Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[CH:24]([CH3:26])[CH3:25]>>[C:1]([C:5]1[CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:10]=1[O:11][CH2:23][CH:24]([CH3:26])[CH3:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)c(O)c(C(C)(C)C)c1
Reactant: CC(C)CBr
Product: COC(=O)c1cc(-c2ccc(C)cc2)c(OCC(C)C)c(C(C)(C)C)c1
Yield: 95 %

Procedure:
In a manner similar to that of Example 1c, by reacting 1.57 g (5.3 mmol) of methyl 5-tert-butyl-6-hydroxy-4′-methyl-3-biphenylcarboxylate with 1.14 mL (10.5 mmol) of isobutyl bromide. A yellow oil is obtained (m=1.8 g; yield=95%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C@H:4]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1.C(N(CC)CC)C.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C.O>C1COCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C@H:4]2[C@H:3]([CH2:2][NH:1][C:36](=[O:35])[CH2:37][OH:38])[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CN)[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](CNC(=O)CO)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (170 mg) and triethylamine (0.126 mL) in THF (4.0 ml) was added acetoxyacetyl chloride (93 mg), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in methanol (4.0 mL) was added potassium carbonate (273 mg), and the mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure, the residue was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (183 mg).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=1.[CH3:22][O:23][C:24]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([CH3:36])[C:25]=1[CH:26]=[O:27]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:22][O:23][C:24]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([CH3:36])[C:25]=1[CH:26]([C:18]1[C:17]([Cl:21])=[CH:16][N:15]=[C:14]([Cl:13])[C:19]=1[Cl:20])[OH:27]
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cc(C)c(C(O)c2c(Cl)cnc(Cl)c2Cl)c(OC)c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
17.2 ml (26.7 mmol) of n-butyllithium (1.56 M hexane solution) was dropwise added to a diethyl ether (20 ml) solution of 2.7 g (26.7 mmol) of diisopropylamine at 0° C., followed by stirring for 1 hour. The solution was cooled to −78° C., a toluene solution of 4.8 g (26.7 mmol) of 2,3,5-trichloropyridine was dropwise added thereto, and then a toluene solution of 5.0 g (24.0 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde was dropwise added thereto, followed by stirring for 30 minutes. The temperature was recovered to room temperature, and stirring was carried out further for 1 hour. 30 ml of water was added to the mixture to terminate the reaction, and ethyl acetate was added for extraction. The organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 6.7 g (yield 72%) of amorphous (2,3,4-trimethoxy-6-methylphenyl)(2,3,5-trichloro-4-pyridyl)methanol.
Reaction SMILES: CN(CCCC1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)OCC2C=C(C#N)C=CC1=2)C.[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:31](=[O:32])[O:30][CH2:29]2.FC1C=CC(Br)=CC=1.[Mg]>CCOCC>[OH:30][CH2:29][C:28]1[CH:27]=[C:26]([Br:25])[CH:35]=[CH:34][C:33]=1[C:31]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:32]
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Reactant: O=C1OCc2cc(Br)ccc21
Agent: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)c1ccc(Br)cc1CO

Procedure:
The preparation of citalopram and its hydrobromide salt from 5-bromophthalide and the properties of such compounds was first reported in U.S. Pat. No. 4,136,193, which corresponds to German Offenlegungsschrift No. 2,657,013. U.S. Pat. No. 4,136,193 discloses a synthesis of citalopram starting from 5-bromophthalide, which involves the use of two successive Grignard reactions. In a first reaction, a Grignard reagent prepared from p-fluorobromobenzene and magnesium turnings in ether was reacted with 5-bromophthalide to give 2-hydroxymethyl-4-bromo-4′-fluorobenzophenone. The latter was isolated as a crude oil before, in a second reaction, being added to N,N-dimethylaminopropylymagnesium chloride to give (4-bromo-2-(hydroxymethyl)phenyl)-(4′-fluorophenyl)-(3-dimethylaminopropyl)-methanol. The latter was dehydrated with 60 aqueous phosphoric acid to yield 1-(4′-fluorophenyl)-1-(3-dimethylaminopropyl)-5-bromophthalane, which was then refluxed with cupric cyanide in dimethylformamide to give citalopram.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].Cl.[CH3:33][O:34][NH:35][CH3:36].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl.C(N(CC)CC)C>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([N:35]([O:34][CH3:33])[CH3:36])=[O:29])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CNOC
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.4 %

Procedure:
To a solution of 4-(3-acetyl-6-bromo-1-oxo-4-phenyl-1H-isoquinolin-2-ylmethyl)benzoic acid (476 mg) in dichloromethane (10 ml) were added O,N-dimethylhydroxylamine hydrochloride (117 mg), 1-hydroxy-1H-benzotriazole (184 mg) and triethylamine (0.21 ml) and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (287 mg) was added at room temperature, and the mixture was stirred at room temperature for 15 hrs. Dichloromethane was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and sodium sulfate was added to dry the mixture. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1→1/9) to give the title compound (407 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[CH:4][C:3]=1[F:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:56][S:57][C:58]1[N:63]=[C:62]([C:64]2[CH:69]=[CH:68][NH:67][C:66](=[O:70])[CH:65]=2)[CH:61]=[CH:60][N:59]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:67]2[CH:68]=[CH:69][C:64]([C:62]3[CH:61]=[CH:60][N:59]=[C:58]([S:57][CH3:56])[N:63]=3)=[CH:65][C:66]2=[O:70])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[CH:4][C:3]=1[F:22].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:67]2[CH:68]=[CH:69][C:64]([C:62]3[CH:61]=[CH:60][N:59]=[C:58]([S:57][CH3:56])[N:63]=3)=[CH:65][C:66]2=[O:70])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[CH:4][C:3]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(O)c2ccc(Cl)c(F)c2)C1
Reactant: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1nccc(-c2ccn([C@@H](c3ccc(Cl)c(F)c3)[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(=O)c2)n1
Product: CSc1nccc(-c2ccn([C@H](c3ccc(Cl)c(F)c3)[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(=O)c2)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(3R)-tert-Butyl 3-((4-chloro-3-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (640 mg, 1.943 mmol) was dissolved in DCM (4.9 mL, 0.2M) under nitrogen, treated with triphenylphosphine (637.0 mg, 2.429 mmol) and cooled to 0° C. Diisopropyl azodicarboxylate (478.2 μL, 2.429 mmol) was added by syringe. After 5 minutes, the mixture was warmed to room temperature and stirred for 10 minutes prior to being treated with 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (213 mg, 0.9714 mmol). The mixture was then stirred at room temperature for 16 hours. After concentration by rotovap and high vacuum, the mixture was loaded onto a C18 reverse phase column and eluted with a gradient of 5% acetonitrile to 100% acetonitrile in water. The mixture of diastereomers isolated were then loaded onto an SP1 samplet and purified by silica gel chromatography using a 20% to 80% gradient of MTBE in dichloromethane. Fractions containing each diastereomer were isolated and concentrated to afford (R)-tert-butyl 3-((R)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate from the higher rf spot and (R)-tert-butyl 3-((5)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate as the lower rf spot, both as oils (54 mg, 10% yield and 48 mg, 9% yield respectively).
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH:3]=[CH:2]1.C[N+](C)=CCl.[Cl-].[NH2:26][CH:27]1[C:38](=[O:39])[N:29]2[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]([CH3:34])[S:33][C@H:28]12.C[Si](CC(N)=O)(C)C>O1CCCC1.C(OCC)(=O)C.O>[CH:1]1([O:6][N:7]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=2)[C:9]([NH:26][CH:27]2[C:38](=[O:39])[N:29]3[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]([CH3:34])[S:33][C@H:28]23)=[O:11])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Reactant: O=CNc1nc(C(=NOC2C=CCC2)C(=O)O)cs1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2S1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of 2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.5 g) in dry tetrahydrofuran (12 ml) was added to the stirred suspension of the solution of Vilsmeier reagent under ice-cooling. The resulting mixture was added to a solution of 7-amino-2-methyl-3-cephem-4-carboxylic acid (1.37 g) and trimethylsilylacetamide (5.04 g) in ethyl acetate (14 ml) at -30° to -20° C. and the mixture was stirred at -5°~-10° C. for 2 hours. After the addition of water and ethyl acetate to the reaction mixture, the ethyl acetate layer was separated and adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated and thereto was added ethyl acetate. The mixture was adjusted to pH 2.5 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated. The residue was pulverized in diisopropyl ether to give 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer) (1.98 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[C:10]2[C:11]([O:13][C:14](=[O:15])[C:9]=2[CH:8]=[C:7]2[C:16]([O:18][C:19](=[O:20])[C:6]=12)=[O:17])=[O:12].[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:22].C(N(CC)[CH:39]([CH3:41])[CH3:40])(C)C.Cl>ClCCCl>[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:19]([C:6]2[CH:5]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([C:14](=[O:15])[C:28]3[CH:27]=[CH:26][C:25]([CH2:24][CH:41]([CH2:39][CH3:40])[CH2:31][CH2:23][CH2:21][CH3:22])=[CH:30][CH:29]=3)=[CH:8][C:7]=2[C:16]([OH:18])=[O:17])=[O:20])=[CH:29][CH:30]=1)[CH3:22]
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Reactant: CCCCC(CC)Cc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCCC(CC)Cc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CC(CC)CCCC)cc3)cc2C(=O)O)cc1
Temperature: 0 °C

Procedure:
A mixture of 215.39 grams of aluminum chloride, 83.89 grams of benzene-1,2,4,5-tetracarboxylic acid dianhydride (pyromellitic dianhydride), and 533.85 grams of 1,2-dichloroethane was stirred at 15° C. to 16° C. To this mixture was added a solution of 183 grams of (2-ethylhexyl)benzene and 53.685 grams of N,N-diisopropylethylamine in 198 mL of 1,2-dichloroethane over a period of 3.5 hours keeping the reaction temperature between 15° C. and 20° C. The mixture was stirred overnight at room temperature and then added to 400 g of ice and 400 mL concentrated hydrochloric acid. This mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried, and stripped. The resulting solid was stirred with 700 mL ethyl acetate for 10 minutes and 2000 mL of heptane was added. This mixture was stirred for 15 minutes and then filtered. The residue was washed with a mixture of 275 mL ethylacetate/825 mL heptane and air dried to give 2,5-Bis(4-(2-ethylhexyl)benzoyl)terephthalic acid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:15](/[CH:16]=[CH:17]/[C:18]([CH3:31])([O:24]C2CCCCO2)[CH2:19][CH2:20][C:21]#[C:22][CH3:23])[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:4](=[O:32])[CH2:3]1>C(O)(=O)C.O.C1COCC1>[OH:1][C@H:2]1[C@H:15](/[CH:16]=[CH:17]/[C:18]([OH:24])([CH3:31])[CH2:19][CH2:20][C:21]#[C:22][CH3:23])[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:4](=[O:32])[CH2:3]1
Reactant: CC#CCCC(C)(/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC#CCCC(C)(O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
From 270 mg. of (13E)-(11R,15RS)-11-hydroxy-15-methyl-9-oxo-15-(tetrahydropyran-2-yloxy)-13-prosten-18-ynoic acid and 9 ml. of a mixture of glacial acetic acid/water/THF (65/35/10), 190 mg. of the title compound is obtained as an oil in the usual way.
Reaction SMILES: O=[C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])[NH:22][NH2:23].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(O)(=O)C.C(OCC)C>[C:26]([O:25][C:21]([NH:22][NH:23][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)CCCC(=O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CCCC(NNC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Ethyl 5-oxo-5-(3-trifluoromethylphenyl)pentanoate (CAS No. 898777-75-8, 330 mg) and tert-butyl carbazate (227 mg) were dissolved in a mixed solvent of THF (6 mL) and acetic acid (3 mL). After stirring at room temperature for 25 minutes, sodium cyanoborohydride (108 mg) was added. After further one hour and 30 minutes, sodium cyanoborohydride (108 mg) was added and the mixture was stirred at room temperature for one hour. A saturated sodium bicarbonate solution and diethyl ether were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with a saturated sodium bicarbonate solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (324 mg). The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2I)[O:9][C:8]1=[O:24].[F:34][C:35]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][C:38](B(O)O)=[C:37]([O:47][CH3:48])[CH:36]=1>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[C:38]2[CH:39]=[C:40]([CH:41]([CH3:43])[CH3:42])[C:35]([F:34])=[CH:36][C:37]=2[O:47][CH3:48])[O:9][C:8]1=[O:24]
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Following the procedure described in EXAMPLE 81, 38.5 mg of (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one and 18 mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78) gave the title compound. Mass spectrum (ESI) 638.3 (M+1). 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.55-7.80 (m, 5H), 7.29 (d, J=8 Hz, 1H), 7.00, 6.77 (d, J=8.5 Hz, 1H), 6.68, 6.63 (d, J˜12 Hz, 1H), 5.08, 5.04 (d, J˜5 Hz, 1H), 4.81, 4.75 (d, J=16 Hz, 1H), 4.26, 4.23 (d, 15.5 Hz, 1H), 3.75 (s, 2H), 3.50 (s, 1H), 3.43 (m, 0.5H), 3.12-3.24 (m, 1.5H), 1.24, 1.22 (d, J˜5 Hz, 3H), 1.17, 1.06 (d, J=7 Hz, 3H), 0.84, 0.70 (d, J=6 Hz, 3H).
Reaction SMILES: [CH2:1]([C:4]1([CH2:30][CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=O)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:39][S:40]([O:43]S(C)(=O)=O)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O-:43])(=[O:42])=[O:41].[CH2:1]([C@@:4]1([CH2:30][CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N+:6]2[C@@H:24]([CH2:27][CH3:28])[CH2:25][O:26][C:5]1=2)[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: C=CCC1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@@]1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2CC
Product: CS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (300 mg, 0.652 mmol) (Example 202, Step B) in DCM (6 mL) was added triethylamine (270 μl, 1.955 mmol) and methanesulfonic anhydride (170 mg, 0.977 mmol) successively at 0° C. The reaction was allowed to warm to rt. After being stirred at rt for 2 h, the reaction was quenched with 10% aq. citric acid, extracted with DCM and the combined extracts were washed with water, dried over Na2SO4, filtered and the filtrate was and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:36]([CH:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:37])[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Reactant: CN1CCC(C(=O)O)CC1
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)C1CCN(C)CC1

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 1-methyl-piperidine-4-carboxylic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 522. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (s, 1H) 8.3 (m, 1H) 7.8 (m, 2H) 7.4 (m, 1H) 7.2 (s, 1H) 6.9 (m, 3H) 5.0 (s, br, 1H) 4.8 (m, 1H) 4.5 (d, 2H) 4.2 (m, 1H) 3.7 (m, 2H) 3.4 (s, 1H) 3.2 (m, 2H) 2.8 (m, 2H 2.5 (m, 5H) 2.0 (s, br, 2H) 1.9 (s, br, 1H) 1.2 (d, 3H) 1.0 (d, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([CH2:20]Br)[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([F:33])[C:24]=1[C:25]([NH2:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([CH2:20][O:32][C:31]3[C:23]([F:22])=[C:24]([C:28]([F:33])=[CH:29][CH:30]=3)[C:25]([NH2:27])=[O:26])[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1nc(-c2ccc(OCc3ccccc3)cc2)ns1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(OCc4ccccc4)cc3)ns2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of 3-(4-benzyloxyphenyl)-5-bromomethyl-[1,2,4]thiadiazole (0.04 g, 0.11 mmol) in DMF (2 ml) was added 2,6-difluoro-3-hydroxybenzamide (0.017 g, 0.10 mmol) and potassium carbonate (0.53 g, 0.39 mmol). The reaction mixture was stirred at 25° C. overnight under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 20 ml water and extracted with ethyl acetate (3×20 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 40% EtOAc-Hexane) to get the desired product (0.025 g, 50%). MS ES+ (454.13).