Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C([O-])(O)=O.[Na+].O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[C:4]([CH:3]=1)[CH:9]=[O:10]
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5,6-dichloro-3-pyridinemethanol (2.9967 g, 16.8 mmol) in DCM (3.00 mL, 46.6 mmol) was treated with Dess-Martin periodinane (7.14 g, 16.8 mmol) at room temperature and the mixture was stirred at room temperature overnight. The resulting reaction mixture was diluted with NaHCO3(aq) and water (5 mL each) and diluted with DCM (5 mL). The separated aqueous layer was extracted with DCM (2×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a pale-yellow solid which was used directly for the next step.
Reaction SMILES: [CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[C:35](=[O:43])[C:36](=[O:42])[C:37]=2[O:38][CH:39]([CH3:41])[CH3:40])=[CH:24][CH:23]=1>CN(C)C=O>[CH2:1]([C:3]1[N:13]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[C:35](=[O:43])[C:36](=[O:42])[C:37]=3[O:38][CH:39]([CH3:41])[CH3:40])=[CH:26][CH:27]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CC(C)Oc1c(-c2ccccc2-c2ccc(CBr)cc2)c(=O)c1=O
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (0.66 g; preparable as described in Mantio et al, J. Med. Chem. 34, (1991), pp 2919/2922 and in EP-A-0400914; Merck), and anhydrous potassium carbonate (1.02 g) were added to a solution of 3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione (1.88 g; preparable as described in Example 1(c)) in dry dimethylformamide (10 ml) and the resulting mixture was stirred at ambient temperature for approximately 16 hours. More 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (0.33 g) was added to the dark reaction solution obtained, and stirring was continued at ambient temperature for an additional 24 hours. The resulting dark mixture was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was then separated, washed with water (50 ml), and dried over magnesium sulphate. The resulting solution was evaporated to leave a dark oil which was purified by flash chromatography on silica gel (eluting with 1% industrial methylated spirit in dichloromethane) followed by flash chromatography on silica gel (eluting with ethyl acetate) and flash chromatography on silica gel (eluting with 0% rising to 2% methanol in dichloromethane) to give 3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl -2-yl]-4-isopropoxycyclobut-3-ene-1,2-dione, an active compound of the present invention, as a yellow foam (0.176 g) which melted slowly at 60° C. or above.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][C@H:13]([CH2:15][CH3:16])[CH3:14])[C:6]([OH:8])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CC(C)CC1C=CC(C2O[N:45]=[C:44]([C:47]3[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[CH:49][CH:48]=3)[N:43]=2)=CC=1>CN(C=O)C>[CH3:14][C@H:13]([O:12][C:11]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][N:45]=[C:44]([C:47]3[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[CH:49][CH:48]=3)[N:43]=2)=[CH:4][C:3]=1[C:2]([F:1])([F:18])[F:17])[CH2:15][CH3:16]
Reactant: CC[C@H](C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)Oc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 59.1 %

Procedure:
A solution of 600 mg (2.2 mmol) of 3-trifluoromethyl-4-(2-(S)-methylpropyloxy)benzoic acid (from Step B), 542 mg (2.2 mmol) of EDC and 357 mg (2.2 mmol) of HOBT in 6 mL of DMF were stirred at rt for 1 h. The reaction was subsequently treated with 350 mg (2.2 mmol) of N-hydroxy-4-(hydroxymethyl)benzamidine (from Aldehyde 1, Step A) and heated to 80° C. for 12 h. The reaction mixture was cooled and purified via chromatography on a Biotage 40M cartridge using 2:1 v/v hexanes/EtOAc as the eluant affording 510 mg of the title compound: 1H NMR (500 MHz) δ 1.01 (t, J=7.3, 3H), 1.38 (d, J=5.9, 3H), 1.73–1.83 (m, 2H), 4.55 (septet, 1H), 4.79 (s, 2H), 7.12 (d, J=8.9, 1H), 7.51 (d, J=8.2, 2H), 8.15 (d, J=8.2, 2H), 8.30 (d, J=8.9, 1H), 8.43 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=O)[NH:5][CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)([Cl:12])=O.C(N(CC)C1C=CC=CC=1)C>O>[Cl:12][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COc1ccc[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: O
Product: COc1cccnc1Cl

Procedure:
3-methoxy-2-(1H)pyridone, 10 g. (0.08 mole), 12.3 g. (0.08 mole) of phosphorus oxychloride, and 11.9 g. (0.08 mole) of N,N-diethylaniline are combined in a suitable reaction vessel and heated at reflux for 20 hrs. The reaction mixture was allowed to cool, and was then mixed with 200 ml. of water and ice. The aqueous mixture was extracted with ether and the extracts dried over magnesium sulfate. The drying agent was then removed by filtration and the solvent was removed from the filtrate by distillation in vacuo. The residue was extracted with 160 ml. of boiling hexane and the hexane extracts decanted from the residue while still hot. The hexane solution was cooled in ice resulting in precipitation of the desired produce, weight 7.5 g., m.p. 46°-48°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:2]1.[C:14](OC(OC(C)(C)C)=O)([O:16]C(C)(C)C)=[O:15]>CC#N>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([CH:3]2[O:4][CH2:5][CH2:6][N:1]([C:14]([OH:16])=[O:15])[CH2:2]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Oc1ccc(C2CNCCO2)cc1
Solvent: CC#N
Product: O=C(O)N1CCOC(c2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-morpholin-2-yl-phenol (0.99 g; 5.41 mmol) and di-tert-butyl dicarbonate (1.18 g; 5.41 mmol) in CH3CN (50 mL) was stirred at RT for 3 days. Subsequently, the resulting mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO2, CH2Cl2:CH3OH 97:3) to afford 2-(4-hydroxy-phenyl)-morpholine-4-carboxylic acid tort-butyl ester (1.15 g).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17](=[O:30])[NH:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:15]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:37].[Li+].[OH-]>COCCOC.O>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][NH:18][C:17]([C:16]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:38])=[O:2])=[C:7]([CH3:37])[CH:8]=2)=[N:13][O:14][C:15]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30]
Reactant: COC(=O)COc1ccc(-c2noc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2noc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (4-{4-[2-(2,4-dichloro-phenoxy)-ethyl-carbamoyl]-5-phenyl-isoxazol-3-yl}-2-methyl-phenoxy)-acetic acid methyl ester is dissolved in DME (1 mL). A solution of 1 M LiOH in H2O (0.2 mL) and is added and the mixture is stirred overnight at room temperature. The mixture is concentrated, then acidified with 1 M HCl, extracted with EtOAc (10 mL), dried over MgSO4, filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound I30 as a white solid: 1H-NMR (400 MHz, CD3CN) δ=7.56 (d, J=1.6, 1H), 7.49 (dd, J=8.4, 2.4 Hz, 1H), 7.45 (m, 5H), 7.39 (d, J=2.4 Hz, 1H), 7.27 (dd, J=8.8, 2.8 Hz, 1H), 7.20 (t, J=5.6 Hz, NH), 6.96 (d, J=8.8 Hz, 1H), 6.73 (d, J=8.8 Hz, 1H), 4.64 (s, 2H), 4.08 (t, J=5.2 Hz, 2H), 3.70 (q, J=5.3 Hz, 2H), 2.23 (s, 3H). MS calculated for C27H23Cl2N2O6 (M+H+) 541.0, found 541.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([CH:35]2[O:39][C:38](=[O:40])[NH:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:37]4[CH2:36][CH:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[O:39][C:38]4=[O:40])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1NCC(c2ccccc2)O1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4CC(c5ccccc5)OC4=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 5-phenyl-oxazolidin-2-one.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([CH3:14])[N:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN([C:27]([O:31][N:32]1N=NC2C=CC=C[C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNOC>C(Cl)Cl>[CH3:27][O:31][N:32]([CH3:33])[C:11]([C:9]1[CH:8]=[C:7]([CH3:14])[N:6]=[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])[N:10]=1)=[O:13]
Reactant: Cc1cc(C(=O)O)nc(NC(C)C)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(C)nc(NC(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
To a solution of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid (2.0 g, 10.2 mmol) in DCM (45 mL), DIPEA (8.8 mL, 51.2 mmol) followed by TBTU (3.9 g, 12.3 mmol) is added. The mixture is stirred at rt for 30 min before N,O-dimethylhydroxylamine (1.20 g, 12.3 mmol) is added. The mixture is stirred at rt for 18 h before it is diluted with DCM, washed with sat. aq. NaHCO3, followed by water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:2 to give 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide (2.39 g) as a yellow oil; LC-MS: tR=0.66 min, [M+H]+=239.03; 1H NMR (D6-DMSO): δ 1.14 (d, J=6.5 Hz, 6H), 2.28 (s, 3H), 3.23 (s, 3H), 3.67 (s, 3H), 4.05 (m, 1H), 6.50 (s br, 1H), 7.12 (s br, 1H).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].[C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)#[N:13]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:17]1[CH:18]=[C:14]([C:12]#[N:13])[NH:15][CH:16]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: N#Cc1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(=O)C(Cl)(Cl)Cl)c[nH]1
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
Trichloracetyl chloride (44.4 g, 27.3 mL, 244 mmol) in dichloromethane (75 mL) was added over 20 min to a mechanically stirred suspension of aluminum trichloride (54.3 g, 407 mmol) in dichloromethane (150 mL). The resulting mixture was stirred for 30 min, and then 2-cyanopyrrole (15.0 g, 163 mmol) in dichloromethane (75 mL) was added over 30 min. The reaction was heated at reflux for 5 h and then allowed to cool. The reaction was diluted with ethyl acetate (600 mL) and then quenched slowly with water (300 mL). The layers were separated and then the organic layer was washed with water and brine, dried (magnesium sulfate) and evaporated under reduced pressure to afford a quantitative yield of desired product (39.0 g, 100%) containing trace impurities. This material was used in the next step without further purification. 1H NMR (DMSO-d6) δ 8.14 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH2:14][CH2:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NC1CC1
Product: Cc1cc([N+](=O)[O-])ccc1NC1CC1
Temperature: 0 °C

Procedure:
1-Fluoro-2-methyl-4-nitrobenzene (3.7 g, 24.8 mmoles) is refluxed for 5 hours with 8.1 g (0.14 moles) of cyclopropylamine. After that, the reaction product is poured onto 250 g of ice/water and the solid obtained is recrystallized from ethanol. A yellow solid with a melting point of 35°-37° C. is obtained.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]2[N:23]([C:37]3[C:38]4[C@H:45]([CH3:46])[CH2:44][C@@H:43]([OH:47])[C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:24][C@@:25]3([CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:26]3)[C:18]=12.[CH3:48][C:49]([CH3:51])=O>ClCCCl.C(Cl)Cl>[CH2:30]([N:27]1[CH2:28][CH2:29][C@:25]2([C:18]3[C:19](=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][NH:15][CH:49]([CH3:51])[CH3:48])[N:23]([C:37]3[C:38]4[C@H:45]([CH3:46])[CH2:44][C@@H:43]([OH:47])[C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:24]2)[CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)=O
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3C[C@@]4(CCN(Cc5ccccc5)C4)c4c(CN)cccc43)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)NCc1cccc2c1[C@]1(CCN(Cc3ccccc3)C1)CN2c1ncnc2c1[C@H](C)C[C@H]2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
NaBH(OAc)3 (57.6 mg, 0.272 mmol) was added to a solution of (5R,7R)-4-((S)-4-(aminomethyl)-1′-benzylspiro[indoline-3,3′-pyrrolidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (40 mg, 0.091 mmol), acetone (52.6 mg, 0.906 mmol) in DCE (1.0 mL), and the resulting solution was stirred at ambient temperature for 8 hours. The reaction mixture was diluted with DCM and washed with 25% NaOH. The aqueous layer was separated and extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to give (5R,7R)-4-((S)-1′-benzyl-4-((isopropylamino)methyl)spiro[indoline-3,3′-pyrrolidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (40.0 mg, 0.083 mmol, 91%). LCMS (APCI+) M+H+ 484 (100%); Rt=2.64 min.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:11]([F:26])[CH:10]=[C:9]([Cl:27])[C:7]=2[CH:8]=1)(=O)[CH3:2].C([O-])(=O)C.[K+].Cl.[CH3:34][O:35][NH2:36]>CO>[Cl:27][C:9]1[C:7]2[CH:8]=[C:4]([C:1](=[N:36][O:35][CH3:34])[CH3:2])[O:5][C:6]=2[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:11]([F:26])[CH:10]=1
Reactant: CC(=O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CON=C(C)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
20 ml of methanol was added to 0.4 g (1 mmol) of 3-(2-acetyl-4-chloro-6-fluorobenzofuran-7-yl) -1-methyl-6-trifluoromethyluracil, 0.4 g (4 mmol) of potassium acetate and 0.33 g (4 mmol) of methoxyamine hydrochloride, followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue was purified directly by silica gel column chromatography to obtain 0.28 g (yield: 64.6%) of the desired product as white powder. Melting point: 176-178° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:24][C:25]([F:31])([F:30])[S:26](Cl)(=[O:28])=[O:27]>CCCCC.C(OCC)C>[F:23][C:4]([F:3])([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C@H:5]([O:6][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: CSc1ccc(OC(F)(F)[C@H](O)c2ccc(F)cc2)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CCOCC
Product: CSc1ccc(OC(F)(F)[C@H](OS(=O)(=O)C(F)(F)F)c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
NaH (60% in oil, 1.54 g, 4.9 mmol) was washed several times with pentane, under nitrogen and then suspended in anhydrous ethyl ether (10 m) and cooled at 0° C. A solution of 2,2-difluoro-1(R)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethanol in ethyl ether (10 ml) was added. After stirring the reaction mixture for 15 min, trifluoromethylsulfonyl chloride was added and the resulting mixture was stirred for 2 h at 0° C. The reaction mixture was diluted with hexanes (20 ml) and washed with saturated solution of NaHCO3 and brine. After drying over magnesium sulfate, the solution was concentrated to give trifluoromethanesulfonic acid 2,2-difluoro-1(R)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethyl ester (1.70 g, 77%) as an oil.
Reaction SMILES: C[Si](C)(C)[Br:3].[CH3:6][CH:7]([CH2:9][C@@H:10]1[N:19]2[C:20]([C@@:22]([NH:27][C:28]([C@@H:30]3[CH:45]=[C:44]4[C@@H:33]([CH2:34][C:35]5[C:39]6[C:40]4=[CH:41][CH:42]=[CH:43][C:38]=6[NH:37][CH:36]=5)[N:32]([CH3:46])[CH2:31]3)=[O:29])([CH:24]([CH3:26])[CH3:25])[O:23][C@@:18]2([OH:47])[C@H:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:11]1=[O:12])=[O:21])[CH3:8].N>CS(C)=O>[CH3:8][CH:7]([CH2:9][C@@H:10]1[N:19]2[C:20]([C@@:22]([NH:27][C:28]([C@@H:30]3[CH:45]=[C:44]4[C@@H:33]([CH2:34][C:35]5[C:39]6[C:38](=[CH:43][CH:42]=[CH:41][C:40]=64)[NH:37][C:36]=5[Br:3])[N:32]([CH3:46])[CH2:31]3)=[O:29])([CH:24]([CH3:25])[CH3:26])[O:23][C@@:18]2([OH:47])[C@H:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:11]1=[O:12])=[O:21])[CH3:6]
Reactant: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Reactant: C[Si](C)(C)Br
Agent: N
Solvent: CS(C)=O
Product: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]c(Br)c(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.3 ml of trimethylbromosilane (6 equivalents as calculated for α-ergocryptine to be brominated) are added to 40 ml of anhydrous dimethylsulfoxide and the solution is stirred at room temperature for 15 minutes. After adding 1 g (0.001739 mole) of α-ergocryptine, the mixture is stirred at room temperature for 10 minutes, then poured into 200 ml of ice-water and the pH value is adjusted to 8-9 by adding aqueous ammonia. The aqueous solution is extracted 3 times with 50 ml of dichloromethane each, then the combined organic phase is washed 3 times with 30 ml of 10% sodium chloride solution each. The dichloromethane solution is dried over anhydrous sodium sulfate, filtered and evaporated to 10 ml under reduced pressure. The residue is led through an aluminum oxide column moistened with 10 g of an 1:1 mixture of dichloromethane and ethyl acetate. The first fraction of 50 ml volume (containing the 2-bromo-α-ergocryptine) is evaporated to dryness, the residue is dissolved in 10 ml of dichloromethane, then 30 ml of diisopropyl ether are added to the residue and concentrated to its half volume under environmental pressure. The white crystalline precipitate is filtered off, washed and dried to give the title compound in a yield of 1.06 g (0.001617 mole, 93%), m.p.: 218° C., [α]D20 =-195° (c=1, dichloromethane).
Reaction SMILES: CC1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:54])[CH2:13][NH:14][CH2:15][CH2:16][C:17]3[CH:53]=[CH:52][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:27]=[C:28]([S:32]([N:35](COCC[Si](C)(C)C)COCC[Si](C)(C)C)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=4)=[CH:19][CH:18]=3)=[CH:11][C:5]=2[CH2:4][O:3]1>C(O)(=O)C.O>[OH:54][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][C:17]1[CH:53]=[CH:52][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]2[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=2)=[CH:19][CH:18]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(OCCOCc4cccc(S(=O)(=O)N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c4)cc3)ccc2O1
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1cccc(COCCOc2ccc(CCNC[C@H](O)c3ccc(O)c(CO)c3)cc2)c1
Yield: 39 %

Procedure:
3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (0.015 g) was heated at 75° for 6 h in acetic acid (1.5 ml) and water (0.75 ml). The solution was evaporated to dryness and re-evaporated twice with methanol to give crude product (0.012 g). This was purified by preparative layer chromatography on a silica plate (20×20 cm) which was developed twice in dichloromethane:ethanol: 0.880 ammonia solution, 25:8:1. After elution of the required band using methanol in dichloromethane, the eluate was evaporated to dryness and re-evaporated successively with acetic acid in methanol and then methanol to give the title compound (0.0037 g) LCMS RT=2.19 min. ES+ve 517 (MH)+
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][OH:8].Br[C:10]1[CH:15]=[C:14]([CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:13]=[CH:12][N:11]=1>O1CCCC1>[CH2:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([O:8][CH2:7]/[CH:6]=[CH:5]/[CH2:4][NH2:3])[CH:15]=2)[CH2:18][CH2:19]1
Reactant: NC/C=C\CO
Reactant: Brc1cc(CN2CCCCC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC/C=C/COc1cc(CN2CCCCC2)ccn1
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
0.78 g of 60% sodium hydride was suspended in 20 ml of anhydrous tetrahydrofuran, and 1.54 g (17.7 mM) of 4-amino-cis-2-buten-1-ol was slowly added. The mixture was refluxed with stirring for 20 minutes. Then, under ice cooling, a solution of 3.00 g (11.8 mM) of 2-bromo-4-(piperidinomethyl)pyridine in 10 ml of tetrahydrofuran was added slowly to the mixture, and the entire mixture was then refluxed for 48 hours with stirring. After the reaction, the insoluble matter was removed by filtration, and the solvent was evaporated from the filtrate. The residue was extracted with 100 ml of dichloromethane three times. The extracts were dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography using a 1:3 mixture of methanol and ethyl acetate as an eluent to give 1.49 g (yield 48%) of the compound as a pale brown oil.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])=[N:10][CH:9]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(S(C)(=O)=O)=CC=2)CCCC1.C(OC(=O)CCSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:16]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:9][N:10]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CCSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: CCOC(=O)CCSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CS(=O)(=O)c1ccc(NCC2CCCC2)cc1
Product: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCCC(=O)O)s2)cc1

Procedure:
The title compound was prepared via 3-{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.