Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[C:20]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:27])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:28]([O:30]C)=[O:29])[CH:17]=3)[N:12]=1)=[CH:6][CH:5]=2.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[C:20]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:27])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:28]([OH:30])=[O:29])[CH:17]=3)[N:12]=1)=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCCC[C@@H]3C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2cc(-c3nc4ccc(C(=O)O)cc4nc3N3CCCC[C@@H]3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
To a solution of (S)-methyl 2-(2-methyl-1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate (142.1 mg, 0.34 mmol) in methanol (30 ml) was added NaOH (55 mg, 1.38 mmol) and water (2 ml). The resulting solution was stirred overnight at room temperature and concentrated under vacuum to give a residue, which was dissolved in water (20 ml), and the pH adjusted to 4 with HCl (3N). The solids were collected by filtration to afford (S)-2-(2-methyl-1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (11.9 mg, 9%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>C(O)(=O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]2=[O:16])=[CH:5][CH:4]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1Nc1ccc(Br)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
To a stirred solution of (4-bromophenyl)hydrazine hydrochloride (0.5 g, 2.2 mmol) in glacial acetic acid (8 mL) was added phthalic anhydride (0.398 g, 2.690 mmol), and the reaction mixture was stirred at 130° C. for 1 h under a nitrogen atmosphere. The reaction mixture was quenched with satd aq. NaHCO3 solution and filtered to give a solid. Purification by column chromatography (SiO2, 0-10% EtOAc in petroleum ether) afforded the title compound as a solid (60 mg, 84%): mp 205-206° C.; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.99 (m, 4H), 7.32 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H); ESIMS m/z 314.95 ([M−H−]).
Reaction SMILES: OS(O)(=O)=O.[OH:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=1.CC([OH:21])C.C(OCC)(=O)C>O.CC(C)=O.[Cl-].[Na+].O.[O-2].[Cr+6].[O-2].[O-2]>[CH2:16]([O:15][C:13]([C:10]1[CH:9]=[C:8]([C:7]([OH:21])=[O:6])[O:12][N:11]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cc(CO)on1
Reactant: CC(C)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(=O)O)on1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70 %

Procedure:
A 2M solution of the Jone's reagent was prepared by addition of 6 g of chromium (VI) oxide to a solution of H2SO4 (8.1 g) in water (25.5 mL). To a solution of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (4.00 g; 23.37 mmol) in acetone in an ice bath was added dropwise during a period of 20 min the Jone's reagent (27.71 mL; 51.42 mmol). The reaction mixture was then stirred at room temperature for additional 3.5 hours. 5 mL of 2-propanol were added and the stirring continued for further 1 hour. The solution became green. Brine (60 mL) and ethyl acetate (150 mL) were added to the reaction mixture and after separation, the organic layer was washed with an aqueous solution of sodium bisulphite (15 g in 100 mL of H2O) and with brine (100 mL). The organic layer was dried over magnesium sulfate. The evaporation of the solution furnished 3.03 g (70%) of 3-(ethoxycarbonyl)isoxazole-5-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=O)=[CH:5][C:4]=1[O:15][CH2:16][C:17]#[CH:18].[CH3:19][CH2:20][O:21][C:22]([CH2:24][C:25]#[N:26])=[O:23].N1CCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C(C)=CC=CC=1.O>[CH2:20]([O:21][C:22](=[O:23])[C:24]([C:25]#[N:26])=[C:9]1[C:10]2[C:6](=[CH:5][C:4]([O:15][CH2:16][C:17]#[CH:18])=[C:3]([O:2][CH3:1])[CH:11]=2)[C:7]([CH3:14])([CH3:13])[CH2:8]1)[CH3:19]
Reactant: C#CCOc1cc2c(cc1OC)C(=O)CC2(C)C
Reactant: CCOC(=O)CC#N
Agent: O=C(O)c1ccccc1
Solvent: C1CCNC1
Solvent: Cc1ccccc1C
Solvent: O
Product: C#CCOc1cc2c(cc1OC)C(=C(C#N)C(=O)OCC)CC2(C)C
Yield: 20.6 %

Procedure:
The above 6-methoxy-3,3-dimethyl-5-prop-2-ynyloxy-indan-1-one (2.44 g) was treated with 1.13 g of ethyl cyano acetate in the presence of 0.1 equivalents of pyrrolidine and benzoic acid in 20 ml of xylene. The reaction mixture was refluxed for 30 hours with simultaneous separation of water. Then, the cold reaction mixture was washed with water, concentrated and chromatographed in hexane/ethyl acetate through SiO2 to yield 0.7 g of yellow crystals. m.p. 132-136° C. UV 362 nm (ε=23′222), MS: 339(M+), 324, 300 (100%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=1.C(N(CC)CC)C.ClCCl.CS(C)=O>O>[CH:2]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=1)=[O:1]
Reactant: COc1cc(CO)ccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc(C=O)ccc1C(=O)O
Reaction time: 1.5 h

Procedure:
To a mixture of 4-hydroxymethyl-2-methoxybenzoic acid (1.5 g), triethylamine (5 g), dichloromethane (3 ml) and dimethyl sulfoxide (3 ml) was added portionwise sulfur trioxide pyridine complex (3.93 g) in water bath, and the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 4-formyl-2-methoxybenzoic acid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:37])=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)(=O)C>O1CCCC1>[F:37][C:21]([CH2:20][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(OC(F)(F)F)cc2)CC1)Cc1cccc(Oc2ccccc2)c1
Yield: 26.7 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.16 g), tetrahydrofuran (2 ml) and magnesium (17 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-trifluoromethoxyphenyl)cyclopropane (Example 19) (0.128 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C8; solvent: methanol; flow rate: 3 ml/min) to afford 1-(2-fluoro-3-(3-phenoxyphenyl)prop-1-enyl)-1-(4-trifluoromethoxyphenyl) cyclopropane (46 mg, 25%).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:18].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].[H-].[Na+]>CN(C=O)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1ccccc1-c1ccccc1
Yield: 77.3 %

Procedure:
1-([1,1'-Biphenyl]-2-ylmethyl)-4-hydroxy-2-methyl-1H-indole (767 mg, 2.45 mmol) was alkylated by treating with 0.23 mL (2.45 mmol) of methyl bromoacetate and 98 mg (2.45 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 730 mg (77% yield) of [[1-([1,1'-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, 99°-101° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([F:14])=[C:7]([Br:15])[CH:6]=1)[CH3:2]>CCO.[Ni]>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:6]=[C:7]([Br:15])[C:8]([F:14])=[C:9]([NH2:11])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(F)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cc(N)c(F)c(Br)c1

Procedure:
A mixture of 3-bromo-4-fluoro-5-nitro-benzoic acid ethyl ester (20 g, 2.2 mol) and 3 g of Raney-Ni in EtOH (250 mL) was hydrogenated at RT (1 atm) overnight. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was washed with petrol ether to afford the title compound as a white solid. (400 MHz, DMSO-d6): δ (ppm) 7.38 (dd, 1H), 7.26 (dd, 1H), 5.81 (s, 2H), 4.26 (q, 2H), 1.29 (t, 3H).
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][CH2:11][CH3:12])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:37][C:38]([NH2:40])=[NH:39])[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1>>[CH2:11]([O:10][CH:6]1[C:5]2[N:40]=[C:38]([NH:37][C:27]3[CH:28]=[CH:29][C:30]([N:31]4[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]4)=[C:25]([O:24][CH3:23])[CH:26]=3)[N:39]=[CH:3][C:4]=2[CH2:9][CH2:8][CH2:7]1)[CH3:12]
Reactant: CCOC1CCCC(=CN(C)C)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: CCOC1CCCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from 2-[1-dimethylamino-methylidene]-6-ethoxy-cyclohexanone (232 mg, 1.0 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (223 mg, 0.60 mmol) using in analogous manner the procedure described in example 45b). Obtained as a white solid (50 mg, 22%). MS ISP (m/e): 380.4 (100) [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:22][C:23]1[C:28]([Br:29])=[CH:27][C:26]([O:30][CH2:31][CH2:32][CH2:33][NH:34][CH3:35])=[CH:25][C:24]=1[Br:36]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:34]([CH3:35])[CH2:33][CH2:32][CH2:31][O:30][C:26]3[CH:25]=[C:24]([Br:36])[C:23]([NH2:22])=[C:28]([Br:29])[CH:27]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCCOc1cc(Br)c(N)c(Br)c1
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCCl)CC2
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCN(C)CCCOc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-1-chloropropane, N-[3-(4-amino-3,5-dibromophenyloxy)-propyl]-methylamine and triethylamine analogously to Example 6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(Cl)Cl.CN1CCOCC1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:33])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc(NS(=O)(=O)c2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To 5.0 g (33 mmol) of methyl 3-aminobenzoate (4) in 70 mL of methylene chloride containing 4.0 mL (36 mmol) of N-methylmorpholine was added 7.49 g (33 mmol) of 2-naphthalenesulfonyl chloride. After stirring at room temperature overnight, the reaction mixture was quenched with 1N HCl (100 mL). The suspension was dissolved in ca. 250 mL of tetrahydrofuran and enough ether was added to induce phase separation. The organic extract was washed with saturated sodium chloride solution (2×). The organic phase was dried (MgSO4), and concentrated to give 11.0g (97% yield) of the title compound as a pale yellow solid: 1H-NMR (200 MHz; DMSO-d6) δ8.46 (s, 1H), 8.13 (t, 2H), 7.99 (d, 1H), 7.55-7.75 (m, 5H), 7.43 (dd, 21H), 7.38 (d, 1H), 3.79 ppm (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(OC(C)C)(C)C.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>O>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:20](=[O:21])[CH2:19][CH2:18][Cl:17]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)CCCl
Solvent: CC(C)OC(C)C
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CCCl
Reaction time: 3 h
Yield: 59.7 %

Procedure:
A 2 l three-necked flask, is charged with 121.8 g of 2,6-dimethylaniline, 300 ml of isopropyl ether and 150 ml of water. 126.5 g of 3-chloropropanoyl chloride are added at a rate such that the internal temperature is between 5 and 10° C. At the end of the addition, the reaction medium is stirred for 3 h. The precipitate formed is filtered off with suction, washed with isopropyl ether and then with water and finally dried. 126 g of white crystals are obtained.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[F:23])=O>O1CCCC1>[F:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[C:13]([CH3:1])=[CH2:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(OC)cc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium bis(trimethylsilyl)-amide, 1.0M in tetrahydrofuran (714 ml, 0.714 m) was added to a suspension of methyltriphenylphosphonum bromide (255 g, 0.714 m) in THF (2.50 L) cooled with an ice bath. The resultant yellow colored suspension was stirred for 30 minutes at ice bath temperature and then cooled to −78° C. A total of 2-fluoro-4-methoxyacetophenone (10 g, 0.595 m) in THF (200 ml) was added dropwise and stirred at −78° C. for 1.5 hours. Reaction mixture was allowed to warm to room temperature for one hour, quenched with acetic acid (˜80 ml) where color change was observed from yellow to off white and stirred for 30 minutes (pH˜7)(slight exotherm noted). The mixture was concentrated to a slush, diluted with 7:2 hexane:ethyl acetate, and was allowed to sit overnight. Solids were removed by filtration and the filtrate was concentrated to yellow oil. The title compound was obtained after flash column using 9:1 hexane:ethyl as the eluant.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=O)[CH2:2]1)[CH2:8]2.[NH2:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O>[Cl:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C@H:4]2[CH:5]3[CH2:10][N:1]4[CH2:8][CH:7]([CH2:9][CH:3]2[CH2:2]4)[CH2:6]3)=[CH:18][CH:17]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1ccc(NC2C3CC4CC2CN(C4)C3)cn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 1-azatricyclo[3.3.1.13,7]decan-4-one (1.51 g, 10 mmol; see Becker, D. P.; Flynn, D. L. Synthesis 1992, 1080) in HOAc (50 mL) was treated with 3-amino-6-chloropyridine (1.90 g, 15 mmol; Aldrich), anhydrous Na2SO4 (18.5 g, 0.13 mol; Aldrich), and NaBH(OAc)3 (4.22 g, 20 mmol; Aldrich) and was stirred at ambient temperature for 10 hours. After the reaction was complete, the solid was filtered off, and the filtrate was concentrated. The residue was carefully basified with saturated aqueous Na2CO3 (pH 10), extracted with CHCl3 (3×100 mL), and the combined extracts were purified by flash chromatography [silica gel, ammonium hydroxide-methanol-chloroform (2:10:90)] to afford the title compounds:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[CH:25][CH:24]=2)[CH2:11][CH2:12][CH2:13][C:14]2[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=2)(=[O:9])=[O:8])[CH:2]=1.Cl.N1C=CC=C(S(Cl)(=O)=O)[CH:36]=1>C(N(CC)CC)C>[CH3:36][O:20][C:19]([C:17]1[S:18][C:14]([CH2:13][CH2:12][CH2:11][N:10]([S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:8])=[O:9])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[CH:27][CH:28]=2)=[CH:15][CH:16]=1)=[O:21]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=C(O)c1ccc(CCCN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)s1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCCN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)s1

Procedure:
The title compound of Step B was prepared from 5-[3-(4-thiazol-2-yl-benzylamino)-propyl]-thiophene-2-carboxylic acid methyl ester of Step A and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. MS 514 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(B(CC)[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)C.[OH-].[K+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCB(CC)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(-c3ccncc3)cc2)CC1

Procedure:
To a solution of 1-(4-bromobenzenesulfonyl)-4-(tert-butoxycarbonyl)piperazine (1.00 g) in tetrahydrofuran (50 ml) were added diethyl(pyridin-4-yl)boron (470 mg), tetrabutylammonium bromide (480 mg), potassium hydroxide (625 mg), tetrakistriphenylphosphine palladium (285 mg) and water (800 μl) at room temperature. The resulting mixture was heated under reflux for 1 hour. After allowed to cool down, the reaction mixture was added with ethyl acetate (50 ml) and water (100 ml). The water layer thus separated was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with saturated aqueous NaCl solution (50 ml), dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:ethyl acetate=1:1), whereby the title compound (540 mg) was obtained as a colorless transparent viscous substance.
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([N:10]([CH2:25][C@H:26]([OH:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:11]1[CH2:17][CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][C:20]([N+:22]([O-])=O)=[CH:21][C:13]=2[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.O.[Fe]>[NH2:22][C:20]1[CH:19]=[CH:18][C:14]2[CH2:15][CH2:16][CH2:17][CH:11]([N:10]([CH2:25][C@H:26]([OH:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:12][C:13]=2[CH:21]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Yield: 82.8 %

Procedure:
A suspension of powdered iron (160 mg) and ammonium chloride (15 mg) in a mixture of ethanol (6 ml) and water (2 ml) was refluxed, and to this one was dropwise added (2S)-1-[N-benzyl-N-(3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (158 mg) in ethanol (3 ml). After being further refluxed for 1 hour, insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved into a mixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 1:1) to give (2S)-1-[N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (122 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.C([Li])CCC.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[S:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1csc(-c2ccccc2[N+](=O)[O-])n1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 16.9 %

Procedure:
A solution of 4-methylthiazole (4.0 g, 40.33 mmol) in THF (80 mL) was cooled to −78° C. under nitrogen. n-Butyl lithium (20.4 mL of 2M in hexanes, 40.8 mmol) was added to the reaction mixture slowly over 3 minutes. The reaction mixture was stirred for about 1.5 hours at −78° C., and then 2-fluoronitrobenzene (6.24 g, 44.23 mmol) was added. After stirring at −78° C. for another 30 minutes, the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for about 2 hours at room temperature and then the reaction was quenched with water (70 mL). The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered and concentrated. The product was isolated by silica gel chromatography (5-10% ethyl acetate in hexanes) to give the title compound as an orange/brown oil (1.5 g). MS m/z: [M+H+] calcd for C10H8N2O2S 221.03; found 221. Retention time (HPLC 2-90)=4.54
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:32][CH3:33])=[CH:20][C:21]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:30][CH3:31])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].OO.CC[O:38]C(C)=O>C(O)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:32][CH3:33])=[CH:20][C:21]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:30]([CH3:31])=[O:38])=[CH:22][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3SC)cc(OC)c21
Agent: OO
Solvent: CC(=O)O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3S(C)=O)cc(OC)c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 714 mg (1.32 mmol) of 2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methylsulfanyl-benzyl)-1H-benzoimidazole and 142 μl (1.39 mmol) hydrogen peroxide solution (30%) in 13 ml acetic acid is stirred at room temperature for 1.5 h. After that 25 ml EtOAc are added and this solution is washed with 4n NaOH (2×), water and sodiumhydrogensulfite solution, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (EtOAc) to afford 496 mg of the title compound as colorless crystals.