Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH2:14][C:15]1([CH3:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:9])[N:14]([C:15]1([CH3:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:5]2=[O:7]
Reactant: CC1(N)CCC(=O)NC1=O
Reactant: Cc1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O

Procedure:
4-Methyl-2-(2,6-dioxo-3-methyl-(3-piperidyl))isoindoline-1,3-dione was prepared by the procedure of Example 1 from 3-methylphthalic anhydride (0.27 g, 1.7 mmol), 3-amino-3-methylpiperidine-2,6-dione hydrogen chloride (0.30 g, 1.7 mmol) and sodium acetate (0.15 g, 1.8 mmol) in acetic acid (10 mL). The product was a white solid (0.13 g, 27 % yield); mp, 248.0-250.0° C.; 1H NMR (DMSO-d6) δ1.89 (s, 3H, CH3), 2.01-2.08 (m, 1H, CHH), 2.49-2.70 (m, 3H, CHH, CH2), 2.55 (s, 3H, CH3), 7.62-7.74 (m, 3H, Ar), 10.99 (br s, 1H, NH); 13C NMR (DMSO-d6) δ17.0, 21.0, 28.6, 29.1, 58.6, 120.7, 127.5, 131.5, 134.2, 136.8, 137.2, 167.7, 168.6, 172.1, 172.3; Anal. Calcd. for C15H14N2O4+0.3 H2O: C, 61.77; H, 5.05; N, 9.60. Found: C, 62.05; H, 4.94; N, 9.20.
Reaction SMILES: [ClH:1].CCOCC.C(OC([N:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[C:22]([C@H:26]2[CH2:28][C@@H:27]2[CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH:23]=[N:24][CH:25]=1)=O)(C)(C)C>CO>[ClH:1].[NH:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[C:22]([C@H:26]2[CH2:28][C@@H:27]2[CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH:23]=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CCCCO)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: OCCCC[C@H]1C[C@@H]1c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2M anhydrous HCl/ether (2.0 mL) was added to a stirred solution of 4-[(1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]-1-butanol (200 mg, 0.53 mmol) in dry MeOH (2.0 mL) at 0° C. The mixture was stirred at room temperature for 12 h. The above solution was concentrated in vacuo and purified by HPLC to obtain 4-[(1S,2S)-2-[5-[(2(S)-azetidinyl)methoxy]-3-pyridyl]cyclopropyl]-1-butanol hydrochloride (128 mg). 1H NMR (CD3OD, 300 MHz) δ 8.25 (br s, 2H), 7.51 (s, 1H), 5.02-4.93 (m, 2H), 4.55-4.38 (m, 2H), 4.21-4.00 (m, 2H), 3.56 (t, 2H, J=6.2 Hz), 2.82-2.55 (m, 2H), 1.93-1.75 (m, 1H), 1.70-1.36 (m, 6H), 1.33-1.17 (m, 1H), 1.16-1.06 (m, 1H), 1.05-0.93 (m, 1H). MS (ESI) m/z 277 (M+H+).
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][C:4](=O)[CH2:5][CH3:6].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:5]([CH3:6])=[CH:4][CH:3]=[C:2]2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCC(=O)CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(N)(=O)=O)cc2)n1-c1ccc(F)cc1
Yield: 44.2 %

Procedure:
A mixture of 4-(1,3-dioxopentyl)benzenesulfonamide (160 mg, 0.63 mmol) of (Step 5), 4-fluoroaniline (65 μl, 0.69 mmol) and p-toluenesulfonic acid (6.7 mg) in toluene (25 ml) was heated at reflux for 20 hours. The reaction mixture was cooled, filtered and concentrated. The crude mixture (820 mg) was purified by chromatography (silica gel, toluene/ethyl acetate, 8/2) to give 4-[1-(4-fluorophenyl)-5-methyl-1H-pyrrol-2-yl]benzenesulfonamide (92 mg, 45%) as a white solid: mp 147-48° C. Anal Calc'd. for C17H15N2FSO2 : C, 61.14; H, 4.65; N, 8.39; S, 9.60. Found: C, 61.34; H, 4.70; N, 8.21; S, 9.63.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:15])=[CH:4][CH:3]=1
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Clc1nccc2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
7-Bromo-2H-isoquinolin-1-one (3.0 g, 13.4 mmol), phosphorus oxychloride (8.22 g, 53.6 mmol), and chloroform (25 mL) combined in a sealed tube and heated with stirring at 100° C. for 4 hours. Cooled to ˜60° C., poured into ice water (100 mL), neutralized carefully with saturated aqueous sodium hydrogencarbonate, extracted into methylene chloride and dried over magnesium sulfate. Flash column chromatography on silica gel gave the product as a pale cream solid (2.01 g, 8.3 mmol). 1H NMR (CDCl3) δ 8.51 (d, 1H), 8.30 (d, 1H), 7.82 (dd, 1H), 7.72 (d, 1H), 7.57 (dd, 1H). ESI MS (M+1)+: 242, 244, 246 (Br, Cl).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH:10][C:13]([NH:14][N+:15]([O-:17])=[O:16])=[NH:18])=[N:2]1
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCNCc1ccsn1
Product: N=C(NCCNCc1ccsn1)N[N+](=O)[O-]

Procedure:
Reaction of N-(3-isothiazolylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-[2-(3-isothiazolylmethylamino)-ethyl]-N'-nitroguanidine.
Reaction SMILES: C(O[C:4](=[O:42])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:41])[N:15]=[C:16]([NH:17][CH2:18][C@@H:19]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH:20][S:21]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:11]=2[CH:10]=[CH:9]1)C.[NH:43]1[CH2:48][CH2:47][CH2:46][N:45]=[C:44]1[NH2:49]>CN(C=O)C>[C:37]([O:36][C:34](=[O:35])[C@@H:19]([NH:20][S:21]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:22])=[O:23])[CH2:18][NH:17][C:16]1[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][CH2:5][C:4](=[O:42])[NH:49][C:44]3[NH:45][CH2:46][CH2:47][CH2:48][N:43]=3)[C:12]=2[N:13]=[C:14]([CH3:41])[N:15]=1)([CH3:38])([CH3:39])[CH3:40]
Reactant: CCOC(=O)CCCn1ccc2c(NC[C@H](NS(=O)(=O)c3cccc4ccccc34)C(=O)OC(C)(C)C)nc(C)nc21
Reactant: NC1=NCCCN1
Solvent: CN(C)C=O
Product: Cc1nc(NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)OC(C)(C)C)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 128 mg (0.215 mmol) of 4-{4-[(2S)-2-tert-butoxycarbonyl-2-(naphthalene-1-sulfonylamino)-ethylamino]-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl}-butyric acid ethyl ester (example 3b) in 1 ml of DMF was added 105 mg (1.05 mmol) of 1,4,5,6-tetrahydro-pyrimidin-2-ylamine and the reaction mixture was stirred at room temperature for 4.5 hours. The solvent was removed in vacuo and the residue was taken up in DCM and washed with a saturated NaCl solution. The organic phase was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with DCM/MeOH/AcOH/H2O (95:5:0.5:0.5). Yield: 72 mg.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:23]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:34]([N:36]1[C:40]([CH2:41]O)=[N:39][CH:38]=[N:37]1)[CH3:35].[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:23][CH2:41][C:40]3[N:36]([CH2:34][CH3:35])[N:37]=[CH:38][N:39]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2C2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nnc(C)c2c1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (230 mg, 0.494 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (75.6 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (22 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (34.5 mg, mp =105° C.). 1H NMR (360 MHz, CDCl3) δ 1.36 (3H, t, J=7.3 Hz), 1.53-1.91 (8H, m), 2.87 (3H, s), 3.41 (1H, m), 4.10 (2H, q, J=7.3 Hz), 5.45 (2H, s), 7.23-7.36 (2H, m), 7.58-7.75 (2H, m), 7.88 (1H, s); MS (ES+) m/e 422 [MH]+. Anal. Found C, 62.56; H, 5.67; N, 23.18%. C22H24FN7O requires C, 62.69; H, 5.74; N, 23.26%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)[CH3:2].Cl.C[OH:23]>[C].[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[OH:23])[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CO
Reactant: CCc1ccc(C(O)c2cccc(C(=O)OC)c2)cc1
Agent: [Pd]
Agent: Cl
Product: CCc1ccc(Cc2cc(C(=O)OC)ccc2O)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88 %

Procedure:
The thus obtained methyl 3-[(4-ethylphenyl)hydroxy-methyl]benzoate (2.88 g, 10.0 mmol), 10% palladium carbon (200 mg), concentrated hydrochloric acid (0.5 mL) and methanol (15 mL) were mixed and stirred under a hydrogen atmosphere at room temperature for 14 hours. After filtration to remove the insoluble materials, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to give methyl 3-(4-ethylbenzyl)-4-hydroxybenzoate (2.38 g, 88%) as a colorless powder.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:25])([CH2:23]Cl)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>C(#N)C>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:25])([CH2:23][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(CCl)(Cc1ccc(Cl)cc1Cl)c1ccc(C2CCCCC2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: OC(Cc1ccc(Cl)cc1Cl)(Cn1ccnc1)c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Yield: 58 %

Procedure:
A solution of 39.8 g (0.1 mol) of 2-(4-cyclohexylphenyl)-3-chloro-1-(2,4-dichlorophenyl)-propan-2-ol in 200 ml of acetonitrile is added dropwise to a suspension of 3.6 g (0.12 mol) of sodium hydride and 8.2 g (0.12 mol) of imidazole in 200 ml of acetonitrile. After heating the mixture to 80° C. for three hours, it is filtered and the crystal mass is washed with water and recrystallised from acetonitrile. 24.9 g (58% of theory) of 2-(4-cyclohexylphenyl)-1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-propan-2-ol of melting point 142° C. are obtained.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.O>CN(C)C=O>[CH2:1]([S:3][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCS
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Ethanethiol (6.11 ml, 0.082 mol) was added slowly to a suspension of sodium hydride (3.3 g, 60% dispersion) in dry dimethylformamide (225 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 15 min before the addition of 1-chloro-4-nitrobenzene (10 g, 0.063 mol) dissolved in dry dimethylformamide (25 ml). After addition, the resultant mixture was allowed to warm to 60° C. and was stirred for 24 hr. The mixture was then concentrated in vacuo to yield a yellow oil. Ice and water were added and a yellow solid was precipitated and filtered off. The solid was then dissolved in methanol (100 ml) and insoluble by-products were isolated by filtration. The filtrate was then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was then dried (MgSO4) and concentrated in vacuo to afford 1-(ethylthio)-4-nitrobenzene as a yellow solid. δ(1H NMR, DMSO, ppm): 1.15 (3H, t), 3.05 (2H, q) 7.45 (2H, d), 8.10 (2H, d)
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:8]2[CH:9]=[C:5]([C:3]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:4])[NH:6][N:7]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: C1COCCN1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)N2CCOCC2)[nH]n1
Yield: 51 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using morpholine instead of 4-aminotetrahydropyran, to the title compound (61 mg, 51%) which was obtained as a colorless oil. MS: m/e=349.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:58]1([NH2:64])[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:64][N:58]5[CH2:63][CH2:62][O:61][CH2:60][CH2:59]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: NN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and morpholin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.41 (m, 2H) 1.59-1.86 (m, 8H) 2.94 (br. s., 4H) 3.31 (s, 3H) 3.67 (br. s., 4H) 3.94 (s, 3H) 4.16 (t, 2H) 4.38-4.54 (m, 1H) 7.45 (d, J=8.7 Hz, 1H) 7.48 (s, 1H) 8.14 (d, 1H) 8.23 (s, 1H) 8.57 (br. s., 1H) 9.57 (s, 1H). [M+H] calc'd for C26H33F2N7O4 546. found 546.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[C:16]2[C:17](=[O:31])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:15]=2[NH:14][N:13]=1)([O-])=O>CN(C=O)C.CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[C:16]2[C:17](=[O:31])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:15]=2[NH:14][N:13]=1
Reactant: O=c1c2c(CCc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccccc1CCc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Reaction time: 8 h
Yield: 8.7 %

Procedure:
To a solution of 3-[2-(2-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (420 mg, 11.0 mmol, prepared in Example 16) in DMF (45 ml) and methanol (20 ml) was added activated carbon-palladium (45 mg), and the mixture was stirred overnight under hydrogen atmosphere, and filtered. After methanol was distilled off, the resultant solution was admixed with water, and filtered to give precipitates which were dried to afford 3-[2-(2-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (364 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[S:3][N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[OH:11][S:12](O)(=[O:14])=[O:13]>CC(C)=O>[NH2:1][C:2]1[S:3][N:4]=[C:5]2[C:10]([S:12]([OH:14])(=[O:13])=[O:11])=[CH:9][CH:8]=[CH:7][C:6]=12
Reactant: Nc1snc2ccccc12
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Product: Nc1snc2c(S(=O)(=O)O)cccc12

Procedure:
A solution of 10.0 g. of 3-amino-2,1-benzisothiazole in 100 g. of concentrated H2SO4 was heated at 50°-55° C. for one-half hour, then cooled and added to 500 ml. of cold acetone. The product was removed by filtration and then reprecipitated from bicarbonate solution by addition of sufficient acetic acid to give a pH of 4.75-4.80. 8.5 Grams of purified 3-amino-2,1-benzisothiazole-7-sulfonic acid product was obtained.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:22])=[O:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1

Procedure:
Under an argon atmosphere, to a solution of 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetic acid (9) (2.12 g, 7.96 mmol) in CH2Cl2 (10 mL) was added DMF (3 drops) by a Pasteur pipette at room temperature. To this was added oxalyl dichloride (1.35 mL, 16.0 mmol) at 0° C. and the mixture was stirred for an hour while elevating to room temperature. The mixture was concentrated under reduced pressure to give crude 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) as a colorless oil, which was used in the following reaction without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O>COCCOC.O>[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(I)cc1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)/C=C(\C)c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Tetrakis(triphenylphoshine)palladium(0) (0.69 g, 0.60 mmol, 6 mol %) was added, under nitrogen, to a stirred solution of (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (3.16 g, 10.0 mmol) in DME (100 ml), and the resulting orange coloured solution stirred at room temperature for 10 min. Aqueous 2M sodium carbonate (30.0 ml, 60.0 mmol) was then added, the mixture stirred for 10 min, then furan-2-boronic acid (2.25 g, 20.11 mmol) was added, and the reaction mixture heated to 80° C. for 20 h, under reflux. The reaction mixture was cooled, diluted with water (100 ml) and the products extracted into ethyl acetate (3×100 ml). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give the crude product, which was purified by column chromatography on silica gel (3% diethyl ether in n-heptane eluent) to give the product, (E)-ethyl 3-(4-furan-2-yl-phenyl)-but-2-enoate as an off-white solid; 2.46 g (96%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][C:7]2=[O:18])(=[O:3])[CH3:2].[CH3:19][Mg]Br>O1CCCC1.C(OCC)C>[CH2:14]([C:9]1[NH:10][C:11]2[C:6]([C:7](=[O:18])[N:8]=1)=[CH:5][C:4]([C:1]([OH:3])([CH3:19])[CH3:2])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCc1nc(=O)c2cc(C(C)(C)O)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.00 g 6-acetyl-2-butyl-4-(1H)-quinazolinone in 250 ml of dry tetrahydrofuran, cooled to 0° C., is added dropwise 16.4 ml of 3.0M methylmagnesium bromide in diethyl ether. The reaction is stirred at 0° C. for 0.5 hours and then allowed to warm to room temperature followed by quenching with 100 ml of saturated ammonium chloride solution. The mixture is diluted with 50 ml of water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 100:0.25 chloroform-methanol to give 2.75 g of the desired product as a white solid. CI MASS SPEC 261(MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:25])=[CH:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc(NC(=O)C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
4-(4-Isopropyl-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.68 g) was dissolved in methylene chloride (50 ml), trifluoroacetic acid (2.75 g) was added at 0° C. and under an argon atmosphere and the mixture was stirred for 12 h at RT. Further trifluoroacetic acid (1.1 g) was added and stirring was continued for 1.5 h to complete the reaction. The reaction mixture was partitioned between methylene chloride and aqueous 1M NaOH, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue was triturated with diethyl ether/heptane to give the desired piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide (1 g) as a white solid that was directly used in the next step.
Reaction SMILES: [CH:1]([CH:3]1[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6][CH2:5][CH2:4]1)=[O:2].[H-].[Na+].[CH3:19]I>O1CCCC1>[CH:1]([C:3]1([CH3:19])[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6][CH2:5][CH2:4]1)=[O:2]
Reactant: Cn1c2c(c3ccccc31)SCCC2C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c2c(c3ccccc31)SCCC2(C)C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.1 %

Procedure:
A solution of 4-formyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (2.31 g) in dry tetrahydrofuran (25 ml) is mixed with 50% sodium hydride (480 mg) and stirred at room temperature for 1.5 hours. Under ice cooling, a solution of methyl iodide (1.7 g) in dry tetrahydrofuran (5 ml) is added dropwise thereto over 5 minutes. The mixture is stirred further for 1.5 hours at room temperature and poured into ice water, which is extracted with ether. The extract is washed with water, dried and evaporated to dryness. The residue is applied to liquid chromatography eluted with benzene/hexane (5:1) to give the title compound (1.62 g): Yield 66.2%.