Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(CC1C=CC([NH:10][C:11]([C:13]2[CH2:14][CH2:15][O:16][C:17]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)=[CH:20][C:18]=3[CH:19]=2)=[O:12])=CC=1)#N.Cl.C(O)C.O1CCOCC1>>[CH3:30][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:22]=[CH:23][C:17]3[O:16][CH2:15][CH2:14][C:13]([C:11]([NH2:10])=[O:12])=[CH:19][C:18]=3[CH:20]=2)=[CH:29][CH:28]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CC#N)cc2)CCO3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(N)=O)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To N-(4-cyanomethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (200 mg) was added a solution of a 28% hydrogen chloride/ethanol/dioxane (2 ml). The resulting mixture was kept overnight in a refrigerator and then was concentrated, and ethanol (4 ml) and piperidine (1 ml) were added to the residue. After being stirred at room temperature for one hour, the reaction mixture was concentrated and was mixed with an aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate/methanol. The extract was dried (magnesium sulfate) and was then concentrated. To the residue was added 4 N hydrochloric acid/ethyl acetate, and the precipitate was collected by filtration and was washed with ethyl acetate to obtain N-[4-(1-piperidino)carbonimidoylmethyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 46) (103 mg) as a white powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:20][CH2:19]1)[C:12](O)=[O:13])=[O:7].C(N(CC)CC)C.[C:38]1([CH2:44][CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[C:38]1([CH2:44][CH2:45][CH2:46][NH:47][C:12]([C:11]2[CH:15]=[CH:16][C:17]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH2:20][CH2:19]3)=[C:9]([NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH:10]=2)=[O:13])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCCCc1ccccc1
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)O)cc2NC(=O)c2ccco2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCc3ccccc3)cc2NC(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a suspension of 3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (0.1 g, 0.246 mmol) in methylene dichloride (5 ml), triethylamine (0.074 g, 0.74 mmol), (3-phenylpropyl)amine (0.044 g, 0.370 mmol) and 1-propane phosphonic cyclic anhydride (0.23 g, 0.74 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and extracted with dichloromethane (10 ml×1). The organic layer was washed with water (10 ml×2) and dried over anhydrous sodium sulfate. The organic layer was concentrated and the crude product obtained was purified by flash chromatography using silica gel column to get (0.070 g, 67.9%) of the titled compound as a brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].[CH3:13]O>CN(C)C1C=CN=CC=1>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:12]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: CO
Agent: CN(C)c1ccncc1
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Cyano-2-fluorobenzoic acid (1 g; 6.06 mmol) was suspended in MeOH (10 mL) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.39 g; 7.27 mmol; 1.20 eq.) and 4-dimethylaminopyridine (70 mg; 0.61 mmol; 0.10 eq.) were added. The mixture was stirred at RT overnight.
Reaction SMILES: [NH2-].[Na+].CCOCC.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]#[N:18])[CH:12]=[CH:13][C:14]=1[Cl:15].[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33]Cl)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH:16]([C:11]2[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=2)[C:17]#[N:18])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: ClCCN1CCC(Cc2ccccc2)CC1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#CC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reaction time: 5 h
Yield: 67.6 %

Procedure:
1.95 g of sodium amide are added in small quantities to an ether solution of 9.3 g of 3,4-dichlorophenylacetonitrile. The mixture is heated for 2 hours to reflux, 11.8 g of 2-(4-benzylpiperidino)-1-chloro ethane are added and heating is repeated for another 5 hours to reflux. The resulting mixture is cooled and 200 ml of water are added, after what the organic phase is decanted, washed with water and extracted with a 10% solution of hydrochloric acid. The aqueous phase is then neutralized with soda, extracted with ether, washed with water, dried over magnesium sulfate and evaporated. 13 g of oily product are thus obtained.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CC(C)=[O:14].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:14])=[O:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1sc(Br)cc1[N+](=O)[O-]
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1sc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
5Bromo-3-nitrothiophene-2-carbaldehyde (0.5953 g, 2.5012 mmol, prepared according to Sone, C; Matsuki, Y Bull Chem Soc Japan, 1963, 36(5), 618-20.) was dissolved in acetone (5 mL) and Jones Reagent (1.5 mL) was added. The reaction was stirred at RT for 1 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed With water (4×100 mL), dried over MgSO4 filtered and concentrated to give 0.4993 g (1.9892 mmol, 80%) of the product as a light yellow solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:16][N:15]=[C:10]1[CH2:11][CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: NO
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCC(c2ccccc2)CC1
Temperature: 70 °C
Yield: 97 %

Procedure:
A mixture of 4-phenylcyclohexanone (28.7 mmol), hydroxylamine hydrochloride (36.0 mmol), and sodium acetate (60.95 mmol) in ethanol and water was heated at 70° C. overnight. Ethanol was removed, and the residue was dissolved in water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to give 1-(hydroxyimino)-4-phenylcyclohexane (97%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[CH:7]=1.[C:15]1([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN1C(=O)CCC1>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([N:26]2[CH2:27][CH2:28][N:23]([C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:22])[CH2:24][CH2:25]2)=[CH:7][C:6]=1[NH:8][CH2:9][CH2:10][CH3:11])([O-:14])=[O:13]
Reactant: CCCNc1cc(Br)ccc1[N+](=O)[O-]
Reactant: O=C(c1ccccc1)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCNc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 213.7 %

Procedure:
A solution of 5-bromo-2-nitro-N-propylbenzenamine (250 mg, 1.02 mmol) and phenyl(piperazin-1-yl)methanone (578 mg, 3.06 mmol) in NMP (2 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish (4-(4-nitro-3-(propylamino)phenyl)piperazin-1-yl)(phenyl)methanone (520 mg, 2.18 mmol), 56% yield. 1H NMR (500 MHz, DMSO-D6) d (ppm) 8.83 (m, 1H), 7.93 (d, J=9.5 Hz, 1H), 7.50-7.45 (m, 5H), 6.41 (dd, J=2.5 Hz, 10 Hz, 1H), 6.00 (d, J=2.5 Hz, 1H), 3.72-3.40 (m, 8H), 3.29 (q, J=7 Hz, 2H), 1.66 (m, 2H), 0.96 (t, J=7 Hz, 3H).+ESI HRMS (calcd for C20H24N4NaO, M+Na) 391.1746. found 391.1741
Reaction SMILES: N1CC[O:4]CC1.Cl[C:8]1(Cl)[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]1=[O:25].OS(O)(=O)=O>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([CH2:19][N:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][CH2:14][C:8](=[O:4])[C:9]1=[O:25])=[O:21])[CH3:24]
Reactant: CCOC(=O)CN1C(=O)C(Cl)(Cl)CCc2ccccc21
Reactant: C1COCCN1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN1C(=O)C(=O)CCc2ccccc21
Reaction time: 18 h

Procedure:
A mixture of morpholine (0.315 ml, 3.6 mmol) and 3,3-dichloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (0.5 g) was stirred under nitrogen at 110° for 18 hours. The solution was diluted to 10 ml with chloroform and cooled to 0°. 20% H2SO4 (1 ml) was added and the solution stirred for 2 hours at 0°. The solution was extracted with chloroform (2×20 ml) and the extracts washed with 2N HCl (2×10 ml) and saturated brine (5 ml). The solution was dried over magnesium sulfate and evaporated under reduced pressure to yield 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2,3- dione. NMR (CDCl3): δ1.25 (t,3H); 2.6 (m,2H); 3.6 (m, 2H); 4.2 (q, 2H); 7.3 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].[CH:29](Br)([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: CC(C)Br
Reactant: O=C(NCCCCCCCCCCCCO)c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1

Procedure:
A solution of 0.7 g of N-(12-hydroxydodecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 0.24 g of isopropyl bromide and 0.7 g of potassium carbonate in 20 ml of dimethylformamide was stirred at 100° C. for 3 hours. The reaction solution was diluted with chloroform, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was chromatographed over a silica gel column to afford the title compound as a crystal.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][NH:14][CH:13]=1)=[O:11])[CH3:8].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.O>CS(C)=O>[CH2:7]([O:9][C:10]([C:12]1[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][N:14]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:13]=1)=[O:11])[CH3:8]
Reactant: Clc1ccnc2ccccc12
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccnc3ccccc23)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added to 1.036 g (5 mmol) of 3-ethoxycarbonyl-4-trifluoromethyl-1H-pyrrole and 0.82 g (5 mmol) of 4-chloroquinoline dissolved in 10 mL of dimethyl sulphoxide at a temperature in the region of 20° C. under an argon atmosphere. After stirring for 18 hours at a temperature in the region of 110° C., the reaction mixture is poured into 30 mL of water and then left to crystallize for 1 hour at 20° C. After the solid residue has been filtered off and air-dried, 1.48 g of 3-ethoxycarbonyl-4-trifluoromethyl-1-(quinolin-4-yl)-1H-pyrrole are obtained in the form of beige-colored crystals melting at 108° C. IR spectrum (KBr): 3139; 1718; 1564; 1537; 1511; 1306; 1281; 1249; 1169; 1146; 1123; 1036; 846 and 773 cm1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][C@H:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)([O-:31])=[O:30]>C(Cl)Cl>[CH2:7]([N:5]1[CH2:6][C@@H:2]([NH:1][S:38]([C:35]2[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:37][CH:36]=2)(=[O:39])=[O:40])[C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:4]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (3R,4R)-4-amino-1-benzylpyrrolidin-3-ylcarbamate (5.8 g, 20 mmol) in 100 mL of CH2Cl2, triethylamine (4.04 g, 40 mmol) was added following by addition of 4-nitrobenzenesulfonyl chloride (1.1 eq) and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl, extracted with CH2Cl2, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 1-2% MeOH in CHCl3 to give the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[CH:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=Cc2cc(F)cc(F)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCCc2cc(F)cc(F)c2)CC1
Reaction time: 2 h

Procedure:
A mixture of 1-t-butoxycarbonyl-4-(3-(3,5-difluorophenyl) prop-2-enyl)piperidine (from EXAMPLE 95, Step C) and 50 mg of 10% palladium on carbon in MeOH (10 mL) was hydrogenated at 50 psi for 2 h. The suspension was filtered though Celite, the cake washed with MeOH and the filtrate was concentrated. Flash chomatography using 0-15% EtOAc in hexanes (v/v) as the eluant afforded the title compound: 1H NMR (500 MHz ) δ 1.10 (dq, J=4.4, 8.2, 21), 1.25-1.30 (21), 1.37-1.45 (m, 1H), 1.47 (s, 9H), 1.62-1.67 (4H). 2.59 (t, J=7.8, 2H), 2.62-2.78 (2H), 4.08 (bs, 2H), 6.61-6.70 (3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:22]([NH:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23]
Reactant: COC(=O)CN
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)Nc1ccccc1
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
To a stirred suspension of glycine methyl ester hydrochloride (4.52 g, 36 mmol) in methylene chloride (200 mL) was added triethylamine (5.0 mL, 36 mmol) at room temperature and stirred for 15 minutes. To the reaction mixture was added dropwise phenyl isocyanate (3.57 g, 30 mmol). The reaction mixture was stirred at room temperature for 2 hours and washed with 1N HCl (2×80 mL) and brine (80 mL). The organic layer was dried (Na2SO4) and concentrated to give the ester compound (6.2 g, ˜100%). 1H NMR (400 MHz, DMSO-d6) δ: 8.80 (s, 1H), 7.39 (d, 2H), 7.22 (t, 2H), 6.89 (m, 1H), 6.45 (t, 1H), 3.88 (d, 2H), 3.66 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:44])[CH:4]([NH:25][C:26](=[O:43])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH:34][C:35]1[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][CH:36]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][CH:36]=2)=[C:27]([CH:32]=1)[C:26]([NH:25][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1)[C:3]([OH:44])=[O:2])=[O:43]
Reactant: COC(=O)C(Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1Nc1ccc(SC)cc1
Agent: [Li+]
Agent: [OH-]
Product: CSc1ccc(Nc2ccc(Cl)cc2C(=O)NC(Cc2ccc(-c3ccccc3Oc3ccccc3)cc2)C(=O)O)cc1
Yield: 92 %

Procedure:
A solution of (2S)-(2-amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid (0.154 g, 0.307 mmol), prepared by reacting (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester and 2-amino-5-chlorobenzoic acid by the general procedure A) was reacted with 4-(methylthio)phenylboronic acid (0.130 g, 0.768 mmol), copper acetate (0.084 g, 0.460 mmol), and triethyl amine (0.215 mL, 1.535 mmol) by the general procedure G. The crude product was purified by flash column chromatography on silica gel using DCM (+25% hexane) to give 0.075 g (39%) of 2-[5-chloro-2-(4-methylsulfanyl-phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester as a colorless oil. This ester was treated with LiOH (0.019 g, 0.441 mmol) by the general procedure I to give 0.049 g (92%) of 2-[5-chloro-2-(4-methylsulfanyl-phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid. LCMS: 610 (M+1)+. 1H NMR (CDCl3) 8.94 [bs, 1H], 7.49 [d, 2H], 7.47 [d, 1H], 7.22 [m, 10H], 7.06 [d, 2H], 6.99 [d, 2H], 6.88 [d, 2H], 6.50 [d, 1H], 4.99 [m, 1H], 3.30 [m, 2H], 2.45 [s, 3H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=2[O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=2[O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:6][CH:7]=1
Reactant: COCCOc1cc(C(=O)OC)ccc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCOc1cc(C(=O)O)ccc1-c1ccc(F)cc1
Yield: 11.7 %

Procedure:
Methyl 4′-fluoro-2-(2-methoxyethoxy)-1,1′-biphenyl-4-carboxylate (D76) (494 mg) was treated with aq. 2M sodium hydroxide solution (2 ml) in ethanol (3 ml) at 90° C. overnight. After cooling, the ethanol was evaporated off and the residue dissolved in EtOAc and extracted with sat. aq. sodium bicarbonate solution. This was acidified to pH3 with 2M HCl and extracted with EtOAc which was dried over MgSO4 and concentrated in vacuo to give the title compound as a solid (55 mg). MS(ES): M-H+ 289.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[N:34]=[C:35]=[O:36]>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[NH:34][C:35](=[O:36])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C=Nc1c(F)cccc1F
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4c(F)cccc4F)cc3)cc2C1=O

Procedure:
The compound of example 19 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 2,6-difluorophenyl isocyanate. The compound of example 19 was used directly without isolation for the preparation of compound of example 20.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1>C1(C)C(C)=CC=CC=1>[N:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:4](=[O:5])[CH2:3][CH2:2][C:1]2=[O:7])=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1C
Product: O=C1CCC(=O)N1c1ccncc1
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: The mixture of 20 g of succinic anhydride, 19 g of 4-amino-pyridine, and 450 ml of xylene is refluxed for 24 hours with stirring. It is allowed to cool to room temperature and the solids are collected. They are extracted 3 times with 200 ml of methylene chloride at reflux and the combined extracts are evaporated and the residue recrystallized from ethanol, to yield the 1-(4-pyridyl)-pyrrolidin-2,5-dione.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[H][H].[OH-].[Na+]>C(O)C>[C:1]1([C@H:7]2[O:13][C:10](=[O:12])[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CC[C@@H](c2ccccc2)O1
Temperature: 40 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
In a 100 ml autoclave were charged 1.78 g (10 mmole) of 4-phenyl-4oxobutyric acid and 14 ml of ethanol. A solution separately prepared from 44.9 mg (0.05 mmole) of ##STR13## double the molar quantity of concentrated hydrochloric acid, and 5 ml of ethanol was added to the above-prepared solution in a nitrogen atmosphere to conduct hydrogenation at 35° C. and at a hydrogen pressure of 70 kg/cm2 for 230 hours. To the reaction mixture was added 8 ml of a 10% sodium hydroxide aqueous solution, followed by stirring at 40° C. for 3 hours. After cooling to room temperature, the resulting solution was extracted twice with 30 ml portions of methylene chloride. The organic layer was removed, and the aqueous layer was adjusted to a pH of 4 with a 10% hydrochloric acid aqueous solution and then again extracted thrice with 20 ml portions of methylene chloride. The combined extract was concentrated, and the residue was purified by silica gel column chromatography using hexanediethyl ether as a developing solvent to obtain 1.02 g (percent yield: 63%) of (S)-4-phenyl-γ-butyrolactone.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.ON1C2C=CC=CC=2N=N1.NC1C=CC=CC=1.[N:45]1([C:51]2[N:52]=[C:53]([CH2:58][C:59]([O-])=[O:60])[NH:54][C:55](=[O:57])[CH:56]=2)[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.[Na+]>CN(C)C=O>[N:45]1([C:51]2[N:52]=[C:53]([CH2:58][C:59]([NH:8][C:12]3[CH:11]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:60])[NH:54][C:55](=[O:57])[CH:56]=2)[CH2:46][CH2:47][O:48][CH2:49][CH2:50]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.9 %

Procedure:
370 mg of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 113 mg of 1-hydroxybenzotriazole and 0.140 ml of aniline are added to a solution of 200 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 in 3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 3 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off and dried in a rotary evaporator. After purification by silica column chromatography, eluent: dichloromethanemethanol 90/10, 161 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-phenylacetamide are obtained in the form of a white solid, the characteristics of which are the following: