Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:35])[C:9]([S:12][C:13]1[S:14][CH:15]=[C:16]([CH:18]([OH:34])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:17]=1)([CH3:11])[CH3:10])(C)(C)C.[CH3:36]I.O>CN(C=O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH:18]([C:16]3[N:17]=[C:13]([S:12][C:9]([CH3:10])([CH3:11])[C:8]([OH:7])=[O:35])[S:14][CH:15]=3)[O:34][CH3:36])=[CH:22][CH:23]=2)=[CH:32][CH:31]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(O)COc2ccc(-c3ccc(F)cc3)cc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(COc1ccc(-c2ccc(F)cc2)cc1)c1csc(SC(C)(C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% oil suspension, 24 mg) was suspended in DMF (5 mL), and a solution of 2-[(4-{2-[(4′-fluorobiphenyl-4-yl)oxy]-1-hydroxyethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (331 mg) obtained in Example 2-2 in DMF (1.5 mL) was added. After cease of foaming, methyl iodide (0.12 mL) was added, and the mixture was stirred at room temperature for 30 min. Water (20 mL) was added, and the mixture was stirred, extracted with ethyl acetate (50 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography (Fuji Silysia silica gel BW300 was used. elution solvent: hexane/ethyl acetate-9/1-7/3) to give tert-butyl ester of the title compound (222 mg). By an operation similar to that in Example 2-3 and using the compound, the title compound (177 mg) was obtained.
Reaction SMILES: BrC[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1>C1COCC1.O.[Zn+2].[Br-].[Br-]>[CH2:3]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([O:8][CH3:7])=[O:17])[CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CC(C)CCBr
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(CC(C)C)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
In an oven-dried round bottom flask Mg turnings (1.13 g, 46.6 mmol) are suspended in THF (1 mL). 1-Bromo-3-methylbutane (6.37 g, 46.5 mmol) is carefully added while the mixture is initially heated to reflux. The mixture is stirred for approximately 30 min until the Mg has dissolved. The mixture is then added to a cold (5° C.) solution of ZnBr2 (10.47 g, 46.5 mmol) in THF (80 mL). The thick suspension is stirred at 0° C. for 20 min before it is cooled to −75° C. 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (184 mg, 0.225 mmol) followed by methyl-3-bromobenzoate (5.0 g, 23.3 mmo) is then added. The mixture is warmed to rt and stirred for 24 h. The reaction mixture is diluted with water and extracted with EA. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 20:1 to give methyl 3-isobutyl-benzoate (4.34 g) as a colourless oil. This material is dissolved in methanol (50 mL) and 2 N aq. LiOH (10 mL) and stirred at rt for 16 h. The mixture is acidified by adding 1 N aq. HCl and extracted with EA. The org. extracts are dried over MgSO4, filtered and evaporated to give 3-isobutyl-benzoic acid (3.84 g) as a colourless oil; LC-MS: tR=0.91 min; 1H NMR (CDCl3): δ 0.87 (d, J=6.7 Hz, 6H), 1.77-1.94 (m, 1H), 2.48 (d, J=7.0 Hz, 2H), 7.29-7.35 (m, 2H), 7.86 (s, 1H), 7.88-7.94 (m, 1H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:18]([C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:18]([C:21]1[N:26]=[CH:25][C:24]([O:27][C:2]2[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=2)=[CH:23][CH:22]=1)([F:19])[F:20]
Reactant: Oc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Reactant: N#Cc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1cnc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a magnetically stirred mixture of 2-chlorothiazole-5-carbonitrile (14.68 mg, 0.102 mmol) and 6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-ol (V) (25 mg, 0.068 mmol) in dry DMSO (1 mL) was added potassium carbonate (18.71 mg, 0.135 mmol) in a dry 25 mL vial under N2 atmosphere. The reaction mixture was stirred at RT for 4 hours, then diluted with DCM and washed with 2N HCl/water. The organic extract was evaporated and purified on silica (ISCO, 12 gram column, gradient to 50% EtOAc/Hexanes over 15 minutes) to afford the title compound. Yield=18 mg (52.9%) of a yellow white foam. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.63 (d, J=2.5 Hz, 1H), 7.92 (dd, J=8.8, 2.8 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.34 (td, J=8.9, 6.4 Hz, 1H), 6.90 (s, 1H), 6.82-6.73 (m, 1H), 6.73-6.64 (m, 1H), 5.59 (d, J=14.3 Hz, 1H), 5.16 (d, J=15.3 Hz, 1H). 1H-decoupled 19F NMR (376 MHz, CDCl3) δ −103.63 (d, J=16.3 Hz), −104.07 (dd, J=56.5, 10.2 Hz), −104.33 (d, J=16.3 Hz), −107.58 (t, J=6.8 Hz), −110.27 (d, J=39.5 Hz), −110.97 (d, J=40.9 Hz). MS(ESI): m/z 478.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cccc(CN2CCCCC2)n1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
To a solution of 6-bromopyridine-2-carbaldehyde (25 g, 135 mmol) in dichloromethane (500 ml) was slowly added piperidine (12.6 g, 149 mmol) at 10° C. After stirring for 15 minutes at 10° C., acetic acid (8.9 g, 149 mmol) was added, followed by the portionwise addition of sodium triacetoxyborohydride, while the temperature was kept at 5-10° C. After stirring for 2 h at room temperature the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate. The product was extracted into dichloromethane and the combined organic phases were washed with brine, dried over sodium sulphate and concentrated under reduced pressure. Column chromatography afforded 2-bromo-6-(piperidin-1-ylmethyl)pyridine (30 g) as a colourless oil.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([C:21]2[C:26]([O:27][CH3:28])=[C:25]([CH3:29])[C:24]([CH3:30])=[C:23]([CH:31]=[O:32])[C:22]=2[CH3:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:6]=1.S([O-])(O)(=O)=O.[K+]>O1CCCC1>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([C:21]2[C:26]([O:27][CH3:28])=[C:25]([CH3:29])[C:24]([CH3:30])=[C:23]([CH:31]([OH:32])[CH3:1])[C:22]=2[CH3:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C=O)c(C)c(C)c1OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C(C)O)c(C)c(C)c1OC
Reaction time: 0.5 h

Procedure:
To a solution of methylmagnesium bromide in tetrahydrofuran (1M, 54.3 ml) was added anhydrous tetrahydrofuran (90 ml). To the solution was added dropwise a solution of methyl (R)-7-(4-fluorophenyl)-7-(3-formyl-6-methoxy-2,4,5-trimethylphenyl)heptanoate (4.5 g, 10.9 mmol) in tetrahydrofuran (20 ml) at -78° C., followed by stirring for 30 minutes at the same temperature. To the reaction mixture, an aqueous solution of potassium hydrogensulfate, followed by subjected to extraction with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium hydrogencarbonate and water, in the order mentioned, and dried over magnesiumsulfate. The organic layer was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography to give methyl (R)-7-(4-fluorophenyl)-7-[3-(1-hydroxyethyl)-6-methoxy-2,4,5-trimethylphenyl]heptanoate (4.4 g). Physico-chemical properties and spectral data of this compound are shown in [Table 5].
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C@@:12]34[C:15]5[C:21]6[CH2:22][C@@H:6]2[C@@:7]23[CH2:25][CH2:24][C@:10]([O:26][CH3:27])([C@@H:11]4[O:17][C:16]=5[C:18]([OH:23])=[CH:19][CH:20]=6)[C@@H:9]([CH2:28][O:29][CH2:30][C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:34]=[CH:35][CH:36]=3)[CH2:8]2)[CH2:3][CH2:2]1.BrC1C=C(C=CC=1)CBr.NC1C=CC=CC=1.C([Cl:60])(=O)C.C(O)(C(F)(F)F)=O>>[CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C@@:12]34[C:15]5[C:21]6[CH2:22][C@@H:6]2[C@@:7]23[CH2:25][CH2:24][C@:10]([O:26][CH3:27])([C@@H:11]4[O:17][C:16]=5[C:18]([OH:23])=[CH:19][CH:20]=6)[C@@H:9]([CH2:28][O:29][CH2:30][C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:34]=[CH:35][CH:36]=3)[CH2:8]2)[CH2:2][CH2:3]1.[ClH:60]
Reactant: CC(=O)Cl
Agent: BrCc1cccc(Br)c1
Agent: CO[C@]12CC[C@@]3(C[C@@H]1COCc1cccc(NC(C)=O)c1)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Solvent: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cl

Procedure:
In a similar manner N-(3-((((4R,4aS,6R,7R,7aR,12bS)-3-(cyclopropylmethyl)-9-hydroxy-7-methoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)methoxy)methyl)phenyl)acetamide (Compound 72) was prepared from R-101 using 3-bromobenzyl bromide, followed by conversion of the aryl bromide to the aniline, subsequent reaction of the aniline with acetyl chloride and final cleavage of the p-methoxybenzyl group by TFA. Purification by flash column chromatography (silica gel, 0-10% MeOH/DCM) followed by HCl salt formation gave Compound 72 HCl salt as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:26][CH:25]([OH:27])[CH2:24]2)[S:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:24][CH:25]([O:27][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:26]2)[S:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (730 mg, 1.76 mmol) (obtained as described in Reference Example 37(4)) in methylene chloride (37 ml) were added methanesulfonyl chloride (409 μl, 5.29 mmol) and triethylamine (741 μl, 5.29 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (846 mg, yield 98%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(C)CNc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)CN(c1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a mixture of 1.70 g (0.0082 mole) of (rac)-2-methyl-3-phenylamino-propanoic acid ethyl ester, 1.7 g (0.0088 mole) of 2,4-dichloro-5-nitro-pyrimidine and 60 mL of ethyl acetate, was added 4.24 mL (0.0246 mole) of N,N-diisopropylethylamine. The mixture was stirred at room temperature for 2 hours, and then washed with successively with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (80:20) to give 2.99 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-phenyl-amino]-2-methyl-propanoic acid ethyl ester (IV-51) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([OH:15])=[CH:10]2)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=[C:21]([Cl:24])[C:22]=1Cl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([O:15][C:22]1[C:21]([Cl:24])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[Cl:16])=[CH:10]2)=[O:4]
Reactant: COC(=O)c1cccc2cc(O)cnc12
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc2cc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cnc12
Temperature: 25 °C

Procedure:
To a solution of 3-Hydroxy-8-quinolinecarboxylic acid methyl ester (313) (256 mg, 1.26 mmol) and 3,4,5-Trichloronitrobenzene (294 mg, 1.30 mmol) in Acetone (40 ml) was added K2CO3 (870 mg, 6.30 mmol). This mixture was refluxed for 3.5 hr. The reaction mixture was cooled to room temperature and insoluble materials were removed by Celite filtration. The filtrate was concentrated and the residue was purified by column chromatography. (Hexane/AcOEt=4/1, 80 g of silica gel) to afford compound 314.
Reaction SMILES: [C:1]1([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:12][CH2:13][C:14]([C:4]1[CH:3]=[CH:2][C:1]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=1)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: CS(=O)(=O)Nc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)CCl)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
In a flask containing 128.4 g (0.75 mole) of N-phenylmethanesulfonamide, 169.5 g (1.50 mole) of chloroacetyl chloride in 1 L of methylene chloride under an atmosphere of nitrogen and cooled to about -10° C. add 300 g (2.25 mole) of aluminum chloride. Stir the resulting mixture for about 2 hours at -10° C. then warm to room temperature for about 16 hours. Pour the reaction mixture onto 2 Kg of ice containing 600 mL of concentrated hydrochloric acid. Collect the precipitate and wash with methanol (3×300 mL) and dry in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[CH3:24]I>C1COCC1.C(OCC)(=O)C>[Cl:16][C:11]1[CH:10]=[C:9]([C@@H:8]2[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C@H:2]2[NH:1][CH3:24])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Reactant: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) in THF (4 mL) was added methyl iodide (0.026 ml) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (30 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([S:44]([CH3:47])(=[O:46])=[O:45])[CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:42][C:39]([F:40])([F:41])[C:35]1[CH:34]=[C:33]([NH:32][C:31]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([O:21][C:19]4[CH:20]=[C:15]([CH2:14][N:13]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)[N:16]=[CH:17][N:18]=4)=[CH:30][CH:29]=3)[CH:25]=[CH:26]2)=[O:43])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)S(C)(=O)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1)C1CCNC1

Procedure:
(±)-3-(Methanesulfonyl-{6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (12 mg, 0.018 mmol) is stirred in a solution of DCM (2 mL) and TFA (0.5 mL) overnight. After removal of solvents, the residue is quenched with saturated aqueous sodium bicarbonate. The mixture is extracted with EtOAc (3×). The combined organic layers are washed with water and brine and the organic layer is dried with Na2SO4, filtered, and condensed. The residue is then separated by FCC (0-10%, 2 M NH3 in MeOH/DCM) to provide the title compound. MS (ESI) m/z 574.8 (M−1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:21].Cl.[NH2:23][CH2:24][CH2:25][O:26][NH2:27].N1C=CC=CC=1>C(O)C>[ClH:21].[ClH:21].[NH2:23][CH2:24][CH2:25][O:26][N:27]=[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCON
Reactant: O=C(CCCn1ccnc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCCn1ccnc1)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 4-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-butanone (5.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (3.17 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for two hrs. The reaction mixture was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180: 19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 3.1 g (42%) of product, mp 207°-208C. (dec).
Reaction SMILES: C[N:2]([C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)=[CH:10][C:9]=1[CH3:31])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].Cl>CO.O>[Cl:30][C:25]1[CH:24]=[C:23]([C:17]2([C:19]([F:21])([F:20])[F:22])[O:16][N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:2][CH2:3][C:4]([OH:6])=[O:5])=[O:32])=[C:9]([CH3:31])[CH:10]=3)[CH2:18]2)[CH:28]=[C:27]([Cl:29])[CH:26]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)CC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
In a solution of 2.6 g of methyl N-[4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl]glycine (Compound of the present invention No. 5-128) synthesized similarly to Synthetic Example 5 in 10 ml of methanol, a solution of 1.0 g of potassium hydroxide in 10 ml of water was added with stirring at room temperature, and stirred at the same temperature for further 1 hour. After the completion of the reaction, 10 ml of 12N hydrochloric acid was added and extracted with ethyl acetate (50 ml×1), the organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2.4 g of the aimed product as pale yellow resinous resinous substance.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:32][O:33][CH2:34][CH2:35]Br>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH2:35][CH2:34][O:33][CH3:32])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: COCCBr
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Product: COCCn1c(C(=O)N2CCC(F)(F)CC2)cc2cc(OC3CCN(C(C)C)CC3)cnc21
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-methanone (example 13), sodium hydride and 2-bromoethyl methyl ether to give the desired product as light yellow oil (49%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[C:8]4[C:34](=[O:35])[C:33]5[C:28](=[CH:29][CH:30]=[C:31](Br)[CH:32]=5)[C:9]4=[C:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:11]=3[C:12](=[O:15])[C:13]=2[CH:14]=1.C([Sn](CCCC)(CCCC)[C:54]1[S:55][CH:56]=[CH:57][CH:58]=1)CCC>C1(C)C=CC=CC=1.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>[S:55]1[CH:56]=[CH:57][CH:58]=[C:54]1[C:31]1[CH:30]=[CH:29][C:28]2[C:9]3[C:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:11]4[C:12](=[O:15])[C:13]5[C:5](=[CH:4][CH:3]=[C:2]([C:54]6[S:55][CH:56]=[CH:57][CH:58]=6)[CH:14]=5)[C:6]4=[C:7]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:8]=3[C:34](=[O:35])[C:33]=2[CH:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCCCCCCCCCc1c2c(=O)c3cc(Br)ccc3c2c(CCCCCCCCCCCC)c2c(=O)c3cc(Br)ccc3c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1c2c(=O)c3cc(-c4cccs4)ccc3c2c(CCCCCCCCCCCC)c2c(=O)c3cc(-c4cccs4)ccc3c12
Temperature: 25 °C
Yield: 60.1 %

Procedure:
Indenofluorenedione 5 (0.200 g, 0.257 mmol), 2-tributylstannylthiophene (0.231 g, 0.618 mmol), and Pd(PPh3)4 (20 mg) in anhydrous toluene (8.0 mL) were heated overnight at 110° C. under nitrogen. The reaction mixture was cooled to room temperature and concentrated to dryness. The crude product was purified by column chromatography on silica gel (CHCl3/hexanes (7:3)) to give 2,8-dithien-2-yl-5,11-didodecylindeno[1,2-b]fluorene-6,12-dione (5B) as a purple solid (121 mg, 60.0% yield). 1H NMR (CDCl3): δ 0.88-1.66 (m, 46H), 3.41 (b s, 4H), 7.11 (t, 2H), 7.39 (d, 2H, J=3.0 Hz), 7.62 (d, 2H, J=7.5 Hz), 7.74 (d, 2H, J=7.5 Hz), 7.88 (s, 2H) ppm; m.p: 205-206° C.; MS(MALDI-TOF) m/z (M+): 783.0; and Elemental Analysis: C, 79.60; H, 7.82.