Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:18])[C@H:12]([C@H:14]([CH2:16][CH3:17])[CH3:15])[NH2:13])[CH3:9].C(OC(=O)[C@H]([C@H](CC)C)N)C.C(N)C1C=CC=CC=1.[CH3:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH2:50][C:51](Cl)=[O:52].COCCCCCCCCCCCC(Cl)=O>>[CH3:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH2:50][C:51]([NH:13][C@H:12]([C:11]([O:10][CH2:8][CH3:9])=[O:18])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:52]
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)CC
Reactant: COCCCCCCCOCCCC(=O)Cl
Agent: COCCCCCCCCCCCC(=O)Cl
Solvent: NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H](NC(=O)CCCOCCCCCCCOC)[C@@H](C)CC

Procedure:
The title compound is prepared by the method of Example 14 using L-isoleucine ethyl ester trifluoroacetate [the title product of Example 44] as a reactant instead of benzylamine, and using an equivalent amount of 4-[(7-methoxyheptyl)oxy]butanoyl chloride [the title product of Example 100] instead of 12-methoxy-1-docecanoyl chloride [the title product of Example 11].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27]O)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:15]([F:26])[CH:14]=2)[O:10][N:9]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:54]1[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27][N:54]2[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:15]([F:26])[CH:14]=2)[O:10][N:9]=1)[CH3:2]
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using {4-ethyl-5-[5-(3-fluoro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (0.16 g, 0.40 mmol) that was obtained in Example 14 (14a), carbon tetrabromide (0.17 g, 0.52 mmol), triphenylphosphine (0.14 g, 0.52 mmol), methyl 3-azetidinecarboxylate hydrochloride (91 mg, 0.60 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3 to 1:2) as the eluent to afford the title compound (0.15 g) in a yield of 77% as a pale yellow oily product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C@@H:7]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[H][H].[CH3:35][O:36][CH:37]([O:40][CH3:41])[CH2:38]Br>CN(C=O)C>[C:1]([O:5][C:6](=[O:30])[C@@H:7]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:38][CH:37]([O:40][CH3:41])[O:36][CH3:35])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COC(CBr)OC
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(COc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1)OC
Temperature: 70 °C
Reaction time: 8 h

Procedure:
1.8 g (4.34 mmol) of (1.2) were added to a suspension of 176 mg of a 55% strength sodium hydride suspension in oil (4.07 mmol of sodium hydride) in 10 ml of abs. DMF and the mixture was stirred until the evolution of hydrogen was complete (about 30 min). 620 mg (3.7 mmol) of bromoacetaldehyde dimethyl acetal were then added and the mixture was heated at 50° C. for 8 h and at 70° C. for 2 h. After fresh addition of 18 mg of the sodium hydride suspension in oil (0.41 mmol of sodium hydride), the mixture was heated at 70° C. for a further 4 h. After standing overnight, the reaction mixture was concentrated in a rotary evaporator and the residue was partitioned between H2O and CH2Cl2. The organic phase was separated off and dried over MgSO4, and the solvent was removed in vacuo. The residue was chromatographed on silica gel by means of MPLC using heptane/ethyl acetate. (1.3) was obtained as a colorless solid; melting point 115° C.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][C@H:8]([O:20][C@@H:21]2[C@@H:28]([CH2:29][O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:27][C@H:24]([O:25][CH3:26])[C@H:23]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:22]2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:7]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@H:6]1[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)(=O)C.CO.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:39]([O:38][C@@H:23]1[C@@H:22]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@H:21]([O:20][C@H:8]2[O:9][C@H:10]([CH2:11][O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:5]([OH:4])[C@H:6]([O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C@H:7]2[O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@@H:28]([CH2:29][O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:27][C@@H:24]1[O:25][CH3:26])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Methyl 4-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-2,3,6-tri -O-benzyl-α-D-glucopyranoside (2.543 g, 2.71 mmol) was dissolved in hot toluene (20 mL) and methanol (80 mL) was added, followed by a few drops of 1M. methanolic sodium methoxide. The mixture was stirred at room temperature during 2 h. The reaction mixture was made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure to afford methyl 2,3,6-tri-O-benzyl-4-O-(2,3,6-tri-O-benzyl -α-D-galactopyranosyl)-α-D-glucopyranoside (2.42 g, 100%) as an amorphous solid.
Reaction SMILES: [CH3:1][CH:2]([C:6](=[O:8])[CH3:7])[C:3](=[O:5])[CH3:4].[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>N12CCCN=C1CCCCC2.C(OCC)C>[CH2:14]([O:13][C:9](=[O:12])[CH2:10][CH2:11][C:2]([C:6](=[O:8])[CH3:7])([CH3:1])[C:3](=[O:5])[CH3:4])[CH3:15]
Reactant: CC(=O)C(C)C(C)=O
Reactant: C=CC(=O)OCC
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCC(C)(C(C)=O)C(C)=O
Reaction time: 16 h
Yield: 59.3 %

Procedure:
30 g of 3-methyl-2,4-pentandione and 0.4 g of 1,8-diazabicyclo-[5.4.0]-undec-7-ene were mixed and 39.3 g of ethyl acrylate was added dropwise with the temperature being controlled by cooling with ice. Stirring was continued for 16 hours, the base was neutralized, 50 ml of diethyl ether was added, and the mixture was extracted with an aqueous sodium carbonate solution and water. Fractional distillation of the organic layer yielded 33.4 g of 4-acetyl-4-methyl-5-oxo-hexanoic acid ethyl ester (boiling point: 95° C./0.02 mbar; purity: 98%; colorless).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[C@@H:4]([N:26](S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][CH3:29])[CH2:5][C:6]1[CH:25]=[CH:24][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C(=O)C)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.SCC(O)=O.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:48])[C@@H:4]([NH:26][C@H:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:28][CH3:29])[CH2:5][C:6]1[CH:25]=[CH:24][C:9]2[O:10][C@@H:11]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: CC[C@@H](c1ccccc1)N([C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C(O)CS
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(O)cc1)O2)C(=O)OC)c1ccccc1
Yield: 78.7 %

Procedure:
(S)-3-[(S)-2-(4-Acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-[(4-nitro-benzenesulfonyl)-((S)-1-phenyl-propyl)-amino]-propionic acid methyl ester (230 mg) was dissolved in 3 mL dry DMF, then, mercaptoacetic acid and DBU were added at rt. The reaction stirred over night, and was partitioned between saturated aqueous NaHCO3 and diethyl ether. The organic layer was washed successively with aqueous NaHCO3, water, and brine, then was dried with Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 120 mg desired product. LCMS (m/z): 449.
Reaction SMILES: [CH2:1]=[C:2]1[CH:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][C:5]2([C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[CH:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][C:5]2([C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: C=C1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1CCC2(c3c[nH]cn3)Cc3ccccc3C12

Procedure:
4-(3-Methylene-2,3,3a,8-tetrahydro-1H-cyclopenta[a]inden-8a-yl)-1H-imidazole (0.23 g) was dissolved in 20 ml of ethanol and the mixture was hydrogenated at 50-55° C. with 10% palladium on carbon as catalyst until no more hydrogen was consumed. The catalyst was filtered off and the solvent removed under reduced pressure. The residue was crystallized from ethyl acetate. The yield was 0.14 g, m.p. 168-172° C.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[C:5](=[CH:10][C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:6](OC)=[O:7].[CH3:29][NH2:30]>C(O)CO>[NH:21]([C:11]1[CH:10]=[C:5]2[C:6](=[O:7])[N:30]([CH3:29])[C:3](=[O:28])[C:4]2=[CH:13][C:12]=1[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN
Reactant: COC(=O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)OC
Solvent: OCCO
Product: CN1C(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc2C1=O

Procedure:
Analogously to Example 1, 376 mg (1 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester in 33 ml of ethylene glycol are heated at 120° and, with stirring, methylamine is passed through the mixture for 18 hours. Thereaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed onsilica gel with hexane/ethyl acetate 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of slightly yellow crystals, FAB-MS: 344 [M+ +H], m.p. 195°-196° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[F:23][C:24]([F:30])([F:29])[C:25]([CH2:27][F:28])=[O:26].C(OCC)C>O1CCCC1>[F:23][C:24]([F:30])([F:29])[C:25]([OH:26])([CH2:27][F:28])[C:17]#[C:16][C:13]1[CH:12]=[CH:11][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: O=C(CF)C(F)(F)F
Reactant: C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)c1ccc(C#CC(O)(CF)C(F)(F)F)cc1
Reaction time: 0.08 h

Procedure:
To a cooled (-78° C.) solution of 4-phenylsulfonylphenylethyne (1.68 g) in anhydrous tetrahydrofuran (70 mL) was added n-butyl lithium (3.06 mL of a 2.5 M solution in hexanes). The solution was stirred for 15 minutes at -78° C. before 1,1,1,3-tetrafluoroacetone (2.96 mL of a 40% diethyl ether solution) was added. The reaction mixture was kept at -78° C. for five minutes before quenching with 2N hydrochloric acid. Diethyl ether was added and the aqueous layer extracted further with diethyl ether. The combined organic layers were dried, evaporated and the product purified by chromatography, with diethyl ether:chloroform (1:9) as eluent. This yielded the title compound as a white solid (1.64 g) mp 119-120.8; (300 MHz) (CDCl3): 3.77 (s,1, OH), 4.55-4.79 (m,2, CH2F), 7.48-7.61 (m,5, Ar), 7.86-7.94 (m,4, Ar); MS: m/z=373 (M+1). Analysis for C17H12F4O3S: Calculated: C, 54.84; H, 3.25; Found: C, 54.70; H, 3.37.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[F:13][C:14]1[CH:15]=[CH:16][C:17](B2OC(C)(C)C(C)(C)O2)=[C:18]([CH:21]=1)[C:19]#[N:20].C(=O)([O-])[O-:32].[Na+].[Na+].Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=3)[CH:3]=2)=[C:18]([CH:21]=1)[C:19]([NH2:20])=[O:32]
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)c1cc(F)ccc1-c1ccc2cc(O)ccc2c1
Temperature: 80 °C

Procedure:
A mixture of 6-bromo-2-naphthol (12.0 g, 52.2 mmol), 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (16.7 g, 67.6 mmol, prepared according to the method disclosed in patent WO/2003099816), sodium carbonate solution (2M, 75 mL) and tetrakis(triphenylphosphine)palladium (0) (1.2 g, 1.0 mmol) in 1,4-dioxane (360 mL) was heated at 80° C. for 17 hours. It was allowed to cool then poured into dilute hydrochloric acid (1 M, 360 mL) and extracted with ethyl acetate (3×200 mL). These extracts were washed with water and brine then dried (MgSO4), filtered and the solution concentrated in vacuo to a volume of ˜100 mL. Solid was filtered off and sucked dry to give 5-fluoro-2-(6-hydroxy-2-naphthyl)benzamide as a white solid. This solid (6.3 g, 22.4 mmol) was suspended in dichloromethane (130 mL)/pyridine (11 mL) at 0° C. under nitrogen, and trifluoromethane sulfonic anhydride (11 mL, 65.5 mmol) added gradually over 40 minutes before leaving overnight to return to ambient temperature. Solvent was removed in vacuo, water (400 mL) added and extracted into ethyl acetate (2×300 mL). These extracts were washed with water and brine then dried (MgSO4), filtered and solvent removed in vacuo. Purification by flash column chromatography eluting with 10% ethyl acetate/isohexane gave 6-(2-cyano-4-fluorophenyl)-2-naphthyl trifluoromethanesulfonate (8.0 g, 38%). 1H NMR (500 MHz, CDCl3) δ 8.06 (1H, s), 8.01 (2H, dd, J=4.0, 9.0 Hz), 7.82 (1H, d, J=2.3 Hz), 7.73 (1H, dd, J=1.7, 8.5 Hz), 7.60 (1H, dd, J=5.2, 8.6 Hz), 7.53 (1H, dd, J=2.6, 7.9 Hz), 7.47-7.41 (2H, m).
Reaction SMILES: [CH2:1]([C:9](Cl)=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[S:12]1[CH:16]=[C:15]([C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[N:14]=[CH:13]1>N1C=CC=CC=1>[CH2:1]([C:9]([N:21]1[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=[C:17]1[C:15]1[N:14]=[CH:13][S:12][CH:16]=1)=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC(=S)Cl
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Solvent: c1ccncc1
Product: CCCCCCCCC(=S)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
249 G. (1.19 moles) of n-octylthiocarbonyl chloride is added dropwise over a period of 20 minutes to a stirred suspension of 240 g. (1.19 moles) of 2-(4-thiazolyl)-benzimidazole and 2400 ml. of pyridine; a slight heat rise is evidenced. The reaction mixture is stirred at room temperature for 19 hours, filtered and the solid material washed with methylene chloride. The combined filtrate and washings are evaporated to dryness in vacuo. The residue is mixed with 2000 ml. of methylene chloride and filtered. The solid material is washed with methylene chloride and the combined filtrate and washing are wased twice with water, 3 times with cold 0.25 normal hydrochloric acid (5000 ml. total volume), once with saturated cold sodium bicarbonate and twice with water. The methylene chloride is dried, evaporated to dryness in vacuo affording a syrupy oil which crystallizes under vacuum. The solid material is dissolved in 3 liters of hexane and filtered and the hexane evaporated to a small volume and diluted with petroleum ether to a volume of 3000 ml. whereupon crystallization results. The solid material is filtered and washed with cold petroleum ether affording 219.8 g. (54%) of pure 1-n-octylthiocarbonyl-2-(4-thiazolyl)-benzimidazole, melting point 58° to 59° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C@@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[OH:12])[CH:3]=[N:2]1>CCCCCC.C(O)C>[NH:1]1[CH:5]=[C:4]([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:12])[CH:3]=[N:2]1
Reactant: O[C@@H]1CCCC[C@H]1c1cn[nH]c1
Solvent: CCO
Solvent: CCCCCC
Product: O[C@H]1CCCC[C@@H]1c1cn[nH]c1

Procedure:
The (1R*,2S*)-2-(1H-pyrazol-4-yl)cyclohexanol prepared in Example 169a was optically resolved with CHIRALPAK AD-H (Daicel Corp.; hexane/ethanol=8:2) to yield the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([Br:14])[CH:5]=1)=[O:3].[C:15](OCC)(=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[Br:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]2[O:10][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:1][C:2](=[O:3])[C:4]=2[CH:5]=1
Reactant: CC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1cc(=O)c2cc(Br)cc([N+](=O)[O-])c2o1
Yield: 77 %

Procedure:
Following the process described in example 1 (point A), starting from 5-bromo-2-hydroxy-3-nitroacetophenone and diethyl oxalate, the title compound was prepared, which was purified by crystallization in tetrahydrofuran:ethanol mixtures (77% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[Mg:11].[Br:12]CCBr>C1COCC1>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Mg:11][Br:12])=[CH:3][CH:4]=1)[CH3:10]
Reactant: [Mg]
Reactant: CCSc1ccc(Br)cc1
Reactant: BrCCBr
Solvent: C1CCOC1
Product: CCSc1ccc([Mg]Br)cc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
1-Bromo-4-(ethylthio)benzene (0.5 g, 2.3 mmol) was added to a stirred mixture of magnesium turnings (1.96 g, 82 mmol) in THF (10 mL). 1,2-Dibromoethane (30 μL) was then added and the mixture was heated at reflux to initiate the reaction. A solution of 1-bromo-4-(ethylthio)benzene (18.2 g, 84 mmol) in THF (60 mL) was added at such a rate to maintain the reaction mixture at gentle reflux. The reaction mixture was then stirred at 50° C. for 90 min and cooled to ambient temp to give a 1.16M solution of 4-(ethylthio)phenylmagnesium bromide in THF which was used in the next reaction.
Reaction SMILES: N1CCCCC1.[CH2:7]([C@@H:14]1[CH2:19][C@@H:18]([N:20]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][CH:29]=2)[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:17][CH2:16][N:15]1[C:38]([C@H:40]1[N:52](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:51][C:43]2[NH:44][C:45]3[C:50]([C:42]=2[CH2:41]1)=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:39])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[CH2:7]([C@@H:14]1[CH2:19][C@@H:18]([N:20]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][CH:29]=2)[C:21](=[O:26])[C:22]([F:25])([F:23])[F:24])[CH2:17][CH2:16][N:15]1[C:38]([C@H:40]1[NH:52][CH2:51][C:43]2[NH:44][C:45]3[C:50]([C:42]=2[CH2:41]1)=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:39])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([C@@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OCC1c2ccccc2-c2ccccc21)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C([C@@H]1Cc2c([nH]c3ccccc23)CN1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.97 ml, 19.9 mmol) of piperidine are added to a solution of 338 mg (0.399 mmol) of (2R*,4S*)-2-benzyl-1-((3S)-(2-(9-fluorenylmethyloxycarbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl)carbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine in 3 ml of N,N-dimethylformamide, and the mixture is stirred at room temperature for 2 hours. It is then concentrated in a rotary evaporator, and the residue is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (2000:50:1) to separate the diastereomers. TLC: methylene chloride/methanol/conc. ammonia (700:50:1)
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.CN([CH:22]=[O:23])C>>[CH:22]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[NH:6][CH:7]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2[nH]cc(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
To a solution of anhydrous DMF (12 mL) under argon at 0° C. was added POCl3 (446 μL, 4.9 mmol). The reaction mixture has been stirred at 0° C. for 5 min. The methyl 1H-indole-5-carboxylate (854 mg, 4.9 mmol) in solution in DMF was added dropwise. The resulting mixture has been heated at 120° C. for 1 h. Then, it is quenched by addition of a saturated solution of NaHCO3 (2 mL). The mixture is diluted with DCM, washed with brine, dried over MgSO4 and concentrated. The product is precipitated in hexane/diethyl ether (1/1) to yield a red powder (896 mg, 4.4 mmol, 91%). ESI-MS (m/z): 204 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]([C:22]([F:25])([F:24])[F:23])[CH2:10][CH:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:13]=3[O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])O.[Na+]>O>[C:1]1([CH2:7][O:8][CH:9]([C:22]([F:25])([F:23])[F:24])[CH2:10][CH:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([NH:21][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:19]=[CH:20][C:13]=3[O:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC(CC(OCc1ccccc1)C(F)(F)F)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Nc1ccc2c(c1)CCC(CC(OCc1ccccc1)C(F)(F)F)O2

Procedure:
A solution of 3.6 g (10 mmol) of 2-(2-phenylmethoxy-3,3,3-trifluoropropyl)-6-amino-3,4-dihydro-2H-1-benzopyran in 34 ml of a 9/1 mixture of tetrahydrofuran and water is reacted for 20 min with 1.1 ml (11 mmol) of ethyl chloroformate and 1.3 g (15 mmol) of sodium hydrogencarbonate. The mixture is then diluted with water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. By chromatography of the residue on a silica column using a 20/80 mixture of cyclohexane and dichloromethane, 4.2 g of product are obtained.