Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][CH2:13][C:14](=O)[CH3:15])[CH:6]=1)[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][C:13]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:14]=2[CH3:15])[CH:6]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(C)c(SCC(C)=O)c1
Agent: Cl
Product: CCOC(=O)c1ccc(C)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 4-Methyl-3-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [Si:1]([O:18][C:19]1[C:24]([CH3:25])=[C:23]([CH:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:22]([OH:42])=[C:21]([CH3:43])[C:20]=1[CH3:44])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45](Cl)(=[O:47])[CH3:46].O>ClCCl.C(N(CC)CC)C>[C:45]([O:42][C:22]1[C:23]([CH:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[C:24]([CH3:25])[C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:20]([CH3:44])[C:21]=1[CH3:43])(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: COC(=O)CCCCCC(c1ccccc1)c1c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)c(C)c1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCCC(c1ccccc1)c1c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)c(C)c1OC(C)=O
Reaction time: 2 h

Procedure:
4-tert-Butyldiphenylsilyloxy-1-hydroxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene (22.2 g, 36.46 mM) was dissolved in dichloromethane (200 ml) and triethylamine (8.3 ml, 59.9 mM). Acetyl chloride (4.1 ml, 57.7 mM) was added under ice-cooling, and the mixture was stirred for 2 hours. The reaction mixture was poured into ice-cooled water (100 ml) and stirred for 20 minutes. Then the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain 1-acetoxy-4-tert-butyldiphenylsilyloxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene as a pale yellow oil. This oil was dissolved in tetrahydrofuran (70 ml). 1M tetra-n,butylammonium fluoride trihydrate/tetrahydrofuran solution (73 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-cooled water (150 ml) and extracted with ethyl acetate (150 ml). The organic layer was washed with water followed by saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane to obtain the desired compound as pale yellow prisms (9.03 g).
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7](Br)[N:6]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]=1[CH3:19])(=[O:3])[CH3:2].C(B(CC)[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)C.[OH-].[K+]>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>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:6]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CCB(CC)c1ccncc1
Reactant: CC(=O)c1c(C)c(Br)n(COCC[Si](C)(C)C)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)c1c(C)c(-c2ccncc2)n(COCC[Si](C)(C)C)c1C
Yield: 36 %

Procedure:
To a stirred solution of 3-acetyl-5-bromo-2,4-dimethyl-1-{2-(trimethylsilyl)ethoxymethyl}-1H-pyrrole (309 mg, 0.85 mmol) in toluene (5 mL) was added diethyl(4-pyridyl)borane [prepared according to the method of M. Terashima et al., Heterocycles, 1984, 22, 2471] (250 mg, 1.70 mmol), potassium hydroxide (85% purity, 168 mg, 2.55 mmol), and tetrakis(triphenylphosphine)palladium (0) (100 mg, 0.085 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 3 hours. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:1) to give the title product (105 mg, 36% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26]([C:28]5[O:29][C:30]([CH:33]6OCC[O:34]6)=[CH:31][CH:32]=5)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C>C1COCC1.C(O)C.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26]([C:28]5[O:29][C:30]([CH:33]=[O:34])=[CH:31][CH:32]=5)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cn2ncc3cc(Nc4ncnc5cnc(-c6ccc(C7OCCO7)o6)cc45)ccc32)cc1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cn2)o1

Procedure:
(1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolanyl]-furan-2-yl)-pyrido[3,4-d]-pyrimidin-4-yl)-amine (3.03 g) and 2N HCl (50 ml) were stirred in THF (50 ml) for 16 hr. The resulting precipitate was filtered and washed with water to give the thehydrochloride salt of the product; δH [2H6]DMSO 11.70 (1H,s), 9.74 (1H,s) 9.30 (1H,s), 9.27 (1H,s), 8.85 (1H,s), 8.23 (1H,s), 8.18 (1H,s), 7.68-7.87 (3H,m), 7.55 (1H,d), 7.22-7.38 (5H,m), 5.71 (2H,s). Subsequent neutralisation with triethylamine in ethanol/water gave the title compound; δH[2H6]-DMSO 9.64(1H,s), 9.19 (1H,s), 9.09(1H,s), 8.72(1H,s), 8.12(2H,m), 7.71(2H,m), 7.63(1H,dd), 7.43(1H,d), 7.20(5H,m), 5.62(2H,s).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@@:7]12[CH2:13][CH:12]([CH3:14])[CH:11]1[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:8]2)=[O:6].Cl>O1CCCC1.CO>[CH2:18]([O:17][C:15]([N:9]1[CH2:10][CH:11]2[C@@:7]([C:5]([OH:6])=[O:4])([CH2:13][CH:12]2[CH3:14])[CH2:8]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@]12CC(C)C1CN(C(=O)OCc1ccccc1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1C[C@@]2(C(=O)O)CN(C(=O)OCc3ccccc3)CC12
Reaction time: 0.5 h

Procedure:
A 1N sodium hydroxide solution (21 ml) was added dropwise to a mixed solution of (S)-6-methyl-3-azabicyclo[3.2.0]heptane-1,3-dicarboxylic acid 3-benzyl ester 1-methyl ester (3.2 g, 10.4 mmol) in tetrahydrofuran (60 ml) and methanol (20 ml) under ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution was neutralized with 1N hydrochloric acid, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure to give 3.0 g (quantitative) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.[CH3:13][C:14]1[C:20]2[CH:21]=[CH:22][C:23]([O:25]C3OC(CO)C(O)C(O)C3O)=[CH:24][C:19]=2[O:18][C:16](=[O:17])[CH:15]=1>>[CH3:13][C:14]1[C:20]2[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=2[O:18][C:16](=[O:17])[CH:15]=1
Reactant: Cc1cc(=O)oc2cc(OC3OC(CO)C(O)C(O)C3O)ccc12
Agent: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O
Product: Cc1cc(=O)oc2cc(O)ccc12
Reaction time: 0.33 h

Procedure:
α-Gal A was assayed using 4-methylumbelliferyl-α-D-galactopyranoside (4-MU-α-Gal) as previously described (Bishop, et al., 1980, In Enzyme Therapy in Genetic Diseases:2. Desnick, R. J. (Ed.). Alan R. Liss, Inc. New York, p. 17). Briefly, a stock solution of 5 mM 4-MU was prepared in 0.1M citratephosphate buffer, pH 4.6 solubilized in an ultrasonic bath. The reaction mixtures containing 10-50 μl of enzyme preparation or cell extracts and 150 μl substrate, were incubated at 37° C. for 10-30 min. The reactions were terminated with the addition of 2.33 ml of 0.1M ethylenediamine. One unit of activity is that amount of enzyme which hydrolyzes 1 nmol of substrate/hour.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11](Cl)=[CH:10][C:9]=1[NH:15][C:16](=[O:34])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH:21]=1)=O)(C)(C)C.C(O)([C:38]([F:41])([F:40])[F:39])=O>C(Cl)Cl>[CH3:33][O:32][C:29]1[N:28]=[CH:27][C:26]([C:22]2[CH:21]=[C:20]([C:18]3[CH2:17][C:16](=[O:34])[NH:15][C:9]4[CH:10]=[C:11]([C:38]([F:41])([F:40])[F:39])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)cn1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M46) (270 mg, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (79 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:33])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[C:16]2[N:34]=[C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:36]=[CH:37][C:15]=2[C:14]1=[O:44]>CO>[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:33])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[C:16]2=[N+:34]([O-:9])[C:35]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[N:36][CH:37]=[C:15]2[C:14]1=[O:44]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1CCN(CC(=O)N2c3ccccc3N(C)C(=O)c3cnc(-c4ccccc4)nc32)CC1
Solvent: CO
Product: CN1CCN(CC(=O)N2c3ccccc3N(C)C(=O)c3cnc(-c4ccccc4)[n+]([O-])c32)CC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 0.7 g (3.4 mmol) of m-chloroperbenzoic acid (85 percent) in 10 ml of methanol is slowly added at room temperature to a suspension of 1 g (2,3 mmol) of 6-methyl-11-[(4-methyl-1-piperazinyl)acetyl]-2-phenyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 40 ml of methanol. After stirring for 3 hours at 20° C. and filtering, the filtrate is concentrated in vacuo and the residue is purified by chromatography on neutral silica gel using 20:1 chloroform/methanol as the eluant. Yield: 0.5 g (48%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19].[C:20]([S:23][C@@H:24]([C@@H:28]([CH3:31])[CH2:29][CH3:30])[C:25](O)=[O:26])(=[O:22])[CH3:21]>>[C:20]([S:23][C@@H:24]([C@@H:28]([CH3:31])[CH2:29][CH3:30])[C:25]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19])=[O:26])(=[O:22])[CH3:21]
Reactant: CCOC(=O)CN1C(=O)C(N)CCc2ccccc21
Reactant: CC[C@H](C)[C@H](SC(C)=O)C(=O)O
Product: CCOC(=O)CN1C(=O)C(NC(=O)[C@@H](SC(C)=O)[C@@H](C)CC)CCc2ccccc21
Yield: 48.3 %

Procedure:
By using 0.525 g (2.00 mmol) of 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one and 0.418 g (2.20 mmol) of (2S,3S)-2-acetylthio-3-methylpentanoic acid obtained in the Synthesis Example C-2, the treatment of Example C-1 was repeated. Thus, 0.420 g of the title compound was obtained as a colorless amorphous product (yield 48%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.C(NC(C)C)(C)C.[Li].[Br:21]Br>O1CCCC1>[Br:21][C:11]1[S:12][C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=2[Cl:1])[CH:10]=1
Reactant: BrBr
Reactant: N#Cc1cnc2ccsc2c1Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1cnc2cc(Br)sc2c1Cl
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 17 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) in tetrahydrofuran (9.0 mL) at −78° C. is slowly added lithium diisopropylamine (0.62 mL, 1.24 mmol, 2M in tetrahydrofuran) over 10 minutes. After 40 minutes, a solution of bromine (198 mg, 1.24 mmol) in 1.5 mL of tetrahydrofuran is added slowly to the solution of the anion. The temperature is maintained at −78° C. for 5 hours then warmed to room temperature for 1 hour. The reaction mixture is poured into ice water, extracted with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by preparative thin layer chromatography developing with 90% dichloromethane in hexane to provide 48 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as a pink solid, 1H NMR (DMSO-d6) δ 8.13 (s, 1H), 9.12 (s, 1H); MS 272.8, 274.8, 276.8 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[F:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:3]=1
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2ccccc21
Reactant: COc1cccc(B(O)O)c1F
Product: COc1cccc(-c2cccc(C3(c4ccncc4)N=C(N)c4ccccc43)c2)c1F
Yield: 50 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine (Scheme #9, C) as described in Example 67 Scheme #10, D in 50% yield using 2-fluoro-3-methoxyphenyl boronic acid. 1H NMR (DMSO-d6) δ 8.42-8.32 (m, 2 H), 7.78-7.67 (m, 2 H), 7.44-7.34 (m, 3 H), 7.34-7.20 (m, 5 H), 7.15-7.02 (m, 2 H), 6.92-6.74 (m, 3 H), 3.78 (s, 3 H); MS (ESI) m/z 410 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1B(O)O.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16](Cl)[N:15]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:15]=1
Reactant: COc1ccc(C)cc1B(O)O
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Product: COc1ccc(C)cc1-c1cc([N+](=O)[O-])cc(Cl)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1 Step B, by reaction of 2-methoxy-5-methylphenylboronic acid with 2,6-dichloro-4-nitropyridine: LCMS m/z 279.5 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=8.5 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.5, 2.1 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 3.72 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: F[C@H]1CC[C@:5]2([C:20]3[CH:25]=[CH:24]C=CC=3F)[N:6]=[C:7]([NH:10]C(=O)OC(C)(C)C)[S:8][CH2:9][C@@H:4]2C1.Br[C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Br:35])[CH:29]=1>>[Br:35][C:30]1[CH:29]=[C:28]([C@:5]23[CH2:20][CH2:25][CH2:24][C@H:4]2[CH2:9][S:8][C:7]([NH2:10])=[N:6]3)[CH:33]=[C:32]([Cl:34])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@H](F)C[C@H]2CS1
Reactant: Clc1cc(Br)cc(Br)c1
Product: NC1=N[C@@]2(c3cc(Cl)cc(Br)c3)CCC[C@H]2CS1

Procedure:
The title compound was synthesized from hex-5-enal oxime (JOC, 41 (5), 863-9; 1976) according to the method of Preparation Example 8, using 1,3-dibromo-5-chlorobenzene instead of 2-fluorobromobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[CH:34]([C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=1)[C:39]([O:41][CH3:42])=[O:40])=O.CO.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:34][C:36]3[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=3)[C:39]([O:41][CH3:42])=[O:40])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: Oc1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(CN2CCC(Nc3cc(O)nc4ccc(C(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol (100 mg, 0.21 mmol, 1.00 equip), methyl 3-formylbenzoate (68 mg, 0.41 mmol, 2.00 equip), methanol (10 mL), NaBH3CN (66 mg, 1.03 mmol, 5.00 equip), and acetic acid (0.1 mL). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield methyl 3-[[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]methyl]benzoate as a yellow solid. LCMS (ES, m/z) 626 [M+H]+
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:7]>CO.O1CCCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][N:2]([CH3:3])[CH3:1])=[CH:9][CH:10]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CNC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
A 2.0 M solution of dimethylamine (0.5 mmol) in methanol was added to a solution of 2-bromo-1-(4-bromophenyl)ethanone (114.5 mg, 0.41 mmol) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 15 min. The solvent was removed by distillation, and the residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 to 0:100) to give 84.7 mg (yield 86%) of the title compound.
Reaction SMILES: C(O[C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[C:7]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13](O)[CH2:12][CH2:11]1)=[O:8])C=C.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:7]([O:8][C:19]1[CH:20]=[CH:5][C:6]([C:7]([O:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[CH2:14][CH2:15]2)=[O:8])=[CH:17][CH:18]=1)[CH:6]=[CH2:5]
Reactant: C=CCOc1ccccc1C(=O)O[C@H]1CC[C@H](O)CC1
Reactant: O=C(Cl)CCCCCBr
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: C=CCOc1ccc(C(=O)O[C@H]2CC[C@H](C(=O)CCCCCBr)CC2)cc1

Procedure:
55.2 g (0.2 mol) of trans-4-hydroxycyclohexyl allyloxybenzoate prepared as described in Example 1 were dissolved in 300 ml of dry toluene, and 43 g (0.205 mol) of 6-bromohexanoyl chloride (prepared from the free acid by conventional reaction with thionyl chloride; b.p. 60-62° C. at 0.04 mbar) were added dropwise at 105° C. over the course of 60 minutes with stirring. After the mixture had been stirred at 105° C. for a further 90 minutes, the solvent was stripped off under reduced pressure, and the residue was crystallized out using petroleum benzine/methyl tert-butyl ether (20:1), giving 83 g (92%) of trans-[4-(6-bromo-hexanoyl)cyclohexyl] 4-allyloxybenzoate, melting point 56° C. 79 g (0.174 mol) of this ester, 25 g (0.21 mol) of potassium methacrylate and 0.2 g of 2,6-di-tert-butyl-4-methylphenol (stabilizer) were dissolved in 400 ml of dimethylformamide, and the mixture was heated at 70-75° C. for 3 hours with stirring. The solvent was then distilled off under reduced pressure, the residue was taken up in 400 ml of methyl tert-butyl ether, and the solution was washed with water, 0.05 N NaOH, and again with water, dried and evaporated. The residue was recrystallized from methanol, yielding 70 g (87.5%) of the title compound, which melts at 50° C. and clears at 55° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:25]([O:27]C)=[O:26])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:25]([OH:27])=[O:26])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cc(F)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1cc(F)ccc1F)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 98.7 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 15 (4.1 g), 1 mol/L of an aqueous sodium hydroxide solution (16 mL), and methanol (160 mL), to give the captioned compound (3.9 g, 99%) as crystals.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@:9]1([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=4)[CH:29]=[C:28]([CH2:43][OH:44])[CH:27]=3)=[CH:24][N:25]=2)[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[C:11]([CH3:20])([CH3:19])[CH2:10]1.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[OH:8][C@:9]1([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[N:38]=[C:37]([C:39]([F:41])([F:42])[F:40])[CH:36]=[CH:35][N:34]=4)[CH:29]=[C:28]([CH2:43][O:44][S:46]([CH3:45])(=[O:48])=[O:47])[CH:27]=3)=[CH:24][N:25]=2)[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[C:11]([CH3:20])([CH3:19])[CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CO)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(COS(C)(=O)=O)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Temperature: 23 °C
Reaction time: 120 h
Yield: 88.5 %

Procedure:
Triethylamine (0.200 ml, 1.434 mmol, 1.5 equiv) was added to a stirring solution of methyl(1S,4R)-4-hydroxy-4-{5-[3-(hydroxymethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-2,2-dimethylcyclohexanecarboxylate (513 mg, 0.956 mmol) in anhydrous dichloromethane (15 mL). The orange solution was cooled to 0° C. (water/ice) then charged with methanesulfonyl chloride (0.089 ml, 1.147 mmol, 1.2 equiv). The reaction mixture was allowed to slowly warm to 23° C. and stir for 5 d. The mixture was partitioned between methylene chloride (2×90 ml) and water (95 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford methyl(1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-{[(methylsulfonyl)oxy]methyl}-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (520 mg, 71%), as an orange-yellow oil. 1H NMR (500 MHz, CDCl3) δ 8.79 (bs, 1H), 8.66 (d, J=4.9 Hz, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.61 (s, 1H), 7.23 (s, 1H), 7.06 (d, J=4.9 Hz, 1H), 4.59 (s, 1H), 3.90 (s, 2H), 3.69 (s, 3H), 3.01 (s, 2H), 2.38-2.25 (m, 2H), 2.01 (m, 3H), 1.95-1.77 (m, 4H), 1.35-1.20 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[CH2:25][NH:24][CH2:23]4)[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:44](=O)[CH3:45]>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:36])[CH3:37])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[CH2:25][N:24]([CH2:44][CH3:45])[CH2:23]4)[C@H:14]2[CH3:41])[CH:4]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]1C)CNC2
Reactant: CC=O
Product: CCN1Cc2cc(CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(-c3cc(C(C)C)c(F)cc3OC)cc2C1

Procedure:
Following the procedure described for EXAMPLE 92, (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2-ethyl-6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}-4-methyl-4-methyl-1,3-oxazolidin-2-one was synthesized from (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}-4-methyl-1,3-oxazolidin-2-one and acetaldehyde. LCMS calc.=639.2; found 638.9 (M+H)+.