Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37]([C:30]5[C:31]6[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=6)[N:27]=[CH:28][CH:29]=5)=[O:38])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound, light brown solid (98 mg, 82%), MS (ISP) m/z=484.5 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and quinoline-4-carboxylic acid.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.Cl.[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[NH:30])[NH2:29])[CH2:23]1.CC(C)([O-])C.[K+]>C(O)C.O>[CH3:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:5]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:3][N:29]=[C:28]([N:24]2[CH2:25][CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23]2)[N:30]=1
Reactant: Cc1occc1C(=O)C(=CN(C)C)c1ccccn1
Reactant: CC1CCCN(C(=N)N)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1occc1-c1nc(N2CCCC(C)C2)ncc1-c1ccccn1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-furanyl)-2-(2-pyridinyl)-2-propen-1-one (256 mg, 1 mmol) and 3-methyl-1-piperidinecarboximidamide hydrochloride (267 mg, 1.5 mmol) in ethanol (5 ml) was stirred at room temperature. Potassium tert-butoxide (224 mg, 2 mmol) was added and the mixture was heated at reflux for 45 minutes. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate and isohexane followed by mass-directed automated HPLC to give 4-(2-methyl-3-furanyl)-2-(3-methyl-1-piperidinyl)-5-(2-pyridinyl)pyrimidine (223 mg, 67%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[NH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[H-].[Na+].[CH2:14]([O:16][CH2:17]Cl)[CH3:15].Cl>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH2:14]([O:16][CH2:17][N:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:3]1[C:2]([F:1])([F:10])[F:11])[CH3:15]
Reactant: N#Cc1cc[nH]c1C(F)(F)F
Reactant: CCOCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOCn1ccc(C#N)c1C(F)(F)F
Reaction time: 0.33 h

Procedure:
A stirred solution of 2-trifluoromethyl-3-cyanopyrrole (1.0 g, 6.2 mmol) in dry tetrahydrofuran is treated with NaH (0.30 g, 7.5 mmol) as a 60% dispersion in mineral oil, under nitrogen, at room temperature. After 20 minutes, the reaction mixture is treated dropwise with a solution of chloromethyl ethyl ether (0.77 g, 8.1 mmol) in dry tetrahydrofuran, stirred vigorously for 3 hours and treated with a mixture of 1N HCl and ethyl acetate. The phases are separated and the organic phase is washed with brine, dried over Mg SO4 and concentrated in vacuo to afford a residue. Flash chromatography of the residue using silica gel and 3.5:1 hexane: ethyl acetate yields the title compound as a pale yellow oil, 0.83 g (61%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[CH:35]=[C:34]([Cl:40])[C:33]([Cl:41])=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:33]1[C:34]([Cl:40])=[CH:35][C:36]2[C:37]3[CH2:38][CH2:39][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:27][CH2:28][C:29]=3[N:30]([CH2:42][C:43]([NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=3[CH3:1])=[O:44])[C:31]=2[CH:32]=1
Reactant: Cc1cccc(N)c1C
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cc(Cl)c(Cl)cc23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Cn2c3c(c4cc(Cl)c(Cl)cc42)CCN(C(=O)OC(C)(C)C)CC3)c1C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
DMAP (60 mg, 0.49 mmol), 2,3-dimethylaniline (0.065 mL, 0.53 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reaction was diluted with EtOAc followed by washing with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine. The organic layer was then dried over Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc (98:2) to give 0.13 g of impure product. Then, crystallization from EtOAc/heptane gave 96 mg (38%) of a white solid: mp 186-187.5° C.; IR (diffuse reflectance) 3290, 2977, 2939, 1692, 1681, 1662, 1538, 1471, 1450, 1412, 1366, 1338, 1282, 1235, 1163 cm−1; MS (EI) m/z 515 (M+), 375, 373, 226, 225, 223, 120, 84, 76, 56, 51; Anal. Calcd for C27H31Cl2N3O3: C, 62.79; H, 6.05; N, 8.14; found: C, 62.60; H, 6.04; N, 8.07.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]2[O:17][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]([NH2:30])([CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>>[OH:17][CH:15]([CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:16][NH:30][C:19]([CH3:29])([CH3:18])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1
Reactant: c1ccc(CCCCCCOCC2CO2)cc1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COCCCCCCc2ccccc2)cc1

Procedure:
Using the method of Example 9, supra, 6-phenylhexylglycidyl ether (337 mg, 1.44 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (180 mg, 1 mmol) were used to prepare the title compound. Preparative TLC (20 cm×20 cm×2 mm silica, eluted with 1%MeOH/CHCl3) was used to purify the material and yielded 275 mg of free base: GC/EI-MS, m/z (rel. int.) 398 (M+−15, 0.1), 293 (21), 292 (100), 163 (10), 121 (19), 114 (9), 91 (5), 90 (45), 71 (13), 70 (14), 58 (9).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].[C:10](#[N:12])C.CN.Cl.Cl.Cl[CH2:18][C:19]1[N:20]=[C:21]([CH2:24][N:25]([CH3:27])[CH3:26])[S:22][CH:23]=1>O>[CH3:10][NH:12]/[C:5](/[NH:9][CH2:8][CH2:7][S:6][CH2:18][C:19]1[N:20]=[C:21]([CH2:24][N:25]([CH3:27])[CH3:26])[S:22][CH:23]=1)=[CH:4]\[N+:1]([O-:3])=[O:2]
Reactant: CC#N
Reactant: O=[N+]([O-])C=C1NCCS1
Reactant: CN(C)Cc1nc(CCl)cs1
Agent: CN
Agent: Cl
Solvent: O
Product: CN/C(=C\[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1
Temperature: 40 °C
Yield: 70.6 %

Procedure:
A mixture of 2-nitromethylenethiazolidine (11.95 g) and acetonitrile (154 ml) was stirred and heated at 40° C. and then methylamine (31.7 ml of a 40% w/w aqueous solution) was added in one batch. A solution of 4-chloromethyl-2-dimethylaminomethylthiazole dihydrochloride (21.5 g) in water (21.5 ml) was added dropwise to the reaction mixture over 50 minutes. The mixture was then stirred for 2.5 hours and then the solvent was removed under reduced pressure to give an oil. The oil was dissolved in water (150 ml) and extracted with dichloromethane (3×150 ml). The combined extracts were dried and evaporated to give nizatidine (19.2 g, 70.6% yield). The crude material was 86.8% pure by HPLC.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[N:8]=[N:7]1)C.[OH-].[Na+]>CO.O>[OH2:3].[OH:17][C:13]1[CH:12]=[C:11]([C:9]2[N:8]=[N:7][N:6]([CH2:5][C:4]([OH:18])=[O:3])[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)Cn1cc(-c2cccc(O)c2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cn1cc(-c2cccc(O)c2)nn1
Reaction time: 24 h
Yield: 99 %

Procedure:
Ethyl[4-(3-Hydroxyphenyl)-1H-1,2,3-triazol-1-yl]acetate (Preparation 291, 27.2 g, 0.110 mol) was dissolved in methanol (200 mL), and a solution of NaOH (4.84 g, 121 mmol) in water (40 mL) was added. The solution was kept at room temperature for 24 hours. Methanol was evaporated in vacuo, water (120 mL) was added, and the solution was refluxed with activated charcoal. The mixture was filtered, and 11 M HCl was added to the filtrate. The mixture was dissolved by addition of water (120 mL) and cooled to carry out the crystallization. The crystals were filtered, washed with water (2×25 mL), and evaporated to dryness to afford the title compound as brown crystals (mp 186.3-188.7° C.) in 99.0% yield 23.9 g. MS m/z 218 [M−H]−
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH:12]=[CH:11][CH:10]=2)(O)[CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(O)(c2cccc3ccc(O)cc23)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CN1CC=C(c2cccc3ccc(O)cc23)CC1

Procedure:
A mixture of 1-(1-methyl-4-hydroxypiperidin-4-yl)-7-hydroxynaphthalene (7.64 g, 29.7 mmol) and p-toluenesulfonic acid (6.78 g, 35.7 mmol) in dioxane (250 mL) was refluxed overnight. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The naphthol product was extracted from this organic phase with 1N sodium hydroxide, 4N sodium hydroxide and then 1N sodium hydroxide. The combined basic aqueous phase was neutralized to pH 8 with saturated aqueous sodium bicarbonate and extracted with warm chloroform (3×, two phase mixture vigorously magnetically stirred while heat was applied by means of a hot plate.) The combined organic phase (still warm) was washed with brine, dried over calcium sulfate and concentrated to afford 5.01 g (83% for this step) of 1-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)-7-hydroxynaphthalene as a tan solid. A sample recrystallized from ethyl acetate had: mp 182.5°-184° C.; 1H NMR (250 MHz, CDCl3) δ 9.15 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.69 (d, J=9 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 7.25-7.12 (m, 2H), 7.03 (dd, J=2.5, 9 Hz, 1H), 5.70 (sym m, 1H), 3.32 (sym m, 2H), 2.92 (t, J=6 Hz, 2H), 2.70-2.60 (m, 2H), 2.66 (s, 3H). Analysis calculated for C16H17NO·0.25 H2O: C, 78.82; H, 7.23; N, 5.74. Found: C, 78.81; H, 7.21; N, 5.83.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=O.[N+:12]([CH2:15][C:16](OCC)=[O:17])([O-:14])=[O:13].N1CCCCC1>C(O)C>[N+:12]([C:15]1[C:16](=[O:17])[NH:1][C:2]2[C:3]([CH:4]=1)=[C:6]([CH3:11])[CH:7]=[C:8]([CH3:10])[N:9]=2)([O-:14])=[O:13]
Reactant: Cc1cc(C)c(C=O)c(N)n1
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c2cc([N+](=O)[O-])c(=O)[nH]c2n1

Procedure:
A mixture of 2-amino-4,6-dimethylnicotinaldehyde (2.40 g., 16 mmole), ethyl nitroacetate (5.12 g., 32 mmole), piperidine (336 mg., 4 mmole) and ethanol (4 ml.) is heated under reflux with stirring for an hour. The mixture then is cooled, treated with petroleum ether, the solid removed by filtration and recrystallized from methanol yielding 1.55 g. (44%) of product, m.p. 270°-272° C. (dec.). Following recrystallization from the same solvent the product melts at 272°- 274° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CC(C)(C)C(Cl)=O.[CH3:42][O:43][CH2:44][CH2:45][NH2:46].C(N(CC)CC)C>ClCCl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:33])([F:34])[F:32])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][C:28]([NH:46][CH2:45][CH2:44][O:43][CH3:42])=[O:29])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COCCN
Reactant: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCNC(=O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N—[[4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine (i.e. the title product of Step B) (100 mg) and pyridine (0.019 mL) in dichloromethane (3 mL) was added trimethylacetyl chloride (0.029 mL). The reaction mixture was stirred at room temperature for 2 h, and then 2-methoxyethylamine (0.11 mL) and triethylamine (0.68 mL, 5.0 mmol) were added. The reaction mixture was stirred at room temperature overnight, quenched with water, extracted with dichloromethane, washed with brine, dried with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate (3:2 to 1:4) as eluent to afford the title compound, a compound of the present invention, as a white solid (71 mg, 0.13 mmol, 65% yield).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]([C:33]4[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=4)[C:36]([O:38][CH2:39][C:40]4[O:41][C:42](=[O:46])[O:43][C:44]=4[CH3:45])=[O:37])[C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][CH:20]=3)[N:10]=[N:9]2)C=CC=CC=1.C(O)(=O)C.O>O1CCOCC1>[CH3:45][C:44]1[O:43][C:42](=[O:46])[O:41][C:40]=1[CH2:39][O:38][C:36](=[O:37])[C:35]1[CH:47]=[CH:48][CH:49]=[C:33]([N:26]([CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:11]3[NH:10][N:9]=[N:8][N:12]=3)=[CH:20][CH:21]=2)[C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH:34]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1)c1cccc(C(=O)OCc2oc(=O)oc2C)c1
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1cccc(C(=O)OCc2oc(=O)oc2C)c1
Temperature: 40 °C
Reaction time: 7 h
Yield: 61.8 %

Procedure:
To a solution of the obtained (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 3-[N-[[4-[2-(3-triphenylmethyl-3H-tetrazol-5-yl)phenyl]phenyl]methyl]-N-pentanoylamino]benzoate (11.57 g) in dioxane (80 ml) were added acetic acid (60 ml) and water (20 ml), and the mixture was stirred at 40° C. for 7 hrs. The reaction mixture was concentrated to give a solid, and the residue was purified by silica gel column chromatography (methylene chloride-methanol:10-1 v/v) to give the object compound (5.01 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:14])=[CH:5][C:6]([OH:13])=[N:7]2.[N:15]([O-])=[O:16].[Na+].OS(O)(=O)=O>[OH-].[Na+]>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[C:5](=[N:15][OH:16])[C:6](=[O:13])[NH:7]2
Reactant: Oc1cc(O)c2c(Cl)cc(Cl)cc2n1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2cc(Cl)cc(Cl)c2C(=O)C1=NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 147 mg (0.616 mmol) of 5,7-dichloro-2,4-quinolinediol and 126 mg (1.82 mmol) of NaNO2 in 3 mL of 0.2N NaOH in ice-bath was added dropwise 2 mL of aqueous 2N H2SO4. The mixture was stirred in ice-bath for 4 h after addition of H2SO4, filtered and dried to leave an orange solid. The solid was crystallized by boiling with 10 mL of ethanol (95% ). The solution was cooled to room temperature, filtered and dried to leave 132 mg (83%) of 5,7-dichloro-3-oximequinoline-2,4-dione as a yellow solid, mp 244°-245° C. (decomposed). 1H NMR (CDCl3 +DMSO-d6), 7.011 (d, 0.44, J=1.8) 7.080 (m, 1.54), 11.567 (sb, 0.35), 11.821 (s, 0.46). MS, 258 (100, M+), 241 (60), 214 (80), 187 (20), 160 (30). High resolution MS, Calcd for C9H435Cl2N2O3, 257.9595, found 257.9598.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([OH:16])=[C:9]([OH:17])[CH:8]=1)(=O)C>C(O)C.Cl>[OH:4][CH2:5][C:6]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([OH:16])=[C:9]([OH:17])[CH:8]=1)=[O:18]
Reactant: CC(=O)OCC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: O=C(CO)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A suspension of 2.6 g of (3,4-dihydroxy-5-nitrobenzoyl)methyl acetate in 20 ml of ethanol and 20 ml of 1N hydrochloric acid is heated to boiling under reflux for 5 hours. The reaction mixture is then evaporated, the residue is distilled with distilled with toluene and then recrystallized from ethanol. There is obtained 2,3',4'-trihydroxy-5'-nitroacetophenone of m.p. 208°-210°.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>CS(C)=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:26]3[CH2:27][CH2:28][CH2:29][CH:24]([CH3:23])[CH2:25]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: CC1CCCNC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CS(C)=O
Product: CC1CCCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccc(F)cc2)C1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.63 mmol, 1.00 equiv), 3-methylpiperidine (313 mg, 3.16 mmol, 5.00 equiv), DMSO (3 mL). The resulting solution was stirred for overnight at 110° C. in an oil bath. The reaction was then quenched by the addition of water. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solids were collected by filtration. The crude product (240 mg) was purified by Prep-HPLC under the following conditions (1#-UV1-SHIMADZU-SPD-20A): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (30% CH3CN up to 100% in 8 min, hold 100% in 1.5 min, down to 30% in 1 min); Detector, Gilson UV Detector 220 nm. This resulted in 75 mg (32%) of 2-(4-fluorophenyl)-3-(3-methylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28]CC3C=CC=CC=3)=[CH:24][CH:23]=2)=[O:20])=[CH:13][N:12]=1)=[O:10].C(OCC)(=O)C>[Pd].CO>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[O:20])=[CH:13][N:12]=1)=[O:10]
Reactant: Nc1ccccc1NC(=O)c1ccc(CN(CCCCCN2CCOCC2)C(=O)Nc2ccc(OCc3ccccc3)cc2)cn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC(=O)c1ccc(CN(CCCCCN2CCOCC2)C(=O)Nc2ccc(O)cc2)cn1
Yield: 84 %

Procedure:
Under a nitrogen atmosphere, 10% palladium on carbon (30 mg) was added to a solution of N-(2-aminophenyl)-5-[3-(4-benzyloxyphenyl)-1-[5-(morpholin-4-yl)pentyl]ureidomethyl]pyridine-2-carboxylic acid amide (Compound No. 1-182, 45 mg, 0.072 mmol) in a mixed solvent (ethyl acetate (2.0 mL) and methanol (3.0 mL)), and then the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. After the insoluble was filtered off with celite, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 32 mg of the title compound as a yellow oil. (Yield 84%)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32](Cl)=[C:27]3[CH:26]=[N:25]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:1][C:2]4[CH:10]=[CH:9][C:5]([C:6](=[O:7])[NH2:8])=[CH:4][CH:3]=4)=[C:27]3[CH:26]=[N:25]2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(C(N)=O)cc4)ncnc32)CC1
Temperature: 160 °C
Yield: 17.9 %

Procedure:
A mixture of 4-hydroxy-benzamide (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 13 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-carbamoyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (7 mg, 18%) as a white solid. Mass spectrum MH+=439.
Reaction SMILES: II.S(=O)(=O)(O)O.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I:16]([O-])(=O)=O.[Na+]>O.C(O)(=O)C>[I:16][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:15])=[CH:10][CH:11]=1
Reactant: OCc1ccccc1
Reactant: [O-][I+2]([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: OCc1ccc(I)cc1
Reaction time: 1 h

Procedure:
A solution of glacial acetic acid (1350 ml.) and iodine (250 g.) was heated to 100° and then concentrated sulfuric acid (140 ml. of 95-97%) added, followed by benzyl alcohol (216 g.). Sodium iodate (92 g.) in water (500 ml.) was then introduced dropwise with stirring over a period of 1 hour. The temperature was maintained at 100°-110° for an additional 30 minutes before the reaction mixture was poured onto 1 Kg. of crushed ice. The mixture was extracted with chloroform, the combined chloroform solution washed with water, dried, and concentrated. The remaining oil was distilled at reduced pressure to give p-iodobenzyl alcohol. A mass spectrum (70 ev) parent ion was measured at m/e 233.9545; calculated for C7H7IO, 233.9544. The ir and nmr spectrum were in agreement with the proposed structure. The use of a mass spectrum for identification of compounds is shown, for example, in R. Venkataraghaven, R. D. Broad, R. Klimowsky, J. W. Amy, and F. W. McLafferty, Adv. Mass Spec., 4, 65 (1967) and R. Venkataraghaven, R. J. Klimowsky, F. W. McLafferty, Acc. Chem. Res., 3, 158 (1970).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([Cl:15])[CH:7]=1>OS(O)(=O)=O>[Cl:5][C:6]1[C:11]([N+:1]([O-:4])=[O:3])=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([Cl:15])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Ml. 11.3 of fuming nitric acid (0.275 mole) in 96% H2SO4 (50 ml) was dropwise added under stirring at room temperature to 48 g of 1,3-dichloro-4-nitrobenzene (0.25 mole) in 96% H2SO4 (350 ml). The mixture was stirred for two hours, then poured into crushed ice. The separated solid was washed with cold water to neutrality, dried under vacuum and crystallized from ethanol (170 ml) to give the dinitro compound (A), 45.5 g, yield 76.8%, as yellow prisms.