Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20]Cl)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:22][N:23]3[C:27](=[O:28])[C:26]4[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:33])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(O)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)Cn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
A solution of 1-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (1.00 g, 3.28 mmol) in DMF (3.0 mL) was added to a solution of N-hydroxyphthalimide (642 mg, 3.94 mmol) and triethylamine (0.915 mL, 6.56 mmol) in DMF (3.0 mL). The flask containing the solution of 1-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol was rinsed with DMF (3.0 mL), which was added to the reaction solution. The solution was stirred at room temperature for 3 hours and a solid formed. The solid was isolated by filtration, washed with dichloromethane, and dried. The off-white solid was dissolved in hot DMF (20 mL). Acetonitrile (50 mL) was added to the solution, which was then placed in a freezer. Crystals formed and were isolated by filtration, washed with acetonitrile, and dried to provide 288 mg of 2-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-1H-isoindole-1,3(2H)-dione as orange crystals, mp 270-272° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]([C:28](F)(F)F)=O.[CH2:32]([O:39][N:40]1[C:46](=[O:47])[N:45]2[CH2:48][C@H:41]1[CH2:42][CH2:43][C@H:44]2[C:49]([NH:51][NH2:52])=[O:50])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([NH:52][NH:51][C:49]([C@@H:44]1[CH2:43][CH2:42][C@@H:41]2[CH2:48][N:45]1[C:46](=[O:47])[N:40]2[O:39][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:50])(=[O:25])[CH3:28]
Reactant: O=C(O)C(F)(F)F
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
HATU (0.90 g, 2.48 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide TFA salt (1.0 g, 2.48 mmol), acetic acid (0.12 g, 2.07 mmol) and DIPEA (1.1 g, 8.3 mmol) in dry DMF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The mixture was then quenched with saturated sodium chloride (50 mL) and exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10:1 to 1:10 petroleum ether/EtOAc) to afford (2S,5R)—N′-acetyl-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (0.6 g, 73%). ESI-MS (EI+, m/z): 333 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2([C:10]#N)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-:14].[Na+].C[OH:17]>>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2([C:10]([OH:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: [OH-]
Reactant: N#CC1(Cc2ccc(Br)cc2)CC1
Agent: [Na+]
Product: O=C(O)C1(Cc2ccc(Br)cc2)CC1

Procedure:
1-(4-Bromo-benzyl)-cyclopropanecarbonitrile (from the previous step) was dissolved in MeOH and NaOH (35% aq.) and the reaction was heated to reflux for 8 hours. After cooling the reaction was submitted to standard acid-base workup to afford the title compound.
Reaction SMILES: C[C:2]1([OH:19])[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[C:9]4[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=4[S:7][CH2:6][C:5]=3[C:4]=2[CH2:3]1.[CH3:20]CN(CC)CC.[C:27]([C:31]([C:34]([C:37]([S:40](F)(=[O:42])=[O:41])([F:39])[F:38])([F:36])[F:35])([F:33])[F:32])([F:30])([F:29])[F:28].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:20][N:11]1[C:10]2[C:9]3[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=3[S:7][CH2:6][C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([O:19][S:40]([C:37]([F:39])([F:38])[C:34]([F:36])([F:35])[C:31]([F:33])([F:32])[C:27]([F:30])([F:29])[F:28])(=[O:42])=[O:41])[CH:3]=2
Reactant: CC1(O)C=Cc2[nH]c3c(c2C1)CSc1ccccc1-3
Reactant: CCN(CC)CC
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cn1c2c(c3cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc31)CSc1ccccc1-2
Temperature: 25 °C

Procedure:
To a solution of 8-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (180 mg, 0.711 mmol) in CH2Cl2 (20 mL), Et3N (129 μL, 0.924 mmol) was added dropwise followed by CF3(CF2)3SO2F (153 μL, 0.853 mmol) at 0° C. The reaction mixture was slowly warmed up to 25° C. over 2 hours. Then CH2Cl2, water, and saturated aqueous NaHCO3 solution were added to the mixture. The aqueous layer was extracted with CH2Cl2 and the organic layers were washed with brine, dried, and concentrated. Flash chromatography purification (12% EtOAc/Hexane) was used to yield the title as a white solid.
Reaction SMILES: [H-].[Na+:2].CN(C=O)C.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)=[O:11].[H][H]>>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O-:18])=[CH:14][CH:13]=1)([O:9][CH3:8])=[O:11].[Na+:2]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([O-])cc1
Temperature: 0 °C

Procedure:
The (alkylthio)benzoic acids set forth in Table 2 are prepared according to the following general procedure: To a suspension of sodium hydride (one equivalent, 50% dispersion in mineral oil) in DMF (100 ml per 50 mmole), cooled to 0° C., is added slowly methyl p-hydroxybenzoate (one equivalent). The reaction mixture is stirred under a nitrogen atmosphere until the evolution of hydrogen ceases. To the solution of sodium 4-carbomethoxyphenolate so produced, is added N,N-dimethylthiocarbamoyl chloride [(CH3)2N(CS)Cl] (one equivalent) in one portion. The resulting suspension is heated to 70° C. for 1-3 hours and then is poured into an aqueous solution (1%) of potassium hydroxide (large excess). The suspension is extracted twice with toluene-hexane (4:1 v/v). After drying over MgSO4, the organic extracts are filtered and evaporated to an oil. The oil is purified by chromatography over silica gel using 2% methanol in methylene chloride to give O-(4-carbomethoxyphenyl)dimethylthiocarbamate [p-CH3CO2C6H4O (CS)N(CH3)2 ]. (mp 97°-102° C.). This product is heated under a nitrogen atmosphere at 220° C. for 30-60 min. to give S-(4-carbomethoxyphenyl)dimethylthiocarbamate [p-CH3CO2C6H4S(CO)N(CH3)2 ] which is crystallized from methanol. To S-(4-carbomethoxyphenyl)dimethylthiocarbamate, dissolved in DMSO, is added 2 equiv. of sodium hydroxide (10% aqueous). The mixture is heated at 65°-85° C., and the alkyl bromide (1 equiv.) is added. Heating is continued for 2-4 hours after which the mixture is poured into a large volume of water. Upon acidification, a precipitate forms, which is collected by filtration. The (alkylthio)benzoic acid is crystallized from methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[C:22]([NH2:29])[CH:21]=2)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:29][C:22]1[CH:21]=[C:20]([C:11]([C:4]2[CH:5]=[CH:6][C:7]([NH2:8])=[C:2]([NH2:1])[CH:3]=2)([C:12]([F:13])([F:14])[F:15])[C:16]([F:17])([F:18])[F:19])[CH:25]=[CH:24][C:23]=1[NH2:26]
Reactant: [H][H]
Reactant: Nc1cc(C(c2ccc([N+](=O)[O-])c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(c2ccc(N)c(N)c2)(C(F)(F)F)C(F)(F)F)cc1N
Reaction time: 0.25 h

Procedure:
96.7 g (0.23 mol) of 2,2-bis-(3-amino-4-nitrophenyl) hexafluoropropane are dissolved in 1,000 ml of ethyl acetate and reduced with hydrogen (100 bar) at 25° C. in an autoclave after the addition of 3 g of a palladium/charcoal catalyst (5% Pd). After filtering off the catalyst, the ethyl acetate is separated off on the rotary evaporator. The residue is taken up using 1 1 of water and adjusted to a pH of 1 using 1:1 hydrochloric acid. The mixture is then heated to 70°-80° C., 20 g of activated charcoal are added, the mixture is stirred at 70°-80° C. for 15 minutes and the activated charcoal is filtered off. The colorless filtrate is saturated with nitrogen and is adjusted at 10°-20° C. to a pH of 7 using 1:1 ammonia solution under inert gas. The precipitate is separated off, washed well with water and dried to constant weight under reduced pressure. Yield 74 g (0.20 mol); gas chromatographic purity above 99.9%; white solid; m.p. 218°-220° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Br[CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23]>C(#N)C>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)NCCBr
Reactant: OCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)NCCN1CCC(CO)CC1
Yield: 54.8 %

Procedure:
4-Piperidine methanol (1.60 g) was dissolved in dry acetonitrile (40 ml), N,N-diisopropylethylamine (5 ml) was added, followed by N-(2-bromoethyl)methanesulphonamide (2.95 g) in acetonitrile (10 ml), and the resulting mixture heated at reflux for 2 h. The solvent was removed in vacuo to leave a gum. This was purified by FCC eluting with System A (75:8:1) to give the title compound (1.80 g) as a solid, m.p. 81°-82°.
Reaction SMILES: [H-].[Na+].[CH2:3]1COCC1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=[N:26]3)[CH2:19][CH2:18]2)=[CH:9]1.IC>O>[CH3:3][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=[N:26]3)[CH2:19][CH2:18]2)=[CH:9]1
Reactant: C1CCOC1
Reactant: O=c1c2ccccc2nnn1CCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1cc(C2CCN(CCn3nnc4ccccc4c3=O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A dried flask under nitrogen was loaded with sodium hydride (0.015 g, 0.37 mmol) and THF (10 mL). At 0° C. 3-{2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl}-1,2,3-benzotriazin-4(3H)-one (0.07 g, 0.19 mmol), was added and the mixture stirred for 15 minutes. Keeping the reaction temperature at 0° C., the iodomethane was added dropwise (0.01 mL, 0.19 mmol). This was allowed to warm to room temperature and stir overnight. Water was slowly added to the mixture to quench and the organics were extracted in chloroform, washed with water and dried over Na2SO4, filtered and concentrated. The residue was chromatographed using silica and a 2% methanol:chloroform system. 0.03 g of 3-{2-[4-(1-methyl-1H-indol-3-yl)-1-piperidinyl]ethyl}-1,2,3-benzotriazin-4(3H)-one was isolated as an orange solid. Yield 41%; MS: 388.3 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 1.80 (q, 2H), 2.03 (d, 2H), 2.31 (t, 2H), 2.81 (m, 1H), 2.96 (t, 2H), 3.16 (d, 2H), 3.73 (s, 3H), 4.68 (t, J=5.19 Hz, 2H), 6.79 (s, 1H), 7.06 (t, 1H), 7.20 (t, 1H), 7.28 (m, 1H), 7.60 (d, 1H), 7.81 (t, 1H), 7.95 (t, 1H), 8.16 (d, 1H), 8.37 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:37])[N:7]([C:14]1([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:37])[N:7]([C:14]1([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13]
Reactant: [H][H]
Reactant: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)N1
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc2c1C(=O)N(C1(CCCCNC(=O)OCc3ccccc3)CCC(=O)NC1=O)C2=O
Reaction time: 1.5 h
Yield: 0 %

Procedure:
To a suspension of 5 (0.24 g, 0.472 mmol) in ethanol (15 mL) was added Raney Nickel (W.R. Grace and Co. Raney® 4200, slurry, in H2O) under argon. The mixture was subsequently saturated with hydrogen using a hydrogen balloon. After 1.5 h, the mixture was flushed with argon, filtered using EtOH and concentrated. Purification by flash chromatography (95:5 DCM:MeOH) afforded 6 (0.112 mg, 49%) as a bright yellow solid. Rf=0.38 (95:5 DCM:MeOH). 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.09 (s, 1H), 9.04 (s, 1H), 7.71-7.52 (m, 2H), 7.49-7.18 (m, 5H), 7.10 (m, 1H), 5.07-4.85 (m, 2H), 2.96 (m, 2H), 2.55 (m, 2H), 2.44 (m, 1H), 2.22 (m, 2H), 2.02 (m, 1H), 1.40 (m, 2H), 1.22 (m, 2H). MS (ESI) m/z calcd for C25H27N4O6 [M+H]+ 479.5. found 479.9.
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1F)[CH:30]=[O:31].[CH3:36][N:37]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]2[CH:55]=[C:54]([OH:56])[C:48]3[CH2:49][C:50]([CH3:53])([CH3:52])[O:51][C:47]=3[CH:46]=2)=[O:44])=[N:38]1>>[CH3:36][N:37]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]2[CH:55]=[C:54]([O:56][C:34]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][C:27]=3[F:26])[C:48]3[CH2:49][C:50]([CH3:53])([CH3:52])[O:51][C:47]=3[CH:46]=2)=[O:44])=[N:38]1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C=O)cc3F)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 3,4-difluoro-benzaldehyde and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid(1-methyl-1H-pyrazol-3-yl)-amide (31a). 1H NMR (400 MHz, CDCl3) δ 9.92 (d, J=2.02 Hz, 1 H) 8.52 (s, 1 H) 7.72 (dd, J=10.36, 1.77 Hz, 1 H) 7.64 (d, J=8.34 Hz, 1 H) 7.28 (s, 1 H) 7.09 (t, J=7.96 Hz, 1 H) 7.05 (s, 1 H) 6.97 (s, 1 H) 6.77 (d, J=2.02 Hz, 1 H) 3.78 (s, 3 H) 2.98 (s, 2 H) 1.51 (s, 6 H); LCMS for C22H20FN3O4 m/z 410.00 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][OH:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(OCC)(=O)C>CN(C)C=O>[Si:18]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][OH:10])[CH2:5][CH2:4]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1CC[C@H](CO)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](CO)CC1

Procedure:
In 250 ml of dry dimethylformamide were dissolved 10.0 g of trans-1,4-dihydroxymethylcyclohexane and 14.5 ml of triethylamine, and a solution of 10.24 g of t-butyldimethylsilyl chloride dissolved in 50 ml of dry dimethylformamide was added dropwise thereto with stirring under ice-cooling, and the resulting mixture was stirred under ice-cooling for 1 hour. To the reaction mixture were added 200 ml of ethyl acetate, the precipitated triethylamine hydrochloride was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (2:1) as an eluting solvent to obtain 11.9 g of the desired compound as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:29][CH2:30][CH2:31][CH2:32][C@@H:3]12.[Li+].[OH-]>O1CCOCC1>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:29][CH2:30][CH2:31][CH2:32][C@@H:3]12
Reactant: COC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
(S)-methyl 4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate (152 mg, 0.349 mmol) was taken up in dioxane (2 ml) and LiOH (1N, 2 ml, 2.000 mmol) was added. The reaction was stirred 16 h at room temperature. The reaction was concentrated in-vacuo and the residue was taken up in water (5 mL) and acidified (4.5N HCl) to pH 4. A white precipitate formed. The precipitate was filtered off and dried in vacuum to afford the title compound (122.8 mg, 83%) as a white solid. [M+H] calc'd for C23H27N5O3, 422. found, 422.
Reaction SMILES: Cl.C(OCC)(=O)C.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:28])[C:18]=2[N:29]([CH2:33][CH2:34][O:35][CH3:36])[C:30](=O)[CH3:31])=[CH:11][CH:10]=1>C(O)C>[Cl-:8].[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]2[C:17]3[C:26](=[O:27])[C:25]4[C:20]([C:19](=[O:28])[C:18]=3[N+:29]([CH2:33][CH2:34][O:35][CH3:36])=[C:30]2[CH3:31])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:11][CH:10]=1
Reactant: COCCN(C(C)=O)C1=C(NCc2ccc(Cl)nc2)C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCC[n+]1c2c(n(Cc3ccc(Cl)nc3)c1C)C(=O)c1ccccc1C2=O
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 196.3 %

Procedure:
4 M Hydrogen chloride/ethyl acetate solution (10 ml) was added to a solution of N-{3-[(6-chloro-3-pyridyl)methyl]amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl}-N-(2-methoxyethyl)acetamide (0.8 g) in ethanol (10 ml) and the mixture was stirred at room temperature for 1 day. The solvent was evaporated and the residue was collected by filtration and washed with ethyl acetate to give 1-[(6-chloro-3-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium chloride (0.82 g) as a light yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH2:28][C:29]([CH3:31])=[CH2:30]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:16])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:30][C:29]([CH3:31])=[CH2:28])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CNC(=O)OC(C)(C)C
Reactant: C=C(C)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)CN(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82.1 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)glycine tert-butyl ester (3.97 g, 17.2 mmol) in DMF (70 mL) at 0° C. was added sodium hexamethyldisilazide (3.78 g, 20.6 mmol) and the resulting mixture was stirred for 25 min., then allowed to warm to room temp. The resulting solution was treated with 3-bromo-2-methylpropene (2.60 mL, 25.7 mmol), stirred at room temp. for 10 min., and diluted with EtOAc (300 mL). The EtOAc solution was sequentially washed with water (4×500 mL) and a saturated NaCl solution (4×500 mL), dried (MgSO4), and concentrated under reduced pressure to afford N-(tert-butoxycarbonyl)-N-(2-methylprop-2-enyl)glycine tert-butyl ester (4.03 g, 82%): TLC (10% EtOAc/hex) Rf0.51.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16](I)[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[CH3:20][N:21]1[C:25](B(O)O)=[C:24]([CH3:29])[CH:23]=[N:22]1.C([O-])([O-])=O.[Cs+].[Cs+]>ICCC.COCCOC.O>[CH3:20][N:21]1[C:25]([C:16]2[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:19])[CH:17]=2)=[C:24]([CH3:29])[CH:23]=[N:22]1
Reactant: Cc1cnn(C)c1B(O)O
Reactant: Cc1noc(C)c1-c1cc(I)c2c(c1)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCCI
Solvent: COCCOC
Product: Cc1cnn(C)c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)n(C)c12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a microwave vial containing 5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (40 mg, 0.11 mmol, 1 equiv.) were added 1,4-dimethyl-1H-pyrazol-5-ylboronic acid (72 mg, 0.32 mmol, 3 equiv.), Cs2CO3 (141 mg, 0.43 mmol, 4 equiv.) and PEPPSI™-IPr catalyst (8 mg, 0.02 mmol, 0.1 equiv.) and DME-H2O (20 mL, 0.2 M, 2/1, v/v). The mixture was heated to 140° C. After 1 hr, the reaction was complete. Following cooling, the reaction was extracted with EtOAc and the organic solution was washed with water, saturated NH4Cl. After drying with MgSO4, it was filtered and concentrated to dryness under reduced pressure. Purification of the residue was carried out by reverse phase HPLC to furnish the desired product.
Reaction SMILES: [CH2:1]([C@H:5]([CH2:19][C:20]([OH:22])=[O:21])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].[CH2:23]=[C:24]([CH3:26])[CH3:25].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(OCC)C.O>[CH2:1]([C@H:5]([CH2:19][C:20]([O:22][C:24]([CH3:26])([CH3:25])[CH3:23])=[O:21])[C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: C=C(C)C
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)C[C@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77 %

Procedure:
9.4 g of 1-(4-nitrobenzyl) hydrogen 2(R)-isobutylsuccinate were dissolved in 30 ml of dry diethyl ether and the solution was cooled in a dry-ice/acetone bath. There were then added 70 ml of isobutene, followed dropwise by 0.64 ml of concentrated sulfuric acid. The reaction flask was tightly topped and the mixture was stirred at room temperature for 2 days. The mixture was made basic with saturated sodium hydrogen carbonate solution and water was added. The organic phase was separated and the aqueous phase was extracted twice more with diethyl ether. The combined ethereal phases were washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give 8.8 g (77%) of 4-tert.butyl 1-(4nitrobenzyl) 2(R)-isobutylsuccinate in the form of an oil. Rf (System A) 0.87.