Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)=[N:9][C:10]2[S:11][C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)=[N:6][CH:7]=1.[Si]([C:32]#[N:33])(C)(C)C>CO.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:9][C:10]2[S:11][C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)([C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[C:19]([F:27])[CH:18]=2)[C:32]#[N:33])=[N:6][CH:7]=1
Reactant: Cc1nc(N=C(c2cc(F)cc(C(F)(F)F)c2)c2ccc(Cl)cn2)sc1C
Reactant: C[Si](C)(C)C#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Product: Cc1nc(NC(C#N)(c2cc(F)cc(C(F)(F)F)c2)c2ccc(Cl)cn2)sc1C
Temperature: 25 °C

Procedure:
At 0° C. to a solution of N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-4,5-dimethylthiazol-2-amine (848 mg, 2.05 mmol) in MeOH (10 mL) was added ZnCl2 (214 mg, 1.43 mmol), followed by the addition of TMSCN (830 μL, 6.19 mmol). The reaction was allowed to slowly warm up to room temperature and heated at 65° C. for 18 h. The reaction mixture was cooled down to room temperature and concentrated. The residue was diluted by addition of DCM. The solid was removed by filtration and the filtrate was concentrated. A portion of the residue was purified by ISCO chromatography (12 g column) using hexanes/EtOAc (0-300%) over 22 min. Methyl 2-(5-chloropyridin-2-yl)-2-(4,5-dimethylthiazol-2-ylamino)-2-(3-fluoro-5-(trifluoromethyl)phenyl)acetate eluted at a retention time of 7-8 min. LCMS RT=3.25 min [M+H] 473.84 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.74 ppm, 1H, s; 7.67 ppm, 1H, dd, J=8.57, 2.42 Hz; 7.56 ppm, 1H, m; 7.30 ppm, 2H, m; 3.76 ppm, 3H, m; 2.09 ppm, 6H, m.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[O:20][CH2:19][CH2:18][C:17]4[S:16][C:15]([C:21]5[N:22]([CH:26]([CH3:28])[CH3:27])[N:23]=[CH:24][N:25]=5)=[N:14][C:13]=4[C:12]=3[CH:29]=2)=[CH:6][C:5]([CH3:30])=[CH:4][N:3]=1.Cl.C[O:33]CCOC>>[CH:26]([N:22]1[C:21]([C:15]2[S:16][C:17]3[CH2:18][CH2:19][O:20][C:11]4[CH:10]=[CH:9][C:8]([C:7]5[C:2](=[O:33])[NH:3][CH:4]=[C:5]([CH3:30])[CH:6]=5)=[CH:29][C:12]=4[C:13]=3[N:14]=2)=[N:25][CH:24]=[N:23]1)([CH3:28])[CH3:27]
Reactant: Cc1cnc(F)c(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)c1
Reactant: COCCOC
Agent: Cl
Product: Cc1c[nH]c(=O)c(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)c1
Yield: 93 %

Procedure:
Following the procedure for Example 330, 9-(2-Fluoro-5-methyl-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 402 was treated with aqueous HCl in DME to give 415 (0.038 g, 93%). 1H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 8.94 (d, J=2.3, 1H), 8.10 (s, 1H), 7.75 (dd, J=8.4, 2.3, 1H), 7.58 (d, J=2.5, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 7.07 (d, J=8.5, 1H), 5.90 (dt, J=13.2, 6.6, 1H), 4.40 (t, J=4.9, 2H), 3.46 (t, J=4.9, 2H), 2.09 (s, 3H), 1.56 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.1 (M+H)
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O-:12])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH2:15](Br)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:17]([O:11][C:10](=[O:12])[CH:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:22])([CH3:18])[CH3:16]
Reactant: BrCCc1ccccc1
Reactant: CCOP(=O)(CC(=O)[O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(CCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Diethylphosphonoacetate (1.00 g, 3.96 mmol) was added drop wise at 0° C. to a stirring suspension of sodium hydride (0.095 g, 3.96 mmol) in anhydrous THF (50 mL). The mixture was then allowed to stir for 10 minutes at 0° C. and then for 1 hour at room temperature before it was cooled again to 0° C. followed by the addition of phenethyl bromide (0.73 g, 3.96 mmol). The mixture was then allowed to proceed for 24 hours at room temperature. The solvent was evaporated and the residue was taken-up in water and extracted 4 times with ethyl acetate. The organic extracts were combined, washed with water and brine, dried using magnesium sulfate, filtered and evaporated. The crude residue was purified by flash chromatography (ethyl acetate in hexanes, 10%-50%) to afford the desired compound as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.18 (m, 2H), 7.09 (m, 2H), 4.07-3.99 (m, 4H), 2.82-2.72 (m, 1H), 2.69-2.60 (m, 1H), 2.54-2.45 (m, 1H), 2.25-2.12 (m, 1H), 2.08-1.94 (m, 1H), 1.41 (s, 9H), 1.24-1.18 (m, 6H); 13C (CDCl3, 400 MHz) δ 167.7, 140.4, 128.3, 128.2, 125.9, 81.5, 62.2, 46.3, 45.0, 34.1, 28.5, 27.7, 16.1; 31P (CDCl3, 400 MHz) δ 23.7. HRMS calcd. for C18H29O5P 356.1753, found 356.1757.
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][O-:36].[Na+]>CO>[CH3:35][O:36][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: C[O-]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3ccnn3-c3ccc(C#N)cc3)cn2n1
Yield: 27.5 %

Procedure:
A cloudy solution of 4-{5-[2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19, 22 mg, 0.046 mmol) and NaOMe (25% Wt, 0.75 mL, 3.3 mmol) in MeOH (0.75 mL) was heated at 100° C. for 30 mins using microwave irradiation. The cooled reaction mixture was evaporated in vacuo preparative TLC (20×20 cm×1 mm) eluting with 50% EtOAc in cyclohexane to give the title compound as a white solid (6 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:9]2)=[N:6][CH:7]=1.[O-:22][N+:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[C:25]([C@H:33]([NH2:35])[CH3:34])[CH:24]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:35][C@@H:33]([C:25]3[CH:24]=[N+:23]([O-:22])[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:26]=3)[CH3:34])=[O:15])[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Reactant: O=C(O)c1cn(-c2ccc(F)cn2)nc1-c1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)c1cn(-c2ccc(F)cn2)nc1-c1ccccc1)c1ccc(C(F)(F)F)[n+]([O-])c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a solution of 1-(5-fluoropyridin-2-yl)-3-phenyl-1H-pyrazole-4-carboxylic acid (0.10 g, 0.22 mmol) in DMF (1 mL) were added (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (63.5 mg, 0.26 mmol), EDC (73.2 mg, 0.38 mmol), HOAT (14.8 mg, 0.11 mmol) and triethylamine (0.12 mL, 0.87 mmol). The mixture was stirred at 50° C. After 3 h, the mixture was filtered. The filtrate was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% ammonium hydroxide) and gave the title compound (92 mg). The mixture was converted to hydrochloride salt using HCl (4.0 M in dioxane). HRMS 472.1410 (M+1). 1H NMR (500 MHz, DMSO): 9.25 (s, 1H); 8.89 (d, J=7.2 Hz, 1H); 8.60 (d, J=2.8 Hz, 1H); 8.54 (s, 1H); 8.09 (dd, J=9.0, 3.9 Hz, 1H); 8.02 (td, J=8.5, 2.9 Hz, 1H); 7.94 (d, J=8.4 Hz, 1H); 7.79-7.76 (m, 2H); 7.54 (d, J=8.4 Hz, 1H); 7.40 (t, J=3.1 Hz, 3H); 5.13-5.06 (m, 1H); 1.48 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+].N#N>COCCOC.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:28]3[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: Brc1ccc(I)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(Br)cc3)cc2)CC1
Temperature: 80 °C

Procedure:
1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester (2 g, 6.33 mmol), 1-bromo-4-iodo-benzene (1.97 g, 6.96 mmol), and sodium bicarbonate (1.59 g, 18.98 mmol) were dissolved in DME:H2O (2:1). The solution was sparged with N2 (g) for ten minutes then (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.52 g, 0.063 mmol) was added and N2 (g) was introduced for an additional 5 minutes. The reaction was heated to 80° C. for 4 hours then cooled and submitted to EtOAc/H2O workup. The crude material was purified on silica gel (0-70% EtOAc in hexanes) to provide the title compound.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(C)C)(OC(C)C)O[CH:10]([CH3:12])[CH3:11].C(O)(C)C.O.S([O-])(O)(=O)=O.[Na+]>>[CH:10]([O:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)([CH3:12])[CH3:11]
Reactant: CC(C)OC(OC(C)C)OC(C)C
Reactant: O=C1CCCCC1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC1=CCCCC1
Temperature: 60 °C
Yield: 81.7 %

Procedure:
To a mixture at room temperature containing 196.32 grams (2 mol) of cyclohexanone, 390.4 grams (2.06 mol) of triisopropyl orthoformate and 12.00 grams of isopropanol (0.2 mol), was added 7.6 grams (0.055 mol) of sodium hydrogensulfate monohydrate. The reaction was exothermic and upon addition of the catalyst, the temperature of the reaction mixture rose to 35° C., and was heated and maintained at 60° C. for 1 hour. The progress of the reaction was monitored by GC until the cyclohexanone content dropped to less than 2%. The isopropanol and isopropyl formate were distilled off under reduced pressure until the reaction mixture's temperature reached a maximum of 100° C. The reaction mixture was cooled to room temperature and filtered to remove sodium hydrogensulfate monohydrate (recovered). The pH value of the filtrate was adjusted to about 7˜8 by adding 0.8 gram of potassium iso-propoxide. The mixture was then heated under reduced pressure to remove unreacted cyclohexanone. The product, 1-isopropoxy-1-cyclohexene was isolated by distillation as a clear liquid; the yield was 81.7% with a purity exceeding 98%.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3].FC(F)(F)C([NH2:18])=O.[O-2].[Mg+2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH3:1][S:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[NH:18])=[O:3]
Reactant: COC(=O)c1cccc(S(C)=O)c1
Reactant: NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cccc(S(C)(=N)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
A solution of methyl 3-(methylsulfinyl)benzoate (3.23 g, 16.3 mmol), 2,2,2-trifluoroacetamide (3.69 g, 32.6 mmol), magnesium oxide (1.97 g, 48.9 mmol), rhodium(II)acetate dimer (0.18 g, 0.408 mmol), and iodobenzene diacetate (7.88 g, 24.5 mmol) in 150 ml dichloromethane was stirred at room temperature. After 16 hours, the mixture was filtered past filter agent (Celite), rinsed with chloroform, and rotary evaporated. The sample was dissolved in EtOAc, washed with brine/dilute HCl, brine, dried with anhydrous Na2SO4 and rotary evaporated. The yellow-orange oil was dissolved in 60 ml MeOH, K2CO3 (6.76 g, 48.9 mmol) added, and the mixture stirred at room temperature for 12 minutes. The MeOH filtrate was decanted from the solids, which were then rinsed with MeOH and EtOAc. The pH of the combined organic filtrates were adjusted to pH 2 using 4% HCl, then the aqueous layer diluted by adding H2O. The aqueous layer was washed with 30% EtOAc in hexane, then the pH adjusted to pH 9 with saturated Na2CO3. The aqueous layer was extracted with CHCl3, the combined CHCl3 layers washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to give the title compound as a light tan solid (2.58 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12](O)[C:13]([O:15][CH3:16])=[O:14].S(Cl)([Cl:25])=O>ClCCCl>[Cl:25][CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][O:4][C:3]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:2]=1[CH3:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(O)c1ccccc1COc1cc(C)ccc1C
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)C(Cl)c1ccccc1COc1cc(C)ccc1C
Yield: 68.6 %

Procedure:
A solution of methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyacetate (0.50 g, 1.6 mmol) in 1,2-dichloroethane (20 ml) was stirred at room temperature. Thionyl chloride (0.61 g, 5.1 mmol) was added thereto, and the mixture was heated under reflux overnight and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=97/3) to give the desired compound methyl 2-chloro-2-[2-(2,5-dimethylphenoxymethyl)phenyl]acetate (0.35 g, 66%) as an oil.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:41]([CH3:42])[C:36]4=[N:37][CH:38]=[CH:39][CH:40]=[C:35]4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:41]([CH3:42])[C:36]4=[N:37][CH:38]=[CH:39][CH:40]=[C:35]4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(-c3nc4cccnc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2ccc(-c3nc4cccnc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-6-(3-methyl-imidazo[4,5-b]pyridin-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1(N=C=NC2CCCCC2)CCCCC1.O[NH:25][C:26](=[NH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.O>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:8][N:33]=[C:26]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:25]=1
Reactant: N=C(NO)c1cccnc1
Reactant: O=C(O)c1ccco1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: ClCCl
Product: c1cncc(-c2noc(-c3ccco3)n2)c1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Furan-2-carboxylic acid (0.8 g; 7 mmol) in 15 ml of dichloromethane was cooled to 0° C., and 0.76 g of 1,3-dicyclohexylcarbodimide (4 mmol) was added slowly. The reaction mixture was stirred at 0-5° C. for 2 hours and filtered. The filtrate was evaporated, the residue was dissolved in 15 ml of pyridine and added 0.43 g of N-hydroxy-nicotinamidine (3.2 mmol). The reaction mixture was heated at reflux until the reaction was finished (measured by TLC), then cooled to room temperature and poured into 100 ml of water. The precipitate was isolated by filtration and dried under vacuum. The product was isolated by column chromatography. Yield 0.23 g (15%). Mp. 110-114° C.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH2:17][CH2:18][NH2:19])=[CH:13][NH:14]2)=[CH:10][CH:9]=1.BrC1C=CC=C2C=1C(CCN)=CN2.[OH-].[Na+]>Cl>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]3[CH2:17][CH2:18][NH:19][CH:3]([C:2]([OH:6])=[O:5])[C:13]=3[NH:14]2)=[CH:10][CH:9]=1
Reactant: O=CC(=O)O
Reactant: NCCc1c[nH]c2cc(Br)ccc12
Agent: Cl
Agent: NCCc1c[nH]c2cccc(Br)c12
Agent: [Na+]
Solvent: O
Product: O=C(O)C1NCCc2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Glyoxylic acid monohydrate (3.69 g, 40.1 mmol) was added to a solution of a 2:1 mixture of 2-(6-bromo-1H-indol-3-yl)ethanamine and 2-(4-bromo-1H-indol-3-yl)ethanamine (7.38 g, 30.9 mmol) in 0.4 N HCl (50 mL), and the resulting solution was stirred at 25° C. for 30 min. The solution was adjusted to pH 3.5 with 6 N NaOH solution, and the resulting tan suspension was stirred at 25° C. for 22 h. The suspension was adjusted to pH 5 with 6 N NaOH solution, and the resulting suspension was filtered. The filtered solid was dried under reduced pressure to afford 3.85 g (42%) of a 2:1 mixture of the title compound and an undesired regioisomer as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.00 (br s, 1H), 7.63 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.12-7.04 (m, 1H), 4.66 (s, 1H), 3.50-2.70 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]#[C:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[NH:16][N:15]=1>C(O)(=O)C>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([C:13]3[NH:1][C:2]4[C:3]([CH:12]=3)=[CH:4][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:6][CH:7]=4)=[N:15][NH:16]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1C#Cc1n[nH]c2cc(Cl)ccc12
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc2[nH]c(-c3n[nH]c4cc(Cl)ccc34)cc2c1
Reaction time: 2 h

Procedure:
The alkyne (5-4, 56 mg, 0.161 mmol) was dissolved in acetic acid (8 mL) and treated with mercuric acetate (77 mg, 0.24 mmol). After 2 h stirring, the reaction mixture was concentrated in vacuo, suspended in saturated aqueous sodium bicarbonate and treated with sodium borohydride. After 10 min stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Chromatography (SiO2, 50% ethyl acetate in hexanes) afforded the desired product (5-5); 1H NMR (300 MHz, DMSO-d6) δ 13.58 (s, 1H), 12.09 (s, 1H), 8.26 (d, 1H, J=8.7 Hz), 8.11 (s, 1H), 7.72 (d, 1H, J=1.5 Hz), 7.61 (dd, 1H, J=8.7, 1.8 Hz), 7.55 (d, 1H, J=8.4 Hz), 7.36 (d, 1H, J=1.5 Hz), 7.30 (dd, 1H, J=8.7, 1.8 Hz), 7.16 (s, 2H).
Reaction SMILES: C[Si](Cl)(C)C.[Na+].[I-].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:20]=[C:19]([O:21]C)[C:18](=[O:23])[C:17]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:26][CH:25]=2)=[N:16]1.O>CC#N>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:20]=[C:19]([OH:21])[C:18](=[O:23])[C:17]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:26][CH:25]=2)=[N:16]1
Reactant: COc1cn(-c2ccccc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=c1c(O)cn(-c2ccccc2F)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
TMSCl (1.27 mL, 10 mmol) was added at room temperature to a solution of NaI (1.50 g, 10 mmol) in CH3CN (60 mL). After stirring for 30 min, 1-(2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (0.725 g, 2 mmol) was added to the resulting suspension. The mixture was stirred for 30 min at room temperature and then refluxed for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (1/1) and recrystallized from MeOH/H2O to give the title compound (0.648 g, 93% yield) as off-white prisms: mp 218-220° C.; NMR (300 MHz, DMSO-d6): δ ppm 6.99 (1H, d, J=1.9 Hz), 7.10 (1H, dt, J=1.5, 7.9 Hz), 7.21-7.26 (1H, m), 7.32-7.54 (7H, m), 7.80 (1H, d, J=1.9 Hz), 8.44 (1H, d, J=2.6 Hz). Anal. Calcd for C19H13FN4O2: C, 65.51; H, 3.76; N, 16.08. Found: C, 65.73; H, 3.88; N, 16.24.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[CH2:12][C:11](=[O:24])[C:10]=1[C:25](=O)[CH2:26][CH3:27]>C(O)C>[CH2:2]([O:4][N:5]=[C:25]([C:10]1[C:9](=[O:8])[CH2:14][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[CH2:12][C:11]=1[OH:24])[CH2:26][CH3:27])[CH3:3]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Ethoxyamine hydrochloride (0.45 g) and then aqueous 1% sodium hydroxide (18.4 ml) were added to a solution of 3-hydroxy-5-mesityl-2-propionylcyclohex-2-en-1-one (1.2 g; 4.2 mmole) in anhydrous absolute ethanol (200 ml). The mixture was stirred at room temperature for a period of 4 hours and then the ethanol was removed by evaporation under reduced pressure using a rotary evaporator. The residue was treated with dichloromethane and the organic phase was washed twice with dilute aqueous hydrochloric acid and twice with water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure to give the product, 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-mesitylcyclohex-2-en-1-one (1.25 g; 93%), as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:29])[N:9]3[CH2:13][CH:12]([CH2:14][N:15]4[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]4)[C:11]=1[C:10]=23.C(O)(C(F)(F)F)=O>ClCCl>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH:12]2[C:11]3=[C:2]([F:1])[CH:3]=[N:4][C:5]4[CH:6]=[CH:7][C:8](=[O:29])[N:9]([C:10]=43)[CH2:13]2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A solution of 1,1-dimethylethyl {1-[(3-fluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (13.35 g, containing about 12.5% dichloromethane) in dichloromethane (125 ml) was ice-cooled, treated with TFA (100 ml), stirred at room temperature for 1 hour and evaporated. The residue was shaken with aqueous sodium bicarbonate (excess) and 15% methanol/dichloromethane, separated and the aqueous extracted about 50 times with 15% methanol/dichloromethane. The combined organic phases were dried and evaporated and the residue chromatographed using dichloromethane/methanol/0.88 ammonia 9:1:0.1 to give the product (8.1 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:13][CH:12]2[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]2)[CH:8]1[C:22]([O:24][CH3:25])=[O:23].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][S:2]([O:6][CH:7]1[CH2:13][CH:12]2[N:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH:9]([CH2:10][CH2:11]2)[CH:8]1[C:22]([O:24][CH3:25])=[O:23])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1C(O)CC2CCC1N2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1C(OS(C)(=O)=O)CC2CCC1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (1.2 g, 10.6 mmol) was added dropwise to a solution of 8-tert-butyl 2-methyl 3-hydroxy-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (5.29 mmol) and diisopropylethylamine (3.42 g, 26.5 mmol) in dichloromethane (25 ml) at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 h. Dichloromethane (50 ml) was added and washed with saturated sodium bicarbonate solution (50 ml) and brine solution (50 ml). The organic layer was separated, and dried over sodium sulfate. The solution was filtered, concentrated, and used in the next step without further purification.