCCCCC(=O)N1CCN(c2nc(C(=O)O)c(OCc3ccccc3)c3ncccc23)CC1
Reaction time: 48 h
Yield: 52.9 %

Procedure:
Methyl 8-(benzyloxy)-5-(4-(5-(2-((tert-butoxycarbonylamino)methyl)-5-fluorophenoxy)pentanoyl)piperazin-1-yl)-1,6-naphthyridine-7-carboxylate (Example 5.1; 1.1 mmol) was dissolved in a mixture of THF (6 ml), methanol (6 ml) and water (6 ml). Sodium hydroxide (7.5 mmol) was added and stirred for 2 days. The organic solvent was removed under vacuum, and the residue washed with diethyl ether. The aqueous residue was acidified with 1 N HCl to pH=8-9. The mixture was washed with ethyl acetate. The aqueous phase was acidified with 1N HCl to pH 3-4. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over Na2SO4. The solvent was removed under vacuum to afford the title compound (0.4 gr) that was used as such in the next step.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18](O)=[O:19])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:21][CH2:22][C:23]1[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:18]([NH:21][CH2:22][C:23]3[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=3[CH3:29])=[O:19])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([C:14]([CH3:16])([CH3:17])[CH3:15])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nn(C(C)(C)C)c2nc(C3CC3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 6-cyclopropyl-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (210 mg, 0.768 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (158 mg, 1.037 mmol), 1-hydroxy-7-azabenzotriazole (209 mg, 1.537 mmol), EDC (295 mg, 1.537 mmol), N-methylmorpholine (0.338 mL, 3.07 mmol), and DMSO(10 mL). The final product was collected as 0.280 g (89%). LCMS E-S (M+H)=408.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (dddd, 4 H), 1.69 (m, 9 H), 2.12 (s, 3 H), 2.22 (m, 4 H), 2.33 (s, 3 H), 4.34 (d, J=4.80 Hz, 2 H), 5.87 (s, 1 H), 7.04 (s, 1 H), 8.55 (m, 1 H), 11.51 (s, 1 H).
Reaction SMILES: [F-].[Cs+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:11]([O:15][C:16](=[O:40])[N:17]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[C:18]1[CH:19]=[CH:20][C:21]2[NH:22][C:23](=[O:28])[NH:24][CH2:25][C:26]=2[N:27]=1)([CH3:14])([CH3:13])[CH3:12].CN[CH2:43][CH2:44]NC>[Cu]I>[C:11]([O:15][C:16](=[O:40])[N:17]([C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:44]3[CH:43]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=3)[C:23](=[O:28])[N:24]([C:7]3[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=3)[CH2:25][C:26]=2[N:27]=1)[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])([CH3:14])([CH3:13])[CH3:12].[C:11]([O:15][C:16](=[O:40])[N:17]([C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:7]3[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=3)[C:23](=[O:28])[NH:24][CH2:25][C:26]=2[N:27]=1)[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CNC(=O)N3)c(OC)c1
Reactant: CNCCNC
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CN(c2ccc(Cl)cc2)C(=O)N3c2ccc(Cl)cc2)c(OC)c1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CNC(=O)N3c2ccc(Cl)cc2)c(OC)c1
Temperature: 80 °C

Procedure:
Into a reaction tube were placed CsF (1.0 g, 6.5 mmol, 2.5 equiv), CuI (50 mg, 0.26 mmol, 0.1 equiv), 1-chloro-4-iodo-benzene (740 mg, 3.12 mmol, 1.2 equiv), (2,4-dimethoxy-benzyl)-(2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (Example 20, product from Step 4) (1.09 g, 2.6 mmol, 1.0 equiv) and N,N′-dimethyl-ethylene diamine (280 μL, 2.6 mmol, 1.0 equiv). The tube was sealed, evacuated and back-filled with nitrogen, then acetonitrile (5 mL) was added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was cooled, diluted with ethyl acetate and the reaction was quenched with saturated ammonium chloride. The products were extracted with ethyl acetate, the combined organics were washed with brine, dried (MgSO4), filtered and the solvent evaporated. The crude material was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-100%) to afford 490 mg of [1,3-bis-(4-chloro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (high RF compound, MS: [M+H]+=635) and 383 mg of [1-(4-chloro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (low RF compound, MS: [M+H]+=525).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[H-].[Na+].I[CH3:18]>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:18])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CI
Reactant: COC(=O)Cc1ccc(C#N)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)c1ccc(C#N)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a stirred solution of methyl 2-(3-chloro-4-cyanophenyl)acetate (931 mg, 4.441 mmol) in dimethylformamide were added 60% sodium hydride (178 mg, 4.441 mmol) and iodomethane (0.3 mL, 4.441 mmol) at 0° C. The reaction mixture was stirred for 1 h at 0° C., then diluted with water. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to give methyl 2-(3-chloro-4-cyanophenyl)propanoate (642 mg, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[C:7]([N+:17]([O-:19])=[O:18])=[CH:6][C:4]=1[NH2:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:33]1[N:38]=[C:37]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)[C:36]([CH3:48])=[CH:35][N:34]=1>CC(O)CCC>[NH:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]([C:37]2[C:36]([CH3:48])=[CH:35][N:34]=[C:33]([NH:5][C:4]3[CH:6]=[C:7]([N+:17]([O-:19])=[O:18])[C:8]([N:10]4[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]4)=[CH:9][C:3]=3[O:2][CH3:1])[N:38]=2)=[CH:40]1
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCC(C)O
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1
Yield: 43.1 %

Procedure:
A mixture of 2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitroaniline (Intermediate 14, 204 mg, 0.77 mmol), p-toluene sulphonic acid monohydrate (291 mg, 1.53 mmol) and 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (Intermediate 17, 192 mg, 0.77 mmol) were heated at 120° C. in 2-pentanol (15 mL) for 24 h, resulting in a dark brown suspension. The mixture was then concentrated in vacuo and the resulting residue was dissolved in a mixture of CH2Cl2 and CH3OH (50 mL and 5 mL) and this solution was concentrated onto silica in vacuo. Purification by FCC, eluting with 1-5% methanolic ammonia in CH2Cl2 gave the title compound (157 mg, 43%) as an orange gum; m/z: ES+ MH+ 474.24.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[S:15][CH:16]=1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[S:15][CH:16]=2)=[O:10])[CH:3]=1
Reactant: COC(=O)c1cc(N)cs1
Reactant: O=C(O)c1cc(Br)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)c2cc(Br)ccn2)cs1

Procedure:
A solution of 4-bromo-pyridine-2-carboxylic acid (1.98 g, 9.80 mmol), methyl 4-aminothiophene-2-carboxylate (1.40 g, 8.91 mmol), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (4.07 g, 10.7 mmol), and N-methylmorpholine (1.18 mL, 10.7 mmol) in N,N-dimethylformamide (18 mL) was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, the residue suspended in acetonitrile, and the solids were isolated by filtration. The solids were washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 mL), and dried under reduced pressure to afford methyl 4-(4-bromopicolinamido)thiophene-2-carboxylate, a compound of formula (19) as a white powder (2.70 g, 90% yield). M+1=341.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15](I)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.[F:20][C:21]1([F:36])[CH2:26][CH2:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:21]1([F:36])[CH2:26][CH2:25][C:24]([C:15]2[NH:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:18][CH3:19])[C:9]=3[CH:16]=2)=[CH:23][CH2:22]1
Reactant: COc1ccc(F)cc1-c1ncnc2[nH]c(I)cc12
Reactant: CC1(C)OB(C2=CCC(F)(F)CC2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCC(F)(F)CC3)cc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of Example 61A (129 mg, 0.528 mmol), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (129 mg, 0.528 mmol), and bis(triphenylphosphine)palladium(II) dichloride (28.5 mg, 0.041 mmol) in 10 mL dimethoxyethane/ethanol/water (7/2/3) was added sodium carbonate (129 mg, 1.219 mmol). The reaction was stirred at 100° C. for 2 hours, cooled and then extracted with ethyl acetate. The organic fraction was washed with saturated sodium bicarbonate, water and brine, then dried over magnesium sulfate and concentrated. The crude material was triturated with ethyl acetate, and the solid was collected by filtration. The solid was purified via flash chromatography: Analogix Intelliflash™ 280, 24 g silica column, 20% to 60% ethyl acetate/hexanes gradient over 30 minutes to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H) 8.65-8.90 (m, 1H) 7.09-7.48 (m, 3H) 6.45 (s, 1H) 6.37 (s, 1H) 3.73-3.82 (m, 3H) 2.80 (t, J=14.19 Hz, 2H) 2.69 (t, J=5.95 Hz, 2H) 2.08-2.27 (m, 2H). MS (ESI+) m/z 360.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[S-:11][C:12]#[N:13].[NH4+].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>S(Cl)(Cl)=O>[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:12]2[S:11][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:13]=2)[CH2:18][CH2:17]1
Reactant: OC1CCNCC1
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Product: O=c1nc(N2CCC(O)CC2)sc2ncccc12
Yield: 19.1 %

Procedure:
The reaction procedure of Example 106 was followed except that 1.0 g of 2-chloronicotinic acid, 10 ml of thionyl chloride, 531 mg of ammonium thiocyanate and 642 mg of 4-hydroxypiperidine were used. The product was subjected to separation through silica gel column chromatography (eluant: 50:1:0.1 mixture of chloroform, methanol and aqueous ammonia), and then crystallized from isopropanol to obtain 320 mg of 2-(4-hydroxypiperidino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.