Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]2)=[O:22])=[C:8]([CH:19]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1)=[O:10])(=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:38][OH:39]>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:19]=[C:4]([CH:1]([NH:38][OH:39])[CH3:2])[CH:5]=[CH:6][C:7]=2[NH:20][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:30])[CH3:31])[CH2:27][CH2:28]2)=[O:22])=[N:13][CH:14]=1
Reactant: NO
Reactant: CC(=O)c1ccc(NC(=O)C2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(NO)c1ccc(NC(=O)C2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a stirring solution of 5-acetyl-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide (0.25 g, 0.56 mmol) in methanol (2 mL) was added sodium acetate (0.1 g, 1.2 mmol) followed by hydroxylamine hydrochloride (46 mg, 0.67 mmol). The mixture was stirred overnight at room temperature and concentrated in vacuo. The resulting residue was partitioned between I dichloromethane and saturated aqueous sodium bicarbonate, and the layers separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with 3% 2 M ammonia/methanol solution in dichloromethane to give 0.22 g (85%) of a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:27][C:28]([CH:30]1[CH2:34][CH2:33][CH:32]([CH2:35][N:36]([CH2:41][C:42]([OH:44])=O)[C:37]([O:39][CH3:40])=[O:38])[NH:31]1)=[O:29])[CH3:26].CN1CCOCC1>CN(C)C=O>[CH3:40][O:39][C:37]([N:36]1[CH2:41][C:42](=[O:44])[N:31]2[CH:30]([C:28]([O:27][CH2:25][CH3:26])=[O:29])[CH2:34][CH2:33][CH:32]2[CH2:35]1)=[O:38]
Reactant: CCOC(=O)C1CCC(CN(CC(=O)O)C(=O)OC)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCC2CN(C(=O)OC)CC(=O)N21
Yield: 76.5 %

Procedure:
HATU (390 mg, 1.03 mmol) was added to solution of 5-[(carboxymethyl-methoxycarbonyl-amino)-methyl]-pyrrolidine-2-carboxylic acid ethyl ester (187 mg, 0.68 mmol) and 4-methylmorpholine (375 μL, 3.4 mmol) in dimethylformamide (30 mL). After 50 minutes the solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate (20 mL) which was washed with half saturated sodium chloride (2×10 mL), saturated sodium bicarbonate (2×10 mL) and dried over sodium sulfate. The aqueous phase also contained product. The water was removed under reduced pressure and the residue was azeotroped with toluene and then stirred with ethyl acetate (50 mL). The mixture was filtered and combined with the organic extracts. The solvent was removed under reduced pressure and the resulting residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester (141 mg, 0.52 mmol, 76%). C12H18N2O5 calculated 270.1, observed [M+l]+ 271.1; rt=1.54 min.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([CH3:26])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCCc1ccccc1
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Cc1cc2c(NCCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Br)([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[C:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 4-bromobenzoic acid (100 g, 0.5 mol) in dry CH2Cl2 (1.5 L) was added silver carbonate (275 g, 1 mol) and molecular sieves (4A, 100 g). The reaction mixture was cooled to 0° C. and then tert-butyl bromide (115 mL) was added dropwise over a period of 45 min. The reaction mixture was allowed to stir at Rt for 20 h and filtered off the solid. The filtrate was washed with an aqueous solution of NaHCO3 (10%), water, brine and dried. The solvent was removed under vacuum to the title compound (100 g, 79%) as colorless liquid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34].CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:33]([C:24]4[CH:25]=[CH:26][C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:23]=4)=[O:34])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc2ccccc2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccc5ccccc5n4)cc3C2=O)C(=O)N1
Yield: 86.6 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and quinoline-2-carbonyl chloride (0.57 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (100 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH CH2Cl2). The product fractions were combined, concentrated and triturated in Et2O for 18 h. The product was isolated by filtration and dried in vacuo to give quinoline-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (1.15 g, 76% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.08 min (96.58%); mp: 205-207° C.; 1H NMR (DMSO-d6) δ 1.93-2.16 (m, 1H, CHH), 2.53-2.70 (m, 2H, CHH, CHH), 2.77-3.02 (m, 1H, CHH), 4.74 (d, J=6.4 Hz, 2H, CH2), 5.15 (dd, J=5.3, 12.8 Hz, 1H, CH), 7.66-7.82 (m, 1H, Ar), 7.82-7.99 (m, 4H, Ar), 8.03-8.25 (m, 3H, Ar), 8.59 (d, J=8.1 Hz, 1H, Ar), 9.75 (t, J=6.4 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 42.55, 48.99, 118.74, 122.24, 123.55, 128.15, 128.89, 129.15, 129.84, 130.60, 131.59, 133.67, 137.94, 146.05, 147.44, 149.89, 164.48, 169.82, 172.73; LCMS: MH=448; Anal Calcd for C24H18N4O5: C, 65.15; H, 4.10; N, 12.68. Found: C, 65.05; H, 4.05; N, 12.58.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)O1.[Cl:19][C:20]1[N:25]=[C:24](C2C=NN3C=CC=CC=23)[CH:23]=[N:22][CH:21]=1>>[Cl:19][C:20]1[N:25]=[C:24]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)[CH:23]=[N:22][CH:21]=1
Reactant: CC1(C)OB(c2cnn3ccncc23)OC1(C)C
Reactant: Clc1cncc(-c2cnn3ccccc23)n1
Product: Clc1cncc(-c2cnn3ccncc23)n1
Yield: 28 %

Procedure:
Obtained as a yellow solid (28% yield, two steps) from 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 29a) according to the experimental procedure as described in Preparation 27b followed by purification by flash chromatography (2:8 ethyl acetate/hexane).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[Br:18]>CO.Cl>[CH3:6][O:7][C:8](=[O:19])[C:9]1[C:10]([Br:18])=[CH:11][CH:12]=[C:13]([NH2:15])[CH:14]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(N)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tin (II) chloride dihydrate (22.56 g, 100 mmol) was added to a stirred solution of methyl-2-bromo-5-nitrobenzoate (9 g, 34.61 mmol) in methanol (250 mL) and conc. HCl (25 mL). The solution was stirred at RT for 8 h and then treated with satd. aq. KHCO3 solution (600 mL). Additional solid KHCO3 (50 g) was added. The mixture was extracted with EtOAc (200 mL, 5×). The EtOAc extracts were combined, dried (MgSO4), filtered and concentrated. The residue was diluted with EtOAc (250 mL) and washed with brine (50 mL, 2×), dried (MgSO4), filtered and concentrated to obtain the title compound of this step (7.45 g, 94%) as a brown oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1C(=O)N([Br:18])C(=O)C1>OS(O)(=O)=O>[Br:18][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2cnccc2c1
Agent: O=S(=O)(O)O
Product: Brc1cccc2cnccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 250 mL 3-necked round bottom flask was placed H2SO4 (150 mL). To the above was added isoquinoline (17 g, 131.62 mmol) in several batches, while cooling to a temperature of 0° C. To the above was added NBS (29.2 g, 164.04 mmol) in several batches, while cooling to a temperature of −25-−22° C. The resulting solution was allowed to react, with stirring, for 2 hours while the temperature was maintained at −25-−22° C. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:5). The reaction mixture was then quenched by the adding 1000 mL of H2O/ice. Adjustment of the pH to 8-10 was accomplished by the addition of NH3. H2O (30%). The resulting solution was extracted four times with 500 mL of ethyl acetate and the organic layers combined and dried over Na2SO4. The residue was purified by eluting through a column with a 1:5 ethyl acetate/petroleum ether solvent system. This resulted in 22.24 g (81%) of 5-bromoisoquinoline as a white solid.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:6]=[C:7]([NH:19][C:20]2[C:25]3[C:26]4[CH2:34][CH2:33][C:32]5[N:31]([CH2:35][CH2:36]O)[N:30]=[CH:29][C:28]=5[C:27]=4[S:38][C:24]=3[N:23]=[CH:22][N:21]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.S(Br)([Br:41])=O>O>[Br:41][CH2:36][CH2:35][N:31]1[C:32]2[CH2:33][CH2:34][C:26]3[C:25]4[C:24](=[N:23][CH:22]=[N:21][C:20]=4[NH:19][C:7]4[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=5)=[C:5]([Cl:4])[CH:6]=4)[S:38][C:27]=3[C:28]=2[CH:29]=[N:30]1
Reactant: O=S(Br)Br
Reactant: OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Solvent: ClCCl
Solvent: O
Product: Clc1cc(Nc2ncnc3sc4c(c23)CCc2c-4cnn2CCBr)ccc1OCc1ccccn1
Temperature: 25 °C

Procedure:
To 30 mL dichloromethane cooled to 0° C. was added 2-(6-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl)ethanol (800 mg, 1.58 mmol), followed by thionyl bromide (1.15 g, 5.54 mmol). The contents were then stirred with warming to rt over a 24 h period, after which time water (5 mL) was added to quench the reaction mixture. The solvent was removed under reduced pressure. The crude residue was diluted with aq. 1M Na2CO3 and vigorously stirred for 1 h. The mixture was extracted with CH2Cl2, and the combined organic layers dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was triturated with methanol (15 mL) to a light-brown solid (600 mg, 67%) containing 80% of the desired product, and 20% of the aromatized product. A sample of the crude product was purified via reverse phase HPLC to afford the desired product as a white solid. 1H-NMR (DMSO-d6) δ 8.58 (d, 1H), 8.38 (br s, 1H), 8.36 (s, 1H), 7.81 (dd, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.44-7.60 (m, 2H), 7.31 (td, 1H), 7.19 (d, 1H), 5.23 (s, 2H), 4.30 (t, 2H), 3.82 (t, 2H), 3.38 (t, 2H), 3.07 (t, 2H); LCMS RT=2.77 min; [M+H]+=567.0.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH:12]=O)[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[N:11]=[C:10](/[CH:12]=[CH:22]/[CH:23]=[O:24])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cccc(-n2cccn2)n1
Product: O=C/C=C/c1cccc(-n2cccn2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 6-(1H-pyrazol-1-yl)-2-pyridinecarboxaldehyde (prepared as described in J. Med. Chem. 1998, 41, 5070) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:4].[N+:32]([CH:35]=[C:36]1[CH2:39][O:38][CH2:37]1)([O-])=O.CCN(CC)CC>C(Cl)Cl>[NH2:32][CH2:35][C:36]1([NH:1][C@@H:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:3]([N:5]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=2)[CH2:6][CH2:7][C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[O:4])[CH2:39][O:38][CH2:37]1
Reactant: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](N)c2ccccc2)cc1C
Reactant: O=[N+]([O-])C=C1COC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](NC2(CN)COC2)c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of (S)-2-amino-N-(3,4-dimethyl-phenyl)-2-phenyl-N-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide (50 mg, 0.11 mmol, prepared as in example 1) and 3-nitromethylene-oxetane (12 mg, 0.104 mmol, [CAS No. 922500-95-6]) in CH2Cl2 (0.5 mL) was treated with Et3N (11 mg, 0.11 mmol) at 0° C. After stirring for 30 min at ambient temperature, the mixture was concentrated, dissolved in MeOH (1 mL) and treated with a solution of HCO2NH4 (300 mg, 4.76 mmol) in H2O (0.5 mL), 10% Pd/C (100 mg) and the mixture stirred for 12 h at ambient temperature. After the addition of 1N Na2CO3 (15 mL), the aqueous layers were filtered then extracted with CH2Cl2 (3×15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, CH2Cl2:MeOH=100:0 to 90:10) afforded the title compound (26 mg, 46%) as a light yellow oil. MS m/e: 513.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][C:15](Br)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13])=[O:5].[N:19]1([C:24]2[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[N:20]1>>[NH2:1][C:2]1[N:17]=[CH:16][C:15]([C:27]2[CH:26]=[CH:25][C:24]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:29][CH:28]=2)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13])=[O:5]
Reactant: Cc1cnccc1NC(=O)c1cc(Br)cnc1N
Reactant: OB(O)c1ccc(-n2cccn2)cc1
Product: Cc1cnccc1NC(=O)c1cc(-c2ccc(-n3cccn3)cc2)cnc1N

Procedure:
Reaction of 2-amino-5-bromo-N-(3-methyl-pyridin-4-yl)-nicotinamide with [4-(1H-pyrazol-1-yl)phenyl]boronic acid gives the compound “A19”;
Reaction SMILES: C([CH:4]1[CH2:10][CH2:9][CH2:8][NH:7][C:6]2[S:11][C:12]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[CH2:31][C:32]5[NH:36][N:35]=[N:34][N:33]=5)=[CH:19][C:17]=4[CH:18]=3)=[N:13][C:5]1=2)(=O)C.[OH-].[Na+].O.Cl>C(O)C>[N:13]1[C:5]2[CH2:4][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[S:11][C:12]=1[C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]3[NH:33][N:34]=[N:35][N:36]=3)=[CH:19][C:17]=2[CH:18]=1
Reactant: CC(=O)C1CCCNc2sc(-c3cc4cc(OCc5ccccc5Cc5nnn[nH]5)ccc4o3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(Cc2nnn[nH]2)c(COc2ccc3oc(-c4nc5c(s4)NCCCC5)cc3c2)c1
Yield: 58.8 %

Procedure:
A mixture of 5-{2-[2-(8-acetyl-4,5,6,7-tetrahydro-8H-thiazolo[5,4-b]azepin-2-yl)benzofuran-5-yloxymethyl]phenylmethyl}-1H-tetrazole (65 mg) and 2N aqueous sodium hydroxide (0.65 ml) in ethanol (6 ml) was stirred under reflux for 4 hours. After being cooled, the resulting mixture was concentrated under reduced pressure to give residue. Water was added to the residue and adjusted to pH 3 with diluted aqueous hydrochloric acid. The appeared precipitates were collected by filtration and washed with water to give 5-{2-[2-(4,5,6,7-tetrahydro-8H-thiazolo[5,4-b]azepin-2-yl)benzofuran-5-yloxymethyl]phenylmethyl}-1H-tetrazole (35 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N+:26]([O-])=O)[CH:22]=3)[C:17]2=[O:29])=[O:8])=[CH:5][CH:4]=1.C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH2:26])[CH:22]=3)[C:17]2=[O:29])=[O:8])=[CH:30][CH:31]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)Nc2ccccc2N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2N2C(=O)c3ccc(N)cc3C2=O)cc1
Yield: 57.8 %

Procedure:
A solution of N-(4-methoxybenzoyl)-2-(5-nitro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)benzeneamine (1.11 g, 2.66 mmol) and 5% palladium-on-carbon (1.21 g) in 2:1 ethanol:ethyl acetate (200 mL) was placed under 1 atmosphere of hydrogen. After consumption of the starting material (about 2-3 h), the mixture was filtered through diatomaceous earth and the resulting filtrate concentrated in vacuo. Recrystallization from hexanes/ethyl acetate yielded 596 mg (58%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21]C(C)C)=[CH:15][CH:14]=2)=[CH:9]1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21][C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)NCC(C)c1ccc(-c2ccsc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CNC(=O)Nc1ccccc1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl-2-propyl amine trifluoroacetate (prepared in example 1) and phenyl isocyanate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH:37]=[O:38]>N1C=CC=CC=1.[Cu]I>[CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[O:34][C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[CH:37]=[O:38])=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1O
Reactant: FC(F)(F)c1cccc2c(-c3cccc(Br)c3)n(Cc3ccccc3)nc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: O=Cc1ccccc1Oc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)c1

Procedure:
The preparation of this compound is was similar to that described for Example 3. 2-Benzyl-3-(3-bromo-phenyl)-7-trifluoromethyl-2H-indazole (60 mg, 0.139 mmol), cesium carbonate (272 mg, 0.835 mmol), CuI (80 mg, 0.417 mmol) and 2-hydroxy-benzaldehyde (51 mg, 0.417 mmol) were dissolved in 6 ml of dry pyridine. The reaction and work-up were carried out as described for Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[N:10][OH:11])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[ClH:17]>O>[OH:11][N:10]=[C:9]([Cl:17])[C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: Cl
Reactant: COc1ccc(C=NO)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(Cl)=NO)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To oxime 1c (1.25 g; 8.18 mmol) in concentrated hydrochloric acid (6.0 mL) at 0° C., was added dropwise bleach (9 mL). The reaction mixture was stirred at 0° C. for 1 h, diluted with water (20 mL) and brought to about pH=3 with saturated sodium bicarbonate. The resulting solid was collected, washed with water and dried. 2c was isolated as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@H:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[Cl:28])[CH:20]=4)[OH:15])=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@@H](O)c1cn(Cc2ccccc2Cl)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@@H](O)c4cn(Cc5ccccc5Cl)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (R)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2.[Br:22]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:22][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9](=[O:13])[N:8]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-n2ccc3cc(OC)ccc3c2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-n2cc(Br)c3cc(OC)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)isoquinolin-1(2H)-one (0.50 g, 1.78 mmol) was placed in a dry 250 mL single-necked round-bottomed flask fitted with a stirring bar and septa. Acetonitrile (10 mL) was added via a syringe under argon atmosphere at room temperature. N-Bromosuccinimide or NBS (0.33 g, 1.87 mmol) was added portionwise under argon atmosphere at room temperature. The reaction mixture was allowed to stir at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate solution was then added. The mixture was extracted with ethyl acetate (3×10 mL). Organic layers were separated, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, hexanes/EtOAc=2/3 v/v) to give a white solid product, 0.55 g, 85.9% yield. MS: 360.4 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 8.14 (d, 1H, J=8.7 Hz), 7.39-7.34 (m, 3H), 7.19 (d, 1H, J=2.4 Hz), 7.13-7.03 (m, 3H), 6.62 (dd, 1H, J=7.5 Hz), 3.89 (s, 3H), 3.81 (s, 3H).