Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH:19]4[CH:17]([CH:18]4[N:21](CC4C=CC=CC=4)CC4C=CC=CC=4)[CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:16][CH:17]4[CH:19]([CH:18]4[NH2:21])[CH2:20]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CC3C(C2)C3N(Cc2ccccc2)Cc2ccccc2)nn1
Agent: [Pd]
Solvent: CO
Product: NC1C2CN(c3ccc(C(=O)NCCC4CC4)nn3)CC12
Reaction time: 72 h

Procedure:
To a stirred solution of 6-(6-dibenzylamino-3-azabicyclo[3.1.0]hex-3-yl)pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.415 g, 0.90 mmol) in methanol (10 mL) was added Pd/C (0.200 g, 12 mol %). The mixture was placed under an atmosphere of hydrogen for 3 days. The reaction mixture was filtered through celite and concentrated in vacuo. The crude title compound was obtained and used without further purification.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1.[CH2:15]([O:19][C:20]([N:22]([C:33]1[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=1)[S:23]([C:26]1[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24])=[O:21])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:19][C:20]([N:22]([C:33]1[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=1)[S:23]([C:26]1[C:27]([C:9]2[CH:10]=[CH:11][C:6]([C:2]3[O:1][CH:5]=[N:4][N:3]=3)=[CH:7][CH:8]=2)=[N:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: OB(O)c1ccc(-c2nnco2)cc1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(-c2nnco2)cc1

Procedure:
In this aspect of the invention [4-(1,3,4-oxadiazol-2-yl)phenyl]boronic acid is coupled with N-(isobutoxycarbonyl)-2-chloro-N-(3-methoxy-5-methylpyrazin -2-yl)pyridine-3-sulphonamide to form N-(isobutoxycarbonyl) N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulphonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>ClCCl>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][S:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: Sc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CSc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100.2 %

Procedure:
To a solution of 3,5-dichloro-thiophenol (0.50 g, 2.71 mmol) in dichloromethane (8 ml) at 0° C. were added triethylamine (0.49 ml, 3.55 mmol) and a solution of ethyl bromoacetate (0.33 ml, 2.93 mmol) in dichloromethane (2 ml). The resulting solution was stirred at 0° C. for 20 min and then at room temperature for 1 hour. The reaction mixture was then washed sequentially with water and with 1 N aq hydrochloric acid. The organic phase was dried over sodium sulphate, filtered and concentrated in vacuo to yield a light yellow oil (0.72 g, 100%); 1H NMR (300 MHz, CDCl3): 7.26 (2H, d), 7.20 (1H, t), 4.21 (2H, q), 3.65 (2H, s), 1.26 (3H, t).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[C:27]([CH3:32])[CH:28]=[C:29]([O:30][CH3:31])[C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc(C)cc(B(O)O)c1O
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cc(C)cc(OC)c4O)n3)n2)c1
Yield: 43 %

Procedure:
6-(2-Hydroxy-5-methoxyphenyl)-6′-(2-hydroxy-3-methoxy-5-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-3-methoxy-5-methylphenylboronic acid in 43% yield using method F; δH [2H6]-DMSO 13.40,(1H, s), 12.51,(1H, s), 8.37,(1H, d), 8.29,(1H, d), 8.20,(2H, t), 8.14,(2H, d), 7.67,(1H, s), 7.51,(1H, s), 7.00,(1H, d), 6.94,(2H, m), 3.83,(6H, s), 2.34,(3H, s).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[CH:11]=2)[NH:6][C:5]([CH3:22])([CH3:21])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CS(C)=O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH3:22])([CH3:21])[CH:4]=[C:3]2[CH2:2][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccccc1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 60 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline in 1 mL of DMSO was treated with 46 mg of potassium carbonate and 17 μL of aniline at room temperature. The resulting mixture was stirred at room temperature overnight. Then the mixture was quenched with water and the product was extracted into EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give 9 mg of the title compound as a foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:13]([NH:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[C:3]=1[N+:10]([O-:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(O)n1
Solvent: CCO
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(O)n1

Procedure:
Stir a solution of 4-chloro-6-methyl-3-nitro-pyridin-2-ol (10.0 g, 53.0 mmol) and benzyl amine (17.3 g, 159 mmol) in EtOH (30 mL) at ambient temperature for 12 h, then concentrate in vacuo. Pour the resulting residue into water, acidify to pH 3 with 1N HCl and filter. Wash the precipitate several times with water to obtain the title compound as a yellow solid.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])[CH:27]=[CH:28][CH:29]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:37])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: COc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: COc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3-methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.Cl.[CH3:11][NH:12][CH3:13].C(N(CC)CC)C>ClCCl>[CH3:11][N:12]([CH3:13])[S:6]([C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1H-imidazole-4-sulfonyl chloride (0.5 g, 3.0 mmol; Matrix Scientific, Columbia, S.C.) in dichloromethane (10 mL) was added dimethylamine hydrochloride (0.245 g, 3.0 mmol) and triethylamine (1.3 mL, 9.0 mmol) at room temperature. The mixture was stirred for 16 hours at room temperature. TLC (petroleum ether/ethyl acetate=0:1) indicated the reaction was complete. The reaction mixture was washed with aq. ammonium chloride (30 mL) and extracted with dichloromethane: methanol=4:1 (3×50 mL). The combined organic phases were concentrated and precipitated from methanol to afford (I-35a) (0.36 g, 68.2%) as a white solid; 1H NMR (400 MHz, CD3OD): δ 7.74 (1 H), 7.61 (1 H), 2.68 (6 H).
Reaction SMILES: [Si](O[CH2:9][CH:10]=[N:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])(C(C)(C)C)(C)C.[F:18][C:19]1[CH:20]=[CH:21]C(C=O)=[N:23][CH:24]=1.CC([S@@](N)=O)(C)C>>[F:18][C:19]1[CH:20]=[CH:21][C:9]([CH:10]=[N:11][S@:12]([C:14]([CH3:15])([CH3:16])[CH3:17])=[O:13])=[N:23][CH:24]=1
Reactant: O=Cc1ccc(F)cn1
Reactant: CC(C)(C)[S@@](=O)N=CCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[S@@](N)=O
Product: CC(C)(C)[S@](=O)N=Cc1ccc(F)cn1

Procedure:
The title compound was prepared using a procedure similar to the one described for the synthesis of Intermediate 21, using 5-fluoropyridine-2-carbaldehyde and (S)-2-methylpropane-2-sulfinamide as the starting materials. 1H NMR (300 MHz, CDCl3) δ ppm 8.67 (s, 1H) 8.58 (s, 1H) 8.06 (dd, J=8.29, 4.52 Hz, 1H) 7.51 (t, J=7.91 Hz, 1H) 1.20-1.33 (m, 9H). The product was used without purification.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([CH2:22][CH:23]3[CH2:27][CH2:26][N:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[C:24]3=[O:34])=[C:17]([Cl:35])[CH:16]=2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[Cl:35][C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])=[CH:10][CH:11]=2)[CH:20]=[C:19]([Cl:21])[C:18]=1[CH2:22][CH:23]1[CH2:27][CH2:26][N:25]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[C:24]1=[O:34]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(Oc1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)C(=O)O
Temperature: 25 °C
Yield: 72.9 %

Procedure:
Dissolve 2-[3′,5′-Dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-yloxy]-2-methyl-propionic acid ethyl ester (Example 195) (0.20 g, 0.37 mmol) in ethanol (10 mL) and treat with 5 N NaOH (0.4 mL). Heat the reaction to reflux for 1 hour, cool to room temperature and remove the solvent in vacuo. Aqueous 1 N HCl is added to adjust the pH to pH ˜1 and the mixture is extracted with ethyl acetate and water. The organic layer is dried (Na2SO4) to afford 136 mg (72%) of the title compound: LC-MS (ES+) m/z=exact mass calcd for C27H31Cl2NO4 503, found 504 and 506 (M+1 and M+3, 100%) and Rt (Purity at 214 nm)=6.03 min (96.7%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[OH:25]O.O>C(O)(C)C>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:25])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: OO
Solvent: O
Solvent: CC(C)O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 1 h
Yield: 88 %

Procedure:
HCl, 1.376 g of 2-mercaptobenzimidazole, and 0.134 g of benzyl triethyl ammonium chloride as an interphase transfer catalyst were mixed in 24 ml of dichloromethane. 0.9534 g of NaOH (40%)/12 ml water mixture solution was dripped into the above mixture while stirring. The temperature of the resulting solution was raised to 40° C. for about 2 hours. Then, dichloromethane was removed from the mixture under a reduced pressure. The solid obtained was stirred with 50 ml of water, and filtered to obtain 3.28 g of solid Lansoprazole precursor: 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio]-1H-benzimidazole. At room temperature, 3.28 g of the above precursor, 0.1625 g of polyethylene glycol-400 as an interphase transfer catalyst, and 0.3936 g of Mo(acac)2 as an oxidation catalyst were mixed in 45 ml of isopropanol (abbreviated as IPA). To the resulting mixture 3.06 g of 35% H2O2 aqueous solution was added in 5–10 minutes. The reaction was carried out for about one hour, and then 60 ml of water was added, and the reaction was continued for another one hour while stirring. Finally, the precipitate formed was filtered, water washed, and dried to obtain Lansoprazole with a yield of about 88% (HPLC purity>98%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[C:1]([C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7]([O:9][CH3:17])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 2-tert-butyl-5-nitrobenzoic acid (120 mg, 0.53 mmol) and K2CO3 (147 mg, 1.1 mmol) in DMF (5.0 mL) was added CH3I (40 μL, 0.64 mmol). The reaction mixture was stirred at room temperature for 10 min, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After filtration, the filtrate was concentrated to give methyl 2-tert-butyl-5-nitrobenzoate, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=2.6 Hz, 1H), 8.17 (t, J=1.8 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 4.11 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: C[N+]1([O-])CCOCC1.[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:12][C:11]=1[CH2:21][OH:22]>CC#N.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:12][C:11]=1[CH:21]=[O:22]
Reactant: CC(=O)NCc1ccc(Cl)c(CO)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC(=O)NCc1ccc(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
NMO (1.15 g, 8.26 mmol) was added to a sol. of N-(4-chloro-3-hydroxymethyl-benzyl)-acetamide (588 mg, 2.75 mmol) in CH3CN (27 mL). The sol. was stirred for 30 min at rt, and tetrapropylammonium perruthenate (97 mg, 0.28 mmol) was added. The mixture was stirred for 1 h at rt, and was filtered over Celite. The precipitate was washed with CH3CN. The filtrate was evaporated under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 95:5) yielded the title compound (382 mg, 66%). LC-MS: tR=0.71 min; ES+: 253.07.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1-c1ccc(Cl)cc1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 4-chlorophenylboronic acid. Yield 0.63 g
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14](Cl)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[NH3:23]>O>[CH2:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:23]2[CH2:11][CH2:12][N:7]([CH3:5])[CH2:8][CH2:9]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CCN(CC(Cl)c2ccc(F)cc2)CC1
Reactant: N
Agent: Cl
Solvent: O
Product: CCOC(=O)N1CCN(CC(c2ccc(F)cc2)N2CCN(C)CC2)CC1
Temperature: 65 °C

Procedure:
To 7.6 g of 1-ethoxycarbonyl-4-[2-chloro-2-(4-fluorophenyl)ethyl]piperazine hydrochloride were poured 5 ml of 25% aqueous ammonia solution and water and, after extraction with ether, the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 20 ml of benzene, and 5.4 ml of 1-methylpiperazine was added, followed by heating at 65° C. for 3.5 hours. To the reaction solution were poured 25% aqueous ammonia solution and water and, after extraction with ether, the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=4:1) to give 6.58 g of 1-ethoxycarbonyl-4-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]piperazine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].NC1C=CC([N+]([O-])=O)=C[C:15]=1[S:23](N)(=[O:25])=[O:24].CS(O)(=O)=O.CS(Cl)(=O)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:23]([CH3:15])(=[O:25])=[O:24])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)O
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1

Procedure:
The 2-chloro-5-nitro-benzenesulfonamide intermediate (prepared as described in scheme 14) can be treated with a benzylic amine, such as benzylamine, to displace the chloro moiety. Hydrogenation under standard conditions in the presence of an acid (e.g., methanesulfonic acid) can be used to remove the benzylic group and to reduce the nitro group at the same time to afford the 2,5-diamino-benzenesulfonamide intermediate as a salt. Alternatively, the 2,5-diamino-benzenesulfonamide salt can be prepared by reduction of the 2-amino-5-nitro-benzenesulfonamide (prepared as described in schemes 14 and 15) under standard hydrogenation conditions in the presence of an acid (e.g., methanesulfonic acid). Subsequent reaction with methanesulfonyl chloride affords the desired 2-amino-5-methanesulfonylamino-benzenesulfonamide intermediate.
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:12]3[N:13]4[CH2:21][CH2:20][N:19]=[C:14]4[S:15][C:16]=3[CH:17]=[O:18])[CH:10]=[CH:11][C:4]1=2.O>CO>[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:12]3[N:13]4[CH2:21][CH2:20][N:19]=[C:14]4[S:15][C:16]=3[CH2:17][OH:18])[CH:10]=[CH:11][C:4]1=2
Reactant: O=CC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 14.8 %

Procedure:
Sodium borohydride (0.13 g) was added in portions at 0-5° C. to a stirred suspension of 3-(benzo[b]thiophen-5-yl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxaldehyde (0.67 g) in methanol (20 ml), then the mixture was stirred at this temperature for 45 minutes and at ambient temperature for 1.5 hours. Water (10 ml) was added dropwise, the mixture was stirred at ambient temperature for 1 hour, and the resulting solid was collected by filtration and washed with water. The solid was dissolved in ethanol, the solvent was removed in vacuo, and the residue was triturated with dichloromethane 10 ml). The resulting solid was collected by filtration and dried in vacuo to give [3-(benzo[b]thiophen-5-yl)-5,6-dihydroimidazo[2,1-b]-thiazol-2-yl]methanol (0.1 g) as a pale yellow solid, m.p. 149-150° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[ClH:30].[CH2:31]([OH:33])[CH3:32].O1CCOCC1>>[ClH:30].[CH2:31]([O:33][C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:7][CH:8]=1)=[NH:2])[CH3:32]
Reactant: CCO
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C#N)cc2)CCO3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=N)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To N-(4-cyanophenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (347 mg) was added a solution of 28% hydrogen chloride/ethanol/dioxane (5 ml). After the resulting mixture was stirred at room temperature for 20 hours, the precipitate was collected by filtration and was washed with ethyl acetate to obtain N-[4-(ethoxycarbonimidoyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide hydrochloride (369 mg) as yellow crystals.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:34])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[NH:16][C:15]1=[O:33])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl[CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[O:47][CH3:48].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:48][O:47][C:38]1[CH:39]=[CH:40][C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:37]=1[CH2:36][N:16]1[C:15](=[O:33])[C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH3:34])[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Reactant: COc1ccc2ccccc2c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To a rt solution of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (141 mg, 284 μmol) in DMF (710 μl) was added 1-(chloromethyl)-2-methoxynaphthalene (64.6 mg, 312 μmol), cesium carbonate (111 mg, 341 μmol), and sodium iodide (51.1 mg, 341 μmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (151 mg, 80%) as a white solid. MS m/z 689 (MNa)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)C>[CH2:23]([N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCBr
Reactant: CC1(C)CC(O)CC(C)(C)N1
Solvent: CCO
Product: CCCCCCCCCCCCN1C(C)(C)CC(O)CC1(C)C

Procedure:
A mixture of 15.7 parts of 2,2,6,6-tetramethylpiperidin-4-ol and 12.5 parts of n-dodecyl bromide in 50 parts of ethyl alcohol was heated under reflux conditions for 72 hours. The cooled reaction mixture was filtered to remove 2,2,6,6-tetramethylpiperidin-4-ol hydrobromide formed during the reaction and the ethyl alcohol solvent was removed by distillation under reduced pressure. The residue was treated with petroleum under (b.p. 40°-60°C) and filtered to remove the unreacted 2,2,6,6-tetramethylpiperidin-4-ol and the petroleum ether solvent was removed by distillation under reduced pressure. Fractional distillation of the residue gave 1-n-dodecyl-2,2,6,6-tetramethylpiperidin-4-ol having a melting point of 41°-2°C and the following elemental analysis by weight: