Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:11])[C:5](=[CH2:10])[C:6]([O:8]C)=[O:7].COC1C=C(OC)C=CC=1C[NH2:18]>C1(C)C=CC=CC=1>[CH3:11][CH:4]1[C:3](=[O:2])[NH:18][CH2:10][CH:5]1[C:6]([OH:8])=[O:7]
Reactant: C=C(C(=O)OC)C(C)C(=O)OC
Reactant: COc1ccc(CN)c(OC)c1
Solvent: Cc1ccccc1
Product: CC1C(=O)NCC1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 174.1 %

Procedure:
To a solution of 2-methyl-3-methylenesuccinic acid dimethyl ester (9.81 g) in toluene (100 ml) was added 2,4-dimethoxybenzylamine (9.72 g) and the mixture was stirred for 3 days at reflux. This reaction solution was cooled to room temperature and then purified by silica gel column chromatography (eluent: n-hexane/chloroform=1/1 to 0/1) to give the titled compound (14.2 g).
Reaction SMILES: OO.[Si]([O:10][CH2:11][CH:12]1[CH2:27][C:26]2[C:14](=[CH:15][C:16]3[N+:21]([O-:22])=[N:20][C:19]([CH2:23][CH3:24])=[N:18][C:17]=3[CH:25]=2)[CH2:13]1)(C(C)(C)C)(C)C.CC(O)=[O:30].O>CO.CCN(CC)CC>[CH2:23]([C:19]1[N:20]=[N+:21]([O-:22])[C:16]2[CH:15]=[C:14]3[C:26]([CH2:27][CH:12]([CH2:11][OH:10])[CH2:13]3)=[CH:25][C:17]=2[N+:18]=1[O-:30])[CH3:24]
Reactant: CC(=O)O
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CO[Si](C)(C)C(C)(C)C)C3
Agent: OO
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(CO)C3
Temperature: 80 °C
Reaction time: 20 h
Yield: 18 %

Procedure:
H2O2 (70%, 1.5 mL, ca. 30.0 mmol) was added dropwise to a stirred solution of 1-oxide 135 (273 mg, 0.76 mmol) and HOAc (6 mL) at 50° C. and the reaction was stirred at 80° C. for 20 h. The mixture was cooled, water (50 mL) was added and the mixture was extracted with DCM (5×50 mL). The combined organic fraction was dried and the solvent evaporated to give a yellow oil which was treated with Et3N (3 mL) in MeOH (20 mL) at 20° C. for 66 h. The solvent was evaporated and the residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 136 (35 mg, 18%) as a yellow solid: mp (MeOH/DCM) 157-158° C.; 1H NMR δ 8.31 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.72 (br d, J=5.8 Hz, 2H, CH2O), 3.25-3.35 (m, 2H, CH2), 3.20 (q, J=7.5 Hz, 2H, CH2), 3.00-3.10 (m, 2H, CH2), 2.81-2.92 (m, 1H, H-7H), 1.43 (t, J=7.5 Hz, 3H, CH3), OH not observed; HRMS calcd for C13H15N3O3 (M+) m/z 261.1113, found 261.1115. Anal. calcd for C13H15N3O3: C, 59.8; H, 5.8; N, 16.1. Found: C, 59.6; H, 5.9; N, 15.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([CH2:13][C:14](Cl)=[O:15])=[N:9]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH:25]([C:28]1[N:29]=[C:30]([CH2:33][CH2:34][C:35]2[CH:51]=[CH:50][N:38]3[C:39](=[O:49])[CH:40]=[C:41]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[N:42]=[C:37]3[CH:36]=2)[S:31][CH:32]=1)([CH3:27])[CH3:26]>C(Cl)Cl>[CH:25]([C:28]1[N:29]=[C:30]([CH2:33][CH2:34][C:35]2[CH:51]=[CH:50][N:38]3[C:39](=[O:49])[C:40]([C:14](=[O:15])[CH2:13][C:10]4[N:11]=[N:12][N:8]([CH2:7][C:6]5[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[N:9]=4)=[C:41]([N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[N:42]=[C:37]3[CH:36]=2)[S:31][CH:32]=1)([CH3:27])[CH3:26]
Reactant: COc1ccc(Cn2nnc(CC(=O)Cl)n2)cc1
Reactant: CC(C)c1csc(CCc2ccn3c(=O)cc(N4CCOCC4)nc3c2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Cn2nnc(CC(=O)c3c(N4CCOCC4)nc4cc(CCc5nc(C(C)C)cs5)ccn4c3=O)n2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 7.8 %

Procedure:
The 2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]ethanoyl chloride (0.27 g, 1.05 mmol) obtained in (C) was dissolved in methylene chloride (3 ml), added dropwise with pyridine (170.2 μl, 2.10 mmol) under ice cooling, and added dropwise with a solution of 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4 H-pyrido-[1,2-a]pyrimidin-4-one (80.9 mg, 0.21 mmol) in methylene chloride (3 ml). The reaction solution was stirred at room temperature for 23 hours, then further added with a solution of 2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]ethanoyl chloride (0.27 g, 1.05 mmol) in methylene chloride (2 ml) and pyridine (170.2 μl, 2.10 mmol) under ice cooling. Further, the reaction solution was added with the same amounts of the acid chloride and pyridine twice every 24 hours, and stirred at room temperature. The solvent was evaporated, and the residue was added with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by preparative TLC (hexane:ethyl acetate=1:1, v/v and chloroform:methanol=30:1, v/v) to obtain the title compound (10.1 mg, 7.8%) as yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@:7]([CH3:43])([CH2:41][OH:42])[C:8](=[O:40])[C@@H:9]([NH:17][C:18](=[O:39])[C@@H:19]([NH:23][C:24](=[O:38])[C@@H:25]([NH:29][C:30]([C:32]1[S:36][C:35]([CH3:37])=[N:34][CH:33]=1)=[O:31])[CH2:26][O:27][CH3:28])[CH2:20][O:21][CH3:22])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][S:2]([O:42][CH2:41][C@:7]([OH:6])([CH3:43])[C:8](=[O:40])[C@@H:9]([NH:17][C:18](=[O:39])[C@@H:19]([NH:23][C:24](=[O:38])[C@@H:25]([NH:29][C:30]([C:32]1[S:36][C:35]([CH3:37])=[N:34][CH:33]=1)=[O:31])[CH2:26][O:27][CH3:28])[CH2:20][O:21][CH3:22])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(C)(=O)=O

Procedure:
Prepared according to procedures described above, by reacting methanesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C26H36N4O10S2 m/z: 629 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:13][C:14]2[C:22]3[N:21]=[C:20]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[N:19]([CH2:32][CH2:33][CH2:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[C:47]1([CH2:53][CH2:54][CH2:55]Br)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C)C=O>[CH:8]1([O:13][C:14]2[C:22]3[N:21]=[C:20]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[N:19]([CH2:32][CH2:33][CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([CH2:55][CH2:54][CH2:53][C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)[CH2:37][CH2:36]4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Clc1ccc(OCc2nc3c(OC4CCCC4)cccc3n2CCCC2CCNCC2)cc1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2nc3c(OC4CCCC4)cccc3n2CCCC2CCN(CCCc3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-cyclopentoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate (0.29 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by column chromatography to yield the title product as a white crystalline solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11](=[O:30])[C:10]=2[C:9]=1[O:31][CH3:32])=[O:7].[CH3:33][C:34]([CH3:36])=O.CN(C=O)C.C([BH3-])#N.[Na+]>CO.C(=O)([O-])O.[Na+]>[CH3:32][O:31][C:9]1[C:10]2[C:11](=[O:30])[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[S:20][C:8]=1[C:6]([NH:5][CH2:4][CH2:3][NH:2][CH:34]([CH3:36])[CH3:33])=[O:7]
Reactant: CC(C)=O
Reactant: COc1c(C(=O)NCCN)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CN(C)C=O
Solvent: CO
Product: COc1c(C(=O)NCCNC(C)C)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
To a mixed solution of the compound of Example 61 (150 mg, 0.32 mmol) and acetone (0.2 mL) in methanol (5 mL)-DMF (5 mL) was added sodium cyanoborohydride (20 mg, 0.32 mmol), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate), and the obtained white solid was recrystallized from ethyl acetate-hexane to give the title compound (69 mg, 45%) as white crystals.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(O[C:44]([N:46]1[CH2:52][CH2:51][CH2:50][N:49]([C:53](=O)[CH2:54]Cl)[CH2:48][CH2:47]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:54][CH2:53][N:49]2[CH2:50][CH2:51][CH2:52][N:46]([CH3:44])[CH2:47][CH2:48]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)CCl)CC1
Product: CCN(Cc1ccc(OCCN2CCCN(C)CC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 43.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-chloroacetyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.4 mg) was obtained.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)(=O)=O.[CH:36]([NH:39][CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]>>[CH:36]([N:39]([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)[CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]
Reactant: CC(C)NC(C)C
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CC(C)N(c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1)C(C)C

Procedure:
2-(Methylsulfonyl)-4-(3,4-difluorobenzyloxy)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 6, 55 mg, 0.10 mmol) was reacted in neat diisopropyl amine heated at 150° C. overnight in a stainless steel pressure bottle by the general procedure described in Example 31, Step A. Workup (excess isopropyl amine removed under reduced pressure) and flash column chromatography on silica gel (eluted with 97/3 hexanes/ethyl acetate) afforded the title compound. HPLC: Rt=4.22 min. 1H-NMR 500 MHz (CDCl3): δ 1.28 (d, J=6 Hz, 6H), 4.217 (q, J=6 Hz, 1H), 5.39 (s, 2H), 7.04 (d, J=8 Hz, 2H), 7.08-7.14 (m, J=2H), 7.17 (m, 5H), 7.31 (d, J=2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N+:12]([O-:36])[CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][C:20]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)([OH:22])[CH2:19]1)=[O:17].Cl.[O:38]1CCO[CH2:40][CH2:39]1>CO>[C:39]([O:22][C:20]1([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)[CH2:21][N:18]([C:16]([C:15]2[CH:14]=[CH:13][N+:12]([O-:36])=[CH:11][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:17])[CH2:19]1)(=[O:38])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2cc[n+]([O-])cc2Nc2ccc(I)cc2F)C1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: CC(=O)OC1([C@@H]2CCCCN2)CN(C(=O)c2cc[n+]([O-])cc2Nc2ccc(I)cc2F)C1
Yield: 65.6 %

Procedure:
1,1-Dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (57 mg, 0.093 mmol) was dissolved in methanol (2 mL) and treated with 4N hydrochloric acid in dioxane (0.25 mL, 1 mmol) at 50° C. for 2.25 hours. The mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol acetate (35 mg, 0.061 mmol, 66% yield): 1H NMR (400 MHz, d6-DMSO): 7.83 (s, 1H), 7.72 (dt, 2H), 7.55-7.51 (m, 1H), 7.47-7.41 (m, 1H), 7.24 (t, 1H), 4.45-4.32 (m, 1H), 4.14-3.95 (m, 2H), 3.72 (d, 1H), 2.97 (d, 1H), 2.58-2.43 (m, 2H), 1.80-1.73 (m, 1H), 1.67-1.55 (m, 1H), 1.49 (br d, 1H), 1.38-1.16 (m, 2H), 1.16-1.01 (m, 1H); MS (EI) for C20H22FIN4O3: 513 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][C:20]#[N:21])[CH2:15][CH:16]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:15][CH:16]=1
Reactant: N#CCCCN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCCCCN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Yield: 87.1 %

Procedure:
To a solution of 5-fluoro-3-[1-(3-cyanopropyl)-1,2,3,6-tetrahydropyridin-4-yl]indole (10 g, 35 mmol) in 300 ml of dry THF was added slowly LiAlH4 (2.0 g ). The mixture was stirred and heated to reflux for 2 h. Then the reaction mixture was cooled and water (1.9 ml) in THF (10 ml) was added slowly, followed by 2N sodium hydroxide (1.9 ml). This mixture was heated to reflux for 0.25 h , filtered over hyflo and concentrated to give 8.76 g (88%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14](C(=O)C)[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1>Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCC(c2n[nH]c3cc(F)ccc23)CC1
Agent: Cl
Product: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Temperature: -78 °C
Reaction time: 24 h
Yield: 117.4 %

Procedure:
A solution of 1-[4-(6-fluoro-1H-indazol-3-yl)-piperidin-1-yl]-ethanone (0.60 g, 2.3 mmol) in 4 mL of 6 N HCl was stirred at reflux for 6 hours. It was frozen at −78° C. and lyophilized for 24 hours to yield the title compound as a white solid (0.61 g, 2.7 mmol, >99% yield). MS (ESI) m/z 219.9 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 0.96 min.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].N1C=CC=CC=1.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[C:20]([O:8][C:7]1[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9])(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
In 50 ml of toluene, 16.5 g (90 mmol) of pentafluorophenol and 8 ml (99 mmol) of pyridine were dissolved. To the solution, 12.9 g (94 mmol) of ethyl chloroglyoxylate were added dropwise under an ice bath for the reaction. After 1 hour stirring at room temperature, the reaction mixture was filtered and concentrated. The thus obtained crude product was refined by distillation to obtain 13.5 g of pentafluorophenyl ethyl oxalate (colorless liquid). The compound had a melting point of 70 to 71° C./2 mmHg.
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)(=O)C=C>C(Cl)Cl>[C:2]1([CH2:1][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: C=CC(N)=O
Solvent: ClCCl
Product: c1ccc(Cc2ccccc2)cc1

Procedure:
To a solution of benzhydrol (184 mg, 1 mmol) in methylene chloride (1 mL) is added 0.2 g 85 weight percent HF/15 weight percent acrylamide polymer, 175,000 m. wt., and the solution stirred until complete by TLC. The liquid is decanted and the gel washed with 2×1 mL methylene chloride. The organic layers are combined and washed with 1 mL water, 1 mL NaHCO3, dried through MgSO4 and evaporated. Diphenylmethane is afforded.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C([O-])(=O)C.[Na+].Cl.[NH2:14][CH:15]1[C:27]2[N:26]3[CH:28]=[CH:29][N:30]=C3[C:24](=[O:31])[NH:23][C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2.C>CN(C)C=O.C(O)=O>[CH:24]([NH:23][CH:22]1[C:27]2[N:26]3[CH:28]=[CH:29][N:30]=[C:6]3[C:5](=[O:7])[NH:14][C:15]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]1=2)=[O:31]
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: O=CNC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of 21.4 g of acetic anhydride and 11.5 g of formic acid is heated for 2 hours at a temperature between 50° C. and 60° C., and cooled to 20° C. 0.9 g of anhydrous sodium acetate is then added followed, after dissolution, by 2.75 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride. The mixture is stirred for 1 hour at 20° C. and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 50° C. The product obtained (4.3 g) is dissolved in 50 ml of dimethylformamide and, after addition of decolorizing charcoal, the solution is filtered. 200 ml of distilled water are then added to the filtrate and the mixture is stored for 1 hour at a temperature in the region of 5° C. The insoluble product formed is isolated by filtration, washed with 10 ml of distilled water and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 1.2 g of 10-formamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, melting at 280° C. (decomposition) (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 6.22 (d, J=8.5 Hz, 1H: --CH-- 10); 7.36 and 7.45 (2 broad t, J=8 Hz, 2H: --H 7 and --H 8); 7.51 and 7.87 (2 broad d, J=8 Hz, 2H: --H 6 and --H 9); 7.58 and 7.64 (2s, 1H each: --H of the imidazole); 8.44 (s, 1H: --CH=O); 8.78 (d, J=8.5 Hz, 1H: --CONH at 10); 12.50 (broad s, 1H: --CONH-- of the ring)).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17][CH3:18])[CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(C)=O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17][CH3:18])[CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([O:19][CH2:26][CH:28]2[CH2:29][O:30]2)[CH:3]=1
Reactant: ClCC1CO1
Reactant: COc1cccc2c(=O)c3c(O)cc(O)cc3oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc2c(=O)c3c(O)cc(OCC4CO4)cc3oc12
Temperature: 57.5 °C
Yield: 32.1 %

Procedure:
A mixture of 1,3-dihydroxy-5-methoxy-9H-xanthen-9-one (1.13 g, 4.39 mmol) prepared in Step 1 of Example 1 and K2CO3 (1.52 g, 10.98 mmol) in anhydrous acetone (25 mL) was charged to a dry round-bottom flask, and epichlorohydrin (1.73 mL, 21.95 mmol) was added thereto, followed by stirring under reflux at a temperature of 55 to 60° C. for 6 hours. Solid of the reaction mixture was filtered, and the solvent was removed under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1 (v/v)) to give the title compound (443.2 mg, 32%) as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][CH2:23][OH:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:27]([N:29]=C=O)=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[C:27](=[O:28])([O:24][CH2:23][CH2:22][N:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[NH2:29]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCO
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCOC(N)=O
Reaction time: 2 h

Procedure:
To a solution of Example 60A (110 mg, 0.298 mmol) in CH2Cl2 (2 mL) was added trichloroacetyl isocyanate (67.4 mg, 0.358 mmol) and the mixture was stirred for 2 hr. The reaction was concentrated and dissolved in methanol (0.5 mL). A solution of potassium carbonate (140 mg, 1.013 mmol) in water was added and the mixture was stirred for 24 hr. The reaction was concentrated, partitioned between ethyl acetate (3×10 mL) and water (10 mL). The organics were combined, dried, filtered, concentrated and the residue was triturated with CH2Cl2 and hexane (1:3). The solid was collected by filtration (80 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (s, 9 H) 3.79 (s, 3 H) 4.29-4.38 (m, 4 H) 6.55 (s, 1 H) 7.10 (d, J=9.12 Hz, 1 H) 7.19 (s, 1 H) 7.44 (dd, J=9.12, 2.78 Hz, 1 H) 7.67 (d, J=2.78 Hz, 1 H); MS (DCI) m/z 412 (M+H)+. Anal calcd C18H22ClN3O4S.0.5H2O: C, 51.36; H, 5.51; N, 9.98. Found: C, 51.23; H, 5.33; N, 9.92.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CO>[CH2:20]([NH:22][C:23](=[O:24])[O:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1)[CH3:21]
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3O)cc1
Reactant: CCN=C=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCNC(=O)OC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
A cooled (0° C.) solution of (rac)-4-(8-hydroxy-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 11) (50 mg, 200 μmol) in CH2Cl2 (1.4 mL) was treated with ethyl isocyanate (24.8 μL, 300 μmol) and Et3N (24.8 μL, 300 μmol). After stirring 1 night at room temperature and 1 h at reflux again ethyl isocyanate (24.8 μL, 300 μmol) and Et3N (24.8 μL, 300 μmol) were added. The solution was refluxed for 9 h, treated again with ethyl isocyanate (24.8 μL, 300 μmol), Et3N (24.8 μL, 300 μmol) and DMAP (2.4 mg, 20 μmol). After 1 night at room temperature MeOH (2 mL) was added. The reaction mixture was poured on aq. sat. NaHCO3 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. sat. NaCl solution. The combined organic phases were dried (Na2SO4), filtered and purified by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH 1%). Precipitation from CH2Cl2 with n-pentane gave the title compound (33 mg, 51%) as off-white foam. MS: 322.2 (M+H+).