Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1.[CH:16]1([CH:19]=[O:20])[CH2:18][CH2:17]1>C1COCC1.CCOC(C)=O.[Cl-].[NH4+]>[CH:16]1([CH:19]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[OH:20])[CH2:18][CH2:17]1
Reactant: Ic1n[nH]c2ncccc12
Reactant: O=CC1CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1n[nH]c2ncccc12)C1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
i-PrMgCl (0.32 mL, 0.64 mmol) was added to 3-iodo-1H-pyrazolo[3,4-b]pyridine (3.1 mL, 0.61 mmol) in THF (3 mL) at 0° C. After 10 minutes, another portion of i-PrMgCl (0.32 mL, 0.64 mmol) was added. After 10 minutes, neat cyclopropanecarbaldehyde (0.074 mL, 0.98 mmol) was added dropwise and stirred at 0° C. for 1 hour. The mixture was diluted with EtOAc (5 mL) and aqueous ammonium chloride, and extracted with EtOAc (2×5 mL). The resulting residue was purified via flash chromatography eluting with EtOAc to afford cyclopropyl(1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (0.052 g, 0.28 mmol, 44.9% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:14]([O:16][CH3:17])=[O:15])[C:7]2=[O:12].[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]([CH3:39])[C:36](O)=[O:37])[CH:31]=[CH:32][C:33]=1[Cl:34].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[Si:20]([O:19][CH2:18][C@@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:36](=[O:37])[CH:35]([C:30]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:28]([Cl:27])[CH:29]=2)[CH3:39])[C:7]1=[O:12])[C:14]([O:16][CH3:17])=[O:15])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(NC(=O)C(C)c3ccc(Cl)c(Cl)c3)cccc2c1=O
Temperature: 25 °C

Procedure:
A round bottom flask was charged with (R)-methyl 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-3-(tert-butyldimethylsilyloxy)propanoate (300 mg, 0.0008 mol), 2-(3,4-dichlorophenyl)propanoic acid (200 mg, 0.00092 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (600 mg, 0.002 mol), N,N-diisopropylethylamine (0.3 mL, 0.002 mol) and N,N-dimethylformamide (2 mL, 0.03 mol) and the reaction stirred at room temperature over night. The reaction did not go to completion. The solvent was removed and the residue was purified flash chromatography to obtain the product as a solid. MS m/z=578.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[OH:9])=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:27])C>N1C=CC=CC=1>[NH2:1][C:2]1[N+:7]([O-:27])=[CH:6][C:5]([C@H:8]([CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: CC(C)(Cc1c[nH]c2ccccc12)NC[C@H](O)c1ccc(N)nc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(C)(Cc1c[nH]c2ccccc12)NC[C@H](O)c1ccc(N)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.5 g of (R)-6-Amino-α-[[(1,1-dimethyl-2-(1H-indol-3-yl)ethyl)amino]methyl]-3-pyridinemethanol in 20 ml of pyridine under nitrogen, acetic anhydride (10 ml) is added and the reaction mixture stirred at ambient temperature overnight. The mixture is then concentrated under reduced pressure. The crude acetylated product is treated with 0.9 g of m-chloroperbenzoic acid in 20 ml of CH2Cl2 for 4 hours at room temperature. The reaction mixture is concentrated once again and redissolved in 10 ml of methanol and treated with excess methanolic KOH solution at room temperature for 6 hours. The mixture is partially concentrated and then diluted with water and extracted repeatedly with CH2Cl2. The combined extracts is backwashed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solution is concentrated and the residue chromatographed on silica gel to give the (R)-6-Amino-α-[[(1,1-dimethyl-2-(1H-indol-3-yl)ethyl)amino]methyl]-3-pyridinemethanol-1-oxide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH2:29][C:30]1[C:31]([C:37](O)=[O:38])=[N:32][C:33]([Br:36])=[CH:34][N:35]=1>C(#N)C>[NH2:29][C:30]1[C:31]([C:37]([NH:1][C:2]2[CH:7]=[C:6]([C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:5]=[CH:4][C:3]=2[N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[O:38])=[N:32][C:33]([Br:36])=[CH:34][N:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)c3ccccc3)cc2N)CC1
Reactant: Nc1ncc(Br)nc1C(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)c3ccccc3)cc2NC(=O)c2nc(Br)cnc2N)CC1
Yield: 50 %

Procedure:
Following method 11, tert-butyl 4-(2-amino-4-benzoylphenyl)piperazine-1-carboxylate was coupled to 3-amino-6-bromopyrazine-2-carboxylic acid with TEA (1.5 eq) in ACN at 55° C. for 48 hours. Concentrated, triturated in cold ACN, filtered, and dried in vacuo yielding tert-butyl 4-(2-(3-amino-6-bromopyrazine-2-carboxamido)-4-benzoylphenyl)piperazine-1-carboxylate (50%). LCMS (m/z): 581.1 (MH+); LC Rt=4.00 min.
Reaction SMILES: C([O:8][C:9]1[C:10]([F:22])=[C:11]([CH2:18][C:19](=[O:21])[CH3:20])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)C1C=CC=CC=1.Br>C(OC(=O)C)(=O)C.C(O)(=O)C>[F:22][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[C:11]=1[CH2:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Agent: Br
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Temperature: 100 °C
Yield: 79.8 %

Procedure:
Method R-1: To a solution of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (3.03 g, 10 mmol) in acetic anhydride (5 mL) and acetic acid (5 mL) at room temperature was added hydrobromic acid (48% aqueous solution, 3 mL). After addition, the reaction was heated at 100° C. for 30 min and then cooled to room temperature. To this mixture was added 10 mL of hexanes with stirring. The solution was decanted and concentrated. The residue was diluted with ethyl acetate (50 mL) and washed with brine (3×20 mL). The organic layer was dried and concentrated in vacuo to provide 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1.70 g, 80%) as a brown solid, which was used in the next step without further purification. LC/MS; (M+H)+=213.2 Method R-2: A mixture of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (65.0 g, 0.214 mol) and pyridinium chloride (60.74 g, 0.526 mol) was stirred at 180° C. for 1 hr. The reaction mixture was cooled to room temperature, diluted with 3N HCl (100 mL) and ethyl acetate (500 mL) and filtered. The aqueous layer was extracted with ethyl acetate (2×) and the combined organic layers were washed with brine, dried (MgSO4),s filtered through a pad of silica gel and concentrated in vacuo. The residue was decolorized with charcoal in methanol, filtered and concentrated in vacuo to afford 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (37 g, 81%) as a brown solid. LC/MS; (M+H)+=213.2
Reaction SMILES: I[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][NH:20][C:19](=[O:23])[CH2:18]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][N:20]([C:2]2[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=2)[C:19](=[O:23])[CH2:18]1
Reactant: Ic1ccc(C#Cc2ccccc2)nn1
Reactant: CC1(C)CCNC(=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)CCN(c2ccc(C#Cc3ccccc3)nn2)C(=O)C1
Yield: 22.6 %

Procedure:
To a well stirred suspension of 3-iodo-6-(phenylethynyl)pyridazine (Example 151, step 1) (80 mg, 261 μmol), 4,4-dimethylpiperidin-2-one (66.5 mg, 314 μmol, 1.2 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (6.05 mg, 10.5 μmol, 0.04 equiv.) in 2 ml of toluene were added under argon atmosphere tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), (4.79 mg, 5.23 μmol, 0.02 equiv.) and the mixture was stirred for 4 hours at 100° C. The crude mixture was directly purified by flash chromatography over a 20 g silicagel column using a heptane to 50% ethyl acetate in heptane gradient, and yielded 18 mg (23% yield) of the title compound as a white solid, MS: m/e=306.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])=[C:11]([Cl:13])[CH:12]=1)[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:14]([C:17]#[N:18])([CH3:15])[CH3:16])=[C:11]([Cl:13])[CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cnc(C(C)(C)C#N)c(Cl)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCc1cnc(C(C)(C)C#N)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of 3-[5-chloro-6-(cyano-dimethyl-methyl)-pyridin-3-yl]-acrylic acid ethyl ester (0.74 g, 2.65 mmol) from step 3 above was added ethanol (10 mL) and Pd(OH)2/C (0.37 g). The reaction was placed under a hydrogen atmosphere using a balloon filled with hydrogen. The slurry was stirred vigorously for 1 hour. The reaction was filtered to remove all of the solids, and the liquid was concentrated to an white solid which was used in next reaction without further purification. 1H NMR (400 MHz, CDCl3): δ 1.25 (t, J=7.7 Hz, 3 H), 1.85 (s, 6 H), 2.62–2.66 (m, 2 H), 2.92–2.98 (m, 2 H), 4.15 (q, J=14, 7.7 Hz, 2 H ), 7.61 (d, J=2 Hz, 1 H), 8.3 (d, J=2 Hz, 1 H). ESIMS (MH+): 2.89.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[C:24]([O:28][CH3:29])(=[O:27])[CH2:25][SH:26]>C1COCC1>[CH3:29][O:28][C:24](=[O:27])[CH2:25][S:26][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: COC(=O)CS
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 32.7 %

Procedure:
To a solution of 6-chloro-N-(4-fluoro-phenyl)-nicotinamide (0.21 g, 0.84 mmol) in 5 mL of THF was added potassium tert-butoxide (0.19 g, 1.68 mmol) in one portion and stirred for 1 minute. To the suspension was added methyl thioglycolate (0.15 mL, 1.68 mmol) dropwise over 1 minute. The mixture was stirred for 12 h then poured into ice water and the solids collected. Purification by trituration using ethyl acetate/hexanes gave 88 mg (33%) of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s 1H), 8.90 (m, 1H), 8.11 (m, 1H), 7.74 (m, 2H), 7.48 (m, H), 7.17 (m, 2H), 4.10 (s, 2H), 3.63 (s, 3H); MS (EI) m/z 319.13 (M−H)−.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([O:10][C:11]([CH3:19])([CH3:18])[CH2:12][CH2:13][O:14]C(=O)C)([CH3:9])[CH3:8])(=O)C>N>[O:10]([C:11]([CH3:19])([CH3:18])[CH2:12][CH2:13][OH:14])[C:7]([CH3:8])([CH3:9])[CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCC(C)(C)OC(C)(C)CCOC(C)=O
Agent: N
Product: CC(C)(CCO)OC(C)(C)CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing 3,3′-oxybis(3-methylbutan-1-yl) diacetate (0.274 g, 1 mmol), was added 10 mL of 2.0N methanolic ammonia and the reaction was stirred overnight at room temperature. Solvent was then removed under reduced pressure. Compound was then dissolved in 20 mL diethyl ether and precipitate was filtered out. Filtrate was then reduced under vacuum to yield a colorless liquid. (0.187 g yield) 1H NMR (400 MHz, CDCl3): δ 1.61 (s, 12H), 2.04 (t, J=6.6, 4H), 3.88 (t, J=6.6, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9](O)[CH2:8]2)[CH:2]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([N:18]3[C:17](=[O:19])[C:16]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]4[C:14]3=[O:24])[CH2:8]2)[CH:2]=1
Reactant: O[C@H]1CCC[C@@H](c2cccnc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of cis-3-(3-pyridyl)cyclohexanol (5.00 g, 28.2 mmol) in THF (100 mL) was cooled to 4° C. and treated with phthalimide (4.56 g, 31.0 mmol), Diisopropylazodicarboxylate (6.10 mL, 31.0 mmol) and triphenylphosphine (8.13 g, 31.0 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc, and washed with H2O and brine. The organic layers was dried over Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (Hexane/EtOAc=4/1) to yield trans-N-[3-(3-pyridyl)cyclohexyl]phthalimide (5.18 g, 60%) as colorless powder.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[F:14])[NH:7][CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[F:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:7][CH:6]=[C:5]([C:3]3[N:15]=[C:16]([NH2:18])[S:17][CH:2]=3)[C:13]=12
Reactant: O=C(CBr)c1c[nH]c2nccc(F)c12
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(-c2c[nH]c3nccc(F)c23)cs1
Temperature: 70 °C
Yield: 65.7 %

Procedure:
To an ethanol suspension of 2-bromo-1-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (3.00 g 0.0117 mol) was added thiourea (1.18 g, 0.0234 mol), the reaction mixture was heated at 70° C. for 1 h. The suspension was filtered while still warm and to the filtration cake was added sat. sodium carbonate solution until the aqueous phase pH was around 7.5. The suspension was filtered to afford 1.8 g free base (75%). H NMR, DMSO-d6: 6.78 (s, 1H), 6.9 (s, br, 2H), 6.98 (m, 1H), 7.71 (s, 1H), 8.25 (m, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:5])#[N:2].[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.N1CCOCC1>C1(C)C=CC=CC=1>[C:1]([C:3](=[C:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)=[CH:11][CH:12]=1)=[O:5])#[N:2]
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)CC#N)cc2)cc1
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)C(C#N)=C3CCCCC3)cc2)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a mixture of 54.0 g of methyl 4-(2-{4-[(cyanoacetyl)amino]phenyl}ethyl)benzoate, 50.0 mL of cyclohexanone, and 300 mL of toluene was added dropwise 15.0 mL of morpholine at room temperature. A Dean-Stark type dehydrating tube was attached to the reactor, and the reaction mixture was stirred for 3 hours with oil bath heated at 120° C. Thereafter, the reaction mixture was heated to reflux and further stirred for 1 hour. The reaction mixture was cooled to room temperature, followed by concentration under reduced pressure. 200 mL of diisopropylether was further added thereto, followed by stirring for 14 hours. The precipitated solid was collected by filtration, thereby obtaining 53.2 g of methyl 4-[2-(4-{[cyano(cyclohexylidene)acetyl]amino}phenyl)ethyl]benzoate. To a mixture of this solid, 4.5 g of sulfur and 80 mL of DMF was added dropwise 12.0 mL of morpholine at room temperature, and the reaction mixture was stirred for 1 hour at 50° C. Saturated brine was added to the reaction mixture, followed by extraction with ethyl acetate, and then the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, followed by filtration, and then the solvent was removed under reduced pressure. Isopropanol was added to the thus obtained residue, and the precipitated solid was collected by filtration, thereby obtaining 43.1 g of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([CH:12]=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[Br:24]N1C(=O)CCC1=O>C(O)C.O1CCOCC1>[Br:24][C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:16]([Cl:23])=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:2]=3[Cl:1])[C:7]2=[N:14][C:13]=1[CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nc2c(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of 8-(2,6-dichloro-3-nitrobenzyloxy)-2-methylimidazo[1,2-a]pyridine (85 mg) in a mixture of ethanol (1 ml) and 1,4-dioxane (1 ml) was added in one portion N-bromosuccinimide (43 mg) at ambient temperature. After stirring for one hour at the same temperature, the mixture was filtered to give 3-bromo-8-(2,6-dichloro-3-nitrobenzyloxy)-2-methylimidazo[1,2-a]pyridine (85 mg) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:23][CH2:24][C:25](=O)[CH2:26][F:27].C([O-])(O)=O.[Na+]>ClCCl>[F:23][CH2:24][CH:25]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1)[CH2:26][F:27]
Reactant: OCC1CCNCC1
Reactant: O=C(CF)CF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCC1CCN(C(CF)CF)CC1
Reaction time: 8 h

Procedure:
A suspension of piperidin-4-ylmethanol (0.250 g), sodium triacetoxyborohydride (0.690 g) and 1,3-difluoropropan-2-one (0.245 g) were stirred together in dichloromethane. After stirring overnight the reaction was poured into saturated aqueous NaHCO3 solution (10 mL) and stirred for 15 minutes. The reaction was extracted with dichloromethane (3×25 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (GraceResolv 12 g) eluting with a gradient of 0.75% to 3% methanol/dichloromethane gave the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2C(=CC=CC=2)C(=O)[N:3]1[C@@H:12]([CH3:30])[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][C:16]=1[F:29].O.NN>C1COCC1>[C:2]([NH:3][C@@H:12]([CH3:30])[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:17][C:16]=1[F:29])(=[O:1])[CH3:10]
Reactant: C[C@@H](COc1ncc(NC(=O)OC(C)(C)C)cc1F)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)COc1ncc(NC(=O)OC(C)(C)C)cc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
A mixture of tert-butyl (6-(((2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl)oxy)-5-fluoropyridin-3-yl)carbamate (1.62 g), hydrazine monohydrate (0.976 g) and THF (15 mL) was stirred overnight at 60° C. The precipitate was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was mixed with acetic anhydride (0.736 mL), triethylamine (1.09 mL) and ethyl acetate (15 mL), and the obtained mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.05 g).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:14]#CBr>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]#[N:14])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: CN1CCc2cccc(Cl)c2CC1
Solvent: Cc1ccccc1
Product: N#CN1CCc2cccc(Cl)c2CC1

Procedure:
A stirred solution of 1.2 g. of 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 30 ml. of toluene was treated at 50° by dropwise addition with a solution of 0.7 g. cyanogen bromide in 25 ml. of toluene. Following the addition, the mixture was stirred and heated at 50° for one hour. A stream of nitrogen was passed over the surface of the solution during the reaction. The mixture was cooled, filtered and the filtrate concentrated in vacuo to yield 6-chloro-3-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine melting at 81°-82° from hexane-ether solution.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[CH:3]=1.[CH2:14]1[O:16][CH2:15]1>>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH2:14][CH2:15][OH:16])=[CH:3]2)=[CH:8][CH:7]=1
Reactant: COc1ccc2ccc(Br)cc2c1
Reactant: C1CO1
Product: COc1ccc2ccc(CCO)cc2c1

Procedure:
The title compound was synthesized as described above from 2-bromo-7-methoxynaphthalene and ethylene oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=4)[N:13]=[C:12]([OH:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.C(OCC)C.CO>CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=4)[N:13]=[C:12]([OH:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: CCOCC
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(-c3ccc(O)cc3)c(=O)c12
Temperature: 150 °C
Yield: 68.9 %

Procedure:
7-Chloro-4-hydroxy-2-(4-methoxyphenyl)-1,2,5,10-tetrahydropyridazino-[4,5-b]quinoline-1,10-dione (0.800 g, 2.16 mM) was stirred in methanesulfonic acid (16 mL) to give an amber solution. This solution was heated to 150° C. for 6 hours and cooled to room temperature. Addition of ethyl ether (250 mL) and methanol (50 mL) gave a tan precipitate. The solid was collected and washed with methanol/ether to give the title compound (0.530 g, 51%) as a tan powder, mp 316°-318° C.; MS(CI): 356 (M+H). Analysis for C17H10ClN3O4 ·CH3SO3H·1.3 H2O: Calculated: C, 45.49; H, 3.52; N, 8.84; Found: C, 45.45; H, 3.24; N, 8.64; NMR: 12.80 (v br s, 1H, exchangeable), 8.15 (d, J=8.68 Hz, 1H), 8.04 (d, J=1.84 Hz, 1H),7.44 (dd, J=1.84, 8.68 Hz, 1H), 7.28 (d, J=8.74 Hz, 2H), 6.81 (d, J=8.74 Hz, 2H), 2.35 (s, 3H).
Reaction SMILES: CC(C)CCN[C:6]1[CH:13]=[CH:12][C:9](C#N)=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15].[H-].[Na+].CI>CN(C=O)C>[N+:14]([C:7]1[CH:8]=[CH:9][CH:12]=[CH:13][CH:6]=1)([O-:16])=[O:15]
Reactant: CC(C)CCNc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: O=[N+]([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.00 g (4.29 mmole) of 4-(3-methylbutylamino)-3-nitrobenzonitrile was dissolved in 10 mL of DMF, 0.205 g (5.14 mmoles) of NaH was added, and the mixture was stirred for 10 minutes at room temperature. 0.5 mL (5.14 mmole) of methyl iodide was added and the mixture was stirred overnight at room temperature. When the reaction had ended, the solvent was removed under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate. The residue was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure, yielding a nitrobenzene intermediate. Next, the nitrobenzene intermediate was dissolved in 20 mL of ethanol, 50 percent NH2OH aqueous solution was added, and the mixture was stirred overnight at 50° C. When the reaction had ended, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, yielding 1.46 g of amideoxime intermediate.