Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[C:7]2([CH3:17])[CH3:16])[CH:5]=[CH:4][N:3]=[CH:2]1.[N:18]1C=CC=CC=1.Cl.NO.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CO.CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[N:1]1([CH:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[NH:18][C:7]2([CH3:17])[CH3:16])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1ccncc1
Reactant: CC1(C)C(=O)c2ccccc2C1n1ccnc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)NC(=O)c2ccccc2C1n1ccnc1
Temperature: 55 °C
Reaction time: 14 h

Procedure:
To a solution of 3-imidazol-1-yl-2,2-dimethyl-indan-1-one (350 mg, 1.55 mmol) in methanol (19 mL) is added pyridine (1.6 mL, 19.6 mmol) and then hydroxylamine hydrochloride (270 mg, 3.9 mmol). The reaction is stirred at 55° C. for ca. 14 h and then cooled to room temperature. The reaction is concentrated in vacuo to ca. half of the original volume. The mixture is then diluted with ethyl acetate and 50% saturated aqueous NaCl. The layers are separated and the aqueous layer is extracted two additional times with ethyl acetate. The organic layers are combined, dried over Na2SO4, filtered, and concentrated. The resulting residue is dissolved in pyridine (10 mL) and placed at 0° C. The solution is charged with DMAP (ca. 6 mg, 0.05 mmol) and p-toluenesulfonyl chloride (615 mg, 3.22 mmol), and placed at room temperature for 1 h. The reaction is then warmed to 50° C. and stirred for ca. 14 h. The reaction is then cooled to room temperature, diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue is dissolved in pyridine (11 mL) and heated by microwave irradiation at 190° C. for 35 min in a sealed vessel. The reaction is cooled to room temperature quenched with saturated aqueous NaHCO3 (ca. 0.5 mL) and diluted with ethyl acetate. The mixture is then dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:10) to provide 4-imidazol-1-yl-3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-one; HRMS (ESI) m/z 242.1293 [(M+H)+; Calcd for C14H16N3O: 242.1293]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (s, 3 H), 1.40 (s, 3 H), 5.09 (s, 1 H), 5.73 (br. s., 1 H), 6.82 (s, 1 H), 7.04 (s, 1 H), 7.21-7.26 (m, 1 H), 7.50-7.60 (m, 3 H), 8.17-8.26 (m, 1 H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[CH3:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=2[N:25]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:30][C:27]1[CH:28]=[CH:29][C:23]2[S:22][C:21]([CH3:20])=[N:25][C:24]=2[CH:26]=1)(=[O:3])[CH3:2]
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc2sc(C)nc2c1
Yield: 6 %

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 2-methyl-5-hydroxybenzothiazole, the desired product is obtained in the form of white crystals with a yield of 6%.
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[I:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>CCCCC.O1CCCC1>[I:29][CH2:30][CH2:31][CH2:32][C:33]([O:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:34]
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: O=C(Cl)CCCI
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(=O)CCCI)c1coc([Si](C)(C)C)c1
Reaction time: 0.25 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.33 ml, 0.56 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (188.1 mg, 0.56 mmol) in tetrahydrofuran (4 ml) at 0° under argon. After 15 minutes, a solution of 4-iodobutyryl chloride (129 mg, 0.56 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued overnight while the cooling bath attained room temperature. The mixture was quenched with water and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts afforded an oil, which was purified by preparative TLC (20×20 cm, 1000μ silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH:16]([OH:18])[C@@H:15]([NH:19][C:20](=[O:34])[C@@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C@H:12]1[CH3:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)C[C@H](NC(C1C=C2C(=CC=1)N=CC=C2)=O)C(=O)N[C@H]1CC[C@@H](C)N(S(C2C=CC=CN=2)(=O)=O)CC1O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][C:16](=[O:18])[C@@H:15]([NH:19][C:20](=[O:34])[C@@H:21]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C@H:12]1[CH3:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)CC1O
Agent: CC(C)C[C@H](NC(=O)c1ccc2ncccc2c1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)CC1O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)CC1=O

Procedure:
Following the procedure of Example 12 (m), except substituting “(2R,5S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-2-methyl-6-hydroxy-azepane-1-carboxylic acid benzyl ester” for “quinoline-6-carboxylic acid {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide gave the title compound: 1H NMR: 7.40–7.35 (m, 5H), 5.26 (m, 1H), 5.13 (dd, 1H), 4.91–4.78 (m, 2H), 4.47 (m, 1H), 4.12 (m, 1H), 3.64 (dd, 1H), 2.32 (m, 1H), 2.10 (m, 1H), 1.70–1.52 (m, 5H), 1.45 (s, 9H), 1.12 (d, 3H), 0.96 (s, 3H), 0.94 (s, 3H); Electrospray mass spec: M+H+=512.2.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:1]([S:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Sc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)Sc1ccccc1
Reaction time: 18 h
Yield: 91.2 %

Procedure:
A solution of cinnamoyl chloride (14.6 g, 87.68 mmol) in dichloromethane (100 mL) was added to a solution of thiophenol (9.55 g, 86.68 mmol) and pyridine (7 mL) in dichloromethane (150 mL) in an ice-water bath. After 18 hours at room temperature, the reaction mixture was washed with dilute hydrochloric acid (100 mL, 1N), brine (100 mL), dried (MgSO4) and was concentrated to afford 19.0 g (91%) of the desired thioester as a crystalline solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Brc1cccc2[nH]ccc12
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ccccc1-c1cccc2[nH]ccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a mixture of 4-bromoindole (5.5 g, 28 mmol), and 2-chlorophenylboronic acid (4.4 g, 28 mmol) in THF (96 mL) were added Palladium catalyst Pd(PPh3)4 (0.975 g, 0.8 mmol) and the freshly prepared sodium hydroxide solution (3.4 g, 84 mmol in 40 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 2.41 g (38%) of 4-(2-chloro-phenyl)-1H-indole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].C([O-])(=O)C.[NH4+:15].N>>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH2:15])([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: CC(=O)[O-]
Agent: N
Product: Nc1ccncc1[N+](=O)[O-]
Temperature: 135 °C
Yield: 59 %

Procedure:
Five grams (31.5 mmol) of 3-nitro-4-chloropyridine was mixed with 26 g of ammonium acetate, and the mixture was heated at 130-140° C. for 3 hours. The mixture was allowed to cool, and then adjusted to pH 10 with concentrated aqueous ammonia. The precipitated powder was collected by filtration to obtain 2.6 g of the intended yield: 59%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]Cl)[CH:29]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:30]5[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=5)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: ClCc1cccnc1
Reactant: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cn2c3ccc(Br)cc3c3cc(OCc4cccnc4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
10-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (350 mg) obtained in Example 49 was suspended in dimethyl sulfoxide (14 ml), and potassium carbonate (440 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 3-picolylchloride hydrochloride (190 mg) was added to the mixture. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (500 ml). The crystals precipitated were recovered by filtration. The resulting crude crystals were washed with methanol and ether in succession, and recovered by filtration to obtain the title compound (270 mg, 60%).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([NH:10][C@@H:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][OH:14])[C:7]([CH2:18][C:19]2[CH:34]=[CH:33][C:22]([CH2:23][N:24]([CH2:31][CH3:32])[CH2:25][C:26]([O:28]CC)=[O:27])=[CH:21][C:20]=2[O:35][CH3:36])=[C:6]([CH3:37])[N:5]=1.Cl>CO>[NH2:3][C:4]1[N:9]=[C:8]([NH:10][C@@H:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][OH:14])[C:7]([CH2:18][C:19]2[CH:34]=[CH:33][C:22]([CH2:23][N:24]([CH2:31][CH3:32])[CH2:25][C:26]([OH:28])=[O:27])=[CH:21][C:20]=2[O:35][CH3:36])=[C:6]([CH3:37])[N:5]=1
Reactant: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC)CC(=O)OCC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC)CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.7 %

Procedure:
3M-sodium hydroxide (1 mL) was added to a solution of the product from step (viii) (310 mg) in methanol (3 mL). The solution was stirred at RT for 16 h. The reaction mixture was neutralized with 4M-hydrogen chloride (1 mL) and extracted with chloroform/EtOH (3/1). The combined organic layer was dried and concentrated under reduced pressure to afford the sub-title compound (300 mg) as a colourless amorphous solid; 1H NMR (DMSO); 7.00 (1H, s), 6.79 (1H, d), 6.72 (1H, d), 5.87 (2H, br s), 5.63 (1H, d), 4.20-4.14 (1H, m), 3.83 (3H, s), 3.76 (2H, s), 3.60 (2H, s), 3.27 (2H, q), 3.13 (2H, s), 2.66 (2H, q), 2.02 (3H, s), 1.60-1.51 (1H, m), 1.45-1.31 (3H, m), 1.13-1.06 (2H, m), 1.00 (3H, t), 0.75 (3H, t).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C@@H:2]([CH2:11][O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@H:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H](N)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (1S,2S)-2-amino-1-phenyl-1,3-propanediol (2.07 g, 12.4 mmol) in DMF (10 mL) was added imidazole (1.0 g, 14.7 mmol) and tert-butyldimethylsilyl chloride (2.30 g, 15.3 mmol). After stirring at rt for 12 h the mixture was added to diluted brine (150 mL, water/brine:1/1). Extraction with ethyl acetate (4×30 mL), washing of the combined extracts with brine (30 mL) and drying (MgSO4) gave after concentration a residue which was purified by flash chromatography on silica gel (eluent: ethyl acetate). The title compound was obtained as colourless oil. δH (CDCl3): 0.24, 0.26 (6H, 2s), 1.12 (9H, s), 2.50–2.78 (3H, br s), 3.16 (1H, ddd), 3.78 (1H, dd), 3.85 (1H, dd), 4.84 (1H, d), 7.49–7.55 (5H, m); m/z (ES+)=282.32 [M+H]+; RT=2.87 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15]CC)=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[OH-].[K+]>C(O)C>[CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)c1ccc2c(NC)nccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNc1nccc2cc(C(=O)O)ccc12
Temperature: 65 °C
Yield: 72.3 %

Procedure:
To a suspension of ethyl 1-(methylamino)isoquinoline-6-carboxylate (150 mg, 0.65 mmol) in ethanol (2.5 mL) was added 1 N aqueous potassium hydroxide (6.5 mL, 6.5 mmol). The reaction was heated to 65° C. for 1.5 hours. The reaction was cooled to room temperature and concentrated to dryness. The solid was dissolved in water and the solution was acidified with 1 N HCl. The mixture was concentrated. The solid was dissolved in water (50 mL) and extracted twice with 2-butanol (50 mL). The combined organics were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated to give the title compound (95 mg, 72%) as a white solid. +ESI (M+H) 203.2; 1H NMR (400 MHz, DMSO-d6, δ): 13.07 (br.s., 1H), 10.25 (d, J=4.9 Hz, 1H), 8.74 (d, J=8.8 Hz, 1H), 8.51 (s, 1H), 8.15 (dd, J=8.6, 1.8 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.35 (d, J=7.0 Hz, 1H), 3.15 (d, J=4.7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[O:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][C:32]=1[CH2:42][CH2:43]O.C1(C2OC(C(F)(F)F)=C(COC(=O)C3C=CC(CC(SCCC4C=CC(F)=CC=4)C(OCC(Cl)(Cl)Cl)=O)=CC=3)N=2)C=CC=CC=1>>[CH3:30][C:31]1[O:35][C:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[N:33][C:32]=1[CH2:42][CH2:43][O:18][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:13]([CH2:12][CH:11]([S:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:27])[Cl:28])=[O:23])=[CH:14][CH:15]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: O=C(O)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOC(=O)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Yield: 91.5 %

Procedure:
The title compound was prepared from 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxycarbonyl)-ethyl]-benzoic acid (220 mg, 0.46 mmol) and 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol (103 mg, 0.50 mmol) in the same manner as described for 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxy-carbonyl)-ethyl]-benzoic acid 2-phenyl-5-trifluoromethyl-oxazol-4-ylmethylester. The crude product was purified by flash chromatography using n-heptane/EtOAc 7:3 as the eluent to afford the final product as an oil (280 mg, 83.5%). 1H NMR (400 MHz, CDCl3): δ 7.91-7.96 (m, 3H), 7.39-7.41 (m, 3H), 7.22-7.25 (m, 3H), 7.06-7.09 (m, 2H), 6.94 (t, 2H), 4.71 (m, 1H), 4.64 (m, 1H), 4.56 (t, 1H), 3.88-3.92 (m, 2H), 3.55 (m 1H), 3.29 (m, 1H), 2.69-2.04 (m, 6H), 2.32 (s, 3H). Mass Spectrum: M+H+ 666.14, M−H+ 664.39.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[C:9]=2[CH3:20])[N:6]=[N:5][N:4]=1.S(Cl)([Cl:23])=O.O>ClCCl.CN(C)C=O>[Cl:23][CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[C:9]=2[CH3:20])[N:6]=[N:5][N:4]=1
Reactant: Cc1c(-n2nnnc2CO)ccc(C#N)c1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(-n2nnnc2CCl)ccc(C#N)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of 4-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-3-methyl-2-(trifluoromethyl)benzonitrile (Intermediate 48, 294 mg, 1.04 mmol) in dichloromethane (5 mL) and N,N-Dimethylformamide (0.5 mL), cooled in an ice bath under argon, was added dropwise thionyl chloride (0.080 mL, 1.09 mmol). The reaction was stirred at 25° C. for two hours. To the reaction was added water (50 mL) and DCM (100 mL) and the reaction partitioned through a hydrophobic frit. The organic layer was evaporated to dryness under vacuum to afford 240 mg of the title compound as a colourless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:15]=2)[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:9]1[C:28](O)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:34][C:35](=[O:45])[C@H:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH2:37])C>O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH:18]=[CH:19][CH:20]=[CH:21]3)=[CH:14][CH:15]=2)[C:10]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:9]1[C:28]([NH:37][C@H:36]([C:35]([OH:34])=[O:45])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(-n3cccc3)ccc2n1Cc1ccccc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1c(-c2ccccc2)c2cc(-n3cccc3)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 1-benzyl-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylic acid and L-phenylalanine ethyl ester hydrochloride followed the procedure of Example 2 Step 4 as an off-white solid: 1H NMR (DMSO-d6) δ 2.90 (dd, J=13.8, 10.7 Hz, 1 H), 3.17 (dd, J=13.8, 4.3 Hz, 1H), 4.65-4.75 (m, 1 H), 5.23 (d, J=16.2 Hz, 1 H), 5.53 (d, J=16.2 Hz, 1 H), 6.21 (t, J=3.9 Hz, 2 H), 7.10-7.50 (m, 18 H), 7.57 (d, J=9.8 Hz, 1 H), 7.64 (d, J=1.9 Hz, 1 H), 9.09 (d, J=8.0 Hz, 1 H), 12.93 (br s, 1 H); MS (ESI) m/z 540 (MH+); MS (ESI) m/z 538 ([M-H]−); HRMS calcd for C35H30N3O3: 540.2288; found (ESI+): 540.2277; Anal. calcd for C35H29N3O3.0.4 H2O: C, 76.88; H, 5.49; N, 7.68. Found: C, 76.68; H, 5.24; N, 7.87.
Reaction SMILES: [CH:1]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=[C:4]([CH3:5])[C:2]=1[OH:3].[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[K+].[K+]>>[F:24][C:17]1[CH:16]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([O:3][C:2]3[CH:1]=[C:8]([CH:9]([CH3:11])[CH3:10])[CH:7]=[CH:6][C:4]=3[CH3:5])[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:14]=[C:13]([F:12])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: Cc1ccc(C(C)C)cc1O
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(C)C)cc1Oc1nc(C(=O)NC(C)c2cc(F)c(NS(C)(=O)=O)c(F)c2)co1
Yield: 73.7 %

Procedure:
Carvacrol (25 mg, 0.16 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted using K2CO3 (50 mg, 0.36 mmol) as described above to give the title compound (40 mg, 77%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[CH2:17][O:18][C:19]2[C:24](F)=[CH:23][C:22]([CH2:26][CH2:27][C:28](OCC)=[O:29])=[CH:21][C:20]=2F)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C:40]([CH:43](C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].C(OCC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:16])[F:15])=[C:9]2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:26][CH2:27][CH2:28][OH:29])=[C:21]([CH3:20])[C:40]=2[CH3:43])=[CH:6][CH:7]=1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccc(Cl)cc2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(CCCO)ccc(OCc2c(C(F)(F)F)ccn2-c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product prepared in Example 1, Step E (46 mg, 0.10 mmol, 1 eq) in THF (2 mL) at 0° C. under N2 was added LAH (0.20 mL of a 1 M solution in THF, 0.20 mmol, 2 eq). After 1 hr, saturated sodium potassium tartrate (0.5 mL) was added dropwise at first, the solution was warmed to room temperature, diethyl ether was added, washed with brine, dried over MgSO4 and concentrated. The resulting residue was purified by flash chromatography (4 g column) eluting with 10 to 30% EtOAc/heptane to yield 3-(4-{[1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrrol-2-yl]methoxy}-2,3-dimethylphenyl)propan-1-ol.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=1>>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([Cl:2])=[O:17])=[CH:10][CH:9]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccc(CC(=O)O)cc1
Product: Cc1ccc(CC(=O)Cl)cc1
Temperature: 80 °C

Procedure:
Phosphorus pentachloride (1.lg, 0.0053 mol) was added to 4-methylphenylacetic acid (0.76g, 0.0051 mol) and the mixture was allowed to react by heating at about 80° C. POCl3 and excess phosphorus pentachloride were completely removed by evaporation in vacuo to obtain 4-methylphenylacetyl chloride. This chloride was dissolved in toluene (10 ml) and to the mixture were added S-(-)-α(4-n-heptyloxyphenyl)ethyl alcohol (1.0g, 0.0042 mol) and pyridine (1 ml, a dehydrochlorinating agent). The mixture was permitted to stand for 10 hours at room temperature, warmed at 60° C. and maintained as such for 3 hours, and then cooled. The resulting mixture was added to diluted hydrochloric acid and the resultant was extracted with ether. The ether layer was washed with an aqueous solution of NaHCO3 and then with water, and dried over Na2SO4. The ether was distilled off and the residue was purified by means of a column chromatography (solvent : chloroform) and the resultant was recrystallized from ethanol to obtain the objective compound of α-(4-n-heptyloxyphenyl)ethyl 4-methylphenylacetate. The infrared spectrum of said compound is shown in FIG. 4. This compound did not show any liquid crystalline phase and it was a liquid at room temperature. The angle of rotation [α]25D of the compound was -13.1° (solvent : chloroform).