Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:23][CH2:24][CH2:25][CH3:26])[CH3:22])[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[CH3:34][N:35]([CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)[C:36]([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42])=[O:37].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH2:23]([N:21]([CH3:22])[C:19]1[CH:18]=[CH:17][C:16]([NH:27][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[C:38]([C:36]([N:35]([CH3:34])[CH2:47][CH2:48][N:49]3[CH2:50][CH2:51][O:52][CH2:53][CH2:54]3)=[O:37])[CH:39]=2)=[C:15]([C:11]2[CH:10]=[C:9]([C:8](=[O:28])[NH:7][CH2:6][C:5]3[CH:29]=[CH:30][CH:31]=[C:3]([C:2]([F:32])([F:1])[F:33])[CH:4]=3)[CH:14]=[CH:13][N:12]=2)[CH:20]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN(C)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCN(C)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(butyl(methyl)amino)phenyl)isonicotinamide (250 mg, 0.55 mmol, 1.00 equiv) in dichloromethane (10 mL), 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (190 mg, 0.65 mmol, 1.19 equiv), 4-dimethylaminopyridine (133 mg, 1.09 mmol, 1.99 equiv), EDC.HCl (210 mg, 1.09 mmol, 2.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 100 mL of dichloromethane. The resulting mixture was washed with 2×50 mL of NH4Cl aq. and 2×50 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (30% CH3CN up to 42% in 6 min); Detector, UV 220&254 nm. This resulted in 87.2 mg (15%) of N1-(4-(butyl(methyl)amino)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)-N3-methyl-N3-(2-morpholinoethyl)isophthalamide as a yellow solid. LC-MS (ES, m/z): 731 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 11.95 (s, 1H), 9.75 (s, 1H), 9.52 (s, 1H), 8.88 (d, J=5.1 Hz, 1H), 8.27 (s, 1H), 8.10 (d, J=9.3 Hz, 1H), 7.97-7.83 (m, 2H), 7.82 (d, J=5.1 Hz, 1H), 7.70-7.54 (m, 6H), 7.17 (s, 1H), 6.95 (d, J=7.5 Hz, 1H), 4.61 (d, J=5.7 Hz, 2H), 4.02 (s, 2H), 3.90 (s, 2H), 3.65 (s, 4H), 3.45-3.39 (m, 4H), 3.20 (s, 2H), 3.0 (d, J=12.3 Hz, 6H), 1.55-1.50 (m, 2H), 1.35-1.30 (m, 2H), 0.93-0.88 (m, 3H).
Reaction SMILES: ClCCl.C(O)(=O)C.[O:8]1[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9]1.O>C(O)(C)C>[O:8]1[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9]1
Reactant: CCCCCCCCCCC1CO1
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCCCCCCCC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
An oven-dried round bottom flask containing a magnetic stir bar was charged with the (R,R)-HKR catalyst (Schaus, et al., J. Am. Chem. Soc. 2002, 124, 1307-1315); CAS Number 176763-62-5, 1.31 g, 2.17 mmol. Dichloromethane (34 mL) and then glacial acetic acid (1.30 mL) were added to the flask. The resulting solution was stirred vigorously for 1.5 h; during this time the color of the mixture changed from dark red to brown. The solvent was removed by rotary evaporation until the material appeared dry. 1,2-epoxydodecane (40.0 g, 217 mmol) then isopropyl alcohol (reagent grade, 47 mL) were added to the flask containing the oxidized catalyst and a magnetic stir bar. The flask was immersed in an ice bath. H2O (2.15 mL, 119 mmol, 0.55 equiv relative to epoxide) was added dropwise to the stirred mixture. The flask was sealed with a rubber septum and the solution was allowed to warm to room temperature. After stirring for 2 days, the reaction mixture was diluted with ˜200 mL of hexanes. The resulting solution was filtered through paper to remove the white precipitate (1,2-diol). The filtrate was concentrated by rotary evaporation. The resulting dark red oily liquid was dissolved in ˜150 mL of hexanes and filtered in order to remove a substantial amount of white crystalline precipitate (diol). The filtrate was transferred into a 250 mL round bottom flask and concentrated by rotary evaporation. The desired product was isolated by distillation under vacuum (literature: 124° C./15 mm Hg). The desired product (14.3 grams, 71.5% of theoretical yield) was collected as a clear oil. The product was determined to be 100% ee by chiral chromatography of the 2-napthylenethiol derivative.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([S-:12])#[N:11].[NH4+].BrBr>C(O)(=O)C>[NH2:11][C:10]1[S:12][C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[N:1]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1ccc2nc(N)sc2c1
Temperature: 13.5 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a mixture of 4-aminobenzonitrile (23.6 g, 0.2 mol) and ammonium rhodanate (30.4 g, 0.4 mol) was added glacial acetic acid (600 mL) and the resulting solution was cooled to 13.5° C. on an ice-bath. A mixture of bromine and glacial acetic acid was added drop-wise and slowly. The resulting mixture was stirred for 1 hour at 13.5° C. and filtered. The filter cake was washed with glacial acetic (6×100 mL) and placed in hot water (1000 mL) with stirring. The mixture was filtered and pH of the filtrate was adjusted to 7 with a saturated sodium carbonate solution. The precipitate was isolated and dried to give 19.5 g (56%) of 2-amino-benzothiazole-6-carbonitrile. A mixture of concentrated hydrochloric acid (113 mL) and water (52 mL) was heated at 90° C. while 2-aminobenzothiazole-6-carbonitrile (19 g, 0.108 mol) was added. The mixture was cooled to −5° C. on an ice-bath and a solution of sodium nitrite (7.72 g, 0.112 mol) in water (20 mL) was added drop-wise, keeping the temperature below than 0° C. When addition was complete the mixture was stirred for 0.5 hour and a solution of CuCl2 (16 g) in water (108 mL) was added drop-wise. When addition was complete the mixture was stirred for 10 min, and the ice-bath was removed. Stirring was continued for 2 h and the mixture was cooled to room temperature. The mixture was filtered and the solid was washed to neutrality with water and dried. This afforded 12.8 g (61%) of 2-chlorobenzothiazole-6-carbonitrile. 1H-NMR δ 8.14 (s, 1H), 8.03 (d, 1H), 7.75 (d, 1H).
Reaction SMILES: [CH:1]1([C:9]([OH:11])=[O:10])[CH2:5][CH2:4][N:3]2[CH:6]=[CH:7][CH:8]=[C:2]12.[CH3:12]O>Cl>[CH:1]1([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][N:3]2[CH:6]=[CH:7][CH:8]=[C:2]12
Reactant: O=C(O)C1CCn2cccc21
Reactant: CO
Agent: Cl
Product: COC(=O)C1CCn2cccc21

Procedure:
2,3-Dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid is dissolved in methanol containing a small amount of concentrated hydrochloric acid. The resulting solution is heated to reflux, and then cooled. The title compound is isolated by rotary evaporation of the solvent under reduced pressure, and may be purified by chromatography on silica gel with hexane/ethyl acetate as eluent.
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[N:8]=[C:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:19]=1Br.C([Mg]Br)(C)C.O>C(OCC)(=O)C>[Br:6][C:7]1[N:8]=[C:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[CH:19]=1
Reactant: COC(=O)C1CCn2c(nc(Br)c2Br)C1
Agent: CC(C)[Mg]Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1CCn2cc(Br)nc2C1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
A tetrahydrofuran (150 ml) solution of the methyl 2,3-dibromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate (13 g) obtained in (Example 2.7) <Step 1> was cooled to −35° C. Thereafter, isopropylmagnesium bromide (95 ml, 1 M tetrahydrofuran solution) was added to the solution over 20 minutes, while keeping the temperature at −30° C. or less, and the reaction solution was then stirred at −35° C. for 30 minutes. Thereafter, water (350 ml) and ethyl acetate (250 ml) were added to the reaction solution, and insoluble matters were then removed by filtration with Celite. Subsequently, the filtrate was separated into an organic layer and a water layer. The water layer was extracted with ethyl acetate (250 ml), and the organic layers were then gathered. The gathered organic layer was washed with a saturated saline, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=70:30-30:70), so as to obtain the title compound (6.8 g) in the form of a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:30][CH2:31][S:32][CH2:33][C@@H:3]12.[Li+].[OH-]>O1CCOCC1>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:30][CH2:31][S:32][CH2:33][C@@H:3]12
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-ethyl 4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate (180 mg, 0.385 mmol) was taken up in dioxane (2081 μl) and LiOH (1N, 2310 μl, 2.310 mmol) was added. The reaction was stirred 16 h at room temperature. The reaction was concentrated in-vacuo and the residue was taken up in water (5 mL) and acidified (4.5N HCl) to pH 4. A tan precipitate formed which was filtered and the solids were collected, dried and determined to be the product (166 mg, 98%) as a tan solid. [M+H] calc'd for C22H25N5O3S, 440. found, 440.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:33]1([CH2:38][CH2:39][NH2:40])[CH2:37][CH2:36][CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH2:39][CH2:38][N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCN1CCCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NCCN2CCCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 10 %

Procedure:
A mixture of 0.100 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.026 g (0.33 mmole) of 2-pyrrolidin-1-yl-ethylamine, 0.102 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.036 g (0.27 mmole) of 1-hydroxybenzotriazole, 0.195 mL (1.12 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 20:80-100:0) to give 0.012 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2-pyrrolidin-1-yl-ethyl)-benzamide (I-45) as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([I:22])=[N:17][N:16]=[C:15]3I)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:26][O-:27].[Na+].Cl>CN(C=O)C>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([I:22])=[N:17][N:16]=[C:15]3[O:27][CH3:26])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(I)nnc(I)c2c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nnc(I)c2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.3 %

Procedure:
A mixture of 1,4-di-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.59 g, 1.037 mmol), sodium methoxide (0.11 g, 2.036 mmol) in DMF (8 mL) was stirred at room temperature for 18 hours. The reaction was poured onto water, neutralized with 2N HCl. The product was extracted with EtOAc (×3), the combined organic extracts washed with water (×3), brine and dried (Na2SO4). Chromatography (Hex/EtOAc) afforded 1-iodo-4-methoxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (134 mg), m/z 473.91; and 4-iodo-1-methoxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (132 mg), m/z 473.91.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[H-].[Na+].I[CH3:30]>O1CCCC1>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH3:30])[CH:22]=[N:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CI
Reactant: OCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1

Procedure:
This compound is obtained by reacting 1-trityl-4-hydroxymethylpyrazole (555 mg; 1.63 mmol) in dry tetrahydrofuran with sodium hydride (98 mg; 2.44 mmol) and iodomethane (0.5 mL; 8.15 mmol). Yield: 93° A) (536 mg, 1.51 mmol).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>ClCCl>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed tert-butyl N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]carbamate (2.0 g, 7.08 mmol, 1.00 equip), dichloromethane (20 mL), and CF3COOH (4 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum to yield 1-(2,2,2-trifluoroethyl)piperidin-4-amine 2,2,2-trifluoroacetate as a yellow oil. (ES, m/z) 183 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:15][C:16]([OH:18])=O)[O:3]1.Cl.[CH3:20][O:21][C:22](=[O:26])[CH2:23][CH2:24][NH2:25].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:20][O:21][C:22](=[O:26])[CH2:23][CH2:24][NH:25][C:16](=[O:18])[CH2:15][C@@H:4]1[O:3][N:2]([CH3:1])[C@H:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[CH2:5]1
Reactant: CN1O[C@@H](CC(=O)O)C[C@H]1c1ccc(C#N)cc1
Reactant: COC(=O)CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)C[C@H]1C[C@@H](c2ccc(C#N)cc2)N(C)O1
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
To a mixture of 2-[2-methyl-3(S)-(4-cyanophenyl)-isoxazolidin-5(R)-yl]acetic acid (500 mg, 2.0 mmol), b-alanine methyl ester HCl salt (314 mg, 2.4 mmol) and triethylamine (1.7 ml, 12 mmol) in DMF (7 ml), cooled with ice-water, was added PyBOP (1,18 g, 2.0 mmol). After stirring for 12 hrs, the reaction mixture was diluted with ethyl acetate and washed with dilute NaHCO3 and brine, then dried. Concentration followed by chromatography with a mixture of EtOAc and hexane as the eluent gave the product as an amorphous solid (660 mg, 98% yield).1H NMR (300 MHz, CDCl3) δ2.00 (m, 1H), 2.40(dd, 1H), 2.56(t, 2H), 2.60(s, 3H), 2.68(dd, 1H), 2.94(m, 1H), 3.54(qt, 2H), 3.68(t, 1H), 3.70(s, 3H), 4.60(m, 1H), 6.60(s, 1H), 7.46(d, 2H), 7.64(d, 2H); MS (ESI) Calc. for (M+1)+: 332. Found: 332.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[CH:16]([OH:18])[CH3:17]>C(Cl)Cl.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([F:7])=[C:9]([C:16](=[O:18])[CH3:17])[CH:10]=1)#[N:13]
Reactant: CC(O)c1cc(C#N)ccc1F
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)c1cc(C#N)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of pyridine (3.52 mL, 43.6 mmol) in CH2Cl2 (10 mL) was added dry chromium trioxide (2.18 g, 21.80 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 30 min. 4-fluoro-3-(1-hydroxyethyl)benzonitrile (600 mg, 3.63 mmol) dissolved in CH2Cl2 (10 mL) was added via canula. The reaction mixture was stirred for 10 min. and was diluted with ether and celite and stirred for an additional 20 min. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The organic was washed then with 5% HCl and sat'd NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to provide product:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.O[CH2:44][C:45]([O:47][CH3:48])=[O:46]>>[CH3:48][O:47][C:45]([CH2:44][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:46]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: COC(=O)CO
Product: COC(=O)COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with methyl 2-hydroxyacetate to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid methoxycarbonylmethyl ester. MS (ES+) m/z calcd. for C34H34Cl2F2N3O6: [(M+H)+]: 688. found: 688.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[O:14]1>O>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:16]1[C:17](=[O:19])[O:18][C:13]([CH3:21])([CH3:12])[O:14][C:15]1=[O:20]
Reactant: COc1cccc(C=O)c1F
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: COc1cccc(C=C2C(=O)OC(C)(C)OC2=O)c1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A 500 mL round bottom flask was charged with 2-fluoro-3-methoxybenzaldehyde 77.A (available from Aldrich) (28.6 g, 186 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (available from Aldrich) (34.8 g, 241 mmol), and water (350 mL). The heterogeneous mixture was stirred for 2 hours at 90° C. (reflux), cooled to room temperature, and filtered. The resulting off-white solid was triturated with ether to afford 5-(2-fluoro-3-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 77.B (30.6 g, 58.8% yield) as a crystalline white powder.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)[C@H](C1C=CC=CC=1)CN>CC(CC(C)=O)C>[C:1]([C:9]1[CH:10]=[C:11]([C@@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)[C@@H](CN)c1ccccc1
Solvent: CC(=O)CC(C)C
Product: C[C@@H](C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
(±)-2-(3-Benzoylphenyl)propionic acid (13.55 g, 53.3 mmol) was dissolved in MIBK (67.5 g) with heating. Then, (R)-(-)-3-methyl-2-phenylbutylamine (3.92 g, 24 mmol), 0.45 equivalent based on the amount of (±)-2-(3-benzoylphenyl)propionic acid, was added dropwise with stirring at 40°C. After completing the addition, the reaction solution was stirred at 40°C. for 2 hours, followed by stirring at room temperature for 6 hours and then at 10°C. for 2 hours. Then, the crystal precipitated was filtered, and the filter cake was washed with cold MIBK (25 ml) and dried to give a diastereomer salt (6.48 g) of (R)-(-)-2-(3-benzoylphenyl)propionic acid with (R)-(-)-3-methyl-2-phenylbutylamine. The yield of the product based on (R)-2-(3-benzoylphenyl)propionic acid contained in the starting material was 58.3%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(C)C)(=O)C>O.CN(C)C=O>[OH:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[CH:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Solvent: O
Product: COC(=O)c1cc(O)cc(OC(=O)c2ccccc2)c1
Temperature: 47 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a flask fitted with thermometer, condenser, overhead stirrer, pH probe and nitrogen line was added methyl-3,5-dihydroxybenzoate (1.0 eq), 325 mesh potassium carbonate (3.0 eq) and dimethylformamide (DMF) (4 vols) under a nitrogen atmosphere. The mixture was heated to 47° C. for 1 hour, then benzoyl chloride (1.0 eq) was added slowly drop-wise via syringe pump over approximately 2 hours. Further benzoyl chloride was added (0.1 eq) over 20 minutes via syringe pump. The reaction mixture was held for 1.5 hours, then water (10 vols) and iso-propyl acetate (6 vols) were added. The reaction mixture was agitated for 30 minutes and then the layers were separated. The aqueous layer was re-extracted with a further charge of iso-propyl acetate (6 vols). The batch was separated, and the combined organic layers were washed with saturated brine (6 vols), then with a solution of 0.1N hydrochloric acid/brine. The iso-propyl acetate was distilled to dryness on the rotary evaporator. Iso-propyl acetate (6 vols) was added, and distilled to dryness on the rotary evaporator. Toluene (6 vols) was added and distilled to dryness on the rotary evaporator. Toluene (3.5 vols) was added and the reaction slurried for 30 minutes. The solid was filtered off and dried at 20° C.-40° C. to give the desired product as a solid (corrected yield 72%).