Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]#[N:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][NH2:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: N#CC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: NCC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 2-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)-3-phenylpropanenitrile (1.6 g, 4.12 mmol), prepared as described in Procedure 4, in CH3OH (40 mL) was added CoCl2.6H2O (1.07 g, 8.25 mmol). The resulting solution turned purple in color. NaBH4 (1.57 g, 41.2 mmol) was then added in portions over 10 min. The resulting black solution was stirred at rt for 1 h. After this time, the reaction mixture was concentrated under reduced pressure, quenched with 6N HCl (4 mL), and diluted with sat. ammonium chloride (40 mL). The aqueous phase was extracted with CH2Cl2 (4×50 mL). The combined organic portions were washed successively with sat. NaHCO3 (50 mL) and sat. NaCl (50 mL), then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The yellow oil was dissolved in CH2Cl2 and loaded directly onto a silica gel ISCO cartridge (40 g) with elution at 35 mL/min gradient 0 to 5% CH3OH in CH2Cl2 over 22 min (RT=17-19 min) 2-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)-3-phenylpropan-1-amine (1.0 g, 60% yield) was isolated as a pale yellow oil. LCMS: RT=1.68 min [M+H] 393.04 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.31 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) ppm 3.29-3.37 (m, 2 H), 3.59 (t, J=13.2 Hz, 2 H), 6.62 (d, J=7.0 Hz, 2 H), 6.97 (d, J=10.1 Hz, 1 H), 7.06-7.14 (m, 5 H), 7.20 (d, J=8.35 Hz, 1H), 7.34 (td, J=8.57, 3.08 Hz, 1 H), 8.45 (d, J=3.08 Hz, 1 H). The racemate (1.0 g) was dissolved in CH3OH and resolved by chiral prep HPLC (Chiralpak AD 20μ column, 5×50 cm isocratic elution with 100% EtOH/CH3OH(50/50)/0.1% DEA, 50 mL/min, monitoring at 254 nm). Enantiomer 1 (470 mg) was isolated as a yellow oil: analytical chiral HPLC (Diacel Chiralpak AD 10μ column, 4.6×250 mm isocratic elution with 100% EtOH/CH3OH(50/50)/0.1% DEA, 1 mL/min, monitoring at 254 nm), RT=3.70 min. Enantiomer 2 (470 mg) was isolated as a yellow oil: analytical chiral HPLC (Diacel Chiralpak AD 10μ column, 4.6×250 mm isocratic elution with 100% EtOH/CH3OH(50/50)/0.1% DEA, 1 mL/min, monitoring at 254 nm), RT=4.05 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12](N)=[CH:11][C:10]=2[C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[NH:22][C:21]2=[O:31])=[C:4]([F:32])[CH:3]=1.N(OC(C)(C)C)=O.O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:16]([F:17])([F:18])[F:19])=[CH:6][C:5]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[NH:22][C:21]2=[O:31])=[C:4]([F:32])[CH:3]=1
Reactant: Nc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c(F)cc2Cl)c(C(F)(F)F)c1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccccc2C(F)(F)F)c(Cl)cc1F
Reaction time: 0.5 h

Procedure:
3-[4-Chloro-2-fluoro-5-(4-amino-2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (3.0 g) dissolved in anhydrous N,N-dimethylformamide (10 ml) was added to a solution of t-butyl nitrite (1.28 g) in anhydrous N,N-dimethylformamide (40 ml) kept at 60-5° C. under nitrogen. The resulting mixture was stirred for 30 minutes at this temperature. The solution was poured into water and extracted with ethyl acetate:hexane, 1:1, (300 ml). The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was chromatographed on silica gel eluting with ethyl acetate:hexane, 1:2. 3-[4-Chloro-2-fluoro-5-(2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-28) was isolated as an amorphous solid (1.64 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[N:13]([O-])=[O:14].[Na+].N(O)=O>>[Cl:1][CH2:2][C:3](=[O:12])/[C:4](=[N:13]/[OH:14])/[C:5]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:6]
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)CC(=O)CCl
Agent: O=NO
Agent: [Na+]
Product: CC(C)(C)OC(=O)/C(=N\O)C(=O)CCl

Procedure:
treating t-butyl 4-chloro-3-oxobutanoate with sodium nitrite or nitrous acid to produce t-butyl 4-chloro-2-(Z)-hydroximino-3-oxobutanoate;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:22]([C:21]([F:20])([F:35])[F:36])[CH:23]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)CNc1cnccc1-c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Yellow solid (26%). MS (ESI): m/z=517.075 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8](=[O:17])[C:9]([CH3:16])([S:11][C:12]([F:15])([F:14])[F:13])[CH3:10])=[CH:4][CH:3]=1.[Br:20]Br.O>C(Cl)(Cl)Cl>[Br:20][CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1)[C:8](=[O:17])[C:9]([CH3:16])([S:11][C:12]([F:13])([F:14])[F:15])[CH3:10]
Reactant: CC(C)(SC(F)(F)F)C(=O)COc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(SC(F)(F)F)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
45 g (0.15 mol) of 1-(4-chlorophenoxy)-3-methyl-3-trifluoromethylthio-butan-2-one were dissolved in 150 ml of chloroform, and 7.5 ml (0.15 mol) of bromine were added dropwise at 20° C. at such a rate that decolorization occurred continuously. After the end of the addition, the reaction mixture was further stirred at 40° C. for 20 minutes and was then introduced into water. The mixture was extracted with chloroform and concentrated at 40° C. 1-Bromo-1-(4-chlorophenoxy)-3-methyl-3-trifluoromethylthio-butan-2-one was obtained quantitatively and was directly further reacted. ##STR15##
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][O:17][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)[CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:7])[F:8]
Reactant: C1=COCCC1
Reactant: O=C(Nc1ccc(CCO)cc1Cl)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(CCOC2CCCCO2)cc1Cl)C(F)(F)F

Procedure:
To a solution of 2′-chloro-4′-(2-hydroxyethyl)-2,2,2-trifluoroacetanilide (1.4 g) and 3,4-dihydro-2H-pyran (1.4 ml) in dichloromethane (15 ml) was added pyridinium p-toluenesulfonate (14 mg), and the mixture was heated under reflux for 1 hour with stirring. After concentration of the reaction mixture in vacuo, the residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=3/1) gave 2′-chloro-4′-[2-((RS) -tetrahydropyran-2-yloxy)ethyl]-2,2,2-trifluoroacetanilide (1.4 g).
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH:4]([CH3:7])[CH2:5][CH3:6].COC(=O)[C@H]([C@H](CC)C)N.OCCN.NC1C=C2C(=CC=1)C(=O)CC2.[O:34]=[C:35]1[C:43]2[C:38](=[CH:39][C:40]([N:44]=[C:45]=[S:46])=[CH:41][CH:42]=2)[CH2:37][CH2:36]1.[N-]=C=S>>[O:34]=[C:35]1[C:43]2[C:38](=[CH:39][C:40]([N:44]=[C:45]3[NH:8][C@@H:3]([CH:4]([CH2:5][CH3:6])[CH3:7])[CH2:2][S:46]3)=[CH:41][CH:42]=2)[CH2:37][CH2:36]1
Reactant: CCC(C)[C@H](N)CO
Reactant: O=C1CCc2cc(N=C=S)ccc21
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Nc1ccc2c(c1)CCC2=O
Agent: [N-]=C=S
Solvent: NCCO
Product: CCC(C)[C@H]1CSC(=Nc2ccc3c(c2)CCC3=O)N1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 5-Aminoindan-1-one was converted to 1-oxo-5-indanyl isothiocyanate according to Method A2a. The isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(1-oxo-5-indanylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(1-oxo-5-indanylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:7]=[C:6]([NH:16][C:17]([CH:19]2[CH2:23][CH2:22][C:21](=[O:24])[N:20]2[CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([CH3:39])[CH:33]=3)[CH2:27][CH2:26]2)=[O:18])[CH:5]=1.[OH-].[Na+]>CO>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:28]2[CH2:27][CH2:26][CH:25]([N:20]3[C:21](=[O:24])[CH2:22][CH2:23][CH:19]3[C:17]([NH:16][C:6]3[CH:5]=[C:4]([CH:9]=[C:8]([C:10]4[N:14]([CH3:15])[N:13]=[N:12][N:11]=4)[CH:7]=3)[C:3]([OH:40])=[O:2])=[O:18])[CH2:30][CH2:29]2)=[CH:33][C:34]=1[CH3:39]
Reactant: COC(=O)c1cc(NC(=O)C2CCC(=O)N2C2CCN(Cc3ccc(Cl)c(C)c3)CC2)cc(-c2nnnn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CN2CCC(N3C(=O)CCC3C(=O)Nc3cc(C(=O)O)cc(-c4nnnn4C)c3)CC2)ccc1Cl
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 3-({1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carbonyl}-amino)-5-(1-methyl-1H-tetrazol-5-yl)-benzoic acid methyl ester (270 mg) in MeOH (10 ml) at room temperature was added 4M NaOH(aq) (10 ml) and the reaction stirred overnight. The organic and aqueous layers were separated and the organic layer concentrated in vacuum. The residue was triturated in toluene and diethyl ether successively leaving the title compound (220 mg). Rt=0.96 min (method E).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][O:34][Si](C(C)(C)C)(C)C)[NH:9]1)=[O:7])(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:42])([CH3:43])[CH2:33][OH:34])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 105b (1.1 g, 1.68 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]([N:21]=[C:22]=[S:23])=[O:20])[CH3:17]>>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][C:22]([NH:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])=[S:23])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)N=C=S
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Product: CCOC(=O)NC(=S)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of 1.10 g of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester in 25 ml of EtAc 0.58 ml of ethoxycarbonyl-isothiocyanat are added and the mixture obtained is stirred at RT. The precipitate formed is filtered and washed with diethylether. [trans-4-(3-Ethoxycarbonyl-thioureido)cyclohexyl]carbamic acid tert-butyl ester is obtained.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[CH2:10][CH:9]=[CH:8][C:7](=[CH:11][N:12]([CH3:14])[CH3:13])[CH:6]1Br)[CH3:3].C([Li])CCC.[Cl-].[CH3:22][In+:23][CH3:24]>CCCCCC>[CH3:1][N:2]([CH:4]=[C:5]1[CH2:10][CH:9]=[CH:8][C:7](=[CH:11][N:12]([CH3:14])[CH3:13])[CH:6]1[In:23]([CH3:24])[CH3:22])[CH3:3]
Reactant: C[In+]C
Reactant: CN(C)C=C1C=CCC(=CN(C)C)C1Br
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN(C)C=C1C=CCC(=CN(C)C)C1[In](C)C

Procedure:
2.71 g (10.0 mmol) of 2,6-bis(dimethylaminomethylene)phenyl bromide in 40 ml of hexane, 6.3 ml of n-butyllithium (10.0 mmol; 1.6 mol/l in hexane) and 1.8 g (10.0 mmol) of dimethylindium chloride in 20 ml of hexane are reacted analogously to Example 1 to give [2,6-bis(di-methylaminomethylene)phenyl] dimethylindium, which is obtained in the form of colorless crystals, m.p. 53° C., by cooling a concentrated hexane solution to -30° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]#[CH:14])[CH:3]=1>CO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([CH2:13][CH3:14])[CH:3]=1
Reactant: C#Cc1cc(Br)ccc1CC(=O)OC
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CCc1cc(Br)ccc1CC(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
Chlorotris(triphenylphosphine)rhodium (65 mg, 69.9 μmol) was added to a solution of methyl (4-bromo-2-ethynylphenyl)acetate (177 mg, 0.699 mmol) obtained in Example (85-2) in methanol (6 ml), and the mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=15/1) to give methyl (4-bromo-2-ethylphenyl)acetate (138 mg, yield: 77%).
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[NH:10][C:11]3([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[C:12]=2[OH:13])[CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(COC)OC.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>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]3[C:9](=[O:21])[NH:10][C:11]4([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]4)[C:12]=3[OH:13])[CH:7]=2)=[CH:27][CH:26]=1
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(Br)c(F)cc1C)=C2O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CON1CCC2(CC1)NC(=O)C(c1cc(-c3ccc(Cl)cc3)c(F)cc1C)=C2O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 3-(5-bromo-4-fluoro-2-methyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (230 mg) in dimethoxyethane (10 ml) under nitrogen atmosphere is added tetrakis(triphenylphosphine)palladium(0) (35 mg) and the mixture stirred at room temperature for 15 minutes. After further addition of water (2 ml), 4-chlorophenylboronic acid (112 mg) and sodium carbonate (250 mg), the mixture is heated at reflux for 8 hours. The reaction mixture is acidified at room temperature with 1N hydrochloric acid and extracted with ethyl acetate (3×). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (ethyl acetate/cyclohexane 5:1). Yield: 170 mg of 3-(4′-chloro-6-fluoro-4-methyl-biphenyl-3-yl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound C24) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[C:12]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:12]#[N:13])([O-:3])=[O:2]
Reactant: N#Cc1cccc(O)c1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCc2cccc([N+](=O)[O-])c2)c1

Procedure:
1.70 g (10.0 mmol) of 3-nitrobenzyl chloride, 1.48 g (12.4 mmol) of 3-cyanophenol and 3.58 g (25.9 mmol) of potassium carbonate were suspended in 80 ml of dimethylformamide, and the resultant suspension was stirred at 95° C. overnight. After leaving the suspension to cool, 150 ml of water was added to the suspension, and the solid formed was taken by the filtration. The solid was washed with 100 ml of water and then 20 ml of ethyl acetate, and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:28])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(Br)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(Br)c2)cc1
Yield: 64.3 %

Procedure:
In a manner similar to that of Example 2a, by reacting 3 g of ethyl 3′-bromo-4′-hydroxy-biphenyl-4-carboxylate (9.3 mmol) in 100 mL of dimethylformamide with 448 mg (11 mmol) of sodium hydride and 2.6 mL of 1-bromo-3-(tert-butyldimethylsilanyloxy)propane (11 mmol). 2.95 g of ethyl 3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylate are obtained (yield=64%) in the form of an oil.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:15])[O:8][C:7](OC)([O:16]C)[CH2:6]1)(=[O:3])[CH3:2].O.Cl>CO>[O:16]=[C:7]1[CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:9]([CH3:15])[O:8]1
Reactant: COC(=O)C1=C(C)OC(OC)(OC)CC1NC(C)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)C1C(NC(C)=O)CC(=O)OC1C
Reaction time: 5 h
Yield: 34.8 %

Procedure:
To a solution of methyl 4-acetylamino-2,2-dimethoxy-6-methyl-3,4-dihydro-2H-pyran-5-carboxylate (13.7 g) (Example 23) in methanol (100 ml) at 20°-25° C. was added water (4.0 ml) and 1N HCl (0.4 ml). The mixture was stirred at 20°-25° C. for five hours, then the solvents were evaporated at reduced pressure and the residual gum (13 g) was redissolved in trifluoroacetic acid (100 ml), to which was added methylene chloride (25 ml) and triethylsilane (25 ml). The mixture was stirred at 20°-25° C. for 70 hours and then the solvents were evaporated at reduced pressure. The residue was purified by chromatography on K60 silica eluting with ethyl acetate to give methyl 2-oxo-4-acetylamino-6-methyl-3,4,5,6-tetrahydro-2H-pyran-5-carboxylate (4.0 g) m.p. 135°-6° C. (EtOAc/hexane) (4,5-trans: 5,6-trans isomer).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5][CH:4]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1
Product: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Temperature: 130 °C
Yield: 98.7 %

Procedure:
A mixture of p-anisidine (2.20 g, 17.9 mmol) and diethyl ethoxymethylenemalonate 3.6 mL, 17.9 mmol) is heated at 130° C. for 2 h. While warm, the mixture is evacuated, then cooled to give 5.18 g of diethyl (4-methoxyphenylaminomethylene)malonate as an oil.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9](O)=[C:6](OC)[CH:5]=1.C[OH:16]>>[OH:16][C:2](=[CH:3][C:4]1[CH:12]=[CH:11][CH:9]=[CH:6][CH:5]=1)[C:1]([OH:14])=[O:13]
Reactant: CO
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Product: O=C(O)C(O)=Cc1ccccc1
Reaction time: 0.08 h

Procedure:
Ferulic acid determination. Enzymatic hydrolysates were dilued to ½ with methanol 100%, centrifuged at 12,000×g for 5 min and supernatants were filtered through a 0.2 μm nylon filter (Gelman Sciences, Acrodisc 13, Ann Arbor, Mich.). Filtrates were analyzed by HPLC (25 μL injected). HPLC analyses were performed at 280 nm and 30° C. on a HP1100 model (Hewlett-Packard Rockville, Md.) equipped with a variable UV/VIS detector, a 100-position autosampler-autoinjector. Separations were achieved on a Merck RP-18 reversed-phase column (Chromolith 3.5 μm, 4.6×100 mm, Merck). The flow rate was 1.4 ml/min. The mobile phase used was 1% acetic acid and 10% acetonitrile in water (A) versus acetonitrile 100% (B) for a total running time of 20 min, and the gradient changed as follows: solvent B started at 0% for 2 min, then increased to 50% in 10 min, to 100% in 3 min until the end of running. Data were processed by a HP 3365 ChemStation and quantification was performed by external standard calibration.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[C:29](=O)[CH2:28][CH2:27]2.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:29]3[C:30]4[C:26](=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:21])[CH2:27][CH2:28]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: Cc1cccc2c1C(=O)CC2
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: Cc1cccc2c1C(Nc1ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c1)CC2

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 7-methyl-indan-1-one using decaborane yielded a mixture of epimers of the title compound as a colorless waxy solid. MS (ESI): m/z=409.3 [M+H]+.