Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:16]2[O:15][C:14]([CH3:18])([CH3:17])[O:13][C:12]=2[C:11]([C:19]([C:41]2[C:51]3[O:52][C:53]([CH3:56])([CH3:55])[O:54][C:50]=3[C:49]([C:57]([O:59][CH3:60])=[O:58])=[C:43]3[O:44][C:45]([CH3:48])([CH3:47])[O:46][C:42]=23)([C:21]2[C:31]3[S:32][C:33]([CH3:36])([CH3:35])[S:34][C:30]=3[C:29]([C:37]([O:39][CH3:40])=[O:38])=[C:23]3[S:24][C:25]([CH3:28])([CH3:27])[S:26][C:22]=23)O)=[C:10]2[C:6]=1[O:7][C:8]([CH3:62])([CH3:61])[O:9]2)=[O:4].B(F)(F)F.CCOCC.[Sn](Cl)Cl>[Zn]>[CH3:60][O:59][C:57]([C:49]1[C:50]2[O:54][C:53]([CH3:55])([CH3:56])[O:52][C:51]=2[C:41]([CH:19]([C:11]2[C:12]3[O:13][C:14]([CH3:18])([CH3:17])[O:15][C:16]=3[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]3[O:7][C:8]([CH3:61])([CH3:62])[O:9][C:10]=23)[C:21]2[C:31]3[S:32][C:33]([CH3:36])([CH3:35])[S:34][C:30]=3[C:29]([C:37]([O:39][CH3:40])=[O:38])=[C:23]3[S:24][C:25]([CH3:27])([CH3:28])[S:26][C:22]=23)=[C:42]2[C:43]=1[O:44][C:45]([CH3:48])([CH3:47])[O:46]2)=[O:58]
Reactant: COC(=O)c1c2c(c(C(O)(c3c4c(c(C(=O)OC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)OC)c5c3SC(C)(C)S5)SC(C)(C)S4)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: Cl[Sn]Cl
Agent: FB(F)F
Agent: [Zn]
Solvent: CCOCC
Product: COC(=O)c1c2c(c(C(c3c4c(c(C(=O)OC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)OC)c5c3SC(C)(C)S5)SC(C)(C)S4)c3c1OC(C)(C)O3)OC(C)(C)O2

Procedure:
Bis-(8-methoxycarbonyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxol-4-yl)-mono-(8-methoxycarbonyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dithiol-4-yl)methanol (5 mg, 0.005 mmol) was dissolved in dry, degassed acetonitrile under an argon atmosphere. BF3.Et2O (2.0 μL, 0.011 mmol) and tin(II) chloride (3.0 mg, 0.016 mmol) were added. Amalgamated zinc (1.0 mg, 0.015 mmol), was added. The product was purified by flash chromatography (ether/heptane 5:1). Due to the small amount used the yield was not determined.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[O:20]=[C:21]([CH2:27][C:28](=[O:30])[CH3:29])[C:22](OCC)=[O:23]>>[C:28]([C:27]1[CH:16]([C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)[N:8]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:22](=[O:23])[C:21]=1[OH:20])(=[O:30])[CH3:29]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: COc1ccc(CN)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: COc1ccc(CN2C(=O)C(O)=C(C(C)=O)C2c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 57.1 using 4-methoxybenzylamine, 4-chlorobenzaldehyde and ethyl 2,4-dioxovalerate at 120° C. for 3 hr. The title product precipitated at RT. tR: 4.90 min (HPLC 1); tR: 1.03 min (LC-MS 2); ESI-MS: 372 [M+H]+, ESI-MS: 370 [M−H]− (LC-MS 2).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@H:4]([OH:9])[CH2:5][N:6]=[N+:7]=[N-:8].[CH3:17][O:18][C:19]1[C:20](=O)[C:21](=[O:25])[C:22]=1[O:23]C.C(N(CC)CC)C>C(#N)C>[N:6]([CH2:5][C@@H:4]([OH:9])[C@@H:3]([NH:2][C:20]1[C:21](=[O:25])[C:22](=[O:23])[C:19]=1[O:18][CH3:17])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[N+:7]=[N-:8]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: [N-]=[N+]=NC[C@@H](O)[C@@H](N)CC1CCCCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1c(N[C@@H](CC2CCCCC2)[C@H](O)CN=[N+]=[N-])c(=O)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.1 %

Procedure:
The HCl salt of (2R,3S)-3-amino-1-azido-4-cyclohexylbutan-2-ol (˜74 mg, 0.30 mmol) and 3,4-dimethoxycyclobut-3-ene-1,2-dione (70 mg, 0.49 mmol) were dissolved in acetonitrile (3 mL). Triethylamine (84 μL, 0.60 mmol) was added. The reaction was stirred at rt for 4 h. The solvent was evaporated and the crude material was redissolved in CH2Cl2. The solution was washed with 2% aq HCl, followed by brine, and dried over Na2SO4. The solution was filtered and the solvent removed under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with hexanes/EtOAc. 3-((2S,3R)-4-Azido-1-cyclohexyl-3-hydroxybutan-2-ylamino)-4-methoxycyclobut-3-ene-1,2-dione (63 mg) was isolated as a solid; MS m/z 323.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[N:8]=[C:7]([S:9]([CH:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH3:13])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:29][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>O1CCCC1>[CH3:13][C:12]([CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]1)([S:9]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:27])[F:28])[N:8]=1)(=[O:10])=[O:11])[CH3:29]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1cccc(C(F)(F)F)n1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)OC(=O)N1CCC(C(C)(C)S(=O)(=O)c2cccc(C(F)(F)F)n2)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
To a 50 ml round bottom flask was added tert-butyl 4-(1-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}ethyl)piperidine-1-carboxylate (0.78 g, 1.85 mmol) and tetrahydrofuran (10 ml). The resulting solution was cooled with dry ice acetone bath. Sodium bis(trimethylsilyl)amide (NaHMDS) tetrahydrofuran solution (1M, 2.58 ml, 2.58 mmol) was added via a syringe. The resulting reaction solution was stirred at −78° C. for 10 minutes. MeI (0.173 ml, 2.77 mmol) was added. The reaction mixture was allowed to warm up to room temperature and quenched by addition of 50 ml saturated NH4Cl solution. It was diluted with 30 ml ether. The layers were separated, and the organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:4 to 1:2 ethyl acetate/hexane to give 0.806 g desired product (contains solvent).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[CH:27]=1)(=[O:25])=[O:24])(=[O:14])=[O:13].[CH3:35][O-:36].[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:35][O:36][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[CH:27]=1)(=[O:25])=[O:24])(=[O:14])=[O:13]
Reactant: C[O-]
Reactant: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)ccc1Cl)c1cc2ccccc2s1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid [2-(2-chloro-5-trifluoromethylbenzenesulfonylamino)phenyl]-amide (0.5 mmol) in dioxane (5 mL), solid sodium methoxide (2 mmol) was added in one portion and the resulting reaction mixture was then heated to reflux for ca. 4 h. After the completion of the reaction, the reaction mixture was cooled to RT and concentrated in vacuo. The residue obtained was redissolved in EtOAc (10 mL) and was washed with water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 204 mg of benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-5-trifluoromethyl-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.20 min; MS: 544.1 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([SH:13])[CH:9]=[CH:10]2)=[CH:5][CH:4]=1.[O:14]1[CH2:16][CH:15]1[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.O>CN(C)C=O.O1CCCC1>[CH:7]1[C:6]2[C:11](=[CH:12][CH:3]=[CH:4][CH:5]=2)[CH:10]=[CH:9][C:8]=1[S:13][CH2:16][CH:15]([OH:14])[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1cncc(CCC2CO2)c1
Reactant: Sc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OC(CCc1cccnc1)CSc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.05 g) was added to a solution of 2-thionaphthol (0.174 g) in dry dimethylformamide (3 ml). A solution of (±)-3-(2-oxiranylethyl)pyridine (0.15 g) in tetrahydrofuran (1 ml) was added and the reaction mixture stirred for three hours at ambient temperature. The solution was poured into water which was extracted with ethyl acetate. The organic extracts were separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography on silica eluting with ethyl acetate to give the title compound as a white solid (0.15 g).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)N.[CH2:19]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[CH2:20][CH3:21].Cl>C(O)(C)C>[CH2:19]([N:22]1[CH2:27][CH2:26][C:25]2[NH:2][C:4]3[C:18]([C:24]=2[CH2:23]1)=[C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3)[CH2:20][CH3:21]
Reactant: NNc1ccc2scc(-c3ccccc3)c2c1
Reactant: CCCN1CCC(=O)CC1
Agent: Cl
Solvent: CC(C)O
Product: CCCN1CCc2[nH]c3ccc4scc(-c5ccccc5)c4c3c2C1

Procedure:
The compound is formed analogously to that described in Example 40, from 13.8 g of 5-hydrazino-3-phenylbenzothiophene hydrochloride and 7.5 g of 1-propyl-4-piperidone by boiling the starting materials in 120 ml of isopropanol containing hydrogen chloride for 4 hours. Melting point: 187°-188° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[C:3]=1[F:10].ClC(Cl)(Cl)C[O:14][C:15](=O)[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:14])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:24]([CH3:26])[CH3:25])=[O:27])=[CH:19][CH:18]=2)=[C:4]([F:9])[C:3]=1[F:10]
Reactant: CN(C)C(=O)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Nc1ccc(Br)c(F)c1F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(Br)c(F)c2F)cc1
Temperature: 105 °C
Yield: 36.6 %

Procedure:
To a 50 mL round bottom flask, 4-bromo-2,3-difluoroaniline (0.5 g, 0.0024 mol), 2,2,2-trichloroethyl(4-(dimethylcarbamoyl)phenyl)carbamate (0.978 g, 0.00288 mol; from Preparation 5), TEA (1.01 mL, 0.0072 mol) and toluene (20 mL) were added. The reaction mixture was maintained at 105° C. for 12 h. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography using 3% MeOH in chloroform to get the title compound [0.35 g, 36%]. 1H NMR (300 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.96 (s, 1H), 8.0-7.92 (m, 1H), 7.52-7.42 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.20-7.06 (m, 1H), 2.96 (s, 6H); LC-MS (ESI): Calculated mass: 397.0; Observed mass: 400.0 (RT: 1.49 min).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[S:18]([C:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:20])=[O:19]>C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:18]([CH:21]1[C:22]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][C:24]([CH3:27])([CH3:28])[CH2:25][CH2:26]1)(=[O:20])=[O:19]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)C1=C(S(=O)(=O)Cl)CCC(C)(C)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=CC(C)(C)CCC1S(=O)(=O)Nc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
2,4-Difluoroaniline (1.51 g) was dissolved in ethyl acetate (33 ml) and the resultant solution was admixed with triethylamine (2.51 ml) with ice-cooling, and then treated dropwise with a solution of ethyl 2-chlorosulfonyl-5,5-dimethyl-1-cyclohexene-1-carboxylate (2.53 g) obtained in Reference Example 18 in ethyl acetate (17 ml). The reaction mixture was stirred under nitrogen flow at 0° C. for 30 minutes then at room temperature for 64.5 hours. The reaction mixture was diluted with ethyl acetate, and washed successively with water (120 ml), 0.5 N HCl (120 ml), water (120 ml×2) and saturated brine (120 ml). The ethyl acetate layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/9→1/7). A desired fraction was concentrated under reduced pressure, and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-3,3-dimethyl-1-cyclohexene-1-carboxylate (Compound 83; 0.83 g) as white crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH2:23][C:24]([OH:26])=O)[CH:17]=[CH:16]2.C[N:28]([CH3:31])C=O.C(OCC)(=[O:34])C>>[OH:34][N:28]([CH3:31])[C:24](=[O:26])[CH2:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH:14]=2)[CH:19]=1
Reactant: O=C(O)Cc1ccc2cc(OCc3ccc4ccccc4n3)ccc2c1
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Product: CN(O)C(=O)Cc1ccc2cc(OCc3ccc4ccccc4n3)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 24 using the acid from Example 21 and omitting the dimethylformamide. The crude product is added to ethyl acetate, washed sequentially with saturated sodium bicarbonate and water, dried over magnesium sulfate to give a crude solid. Recrystallization of this solid from acetone affords the desired product as a crystalline solid having a melting point of 145°-146° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=O)[C@@H:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3]1.[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C.C(Cl)Cl.Cl[C:72]([O:74][CH3:75])=[O:73]>CN(C1C=CN=CC=1)C>[OH:1][C@@H:2]1[CH2:7][N:6]([C:72]([O:74][CH3:75])=[O:73])[C@H:5]([C:8]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23]2)=[O:10])[C@@H:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3]1
Reactant: COC(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](O)CN[C@@H]1C(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a mixture of (2S,3S,5S)-5-hydroxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid (1.10 g, 0.00541 mol), 1-phenyl-piperazine, (0.910 mL, 0.00595 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.63 g, 0.00595 mol) in N,N-dimethylformamide (6.00 mL, 0.0775 mol) was added N,N-diisopropylethylamine (1.04 mL, 0.00595 mol) at 0 Celsius. The reaction was stirred at rt for 3 h. To the reaction mixture was added methylene chloride (40.00 mL, 0.6240 mol), cat. amount of DMAP, N,N-diisopropylethylamine (2.36 mL, 0.0135 mol), followed by methyl chloroformate (0.836 mL, 0.0108 mol) at 0 Celsius. The resulting reaction mixture was stirred at rt overnight. After quenched with water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to dry. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to give the titled compound (1.88 g, 85.7%). MS (ESI): (M+H)+=406.2.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:51][CH:52]1[C@H:56]2[C@H:57](OC3CCCCO3)[N:58](C(OC(C)(C)C)=O)[C:59]3[CH:66]=[C:65]([O:67][CH3:68])[CH:64]=[CH:63][C:60]=3[C:61](=[O:62])[N:55]2[CH2:54][CH2:53]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]1[C@H:24]2[C@H:25](OC3CCCCO3)[N:26](C(OC(C)(C)C)=O)[C:27]3[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=3[C:29](=[O:30])[N:23]2[CH2:22][CH2:21]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:18]([O:19][CH:20]1[C@@H:24]2[CH:25]=[N:26][C:27]3[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=3[C:29](=[O:30])[N:23]2[CH2:22][CH2:21]1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:51][CH:52]1[C@@H:56]2[CH:57]=[N:58][C:59]3[CH:66]=[C:65]([O:67][CH3:68])[CH:64]=[CH:63][C:60]=3[C:61](=[O:62])[N:55]2[CH2:54][CH2:53]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 85 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8i (217 mg, 0.20 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9i (113 mg, 0.17 mmol, 87%) as a solid: [α]20D=+401° (c=0.19, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.26-1.52 (m, 14H, 14-H, 14′-H, 15-H, 15′-H, 16-H, 16′-H, 17-H), 1.84-1.92 (m, 4H, 13-H, 13′-H), 2.01-2.11 (m, 4H, 2-H, 2′-H), 2.27-2.36 (m, 4H, 1-H, 1′-H), 3.55-3.64 (m, 2H, 3-H, 3′-H), 3.70-3.76 (m, 2H, 11a-H, 11a′-H), 3.78-3.87 (m, 2H, 3-H, 3′-H), 3.92 (s, 6H, 7-OMe, 7′-OMe), 4.02-4.20 (m, 4H, 12-H, 12′-H), 6.81 (s, 2H, 9-H, 9′-H), 7.52 (s, 2H, 6-H, 6′-H), 7.67 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.9, 29.0, 29.3, 29.5, 29.6, 46.6, 53.7, 56.0, 69.1, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.2, 164.6; IR (neat): 3325, 2928, 1600, 1507, 1448, 1261, 1217, 1023 cm−1; MS (FAB) m/z (relative intensity) 709 ([M+2×MeOH]+., 14), 677 ([M+MeOH]+., 20), 645 (M+., 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc(C#N)cc2)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (300 mg, 0.79 mmole), para-cyanophenylboronic acid (233 mg, 1.59 mmole), cesium carbonate (776 mg, 2.38 mmole) and tetrakis(triphenylphosphine)palladium (92 mg, 0.08 mmole) in dioxane (4 ml) was refluxed for 16 h before it was cooled to room temperature, quenched with water and filtered. The filtrate was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a white solid (136 mg). MS: (+) m/z 402.32 (M+H+)
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([C:12]3[N:13]=[N:14][C:15](=[O:17])[CH:16]=3)=[CH:6][C:5]=2[O:4]1.[H][H].S(O[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([C:40]1[CH:41]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([N+:58]([O-:60])=[O:59])[CH:53]=2)[C:42]([C:48]([O:50][CH3:51])=[O:49])=[C:43]([CH3:47])[NH:44][C:45]=1[CH3:46])=[O:39])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([C:12]3[NH:13][N:14]=[C:15]([O:17][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([C:40]4[CH:41]([C:52]5[CH:57]=[CH:56][CH:55]=[C:54]([N+:58]([O-:60])=[O:59])[CH:53]=5)[C:42]([C:48]([O:50][CH3:51])=[O:49])=[C:43]([CH3:47])[NH:44][C:45]=4[CH3:46])=[O:39])[CH:16]=3)=[CH:6][C:5]=2[O:4]1
Reactant: O=C1C=C(c2ccc3c(c2)OCO3)N=N1
Reactant: [H][H]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOS(=O)(=O)c2ccc(C)cc2)C1c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOc2cc(-c3ccc4c(c3)OCO4)[nH]n2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
0.24 g (10 mmole) of sodium hydride was suspended in 10 ml of N,N-dimethylformamide, to which was added 2.45 g (12 mmole) of 3-(3,4-methylenedioxyphenyl)-5-pyrazolone with stirring at room temperature. After evolution of hydrogen had ceased, to this solution was added dropwise 10 ml of a solution of 5.87 g (10 mmole) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester in N,N-dimethylformamide, and the mixture was stirred and heated at 90° C. for an hour. The resultant reaction mixture was poured into 200 ml of ice water, and the separated solid was filtered off. This solid was recrystallized from ethyl acetate to obtain 3.21 g (yield 51.9%) of the 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-[5-(3,4-methylenedioxyphenyl)-3-pyrazolyloxy]hexyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]2)[C:5]([F:16])=[CH:4][C:3]=1[NH-:17].[O:18]=[C:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:32](O)=O)[C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2>C(O)(=O)C>[F:16][C:5]1[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]2)=[CH:7][C:2]2[NH:1][C:32]([C:27]3[C:26]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19](=[O:18])[C:31]=4[CH:30]=[CH:29][CH:28]=3)=[N:17][C:3]=2[CH:4]=1
Reactant: CN1CCCN(c2cc(N)c([NH-])cc2F)CC1
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Solvent: CC(=O)O
Product: CN1CCCN(c2cc3[nH]c(-c4cccc5c4-c4ccccc4C5=O)nc3cc2F)CC1

Procedure:
The procedure used in Example 68 is followed. In a 100 ml round-bottomed flask under an argon atmosphere, reflux, for 6 hours, a suspension of 950 mg of [2-amino-5-fluoro-4-(4-methylperhydro-1,4-diazepin-1-yl)phenyl]-amide of 9-oxo-9H-fluorene-4-carboxylic acid, obtained in the previous stage, in 15 ml of acetic acid. After purification by formation of a paste with diisopropyl ether, in this way we obtain 950 mg of 4-[5-fluoro-6-(4-methyl-perhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-9H-fluoren-9-one, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics: