Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11]C)=[C:6]([CH:9]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([OH:18])[CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1ccc(Br)cc1C=O
Solvent: ClCCl
Product: COc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
A solution of 5-bromo-2-ethoxy-benzaldehyde (50 g, 233 mmol), in CH2Cl2 (150 mL) at 0-5° C., was treated with a solution of 3-chloroperoxybenzoic acid (70-75% purity) (68.1 g, 276 mmol) in CH2Cl2 (500 mL) and the reaction mixture allowed to warm slowly to room temperature and stirred for 72 h. The resulting precipitate was filtered and the filtrate then stirred for 2 h with a 2 N aqueous Na2SO2O3 solution (200 mL). The organic layer was then concentrated, dissolved in diethyl ether, and washed with an aqueous 1 N Na2SO3 followed by a half saturated NaHCO3 solution. The organic phase was extracted with a 2 N aqueous NaOH solution and the combined basic extract acidified (pH ˜3-4) with concentrated HCl. The acidified mixture was extracted with diethyl ether, dried over MgSO4, filtered, and evaporated to afford intermediate 5-bromo-2-methoxy-phenol (43.5 g, 90%). 1H NMR (CDCl3) 7.06 (br s, 1H), 6.96 (dd, J=8.6, 2.3, 1H), 6.70 (d, J=8.6, 1H), 5.67 (s, 1H), 4.05 (q, J=7.1, 2H), 1.44 (t, J=7.1, 3H).
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.F[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=2[N+:17]([O-:19])=[O:18])[CH:4]=[C:5]([CH3:7])[N:6]=1
Reactant: COc1cccc(F)c1[N+](=O)[O-]
Reactant: Cc1c[nH]c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-n2cc(C)nc2Br)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
2-bromo-4-methyl imidazole (3.7 g, 23.4 mmol) and 2-fluoro-6-methoxy-nitrobenzene were dissolved in DMF (80 mL). To this was then added potassium carbonate (6.3 g, 46.8 mmol). The reaction was heated to 90° C. for 16 hrs then poured into water and extracted with ethyl acetate. The organic layer was separated and washed with water then brined, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the crude purified by flash chromatography on silica gel in 20:1 ethyl acetate/methylene chloride. A tan solid (2.6 g) was recovered. MS (ES) m/z 311.9 [M+1]+
Reaction SMILES: [OH-:1].[K+].[CH2:3]([OH:5])[CH3:4].C(C1[CH:13]=[CH:12][N:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1)#N.O>C(OCC)C>[CH:14]([C:10]1[CH:9]=[C:4]([CH:13]=[CH:12][N:11]=1)[C:3]([OH:1])=[O:5])([CH3:16])[CH3:15]
Reactant: CCO
Reactant: CC(C)c1cc(C#N)ccn1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CC(C)c1cc(C(=O)O)ccn1
Temperature: 25 °C

Procedure:
A 7.5 ml portion of 8 N aqueous potassium hydroxide was added to 50 ml of ethanol solution containing 2.7 g of 4-cyano-2-isopropylpyridine, and the mixture was heated under reflux for 12 hours. After cooling to room temperature, the reaction mixture was mixed with water and diethyl ether and the aqueous layer was separated. The aqueous layer was adjusted to an acidic pH of 3 using 4 N hydrochloric acid and then saturated with sodium chloride. This was extracted with a mixed solvent of ethyl acetate-isopropanol (5:1, v/v) and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 3.1 g of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[C@@H:6]([CH3:24])[CH2:7][CH:8]([NH2:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH2:2]([O:4][C:5](=[O:25])[C@@H:6]([CH3:24])[CH2:7][CH:8]([N:23]=[C:27]=[O:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)N=C=O

Procedure:
(S)-5-(3′-Chloro-biphenyl-4-yl)-4-isocyanato-2-methyl-pentanoic acid ethyl ester is prepared from (S)-4-amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 31) and triphosgene analogous to the procedure described for Example 6-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:15][NH:16][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl.S(=O)(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:15][N:16]([C:25](=[O:27])[CH3:26])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNCC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C)CC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15.9 %

Procedure:
To 4-[1-(2-Fluoro-phenyl)-2-methylamino-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (425) (0.95 g, 2.81 mmol) in MeCl2(10 mL) was added TEA (0.43 mL, 3.10 mmol). The solution was cooled to 0° C. and allowed to stir for 15 min. Acetyl chloride (0.20 mL, 2.81 mmol) was then added. The reaction was allowed to stir at 0° C. for 35 min and then at room temperature for 132 h. Additional triethylamine (0.39 mL, 2.81 mmol), and acetyl chloride (0.2 mL, 2.81 mmol) were added. The reaction mixture was then diluted with 10% aq. sodium bisulfate (20 mL). The organic layer was separated and the aqueous portion was extracted with dichloromethane (3×). The organics are combined, dried with sodium sulfate and concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 2% (2M NH3 in MeOH) in MeCl2) yielding 0.17 g (16%) pure product.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43](=O)[CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:40][C:43]([CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:52])([CH3:53])[CH3:51])=[N:42][N:41]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
To s solution of PPh3 (2.6 g, 10.0 mmol) in dry DCM (60 mL) was added I2 (2.6 g, 10.0 mmol). After I2 was dissolved completely, TEA (3.5 mL, 25.0 mmol) was added quickly at rt. The mixture was stirred for 15 mins. Tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-4-oxobutylcarbamate (2.4 g, 5.0 mmol) was added. The mixture was stirred at rt for 1 hr. The solvent was concentrated. EtOAc (250 mL) was added, and the solution was filtrated to remove POPh3. The filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (gradient elution 0-40% EtOAc/petroleum ether) to afford tert-butyl 3-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)propylcarbamate (2.0 g, 86%) as a white solid. ESI-MS (EI+, m/z): 458 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]1[CH2:20]CC[CH2:17][CH2:16]1.C([Li:25])(CC)C>C1(C)C=CC=CC=1>[C:1]1([C:7]([Li:25])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:8][CH:15]([CH3:20])[CH2:16][CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCCCC1
Reactant: C=C(c1ccccc1)c1ccccc1
Reactant: [Li]C(C)CC
Solvent: Cc1ccccc1
Product: [Li]C(CC(C)CC)(c1ccccc1)c1ccccc1

Procedure:
To a 500 ml Schlenk tube, in which a magnetic stirrer chip was put, was added 2.0 g of 1,1-diphenylethylene and then the inside thereof was replaced by nitrogen. Thereto were added 190 ml of toluene and 7.7 ml of a cyclohexane solution of sec-butyllithium (concentration: 1.3 M). The resultant solution was stirred at room temperature for 2 days to conduct reaction. In this way, a toluene solution of 1,1-diphenyl-3-methylpentyllithium (DPMPLi) (concentration: 0.05 M) was obtained.
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16](CC3C=CC(OC)=CC=3OC)[C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:33]#[N:34])=[C:4]([C:37]2[N:38]([CH3:42])[N:39]=[CH:40][CH:41]=2)[CH:3]=1.[CH3:43][O:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.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:33]([C:8]1[CH:9]=[C:10]([S:13]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:14])=[O:15])[CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:35]=[CH:36][C:2]([C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([O:44][CH3:43])[CH:50]=2)=[CH:3][C:4]=1[C:37]1[N:38]([CH3:42])[N:39]=[CH:40][CH:41]=1)#[N:34]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Oc3ccc(Br)cc3-c3ccnn3C)c(C#N)c2)c(OC)c1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cccc(-c2ccc(Oc3ccc(S(=O)(=O)Nc4nccs4)cc3C#N)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 4-[4-bromo-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-3-cyano-N-(2,4-dimethoxy-benzyl)-N-thiazol-2-yl-benzenesulfonamide (Preparation 88, 98.5 mg, 0.148 mmol), 3-methoxyphenylboronic acid (48 mg, 0.32 mmol), and potassium carbonate (62.5 mg, 0.452 mmol) in toluene (3 mL) was added tetrakistriphenylphosphinepalladium (0) (22.5 mg, 0.0195 mmol) and the mixture was sparged two times with argon. The reaction mixture was heated at reflux for 4.5 hours. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with saturated sodium chloride solution, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by automated flash column chromatography using a 0-100% EtOAc/hexanes gradient to yield a clear oil. This oil was dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (1 mL, 10 mmol). After stirring for 1 hour, the reaction mixture was concentrated in vacuo and purified by automated flash column chromatography (0%-5% methanol in dichloromethane gradient elution) to yield the title compound (49 mg, 61%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:19]([O-])=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:7]=[CH:6]2.CO>[Pd]>[NH2:19][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[C:9]2=[O:13]
Reactant: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1N
Reaction time: 3 h

Procedure:
A mixture of (R)-2-(6-methoxy-5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (200 mg, 0.0007 mol), methanol (20 mL, 0.5 mol) and palladium, 10% weight on charcoal (21 mg, 0.00017 mol) was stirred under hydrogen (1 atm) for 3 h. The reaction mixture was filtered over celite and the solvent removed to obtain the product as a brown solid. MS m/z=263.3 (M+H).
Reaction SMILES: C(OC(=O)[NH:7]CCCCNC1C2C(=CC(Br)=CC=2)N=CC=1N)(C)(C)C.C(Cl)(=O)CCC.[C:32]([O:36][C:37](=[O:60])[NH:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]1[C:55]2[C:54]3[CH:53]=[CH:52][C:51]([Br:56])=[CH:50][C:49]=3[N:48]=[CH:47][C:46]=2[N:45]=[C:44]1[CH2:57][CH2:58][CH3:59])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:60])[NH:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]1[C:55]2[C:54]3[CH:53]=[CH:52][C:51]([Br:56])=[CH:50][C:49]=3[N:48]=[C:47]([NH2:7])[C:46]=2[N:45]=[C:44]1[CH2:57][CH2:58][CH3:59])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(Br)ccc12
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: CCCC(=O)Cl
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNC(=O)OC(C)(C)C

Procedure:
tert-Butyl[4-(3-amino-7-bromoquinolin-4-ylamino)butyl]carbamate was treated with butyryl chloride and cyclized according to the methods described in Part C and D of Examples 125–135. The resulting product, tert-butyl[4-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate was oxidized and aminated according to the methods described in Parts H and I of Example 1 to afford tert-butyl[4-(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate, which was coupled with 3-pyridylboronic acid according to the method described in Part J of Example 1. The reaction was heated at reflux for four hours, and the work-up procedure described in Part F of Examples 125–135 was followed. The crude product was recrystallized from toluene (1 mL/g) to provide tert-butyl {4-[4-amino-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as a tan powder, mp 136–138° C.
Reaction SMILES: [Li].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[CH:3]1.[CH3:20][C:21]([NH:24][Si:25](Cl)([CH3:27])[CH3:26])([CH3:23])[CH3:22]>C1COCC1>[CH2:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][N:11]1[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([Si:25]([CH3:27])([CH3:26])[NH:24][C:21]([CH3:23])([CH3:22])[CH3:20])[CH:3]=1
Reactant: CC(C)(C)N[Si](C)(C)Cl
Reactant: C1=C(N2Cc3ccccc3C2)c2ccccc2C1
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)C1C=C(N2Cc3ccccc3C2)c2ccccc21
Yield: 99 %

Procedure:
2,3-Dihydro-2-(1H-inden-3-yl)-1H-isoindole lithium salt (1.64 g, 6.86 mmol) was dissolved in 10 mL of THF and this solution was added dropwise to N-(tert-butyl)-N-(1-chloro-1,1-dimethylsilyl)amine reagent (1.47 g, 8.91 mmol, 1.3 eq) in 40 mL of THF. The reaction was allowed to stir for several hours, and THF and excess electrophile were removed under reduced pressure. The crude oil was extracted into hexane and filtered through a medium porosity frit. Solvent was removed under reduced pressure to give the desired product as an emerald green oil (2.40 g, 6.79 mmol, 96.5 percent).
Reaction SMILES: C([C@H]1COC(C)(C)N1C(=O)CC1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)C1C=CC=CC=1.C(O[CH:39]([C:56]1[O:60][C:59]([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:63][CH:62]=2)=[CH:58][CH:57]=1)[C:40]([N:42]1[C@@H:46]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:45][O:44][C:43]1([CH3:55])[CH3:54])=[O:41])(=O)C>>[CH2:47]([C@H:46]1[CH2:45][O:44][C:43]([CH3:55])([CH3:54])[N:42]1[C:40](=[O:41])[CH2:39][C:56]1[O:60][C:59]([C:61]2[CH:62]=[CH:63][C:64]([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:65][CH:66]=2)=[CH:58][CH:57]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(=O)OC(C(=O)N1[C@@H](Cc2ccccc2)COC1(C)C)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cc1ccn(-c2ccc(-c3ccccc3)cc2)c1
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 42 %

Procedure:
According to the procedure described in Example 13 for the preparation of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)-ethanone, 2-acetoxy-1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)-ethanone was hydrogenolyzed to provide in 42% yield 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)-ethanone as an amorphous solid. 1H NMR: δ 7.68 (d, 2H, J=8.1 Hz), 7.62-7.58 (m, 4H), 7.44 (t, 2H, J=7.5 Hz), 7.37-7.25 (m, 6H), 6.64 (d, 1H, J=3.3 Hz), 6.32 (d, 1H, J=2.9 Hz), 4.17-4.14 (m, 1H), 3.87 (m, 2H), 3.77, 3.65 (AB quartet, 2H, J=15.8 Hz), 3.09 (dd, 1H, J=4.8, 13.6 Hz), 2.94 (dd, 1H, J=9.6, 13.6 Hz), 1.78 (s, 3H), 1.59 (s, 3H). Anal. Calculated for C30H29NO3: C, 79.80; H, 6.47; N, 3.10. Found: C, 79.72; H, 6.49; N, 3.03.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][CH:23]([NH:11][C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1cc(Cl)cc2c(-c3ccccc3)c[nH]c12
Reactant: O=C1CCOCC1
Product: Clc1cc(NC2CCOCC2)c2[nH]cc(-c3ccccc3)c2c1

Procedure:
5-Chloro-7-nitro-3-phenyl-1H-indole prepared in Preparation 41 and tetrahydropyran-4-one were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: [OH:1][CH:2]([CH:32]([CH3:34])[CH3:33])[CH2:3][C@@H:4]1[CH2:9][C@H:8]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])[CH2:7][CH2:6][C@@H:5]1[NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[CH:12]([N:10]([CH3:11])[C@@H:8]1[CH2:7][CH2:6][C@H:5]([NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[C@H:4]([CH2:3][C:2](=[O:1])[CH:32]([CH3:34])[CH3:33])[CH2:9]1)([CH3:14])[CH3:13]
Reactant: CC(C)C(O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the isomeric mixture of N-(2-((1S,2S,4R)-2-(2-hydroxy-3-methylbutyl)-4-(isopropyl(methyl)amino)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide (34 mg; see Examples 11p and 11q) in 3 ml of anhydrous CH2Cl2 were added excess amounts of powdered 4A molecular sieves and pyridinium dichromate, and the mixture was stirred for 2 hours at room temperature. After addition of about 15 ml of EtOAc it was filtered through a plug of Celite, and evaporated to give an oily residue, which was purified by chromatography (silica gel, CH2Cl2 then 1:9:90 cNH4OH-MeOH—CH2Cl2) to give N-(2-((1S,2S,4R)-4-(isopropyl(methyl)amino)-2-(3-methyl-2-oxobutyl)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide as an amorphous solid. MS found: (M+H)+=484.3.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:25]([F:28])([F:27])[F:26])([C:5]1[N:6](C)C(C2C=CC(C)=CC=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)[NH2:4].Cl[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](OO)=O)[CH:33]=1.[C:42](=[O:45])(O)[O-:43].[Na+]>C(Cl)(Cl)Cl>[CH3:38][C:34]1[CH:35]=[CH:36][C:37]([O:43][C:42](=[O:45])[N:6]=[C:5]2[NH:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[N:4][C:3]2([C:25]([F:28])([F:26])[F:27])[C:2]([F:1])([F:30])[F:29])=[CH:32][CH:33]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C([O-])O
Reactant: Cc1ccc(-c2nc(C(N)(C(F)(F)F)C(F)(F)F)n(C)c2-c2ccc(C)cc2)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OC(=O)N=C2NC(c3ccc(C)cc3)=NC2(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 14 %

Procedure:
To a solution of α,α-bis(trifluoromethyl)-4,5-bis(4-methylphenyl)-1-methyl-1H-imidazol-2-methanamine (1.0 g, 2.3 mmole) in chloroform (10 mL) was added portionwise, m-chloroperbenzoic acid (1.20 g, 7 mmole). The reaction mixture was refluxed under nitrogen for two hours. The solution was cooled to room temperature and poured into saturated sodium bicarbonate (100 mL). The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue was triturated with petroleum ether to give the title compound (0.15 g, 14%) as a solid: mp 161°-163°; MS m/e 458 (M+ +H); 1H NMR (CDCl3 /TMS) δ 2.43 (s,6H,CH3), 3.06(s,3H,NCH3), 7.23-7.40(m,4H,Harom), 7.50-7.63(m,2H,Harom), 7.87-7.93(m,2H,Harom).
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].N1C=CC=CC=1.C(=O)=O.[CH2:18]([O:20][C:21](Cl)=[O:22])[CH3:19]>COC(C)(C)C>[C:21](=[O:22])([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])[O:20][CH2:18][CH3:19]
Reactant: CCOC(=O)Cl
Reactant: OCC(F)(F)C(F)F
Agent: O=C=O
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: CCOC(=O)OCC(F)(F)C(F)F
Temperature: 25 °C

Procedure:
2,2,3,3-tetrafluoropropan-1-ol (121 g 0.92 mol), pyridine (76 g 0.96 mol) and 350 mL of methyl-t-butyl ether were combined in a 1 L 3-neck round bottom flask. The flask was equipped with an overhead stirring mechanism, thermocouple, addition funnel, cold water condenser, and a dry nitrogen bubbler. The reaction flask was kept cool using solid CO2 in a water bath. Ethylchloroformate (100 g, 0.92 mol) was added via an addition funnel dropwise at a rate such that the temperature of the reaction mix did not exceed 0° C. Once the addition was complete the mix was allowed to warm to room temperature on its own. The reaction mix was then quenched with 100 mL of water. The water portion was extracted with 2×100 mL portions of methyl t-butyl ether. The combined organic extracts were washed with 100 mL of 1N HCl and 100 mL of water. The solvent was removed by rotary evaporation and the carbonate was purified by fractional distillation using a concentric tube column. The structure of the product was confirmed by GC/MS and the purity by GC-FID was 99.05% of the desired compound.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>O1CCOCC1.CO>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:18][CH:17]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Nc1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cnc(-c2ccc(Cl)cc2)cn1
Temperature: 110 °C

Procedure:
Under an argon atmosphere 50 mL 2 M Na2CO3 solution and 1.2 g (1.0 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 8.7 g (50.0 mmol) 5-bromo-pyrazin-2-ylamine and 8.0 g (50.0 mmol) 4-chlorophenyl-boric acid in 150 mL 1,4-dioxane and 50 mL MeOH and the reaction mixture is heated to 110° C. for 2.5 h. The mixture is evaporated down i. vac., the residue is combined with water, extracted exhaustively with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient: DCM to DCM/MeOH 20:1).