Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][N:27]=[N:26]1)[C:10]([C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH:21]([OH:23])[CH3:22])=[CH:15][CH:14]=1)([F:12])[F:11]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][N:27]=[N:26]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([OH:23])[CH3:22])=[CH:15][CH:14]=1)([F:12])[F:11]
Reactant: CC(O)/C=C/c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: [Pd]
Solvent: CO
Product: CC(O)CCc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
To a solution of (E)-4-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)but-3-en-2-ol (46; 150 mg, 0.35 mmol) in CH3OH (10 mL) was added 10% Pd/C (10 mg), and the mixture was stirred under hydrogen atmosphere for 30 min. The reaction mixture was filtered through a pad of Celite®, the Celite® cake was washed with EtOAc (3×20 mL) and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (eluting with EtOAc/hexane) afforded 47 (77 mg, 0.18 mmol, 51%) as a viscous liquid. 1H NMR (500 MHz, CDCl3): δ 8.78 (s, 1H), 8.39-8.38 (m, 1H), 7.68-7.65 (m, 1H), 7.53-7.51 (m, 1H), 7.43-7.36 (m, 1H), 6.80-6.68 (m, 1H), 6.66-6.62 (m, 1H), 5.47-5.45 (m, 1H), 5.18-5.12 (m, 1H), 3.82-3.79 (m, 1H), 2.84-2.81 (m, 1H), 2.79-2.76 (m, 1H), 1.80-1.76 (m, 2H), 1.23 (d, J=7.0 Hz, 3H). MS (ESI): m/z 426 [M+H]+. HPLC: 98%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[O:11][CH2:12][CH3:13])[CH3:2].O[CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].S(=O)(=O)(O)O.O>COCCOC>[CH2:12]([O:11][C:5]1[C:6]([F:10])=[C:7]([CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[CH2:15][N:16]1[C:20](=[O:21])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]1=[O:26])[CH3:13]
Reactant: CCOc1cccc(F)c1OCC
Reactant: O=C1c2ccccc2C(=O)N1CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: COCCOC
Product: CCOc1ccc(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Temperature: 25 °C
Yield: 0 %

Procedure:
To a solution of 1,2-diethoxy-3-fluorobenzene (2.28 g, 12.4 mol) and N-(hydroxymethyl)phthalimide (2.41 g, 13.6 mol) in 1,2-dimethoxyethane (8 mL), a solution of sulfuric acid (8 mL) in 1,2-dimethoxyethane (8 mL) was added dropwise on ice, and the mixture was stirred at room temperature for twelve hours. The reaction mixture was poured into water (100 mL), and crystals were filtered. The obtained crystals were recrystallized from acetone and water, and the precipitated crystals were filtered. After the filtrate was concentrated under reduced pressure, the residue was crystallized from acetone to give 0.96 g of the title compound (yield: 23%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:4].[N+:10]([O-])([OH:12])=[O:11].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccsc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1csc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 3-thiophene carboxylic acid methyl ester (1.8 g, 12.68 mmol) in acetic acid (7.5 ml) was added a mixture of nitric acid (0.67 ml), acetic acid (7.5 ml) and acetic anhydride (4.3 ml) at 0-10° C. The reaction mixture was stirred at 40° C. for 1 hr and then poured into crushed ice. The solid was filtered, washed with cold water and dried. The compound was recrystallised using ether/hexane to give 5-nitro-thiophene-3-carboxylic acid methyl ester (1.0 g, 42%).
Reaction SMILES: [Mg].C(I)C.II.Br[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=1.S(=O)(=O)(O)O>C1COCC1>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)=[CH2:23])=[CH:9][CH:10]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CC(=O)c1ccc(C)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCI
Product: C=C(c1ccc(C)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
15.6 g (0.65 mol) of magnesium and 20 ml of THF were placed in a 1-liter reaction flask in a stream of nitrogen, the reaction was initiated with a small amount of ethyl iodide and iodine, and a solution of 111.15 g (0.65 mol) of p-bromotoluene in 500 ml of THF was added dropwise at a temperature from room temperature to 40° C. for 2 hours to prepare a Grignard reagent. A solution of 83.75 g (0.625 mol) of p-methylacetophenone (11c) in 200 ml of THF was added dropwise thereto at the same temperature for 3 hours. The resulting solution was stirred at room temperature for 3 hours, and subsequently stirred under reflux for 4 hours. Then, the solution was cooled, and poured into 1 liter of 5% aqueous sulfuric acid to conduct hydrolysis. The resulting product was extracted with toluene, and the extract was washed with aqueous soda ash, washed with water, and concentrated. Then, 300 ml of toluene and 0.5 g of PTSA were added thereto, followed by stirring under reflux for 4 hours to carry out azeotropic dehydration. The resulting product was washed with aqueous soda ash, washed with water, and concentrated. Crude 1,1-di(p-tolyl)ethylene (9c) was distilled in a Claisen flask equipped with a vigreux to obtain 98.5 g.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[N-:21]=[N+:22]=[N-:23].[Na+].O.C([O-])(O)=O.[Na+]>CS(C)=O>[N:21]([CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1)=[N+:22]=[N-:23]
Reactant: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CBr)c2F)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
2-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (2.00 g, 5.32 mmol) and sodium azide (0.346 g, 5.32 mmol) were combined in DMSO (10 mL) and stirred 16 h at 25° C. at which time TLC indicated complete conversion (10% Et2O/hexanes). Water (150 mL) and saturated aqueous NaHCO3 (30 mL) were added and the mixture stirred vigorously for 30 min. The resultant precipitate was filtered off, washed with water, and air dried to give 2-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (1.76 g, 5.21 mmol, 98% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (d, J=0.73 Hz, 1H), 7.96 (d, J=0.73 Hz, 1H), 7.48-7.60 (m, 2H), 4.60 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[Cl:44][C:39]1[CH:38]=[C:37](/[C:35](/[CH3:36])=[CH:34]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)[CH:42]=[CH:41][C:40]=1[Cl:43]
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC(=CBr)c1ccc(Cl)c(Cl)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (67 mg, 0.31 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (6 mg, 0.032 mmol), L-proline (7 mg, 0.063 mmol) and K3PO4 (134 mg, 0.63 mmol) were added and the reaction mixture was stirred for 10 min at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 53 mg. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.82 (s, 1H), 7.60 (s, 2H), 7.36 (d, 1H), 7.10 (d, 1H), 7.0 (m, 2H), 3.78 (m, 2H), 3.40 (m, 2H), 3.20 (m, 4H), 3.08 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32]C)=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[C:11]2[C:6]([C:7](=[O:36])[CH2:8][C:9]([CH3:35])([CH3:34])[O:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([OH:32])=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:19][CH2:20]2)=[C:11]2[C:6]([C:7](=[O:36])[CH2:8][C:9]([CH3:34])([CH3:35])[O:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5=O)CC3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(=O)O)cc43)CC1)OC(C)(C)CC2=O
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
3.5 g of the above crude product of methyl 1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxylate was dissolved in 28.0 mL of tetrahydrofuran and added with 14 mL of 1 N aqueous sodium hydroxide. 14 mL of methanol was added and the mixture was heated to 40° C. and stirred for 30 minutes. 7 mL of tetrahydrofuran and 3.5 mL of methanol were added and the mixture was stirred for 2 hours and further stirred at the same temperature for about 16 hours. When the reaction mixture was cooled with an ice-water bath and the pH was adjusted to 7 with 12.2 mL of 1 N hydrochloric acid and 0.5 mL of 1 N sodium hydroxide, crystals precipitated. 10 mL of water was further added to this slurry, and crystals were obtained by filtration and the crystals were washed with 21 mL of a mixture of 2-propanol and water (5:1). The crystals were dried in vacuo and 2.45 g of the title compound was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)NC(CC)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 90 mg (0.74 mmol) pentanoyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([OH:10])[CH2:9][C@H:2]12.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:24][C:12]([F:11])([F:23])[C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][C@@H:8]([OH:10])[CH2:9][C@@H:2]3[CH2:1]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: O[C@H]1C[C@@H]2CNCCN2C1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCN2C[C@@H](O)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol (0.208 g, 1.463 mmol) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (0.358 g, 1.463 mmol) in dichloromethane (3 mL) was added triethylamine (303 mg, 3 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by chromatography on silica gel (CH2Cl2/CH3OH=10:1) to give the title compound (0.4 g, 78% yield). MS (ESI) m/z 421 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[O:40])[CH2:36][C:37](=O)[CH3:38]>>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[O:40])/[CH:36]=[C:37](\[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])/[CH3:38]
Reactant: CC(=O)CC(=O)c1ccccc1F
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1ccccc1F)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 58 mg (0.32 mmol) of Intermediate 20 to yield 55 mg of Example 37: TLC (EtOAc/MeOH (7:3): Rf=0.25; 1H NMR (DMSO-d6, 400 MHz) δ11.42 (d, 1H, J=8.93), 7.95 (m. 2H), 7.70 (dd, 1H, J=1.78, 7.69), 7.51 (m, 4H), 7.23 (m, 4H), 6.88 (d, 2H, J=8.50), 5.36 (s, 1H), 4.22 (m, 2H), 4.16 (brs, 1H), 3.18 (m, 1H), 2.94 (m, 2H), 2.84 (m, 1H), 2.40 (s, 3H), 1.70 (s, 3H); low resolution MS (ES−)m/e 545.1 (M-H); RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 30-100% CH3CN in H2O) with 0.1% HCO2H buffer: 30 minutes; 1 mL/min: tr=19.47 min (to=1.43).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:31]=[N:30][C:12]3[N:13]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=4[C:11]=3[CH:10]=2)O1.C[N+]1([O-])CC[O:37]CC1>C1COCC1>[OH:37][C:9]1[CH:31]=[N:30][C:12]2[N:13]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:14]3[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=3[C:11]=2[CH:10]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC1(C)OB(c2cnc3c(c2)c2cc(C#N)ncc2n3COCC[Si](C)(C)C)OC1(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(O)cnc21
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (245 mg, 0.54 mmol) in THF (2.0 mL), under an inert atmosphere, was added N-methylmorpholine-N-oxide (191 mg, 1.63 mmol) and the reaction mixture was heated under reflux for 90 minutes. The reaction mixture was allowed to cool to ambient temperature and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, 12 g column, ISCO 0-50% ethyl acetate in cyclohexane) to afford the title compound as a white solid (180 mg, 97%). 1H NMR (CD3OD, 300 MHz): 9.10 (d, J=1.0 Hz, 1H), 8.64 (d, J=1.3 Hz, 1H), 8.35 (d, J=2.7 Hz, 1H), 8.04 (d, J=2.7 Hz, 1H), 5.99 (s, 2H), 3.59 (t, J=8.0 Hz, 2H), 0.86 (t, J=8.0 Hz, 2H), −0.14 (s, 9H). LCMS (Method B): RT=3.75 min, M+H+=341.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][CH2:17]N(C(C)C)C(C)C.C(OS(C(F)(F)F)(=O)=O)C.N1CCOCC1>>[CH2:16]([N:13]1[CH2:12][CH2:11][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1)[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Agent: CCOS(=O)(=O)C(F)(F)F
Solvent: C1COCCN1
Product: CCN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-Nitrophenyl)piperidine (255, 500 mg g, 2.4 mmol) was dissolved in 30 mLMeCN. To it were added DIEA (830 μL, 4.8 mmol) and then EtOTf (460 μL, 3.6 mmol). The mixture was stirred at RT for 10 min, and to it was added 0.5 mL morpholine. It was concentrated in vacuo and subjected to silica flash column using 0 to 7% MeOh in DCM to isolate 1-ethyl-4-(4-nitrophenyl)piperidine (259). It was dissolved in 40 mL EtOAc. To it was added 10% Pd/C (0.3 g), and the mixture was hydrogenated using a H2 balloon at RT for overnight. The mixture was filtered through celite, and concentrated in vacuo to give 4-(1-ethylpiperidin-4-yl)aniline (260) (410 mg, 83% overall) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].NCCCCN.[F:25]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O.[Cl-].[NH4+]>C1COCC1>[F:25][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(OC)c1
Agent: NCCCCN
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(F)c(NC(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.5 %

Procedure:
To a solution of tert-butyl (2,4-dimethoxyphenyl)carbamate (1.0 g) and tetramethylenediamine (1.4 mL) in THF (10 mL) was added 1.6 M n-butyllithium-hexane solution (7.5 mL) at −78° C., and the mixture was stirred at the same temperature for 20 min and then at 0° C. for 1 hr. To the reaction mixture was added a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (1.8 g) in THF (10 mL) at −78° C., and the mixture was allowed to warm to room temperature and stirred for 15 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (530 mg).
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]Br)=[CH:10][CH:9]=1>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][S:1]([O-:4])(=[O:3])=[O:2])=[CH:10][CH:9]=1.[Na+:5]
Reactant: BrCCc1ccc(Br)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCc1ccc(Br)cc1
Temperature: 106 °C
Yield: 79.6 %

Procedure:
Sodium sulfite (4.75 g, 37.68 mmol) was added to a suspension of 1-bromo-4-(2-bromo-ethyl)-benzene (5.00 g, 18.94 mmol) in water (60 mL). The reaction mixture was heated at 105-107° C. for 18 hours and then cooled to −5° C. The formed precipitate was removed by filtration, washed with water (50 mL) and dried under vacuum to give 4.33 g (86% yield) of the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([NH:14][C:15](=O)[CH2:16][Cl:17])[CH:7]=1)[CH2:2][CH3:3]>C(O)(=O)C>[CH2:1]([N:4]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:5]([C:6]1[CH:11]=[CH:10][C:9]2[N:12]([CH3:13])[C:15]([CH2:16][Cl:17])=[N:14][C:8]=2[CH:7]=1)=[O:19])[CH2:2][CH3:3]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc(NC)c(NC(=O)CCl)c1
Solvent: CC(=O)O
Product: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CCl)n2C

Procedure:
1.6 g (4.3 mMol) of 4-methylamino-3-chloracetamido-benzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide were heated to 100° C. in 25 ml of acetic acid for 30 minutes. Then the solvent was distilled off, the crude product was taken up in 40 ml methylene chloride/ethanol (9:1) and washed with 20 ml saturated sodium hydrogen carbonate solution. The organic phase was dried with sodium sulphate and evaporated down. Yield: 1.5 g (100% of theory) of brown oil, Rf value: 0.63 (silica gel; ethyl acetate/ethanol/ammonia =90:10:1)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH:25]=[CH:24]2)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])=[O:6].[NH:32]1[CH:36]=[N:35][CH:34]=[N:33]1>O1CCOCC1>[N:32]1([CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[CH:25]=[CH:24]3)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:7])=[O:6])[CH:36]=[N:35][CH:34]=[N:33]1
Reactant: c1nc[nH]n1
Reactant: O=c1ccc2cc(OCCCCN(Cc3ccccc3)S(=O)(=O)CCCCl)ccc2[nH]1
Solvent: C1COCCO1
Product: O=c1ccc2cc(OCCCCN(Cc3ccccc3)S(=O)(=O)CCCn3cncn3)ccc2[nH]1
Yield: 30.5 %

Procedure:
1.0 g of 6-{4-[N-(3-chloropropylsulfonyl)-N-benzylamino]butoxy}carbostyril and 600 mg of 1,2,4-triazole were stirred at 140° C. for 3 hours. The reaction mixture was diluted with dioxane. The resulting crystals were collected by filtration and purified by a column chromatography (eluant: 3% methanol/chloroform). The purified crystals were recrystallized from ethyl acetate to obtain 327 mg of 6-[4-{N-[3-(1,2,4-triazol-1-yl)-propylsulfonyl]-N-benzylamino}butoxy]-carbostyril.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([CH3:32])[CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21](C(C)=C)[C:20]4=[O:31])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C(O)C.Cl>CC(O)C>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([CH3:32])[CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:31])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: C=C(C)n1c(=O)n(CC(C)CN2CCC(n3c(=O)[nH]c4cc(Cl)ccc43)CC2)c2ccccc21
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: CC(CN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1)Cn1c(=O)[nH]c2ccccc21
Reaction time: 0.08 h
Yield: 19.7 %

Procedure:
A solution of 7 parts of 5-chloro-1-[1-{3-[1,3-dihydro-3-(1-methylethenyl)-2-oxo-2H-benzimidazol-1-yl]-2-methylpropyl}-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one in 120 parts of ethanol is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride. The whole is boiled for 5 minutes. The reaction mixture is evaporated and the residue is taken up in water. The mixture is alkalized with a concentrated ammonium hydroxide solution. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and ethanol. The product is filtered off and dried, yielding 1.3 parts (19.7%) of 5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-2-methylpropyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 244° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:19])C(=O)C1.O>CN(C=O)C>[Br:19][C:7]1[CH:6]=[CH:5][C:4]([NH2:8])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[F:1]
Reactant: Nc1cccc(F)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 138 (25 g, 0.160 mol) in DMF (250 mL) at 0° C. was added dropwise a solution of NBS (28.5 g, 0.160 mol) in DMF (100 mL). The resulting mixture was stirred at 0° C. for 1 h and then at RT for another hour. After the completion of the reaction, the mixture was poured into water (4 L) and extracted with EtOAc. The combined organic layers were washed with water and brine solution, dried (Na2SO4), filtered and concentrated in vacuo to afford 34 g (90%) of 4-bromo-3-fluoro-2-nitro-phenylamine (140) as a yellow solid which was used without further purification.