Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1.C([O-])([O-])=O.[K+].[K+].[F:21][CH:22]([F:25])[CH2:23]I.C(Cl)Cl>CN(C=O)C.CO>[F:21][CH:22]([F:25])[CH2:23][N:5]1[CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)[C:2]([I:1])=[N:6]1
Reactant: FC(F)CI
Reactant: CSc1nccc(-c2cn[nH]c2I)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1nccc(-c2cn(CC(F)F)nc2I)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Intermediate A (83 g, 0.26 mol) in DMF (600 mL) were K2CO3 (58 g, 0.417 mol) and 1,1-difluoro-2-iodo-ethane (60 g, 0.313 mol). Then the mixture was stirred at room temperature overnight. TLC (CH2Cl2: MeOH=20:1) showed the reaction was complete. The mixture was concentrated and the solid was diluted with CH2Cl2 (500 mL). The slurry was filtered and the filtrate was concentrated to give crude product, which was purified via prep. SFC to give compound B-33-1 (41.1 g, 41.3%) as a white solid.
Reaction SMILES: [OH-].[Na+].CCO.[CH3:6][O:7][C:8]1[CH:35]=[CH:34][C:11]([O:12][C:13]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][C:28]4[O:31][CH2:32][O:33][C:27]=4[CH:26]=3)[C:14]=2[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1>>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][C:28]4[O:31][CH2:32][O:33][C:27]=4[CH:26]=3)[C:14]=2[C:15]([OH:17])=[O:16])=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1c(Oc2ccc(OC)cc2)cccc1Oc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Oc2cccc(Oc3ccc4c(c3)OCO4)c2C(=O)O)cc1
Yield: 80.9 %

Procedure:
NaOH/EtOH (0.5 M) was added to ethyl 2-(4-methoxyphenoxy)-6-[3,4-(methylenedioxy)phenoxy]benzoate (175 mg, 0.429 mmol) at 25° C. The mixture (solid and solution) was heated under reflux for 20 hr. until TLC indicated the absence of starting material and the formation of a polar material. The solvent was evaporated and the residue was diluted with H2O (7 ml, pH≈7.5) and extracted with EtOAc (2×7ml) to give 132 mg 2-(4-methoxyphenoxy)-6-[3,4-(methylenedioxy)phenoxy]benzoic acid as a yellow foam which was recrystallized from MeOH/H2O (twice) to give 102 mg of colorless needles, m.p. 164-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:42][N:43]1[CH2:50][C@@H:49]2[C@@H:45]([CH2:46][NH:47][CH2:48]2)[CH2:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:47]3[CH2:48][C@@H:49]4[C@@H:45]([CH2:44][N:43]([CH3:42])[CH2:50]4)[CH2:46]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CN1C[C@H]2CNC[C@H]2C1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C[C@@H]2CN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of {3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (20.0 g, 43.2 mmol) in DMF (150 mL) was treated with DIPEA (6.7 g, 5.2 mmol), cis-2-methyloctahydropyrrolo[3,4-c]pyrrole (6.27 g, 49.7 mmol) and HATU (18.9 g, 49.7 mmol) and the mixture left to stir at room temperature for 1 hour. The reaction mixture was diluted with 0.5M aqueous K2CO3 solution and extracted with ethyl acetate (×2). The combined organic extract was washed with water (×2) and brine, dried (Na2SO4) and evaporated to afford a solid. The resultant solid was purified by flash chromatography on silica eluting with 0-10% 2M NH3/MeOH in DCM. Collecting appropriate fractions, followed by evaporation gave the title compound as a cream solid (17.1 g, 69%). LCMS (Method 5) [M+H]+=570.9, RT=2.82. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.70 (s, 1H), 9.30 (dd, 1H, J=7.0, 1.6 Hz), 8.62-8.63 (m, 2H), 8.27 (s, 1H), 7.59 (dd, 1H, J=8.8, 2.7 Hz), 7.52 (d, 1H, J=2.7 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.25 (dd, 1H, J=7.0, 4.2 Hz), 7.11 (t, 1H, J=73.3 Hz), 5.07 (d, 2H, J=5.9 Hz), 3.69 (dd, 1H, J=10.8, 8.6 Hz), 3.56 (dd, 1H, J=12.2, 8.8 Hz), 3.36 (dd, 1H, J=10.8, 4.4 Hz), 3.22 (dd, 1H, J=12.3, 4.5 Hz), 2.45-2.46 (m, 3H), 2.37-2.39 (m, 3H), 2.17 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([O:17][CH3:18])[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([N+:13]([O-])=O)[CH:5]=1>[Pd].O1CCCC1.C(O)C>[CH3:1][N:2]([O:17][CH3:18])[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:13])[CH:5]=1
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CON(C)C(=O)c1ccc(N)c(N)c1
Reaction time: 6 h
Yield: 97.1 %

Procedure:
Add 18.0 g of 10% weight Pd/C catalyst to a solution of N-[methyl] N-[methoxy] 3,4-dinitrobenzamide (182 g, 0.712 moles) in 900 mL tetrahydrofuran and 900 mL ethanol under a nitrogen atmosphere. Hydrogenate at room temperature for 6 hours under 60 p.s.i. Filter the mixture through Celite® and concentrate the filtrate under reduced pressure. Suspend the residue in 500 mL dichloromethane, concentrate under reduced pressure and dry the residue under reduced pressure to provide 135 g (97%) of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:11]=1)([O-])=O>CC(O)=O.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cnccc1C1CCCC(N2C(=O)c3ccccc3C2=O)C1

Procedure:
A solution of 2-[3-(3-nitropyridin-4-yl)cyclohex-2-en-1-yl]-1H-isoindole-1,3(2H)-dione (0.100 g, 0.286 mmol) in AcOH (3.0 mL) was mixed with 10% Pd on carbon (0.046 g, 0.043 mmol) and hydrogenated at 30 psi for 16 h. The reaction mixture was diluted in MeOH (50 mL), filtered and concentrated under vacuum. The residue was dissolved in EtOAc and washed with 1 M NaOH. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound. LCMS calc. for C19H20N3O2 (M+H)+: m/z=322.2. Found: 322.1.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[N:9][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([N:23]=[N+]=[N-])[CH3:22])[C:14](=[O:16])[C:15]=3[N:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)C.[H][H]>[Pd].CO>[C:1]([N:4]1[C:8]2=[N:9][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH2:23])[CH3:22])[C:14](=[O:16])[C:15]=3[N:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)N=[N+]=[N-])c(=O)n1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)N)c(=O)n1C

Procedure:
A mixture of (R)-8-acetyl-3-(5-azidohexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (200 mg, 0.534 mmol) and 10% palladium on carbon (50% water, 150 mg) in a solution of ethanol (50 ml) and methanol (10 ml) was treated with hydrogen gas (50 psi) on a Parr sharker at room temperature for 18 hours. After filtering through a pad of celite, the filtrate was concentrated under reduced pressure to provide (R)-8-acetyl-3-(5-aminohexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione as a white powder.
Reaction SMILES: I[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([C:15]1[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[C:17]([F:23])[CH:16]=1)#[CH:14]>C(#N)C.[Cu]I>[F:23][C:17]1[CH:16]=[C:15]([C:13]#[C:14][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH:22]=[CH:21][C:18]=1[NH:19][CH3:20]
Reactant: COc1ccc2nc(I)sc2c1
Reactant: C#Cc1ccc(NC)c(F)c1
Agent: [Cu]I
Solvent: CC#N
Product: CNc1ccc(C#Cc2nc3ccc(OC)cc3s2)cc1F
Temperature: 25 °C
Yield: 39.5 %

Procedure:
A 5 mL microwave tube was charged with 2 (0.2 g, 0.68 mmol), 7 (0.1 g, 0.68 mmol) [Pd(PPh3)4] (0.08 g, 0.034 mmol), CuI (0.02 g, 0.05 mmol) and TEA (0.28 mL, 2.04 mmol) in ACN (2.0 mL). The suspension was irradiated in a Biotage Emrys Optimizer microwave reactor (250 W) at 100° C. for 5 min. After cooling to room temperature the solvent was evaporated in vacuo. The residue was purified over silica gel using Hexanes:Dichloromethane (DCM) (0-100%) as the eluent to afford the coupling product 8 (0.084 g, 39%) as yellow solid. 1H NMR (400 MHz, CDCl3), δ: 2.92 (s, 3H), 3.87 (s, 3H), 6.64 (t, J=8.4 Hz, 1H), 7.11 (dd, J=12.0, 4.0 Hz, 1H), 7.22 (dd, J=10.4, 2 Hz, 1H), 7.27 (d, J=2.4, 1H), 7.33-7.35 (m, 1H), 7.96 (d, J=12 Hz, 1H); MS (ESI): 313.0 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]4[CH2:58][O:57][CH2:56]4)[CH2:51][CH2:50]3)=[CH:45][N:44]=2)[C:28]1=[O:59].O>C1COCC1.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:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:31]3[CH:30]=[C:29]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([N:49]5[CH2:54][CH2:53][N:52]([CH:55]6[CH2:56][O:57][CH2:58]6)[CH2:51][CH2:50]5)=[CH:45][N:44]=4)[C:28](=[O:59])[N:27]([CH3:26])[CH:32]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 70 °C
Yield: 80.6 %

Procedure:
A mixture of 103b (100 mg, 0.28 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridine-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (131 mg, 0.28 mmol), PdCl2(dppf) (25 mg, 0.03 mmol), and K3PO4.3H2O (149 mg, 0.56 mmol) was suspended in THF (10 mL)/H2O (5 mL). After three cycles of vacuum/argon flash, the mixture was heated at 70° C. for 6 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 103c as a yellow solid (150 mg, 60%). LCMS: [M+H]+ 665
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][NH:28][CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:32])[N:17]=2)[CH2:12][CH2:11]1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][C:47](O)=[O:48])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[NH2:32][C:18]1[N:19]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([C:47](=[O:48])[CH2:46][CH:43]4[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[CH2:41][CH2:42]4)[CH2:29]3)=[CH:24][CH:23]=2)[CH:21]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]2)[N:17]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
Triethylamine (40 uL, 0.29 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (25 mg, 0.058 mmol), [1-(tert-butoxycarbonyl)piperidin-4-yl]acetic acid (17 mg, 0.069 mmol) (AstaTech Cat. #66860), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (28 mg, 0.063 mmol) in N,N-dimethylformamide (0.8 mL). The mixture was stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH in dichloromethane (0-10%) to afford the desired product (25 mg, 79%). Analytic LCMS (M+H)+: m/z=550.3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:12]=2[Cl:23])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.[CH2:24]([O:26][C:27](OCC)(OCC)OCC)[CH3:25]>C(O)(=O)C>[Br:8][C:5]1[N:4]=[C:3]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:12]=3[Cl:23])[C:27]([O:26][CH2:24][CH3:25])=[N:1][C:2]2=[CH:7][CH:6]=1
Reactant: Nc1ccc(Br)nc1NCc1ccc(-c2ccccc2)cc1Cl
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CC(=O)O
Product: CCOc1nc2ccc(Br)nc2n1Cc1ccc(-c2ccccc2)cc1Cl
Temperature: 70 °C
Reaction time: 7 h
Yield: 2.6 %

Procedure:
A mixture of 3-amino-6-bromo-2-(N-(2-chloro-4-phenylbenzyl)amino)pyridine (1.85 g), tetraethoxymethane (4.3 g) and acetic acid (18.5 ml) was stirred at room temperature overnight and at 70° C. for 7 hr. The reaction mixture was concentrated to dryness under reduced pressure, and toluene was added, which was followed by concentration under reduced pressure. The residue was dissolved in ethyl acetate and washed twice with saturated aqueous sodium hydrogen carbonate solution and once with saturated brine. The organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was applied to silica gel column (n-hexane:ethyl acetate=9:1) to give a single product (55 mg) of 5-bromo-3-(2-chloro-4-phenylbenzyl)-2-ethoxy-3H-imidazo[4,5-b]pyridine and a mixture (977 mg) with a byproduct each as pale-brown amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:7].C(N(CC)C(C)C)(C)C.[Cl:36][C:37]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C(Cl)Cl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:25]([NH:26][C:39](=[O:40])[C:38]4[CH:42]=[CH:43][C:44]([Cl:46])=[CH:45][C:37]=4[Cl:36])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
A mixture of 1.0 g of 5-(3-methoxy-4-amino-benzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.47 g of N,N-diisopropylethylamine and 0.76 g of 2,4-dichlorobenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to give 1.39 g of the desired product as a crystalline solid, m.p. 212°-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([CH:51](O)[CH2:52][S:53][CH2:54][CH:55](O)CC)C.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:51][CH2:52][S:53][CH2:54][CH3:55])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCC(O)CSCC(O)CC
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCSCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (393 mg), ethyl 2-hydroxyethylsulfide (0.16 mL) and diethyl azodicarboxylate (0.18 mL). The mixture is stirred at room temperature overnight then concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from ethanolcyclohexane to afford 0.21 gm of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](I)=[N:11][CH:10]=1.C(N(CC)CC)C.[CH3:41][Si:42]([C:45]#[CH:46])([CH3:44])[CH3:43]>O1CCCC1.COC(C)(C)C.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.[Cu]I>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:46]#[C:45][Si:42]([CH3:44])([CH3:43])[CH3:41])=[N:11][CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(C#C[Si](C)(C)C)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 17 h
Yield: 83.2 %

Procedure:
To a mixture of 200 mg (0.346 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4), 0.073 ml (0.52 mmol) triethylamine, 5 mg (0.007 mmol) bis(triphenylphosphine)palladium(II) chloride and 3 mg (0.014 mmol) copper(I) iodide in 1 ml tetrahydrofuran a solution of 0.098 ml (0.69 mmol) trimethylsilylacetylene in 0.5 ml tetrahydrofuran was added at room temperature. After stirring for 17 h the mixture was diluted with tert-butyl methyl ether. Washing with a saturated aqueous solution of ammonium chloride was followed by drying with sodium sulfate and evaporation of the solvent. Column chromatography afforded 158 mg (83%) of the title compound as a light brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
Methyl 3-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)propanoate (2.00 g, 5.41 mmol) was dissolved in THF (5 mL), and a solution of lithium hydroxide monohydrate (469 mg, 11.18 mmol) in water (1 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo to remove most of the THF, and the resulting aqueous phase was acidified to pH 3 with 2 M aqueous HCl. The resulting cloudy mixture was extracted with CH2Cl2 (3×10 mL), and the combined organic phases were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to a white solid. The solid was further dried under high vacuum overnight to provide the title compound as an off-white powder (1.79 g, 5.04 mmol, 93% yield). 1H NMR (DMSO-d6) δ 2.60 (t, J=7.0 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H), 5.26 (s, 2H), 6.62 (s, 1H), 6.89 (dd, J=7.8, 5.1 Hz, 1H), 7.35 (m, 4H), 7.57 (s, 1H), 7.58 (m, 1H), 7.86 (dd, J=1.5, 5 Hz, 1H), 9.96 (br s, 1H), 12.14 (br s, 1H); Mass spectrum (apci) m/z 354.0 (M−H).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[C:9]([C:11](=[O:32])[NH:12][C:13]2[CH:14]=[N:15][C:16]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:18]=2)[CH:8]=[N:7][CH:6]=1)C.C1COCC1.CO>O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[CH:18]=[C:13]([NH:12][C:11]([C:9]3[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=3)[C:4]([OH:33])=[O:3])=[O:32])[CH:14]=[N:15][C:16]=2[O:26][CH2:27][C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)c1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)c1
Reaction time: 4 h

Procedure:
5-[5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylcarbamoyl]-nicotinic acid ethyl ester (510 mg, 1.06 mmol) was combined with THF (25 mL), methanol (5 mL) and water (5 mL) to give a light yellow suspension. The reaction mixture was stirred for 4 h, and concentrated in vacuo. The reaction mixture was poured into 100 mL ethyl acetate and extracted with 1 M HCl (1×25 mL) and brine (1×25 mL). The aqueous layer phases were extracted with ethyl acetate (1×50 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 100% ethyl acetate in heptane) to deliver 0.17 g (48.7%) of the title compound as white solid; MS (ESI) 450.0(M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.C(OCC)(=O)C>[N:27]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][CH:11]([CH:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)[CH2:10][CH2:9]3)[CH:3]=2)[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(-n4cncn4)ncn3)CC2)CC1
Temperature: 140 °C

Procedure:
The tert-butyl 1′-(6-chloropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (190 mg, 0.50 mmol), 1,2,4-triazole (69 mg, 1.0 mmol), cesium carbonate (488 mg, 1.5 mmol) were added in NMP (5 mL) and heated to 140° C. for 1.5 hours. The reaction crude were cooled down to r.t. and diluted with ethyl acetate (10 mL), washed with water (5 mL, ×1) and brine (5 mL, ×1). The organic phase was dried over magnesium sulfate, filtered and concentrated on rotavapor. The crude mixture was purified by preparative TLC with 50% ethyl acetate:hexane to yield the title compound.