Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH:17]=[CH:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:28]#[N:29].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][C@H:16]4[C:28]#[N:29])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C=CC2=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@H](C#N)CC2=O
Temperature: 75 °C
Yield: 50.2 %

Procedure:
This procedure is based on the literature method.22,23 A solution of 1.03 g (2.88 mmol) of 44, 2.03 g (41.5 mmol) of NaCN in THF (30 mL) with 21 drops of H2O was stirred and heated at 75° C. under reflux for 2 h. The reaction mixture was poured into ice water (300 mL) and extracted with CH2Cl2 (3×, 100 mL). Combined organic extracts were washed with H2O (100 mL), dried over Na2SO4 and concentrated in vacuo giving a brown oil. Purification by flash chromatography on a 3×17 cm column of silica gel using 2:1 hexanes/EtOAc as eluent gave 557 mg (50%) of 45 as a white solid. Data for 45: TLC, T-1, Rf 0.3; 1H NMR (400 MHz, CDCl3) δ 1.24 (s, 3H, H-18), 5.06 (s, 2H, benzylic-H), 6.76 (d, 1H, J=2.7 Hz, H-4), 6.81 (dd, 1H, J=8.6, 2.7 Hz, H-2), 7.20 (d, 1H, J=8.6 Hz, H-1), 7.33–7.45 (m, 5H, Ar—H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:19]([O:21]CC2C=CC=CC=2)=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1>CCO.[Pt](=O)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[C:19]([OH:21])=[O:20])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CC(C(=O)OCc2ccccc2)c2ccc(Br)cc2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)c1ccc(CC(C(=O)O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a stirred solution of 4-[2-benzyloxycarbonyl-2-(4-bromo-phenyl)-ethyl]-benzoic acid methyl ester (0.7 g, 1.54 mmol) in EtOH (25 mL) at rt, was added platinum (IV) oxide (0.1 g) and the reaction mixture was stirred at room temperature for 3 h under H2 gas (1 atm). The reaction mixture was filtered through a celite plug, washed with ethyl acetate (50 mL) and concentrated under reduced pressure. The crude product was dried under vacuum for 3 h to afford 4-[2-(4-bromo-phenyl)-2-carboxy-ethyl]-benzoic acid methyl ester (0.51 g, 91%): 1H NMR (300 MHz, DMSO-d6): δ 12.52 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 3.93 (t, J=7.8 Hz, 1H), 3.79 (s, 3H), 3.30 (dd, J=8.4, 13.8 Hz, 1H), 3.0 (dd, J=8.1, 13.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].B>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Step H (14.69 g, 67.0 mmol) in 40 mL of tetrahydrofuran at 0° C. was added borane in THF (141 mL, 141 mmol, 1M) dropwise, keeping the reaction temperature below 5° C. The solution was allowed to warm to room temperature, then stirred for one hour. The reaction was cautiously quenched at 0° C. with 50 mL of water, concentrated in vacuo, and partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)O.[OH-].[Na+]>C(C(C)=O)C(C)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Reactant: c1c[nH]cn1
Agent: [Na+]
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
A mixture of methyl isobutyl ketone (150 ml), diphenyl phosphite (32.8 g), imidazole (13.6 g) and o-chlorophenyldiphenylmethanol (29.5 g) obtained in Example 1 (A) was refluxed for 4 hours. A 10% aqueous sodium hydroxide solution (250 ml) was added thereto and the resultant mixture was refluxed for 1 hour. After cooling to room temperature, the organic layer was separated, washed with water, and evaporated to give a crystalline mass. Recrystallization from methyl isobutyl ketone gave 26.5 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 77%. M.P., 142°-143° C.
Reaction SMILES: C(O[C:5]1[CH:45]=[CH:44][C:8]([CH2:9][O:10][CH:11]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[CH:19][CH:18]=3)[CH2:15][CH2:14][N:13]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:12]2)=[CH:7][C:6]=1[N+:46]([O-])=O)C=C.[BH4-].[Li+].C(=O)([O-])[OH:52].[Na+]>O1CCCC1.CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2]>[NH2:46][C:6]1[CH:7]=[C:8]([CH:44]=[CH:45][CH:5]=1)[CH:9]([OH:52])[O:10][CH:11]1[CH:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[CH:21][CH:22]=2)[CH2:15][CH2:14][N:13]([C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[CH2:12]1
Reactant: C=CCOc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OC(O)c2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The solution of 2.16 g of tert-butyl 3-(4-allyloxy-3-nitrobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 15 ml of tetrahydrofuran is admixed with stirring at room temperature with 0.025 g of bis(triphenylphosphine)palladium(II) acetate and 0.075 g of lithium borohydride and stirred at room temperature for 2.5 hours. The reaction mixture is poured onto 1M sodium hydrogencarbonate (50 ml) and extracted with tert-butyl methyl ether (2×50 ml). The organic phases are washed with water (50 ml) and brine (50 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (1:1 EtOAc-heptane); Rt=6.02.
Reaction SMILES: CC(C)[C@@H](N1CC2C(=CC(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)=CC=2)C1=O)C(O)=O.[O:38]=[C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:48]3[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=4)=[O:56])=[CH:50][CH:49]=3)[CH:46]=2)[CH2:41][N:40]1[C@@H:68]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:69]([O:71]C)=[O:70]>>[O:38]=[C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:48]3[CH:49]=[CH:50][C:51]([NH:54][C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:66])([F:65])[F:67])[CH:59]=4)=[O:56])=[CH:52][CH:53]=3)[CH:46]=2)[CH2:41][N:40]1[C@@H:68]([C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1)[C:69]([OH:71])=[O:70]
Reactant: COC(=O)[C@H](c1ccccc1)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Agent: CC(C)[C@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Product: O=C(Nc1ccc(-c2ccc3c(c2)C(=O)N([C@H](C(=O)O)c2ccccc2)C3)cc1)Nc1cccc(C(F)(F)F)c1
Yield: 82 %

Procedure:
The compound of example 346 was prepared analogous to compound of example 331 by hydrolysis of the compound of example 345.
Reaction SMILES: [Na].C([S:9][C:10]1[N:11]([C:18]2[C:23]([CH2:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:26][CH3:27])[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=1)C1C=CC=CC=1.N.[Cl-].[NH4+].Cl>O>[CH2:26]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH2:24][CH3:25])[C:18]=1[N:11]1[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=[C:10]1[SH:9])[CH3:27]
Reactant: CCc1cccc(CC)c1-n1c(C(=O)O)cnc1SCc1ccccc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: O
Product: CCc1cccc(CC)c1-n1c(C(=O)O)cnc1S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.3 g (0.1 mol) of sodium were added in portions to a suspension of 5 g (0.014 mol) of 2-benzylthio-1-(2,6-diethylphenyl)-imidazole-5-carboxylic acid in 50 ml of liquid ammonia at -40° to -50° C. After 1 hour, 6 g of ammonium chloride were added at the same temperature, and the mixture was allowed to warm up to room temperature overnight. The residue was taken up in 200 ml of water, and the solution was acidified to pH 3 with semiconcentrated hydrochloric acid and filtered under suction. 3.0 g (79% of theory) of 1-(2,6-diethylphenyl)-2-mercaptoimidazole-5-carboxylic acid, a solid having a melting point above 230° C., were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[H-].[Na+].[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH:7]=1
Reactant: c1cc[nH]c1
Reactant: Clc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Clc1cncc(-n2cccc2)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 3.5 dichloropyridine (10.0 g, 67.6 mmol), pyrrole (5.50 g, 81.1 mmol), sodium hydride 60% (3.52 g, 87.9 mmol) and dimethyl sulfoxide (50 ml) was stirred at 70° C. for 2 hours. Aqueous sodium hydroxide (200 ml, 1 M) was added and the mixture was extracted three times with diethyl ether (100 ml). The mixture was evaporated and purified by chromatography on silica gel with dichloromethane and ethanol (4%) as solvent. Yield 6.3 g, 52%. Mp 70.5-72.0° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>ClCCl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CCOCC2)C1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
(R)-Pyrrolidin-3-yl carbamic acid tert-butyl ester (200 mg; 1.074 mmol) was suspended in 7 ml of dichloromethane and sodium triacetoxyborohydride (455 mg; 2.15 mmol) was added. A solution of tetrahydro-4H-pyran-4-one (0.297 ml; 3.22 mmol) in 3 ml of dichloromethane was added drop-wise to the reaction mixture. The reaction mixture was maintained at room temperature overnight, it was then diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried with MgSO4 and concentrated in vacuo. The product was obtained after loading the crude on a SCX-cartridge and recovering with MeOH/ammonia solution. 220 mg (0.641 mmol; 60% yield) of (R)-[1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester were obtained as colourless oil.
Reaction SMILES: C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=CC3[O:10][C:11]([F:14])([F:13])[O:12]C=3C=2)C)CC1.Cl[C:30]1[CH:35]=[CH:34][C:33]([C:36]([C:41]2[C:49]3[C:44](=[C:45]([CH2:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=2)([CH:38]2[CH2:40][CH2:39]2)[CH3:37])=[CH:32][CH:31]=1>>[CH:38]1([C:36]([C:41]2[C:49]3[C:44](=[C:45]([CH2:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=2)([C:33]2[CH:34]=[CH:35][C:30]3[O:10][C:11]([F:14])([F:13])[O:12][C:31]=3[CH:32]=2)[CH3:37])[CH2:40][CH2:39]1
Reactant: CSCc1cccc2c(C(C)(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Product: CC(c1ccc2c(c1)OC(F)(F)O2)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 33 mg (0.08 mmol) of the compound from Example 190 in analogy to the synthesis of the compound from Example 209. 27 mg (76% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3S(C3C=CC=C(C(F)(F)F)C=3)(=O)=O)=[C:16]([O:36][CH3:37])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:38]OC(=O)C1C=CC(N)=CC=1Cl>>[CH3:38][O:6][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][NH:20]3)=[C:16]([O:36][CH3:37])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(Cl)c2)cc2c1CCN2S(=O)(=O)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1ccc(NC(=O)c2cc3c(c(OC)c2)CCN3)cc1Cl

Procedure:
2-Chloro-4-{[4-methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 555.3 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 4 was performed using 4-amino-2-chlorobenzoic acid methyl ester, yielding 2-chloro-4-[(4-methoxy-2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester. This was reacted with 3-trifluoromethyl-benzenesulfonyl chloride in step 5, yielding 2-chloro-4-{[4-methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([N:43]2[CH2:46][CH:45]([F:47])[CH2:44]2)=[N:41][CH:42]=1>>[F:47][CH:45]1[CH2:46][N:43]([C:40]2[N:39]=[CH:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42][N:41]=2)[CH2:44]1
Reactant: FC1CN(c2ncc(Br)cn2)C1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnc(N3CC(F)C3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared following a procedure analogous to Example 31 using (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 5-bromo-2-(3-fluoroazetidin-1-yl)pyrimidine. LC (method 5): tR=1.55 min; Mass spectrum (ESI+): m/z=505 [M+H]+; 1H NMR (CD3OD) δ 0.95 (s, 3H), 1.25 (s, 3H), 1.54 (d, 3H), 2.12 (s, 2H), 2.20 (m, 1H), 2.44 (m, 2H), 3.03 (m, 1H), 4.21 (m, 2H), 4.46 (m, 2H), 5.45-5.60 (m, 2H), 7.03 (d, 2H), 7.25-7.40 (m, 7H), 8.53 (s, 2H).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1([CH3:26])[C:11](=[O:12])[N:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)[C:9](=[O:25])[NH:8]1.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.CO>O>[CH3:6][C:7]1([CH3:26])[C:11](=[O:12])[N:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:14]=2)[C:9](=[O:25])[N:8]1[CH2:34][CH2:33][CH2:32][CH2:31][OH:30]
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: CC(=O)OCCCCBr
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCO
Temperature: 30 °C
Yield: 89.7 %

Procedure:
300 ml of dimethylformamide and 100 g of the product of Example 3 are introduced at 20°/22° C. and the reaction medium is maintained under agitation at this temperature for approximately 5 minutes then 98.5 g of 4-bromobutyl acetate then 20 g of soda are added and the whole is maintained under agitation and under a nitrogen atmosphere at +20°/+22° C. for approximately 22 hours. While maintaining agitation, at this temperature, 20 g of soda is added then over approximately 5 minutes 400 ml of methanol is added and the whole is maintained in this way for 1 hour. While leaving the temperature to rise, 500 ml of demineralized water at +20° C. is introduced under agitation, then the reaction medium is placed under agitation, 500 ml of demineralized water is added at +20° C. and the whole is maintained under agitation for 1 hour at 25°/30° C., then cooled down under agitation to +0°/+5° C., and maintained for 2 hours, followed by separating, washing with 4×100 ml of demineralized water and drying. Purification is carried out by adding 696 ml of methylene chloride at 20°/22° C. and washing with 3×232 ml of demineralized water then drying, 5.8 g of supra black is added, the medium is maintained under agitation at 20°±2° C. for 2 hours followed by filtering and rinsing with 2×116 ml of methylene chloride. After concentrating under agitation, 116 ml of denat. ethanol toluene is added at 20° C. then 174 ml of demineralized water is added. The reaction medium is cooled down under agitation to 20°/22° C., maintained under agiatation for 2 hours at this temperature then cooled down to 0°±2° C. and maintained for 1 hour under these conditions, followed by separating, washing with 2×58 ml of ethanol with 50% water at 0°/+2° C. and drying. In this way 111.5 g of expected product (white powder) is obtained. M.p.=102° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[CH2:11][C:12]1[C:13]([O:21][C@@H:22]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]2[OH:24])=[N:14][NH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[CH2:11][C:12]1[C:13]([O:21][C@@H:22]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]2[OH:24])=[N:14][N:15]([CH2:38][CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:16]=1[C:17]([F:18])([F:20])[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCOCc1ccccc1
Reactant: OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccccc2OCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](Oc2nn(CCOCc3ccccc3)c(C(F)(F)F)c2Cc2ccccc2OCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
To a solution of 4-(2-benzyloxybenzyl)-3-(β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole (300 mg) in N,N-dimethylformamide (3 mL) were added (2-bromoethoxymethyl)benzene (379 mg) and cesium carbonate (957 mg), and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give the title compound (154 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:14]=1[CH2:15][SH:16].[Na]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[OH:8])/[CH:9]=[CH:10]\[CH:15]([S:16][CH:15](/[CH:10]=[CH:9]\[C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:14]1[C:17]([O:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:13]=1[O:12][CH3:11])[C:14]1[C:17]([O:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:13]=1[O:12][CH3:11]
Reactant: COc1cc(OC)c(CS)c(OC)c1
Reactant: C#Cc1ccc(O)c(O)c1
Agent: [Na]
Product: COc1cc(OC)c(C(/C=C\c2ccc(O)c(O)c2)SC(/C=C\c2ccc(O)c(O)c2)c2c(OC)cc(OC)cc2OC)c(OC)c1

Procedure:
A solution of 3,4-dihydroxyphenylacetylene (0.02 mol), 2,4,6-trimethoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to General Procedure 2 to form (Z)-3,4-dihydroxystyryl-2,4,6-trimethoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to General Procedure 2.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:13]>C(O)C.ClCCl>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([CH2:4][NH:2][CH3:1])=[C:6]([F:13])[CH:7]=1)#[N:10]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Product: CNCc1ccc(C#N)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 ml of a 16.5% solution of methanamine in ethanol is cooled by an ice bath and a solution of 120 mg (0.56 mM) of 4-(bromomethyl)-3-fluoro-benzonitrile in 1 ml of dichloromethane is added dropwise. The reaction medium is then agitated for 4 hours at ambient temperature and is then concentrated under reduced pressure. The residue is taken up with ethyl acetate and washed with a solution of sodium bicarbonate. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The crude product is purified by chromatography on silica gel in eluting with the aid of a mixture of dichloromethane/methanol (98/0.05; v/v). The expected amine is thus obtained as a colourless oil (yield=49%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[CH2:13][N:12]([S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH2:11][CH2:10][N:9]2[C:22]2[CH:27]=[CH:26][C:25]([C@:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C[C@@H]2CN(S(C3SC=CC=3)(=O)=O)CCN2C2C=CC([C@@](O)(C)C(F)(F)F)=CC=2)CCCCC1.C1(C[C@H]2CN(S(C3SC=CC=3)(=O)=O)CCN2C2C=CC([C@@](O)(C)C(F)(F)F)=CC=2)CCCCC1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[CH:1]1([CH2:7][C@@H:8]2[CH2:13][N:12]([S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH2:11][CH2:10][N:9]2[C:22]2[CH:23]=[CH:24][C:25]([C@:28]([OH:34])([CH3:33])[C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CC2CCCCC2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CC2CCCCC2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CC2CCCCC2)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CC2CCCCC2)cc1)C(F)(F)F

Procedure:
(2R)-2-(4-((2S)-2-(cyclohexylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2R)-2-(cyclohexylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-2-(cyclohexylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1H NMR (400 MHz, CDCl3) δ 7.64-7.62 (m, 1H), 7.57-7.55 (m, 1H), 7.43-7.40 (d, J=8.6 Hz, 2H), 7.17-7.14 (m, 1H), 6.81-6.79 (d, J=8.6 Hz, 2H), 3.97-3.90 (m, 1H), 3.77-3.65 (m, 2H), 3.44-3.39 (m, 1H), 3.34-3.27 (m, 1H), 2.73-2.67 (m, 1H), 2.63-2.56 (m, 1H), 2.32-2.31 (m, 1H), 1.83-1.74 (m, 2H), 1.74 (s, 3H), 1.69-1.62 (m, 4H), 1.28-1.15 (m, 4H), 0.90-0.84 (m, 2H). m/z (ESI, +ve ion) 517.2 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=1.00 μM; GK-GKRP EC50 (LC MS/MS)=1.32 μM.