Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][NH:6][C:7](=[O:40])[C@H:8]([C:17]([S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:19])[CH3:18])[NH:9]C(OC(C)(C)C)=O)[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][NH:6][C:7](=[O:40])[C@H:8]([C:17]([S:20][C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:19])[CH3:18])[NH2:9])[CH3:2]
Reactant: CCOC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)[C@@H](N)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
To the solution of N-t-butoxycarbonyl-S-trityl-L-penicillamylglycine ethyl ester (B-2) (4.5 g) and 2,6lutidine (2.8 ml) in dichloromethane (100 ml), was added dropwise at 0° C. the solution of trimethylsilyl trifluoromethanesulfonate (3.9 ml), and the mixture was stirred for 1 hour while the temperature was gradually returned to the room temperature. To the reaction mixture was added ice-water, and the organic layer was washed with 1N-hydrochloric acid, water, an aqueous solution of sodium hydrogencarbonate, water, and saturated saline, in this order, and dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, to give S-trityl-L-penicillamylglycine ethyl ester (3.8 g)
Reaction SMILES: [CH3:1][C:2]1([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[C:7](O)[CH:8]=2)[O:3]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH3:1][C:2]1([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[C:7]([C:20](=[O:22])[CH3:21])[CH:8]=2)[O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)cc2c(c1C)OC(C)(CCC(=O)O)CC2
Solvent: c1ccncc1
Product: CC(=O)c1cc2c(c(C)c1C)OC(C)(CCC(=O)O)CC2
Temperature: 25 °C

Procedure:
Racemic 2,7,8-Trimethyl-2-(β-carboxyethyl)-6-hydroxy chroman (500 mg) (see Example 11) was dissolved in pyridine (20 mL) at room temperature, and acetic anhydride (10 mL) was added. The solution was maintained at room temperature for 5 hours, solvent was removed under vacuum, methanol (4×10 mL) was added and then removed under reduced pressure. The residual oil was dissolved in ethyl acetate (150 mL) and the organic phase was washed with water (50 mL), aqueous HCl (1 N, 50 mL) and water (50 mL), then dried over sodium sulfate. Solvent was then removed, and the residual oily material was purified on a silica gel column with hexane/ethyl acetate (1:1). The desired product crystallized from acetone/hexane, m.p. 105-107° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.C(N(CC)CC)C.C(O[CH:20]=[C:21]([C:27](=O)[C:28]([F:31])([F:30])[F:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:8]2[C:27]([C:28]([F:29])([F:30])[F:31])=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=[N:9]2)[CH:5]=[CH:6][N:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Reactant: NNc1ccnc(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(-c2ccnc(Cl)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution 2-chloro-6-hydrazinopyrimidine (1.00 g, 6.92 mmol) and triethylamine (0.964 mL, 6.92 mmol) in acetonitrile (35 mL) was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (1.35 mL, 6.97 mmol). After 45 min, the reaction mixture was placed in a 90° C. oil bath. After 1 h, the reaction mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 60% EtOAc in hexanes, then 60 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 321.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.80 (d, J=5.5 Hz, 1H), 8.12 (s, 1H), 7.76 (d, J=5.5 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][NH:29][C:30]([O:32][CH3:33])=[O:31])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][NH:29][C:30]([O:32][CH3:33])=[O:31])[N:27]=2)[CH2:22]1
Reactant: COC(=O)NCc1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)NCc1csc(N2CC(O)C2)n1
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-[4-(methoxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (1.88 g, 3.90 mmol) (obtained as described in Reference Example 63(1)) in anhydrous tetrahydrofuran (94 ml) were added acetic acid (0.27 ml, 4.68 mmol) and 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran (4.68 ml, 4.68 mmol) in an ice bath and the mixture was stirred in an ice bath for 30 minutes. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-hydroxy-1-[4-(methoxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (426 mg, yield 45%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([CH3:10])[C:4]=1[CH2:11][OH:12]>[O-2].[Mn+4].[O-2].ClCCl>[CH3:9][C:8]1[CH:7]=[CH:6][C:5]([CH3:10])=[C:4]2[C:3]=1[CH2:2][O:1][C:11]2=[O:12]
Reactant: Cc1ccc(C)c(CO)c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(C)c2c1COC2=O
Reaction time: 22 h
Yield: 91.7 %

Procedure:
A 1 L 3-necked RBF is charged with 1,2-bis(hydroxymethyl)-3,6-dimethyl-benzene 3 (22.05 g, 0.133 mol), activated 85% manganese(IV) oxide (135.69 g, 1.327 mol), 4 Å molecular sieves (12.00 g) and anhydrous dichloromethane (500 mL), and placed under nitrogen. The reaction mixture is heated to reflux and stirred for 22 h. The reaction mixture is filtered through Kieselguhr and washed thoroughly with dichloromethane. The filtrate is concentrated in vacuo to yield the product 4 as a cream solid (19.79 g, 92%): 1H-NMR (300 MHz, CDCl3) δ 7.31 (d, 1H, 3J=7.5 Hz), 7.18 (d, 1H, 3J=7.5 Hz), 5.18 (s, 2H), 2.65 (s, 3H), 2.29 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 171.7, 145.8, 136.9, 134.5, 130.8, 129.3, 122.9, 68.3, 16.96, 16.91.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.I[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: Cc1ccc(S)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSc1ccc(C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A mixture of 4-methylbenzenethiol (100 g, 0.8 mol) in acetone (1 L) was added iodoethane (190 g, 1.2 mol) and potassium carbonate (220 g, 1.6 mol). The mixture was stirred at 60° C. overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude ethyl(p-tolyl)sulfane (120 g, 99%) as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:8][CH:7]=1.CS[C:18](SC)=[CH:19][N+:20]([O-:22])=[O:21]>>[CH:13]1([NH:12][CH2:11][C:9]2[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:18]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]3[O:10][C:9]([CH2:11][NH:12][CH:13]4[CH2:15][CH2:14]4)=[CH:8][CH:7]=3)=[CH:19][N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[CH2:15][CH2:14]1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ccc(CNC2CC2)o1
Product: O=[N+]([O-])C=C(NCCSCc1ccc(CNC2CC2)o1)NCCSCc1ccc(CNC2CC2)o1
Yield: 55.6 %

Procedure:
A mixture of 5-[[(2-aminoethyl)thio]methyl]-N-cyclopropyl-2-furanmethanamine (1.67 g) and 1,1-bis-(methylthio)-2-nitroethene (0.61 g) was heated at 98°-100° for 3 hr. The oily residue was chromatographed (silica/methanol-0.88 ammonia 79:1) and the appropriate eluate evaporated to dryness to give the title compound (1.07 g) as an oil.
Reaction SMILES: [CH2:1]([NH:5][S:6]([NH:9][C@@H:10]([CH2:16][NH:17]C(OC(C)(C)C)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C>[CH2:1]([NH:5][S:6]([NH:9][C@@H:10]([CH2:16][NH2:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:7])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNS(=O)(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)OCC
Solvent: CCOC(C)=O
Product: CCCCNS(=O)(=O)N[C@@H](CN)C(=O)OCC

Procedure:
A solution of 9-2 (612 mg, 1.65 mmol) in ethyl acetate (50 ml) was cooled to -5° and anhydrous HCl was bubbled in for 30 min. The reaction was concentrated and the product isolated by filtration to give 9-3 as a white solid.
Reaction SMILES: [CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>C(Cl)Cl>[CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19]
Reactant: Cn1nc(-c2ccc(N)cc2)c2ccccc2c1=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1nc(-c2ccc(NS(C)(=O)=O)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.3 %

Procedure:
To a mixture of 2-methyl-4-(4-aminophenyl)-1-(2H)-phthalazinone (8.77 g, 34.9 mmol), CH2Cl2 (300 mL) and pyridine (3.11 mL, 38.4 mmol) at 0° C. was added dropwise methanesulfonyl chloride (2.97 mL, 38.4 mmol) in CH2Cl2 (20 mL) over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 12 hours. Additional pyridine (0.5 mL) and methanesulfonyl chloride (0.5 mL) was added and the mixture was stirred as such for 2 hours. The reaction mixture was poured into 2N HCl, the organic layer was separated and then washed with water and dried over Na2SO4. The solvent was removed in vacuo and the residue was azeotroped with toluene and CH2Cl2 to afford 9.0 g (78%) of 2-methyl-4-(4-methylsulfonylaminophenyl)-1-(2H)-phthalazinone as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:32])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:14][C:15]([C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH2:25][N:26]([CH2:28][CH3:29])[CH3:27])[CH:19]=3)=[N:16][N:17]=2)=[CH:8][C:7]=1[CH2:30][CH3:31].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:56](O)(=[O:59])[CH2:57][OH:58]>C1COCC1.CN(C=O)C>[CH2:30]([C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]([C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH2:25][N:26]([CH2:28][CH3:29])[CH3:27])[CH:19]=3)=[N:16][N:17]=2)[CH:10]=[C:11]([CH3:12])[C:6]=1[O:5][CH2:4][C@@H:3]([OH:32])[CH2:2][NH:1][C:57](=[O:58])[CH2:56][OH:59])[CH3:31]
Reactant: O=C(O)CO
Reactant: CCc1cc(-c2nnc(-c3cc(C)cc(CN(C)CC)c3)o2)cc(C)c1OC[C@@H](O)CN
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCc1cc(-c2nnc(-c3cc(C)cc(CN(C)CC)c3)o2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
To a solution of (5)-1-amino-3-[2-ethyl-4-(5-{3-[(ethyl-methyl-amino)-methyl]-5-methyl-phenyl}-[1,3,4]oxadiazol-2-yl)-6-methyl-phenoxy]-propan-2-ol (214 mg, 488 μmol) in THF (5 mL), DIPEA (91 mg, 732 μmol), HOBt (66 mg, 488 μmol), EDC (94 mg, 488 μmol) and glycolic acid (37 mg, 488 μmol) is added. The mixture is stirred at rt for 1 h before DMF (2 mL) is added. Stirring is continued for 30 min. The mixture is concentrated in vacuo and then separated by prep. HPLC to give the title compound as a colourless oil (38 mg). LC-MS: tR=0.71 min; [M+1]+=497.23.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C1(C)C=CC=CC=1.ClS([N:25]=[C:26]=[O:27])(=O)=O>O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH:6][C:26]([NH2:25])=[O:27])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
311 Parts of 2,4-dinitroaniline are stirred in 2600 parts of toluene with 312 parts of chlorosulfonyl isocyanate for 4hours at 80° C. At 25° C., 360 parts of water are added to the resulting suspension of N-2,4-dinitrophenyl- N'-chlorosulfonyl urea without intermediate isolation of the latter, and the mixture obtained is saponified at 60° C. within 4 hours to yield 2,4-dinitrophenyl urea. After diluting it with water, the mixture is filtered, while hot, and the product is washed with hot toluene and water. After drying in vacuo, there are obtained 347 parts of 2,4-dinitrophenyl urea having a melting point of from 195° to 197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11]C)=[O:10])[C:3]=1[Cl:13].[OH-].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3]=1[Cl:13]
Reactant: COC(=O)c1nc(Br)cc(N)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(Br)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
To methyl 4-amino-6-bromo-3-chloropyridine-2-carboxylate (200mg; 0.8 mmol) in 10 mL of methanol was added excess 2N NaOH (10 mL). The mixture was stirred for 1 hr at ambient temperature and then evaporated to dryness in vacuo. The residue was dissolved in water and diethyl ether. After separation of the phases, the aqueous layer was acidified with 1N HCl to a pH=2. The aqueous layer was evaporated to dryness and the residue was dissolved in 50 mL of methanol and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with 5 percent diethyl ether in petroleum ether to give 70 mg of 4-amino-6-bromo-3-chloropyridine-2-carboxylic acid, mp 182-183° C.
Reaction SMILES: Br.C(O)(=O)CC.C1(O)C=CC=CC=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][N:19](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:18]2>O>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][NH:19][CH2:18]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(Br)cc3C2)cc1
Agent: Br
Solvent: O
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: Brc1ccc2c(c1)CNC2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of aqueous hydrobromic acid (16 mL, 48% solution in water), propionic acid (2.8 mL) and phenol (2 g) was added 5-bromo-2-(p-tolylsulfonyl)isoindoline (2.4 g, 6.8 mmol). The resulting mixture was heated to reflux and stirred at this temperature for 10 hr then cooled to room temperature. This mixture was diluted with water (20 mL) and extracted with ether (2×50 mL). The aqueous extract was brought to pH 14 with 5M sodium hydroxide solution. This solution was extracted with ether (3×). The ether extract is washed with brine, dried over magnesium sulfate, and concentrated to give the title compound as an oil.
Reaction SMILES: C([N:8]1[CH2:24][CH2:23][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].C(Cl)Cl>[C:17]1([CH:12]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:24][CH2:23]3)[C:15](=[O:16])[NH:14][CH2:13]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1NCC(c2ccccc2)C12CCN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: ClCCl
Product: O=C1NCC(c2ccccc2)C12CCNCC2
Yield: 63.2 %

Procedure:
A suspension of rac-8-benzyl-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one (28.8 g, 90 mmol) in MEOH:DCM (4:1, 500 mL) was hydrogenated in the presence of Pd (10% on C, 14 g, 132 mmol) at 2 bar for 48 h at room temperature. After filtration over celite, the reaction mixture was evaporated and the residue dissolved in NaOH (2 N, 200 mL). The product was extracted with DCM (3×150 mL) and the combined organic extracts dried over sodium sulfate. Filtration and evaporation afforded the title compound (13.1 g, 63%) as a white solid after trituration from diethylether. MS: m/e=231.4 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CO>C1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[O:13][CH3:14])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: COc1cc(F)ccc1C(=O)N1CC1
Solvent: c1ccccc1
Solvent: CO
Product: COc1cc(F)ccc1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 8 parts of 1-(4-fluoro-2-methoxybenzoyl)-aziridine, 3.7 parts of 4-(4-chlorophenyl)-4-piperidinol, 54 parts of benzene and 8 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled to room temperature and 90 parts of benzene are added. The whole is washed with water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 3.5 parts of N-{2-[4-(4-chlorophenyl)-4- hydroxy-1-piperidinyl]ethyl}-4-fluoro-2-methoxybenzamide; mp. 156.7° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]1[C:8](=[O:9])[CH:7]=[CH:6][CH2:5]1.[N+:10]([CH3:13])([O-:12])=[O:11]>>[CH2:3]([CH:4]1[CH2:5][CH:6]([CH2:13][N+:10]([O-:12])=[O:11])[CH2:7][C:8]1=[O:9])[CH:2]=[CH2:1]
Reactant: C[N+](=O)[O-]
Reactant: C=CCC1CC=CC1=O
Product: C=CCC1CC(C[N+](=O)[O-])CC1=O
Temperature: 60 °C
Yield: 57 %

Procedure:
A stirred solution of 5-(propene-3-yl)cyclopent-2-enone (0.428, 3.5 mmol) in nitromethane (2 mL) under nitrogen was treated with DOWEX® 550A-OH resin (0.80 g, rinsed with methanol and partially air dried), and heated to 60° C. for 2 h. The mixture was cooled to room temperature, diluted with dichloromethane (20 mL), and filtered. The filtrate was concentrated in vacuo, redissolved in minimum dichloromethane, and added to a silica gel column (˜100 cc) and eluted with dichloromethane to afford the subject compound (0.368 g, 57%) as a colorless oil. NMR (CDCl3): δ 5.65-5.80 (m, 1 H), 5.00-5.15 (m, 2 H), 4.40-4.50 (m, 2 H), 2.85-3.15 (m, 1 H), 2.30-2.70 (m, 4 H), 1.90-2.20 (m, 3 H). MS (M+1): 183.9.
Reaction SMILES: F[C:2](F)(F)C(O)=O.C([Zn]CC)C.ICI.[I:16][C:17](=[CH2:37])[CH2:18][C@@H:19]([CH2:28][O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:20][Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>ClCCCl>[I:16][C:17]1([CH2:18][C@@H:19]([CH2:28][O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:20][Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:2][CH2:37]1
Reactant: C=C(I)C[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: CC[Zn]CC
Solvent: ClCCCl
Solvent: ICI
Product: CC(C)(C)[Si](C)(C)OC[C@H](CC1(I)CC1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.58 h

Procedure:
Trifluoroacetic acid (8 eq) is added to a solution of diethyl zinc (16 eq) in DCE at 0° C. and stirred for 35 mins. Diiodomethane (8 eq) is added at 0° C., and the mixture stirred for an additional 20 min. A solution of (S)-5-(2-iodoallyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (1 eq) in DCE is added and the reaction stirred at room temperature overnight. The reaction is quenched by addition of a mixture of methanol and brine. After stirring for an additional hour, the mixture is concentrated under reduced pressure. The crude material is extracted with aqueous NH4Cl/CHCl3 and the organic layer washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude material is triturated in hexane and the solution filtered and evaporated to afford (S)-5-((1-iodocyclopropyl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane.
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]([OH:36])[CH2:20][NH:21][C:22]([CH3:35])([CH3:34])[CH2:23][CH2:24][N:25]3[CH:29]=[C:28]([C:30]([O:32]C)=[O:31])[N:27]=[CH:26]3)[CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1>[C:3]1([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]([OH:36])[CH2:20][NH:21][C:22]([CH3:34])([CH3:35])[CH2:23][CH2:24][N:25]3[CH:29]=[C:28]([C:30]([OH:32])=[O:31])[N:27]=[CH:26]3)[CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cn(CCC(C)(C)NCC(O)c2cccc(NS(=O)(=O)c3ccccc3)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(CCn1cnc(C(=O)O)c1)NCC(O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 3.5 %

Procedure:
4.00 mL sodium hydroxide solution (1M) was added to 7.81 g (23.3 mmol) methyl 1-{3-[2-(3-benzenesulphonylamino-phenyl)-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-imidazole-4-carboxylate in 8 mL tetrahydrofuran and stirred for 4 h at ambient temperature. The solvent was eliminated from the reaction mixture using the rotary evaporator and the residue was combined three times with 20 mL methanol and filtered. The combined methanolic phases were freed from solvent using the rotary evaporator and 0.390 g (0.825 mmol, 98%) 1-{3-[2-(3-benzenesulphonylamino-phenyl)-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-imidazole-4-carboxylic acid were obtained as a colourless solid.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH:20]1([C:23]2[C:24]([O:31][CH:32]([F:34])[F:33])=[N:25][CH:26]=[C:27]([CH:30]=2)[CH:28]=O)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:30]=[C:27]([CH2:28][N:1]3[CH:2]([C:10]4[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=4[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]3=[O:8])[CH:26]=[N:25][C:24]=2[O:31][CH:32]([F:34])[F:33])[CH2:21][CH2:22]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cnc(OC(F)F)c(C2CC2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cnc(OC(F)F)c(C2CC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 5-cyclopropyl-6-(difluoromethoxy)nicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 432.88 g/mol.