Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[Si]([O:31][CH2:32][C:33]1[N:34]=[C:35]([CH3:66])[N:36]2[CH:40]=[C:39]([C:41]3[C@H:42]([CH3:65])[C@@H:43]4[C@@H:60]([C@H:61]([OH:63])[CH3:62])[C:59](=[O:64])[N:44]4[C:45]=3[C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=3)=[O:47])[S:38][C:37]=12)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>C(O)(=O)C>[OH:63][C@@H:61]([C@H:60]1[C:59](=[O:64])[N:44]2[C:45]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=3)=[O:47])=[C:41]([C:39]3[S:38][C:37]4=[C:33]([CH2:32][OH:31])[N:34]=[C:35]([CH3:66])[N:36]4[CH:40]=3)[C@H:42]([CH3:65])[C@H:43]12)[CH3:62]
Reactant: Cc1nc(CO[Si](C)(C)C(C)(C)C)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1nc(CO)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 109 %

Procedure:
Acetic acid (0.28 ml) and 1.6 ml of a 1 M tetrabutylammonium fluoride/THF solution were added to 313 mg of 4-nitrobenzyl(1S,5R,6S)-2-[7-(t-butyldimethylsilyloxy)methyl-5-methylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate. The mixture was stirred at room temperature for 3.5 hr. The reaction solution was adjusted to pH 7 by the addition of a saturated aqueous sodium hydrogencarbonate solution. The reaction solution was then extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The reaction solution was then concentrated under the reduced pressure. The residue was purified by column chromatography to give 279 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethyl-5-methylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [OH-].[Na+].[CH3:3][C@:4]12[C:11]3[CH:12]=[C:13]([O:16]C(NC)=O)[CH:14]=[CH:15][C:10]=3[N:9]([CH3:21])[C@H:8]1[N:7]([CH3:22])[CH2:6][CH2:5]2.C1C=CC(O)=C(C(O)=O)C=1.COC(C)(C)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O>[CH3:3][C@:4]12[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[N:9]([CH3:21])[C@H:8]1[N:7]([CH3:22])[CH2:6][CH2:5]2
Reactant: CNC(=O)Oc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Agent: O=C(O)c1ccccc1O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: CN1CC[C@@]2(C)c3cc(O)ccc3N(C)[C@@H]12
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
Under an argon atmosphere, a 50 wt % sodium hydroxide solution (67.7 g, 0.8462 mol) was added dropwise to a slurry of physostigmine salicylate (100 g, 0.2418 mol) in degassed DI water (300 mL) at 45° C. During the addition the temperature was kept between 45 and 55° C. After about 3 hours at 45° C. the yellow solution was cooled to 25 to 30° C. and tert.-butyl methyl ether (300 mL) was added. The pH of the aqueous phase was adjusted to 9.1 with an aqueous solution of sodium meta bisulfite (54 g, Na2S2O5, 250 mL water). The mixture was stirred for 30 minutes, the phases were allowed to settle and then separated. The aqueous phase was extracted twice for 30 minutes each with tert.-butyl methyl ether (300 mL each). The organic phases were combined and washed three times with 20 wt % sodium chloride solution (200 mL each), then dried over magnesium sulfate (150 g) overnight. The slurry was filtered through Celite and the filter cake washed with tert.-butyl methyl ether. The filtrate was concentrated to 300 mL at 25 to 29 in of vacuum and the residue co-distilled twice with diethoxymethane (300 mL each). The residue was diluted with diethoxymethane (300 mL) and heated to 50° C. The obtained light slurry was cooled to 5° C., stirred for 45 minutes, then concentrated to about 300 mL. Cold heptane (300 mL) was added dropwise, the slurry stirred for 20 minutes and the volume increased by addition of cold heptane (125 mL). After stirring for about 2 hours the slurry was filtered via a Buchner funnel. The collected solid was washed with cold heptane (200 mL) then dried in vacuo overnight. Eseroline base (35.6 g) was obtained as a white solid in 67.4% yield and 98.3% purity.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=C(O)CCCCCCCCCCCCCCCCCCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: O=CCCCCCCCCCCCCCCCCCCCCC(=O)O

Procedure:
3.9 g 22-Hydroxy-docosanoic acid (1 eq.) was oxidized with 4.72 g PCC (Pyridinium chlorochromate) (2 eq.) for about 2 hours under reflux as described in example 1, step a.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.S(=O)(=O)(O)O.[Br:23]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:23][C:10]1[CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])[C:7]([NH2:12])=[N:8][CH:9]=1
Reactant: BrBr
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1OCc1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
32.6 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 1A; 138 mmol, 1 equivalent) were suspended in 552 ml of 10% strength sulphuric acid, and the mixture was cooled to 0° C. 8.5 ml of bromine (165 mmol, 1.2 equivalents) were dissolved in 85 ml of acetic acid and then, over a period of 90 min, added dropwise to the ice-cooled reaction solution. After the dropwise addition had ended, the mixture was stirred at 0° C. for 90 min and then diluted with 600 ml of ethyl acetate, and the aqueous phase was separated off. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, dried and concentrated. The residue was dissolved in dichloromethane and chromatographed on silica gel (petroleum ether/ethyl acetate gradient as mobile phase). This gave 24 g (55% of theory) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1>>[CH3:14][O:13][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=1)[C:3]([OH:2])=[O:15]
Reactant: BrCCCOc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)C(Cc1cccc(O)c1)OC
Product: COC(Cc1cccc(OCCCOc2ccc(Oc3ccccc3)cc2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester from Example 152, Step D with 4-(3-bromopropoxy)1-phenoxybenzene in a manner analogous as in Example 152, Step E. MS (ES) for C25H26O6 [M+NH4]+: 440.2, [M+Na]+: 445.2. 1H-NMR (CDCl3, 200.15 MHz): 7.33–7.17 (m, 3H), 7.07–6.78 (m, 10H), 4.15 (dt, 4H, J=1.9, 6.2), 4.03 (dd, 1H, J=7.3, 4.3), 3.40 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.98 (dd, 1H, J=14.0, 7.5), 2.25 (qui, 2H, J=5.9)ppm.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][C:16]=2[O:18][CH3:19])[C:11](Cl)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:26][CH2:25]1>>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][C:16]=2[O:18][CH3:19])[C:11]([NH:23][CH:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=3)[CH2:28][CH2:29]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)c2c(Cc3ccccc3)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1cc(OC)c2c(Cc3ccccc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 4-benzyl-1-chloro-5,7-dimethoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [Br:1][C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH:9](Br)([Br:11])[Br:10].[OH-].[K+]>[Br-].[Br-].C([N+](C)(C)CC[N+](CC1C=CC=CC=1)(C)C)C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]12[C:9]([Br:11])([Br:10])[CH:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2
Reactant: BrC(Br)Br
Reactant: BrC1=CCCCCC1
Agent: C[N+](C)(CC[N+](C)(C)Cc1ccccc1)Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: BrC1(Br)C2CCCCCC21Br
Yield: 327.8 %

Procedure:
To a solution of 12 g (6.86 mmol) of 1-bromo-cycloheptene in 52 g (206 mmol) of bromoform and 56 g of methylene chloride was added 0.73 g (1.59 mmol) of N,N′-dibenzyl-N,N,N′,N′-tetramethylethylenediammonium dibromide and 18.8 g (152 mmol) of 45% aqueous potassium hydroxide. After 24 hours the reaction mixture was poured onto water. The resulting mixture was transferred to a separatory funnel and the phases were separated. To the isolated organic layer was added 0.73 g (1.59 mmol) of N,N′-dibenzyl-N,N,N′,N′-tetramethylethylenediammonium dibromide and 18.8 g (152 mmol) 45% aqueous potassium hydroxide. After 24 hours the reaction mixture was poured onto water. The resulting mixture was transferred to a separatory funnel and the phases were separated. The isolated organic layer was dried over magnesium sulfate and filtered. The filtrate was dried in vacuo. The residue obtained was purified by column chromatography with hexanes. The resulting oil was purified by vacuum distillation to yield 7.8 g of 1,8,8-tribromo-bicyclo[5.1.0]octane.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)([O:3][C:4]([CH3:7])(C)C)=[O:2].C(OCC)(=O)C.C(N(CC)CC)C.[CH:30]1[CH:35]=[CH:34]C(COC(Cl)=O)=[CH:32][CH:31]=1>FC(F)(F)C(O)=O.CCCCCC>[C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)([O:3][CH2:4][C:7]1[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=1)=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=N[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 0 °C
Yield: 97 %

Procedure:
A sample of the (3S,4S)—N-Boc-3-azido-4-hydroxypyrrolidine (80 mg, 0.35 mmol) was dissolved in trifluoroacetic acid (1 mL) and was stirred until no starting material was detected on TLC (25% ethyl acetate in hexane). The solution was evaporated under reduce pressure and the residue was dissolved in CH2Cl2 (2 mL). The solution was cooled to 0° C., triethylamine (117 μL, 0.84 mmol) and Cbz-Cl (60 mg, 0.35 mmol) were added, and the resulting solution was stirred for 2 hr at room temperature. The reaction mixture was washed with water, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography (25% ethyl acetate in hexane) to give (3S,4S)—N-Cbz-3-azido-4-hydroxypyrrolidine (89 mg, 97%): [α]20D=+ 16.1° (c=1.00, CHCl3). Lit. [Kamal, A.; Shaik, A. A.; Sandbhor, M.; Malik, M. S.; Kaga, H. Tetrahedron Lett. 2004, 45, 8057-8059] for (3S,4S)—N-Cbz-3-azido-4-hydroxypyrrolidine: [0]25D=+14.3° (c=1.06, CHCl3).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([S:38](C)=O)=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([SH:38])=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(S(C)=O)cn2)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(S)cn2)cc1
Yield: 118.4 %

Procedure:
A solution of 4-tert-butyl-N-{6-[2-(5-methylsulfinylpyrimidin-2-yl-oxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (471 mg) in trifluoroacetic anhydride (5 ml) and methylene chloride (5 ml) is refluxed for 30 minutes, and the mixture is evaporated to remove the solvent. The residue is dissolved in methanol/triethylamine (1:1) (20 ml), and concentrated to dryness under reduced pressure. The residue is dissolved in chloroform, washed with saturated aqueous ammonium chloride solution and brine, dried over sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to give 4-tert-butyl-N-{6-[2-(5-mercaptopyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide as pale yellow foam (529 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[OH:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:15][C:10]1[N:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8](=[O:16])[N:7]([CH3:17])[C:6]1[CH:18]=[C:2]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:3]=[CH:4][C:5]2=1
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Temperature: 100 °C
Yield: 53.9 %

Procedure:
A mixture of 8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (60 mg, 0.232 mmol), (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (101 mg, 0.464 mmol), Cs2CO3 (113 mg, 0.348 mmol), Pd(OAc)2 (15.6 mg, 0.070 mmol) and 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (5.91 mg, 0.014 mmol) in toluene (5 mL) was purged with nitrogen for 5 min and heated at 100° C. overnight (14 h). After cooling, the reaction mixture was filtered through diatomaceous earth (Celite®), concentrated under reduced pressure and dissolved in ethyl acetate (5 mL). The organic layer was washed with brine (2×10 mL) and water (20 mL); dried over Na2SO4 and concentrated under reduced pressure to afford (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (55 mg crude) as a gummy solid. The crude product was used in the next step without further purification. LC/MS, (ESI) m/z 440.4 [(M+H)+, calcd for C25H34N3O4, 440.2]; LC/MS retention time (method D): tR=0.89 min.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:24])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][CH2:21][CH2:22][OH:23])[CH:14]=2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].[CH2:28](I)C.CCOC(C)=O>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][CH:2]([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:24])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][CH2:21][CH2:22][O:23][CH3:28])[CH:14]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(C(=O)c1cccc(C#CCCO)c1)c1ccc(OC(F)F)cc1
Reactant: CCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCC#Cc1cccc(C(=O)C(=O)c2ccc(OC(F)F)cc2)c1
Reaction time: 48 h

Procedure:
To a solution of 1-(4-(difluoromethoxy)phenyl)-2-(3-(4-hydroxybut-1-ynyl)phenyl)ethane-1,2-dione (344 mg, 1.0 mmol) from the previous step in DCM (5 mL) was added tetrabutylammonium bromide (64 mg, 0.2 mmol) followed by NaOH (2.5N, 5 mL). Ethyl iodide (3.9 g, 2.0 mL, 25 mmol) was added and the mixture was stirred vigorously for 2 d then worked up as follows. The reaction mixture was diluted with water and DCM. The aqueous layer was separated and extracted once with DCM. The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to give an oil. Flash chromatography (SiO2, 1:9 EtOAc:Hexanes to 1:1 EtOAc:Hexanes) to provide 100 mg, 26%, of the title compound as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([N+:17]([O-])=O)[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.CO.[Pd]>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH2:17])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccccc3)ccc2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2nc(-c3ccccc3)ccc2c1

Procedure:
Pd/C (10%; 0.60 g) is added to 2-phenyl-6-nitroquinoline (7 g, 0.028 mol) in THF (300 ml) and methanol (300 ml). The mixture is hydrogenated at room temperature and at 1 atm. The catalyst is filtered off, the filtrate is evaporated and the product is recrystallized from isopropyl ether. Yield: 5.7 g (92%); Rf (9/1 chloroform/methanol): 0.56; IR (KBr): 3455, 3320, 3205, 1625, 1495 cm−1.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:43]1[CH:48]=[C:47]([C:49](OC)=[O:50])[C:46]([O:53][CH2:54][CH3:55])=[CH:45][C:44]=1[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[F:62]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:1]1([C:43]2[CH:48]=[C:47]([CH2:49][OH:50])[C:46]([O:53][CH2:54][CH3:55])=[CH:45][C:44]=2[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:3][CH2:2]1
Reactant: CCOc1cc(-c2ccccc2F)c(Br)cc1C(=O)OC
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2ccccc2F)c(C2CC2)cc1CO
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Cyclopropylboronic acid (0.504 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.241 g), a 2 M aqueous sodium carbonate solution (5.86 mL), and tris(dibenzylideneacetone)dipalladium(0) (0.251 g) were added to a mixture of methyl 2-bromo-5-ethoxy-2′-fluorobiphenyl-4-carboxylate (1.38 g) and toluene (20 mL), and the resultant mixture was stirred at 100° C. for 6 hours in an argon atmosphere. Water was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was subjected to extraction with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). A THF (5 mL) solution of the purified product was added at 0° C. to a THF (5 mL) suspension of lithium aluminum hydride (0.326 g). After stirring at the same temperature as above for 2 hours, water (0.5 mL), a 1 M aqueous sodium hydroxide solution (0.5 mL), and water (1.5 mL) were added thereto in this order. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.07 g).
Reaction SMILES: C(C[CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])(OCC)=O.CNC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2C)[C@H](O)[C@@H]1O.ClC[C:52]([O:54][CH2:55][CH3:56])=[O:53].CCN(C(C)C)C(C)C>CN(C=O)C>[C:52]([CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])([O:54][CH2:55][CH3:56])=[O:53]
Reactant: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCOC(=O)CCl
Agent: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 13c was prepared by the same procedure as described for the preparation of 13a using 4a (415 mg, 1.41 mmol), ethyl chloroacetate (207 mg, 0.18 mL, 1.68 mmol), DIEA (91 mg, 0.12 mL, 0.70 mmol), and DMF (5 mL): yield 204 mg (38%), MS: m/z 381 (M+H)+; 1HNMR (DMSO-d6) δ 8.06 (s, 1H, H-2), 7.11 (bs, 2H, 6-NH2), 5.73 (d, 1H, H-1′, J1′,2′=5.4 Hz), 5.33 (bd, 1H, OH-2′, J2′-2′OH=4.7 Hz), 5.19 (bd, 1H, OH-3′, J3′-3′OH=4.9 Hz), 5.03 (ddd, 1H, H-2′, J1′,2′=5.4 Hz, J2′,3′=5.7 Hz, J2′-2′OH=4.7 Hz), 4.17 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.4 Hz, J3′-3′OH=4.9 Hz), 4.02 (q, 2H, OCH2CH3), 3.92-3.99 (m, 1H, H-4′), 3.27 (bs, 2H, N(CH3)—CH2), 2.83-2.90 (m, 1H, 5′-CH2), 2.70-2.79 (m, 1H, 5′-CH2), 2.53 (s, 3H, 8-CH3), 2.31 (s, 3H, N—CH3), 1.13 (t, 3H, OCH2CH3); UV λmax, nm, pH 1, 258.9 (∈ 16,100), pH 7, 260 (∈ 15,900), pH 13, 260.1 (∈ 16,200). Anal. (C16H24N6O5.0.5CHCl3.0.3CH3OH) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH2:18][CH:11]2[C:12](=[CH:20]O)[C:13](=O)[CH2:14]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>C(O)(=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH2:18][CH:11]2[C:12]2[CH:20]=[N:23][NH:24][C:13]=2[CH2:14]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)s1
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(Cl)s1)N1C2CCCC1c1cn[nH]c1C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 9-(5-chloro-thiophene-2-sulfonyl)-2-hydroxymethylene-9-aza-bicyclo[3.3.1]nonan-3-one crude mixture in glacial acetic acid (3 mL) followed by hydrazine monohydrate (1 mL). The reaction mixture was stirred at 100° C. for 1 h after which the solution was cooled to room temperature and quenched by the addition of saturated NaHCO3 solution (until pH>7). The resulting solution was extracted with EtOAc (3×20 mL), the organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography (Elution with 50% EtOAc/hex, 80% EtOAc/hex, 100% EtOAc, and 5% MeOH/EtOAc) and preparative HPLC to give 12-(5-chloro-thiophene-2-sulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene as a white solid. Retention time (min)=1.649 min, Method 1, MS (ESI) 344.0 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.47 (s, 1H), 7.25 (s, 1H), 7.22 (d, =4.4 Hz, 1H), 5.28 (b s, 1H), 4.56 (t, J=6.04 Hz, 1H), 3.11 (dd, J=17.58, 7.69 Hz, 1H), 2.66 (d, J=17.58 Hz, 1H), 2.09-1.92 (m, 2H), 1.74-1.57 (m, 3H), 1.44-1.29 (m, 1H); 13C-NMR (75 MHz, CDCl3) δ 143.4, 139.2, 137.7, 131.8, 127.4, 127.0, 117.0, 48.0, 47.9, 32.3, 31.7, 25.4, 15.3 ppm.