Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:31]([O-])([N+]([O-])=O)=[O:32]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:31]=[O:32])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 77.7 %

Procedure:
3.7 g of 1-(2-chloroethyl)-3-n-hexyl-3-D-glucopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 3.1 g of 1-(2-chloroethyl)-1-nitroso-3-n-hexyl-3-D-glucopyranosylurea are thereby obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)(=[O:25])=[O:24])COC)[C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[N:6][CH:7]=1.O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)(=[O:24])=[O:25])[C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[N:6][CH:7]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A mixture of 2-{5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-benzoic acid (150 mg, 0.27 mmol) in 3 ml of 4M HCl in dioxane and 1 mL of water was refluxed for 2 hours. After cooling to room temperature the mixture was concentrated and then diluted with water. Sodium bicarbonate was added until pH was 6. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was further purified via flash column (70% ethyl acetate in hexane) to afford 60 mg of title compound as an off white solid. MS: (M+H)/z =519.4.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([C:15]2[O:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1.[OH2:32]>CS(C)=O>[Br:1][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1([C:15]1[O:16][C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1)[OH:32]
Reactant: O
Reactant: C1=C(c2nc(-c3ccccc3)c(-c3ccccc3)o2)CCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Product: OC1(c2nc(-c3ccccc3)c(-c3ccccc3)o2)CCCCC1Br
Reaction time: 19 h
Yield: 38.3 %

Procedure:
N-Bromosuccinimide (2.64 g) was added to a stirred suspension of 2-(1-cyclohexenyl)-4,5-diphenyloxazole (3.00 g) in dimethyl sulfoxide (20 ml) and water (267 mg) at room temperature and the resulting mixture was stirred at the same temperature for 19 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography to afford 2-bromo-1-(4,5-diphenyl-2-oxazolyl)cyclohexanol (1.52 g) as a yellow solid.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12.O=[C:20]1[CH2:29][CH2:28][C:27]2[CH:26]=[C:25]([C:30]#[N:31])[CH:24]=[CH:23][C:22]=2[CH2:21]1>>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH:20]4[CH2:29][CH2:28][C:27]5[CH:26]=[C:25]([C:30]#[N:31])[CH:24]=[CH:23][C:22]=5[CH2:21]4)[CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: O=C1CNCCN1CCc1ccc2nonc2c1
Reactant: N#Cc1ccc2c(c1)CCC(=O)C2
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4nonc4c3)C(=O)C1)C2

Procedure:
The title compound was prepared from 1-[2-(2,1,3-Benzoxadiazol-5-yl)ethyl]piperazin-2-one and 6-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 402 [M+1]+.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([OH:15])(=[O:14])[CH:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10].CI>CCCCCC>[CH3:1][C:7]([CH2:11][CH2:12][CH3:13])([CH2:8][CH2:9][CH3:10])[C:6]([OH:15])=[O:14]
Reactant: [Li]CCCC
Reactant: CCCC(CCC)C(=O)O
Solvent: CCCCCC
Solvent: CI
Product: CCCC(C)(CCC)C(=O)O

Procedure:
The alkylation of the carboxylic acids at position 2 using alkyl halides is very generally possible with the aid of n-butyllithium at elevated temperature (Pfeffer et al., Alpha-anions of carboxylic acids. II. The formation and alkylation of alpha-metalated aliphatic acids. Journal of Organic Chemistry 37, 451-458 (1972). The methylation of the tertiary carbon atom of valproic acid is possible, for example, by deprotonation of the α-hydrogen atom at C-2 using n-butyllithium in hexane at 50° C. and subsequent methylation with methyl iodide at room temperature in a yield of 32%. The other 2-alkylated carboxylic acids can also be prepared in accordance with this method.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][NH:27][CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([N:27]([CH3:28])[CH3:26])=[O:16])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1ccc(NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 62 %

Procedure:
A solution of 4-diphenylacetylamino-benzoic acid (150 mg, 0.45 mmol), dimethylamine (2.0 M in THF, 203 mg, 0.24 mL, 4.5 mmol), EDC (86 mg, 0.45 mmol) and HOBT (61 mg, 0.45 mmol) in CH2Cl2 (15 mL) was stirred at room temperature for 17 h. The reaction mixture was diluted with CHCl3 and washed with 10 N HCl (4 mL), sat'd aq NaHCO3 (4 mL) and sat'd aq brine. The organic solution was dried and concentrated in vacuo to give the title compound as a white solid (100 mg).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[CH:13][C:12]([O:19][C@@H:20]4[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]([OH:29])[C@H:21]4[OH:30])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:31])[CH:2]=1.C1C(C2C(=O)C3C=CC([O:49][C@@H:50]4[O:55][C@H](CO)[C@@H](O)[C@H:52]([OH:59])[C@H:51]4O)=CC=3OC=2)=CC=C(O)C=1>C(O)C>[CH:5]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12]([O:19][C@@H:20]4[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]([OH:29])[C@H:21]4[OH:30])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:1][CH:2]=[C:3]([OH:31])[CH:4]=1.[C:50]([O-:49])(=[O:55])[CH2:51][C:52]([O-:59])=[O:9].[CH:5]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([O:19][C@@H:20]4[O:25][C@H:24]([CH2:26][O:27][C:52]([CH2:51][C:50]([OH:55])=[O:49])=[O:59])[C@@H:23]([OH:28])[C@H:22]([OH:29])[C@H:21]4[OH:30])=[CH:13][C:14]=3[OH:18])[O:9][CH:8]=2)=[CH:1][CH:2]=[C:3]([OH:31])[CH:4]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(O)c12
Agent: O=c1c(-c2ccc(O)cc2)coc2cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc12
Solvent: CCO
Product: O=C(O)CC(=O)OC[C@H]1O[C@@H](Oc2cc(O)c3c(=O)c(-c4ccc(O)cc4)coc3c2)[C@H](O)[C@@H](O)[C@@H]1O
Product: O=C([O-])CC(=O)[O-]

Procedure:
A chromatography column containing a gel (Sephadex LH-20) 3 cm in diameter and 50 cm tall is prepared. 2.4 g of the impure extract obtained in step iii) diluted with ethanol is introduced into the column. The impure extract is eluted with ethanol at a rate of 2 ml per minute. A total of 17 fractions are obtained, 6 of these fractions containing the malonates of genistin and daidzin. These 6 fractions are subjected to a second chromatography in a column containing octadecyl silane groups attached to silica (Lobar RP-18). A 10% aqueous ethanol solution is used as the eluent at a rate of 2 ml per minute. Two fractions each containing a different product are finally obtained. These fractions are dried under reduced pressure in an evaporator at a temperature of 40° C. 25 mg daidzin malonate and 80 mg genistin malonate, both highly pure (92-98%), are obtained in the form of amorphous solids, the first white in colour and the second pale yellow in colour.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:41]=[CH:40][C:22]([O:23][C:24]2[CH:25]=[C:26]([NH2:39])[CH:27]=[C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=3)[CH:29]=2)=[CH:21][CH:20]=1)#[N:18]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:39][C:26]2[CH:27]=[C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=3)[CH:29]=[C:24]([O:23][C:22]3[CH:40]=[CH:41][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)[CH:25]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(Oc2cc(N)cc(Oc3ccc(C#N)cc3)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 51.7 %

Procedure:
Following the procedure of Example 9(e) piperidine-1,4-dicarboxylic acid mono-tert-butyl ester 0.7 g (3.05 mmol) and [3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (1.0 g, 3.05 mmol) were used to afford 0.85 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (4H, m), 1.31 (9H, s), 1.8 (4H, d), 2.21 (1H, t), 3.1 (1H, m), 6.81 (1H, d), 7.04 (1H, s), 7.2 (6H, m), 7.91 (4H, dd), 10.0 (1H, brs).
Reaction SMILES: C[Si]([PH:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([O-:9])[O:6][CH2:7][CH3:8])(C)C.[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18].C(Cl)(Cl)Cl>O>[O:20]=[C:19]([CH3:21])[CH2:17][CH2:18][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: C=CC(C)=O
Reactant: CCOC(OCC)[PH]([O-])(OCC)[Si](C)(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(OCC)P(=O)(CCC(C)=O)OCC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
The starting material may be prepared as follows: 15.0 g of ethyl trimethylsilyl(diethoxymethyl)phosphonite are added dropwise to a stirred solution of 3.9 g of methyl vinyl ketone under an atmosphere of nitrogen at room temperature. The mixture is then heated to 50° C. for a period of 1 hour. The mixture is then allowed to cool to room temperature, 25 ml of chloroform is then added followed by 10 ml water and this mixture is vigorously stirred for a period of 0.5 h. The organic layer is then separated, dried over magnesium sulphate and concentrated under reduced pressure and the crude product distilled under reduced pressure to give ethyl 3-oxobutyl(diethoxymethyl)phosphinate, b.p. 130°-135° C./0.02 mbar, 31P=+45.3 ppm (CDCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([NH2:11])[CH2:6][CH2:5]2.[F:12][C:13]([F:25])([F:24])[C:14]([NH:16][C:17]1([C:21](O)=[O:22])[CH2:20][O:19][CH2:18]1)=[O:15].NC1(C(O)=O)COC1.C(OC(=O)C(F)(F)F)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([NH:11][C:21]([C:17]1([NH:16][C:14](=[O:15])[C:13]([F:25])([F:12])[F:24])[CH2:18][O:19][CH2:20]1)=[O:22])[CH2:6][CH2:5]2
Reactant: O=C(NC1(C(=O)O)COC1)C(F)(F)F
Reactant: N[C@H]1CCc2cc(Br)ccc21
Agent: CCOC(=O)C(F)(F)F
Agent: NC1(C(=O)O)COC1
Product: O=C(NC1(C(=O)N[C@H]2CCc3cc(Br)ccc32)COC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B] and A-1 [C], (S)-5-bromo-indan-1-ylamine has been coupled with 3-(2,2,2-trifluoro-acetylamino)-oxetane-3-carboxylic acid (prepared from 3-amino-oxetane-3-carboxylic acid and trifluoro-acetic acid ethyl ester in analogy to the procedure described for the preparation of intermediate A-1 [A]) to give 3-(2,2,2-trifluoro-acetylamino)-oxetane-3-carboxylic acid ((S)-5-bromo-indan-1-yl)-amide, which was subsequently reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to yield the title compound as dark brown viscous oil. MS: 453.3 (M−H−).
Reaction SMILES: [H-].[Na+].CI.[CH3:5]N(C=O)C.[CH2:10]([O:17][C@@H:18]([CH3:31])[C@@H:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([OH:22])=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C@@H:18]([CH3:31])[C@@H:19]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:5])[C:20]([OH:22])=[O:21])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H](OCc1ccccc1)[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
In a round bottom flask, under argon atmosphere, commercially available (2R,3S)-3-benzyloxy-2-(tert-butoxycarbonyl-amino)-butanoic acid was dissolved in dry THF (15 mL). Subsequently at 0° C., NaH (60% dispersion in mineral oil, 0.21 g, 5.33 mmol) was added in one portion. The reaction mixture was left to stir at the same temperature for 10 min and then MeI (0.95 mL, 15.22 mmol) followed by DMF (0.75 mL) were sequentially added. The reaction was left for 2.0 h at 0° C. and for 15 h at rt, then quenched with H2O (15 mL), diluted with EtOAc (30 mL) and acidified to pH 2 by dropwise addition of 2.0 N HCl aqueous solution. The organic layer was separated and the aqueous phase was back-extracted with EtOAc (2×30 mL). The organic phase was dried over Na2SO4, filtered and concentrated to dryness. The crude mixture was purified by column chromatography using a Teledyne ISCO apparatus eluting with Cy:TBME (60:40) to give the title compound (1.1 g, 67%), as a mixture of two rotamers (2:1 ratio), as a colorless oil. 1H NMR (DMSO-d6) δ 1.13-1.20 (m, 6H), 1.36 (s, 9H, minor rotamer), 1.41 (s, 9H, major rotamer), 2.84 (s, 3H, minor rotamer), 2.87 (s, 3H, major rotamer), 4.13-4.24 (m, 2H), 4.34-4.40 (m, 2H), 4.49 (d, J=5.5 Hz, 1H, minor rotamer), 4.57-4.62 (m, 2H), 4.71 (d, J=5.2 Hz, 1H, major rotamer), 7.23-7.35 (m, 10H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)=[N:3][C:4]=1[CH3:12]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)nc1C
Reactant: Nc1ccc(CCO)cc1
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)nc1C
Yield: 37 %

Procedure:
A mixture of 2-chloro-5,6-dimethyl-3-nitropyridine (Godard, A.; Rocca, P.; Pomel, V.; et al. J. Organomet. Chem., 1996, 517, 25. ; Rocca, P.; Marsais, F.; Godard, A.; et al. Tetrahedron Lett., 1993, 34, 2937., 3.3 g, 17.5 mmol), 4-aminophenylethyl alcohol (3.6 g, 26.3 mmol) and 2,6-lutidine (3.7 mL) in toluene (80 mL) was stirred under reflux temperature for 19 h. The mixture was diluted with ethyl acetate (100 mL) and washed with 1N aqueous NaOH (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 1.8 g (37%) of the title compound as orange solids: 1H-NMR (CDCl3) δ 8.24 (1H, br.s), 7.68 (2H, d, J=8.6 Hz), 7.24 (2H, d, J=8.6 Hz), 3.88 (2H, dt, J=6.1, 7.6 Hz), 2.88 (2H, t, J=7.6 Hz), 2.49 (3H, s), 2.26 (3H, s), 1.43 (1H, t, J=6.1 Hz).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].C(N(CC)CC)C.[CH3:15][O:16][C:17](=[O:33])[C@H:18]([CH3:32])[NH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH3:30])[C:21]=1[CH3:31]>C1(C)C=CC=CC=1>[CH3:15][O:16][C:17](=[O:33])[C@H:18]([CH3:32])[N:19]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH3:30])[C:21]=1[CH3:31])[C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2]
Reactant: COC(=O)[C@H](C)Nc1c(C)c(C)cc2ccccc12
Reactant: CCOCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOCC(=O)N(c1c(C)c(C)cc2ccccc12)[C@@H](C)C(=O)OC
Reaction time: 12 h

Procedure:
During 30 minutes 0.07 g-moles of ethoxyacetyl chloride, dissolved in 20 ml of toluene, and 0.07 g-moles of triethylamine, dissolved in 20 ml of toluene, are dropped at room temperature simultaneously to 0.06 g-moles of N-(2,3-dimethylnaphthyl)-alanine methyl ester, dissolved in 100 ml of toluene. Thereby the temperature rises to 43°. The reaction mixture is then stirred at about 40° during 12 hours. From the resulting yellow suspension the inorganic salt is filtered off and the filtrate is washed with water until neutral. Then the organic phase is dried over sodium sulfate and concentrated by evaporation. The crude oil is purified by column chromatography using silicagel 60 and diethylether as the eluant. After removal of the solvent 18.8 g (=91% of theory) of the final product are obtained in crystallised form, m.p. 96° to 108°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][S:16][C:17]1[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=1)=[N:8][CH:7]=[CH:6]2.C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C([O-])(O)=O.[Na+].OS([O-])=O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][S:16]([C:17]1[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=1)=[O:34])=[N:8][CH:7]=[CH:6]2
Reactant: COc1cc2ccnc(CSc3nc4ccccc4[nH]3)c2cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2cc1OC
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To a solution of 246.0 mg of 2-[(6,7-dimethoxyisoquinolin-1-yl)methylthio]benzimidazole (Ia-1) (0.700 mmol) in 10 ml of CHCl3 was added 151.0 mg of 80% 3-CPBA (0.700 mmol) at -10°--15° C., and the mixture was stirred for 30 min. at the same temperature. The reaction mixture was mixed with 3 ml of saturated aqueous solution of NaHCO3 and 0.3 ml of 10% aqueous solution of NaHSO3. The reaction temperature was returned to room temperature, and the reaction mixture was mixed with 2 ml of water and extracted with CHCl3. The CHCl3 layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography, eluting with AcOEt-MeOH. The obtained crystals were washed with CH2Cl2 -benzene to give 216.2 mg of the objective compound 2-[(6,7-dimethoxyisoquinolin-1-yl)methylsulfinyl]benzimidazole (Ic-1) (Yield: 83.7%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1C(Cl)=O)=[O:4].[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([CH2:23][NH:24][C:25]([C:27]3[C:28]4[CH2:36][CH2:35][CH2:34][CH2:33][C:29]=4[S:30][C:31]=3[NH2:32])=[O:26])=[CH:22][C:17]=2[O:16][CH2:15]1.[C:37]1(=[O:43])CCCCC1.O1C2C=CC(CNC(=O)CC#N)=CC=2OC1.[S]>ClCCl.N1C=CC=CC=1>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([CH2:23][NH:24][C:25]([C:27]3[C:28]4[CH2:36][CH2:35][CH2:34][CH2:33][C:29]=4[S:30][C:31]=3[NH:32][C:37]([C:11]3[CH:10]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)=[O:43])=[O:26])=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: O=C1CCCCC1
Reactant: Nc1sc2c(c1C(=O)NCc1ccc3c(c1)OCO3)CCCC2
Reactant: COC(=O)c1ccccc1C(=O)Cl
Agent: N#CCC(=O)NCc1ccc2c(c1)OCO2
Agent: [S]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2sc3c(c2C(=O)NCc2ccc4c(c2)OCO4)CCCC3)cc1
Reaction time: 2 h

Procedure:
1.0 g of methoxycarbonylbenzoyl chloride ("A") is added to a solution of 1.5 g of N-(benzo[1,3]dioxol-5-ylmethyl)-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide [obtainable by reacting cyclohexanone with N-benzo[1,3]dioxol-5-ylmethyl-2-cyanoacetamide in the presence of sulphur) in 50 ml of dichloromethane and 2 ml of pyridine and stirring is carried out for 2 hours at room temperature. The solvent is removed and is worked up in the customary manner. 1.3 g of methyl 4-{3-[(benzo[1,3]dioxol-5-ylmethyl)carbamoyl]-4,5,6,7-tetrahydrobenzo[b]thiophene-2-ylcarbamoyl}benzoate, m.p. 165°, are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@:12]([CH2:22][OH:23])([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1.C(OCC)(=O)C.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@@:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[CH:19][CH:20]=2)([CH2:22][OH:23])[CH2:11][O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(CO)CCc1ccc(O)cc1
Reactant: Fc1cccc(OCCBr)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(CO)CCc1ccc(OCCOc2cccc(F)c2)cc1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-4-hydroxymethyl-4-[2-(4-hydroxy-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (100 mg, 0.28 mmol) in DMF (5 ml) is added CsCO3 (120.5 mg, 0.37 mmol, 1.3 eq) and 1-(2-bromo-ethoxy)-3-fluoro-benzene (80.7 mg, 0.37 mmol, 1.3 eq). The reaction mixture is stirred at 85° C. for 4 hours. Ethyl acetate and water are then added, the organic layer is separated and the aqueous phase is extracted with ethylacetate (3×50 ml). The combined organic extracts are washed with brine, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (AcOEt/Hx 9:1) affords (S)-4-(2-{4-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-ethyl)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as colorless oil.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.Br[C:21]1[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:25][CH:26]=1.C([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=C.CCCCCCCCCCCCCCCC>C(OCC)C>[F:28][C:27]([F:30])([F:29])[C:23]1[CH2:22][C:21]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH:26]=[CH:25][CH:24]=1)[CH:1]=[CH2:2]
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=COCCCC
Solvent: CCOCC
Solvent: CCCCCCCCCCCCCCCC
Product: C=CC1(OCCCC)C=CC=C(C(F)(F)F)C1
Temperature: 120 °C

Procedure:
26 mg (0.025 mmol) bis-(dibenzalacetone)-chloroform-palladium and 27mg (0.1 mmol) triphenyl phosphine are placed in a Schlenk-tube under argon. 4 ml solvent, 1.12 g (5 mmol) 3-bromo-benzotrifluoride 0.76 g (7.5 mmol) triethyl amine and 0.75 g (7.5 mmol) butyl vinyl ether are added. The reaction mixture is heated to 120° C. for 20 hours. It is cooled to room temperature and 200 mg hexadecane (internal standard) and 15 ml diethylether are added. The mixture is analysed by GC.