Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:15]([CH:24]=1)[C:16]([NH:18][C:19]([CH3:23])([CH3:22])[CH2:20]O)=[O:17])[CH2:2][CH2:3][CH3:4].C(N=C=NC(C)C)(C)C>FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O.O1CCOCC1>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:32][CH:33]2[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[C:15]([C:16]2[O:17][CH2:20][C:19]([CH3:22])([CH3:23])[N:18]=2)[CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)NC(C)(C)CO)c1
Agent: [Cu+2]
Agent: CC(C)N=C=NC(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C2=NC(C)(C)CO2)c1
Temperature: 100 °C
Yield: 59.4 %

Procedure:
A mixture of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide (0.163 mmol, 87.7 mg), copper(II) trifluoromethanesulfonate (0.01 mmol, 3.6 mg), N,N′-diisopropylcarbodiimide (0.163 mmol, 20.6 mg) and dioxane (1 mL) was heated at 100° C. for 1 h. Copper(II) trifluoromethanesulfonate (0.01 mmol, 3.6 mg) and N,N′-diisopropylcarbodiimide (0.163 mmol, 20.6 mg) were added again and the reaction mixture was heated at 100° C. for another 1 h. The crude material was purified by column chromatography on basic alumina using 10-80% ethyl acetate in DCM to provide 3-butyl-4-[4-cyclohexyloxy-3-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-6-(1-methyl-piperidin-4-yloxy)-pyridazine (50.4 mg). LCMS: m/z 522 [M+1] 1H NMR (400 MHz, CDCl3) δ 7.61 (1H, s), 7.31 (1H, d), 7.05 (1H, dd), 6.79 (1H, d), 5.39 (1H, bs), 4.41 (1H, bs), 4.18 (4H, bs), 4.11 (3H, s), 3.41-3.97 (6H, m), 1.13-2.89 (22H, m), 0.84 (3H, t).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)=O.[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[F:1][C:2]([F:16])([F:17])[CH2:3][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: ClCCl
Product: COC(=O)c1ccc(NCC(F)(F)F)cc1
Temperature: 50 °C
Yield: 37 %

Procedure:
step c—A vial was charged with 122 (1.0 g, 4.05 mmol) and DCM (15 mL) then tetrabutylammonium borohydride was added. The vial was capped and heated overnight in an oil bath at 50° C. The reaction mixture was cooled to RT and the DCM was evaporated. HOAc was added dropwise until H2 evolution ceased. The solvents were evaporated and toluene was added. The mixture was made basic with dilute NaHCO3, extracted with EtOAc, dried (MgSO4), filtered and evaporated. The resulting solid was recrystallized from hexane to afford 0.349 g of methyl 4-(2,2,2-trifluoro-ethylamino)-benzoate (124)
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH2:17][N:18]([CH3:29])[S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:30]([C:32]1[CH:37]=[C:36]([C:2]2[CH:16]=[C:15]([CH2:17][N:18]([CH3:29])[S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=2[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:35]=[CH:34][CH:33]=1)#[N:31]
Reactant: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1)S(=O)(=O)c1ccc(F)cc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(-c2cccc(C#N)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
To a DMF (50 mL) solution of t-butyl 2-(2-bromo-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (3) (1.25 g, 2.6 mmol, 1 eq) was added 3-cyanobenzeneboronic acid (0.57 g, 3.8 mmol, 1.5 eq, Frontier Scientific, Inc., Logan, Utah, USA), potassium carbonate (1 g, 7.7 mmol, 3 eq), and tetrakis(triphenylphoshine)palladium (0.15 g, 0.13 mmol, 0.05 eq). The mixture was stirred at 90° C. for 18 h. After concentration in vacuo, the residue was extracted between EtOAc (100 ml) and brine (100 mL). The separated EtOAc layer was dried (Na2SO4), concentrated and purified via silica gel chromatography (linear gradient of 0% EtOAc/hexanes to 100% EtOAc/hexanes) to yield 0.78 g (59.8%) of t-butyl 2-(2-(3-cyanophenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (4). 1HNMR (CDCl3, 300 MHz): δ 7.80 (m, 4H), 7.58 (m, 1H), 7.48 (t, 1H), 7.21 (m, 4H), 6.79 (d, 1H), 4.52 (s, 2H), 4.11 (s, 2H), 2.61 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: OC1C(C(F)(F)F)=C(OCC2C=CC(OC3C=CC=C(C4[N:28]=[N:29][NH:30]N=4)C=3)=CC=2)C=CC=1C(=O)C.[C:35]([C:38]1[CH:60]=[CH:59][C:41]([O:42][CH2:43][C:44]2[CH:58]=[CH:57][C:47]([CH2:48][C:49]3[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=3)[C:52]#[N:53])=[CH:46][CH:45]=2)=[C:40]([C:61]([F:64])([F:63])[F:62])[C:39]=1[OH:65])(=[O:37])[CH3:36]>>[OH:65][C:39]1[C:40]([C:61]([F:63])([F:64])[F:62])=[C:41]([O:42][CH2:43][C:44]2[CH:58]=[CH:57][C:47]([CH2:48][C:49]3[CH:56]=[CH:55][CH:54]=[C:51]([C:52]4[N:28]=[N:29][NH:30][N:53]=4)[CH:50]=3)=[CH:46][CH:45]=2)[CH:59]=[CH:60][C:38]=1[C:35](=[O:37])[CH3:36]
Reactant: CC(=O)c1ccc(OCc2ccc(Cc3cccc(C#N)c3)cc2)c(C(F)(F)F)c1O
Reactant: CC(=O)c1ccc(OCc2ccc(Oc3cccc(-c4nn[nH]n4)c3)cc2)c(C(F)(F)F)c1O
Product: CC(=O)c1ccc(OCc2ccc(Cc3cccc(-c4nn[nH]n4)c3)cc2)c(C(F)(F)F)c1O

Procedure:
The title compound is prepared essentially as described for 1-(2-hydroxy-4-{4-[3-(2H-tetrazol-5-yl)-phenoxy]-benzyloxy}-3-trifluoromethyl-phenyl)-ethanone employing 3-[4-(4-acetyl-3-hydroxy-2-trifluoromethyl-phenoxymethyl)-benzyl]-benzonitrile (58%). LC-MS (m/e): 467 (M−1); 1H NMR (DMSO-d6) δ 13.79 (1H, s), 8.21 (1H, d), 7.80-8.00 (2H, m), 7.30-7.60 (6H, m), 6.92 (1H, d), 5.35 (2H, s), 4.08 (2H, s), 2.65 (3H, s).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.[CH:22]1([C:25]#[CH:26])[CH2:24][CH2:23]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.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].[Cu]I>[CH:22]1([C:25]#[C:26][C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: C#CC1CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(C#CC2CC2)CC1

Procedure:
A RT mixture of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.750 g, 2.264 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.081 g, 0.115 mmol) and copper (I) iodide (0.023 g, 0.121 mmol) in toluene (10 mL) was bubbled with argon for 15 min. cyclopropylacetylene (0.600 ml, 7.08 mmol, Aldrich) and triethylamine (0.350 ml, 2.52 mmol) were added resulting in a brown mixture after 5 min. The reaction mixture was partitioned between CH2Cl2/water and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine and dried over MgSO4. The solution was filtered and the filtrate was evaporated onto silica gel and purified by flash chromatography (Isco (80 gram)) eluting with (EtOAc):hexanes (0:1→1:9) to give tert-butyl 4-(cyclopropylethynyl)-5,6-dihydropyridine-1(2H)-carboxylate as a yellow tar (344 mg, 61%). MS m/z=192 [M+H-tBu]+. Calculated for C11H13NO2: 191
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:11][C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc(C)c(N)c1
Temperature: 80 °C
Yield: 89.4 %

Procedure:
A mixture of 1-(4-methyl-3-nitrophenyl)ethanone (5.37 g, 30 mmol), iron powder (8.4 g, 150 mmol) and NH4Cl (1.62 g, 30 mmol) in ethanol (100 mL) and water (10 mL) was heated at 80° C. overnight. The mixture was then heated at 110° C. for 5 hours and allowed to cool to room temperature. The resulting suspension was filtered and the filter cake was washed with ethanol. The filtrate was concentrated and the residue was dissolved in ethanol and filtered. The filtrate was concentrated to give 4 g of the title compound as a yellow solid. MS(ESI(+)) m/e 149.8 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][C:14](=[O:17])[CH:15]=[CH2:16])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)#[N:2].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][C:14](=[O:17])[CH2:15][CH2:16][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1)#[N:2]
Reactant: C=CC(=O)NC(C)(C)c1ccc(CC#N)cc1
Reactant: c1c[nH]cn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(NC(=O)CCn1ccnc1)c1ccc(CC#N)cc1

Procedure:
A mixture of N-{1-[4-(cyanomethyl)phenyl]-1-methylethyl}acrylamide (20.5 g), imidazole (6.11 g), benzyltrimethylammonium hydroxide (74 mg) and 1,4-dioxane (300 ml) gave N-{1-[4-(cyanomethyl)phenyl]1-methylethyl}-3-(imidazol-1-yl)propionamide as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:9]([Cl:17])=[CH:8][C:7]=1[N+:18]([O-])=O.Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:9]([Cl:17])=[CH:8][C:7]=1[NH2:18]
Reactant: COCCOc1cc(/C=C/C(=O)OC)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COCCOc1cc(/C=C/C(=O)OC)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
(E)-3-[4Chloro-5-(2-methoxyethoxy)-2-nitrophenyl]-acrylic acid methyl ester (910 mg; 2.88 mmol) was dissolved in MeOH (160 ml)/HClconc (50 ml). SnCl2 (7.4 g; 39 mmol) was added and the reaction mixture stirred for 1 h at room temperature, poured on saturated Na2CO3 and extracted with TBME three times. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield the intermediate (E)-3-[2-amino-4-chloro-5-(2-methoxyethoxy)-phenyl]acrylic acid methyl ester (740 mg; 90%).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[C:14]([F:26])[CH:13]=3)[CH:6]=[N:5][C:4]=2[CH:3]=1.[C:27]([C:29]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]1)#[CH:28]>>[F:26][C:14]1[CH:13]=[C:12]([N:7]2[C:8](=[O:11])[C:9]3[S:10][C:2]([C:28]#[C:27][C:29]4([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:3][C:4]=3[N:5]=[CH:6]2)[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C#CC1(O)CCCC1
Reactant: O=c1c2sc(Br)cc2ncn1-c1ccc(OCCN2CCCC2)c(F)c1
Product: O=c1c2sc(C#CC3(O)CCCC3)cc2ncn1-c1ccc(OCCN2CCCC2)c(F)c1

Procedure:
6-Bromo-3-[3-fluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]-3H-thieno[3,2-d]pyrimidin-4-one was reacted with 1-ethynylcyclopentanol by method R.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=3)[N:6]2[N:5]=[CH:4][N:3]=1>C(O)(=O)C.[Pt](=O)=O>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:12][CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)CCC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc3c(N)ncnn23)CC1
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To a dry flask purged with N2 was added platinum (IV) oxide (114 mg, 0.50 mmol) followed by tert-butyl 5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (1.66 mg, 5.04 mmol) as a solution in acetic acid (25 mL). The mixture was stirred under an H2 atmosphere for 16 h. Additional platinum (IV) oxide (114 mg, 0.50 mmol) was added and the reaction continued to stir under an H2 atmosphere for 20 h. The mixture was filtered through a pad of Celite® rinsing with acetic acid. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (200 mL). The organic mixture was washed with saturated, aqueous NaHCO3 (1×200 mL) and the aqueous mixture was back extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to dryness to afford 1.44 g (86%) of the desired product. ES-MS m/z 332.11 [M+H]+, HPLC RT (min) 2:46.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[C:25]#[CH:26])=[O:15].[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1>COCCOC>[C:25]([C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:17]=2)[N:21]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[N:20]=1)#[CH:26]
Reactant: C1=COCCC1
Reactant: C#Cc1n[nH]c2ccc(C(=O)OC)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCOC
Product: C#Cc1nn(C2CCCCO2)c2ccc(C(=O)OC)cc12

Procedure:
PTSA (0.99 g; 5.77 mmol; 0.11 eq.) was added to a solution of 3-Ethynyl-1H-indazole-5-carboxylic acid methyl ester (10.1 g; 50.2 mmol; 1.0 eq.) and 3,4-dihydro-2H-pyran (10.5 mL; 116 mmol; 2.3 eq.) in DME (100 mL). The reaction mixture was refluxed for 3 h, then cooled and concentrated. The residue was redissolved in DCM and washed sequentially with NaHCO3 (sat) and NaCl (sat) solutions, dried over magnesium sulfate, filtered and concentrated. The crude was triturated with Et2O to give the title compound as a yellow solid
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:14]([CH3:17])([OH:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+].C([O-])(O)=O.[Na+].C(Cl)[Cl:41]>N1C=CC=CC=1.F>[Cl:41][C:7]1[CH:6]=[C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:14]([CH3:15])([OH:16])[CH3:17])[CH2:10]2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: CC(C)(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(Cl)c2)C1
Temperature: 42 °C
Reaction time: 9 h

Procedure:
To a solution of 175 mg (0.368 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol (1) in 3 mL of CH2Cl2, 1 mL of hydrogen fluoride-pyridine was added. The reaction was stirred for 9 h at 42° C. Then the reaction mixture was poured to 7 mL of 5N NaOH, 7 mL of aq NaHCO3 and 30 mL of CH2Cl2. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/methyl tert-butyl ether to afford the title compound as a white solid; 1NMR(CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.20 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.33 (m, 8H); Mass Spectrum: m/e=478 (M+1 35Cl, 35Cl) and 480 (M+1 35Cl, 37Cl).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9](=[O:11])[NH:10][C:5]2=[N:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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:14]1([CH:12]([N:8]2[C:6]3=[N:7][C:2]([C:24]4[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=4)=[CH:3][N:4]=[C:5]3[NH:10][C:9]2=[O:11])[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(c1ccccc1)n1c(=O)[nH]c2ncc(Br)nc21
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(-c2cnc3[nH]c(=O)n(C(C)c4ccccc4)c3n2)cc(OC)c1OC
Temperature: 95 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
To a solution of 6-bromo-1-(1-phenylethyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one (47.2 mg, 0.15 mmol), 3,4,5-trimethoxyphenyl boronic acid (31.8 mg, 0.15 mmol) and potassium carbonate (62.2 mg, 0.45 mmol) in degassed 20% aq. dioxane (5 mL) was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (12 mg, 0.015 mmol) under an argon atmosphere. The mixture was stirred at 95° C. for 20 h, then cooled to room temperature and concentrated under reduced pressure. Purification of the resultant residue by flash chromatography [hexanes/ethyl acetate (2:1)] afforded 1-(1-phenylethyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one as a white solid (36.6 mg, 60%). 1H NMR (300 MHz, DMSO): δ 12.10 (s, 1H), 8.53 (s, 1H), 7.51 (d, J=5.7 Hz, 2H), 7.33 (dd, J=5.7, 6.0 Hz, 2H), 7.26-7.22 (m, 1H), 7.23 (s, 2H), 5.71 (q, J=5.1 Hz, 1H), 3.84 (s, 6H), 3.67 (s, 3H), 1.97 (d, J=5.1 Hz, 3H). MS: 407.4 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][S:6][C:7]1[C:11]([CH3:13])([CH3:12])[NH:10][C:9](=[O:14])[N:8]=1.[CH3:20]I>>[CH3:20][N:10]1[C:11]([CH3:13])([CH3:12])[C:7]([S:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=2[N:2]([CH3:1])[CH3:19])=[N:8][C:9]1=[O:14]
Reactant: CI
Reactant: CN(C)c1ccccc1CSC1=NC(=O)NC1(C)C
Product: CN(C)c1ccccc1CSC1=NC(=O)N(C)C1(C)C

Procedure:
Initially, 0.5 g of 4-(2-dimethylaminobenzylthio)-5,5-dimethyl-3-imidazolin-2-one was reacted with 1 mL of methyl iodide following the procedure used in Example 35. The desired compound was obtained in the form of a syrup. The yield of this compound was 0.43 g with a yield ratio of 81.9%. A result of a 1 H-NMR analysis of the compound is as follows:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:11]([CH2:27][OH:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].CO>[Si:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([CH2:27][OH:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CN[C@H](CO)C1

Procedure:
A mixture of (2S, 4R)-4-t-butyldimethylsilyloxy-2-hydroxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (10.0 g), methanol (100 ml) and 20% palladium hydroxide on carbon (0.5 g) was stirred under atmospheric pressure of hydrogen at ambient temperature for 3 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give (2S,4R)-4-t-butyldimethylsilyloxy-2-hydroxymethylpyrrolidine. To a solution of the compound obtained above in a mixture of tetrahydrofuran (100 ml) and water (100 ml) was dropwise added a solution of chloroacetyl chloride (5.0 ml) in tetrahydrofuran (10 ml) under ice-cooling with stirring, keeping the pH between 8-9 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for 2 hours and extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1 V/V) (100 ml ×5). The solution was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (200 g) and eluted with a mixture of methanol and dichloromethane (1:99 V/V) to give (2S,4R)-4-t-butyldimethylsilyloxy-1-chloroacetyl-2-(hydroxymethyl)pyrrolidine (4.22 g).
Reaction SMILES: Br[CH2:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:4]1=[O:17].[CH2:18]([SH:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:18]([S:20][CH2:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:4]1=[O:17])[CH3:19]
Reactant: COC(=O)c1cc2cccnc2n(CBr)c1=O
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCn1c(=O)c(C(=O)OC)cc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
3.00 g (10.1 mmol) of methyl 1-(bromomethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in N,N-dimethylformamide (40 mL), and 0.94 g (15.1 mmol) of ethanethiol and 2.09 g (15.1 mmol) of potassium carbonate were added to the solution. The resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried, and concentrated. Thus, 2.85 g (yield: quantitative) of the title compound was obtained as pale yellow crystals.
Reaction SMILES: CS(C1C=CC(CCC)=C(C=1)N)(=O)=O.[C:15]([C:18]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:19]=1[NH2:20])([CH3:17])=[CH2:16]>>[CH:15]([C:18]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][C:19]=1[NH2:20])([CH3:17])[CH3:16]
Reactant: C=C(C)c1ccc(S(C)(=O)=O)cc1N
Agent: CCCc1ccc(S(C)(=O)=O)cc1N
Product: CC(C)c1ccc(S(C)(=O)=O)cc1N
Yield: 81 %

Procedure:
Following the general method as outlined in Intermediate 61, starting from 2-isopropenyl-5-(methylsulfonyl)aniline (Intermediate 89), the title compound was obtained as a green solid in 81% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:19](=O)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:17]=1[CH3:18])=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:17]=1[CH3:18])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1[nH]cc(C(=O)Cc2ccc(Cl)cc2)c1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]cc(CCc2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
Triethylsilane (3 equivalents) was added to a solution of 85 in trifluoroacetic acid (2 mL per mmol). The mixture was stirred for 48 h at room temperature. The TFA was removed under vacuum and the crude product was taken up in AcOEt, washed with NaOH (2 M), brine, dried with Na2SO4, filtered and concentrated to give crude product. The residue was purified by HPLC. Yield: 46% for two steps. 1H-NMR (400 MHz, CDCl3): δ 1.35 (t, 3H), 2.26 (s, 3H), 2.69 (m, 2H), 2.78 (m, 2H), 4.31 (q, 2H), 6.55 (d, 1H), 7.08 (d, 2H), 7.22 (d, 2H), 8.86 (s broad, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([NH:17][C:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OCC4C=CC=CC=4)=O)[CH2:22][CH2:21]3)=[O:19])=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[C+4].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([NH:17][C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2c(NC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)ccnc21
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)n1ccc2c(NC(=O)C3CCNCC3)ccnc21
Yield: 83.4 %

Procedure:
N-(1 -tert-Butoxycarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)- 1-benzyloxycarbonyl-4-piperidinecarboxamide (2 g) was dissolved in methanol (30 ml) and 10% palladium carbon hydroxide (0.5 g) was added for hydrogenation (normal pressure). After the completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 1.2 g of N-(1-tert-butoxycarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperidinecarboxamide.