Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:17][CH2:16][CH2:15][CH:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:14]2)[CH2:30][CH2:29]1
Reactant: O=CCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(CCCC2CC(c3cccc([N+](=O)[O-])c3)=NO2)CC1
Yield: 84.5 %

Procedure:
3-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl] propanal (23.8 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.5 mg, 0.262 mmol) and diisopropylethylamine. (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 31.2 mg (78.6%) of the target compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:24])[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]4[CH2:23][O:22]4)=[CH:15][CH:14]=3)=[CH:9][O:10]2)=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(O)C>[OH:22][CH:21]([CH2:23][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[C:7](=[O:24])[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[O:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc2c(=O)c(-c3ccc(OCC4CO4)cc3)coc2c1
Reactant: C1COCCN1
Solvent: CCO
Product: COc1ccc2c(=O)c(-c3ccc(OCC(O)CN4CCOCC4)cc3)coc2c1
Yield: 68.1 %

Procedure:
A mixture of compound 3 (obtained from example 1) (0.32 g, 1 mmol), morpholine (0.43 g, 5 mmol), and ethanol (30 mL) was refluxed for 4 hrs (TLC monitoring). After removal of solvent in vacuo, the residue was treated with H2O (50 mL). The resulting precipitate was collected and purified by column chromatography (MeOH/CH2Cl2=1:20) to give the title compound 5a (0.28 g, 68% yield). M.p.: 117-118° C.
Reaction SMILES: [CH3:1][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)[N:17]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[C:16]1=[O:38])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].Cl.N1C=CC=CC=1.[OH-].[NH4+]>O>[CH3:3][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[N:17]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:32][CH:33]=2)[C:16]1=[O:38])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:1]
Reactant: COc1cccc([C@H]2C[C@@H](NC(C)(C)c3cccc(C(F)(F)F)n3)C(=O)N2c2ccc(C(F)(F)F)cc2)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(N[C@@H]1C[C@H](c2cccc(O)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Temperature: 185 °C
Yield: 32.6 %

Procedure:
Add (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-(3-methoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (1.9 g, 3.4 mmol) to pyridine hydrochloride (28.6 g, 247.8 mmol). Plunge the mixture into a 185° C. oil bath and heat for 2 hours. Cool to ambient temperature and dilute with water (175 mL). Make the pH basic by ammonium hydroxide addition and extract with EtOAc. Wash with brine, dry over sodium sulfate, filter and concentrate the organic to residue. Purify the residue by silica gel chromatography (20%-30% EtOAc-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-(3-hydroxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (0.58 g, 32%) as a white foam. LC-MS ESI m/z: 524.2 (M+H)+, Tr=2.91 min., method 1.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH3:18])[CH:16]=[CH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([Si:23]([CH3:26])([CH3:25])[CH3:24])C=C>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH3:18])/[CH:16]=[CH:17]/[CH2:20][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C=CC[Si](C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: C[C@H](/C=C/C[Si](C)(C)C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1

Procedure:
To a solution of (4R)-4-benzyl-3-[(2R)-2-methylbut-3-enoyl]-1,3-oxazolidin-2-one (0.65 mmol, 170 mg) and allyltrimethyl silane (1.9 mmol, 0.31 mL) in DCM (2 mL) at reflux was added 5 mol % of Grubbs' second generation catalyst (28 mg). After 72 hrs the solvent was removed in vacuo. The crude product was purified by column chromatography to a colourless oil. (83 mg, 77%) E/Z 3:1. NMR data of the mixture of E/Z isomers. 1H NMR (400 MHz, CDCl3): δ=7.21-7.36 (m, 5H), 5.64 (dt, J=8.1, 15.4, 1H), 5.41-5.58, (m, 2 HZ) 5.32-5.39 (m, 1H), 4.68-4.78 (m, 1 HZ) 4.59-4.68 (m, 1H), 4.38-4.48 (m, 1H), 4.14-4.19 (m, 2H), 3.30 (dd, J=3.28, 13.14, 1H), 2.78 (dd, J=9.6, 13.14, 1H), 1.48-1.63 (m, 2 HZ), 1.46 (d, J=8.1, 2H), 1.31 (d, J=6.8, 3 HZ), 1.30 (d, J=6.8, 3H), 0.0 (s, 9 HZ), −0.02 (s, 9H); 13C NMR (100 MHz, CDCl3): δ=175.5, 152.3, 135.4Z or E, 135.3Z or E, 129.7Z or E, 129.5Z or E, 128.9Z or E, 128.1Z, 127.3, 126.9, 126.1Z, 66.03, 66.0Z, 55.6, 55.5Z, 40.9, 37.9, 37.8Z, 35.8Z, 22.9, 19.0Z, 17.9, −1.8Z, −1.9; IR (CHCl3): v 2955, 1783, 1699, 1454, 1381, 853; HMRS required for C19H27NO3Si ([M+H]+) 346.1838 found 346.1847; [α]D23=−131.6 (c, 2, CHCl3).
Reaction SMILES: [BrH:1].[C:2]([OH:5])(=[O:4])[CH3:3]>C(Cl)(Cl)Cl>[Br-:1].[C:2]([O-:5])(=[O:4])[CH3:3].[C:2]([O-:5])(=[O:4])[CH3:3].[C:2]([O-:5])(=[O:4])[CH3:3].[C:2]([O-:5])(=[O:4])[CH3:3].[C:2]([O-:5])(=[O:4])[CH3:3].[C:2]([O-:5])(=[O:4])[CH3:3].[C:2]([O-:5])(=[O:4])[CH3:3].[C:2]([O-:5])(=[O:4])[CH3:3].[C:2]([O-:5])(=[O:4])[CH3:3].[C:2]([O-:5])(=[O:4])[CH3:3]
Reactant: CC(=O)O
Reactant: Br
Solvent: ClC(Cl)Cl
Product: CC(=O)[O-]
Product: [Br-]
Temperature: 0 °C

Procedure:
A 75 ml portion of 30-32% hydrogen bromide in glacial acetic acid is cooled in an ice bath. A solution of 15.0 g of [glc 1α,4 glc 1α,4 glc undecaacetate] in 125 ml of chloroform is added with swirling. The mixture is allowed to remain in the ice bath for 2 hours with occasional swirling and then poured into crushed ice with vigorous swirling. The mixture is extracted into 100 ml of chloroform. The aqueous layer is washed with two 75 ml portions of chloroform. The combined chloroform extracts are washed with five 250 ml portions of ice-cold water rendering it neutral. The chloroform layer is dried over anhydrous calcium chloride and evaporated to dryness in vacuo giving 13.0 g of [glc 1α,4 glc 1α,4 glc decaacetate bromide] as a colorless glass.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][O:41][CH:40]([CH2:44]O)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][O:41][CH:40]([CH2:44][N:24]2[C:20](=[O:30])[C:21]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:22]3[C:23]2=[O:25])[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97 %

Procedure:
Triphenylphosphine (506 mg, 1.87 mmol) and phthalimide (275 mg, 1.87 mmol) were added to 4-(tert-butoxycarbonyl)morpholin-2-yl methanol (340 mg, 1.56 mmol) in tetrahydrofuran (3 mL). The mixture was stirred at room temperature for 5 min, followed by addition of a 40% diethyl azodicarboxylate/toluene solution (1.06 mL, 2.34 mmol) and stirring at room temperature for 4 hours. Subsequently, ethyl acetate was added and the mixture washed sequentially with tap water and brine. The mixture was then dried over magnesium sulfate and the solvent was evaporated. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=10:1->3:1) gave 524 mg (97%) of the desired compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]#N)[C:9]2=[O:17])=[CH:4][C:3]=1[CH3:18].[OH2:19].S(=O)(=O)(O)[OH:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([OH:21])=[O:19])[C:9]2=[O:17])=[CH:4][C:3]=1[CH3:18]
Reactant: O
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(-n2c(C)ccc(C#N)c2=O)ccc1F
Product: Cc1cc(-n2c(C)ccc(C(=O)O)c2=O)ccc1F
Temperature: 25 °C
Yield: 58 %

Procedure:
An aqueous solution (98% sulfuric acid 8 mL, water 8 mL) of 1-(4-fluoro-3-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1.60 g, 6.60 mmol) in sulfuric acid was stirred at 130° C. for 10 hr. The reaction solution was cooled to room temperature, water was added, and the precipitated solid was collected by filtration. The obtained solid was washed with ethyl acetate to give the title compound (1.00 g, 58%) as a brown solid.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1)[C:13]([OH:15])=O)[CH2:3][CH2:2]2.[NH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1)[C:13]([NH:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])=[O:15])[CH2:3][CH2:2]2
Reactant: CC(C)(CN)CO
Reactant: O=C(O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(CO)CNC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-nitroisonicotinic acid (Intermediate 29A) (2.0 g, 6.8 mmol) in DMF (25 mL) was added 3-amino-2,2-dimethylpropan-1-ol (0.85 g, 8.2 mmol), triethylamine (1 g, 10.3 mmol) and HATU (3.16, 10.3 mmol) under nitrogen, reaction then stirred overnight. The reaction mixture was concentrated and purified by HPLC to afford 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(3-hydroxy-2,2-dimethylpropyl)-5-nitroisonicotinamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C1CCN2C(=NCCC2)CC1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([CH3:30])[C:22]=1[CH3:31].CN(C=O)C>CC#N>[CH3:31][C:22]1[C:23]([CH3:30])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Nc1cc(O)ccn1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1C
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1c(Oc2ccnc(N)c2)ccc([N+](=O)[O-])c1C
Temperature: 25 °C

Procedure:
To a suspension of 2-aminopyridin-4-ol (339 mg, 3.07 mmol) in MeCN (4.0 mL) at RT was added DBU (570 μL, 3.78 mmol) and after 30 min a solution of 1-fluoro-2,3-dimethyl-4-nitrobenzene (400 mg, 2.36 mmol) in MeCN (2.0 mL) was added dropwise. The reaction mixture was maintained at RT for 16 hr; DMF (2.0 mL) was added and the mixture heated to 80° C. for 72 hr and then cooled to RT for 64 hr. The resulting mixture was evaporated in vacuo and the residue was partitioned between DCM (50 mL) and brine (30 mL). The organic layer was separated and dried (MgSO4) and was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 20-100%, gradient elution and then SiO2, 12 g, 50% EtOAc in isohexane, isocratic elution) to afford 4-(2,3-dimethyl-4-nitrophenoxy)pyridin-2-amine, as a yellow solid (117 mg, 19%); Rt 1.47 min (Method 2); m/z 260 (M+H)+ (ES+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]1([CH3:17])[CH:16]=CC=C[CH:12]=1>C(OCC)(=O)C>[C:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH3:17])([CH3:16])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1ccc([N+](=O)[O-])cc1

Procedure:
43.79 mmol of N-N-dimethylformamide di-tert-butyl acetal are added, at ambient temperature, to a solution of 10.78 mmol (1.5 g) of 4-nitrophenol in 10 ml of toluene. The reaction mixture is heated at reflux, with vigorous stirring, for 5 hours. The reaction mixture is diluted with ethyl acetate and then washed with water, with saturated aqueous sodium bicarbonate solution and then with 10% aqueous sodium chloride solution. The expected product is obtained by drying the organic phase and then concentrating.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:17].[K+]>C(O)(C)(C)C.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH2:14])=[O:17])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 78 °C
Yield: 101.3 %

Procedure:
To a solution of 4-benzyloxybenzonitrile (0.61 g, 2.91 mmol) in 15 ml of tert-butanol was added fine powder of KOH (1.22 g, 21.78 mmol) and the resulting reaction mixture was refluxed for 4 h at 78° C. After the completion of the reaction (TLC monitoring), added brine solution and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum, to get the product (0.67 g) that was used as such for the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([O:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6].O[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>C(Cl)Cl.O>[O:22]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[O:1][CH2:2][CH2:3][C@H:4]([O:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COC(=O)[C@H](CCO)OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](CCON1C(=O)c2ccccc2C1=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.6 %

Procedure:
To a solution of (S)-methyl 4-hydroxy-2-methoxybutanoate (46b, 1.48 g, 10.0 mmol) in CH2Cl2 (25.0 mL) was added 2-hydroxyisoindoline-1,3-dione (1.63 g, 10.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (2.95 ml, 15.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to afford (S)-methyl 4-(1,3-dioxoisoindolin-2-yloxy)-2-methoxybutanoate (46c, 1.25 g, 42%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.98-2.10 (m, 1H) 2.23-2.37 (m, 1H) 3.51 (s, 3H) 3.79 (s, 3H) 4.24 (dd, J=9.47, 3.66 Hz, 1H) 4.31-4.40 (m, 2H) 7.74-7.82 (m, 2H) 7.81-7.90 (m, 2H).
Reaction SMILES: CO.[CH3:3][O:4][C:5](=[O:38])[C@H:6]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:7][C:8](=[O:30])[C@H:9]([CH2:26][C:27](=[O:29])[OH:28])[NH:10][C:11](=[O:25])[C@@H:12]([CH3:24])[NH:13]C(OCC1C=CC=CC=1)=O.[H][H]>[C].[Pd].O>[CH3:3][O:4][C:5](=[O:38])[C@H:6]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:7][C:8](=[O:30])[C@H:9]([CH2:26][C:27](=[O:28])[OH:29])[NH:10][C:11](=[O:25])[C@@H:12]([CH3:24])[NH2:13]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N

Procedure:
In a solvent mixture of 75 ml of methanol and 75 ml of water was dissolved 2.1 g of N-benzyloxycarbonyl-D-alanyl-α-L-aspartyl-L-phenylalanine methyl ester, followed by reduction at room temperature for 4 hours in a hydrogen flow using palladium-carbon as a catalyst. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from water-acetone. Yield, 1.3 g; m.p., 228°-230° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]1([NH:15][NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[C:9]1([NH:15][N:16]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1cccnc1
Reactant: NNc1ccccc1
Solvent: CCO
Product: C(=NNc1ccccc1)c1cccnc1

Procedure:
10.8 g of 3-pyridinecarbaldehyde was dissolved in 30 ml of ethanol. 10.8 g of phenylhydrazine was added to the stirred solution, at room temperature. 3 crystallized out as yellow prisms, mp 158-160.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:32])[N:20]([CH2:22][CH2:23][CH2:24][S:25]([CH2:28][CH2:29][CH2:30][OH:31])(=[O:27])=[O:26])[N:21]=[C:8]2[N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[C:6]=1[CH3:43])=[O:4].[H-].[Na+].[C:46]1(C)[C:47]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:49]=[CH:50][CH:51]=1.[CH2:57]1COCC1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:9]2[C:19](=[O:32])[N:20]([CH2:22][CH2:23][CH2:24][S:25]([CH2:28][CH2:29][CH2:30][O:31][S:52]([C:47]3[CH:46]=[CH:51][C:50]([CH3:57])=[CH:49][CH:48]=3)(=[O:53])=[O:54])(=[O:26])=[O:27])[N:21]=[C:8]2[N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:42])[F:41])[CH:34]=2)[C:6]=1[CH3:43])=[O:4]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCS(=O)(=O)CCCO)c(=O)n2C1c1ccc(C#N)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCS(=O)(=O)CCCOS(=O)(=O)c3ccc(C)cc3)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Intermediate 22 (89 mg, 0.14 mmol) was dissolved in THF (3 ml), and then sodium hydride (6 mg, 0.2 mmol) was added under an atmosphere of N2. The reaction mixture was stirred at RT for 10 mins, then toluenesulfonyl chloride (31 mg, 0.16 mmol) was added and stirring was continued for 16 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluding with a gradient of 50-80% EtOAc in cyclohexane to yield the title compound as a colourless oil (70 mg).
Reaction SMILES: O=[CH:2][CH2:3][C@H:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[NH2:20][C:21]1([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.O>[C:14]([O:13][C:12]([NH:11][C@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][NH:20][C:21]1([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)C1(N)CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NCC[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl [(1S)-3-oxo-1-phenylpropyl]carbamate from Step B (0.820 g, 3.29 mmol) and methyl 1-aminocyclopentanecarboxylate hydrochloride (0.591 g, 3.29 mmol) in chloroform (33 mL) was added Hunig's base (0.574 mL, 3.29 mmol). After stirring at ambient temperature for 20 min, NaHB(OAc)3 (1.74 g, 8.22 mmol) was added as a solid. Upon completion of the reaction, saturated aqueous NaHCO3 (3 mL) was added and the mixture was allowed to stir for at least 2 h. Water (5 mL) and additional saturated NaHCO3 (3 mL) was then added to form two layers. The aqueous layer was extracted once with chloroform (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM 1:99 to 6:94, to give the title compound. MS: m/z=377 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[S:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=3)[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCC[CH2:33]1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([CH:7]2[S:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:33]=[C:29]4[S:25][C:26](=[O:31])[NH:27][C:28]4=[O:30])=[CH:18][CH:17]=3)[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNCC1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(OCCN2C(=O)SC(c3ccccc3)C2=O)cc1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc(OCCN3C(=O)SC(c4ccccc4)C3=O)cc2)S1
Temperature: 25 °C

Procedure:
A mixture of 4-[2-(5-phenyl-2,4-thiazolidinedion-3-yl) ethoxy]-benzaldehyde) (1.5 g) 2,4-thiazolidinedione (0.54 g), piperidine (0.4 ml) and benzoic acid (0.2 g) was heated at reflux in toluene (100 ml) in a Dean and Stark apparatus. After 4 hours at reflux the mixture was allowed to cool to room temperature overnight and then evaporated to dryness. The residue was then triturated with diisopropyl ether for 24 hours. The resulting solid was filtered off, washed with ether and dried in vacuo to afford the title compound which softened at 80° C. and melted at 120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14]CC#N)[CH:3]=1.[OH-:18].[Na+].[CH2:20]([OH:22])[CH3:21]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][CH2:21][C:20]([OH:18])=[O:22])[CH:3]=1
Reactant: [OH-]
Reactant: CCO
Reactant: N#CCCc1cc(Cl)ccc1-c1ccccc1
Agent: [Na+]
Solvent: O
Product: O=C(O)CCc1cc(Cl)ccc1-c1ccccc1
Yield: 56.6 %

Procedure:
A mixture composed of 280 mg (1.16 mmol) of 3-(4-chlorobiphenyl-2-yl)propanenitrile prepared in Example 53, 138 mg (3.475 mmol) of NaOH, 4 ml of ethanol and 4 ml water is refluxed for 6 hours. After cooling, the ethanol is concentrated under vacuum. 16 ml of water are then added and the mixture is washed with ethyl ether (2×20 ml), followed by acidification of the aqueous phase with 16% HCl. The resulting mixture is extracted with dichloromethane and the extracts are then dried over sodium sulfate. After concentrating the organic phase under vacuum, an oil is obtained, which crystallises after stirring in pentane, to give 171 mg of a white solid.