Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2](C(O)=O)CCCCN.N[CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:20])[C:17]([OH:19])=[O:18]>>[NH2:1][CH2:2][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:20])[C:17]([OH:19])=[O:18]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: NCCCCC(=O)C(=O)O
Product: NCCCCCC(=O)C(=O)O

Procedure:
In an alternative embodiment, lysine is first converted to 6-amino-2-oxohexanoic acid by an aminotransferase enzyme (EC 2.6.1.x) or a dehydrogenase (EC 1.4.1.x or EC 1.4.3.x). Preferred enzymes are listed in Table 7 and may be engineered to catalyze the desired substrate to product reaction. In a subsequent step, 6-amino-2-oxohexanoic acid is subjected to a carbon elongation enzymatic step to produce 7-amino-2-oxoheptanoic acid.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](OCC)=[O:9].C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([NH:1][NH2:2])=[O:9]
Reactant: CCOC(=O)C(C#N)(CCCCl)c1ccccc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC(CCCCl)(C(=O)NN)c1ccccc1

Procedure:
Hydrazine (1.2 g) was added to a solution of ethyl 5-chloro-2-cyano-2-phenylpentanoate (CAS No. 52370-87-3, 1 g) in ethanol (5 mL), and the reaction solution was stirred at room temperature for one hour. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was filtered through a silica gel, and the filtrate was concentrated under reduced pressure to obtain a crude product of 5-chloro-2-cyano-2-phenylpentanoic acid hydrazide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25]([C:10]1[C:11]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=2[S:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:26]
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC)c(OC)c2)cc1
Reaction time: 7 h
Yield: 76 %

Procedure:
To a well stirred solution of 2-(4′-methoxyphenyl)-6-methoxybenzo[b]thiophene (0.327 g, 1.21 mmol) and 3,4-dimethoxybenzoyl chloride (0.557 g, 2.77 mmol) in CH2Cl2 (20 ml) was added AlCl3 (0.616 g, 4.62 mmol) portion-wise over a 15 minute period. After 7 hours, water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 60:40 Et2O/hexanes) afforded the title compound (0.402 g, 0.92 mmol, 76%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[CH:9]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:3]1=[O:27].C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C)C=O>[CH3:1][C:2]1([CH3:28])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:9]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:3]1=[O:27]
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc(Cl)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc(N2CCOCC2)c1
Temperature: 210 °C
Reaction time: 0.83 h

Procedure:
A sealed 2.5 ml tube containing 0.05 g of 5,5-dimethyl-1-(2-chloropyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione, 0.5 ml of dimethylformamide, 0.034 g of potassium carbonate and 0.021 ml of morpholine is placed in a Personal Chemistry Emrys Optimiser microwave oven. The mixture is irradiated with magnetic stirring at 210° C. for about 50 minutes. The reaction mixture is placed on a Bond Elut Varian cartridge of reference 1225-6053 containing 2 g of SCX phase conditioned with dimethylformamide. The cartridge is washed with methanol and then eluted with 2M ammoniacal methanol. The ammoniacal fractions are concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography using a cartridge 16 mm in diameter packed with 2 g of conditioned 15-35 μm silica, and then eluted with a mixture (cyclohexane/ethyl acetate)(8/2)(v/v) at a flow rate of 10 ml/minute. The fractions between 160 and 260 ml are concentrated to dryness under reduced pressure. 0.01 g of 5,5-dimethyl-1-(2-morpholinopyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained in the form of a powder, the characteristics of which product are as follows:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1)=[O:4].S(Cl)([Cl:19])(=O)=O.CCOCC>CC#N>[NH2:11][C:9]1[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=[C:5]([C:3]([OH:2])=[O:4])[C:10]=1[Cl:19]
Reactant: COC(=O)c1cc(N)cc(C(F)(F)F)n1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Solvent: CCOCC
Product: Nc1cc(C(F)(F)F)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a solution containing 4-amino-6-trifluoromethylpyridine-2-carboxylic acid methyl ester (0.75 g, 3.4 mmol) in 5 mL of CH3CN was added dropwise a solution of sulfuryl chloride (0.27 mL, 3.4 mmol) in 1 mL of CH3CN. After stirring at RT for 1 hr, reaction mixture was added to 50 mL of Et2O and washed with aqueous NaHCO3, dried over MgSO4, filtered and concentrated to give a solid. The crude product was purified by chromatography, eluting with 10% ethyl acetate-hexane to give 200 mg of product as a white solid; mp 131-3° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:27])[CH:13]=[C:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2.CO.[Li+].[OH-].Cl>O>[CH:16]1[C:15]2[C:14](=[CH:13][C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[O:27])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CCCCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
8-(2-(9H-fluoren-9-ylidene)acetamido)octanoic acid methyl ester (377 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (345 mg, 95% yield) as a white solid. 1H NMR (DMSO-d6) δ1.23 (m, 2H, CH2), 1.45 (m, 6H, 3×CH2), 1.49 (m, 2H, CH2), 2.18 (t, J=8.0 Hz, 2H, CH2CO), 3.23 (m, 2H, NCH2), 7.08 (s, 1H, ═CH—CO), 7.34 (m, 2H, Ar—H), 7.41 (t, J=8.0 Hz, 2H, Ar—H), 7.76 (d, J=8.0 Hz, 1H, Ar—H), 7.81 (m, 2H, Ar—H), 8.50 (t, J=4.0 Hz, 1H, CONH), 8.67 (d, J=8.0 Hz, 1H, Ar—H). LC-MS (m/z) 364 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[CH2:8][Cl:9].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH:18]([OH:25])[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>C(O)C>[ClH:9].[Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[CH2:8][O:25][CH:18]([C:12]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=1[Cl:10])[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: Cc1nc(CCl)c(Br)s1
Solvent: CCO
Product: Cc1nc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Br)s1
Product: Cl

Procedure:
Following the procedure of Example 1b, reaction of 5-bromo-4-chloromethyl-2-methylthiazole and 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol, yields the title compound, m.p. 247°-248° C. (absolute ethanol).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[C:25]2[O:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[C:26]3[CH2:32][CH:31]4[N:33]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH:28]([CH2:29][CH2:30]4)[CH2:27]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1>C1COCC1.C(Cl)Cl>[F:38][C:35]([F:36])([F:37])[C:34]([N:33]1[CH:31]2[CH2:30][CH2:29][CH:28]1[CH2:27][C:26](=[C:17]1[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][CH:8]=[O:10])[C:25]=3[O:24][C:23]3[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:32]2)=[O:39]
Reactant: O=CO
Reactant: Nc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=CNc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Temperature: 50 °C

Procedure:
Into a flask was placed acetic anhydride (4 mL) and the reaction was cooled in an ice bath. Upon cooling, formic acid (2 mL) was added and the mixture was heated to 50° C. for 15 min, and then cooled to rt. Upon cooling, the resulting solution (0.6 mL) was added to an ice bath-cooled solution of compound 4k (0.300 g, 6.0 mmol) in THF (2 mL), and the reaction was heated to 50° C. for 1 h. The mixture was cooled to rt, diluted with methylene chloride, and the organic phase was washed sequentially with saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried over MgSO4, filtered, and concentrated to yield 0.42 g of the title compound 5k.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.5 gms, 1.41 mmole) was dissolved in 20 mL methylene chloride and 0.5 mL pyridine, and the mixture was cooled in an ice bath. Methanesulfonyl chloride (0.16 g, 1.41 mmol) was added dropwise, and the reaction mixture was stirred for five minutes at ice bath temperature, then allowed to warm to room temperature. The reaction mixture was quenched by addition of water, and was extracted with methylene chloride. The organic layer was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 0.39 g of (R)-N-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methanesulfonamide, M+H=398.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]4[CH:18]=[CH:17][C:16]([C:19]5[NH:23][C:22]([C@@H:24]6[CH2:28][CH2:27][CH2:26][N:25]6C(OCC6C=CC=CC=6)=O)=[N:21][CH:20]=5)=[CH:15][C:11]4=[CH:12][CH:13]=3)[O:8][CH2:7][C:6]=2[CH:39]=1.Br.[CH3:41][O:42][C:43]([NH:45][C@@H:46]([CH:50]([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(OCC)(=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]4[CH:18]=[CH:17][C:16]([C:19]5[NH:23][C:22]([C@@H:24]6[CH2:28][CH2:27][CH2:26][N:25]6[C:47](=[O:48])[C@@H:46]([NH:45][C:43](=[O:44])[O:42][CH3:41])[CH:50]([CH3:52])[CH3:51])=[N:21][CH:20]=5)=[CH:15][C:11]4=[CH:12][CH:13]=3)[O:8][CH2:7][C:6]=2[CH:39]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(Br)cc2CO4)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(Br)cc2CO4)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A solution of (S)-benzyl 2-(5-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (485 mg, 0.84 mmol), hydrogen bromide (33% in acetic acid, 1 mL) and dichloromethane (2 mL) was stirred at room temperature for one hour. The reaction was concentrated, suspended in toluene, sonicated for one minute and re-concentrated. The resulting residue was suspended in methanol, sonicated for one minute and concentrated. The resulting residue was suspended in diethyl ether and the solids collected by filtration. This crude amine was dissolved in dimethylformamide (7 mL). To this solution were added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (192 mg, 1.1 mmol), HATU (418 mg, 1.1 mmol) and N-methylmorpholine (0.24 mL, 2.2° mmol). The reaction was stirred at room temperature for one hour, and then diluted ethyl acetate. The organic layer was washed with 5% aqueous LiCl solution, saturated aqueous NaHCO3 solution and brine, then dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield methyl (S)-1-((S)-2-(5-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (466 mg, 92%).
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[F:9][C:10]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=1[NH2:12].C(C(Br)C1C=CC=C(OC2C=CC=CC=2)C=1)#C>>[F:9][C:10]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=1[NH:12][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([CH3:8])[CH3:7]
Reactant: Cc1ccc(N)c(F)c1
Reactant: CC(C)C(Br)C(=O)O
Agent: C#CC(Br)c1cccc(Oc2ccccc2)c1
Product: Cc1ccc(N[C@H](C(=O)O)C(C)C)c(F)c1

Procedure:
N-(2-fluoro-4-methylphenyl)valine is prepared from α-bromoisovaleric acid and 2-fluoro-4-methylaniline and then reacted with α-ethynyl-m-phenoxybenzyl bromide to yield the α-ethynyl-m-phenoxybenzyl ester of N-(2-fluoro-4-methylphenyl)valine, MS m/e 431 (M+, 180).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:11]=[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[N:4]=1.[C:14]([O:18][C:19]([NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:23][C:24](O)=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:14]([O:18][C:19]([NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:23][C:24]([N:8]1[CH2:9][CH2:10][N:5]2[N:4]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:11]=[C:6]2[CH2:7]1)=[O:25])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: FC(F)(F)c1nc2n(n1)CCNC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2nc(C(F)(F)F)nc2C1)Cc1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine (28.8 mg, 0.15 mmol, from Step D) and (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 50.0 mg, 0.15 mmol) in DMF (3 mL) was added hydroxybenzotriazole (HOBT, 26.1 mg, 0.19 mmol) at 0° C. The reaction was stirred at 0° C. for 5 min, then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 37.0 mg, 0.19 mmol) was added. After removal of the ice-bath, the reaction was allowed to stir at ambient temperature for 16 h. After removal of the DMF by evaporation, the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Concentration followed by preparative TLC (10% methanol/dichloromethane) gave the title compound as a foamy solid.
Reaction SMILES: C([N:4]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.C(O)C.Cl>C1(C)C=CC=CC=1>[CH2:17]([C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH3:18]
Reactant: CCc1ccc(-c2ccc(N(C(C)=O)c3ccc(C)cc3)cc2)cc1
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(Nc3ccc(C)cc3)cc2)cc1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To 19.96 g of the thus obtained N-acetyl-N-(4-methylphenyl) -4'-ethyl-[1,1'-biphenyl]-4-amine were added 150 ml of ethanol and 150 ml of concentrated hydrochloric acid. The reaction mixture was refluxed with stirring for 7 hours and then added to 1 l of ice water. The reaction mixture was then extracted with toluene and the obtained organic portion was washed with water two times, with a saturated aqueous solution of sodium hydrogencarbonate one time, and then with water two times, and dried by use of magnesium sulfate, and condensed under reduced pressure, whereby brown crystals were obtained. The thus obtained product was subjected to a silica gel column chromatography by use of toluene as an eluent, and recrystallized from a mixed solvent of n-hexane and toluene, whereby 4'-ethyl-N-(4-methylphenyl)-[1,1'-biphenyl]-4-amine (Aminobiphenyl Compound No. 2-62 in Table 3) was obtained in the form of colorless plates with a yield of 15.84 g (91.0%). The melting point of the product was 132.5° C. to 133.0° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2].[OH-].[K+]>C(O)C.O>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(C#N)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C(=O)O)c(F)c1
Yield: 82.2 %

Procedure:
Dissolve methyl 4-cyano-2-fluoro-benzoate (2.9 g, 16.2 mmol) in absolute ethanol (100 mL). Add potassium hydroxide (4.5 g, 80.2 mmol) and stir the milky white mixture for 1.5 h. Dilute the mixture with water (125 mL) and wash with diethyl ether (50 mL). Collect the aqueous layer and concentrate in vacuo until solids start to appear in the flask, then adjust the mixture to pH 1 with concentrated HCl. Extract the aqueous mixture with diethyl ether (3×500 mL). Combine the organic extracts and concentrate in vacuo to obtain the desired intermediate as a white solid (2.2 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:25])[O:20]C(C)(C)C)[C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)O)[C:5]([F:26])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:20][C:19](=[O:25])[NH:18]2)[C:5]([F:26])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Br)ncc1F)[C@H](O)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N[C@H](c2cc(Br)ncc2F)[C@@H](c2ccc(F)cc2)O1
Temperature: 25 °C
Yield: 17.1 %

Procedure:
To a 25 mL round bottom flask was added tert-butyl (1R,2R)-1-(2-bromo-5-fluoropyridin-4-yl)-2-(4-fluorophenyl)-2-hydroxyethylcarbamate (141 mg, 0.328 mmol) in dichloromethane (4 mL). To this solution was added trifluoroacetic acid (0.253 mL, 3.28 mmol) and the reaction was allowed to stir over night at room temperature. The next day the reaction was checked by LC/MS and was complete. The reaction solvent was evaporated in vacuo and the crude oil was diluted with diethylether and washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and the solvent was then evaporated in vacuo and the crude residue was diluted with dry tetrahydrofuran. The solution was cooled to 0° C. and carbonyldiimidazole (53.3 mg, 0.328 mmol) was added and the reaction was allowed to stir overnight. The reaction was complete by LC/MS. The reaction solvent was then evaporated in vacuo and the crude solid was purified by silica gel chromatography 15% EtOAc/85% Hexanes to 50% EtOAc/50% Hexanes affording (4R,5R)-4-(2-bromo-5-fluoropyridin-4-yl)-5-(4-fluorophenyl)oxazolidin-2-one (20 mg, 0.056 mmol, 42.9% yield) and its regioisomer as an inseparable mixture. LC/Mass spec. (Analytical HPLC method 2): RT=1.79 min. Mass=354.89 (MH)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:34][C:35]1[O:36][CH:37]=[CH:38][N:39]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:34][C:35]3[O:36][CH:37]=[CH:38][N:39]=3)[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ncco1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OCc3ncco3)cc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8) and 2-(chloromethyl)oxazole by General Procedure N.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:25](=[O:27])[CH3:26])[CH2:7][C:8]3[CH:15]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:4]=2[CH:3]=1.[CH3:30][O:31][C:32](=[O:49])[C:33]1[CH:38]=[C:37]([CH:39]=[O:40])[CH:36]=[CH:35][C:34]=1OS(C(F)(F)F)(=O)=O.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.O.CCO>[CH3:30][O:31][C:32](=[O:49])[C:33]1[CH:38]=[C:37]([CH:39]=[O:40])[CH:36]=[CH:35][C:34]=1[C:14]1[CH:13]=[CH:12][C:9]2[CH:10]=[CH:11][C:4]3[CH:3]=[C:2]([Cl:1])[CH:29]=[CH:28][C:5]=3[N:6]([C:25](=[O:27])[CH3:26])[CH2:7][C:8]=2[CH:15]=1
Reactant: COC(=O)c1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)N1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C=Cc2cc(Cl)ccc21
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C=O)ccc1-c1ccc2c(c1)CN(C(C)=O)c1ccc(Cl)cc1C=C2
Temperature: 75 °C
Yield: 54.2 %

Procedure:
A 15 mL three necked oven dried round bottom flask was cooled under argon and charged with Example 21A (50 mg, 0.12 mmol), Example 236A (47 mg, 0.15 mmol) and toluene (2 mL)/EtOH (1 mL). The mixture was purged with argon for 30 minutes. Pd(PPh3)4 (14 mg, 0.012 mmol) and 2 M Na2CO3 (187 μl, 0.36 mmol were added and the reaction was heated at 75° C. for 2 hours. The resulting mixture was poured into water (10 mL) and extracted with EtOAc (3×10 mL). The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by radial chromatography (2 mm plate, 30% to 50% EtOAc/Hexanes) to give the desired product Example 236B (29 mg, 55%).