Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH:12]([CH2:13][CH2:14]Cl)[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>C(O)CO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH:12]([CH2:13][CH2:14][N:29]3[CH2:28][CH2:27][N:26]([C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=4)[CH2:31][CH2:30]3)[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: COc1cc2c(cc1OC)C(CCCl)OCCC2
Solvent: Cc1ccccc1
Solvent: OCCO
Product: COc1cc2c(cc1OC)C(CCN1CCN(c3cccc(Cl)c3)CC1)OCCC2
Yield: 34.2 %

Procedure:
A mixture of 2.00 g (7.39 mmol) of 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)]ethyl chloride and 2.8 g (14.5 mmol) of 1-(3-chlorophenyl)piperazine is stirred at 85° for 36 hours in 1 ml of ethylene glycol and 10 ml of toluene. Excess toluene is added and the solids are removed by filtration from the warm solution. The organic phase is concentrated. The product was recrystallized from CH2Cl2 and toluene to give 1.09 g of product, m.p. 125°-126°.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S([CH2:22][N+:23]#[C-:24])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:9][CH:24]=[N:23][CH:22]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2cnco2)cc1
Yield: 89 %

Procedure:
A mixture of 4-nitro-benzaldehyde (5.0 g, 33.1 mmol), tosylmethyl isocyanide (6.4 g, 33.1 mmol) and potassium carbonate (7.8 g, 82.7 mmol) in methanol (100 ml) was heated under reflux for 30 minutes. After concentrating under reduced pressure, the residue was stirred with water (50 ml). The solid that was filtered to afford 5-(4-nitro-phenyl)-oxazole (5.6 g, 89% yield). 1H NMR (acetone-d6) δ 7.89 (s, 1H, Ar), 8.05 (d, 2H, J=9.3 Hz, Ar), 8.35-8.38 (m, 3H, Ar).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:14]([CH:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1)=[CH2:15].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2](/[CH:15]=[CH:14]/[CH:16]3[CH:21]4[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]4)[CH2:17]3)=[CH:3][CH:4]=2)[N:12]=1
Reactant: C=CC1CN2CCC1CC2
Reactant: Cc1nc(-c2ccc(I)cc2)no1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(/C=C/C3CN4CCC3CC4)cc2)no1
Temperature: 100 °C
Reaction time: 5 h
Yield: 10.2 %

Procedure:
A mixture of 3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole (1.43 g), 3-vinylquinuclidine (685 mg), bis(triphenylphosphine)palladium (II) chloride (175 mg), copper (I) iodide (90 mg) and triethylamine (5.0 ml) in dry dimethylformamide (10 ml) was stirred under argon at 100° C. for 5 hours. The dimethylformamide and triethylamine were removed by evaporation. The residue was treated with 2M aqueous sodium hydroxide solution (20 ml) and extracted with dichloromethane (3×20 ml). The organic extracts were washed with water (20 ml), dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using 5% methanol in dichloromethane containing 0.5% ammonia (density, 0.88 g/cm3) as eluent to give E-3-[2-{4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl}ethenyl]quinuclidine (150 mg) as a solid, m.p. 93°-97° C.; NMR: 1.4(1H,m), 1.65(2H,m), 1.8(2H,m), 2.55(1H,m), 2.65(3H,s), 2.8(4H,m), 3.08(1H,m), 3.45(1H,m), 6.5(1H,d), 6.62(1H,d,d), 7.6(2H,d) and 7.82(2H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH:29]([F:31])[F:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:17](O)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH:29]([F:30])[F:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:17]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=3)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@@H]2CCCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)C(C[C@@H]2CCCCO2)n2cc(OC)c(-c3cc(Cl)ccc3OC(F)F)cc2=O)cc1

Procedure:
Two fractions, 312 mg (purity 87%, 0.59 mmol) and 86 mg (0.19 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoic acid (mixture of enantiomerically pure diastereomers 1 and 2), were reacted with in total 202 mg (1.23 mmol, 1.6 eq.) of ethyl 4-aminobenzoate according to General Method 5B. Yield: 315 mg (83% of theory)
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22]>C(#N)C>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:21]([N:20]([CH3:24])[CH3:19])=[S:22])=[CH:7][CH:6]=1)=[O:2]
Reactant: CN(C)C(=S)Cl
Reactant: Nc1ccc(NNC=O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C)C(=S)Nc1ccc(NNC=O)cc1
Temperature: 60 °C

Procedure:
1-Formyl-2-(4-aminophenyl)hydrazine (1.51 g, 0.01 mole) and triethylamine (1.0 g, 0.01 mole) were mixed with dry acetonitrile (30 ml). The mixture was kept under a nitrogen atmosphere and a solution of dimethylthiocarbamoyl chloride (1.24 g, 0.01 mole) in acetonitrile (10 ml) was added dropwise at room temperature. After the addition was complete, the reaction mixture was chilled in ice, then filtered. The solid was washed with ethanol and allowed to dry. The material was stirred in water (40 ml) and heated to 60° C. to remove any hydrochloride salts. The aqueous mixture was filtered; the solid was washed with ether and dried. This gave 0.60 g (25 percent) of product as a pale tan powder, m.p. 187°-189° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][N:8]([CH3:15])[CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[N:18]=[C:19]2[N:23]([C:24]=1[S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:21][S:20]2.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:15][N:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([NH:1][S:25]([C:24]4[N:23]5[C:19]([S:20][CH:21]=[CH:22]5)=[N:18][C:17]=4[Cl:16])(=[O:26])=[O:27])[CH:3]=3)[NH:11][C:10]=2[CH2:9]1
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Reactant: CN1CCc2c([nH]c3ccc(N)cc23)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1CCc2c([nH]c3ccc(NS(=O)(=O)c4c(Cl)nc5sccn45)cc23)C1
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To a solution of 6-amino-2-methyl-2,3,4,9-tetrahydro-1H-β-carboline (description 2) (150 mg, 0.68 mmol) in pyridine (5 mL) cooled in an ice bath, were added 200 mg of 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride (0.68 mmol). Under N2, the reaction mixture was left to reach room temperature and stirred for 1 h at this temperature. The reaction mixture was basified with aqueous saturated solution of NaHCO3 and the pyridine evaporated. The mixture was treated with EtOAc and H2O, the organic phase washed with aqueous saturated solution of NaHCO3, separated and dried with Na2SO4. The crude was further purified using SiO2 column chromatography with EtOAc/MeOH/NH3 mixtures to yield 130 mg of 6-chloro-imidazo[2,1-b]thiazole-5-sulfonic acid (2-methyl-2,3,4,9-tetrahydro-1H-β-carbolin-6-yl)-amide. Cream colored amorphous solid, mp 232-233° C. 1H-NMR (300 MHz, DMSO-d6): (ppm) 2.36 (s, 3H); 2.54 (bb, 2H); 2.61 (bb, 2H); 3.45 (bb, 2H); 6.65 (dd, 1H, J=8.7, 2.1 Hz); 6.99 (d, 1H, J=1.8 Hz); 7.09 (d, 1H, J=8.7 Hz); 7.53 (d, 1H, J=4.5 Hz); 7.81 (d, 1H, J=4.5 Hz); 10.37 (bb, 1H); 10.74 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH3:8][Si:9]([O:12][C:13](=[O:19])[C@H:14]([CH:16]([CH3:18])[CH3:17])[NH2:15])([CH3:11])[CH3:10]>>[CH3:11][Si:9]([O:12][C:13](=[O:19])[C@H:14]([CH:16]([CH3:17])[CH3:18])[NH:15][C:1](=[O:5])[C:2]([CH3:4])=[O:3])([CH3:8])[CH3:10]
Reactant: CC(C)[C@H](N)C(=O)O[Si](C)(C)C
Reactant: CC(=O)C(=O)Cl
Agent: Cl
Product: CC(=O)C(=O)N[C@H](C(=O)O[Si](C)(C)C)C(C)C

Procedure:
A method of synthesizing pyruvyl-valine according to the invention comprises the steps of reacting sodium pyruvate with oxalyl chloride to yield pyruvyl chloride, then reacting the pyruvylchloride with a suspension of valine trimethylsilyl ester hydrochloride to yield pyruvyl-valine trimethylsilyl ester and then subjecting the pyruvyl-valine trimethylsilyl ester to hydrolysis to yield pyruvyl-valine. The pyruvyl-valine synthesized via the route set forth above serves as a pyruvyl-amino acid pyruvate precursor.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH2:24]([N:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])[CH3:25]>>[CH2:24]([N:26]([CH2:30][CH3:31])[C:27]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:28])[CH3:25]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CCN(CC)C(=O)Cl
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CC

Procedure:
1,1-Diethyl-3-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.97 mmol) and diethylcarbamoyl chloride (134 μl, 1.06 mmol). The title compound was obtained as yellow powder (85 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:29]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCCCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Yield: 26.2 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)octanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (581 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.66 ml) and 1-methyl-2-chloropyridinium iodide (918 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)octanamide (350 mg).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH3:12])=[N:10][N:9]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:8]=2[NH2:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(N=[C:22]=[O:23])C.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][N:9]1[C:8]2[NH:18][C:22](=[O:23])[C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[C:7]=2[C:11]([CH3:12])=[N:10]1
Reactant: Cc1nn(CCN(C)C)c(N)c1C1=CCCCC1
Reactant: CCN=C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1nn(CCN(C)C)c2[nH]c(=O)c3c(c12)CCCC3
Yield: 68.5 %

Procedure:
To a solution of EXAMPLE 8A (1.05 g, 4.22 mmol) in pyridine (10 mL) was added ethyl isocyanate (1.0 mL, 12.68 mmol) and the solution heated at reflux overnight. The mixture was cooled, stirred with 15 mL ethyl acetate at ambient temperature for 5 minutes and the solid collected by filtration, washed with ethyl acetate and dried to give 793 mg of the title compound. The mother liquor was concentrated and the residue recrystallized from ethyl acetate to give an additional 300 mg of the title compound (94% overall yield). 1H NMR (DMSO-d6) 1.64-1.75 (m, 4H), 2.16 (s, 6H), 2.34-2.39 (m, 5H), 2.59 (t, J=6.4 Hz, 2H), 2.83-2.87 (m, 2H), 4.18 (t, J=6.6 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[F:17][C:18]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:27][C:26]2[C:18]([F:17])=[C:19]([C:23]([F:28])=[CH:24][CH:25]=2)[C:20]([NH2:22])=[O:21])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: COc1ccc(-c2nc(CBr)sc2Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
To a solution of 5-Bromo-2-bromomethyl-4-(4-methoxy-phenyl)-thiazole (0.50 g, 1.37 mmol) in 5 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.23 g, 1.37 mmol) and potassium carbonate (0.75 g, 5.43 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (30:70) as the eluent to provide the title compound (0.30 g, 48%).
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)=[CH:10][C:9]=2[F:19])[CH:5]=1.[CH2:20]([C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][C@H:31](O)[C@H:30]([F:35])[CH2:29]2)=[N:26][CH:27]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][C@@H:31]([N:2]3[N:3]=[C:4]([CH2:6][O:7][C:8]4[CH:13]=[CH:12][C:11]([N:14]5[CH:18]=[N:17][N:16]=[N:15]5)=[CH:10][C:9]=4[F:19])[CH:5]=[N:1]3)[C@H:30]([F:35])[CH2:29]2)=[N:26][CH:27]=1)[CH3:21]
Reactant: Fc1cc(-n2cnnn2)ccc1OCc1cn[nH]n1
Reactant: CCc1cnc(N2CC[C@H](O)[C@H](F)C2)nc1
Product: CCc1cnc(N2CC[C@@H](n3ncc(COc4ccc(-n5cnnn5)cc4F)n3)[C@H](F)C2)nc1

Procedure:
The title compound was synthesized using 1-(4-((2H-1,2,3-triazol-4-yl)methoxy)-3-fluorophenyl)-1H-tetrazole (Intermediate 16) and cis-1-(5-ethylpyrimidin-2-yl)-3-fluoropiperidin-4-ol (Intermediate 17) in a manner similar to that described in Example 29. 1H NMR (CDCl3): δ 8.92 (1H, s), 8.21 (2H, s), 7.76 (1H, s), 7.51 (1H, dd), 7.41 (1H, d), 7.26 (1H, m), 5.31 (2H, s), 5.17 (1H, m), 5.03 (1H, m), 4.83 (2H, m), 3.11 (2H, m), 2.50 (2H, q), 2.22 (2H, m), 1.22 (3H, t).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].N1CCCCC1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].Cl>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOc1ccc(/C=C/C(=O)O)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A solution of 4-ethoxybenzaldehyde (1.00 mL, 7.20 mmol) and piperidine (0.11 mL, 1.08 mmol) in 40 mL of pyridine was heated to 120° C. A solution of malonic acid (1.50 g, 14.40 mmol) in 40 mL of pyridine was added dropwise over 30 min and the reaction solution was stirred at 120° C. for 4 h. After cooling down to 0° C., excess amount of concentrated HCl was added carefully to make ˜pH 1. A white crystalline precipitate formed, and the solid was collected by filtration, washed with 0.1 N HCl aqueous solution, and dried to afford compound 19 in 99.5% (1.40 g) of pure 19 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[CH:4][CH:3]=1.[OH:25]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[O:25])=[CH:4][CH:3]=1
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCSc3ccc(F)cc3)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc(F)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-fluorophenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [OH:1][C:2]1([CH:13]([OH:15])[CH3:14])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:16].O1CCOCC1>CO>[ClH:16].[OH:15][CH:13]([C:2]1([OH:1])[CH2:5][NH:4][CH2:3]1)[CH3:14]
Reactant: CC(O)C1(O)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(O)C1(O)CNC1

Procedure:
1,1-Dimethylethyl 3-hydroxy-3-(1-hydroxyethyl)azetidine-1-carboxylate (200 mg, 0.922 mmol) was dissolved in methanol (5 mL) and 4 N hydrochloric acid in dioxane (1 mL, 4 mmol) was added. The mixture was refluxed for 15 minutes and then was concentrated in vacuo to afford 3-(1-hydroxyethyl)azetidin-3-ol hydrochloride (0.922 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].B(Br)(Br)Br>ClCCCl.C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1ccc(C(N)=O)c(N)c1
Agent: BrB(Br)Br
Solvent: ClCCCl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(O)cc1N
Temperature: 40 °C
Yield: 31.3 %

Procedure:
To 2-amino-4-methoxybenzamide (7.0 g, 42 mmol) in 1,2-dichloroethane (100 mL) was added boron tribromide (25 g, 100 mmol) at rt. After heating for 40° C. for 20 h, 1 N boron tribromide in THF (40 mL) was added, and the reaction was heated to 50° C. for 20 h. The mixture was cooled and quenched by addition of aq. sodium bicarbonate. The resulting precipitate was collected by filtration to afford 2-amino-4-hydroxybenzamide as a white solid (2.0 g). The mother liquors were concentrated, diluted with MeOH, filtered and concentrated. The residue was again diluted with MeOH, filtered and concentrated, and the resulting residue was chromatographed on silica gel eluting with 5-15% MeOH/DCM to give 2-amino-4-hydroxybenzamide as a white solid (4.7 grams). The solids were combined for a total yield of 6.7 g (quantitative). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.91 (dd, J=8.67, 2.26 Hz, 1H) 6.03 (d, J=2.45 Hz, 1H) 6.62 (br. s., 2H) 7.38 (d, J=8.67 Hz, 1H) 9.45 (s, 1H). LC-MS (ESI) m/z 153 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[O:9][CH2:10][C:11]1[C:16]([NH:17][OH:18])=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:18][N:17]([C:16]1[C:11]([CH2:10][O:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[CH3:6])=[N:12][CH:13]=[CH:14][CH:15]=1)[C:2](=[O:3])[O:4][CH3:5]
Reactant: Cc1ccccc1OCc1ncccc1NO
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N(O)c1cccnc1COc1ccccc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.1 g (22 mmol) of methyl chloroformate were added dropwise at -10° C. to a mixture of 4.3 g (mmol) of N-[2-(2-methylphenoxymethyl)pyridin-3-yl]hydroxylamine (Example 3.e), 3.3 g (39 mmol) of NaHCO3 (solid) and 50 ml of methylene chloride. After the reaction mixture had been stirred for 4 hours at room temperature (approximately 25° C.), it was washed with water, dried and freed from solvent under reduced pressure. The residue was purified by column chromatography (cyclohexane/ethyl acetate). This gave 0.6 g (10%) of the title compound as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][N:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[O:10]([C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[N:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccccc2)cn1
Reaction time: 18 h
Yield: 96.2 %

Procedure:
2-Nitro-5-phenoxy-pyridine (262 mg) was dissolved in dry ethanol (12 mL) and 10% palladium on charcoal (90 mg) was added. A hydrogen atmosphere was introduced by repeated evacuation/hydrogen introduction. The mixture was then allowed to stir for 18 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to give 5-phenoxy-pyridin-2-ylamine (217 mg) as a yellow foam. This material was used without further purification. MS (EI): 186.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([Br:13])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)Cc2cccc(N)c2O1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(Br)ccc(N)c2O1
Temperature: 0 °C
Yield: 83.3 %

Procedure:
A stirred solution of 10.0 grams (0.061 mole) of 7-amino-2,3-dihydro-2,2-dimethylbenzofuran in 150 mL of N,N-dimethylformamide was cooled in an ice-water bath, and a solution of 10.9 grams (0.061 mole) of N-bromosuccinimide in 50 mL of N,N-dimethylformamide was added in one portion. Upon completion of addition, the reaction mixture was maintained in the ice-water bath for about one hour. After this time the reaction mixture was poured into about 600 mL of water. The mixture was then extracted with two 200 mL portions of diethyl ether. The combined extracts were washed with two 100 mL portions of an aqueous 10% lithium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 12.3 grams of 7-amino-4-bromo-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][N:8]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]cc(Cl)c2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(Cl)c3ccc(Br)cc3c2=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a screw cap pressure vessel, 7-bromo-4-chloroisoquinolin-1(2H)-one (Ark Chemicals, 2.50 g, 9.67 mmol) was added to a vial followed by cesium carbonate (6.30 g, 19.34 mmol) and DMF (9.67 mL). 1-(chloromethyl)-4-methoxybenzene (1.444 ml, 10.64 mmol) was added, the vial was capped and heated to 50° C. for 1 hours. The reaction was cooled to room temperature and water (20 mL) was added. The reaction was stirred for an additional 1 hour and filtered. The solid was collected and dried under a vacuum to yield 2.25 g of 7-bromo-4-chloro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one as an off white solid. m/z (ESI) 380.1 (M+H)+.