Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:9]([C:14]([O:16]C)=[O:15])=[N:10][O:11][C:12]=1[CH3:13])=[O:7])[CH3:4]>O.O1CCCC1>[CH2:3]([O:5][C:6]([C:8]1[C:9]([C:14]([OH:16])=[O:15])=[N:10][O:11][C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1c(C(=O)OC)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C(=O)O)noc1C
Reaction time: 12 h
Yield: 70 %

Procedure:
At -15° to -10° C. and under a nitrogen blanket, 4.7 g (0.117 mol) of sodium hydroxide in 80 ml of water was dripped into 25.0 g (0.117 mol) of methyl 4-ethoxycarbonyl-5-methylisoxazole-3-carboxylate in 200 ml of anhydrous tetrahydrofuran, and the mixture was stirred for 12 hours. The solvents were stripped off in a rotary evaporator (bath temperature: 30°-35° C.), the residue was taken up in 250 ml of water, the pH was adjusted to 8-9 with hydrochloric acid, and the mixture was extracted twice, each time with 150 ml of diethylether. The aqueous phase was acidified to a pH of 2 with 6N HCl and extracted four times, each time with 250 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and the solvent was stripped off under reduced pressure. Yield: 70%; 1H-NMR (250 MHz; CDCl3); δ=1.42 ppm (t; 3H), 2.80 ppm (s; 3H), 4.59 ppm (q; 2H).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:14]2[N:15]=[C:16]([CH2:26][CH2:27][CH3:28])[N:17]([CH2:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:13]=2[C:12]([CH3:29])=[C:11]([CH3:30])[N:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.C(O)C>[NH2:8][C:9]1[C:14]2[N:15]=[C:16]([CH2:26][CH2:27][CH3:28])[N:17]([CH2:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:13]=2[C:12]([CH3:29])=[C:11]([CH3:30])[N:10]=1
Reactant: CCCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(C)c(C)c2n1CC1(O)CCCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CC1(O)CCCCC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 63.8 %

Procedure:
A mixture of 1-{[4-(dibenzylamino)-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl]methyl}cyclohexanol (1.50 g, 3.02 mmol), ammonium formate (2.84 g, 45.0 mmol), and 10% palladium on carbon (1.50 g) in methanol (60 mL) and ethanol (120 mL) was heated at 85° C. for 2 h. More ammonium formate (1.00 g) was added and heating was continued of 3 h, then the reaction mixture was stirred overnight at rt. The mixture was filtered through CELITE filter agent and the filtrate was concentrated in vacuo. The crude product was purified using HPFC (gradient elution with 10-40% CMA/chloroform). The appropriate fractions were concentrated and the resulting solid was triturated with acetonitrile. A solid was isolated by filtration and dried at 100° C. under vacuum to provide 1-[(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclohexanol as a white powder (0.61 g, 64%), mp 214.0-216.0° C. Anal. Calcd for C18H28N4O C, 68.32; H, 8.92; N, 17.71. Found: C, 68.06; H, 8.65; N, 17.45
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([N:11]3[CH2:15][CH2:14][O:13][C:12]3=[O:16])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1>>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[S:10][C:9]([N:11]5[CH2:15][CH2:14][O:13][C:12]5=[O:16])=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: O=C1OCCN1c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: O=C1OCCN1c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl) oxazolidin-2-one (46 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via Procedure A. The product was purified by reverse phase HPLC to yield 8.6 mg of 439. MS (Q1) 423 (M)+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][C:18]=1[CH3:33]>N1C=CC=CC=1>[CH3:31][O:30][C:28]([C:26]1[N:27]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:9]([C:4]3[NH:5][C:6]([CH2:7][CH3:8])=[C:2]([Cl:1])[N:3]=3)=[O:11])=[C:18]([CH3:33])[CH:19]=2)[O:24][C:25]=1[CH3:32])=[O:29]
Reactant: COC(=O)c1nc(-c2ccc(N)c(C)c2)oc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)c(C)o3)cc2C)nc1Cl
Yield: 77.1 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.18 g, 1.03 mmol), thionyl chloride (4 mL), methyl 4-amino-3-methylphenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (108e) (0.28 g, 1.14 mmol) and pyridine (5 mL), to obtain 0.32 g of the title compound as a colorless solid (77%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:30]C=O)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:44][C:45]([O:47][CH3:48])=[O:46])C=CC=CC=1.[C:61]1(C)C=CC=CC=1>>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:30][CH:61]=[CH:44][C:45]([O:47][CH3:48])=[O:46])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC=O)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Product: COC(=O)C=CCC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanal, 83a, (0.295 g, 0.574 mmol) in toluene (5.9 mL) was added methyl 2-(triphenylphosphoranylidene)acetate (0.300 g, 0.862 mmol). The mixture was stirred overnight at room temperature and then purified directly on silica gel (EtOAc/Hexanes) to afford 278 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.54 minutes (M+H) 584.12.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](O)[C:5]2[N:13]3[C:8]([C:9]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=4[CH3:22])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:23]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:4]1[C:5]2[N:13]3[C:8]([C:9]([C:14]4[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=4[CH3:20])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:23]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(O)c23)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(Cl)c23)c(C)c1
Temperature: 25 °C

Procedure:
Heat at 100° C. for 2 h a solution of 2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizin-4-ol (120 mg) in phosphorus oxychloride (2 mL), cool to ambient temperature, and concentrate in vacuo. Partition the residue into ice water and CH2Cl2. Extract the aqueous phase twice with CH2Cl2 and wash the combined organic extracts with a saturated NaHCO3 solution. Dry the solution over Na2SO4, filter, and concentrate in vacuo. Purify the dark residue by column chromatography on silica gel (eluent: 10% to 20% EtOAc in hexane) to obtain the title compound as a greenish yellow foam: 1H NMR (400 MHz, CDCl3) δ 1.99 (s, 6 H), 2.38 (s, 3 H), 2.79 (, 3 H), 6.80 (m, 1 H), 7.00 (s, 2 H), 7.19 (m, 2 H), 9.27 (d, 1 H).
Reaction SMILES: [CH3:1][CH:2]([NH2:26])[CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N:9]=[CH:8]2.CCN(C(C)C)C(C)C.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>C(#N)C>[CH3:36][O:37][CH2:38][C:39]([NH:26][CH:2]([CH3:1])[CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N:9]=[CH:8]2)=[O:40]
Reactant: CC(N)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccccc1
Reactant: COCC(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)NC(C)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
1-Methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethylamine (118a, 14 mg, 0.041 mmol), DIPEA (12 ul, 0.070 mmol) and acetonitrile (2 ml) were charged in a 7 ml vial. Methoxyacetyl chloride (12 ul, 0.13 mmol) was added, the vial was sealed and the solution stirred (magnetic bar) at r.t. for 1 h. Concentration and purification on C18 (Kromasil) with acetonitrile:water:TFA, 45:55:0.1 to 90:10:0.1 over 30 min, afforded 5 mg (29%) of 2-methoxy-N-[1-methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethyl]acetamide.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH:12]2[CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1)([O-])=O>C(O)C.[Pd]>[ClH:1].[CH2:15]([CH:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([NH2:2])[CH:14]=2)[CH2:9][CH2:10][NH:11]1)[CH2:16][CH3:17]
Reactant: CCCC1NCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCC1NCCc2ccc(N)cc21
Reaction time: 3 h
Yield: 64 %

Procedure:
To a suspension of 7-nitro-1-propyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.51 g, 9.78 mmol) in ethanol (150 ml) was added 10% Pd-C (0.3 g) and the reaction mixture was hydrogenated at 50 psi for 3 h. The solution was filtered and the filtrate was concentrated and absolute ethanol was added to help evaporate any excess water. The resulting solid was triturated with isopropanol (30 ml) to give the title compound (1.42 g , 64%) as an off-white solid, m.p. 192-4° C.
Reaction SMILES: C([O:9][CH:10]([CH2:32][O:33][P:34]([OH:37])([OH:36])=[O:35])[CH2:11][NH:12][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=O)C1C=CC=CC=1.[OH-].[Na+]>ClCCl>[OH:9][CH:10]([CH2:32][O:33][P:34]([OH:36])([OH:37])=[O:35])[CH2:11][NH:12][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(COP(=O)(O)O)OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(O)COP(=O)(O)O
Yield: 82 %

Procedure:
12 (1.76 mmol) is dissolved in 20 ml of dichloromethane, and 50 ml of a 1% methanolic NaOH solution is added. This is concentrated after 20 hours at room temperature, and the residue is acidified with 1N HCl. The mixture is extracted with ethyl acetate. The combined organic phases are washed with 50 ml of H2O and dried over MGSO4, filtrated and concentrated. The residue is treated with methanol. Yield: 82% of colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH2:12][CH:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].C(O)(=O)C>[O-2].[O-2].[O-2].[Cr+6].O>[CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH2:12][C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:20])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(CC(O)c2ccccc2)c1C(=O)NC
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: CCc1noc(CC(=O)c2ccccc2)c1C(=O)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 29.0 g. (0.105 mole) of 3-ethyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide and 500 ml. acetic acid at room temperature is treated dropwise rapidly with 12.5 g. (0.125 mole) of chromium trioxide in 125 ml. water. The resulting solution is stirred for 2 hours at room temperature and a portion of the acetic acid is removed in vacuo. The remainder is poured onto ice water and extracted with methylene chloride. The methylene chloride layer is washed with 2 N sodium hydroxide, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with ether and recrystallized from ethanol to give 3-ethyl-N-methyl-5-phenacyl-4-isoxazole carboxamide, m.p. 134° to 136° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([CH3:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O.O>C(#N)C>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([CH3:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: Cc1c([N+](=O)[O-])cc(C(N)=O)c(N)c1[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: Cc1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 83 %

Procedure:
To a mixture of 2-amino-4-methyl-3,5-dinitrobenzamide (7) (12.5 kg) in acetonitrile (78.4 kg) is added phosphorus oxychloride (14.8 kg) over a period of about 35 minutes. The mixture is then heated to reflux. After approximately 3.25 hours, the mixture is cooled to about 25° C. and added to water (245 kg). The vessel that formerly contained the reaction mixture is rinsed with acetonitrile (16 kg) and the rinse solution is also added to the aforementioned water quench solution. The quench solution is then cooled to about 5° C. over a period of about 2 hours. The quench solution is then filtered, the vessel that formerly contained the quench solution is rinsed with water (93 kg), and the rinse solution is passed through the product-containing filter. The product obtained is then dried in a vacuum tray drier, at a temperature of about 47° C. and a vacuum of about 12 torr, to provide 2-amino-4-methyl-3,5-dinitrobenzonitrile (5) (9.6 kg, 83.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[O:14][CH:10]2[CH2:11][CH2:12][CH2:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:15][NH2:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@:9]2([OH:14])[CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:16][CH3:15])[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: COc1cccc(C23CCCC2O3)c1
Product: CN[C@H]1CCC[C@@]1(O)c1cccc(OC)c1

Procedure:
Crude 1-(3-methoxyphenyl)cyclopentene oxide (prepared according to the method of Ger. Offen. No. 2,942,644) is treated with ethanolic methylamine solution by the method of Example 1(b) above to give the title compound.
Reaction SMILES: [CH3:1][NH:2]/[N:3]=[CH:4]/[C:5]1[C:10](F)=[CH:9][C:8]([F:12])=[CH:7][C:6]=1[F:13]>C(Cl)Cl>[F:13][C:6]1[CH:7]=[C:8]([F:12])[CH:9]=[C:10]2[C:5]=1[CH:4]=[N:3][N:2]2[CH3:1]
Reactant: CN/N=C/c1c(F)cc(F)cc1F
Solvent: ClCCl
Product: Cn1ncc2c(F)cc(F)cc21
Yield: 56 %

Procedure:
N-Methyl-N′-[1-(2,4,6-trifluoro-phenyl)-meth-(E)-ylidene]-hydrazine (3.85 g, 20.46 mmol) was heated in a sealed tube at 210° C. for 2 h. After cooling, the black residue was dissovled in DCM and purified by flash chromatography (EtOAc:hexane 10:90) to give the title compound as a light yellow crystal (1.926 g, 56%). 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.05 (s, 1H), 7.16 (d, 1H), 6.75 (t, 1H), 3.32 (s, 3H). LCMS (method B): [MH]+=169, tR=2.28 min.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH3:43])[CH2:29][CH2:30][N:31]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[S:32]([CH3:35])(=[O:34])=[O:33].[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]([CH3:43])[CH2:29][CH2:30][N:31]([C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:41][CH:42]=1)[S:32]([CH3:35])(=[O:34])=[O:33]
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CCN(c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Examples 1 and 187 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C2CCCCO2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[O:23])[CH:17]=1.[BH4-].[Na+].[C:26]([OH:38])(=O)[CH2:27][C:28]([CH2:33][C:34](O)=O)(C(O)=O)O>COCCOC.O1CCCC1>[CH3:15][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][CH:26]2[CH2:27][CH2:28][CH2:33][CH2:34][O:38]2)[CH:17]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1cc(OC2CCCCO2)cc(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1-c1cccc(COC2CCCCO2)c1
Reaction time: 3 h
Yield: 36 %

Procedure:
2′,6′-Dimethyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-carbaldehyde (9.05 g, 29.2 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (50 mL) and tetrahydrofuran (50 mL), and sodium borohydride (0.567 g, 15.0 mmol) was added under ice-cooling. The mixture was stirred at the same temperature for 3 hrs. 10% Aqueous citric acid solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15%-50% ethyl acetate/hexane) to give the title compound (3.24 g, yield 36%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[ClH:1].[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][NH:24][CH3:25])=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(Cl)s2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccc(Cl)s2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 130 %

Procedure:
To a solution of tert-butyl {[1-[(5-chloro-2-thienyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (229 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 130 mg, 65%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Cl:11][C:12]1[CH:22]=[CH:21][C:15]2[S:16][CH:17]=[C:18]([CH2:19]Br)[C:14]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>>[Cl:11][C:12]1[CH:22]=[CH:21][C:15]2[S:16][CH:17]=[C:18]([CH2:19][N:10]([CH2:19][C:18]3[C:14]4[CH:13]=[C:12]([Cl:11])[CH:22]=[CH:21][C:15]=4[S:16][CH:17]=3)[C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)[C:14]=2[CH:13]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2scc(CN(Cc3csc4ccc(Cl)cc34)c3ccc4[nH]cnc4c3)c2c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), (5-chlorobenzo[b]thiophen-3-yl)methylbromide (576 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.187 g (37.9%); MS m/z: 494.4/496.5 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.84 (s, 4H); 6.90-6.92 (m, 2H); 7.37-7.39 (m, 3H); 7.51 (s, 2H); 7.88 (d, 2H); 7.94-7.96 (m, 2H); 7.98 (s, 1H); 12.00 (br s, 1H); HPLC (METHOD [A]): rt 19.77 min (100%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH:63]([F:65])[F:64])=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:57]=[CH:58][C:59]([O:62][CH:63]([F:65])[F:64])=[CH:60][CH:61]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(OC(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccc(OC(F)F)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 105 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-difluoromethoxy-phenyl)-ethyl]-amine in 2 ml DMF were added. After 2.5 h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 114 mg white solid (68%). MS (ISP) 477.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:23][C:24]1[CH:36]=[CH:35][C:27]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1>>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:32]4[CH2:31][CH2:30][N:29]([CH2:28][C:27]5[CH:35]=[CH:36][C:24]([F:23])=[CH:25][CH:26]=5)[CH2:34][CH2:33]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: Fc1ccc(CN2CCNCC2)cc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(Cc5ccc(F)cc5)CC4)cc3nc21
Yield: 58.6 %

Procedure:
1-Ethyl-7-fluoro-8-[4-(4-fluorobenzyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 2, LAW OFFICES but from 1.6 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 3.9 g of 4-(4-fluorobenzyl)piperazine. After recrystallizing twice from 20 cm3 of dimethylformamide on each occasion, 1.4 g of 1-ethyl-7-fluoro-8-[4-(4-fluorobenzyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 286-8° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(C1C=CC(C2C=CC(C(OC(C)C(C3C=CC(OCC=C)=CC=3)=O)=O)=CC=2)=CC=1)CCCCCC.[C:61]([O:67][CH:68]([CH3:78])[C:69]([C:71]1[CH:76]=[CH:75][C:74]([OH:77])=[CH:73][CH:72]=1)=[O:70])(=[O:66])[CH2:62][CH2:63][CH2:64][CH3:65]>CN(C1C=CN=CC=1)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:77][C:74]3[CH:75]=[CH:76][C:71]([C:69](=[O:70])[CH:68]([O:67][C:61](=[O:66])[CH2:62][CH2:63][CH2:64][CH3:65])[CH3:78])=[CH:72][CH:73]=3)=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCCCC(=O)OC(C)C(=O)c1ccc(O)cc1
Agent: C=CCOc1ccc(C(=O)C(C)OC(=O)c2ccc(-c3ccc(CCCCCCC)cc3)cc2)cc1
Agent: CN(C)c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)C(C)OC(=O)CCCC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 500 mg of 4'-octyloxy-biphenyl-4-yl-carboxylic acid chloride, 400 mg of (S) 4-(2-pentanoyloxy-1-keto-propyl)phenol, 600 mg of N,N-dicyclohexylcarbodiimide, and 20 mg of DMAP was stirred at room temperature for three hours. A solid material precipitated was removed by filtration. The organic layer thus obtained was washed with an acid, an alkali, and with water, dried, and then concentrated.