Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]1[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=1[F:1])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(N)ccc2n1Cc1ccccc1F

Procedure:
27.84 g (81.33 mmol) of ethyl 1-(2-fluorobenzyl)-5-nitro-1H-indole-2-carboxylate from Example II are initially charged in 750 ml of ethyl acetate and 750 ml of ethanol. 20.51 g (325.31 mmol) of ammonium formate and 2.78 g of palladium on activated carbon are added. The mixture is boiled at reflux and, after one hour, cooled and filtered off through kieselguhr. The filter cake is washed with ethyl acetate. The solvent is removed under reduced pressure and the residue is dried.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=[O:38])[NH:17][C:18]2[CH:19]=[C:20]3[C:36](=[O:37])[NH:35][N:34]=[CH:33][C:22]4=[C:23]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[NH:24][C:25]([CH:26]=2)=[C:21]34)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[O:37]=[C:36]1[C:20]2[C:21]3[C:22](=[C:23]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:24][C:25]=3[CH:26]=[C:18]([NH:17][C:16](=[O:38])[CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)[CH:33]=[N:34][NH:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCC1CCNCC1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 82 %

Procedure:
Preparation of example 92 from title compound of Example 88 (52 mg, 0.101 mmol) and 45% TFA in CH2Cl2 (1 mL) was carried out analogously to Example 20. Isolation, also in an analogous manner, afforded the title compound (50 mg, 0.084 mmol) as a yellow powder in 82% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:11])([F:20])[F:21])=[CH:14][CH:15]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Br)ccc1Oc1ccc(C(F)(F)F)cc1
Yield: 65.1 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (2.1 g, 11 mmol) (Alfa) was reacted with 4-trifluoromethylphenol (1.9 g, 12 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(4-trifluoromethyl-phenoxy)-benzaldehyde as a yellow solid (Yield 2.47 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([OH:19])[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]1.[C:27](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C)C=O.C(OCC)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([O:19][CH3:27])[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(O)c(F)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OC)c(F)cc2c1=O
Yield: 91.5 %

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 1.00 g of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate, and 570 mg of potassium carbonate and 520 mg of dimethyl sulfate were added thereto at room temperature, after which the resulting mixture was subjected to reaction at the same temperature for 4 hours. To the reaction mixture were added 50 ml of water and 50 ml of ethyl acetate, and the organic layer was separated, washed successively with 100 ml of water and 20 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 5 ml of diethyl ether, after which crystals were collected by filtration to obtain 950 mg (yield 91.5%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 41.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16](N)=[O:17]>O>[O:17]=[C:16]1[NH:15][C:4](=[O:6])[C:3]2[C:2](=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([Cl:14])[CH:7]=2)[NH:1]1
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c(=O)c2cc(Cl)c([N+](=O)[O-])cc2[nH]1
Temperature: 180 °C
Yield: 65 %

Procedure:
A mixture of 6.0 g (27.7 mmol) of 2-amino-5-chloro-4-nitrobenzoic acid and 10.0 g (0.166 mol) of urea was heated at 180° C. for 2.5 hrs. The resulting brown mass was boiled with 200 ml of water. Subsequently, it was filtered off, washed with water and with acetone and dried in a vacuum. 4.35 g (65%) of 2,4-dioxo-6-chloro-7-nitro-1,2,3,4-tetrahydroquinazoline were obtained as a dark brown powder;
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[C@H:7]([CH3:11])[C:8]([OH:10])=[O:9]>C(#N)C>[C:1]([S:3][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: C[C@@H](Br)C(=O)O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a light green solution of potassium thioacetate (3.94 g, 34.5 mmol) in acetonitrile (150 ml) was added a solution of (R)-2-bromopropanoic acid (4.8 g, 31 mmol) in acetonitrile (12 ml) at room temperature under an argon atomosphere. The resulting white slurry was stirred at room temperature for 2 hours then filtered. The filtrate was concentrated in vacuo. The residue was diluted in ethyl acetate (100 ml), washed with a 10% aqueous solution of potassium bisulfate (50 ml) and brine, dried (sodium sulfate), and concentrated in vacuo. The crude product (4.61 g) was purified by flash chromatography (60 g--Merck silica gel, 1:45:54 acetic acid/ethyl acetate/hexane) to afford 3.7 g of the title product as a light yellow oil; [α]D =-114° (c=0.50, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C@@H:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: COC(=O)[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)Oc1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the 2-chloro-5-methylphenol (4.0 g, 28 mmol) in anhydrous THF (24 mL) at 0° C. under argon protection was added triphenylphosphine (9.5 g, 36.4 mmol), followed by addition of the (R)-methyl 2-hydroxypropanoate (3.89 g, 31 mmol). Then DIAD (8.2 mL, 42 mmol) was added slowly to the solution at 0° C. The reaction mixture was stirred at room temperature for 20 h. The solvent was removed and the crude was purified by flash chromatography (AcOEt/hexane 0˜30%) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:25]([C@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:27])=[O:26]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@H](Cc1ccccc1)C(=O)O
Yield: 45 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with D-phenylalanine to provide the title compound in 45% yield as yellow needles (recrystallization from MeOH/water).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]([N:8]2[C@@H:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][O:10][C:9]2=[O:20])=[O:7])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1>[CH:1]1([CH2:4][C@H:5]([C:29](=[O:31])[CH3:30])[C:6]([N:8]2[C@@H:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][O:10][C:9]2=[O:20])=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(CCC1CC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)[C@@H](CC1CC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Under a nitrogen atmosphere, a solution of the (4S)-3-(3-cyclopropyl-1-oxopropyl)-4-(phenylmethyl)-2-oxazolidinone (6.01 g, 22.0 mmol, described in example 3) in anhydrous THF (10 mL) was added to a cold (-78°) stirred solution of lithium diisopropylamide (963 mg, 9.0 mmol) in anhydrous THF (10 mL). The mixture was stirred at -78° for 45 min and then transferred by cannula into a cold (-78°) solution of acetyl chloride (0.86 mL, 12 mmol) in anhydrous THF (5 mL). The resultant mixture was stirred for 15 min at -78° C., then quenched with a saturated aqueous solution of NH4Cl, allowed to warm to room temperature (20°-22°) and diluted with Et2O. The layers were separated and the aqueous phase was extracted with Et2O.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:5][CH:4]=1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40]>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:37]3[CH2:38][CH2:39][NH:34][C:35](=[O:40])[CH2:36]3)=[CH:8][CH:7]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Reactant: O=C1CNCCN1
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CN3CCNC(=O)C3)cc2)C1)c1cc(F)cc(F)c1
Temperature: 20 °C
Reaction time: 96 h
Yield: 39.1 %

Procedure:
The operation is carried out as described in Example 87, but by stirring the reaction mixture for 4 days at 20° C., starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane, and 0.024 g of piperazin-2-one. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.022 g of 1-{(R*)-(4-chlorophenyl)[4-(piperazin-2-on-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (400 MHz, CDCl3, δ in ppm) 2.62 (t, J=5.5 Hz, 2H), 2.80 (s, 3H), 3.11 (s, 2H), 3.34 (mt, 2H), 3.51 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.51 (s, 1H), 5.76 (unresolved complex, 1H), 6.84 (broad t, JHF=9 Hz, 1H), 6.98 (mt, 2H) from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:7][CH2:6]1)=[N+]=[N-].Cl.[H][H]>[Pd].C(O)C.O>[NH2:1][CH2:4][C@@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:9][CH2:10]1
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](CN=[N+]=[N-])CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCOC(=O)[C@H]1CC[C@@H](CN)CC1

Procedure:
A mixture of butyl cis-4-(azidomethyl)cyclohexanecarboxylate (27.85 g, 116 mmol), 6N hydrochloric acid (39 ml, 234 mmol) and 10% palladium on carbon (3.78 g) in ethanol (500 ml) was hydrogenated (hydrogen balloon) for 2.5 days. The catalyst was removed by filtration through Celite. The filter cake was washed with ethanol (3×50 ml) and the filtrate was concentrated under reduced pressure to give a gum. The gum was taken up in water (250 ml) and washed with ether (250 ml). The aqueous layer was basified to pH 10 with 10N sodium hydroxide solution and extracted with ethyl acetate (3×250 ml). The ethyl acetate layer was washed with water (100 ml) and brine (100 ml), dried (sodium sulfate), filtered, and the solvent was evaporated under reduced pressure to give butyl cis-4-(aminomethyl)cyclohexanecarboxylate (15.25 g, 62%) as a gum: 1H NMR (CDCl3) 4.08 (2H, t, J 7 Hz), 2.57 (2H, d, J 8 Hz), 2.02 (2H, m), 1.66-1.51 (6H, m), 1.45-1.23 (5H, m), 0.94 (3H, t, J 7 Hz). MS: 214.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4](/[CH:7]=[CH:8]/[C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:3]1[CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23].[CH2:26]([Mg]Br)[CH2:27][CH2:28][CH2:29][CH3:30].[Cl-].[NH4+]>O1CCCC1>[OH:15][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])/[CH:8]=[CH:7]/[C@H:4]1[CH2:5][CH2:6][C:2](=[O:1])[N:3]1[CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCCCC(=O)/C=C/[C@H]1CCC(=O)N1CCSCCCC(=O)OC
Reactant: CCCCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC(O)(/C=C/[C@H]1CCC(=O)N1CCSCCCC(=O)O)CCCCC
Reaction time: 1 h

Procedure:
To a −24° C. tetrahydrofuran (38 mL) solution of enone (from Example 1, step 3, 1.52 g) was treated with n-pentylmagnesium bromide (1.8 mL, 2 M ether solution from Aldrich). After 1 hour, the mixture was poured into aqueous ammonium chloride and extracted with ethyl acetate. Following drying and filtration, the desired alcohol (780 mg) was obtained after silica gel chromatography (elute with 5% methanol in ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].[CH3:18][CH2:19][C:20](=O)[CH2:21][CH3:22].C(N(CC)CC)C.C([BH3-])#N.[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[C:2]([NH:1][CH:20]([CH2:21][CH3:22])[CH2:19][CH3:18])[CH:7]=1)=[O:9]
Reactant: CCC(=O)CC
Reactant: COC(=O)c1ccc(N2CCCC2=O)c(N)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)Nc1cc(C(=O)OC)ccc1N1CCCC1=O
Yield: 25 %

Procedure:
A solution of 1-(2-amino-4-methoxycarbonylphenyl)pyrrolidin-2-one (0.5 g, 2.1 mmol) from example 2, 3-pentanone (0.19 g, 2.2 mmol) and triethylamine (0.44 g, 4.3 mmol) in 10 mL of dry dichloromethane was treated with 1 m solution of titanium tetrachloride (3.5 mL, 3.5 mmol) in dichloromethane. The resulting mixture was stirred at ambient temperature for 18 h after which time sodium cyanoborohydride (0.41 g, 6.5 mmol) was added. Stirring was continued for an addition 3 h. The reaction mixture was quenched with 1 N sodium hydroxide (2 mL) and the organic layer was separated and concentrated under vacuum. The residue was extracted with ethyl acetate (3×30 mL) and the combined extracts were dried and concentrated to give an oil which was purified by column chromatography (silica gel; 10% ethanol in ether) to yield 0.16 g (25%) of 1-[4-methoxycarbonyl-2-(3-pentylamino)phenyl]pyrrolidin-2-one.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH2:50]([SH:53])[CH2:51][CH3:52].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:46]([N:5]1[C:4](=[O:49])[CH:3]=[C:2]([S:53][CH2:50][CH2:51][CH3:52])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]1=[O:45])[CH2:47][CH3:48]
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 56 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (1 g), propylmercaptan (0.17 ml) and potassium carbonate (0.25 g) in acetonitrile (10 ml) was heated under reflux for 3 hours with stirring. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (30 ml) and then 1N hydrochloric acid (3.0 ml) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless powders (0.4 g, 56%).
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([CH2:19][N:20]3[CH2:25][CH2:24][C:23]([OH:35])([CH2:26][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:22][CH2:21]3)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36](OC(=O)C)(=[O:38])[CH3:37].N1C=CC=CC=1>C(Cl)Cl>[C:36]([N:7]([CH:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([CH2:19][N:20]2[CH2:25][CH2:24][C:23]([OH:35])([CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:22][CH2:21]2)[CH2:9]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: OC1(CCCc2ccccc2)CCN(CC2CC(NC3CCCCC3)CC2c2ccccc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(C1CCCCC1)C1CC(CN2CCC(O)(CCCc3ccccc3)CC2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(RS and SR)-(cyclohexylamino)-3-(SR)-((4-hydroxy-4-(3-phenylprop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane (prepared as in Example 43A) in methylene chloride (2 mL) was added acetic anhydride (0.17 mL, 1.67 mmol) and pyridine (0.17 mL, 2 mmol). The reaction was stirred at rt for 16 h. It was then diluted with methylene chloride and quenched with 1N NaOH. The mixture was washed with 1N NaOH and brine, dried over sodium sulfate and evaporated to dryness. The sample was purified by HPLC and the fractions containing the title compound by HPLC/MS were combined and evaporated.
Reaction SMILES: C([O:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)C.[CH2:11](I)[CH3:12]>>[CH2:11]([CH:9]1[CH2:8][CH2:7][C:6](=[O:10])[CH2:5][C:4]1=[O:3])[CH3:12]
Reactant: CCOC1=CC(=O)CCC1
Reactant: CCI
Product: CCC1CCC(=O)CC1=O

Procedure:
The title compound (D12) was prepared from 3-ethoxy-2-cyclohexen-1-one and ethyl iodide using a procedure similar to that described in Description 11. Product was used in the preparation of D14 without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]3)[CH:19]=[C:18]([F:31])[CH:17]=1)[C:10]([CH3:33])([CH3:32])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[F:31][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:32])([CH3:33])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[C:20]([N:22]2[CH2:23][CH2:24][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:27]2)[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(N3CCN(C(C)C)CC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2cc(F)cc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
A mixture of 2-[3-fluoro-5-(4-isopropyl-piperazin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.27 g, 0.60 mmol), lithium hydroxide hydrate (0.25 g, 6.0 mmol), water (2 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-fluoro-5-(4-isopropyl-piperazin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (89 mg, 35%) as a white solid: LC/MS mrn/e calcd for C25H32FN3O2 (M+H)+: 426.6, observed: 426.3.
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([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.C(N(C(C)C)C(C)C)C.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36].CS(C)=O>C1C=CC=CC=1>[C:34]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:38])[CH:35]([CH3:37])[CH3:36]
Reactant: CCOC(=O)CCCCCNC(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCN(C(=O)C(C)C)C(c1ccccc1)c1ccccc1
Yield: 91.7 %

Procedure:
Analogously to Example 19, 7 g of ethyl 6-benzhydrylaminocaproate and 3.1 g of ethyl diisopropylamine are dissolved in 100 ml of benzene and reacted with 2.5 g of isobutyryl chloride. As reaction product one obtains 7.8 g of ethyl N-isobutyryl-6-benzhydrylaminocaproate as a viscous non-distillable oil. The saponification of this ester yields 6.1 g (77%) of N-isobutyryl-6-benzhydrylaminocaproic acid (M.P. 106° to 107°).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[O:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1.O>[O:26]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1ccccc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3Oc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A degassed solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Inter-mediate 1; 74 mg, 0.2 mmol) in dioxane (4 mL) and a degassed solution of potassium carbonate (83 mg) in water (0.4 mL) were added to a reaction vial containing (2-phenoxy)phenylboronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.; 128 mg, 0.6 mmol). The solution was degassed and bis(tri-cyclohexylphos-phine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 7 mg, 0.01 mmol) was added. The mixture was heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica, and washed with dioxane (1 mL) and dimethylacetamide (1 mL). 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl (0.8 mL) was added. The solvent was evaporated and the residue was triurated with 50% aqueous methanol to give 3-(2′-phenoxy-biphenyl-4-yloxymethyl)-benzoic acid. Mass spectrum MH+=397.