Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5].[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[O:28][CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[N:17][C:2]([O:27][C:24]2[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[C:22]([O:28][CH3:29])[CH:23]=2)=[C:3]([CH:14]=1)[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5]
Reactant: COc1cc(O)ccc1SC
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](O)CC2)ccc1SC
Temperature: 55 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-nicotinamide (150 mg, 0.55 mmol), 4-methylsulfanyl-3-methoxy-phenol (94 mg, 0.55 mmol) and caesium carbonate (358 mg, 1.10 mmol) were suspended in DMF (2 ml) and the reaction was heated to 55° C. and stirred at this temperature under nitrogen for 18 h. The reaction was quenched with sat. ammonium chloride solution (1.5 ml) and water (1.5 ml) and the organic phase was collected by passing the mixture through a Chemelute™ cartridge, washing with ethyl acetate. The solvent was removed on a Genevac™ and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume) to give 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(4-methylsulfanyl-3-methoxy-phenoxy)-nicotinamide (99 mg) as an off-white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=O.[CH3:14][CH:15]([CH2:20][CH2:21][CH3:22])[C:16](OC)=[O:17].O.[NH2:24][NH2:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:15]([CH3:14])([CH2:20][CH2:21][CH3:22])[C:16](=[O:17])[NH:24][N:25]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: CCCC(C)C(=O)OC
Reactant: NN
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: O
Product: CCCC1(C)C(=O)NN=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for example C5 using 3,4-dimethoxybenzoyl chloride, methyl 2-methylpentanoate and hydrazine hydrate as starting compounds.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[C:6]([CH3:16])=[C:5]2[C:17](=[O:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[C:6]([CH3:16])=[C:5]2[CH:17]([OH:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C(O)c1ccc(S(C)(=O)=O)cc1
Yield: 18.2 %

Procedure:
A solution of [6-fluoro-4-(4-methanesulfonyl-benzoyl)-3-methyl-naphthalen-2-yl]-acetic acid (60 mg, 0.15 mmol) (example 6-1) in methanol (12 mL) was hydrogenated using a H-cube hydrogenation reactor with a flow rate of 1.7 mL/min and a 10% palladium on carbon catalyst cartridge at 20° C. under 10 bar hydrogen pressure. The reaction mixture was concentrated in vacuo. The crude product was purified using flash chromatography (RediSep® Flash column, 230-400 mesh, 2%-5% methanol in dichloromethane) to give 11 mg (18%) of {6-fluoro-4-[hydroxy-(4-methanesulfonyl-phenyl)-methyl]-3-methyl-naphthalen-2-yl}-acetic acid as an oil. 1H NMR (300 MHz, CDCl3) δ ppm: 7.82 (d, J=8.2 Hz, 2 H), 7.74 (dd, J=9.1, 6.0 Hz, 1 H), 7.61-7.70 (m, 2 H), 7.49 (d, J=8.2 Hz, 2 H), 7.15 (td, J=8.3, 2.1 Hz, 1 H), 6.73 (s, 1 H), 3.86 (br. s, 1 H), 3.48 (s, 2 H), 3.01 (s, 3 H), 2.41 (br. s, 3 H); HRMS (ESI+) cald. for C21H19FO5S [(M+Na)] 425.0829, obsd. 425.0827.
Reaction SMILES: [C:1]1([CH:7]2[C:12]3[CH:13]=[C:14]([CH:16]=O)[S:15][C:11]=3[C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[O:8]2)[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.C(O)(=O)[CH2:23][C:24]([OH:26])=[O:25].N1C=CC=CC=1.N1CCCCC1>O>[C:1]1([CH:7]2[C:12]3[CH:13]=[C:14]([CH:16]=[CH:23][C:24]([OH:26])=[O:25])[S:15][C:11]=3[C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[O:8]2)[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc2c(s1)-c1ccccc1OC2C1=CCCC=C1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc2c(s1)-c1ccccc1OC2C1=CCCC=C1

Procedure:
A stirred solution of 17.6 g 4H-4-phenyl-thieno[3,2-c][1]benzopyran-2-carboxaldehyde, 12.5 g malonic acid and 24 ml pyridine is slightly heated until a clear solution is obtained. Subsequently, 1 ml piperidine is added and the solution slowly heated to reflux. After 3 h reflux, the solution is cooled and poured into water. After acidification with hydrochloric acid, the crude product is filtered off, dried, recrystallized from ethyl acetate and dried in vacuo. Pure 3-(4H-4-phenyl-thieno[3,2-c][1]benzopyran-2yl)propenoic acid is obtained; m.p. 235° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]1[S:12](=[O:14])(=[O:13])[O:11][CH2:10][CH2:9]1>C(#N)C>[C:2]1([NH2+:1][CH2:10][CH2:9][CH2:8][S:12]([O-:14])(=[O:13])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: O=S(=O)([O-])CCC[NH2+]c1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of aniline (7 mmol) and propane sultone (10 mmol) was heated in 10 mL of acetonitrile at 12.0-130° C. for 9 h in a pressure tube under argon atmosphere. The product was allowed to cool to room temperature and the solid of 3-phenylammonio-1-propanesulfonate was filtered and air-dried. Yield: 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1.[CH3:12][C:13]1[NH:14][C:15](=[O:25])[CH2:16][S:17][C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([O:10][CH:16]1[C:15](=[O:25])[NH:14][C:13]([CH3:12])=[C:18]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[S:17]1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=C(c2ccncc2)SCC(=O)N1
Solvent: ClCCl
Product: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Reaction time: 0.17 h
Yield: 37.6 %

Procedure:
m-Chloroperbenzoic acid (8.97 g, 70% purity) was added to a solution of 5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (5.0 g) in dichloromethane (120 ml) under ice/water-cooling and the mixture was stirred for 10 minutes under ice/water-cooling. The mixture was washed with saturated sodium bicarbonate aqueous solution (2 times) and successively with water (1 time) and was dried over magnsium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from ether-petrolem ether to give the titled compound (3.29 g, yield 37.6%) as pale yellow needles.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:10][C:11]1[C:15](=[CH2:16])[CH:14]=[CH:13][CH:12]=1.B(F)(F)F.CCOCC.O>C(Cl)Cl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([CH2:16][C:15]2[C:11](=[CH2:10])[CH:12]=[CH:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: C=C1C=CC=C1CO
Agent: FB(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: C=C1C=CC=C1Cc1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Anisole (0.04 mL, 0.37 mmol) was added to a solution of hydroxymethylfulvene (10 mg, 0.04 mmol) in dry CH2Cl2 (5 mL). The mixture was cooled to -78° C. and boron triflouride etherate (0.04 mL, 0.36 mmol) was added dropwise. The reaction was stirred at that temperature for 1 hour and water was added to quench the reaction. The organic layer was washed with H2O, saturated NaHCO3 and brine, and dried over MgSO4. Concentration of the solution gave a residue which was dried in vacuo, yielding the product in quantitative yield (14 mg). 1H NMR δ 0.59-1.40 (m, 4 H). 1.36 (s, 3 H), 1.76 (s, 3 H), 2.07 (s, 3 H), 3.78 (s, 3 H), 3.95 (s, 1 H), 3.99 (d, J=16.12 Hz, 2 H), 6.81 (d, J=8.8 Hz, 2 H), 6.96 (d, J=8.3 Hz, 2 H), 7.22 (s, 1 H). MS m/Z 336 (M+), 308 (M+--CH2CH2), 215, 121 ((CH2 --Ph--OCH3)+). UV 410 nm (2.7×103), 325 nm (7.0×103), 267 nm (1.0×104), 245 nm (inflection), 226 nm (1.9×104), 203 nm (1.4×104). The compound has the structure: ##STR18##
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:11]([C:12]([NH:14][O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[N:10]=[C:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:8]1)=[N+:2]=[N-:3].I[CH3:35].[H-].[Na+]>CN(C=O)C>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:11]([C:12]([N:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH3:35])=[O:13])[N:10]=[C:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:8]1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: CC(C)(C)ONC(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(OC(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 2-(3-azidopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (0.061 g, 0.13 mmol) and iodomethane (0.18 g, 1.3 mmol) in DMF (4 mL) was added sodium hydride (0.006 g, 0.26 mmol). After stirring at 0° C. for 30 minutes and then at room temperature for 1 hour, the mixture was partitioned between ethyl acetate (10 mL) and saturated NH4Cl (5 mL). The organic layer was washed with water (2×5 mL), dried and concentrated under reduced pressure to provide the crude product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[NH2:23]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-methoxy-5-trifluoromethylaniline (55 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (27 mg, 34%). 1H NMR (CDCl3): 9.65–9.64 (m, 1H), 8.75–8.70 (m, 2H), 7.46–7.41 (m, 2H), 7.36 (s, 1H), 7.31 (s, 1H), 7.00 (s, 1H), 6.93 (s, 1H), 3.91 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].[C:16]([O-])(O)=O.[Na+].CI.O>CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
1,4-Dihydroxy-2-naphthoic acid (10 g, 49 mmol) and NaHCO3 (4.12 g, 49 mmol) was dissolved in DMF (dimethylformamide) (50 mL). Methyl iodide (6.96 g, 49 mmol) was added and the solution stirred at room temperature for 24 h, poured into water (1 L), filtered and washed with water to give the title compound (8.80 g, 82%) as a green powder.
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH3:22].C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:21]([C:24]1[CH:29]=[C:28]([C:2]2[C:7]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:9]=[N:10][C:6]=3[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCCO
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (7.38 g, 19 mmol), 3-acetylphenyl boronic acid (4.67 g, 28.5 mmol), 1,3-propanediol (6.8 ml, 95 mmol), potassium carbonate (13.1 g, 95 mmol) and bis(triphenylphosphin)palladium dichloride (200 mg, 0.28 mmol) in a mixture of dimethoxyethane (60 ml) and water (30 ml) was stirred at reflux in a nitrogen atmosphere for 1 hour. The cooled reaction mixture was filtered through a pad of Celite and the filter was rinsed with ethyl acetate. The organic layer was collected, dried over magnesium sulphate and concentrated under reduced pressure. The title product precipitated upon addition of diethyl ether to the concentrate (6.17 g, 85%) m/z, 381.1 (M+H)+.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1([CH3:18])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:9]=2[O:8]1.[H-].[Na+].Cl[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1>O>[CH3:6][C:7]1([CH3:18])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:17][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=3)=[CH:16][C:9]=2[O:8]1
Reactant: CC1(C)CCc2ccc(O)cc2O1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CCc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
Five milliliters of an N,N-dimethylformamide solution of 1.5 g of 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-1-benzopyran synthesized by the method of Referential Example 19 was added dropwise to a mixture of 0.35 g of sodium hydride and 4 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 0.5 hour, and 6 ml of an N,N-dimethylformamide solution of 2-chloro-5-nitropyridine (1.3 g) was added to the resulting reddish orange solution, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into 100 ml of water, and extracted with 100 ml of ethyl acetate. The extract was dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography to give 2.1 g (yield 84%) of the desired product as a yellow liquid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:13]([NH:14][C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)=S)=[CH:12][N:11]=[CH:10][N:9]=1>[Hg]=O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][CH:12]=2
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2cncnc2NCc2ccco2)CC1
Agent: O=[Hg]
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2nc3cncnc3n2Cc2ccco2)CC1
Reaction time: 2 h
Yield: 21.5 %

Procedure:
A mixture of 4 parts of ethyl 4-[[[[4-[(2-furanylmethyl)amino]-5-pyrimidinyl]amino]thioxomethyl]-amino]-1-piperidinecarboxylate, 6 parts of mercury(II) oxide and 80 parts of ethanol was stirred for 2 hours at reflux temperature. The whole was filtered while hot over Hyflo® and the filtrate was evaporated. The residue was crystallized from a mixture of acetonitrile and ethanol. The product was filtered off and dried, yielding 0.8 parts (21.5%) of ethyl 4-[[9-(2-furanylmethyl)-9H-purin-8-yl]amino]-1-piperidinecarboxylate; mp. 171.9° C. (compound 7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([OH:28])[CH3:27])=[CH:21][C:20]=3[CH2:29][NH:30][CH3:31])[CH2:15][CH2:14]2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O.CS(C)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[O:28])[CH3:27])=[CH:21][C:20]=3[CH2:29][NH:30][CH3:31])[CH2:15][CH2:14]2)[CH3:12])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CNCc1cc(CC(C)O)ccc1[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: CNCc1cc(CC(C)=O)ccc1[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(Cl)cc2)CC1

Procedure:
285 mg (0,613 mMol) of trans-N-(4-chlorobenzene-sulphonyl)-N-methyl-4-[4-(2-hydroxypropyl)-methylaminomethylphenyl]cyclohexylamine are oxidised using the Pfitzner-Moffatt method (380 mg (1.94 mMol) of dicyclohexylcarbodiimide, 35 mg (0.3 mMol) of trifluoroaceticacid, 0.9 ml (12.8 mMol) of dimethylsulphoxide and 2 ml of benzene). 160 mg (56% of theory) of the title compound are obtained in the form of colourless crystals, melting point 98°-100° C. 1H-NMR spectrum (200 MHz, CDCl3); signals at ppm: 1.35 (m, 1H), 1.5-2.0 (m,9H), 2.15 (s,2H), 2.3 (s,2H), 2.4 (m, 1H) , 2.8 (s, 3H) , 3.15 (s,2H) , 3.55 (S, 2H) , 3.9 (m, 1H) , 7.1-7.7 (2q, 8H).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH:14]([OH:29])[CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.[C:30](Cl)([Cl:32])=[S:31].C.Cl>C(O)(C)C.C(Cl)(Cl)Cl.C(O)C>[ClH:32].[OH:29][CH:14]([CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[CH2:13][O:12][C:6]1[C:5]2[NH:4][C:30](=[S:31])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(CCNCC(O)COc2cccc(N)c2N)cc1OC
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(CCNCC(O)COc2cccc3[nH]c(=S)[nH]c23)cc1OC
Reaction time: 2 h

Procedure:
17.4 g. 2,3-Diamino-1-[2-hydroxy-3-(3,4-dimethoxyphenethylamino)-propoxy]-benzene trihydrochloride are dissolved in 450 ml. chloroform and 50 ml. ethanol and mixed dropwise at ambient temperature with 3.2 ml. thiophosgene in 30 ml. chloroform. After 2 hours, the reaction mixture is treated with active charcoal and then evaporated to dryness. The residue is purified over a column of silica gel, using chloroform/methanol (8:2 v/v) as elution agent, to give 10 g. (62% of theory) of uniform product. After taking up in isopropanol and mixing with ethereal hydrochloric acid, followed by precipitation by the addition of ethyl acetate, there is obtained 4-[2-hydroxy-3-(3,4-dimethoxyphenethylamino)propoxy]-benzimidazoline-2-thione hydrochloride; m.p. 108°-110° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:42]1[CH2:48][CH2:47][CH2:46][C@H:43]1[CH2:44][OH:45]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([N:42]1[CH2:48][CH2:47][CH2:46][C@H:43]1[CH:44]=[O:45])=[O:18])[CH:13]([CH3:14])[CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C=O
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 22.1 g of N-benzyloxycarbonylvaline. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from isopropyl alcohol to obtain a white solid substance which was then dissolved in 470 ml of THF. To this solution was added 8.6 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 43.1 g of WSCD.HCl and 150 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently, 7 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 300 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 200 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 200 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 5.7 g (17.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.[C:19]([CH2:23][CH2:24][C:25](Cl)=[O:26])([O:21][CH3:22])=[O:20]>N1C=CC=CC=1>[CH3:22][O:21][C:19](=[O:20])[CH2:23][CH2:24][C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(N)cc1
Reactant: COC(=O)CCC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)Nc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (500 mg, 1.99 mmol) in anhydrous pyridine (10 mL) was added dropwise 3-carbomethoxypropionyl chloride (Fluka) (300 μL) at rt. After 60 min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 400 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (80 mL) was added into the filtrate and a white solid precipitated out. Filtration and washing with water gave a white solid, which was dried under vacuo at 70° C. for 2 hrs. The title compound (461 mg) was obtained as a white solid (63%) in 96.0% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1)=[O:4].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C1CC[C@H](NC(=O)C(F)(F)F)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
Degassed DMF (argon sparged, 100 mL) was added to Intermediate Ab (8.00 g, 31.3 mmol) and [N-[(1R,2R)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium (Strem Chemicals Inc.; 594 mg, 0.93 mmol). Triethylamine (8.66 mL, 62.6 mmol) was added slowly to ice cold formic acid (2.34 mL, 62.6 mmol) and stirred for 20 min, this was then added to the DMF solution. The reaction was heated to 60° C. for 18 h. After cooling, the mixture was partitioned between DCM (200 mL) and water (600 mL). The aqueous layer was extracted DCM (3×) and the combined organic layers washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, using 0-100% EtOAc in cyclohexane, afforded the title compound (7.10 g, 27.4 mmol, 88%). 1H NMR (400 MHz, CDCl3): 1.88-1.92 (1H, d, J 4.8 Hz), 1.98-2.18 (4H, m), 4.80-4.88 (1H, m), 5.165-5.24 (1H, m), 6.70-6.80 (1H, br s), 7.25-7.30 (1H, m), 7.30-7.40 (2H, m), 7.45-7.50 (1H, m).