Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10].N1C=CC=CC=1>C(#N)C>[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)Sc2ccc(Cl)cc2)cc1
Yield: 89.5 %

Procedure:
4-Chlorothiophenol (21.6 g) was dissolved in dry acetonitrile (500 ml) and a solution of 4-acetoxybenzoyl chloride (29.7 g) in acetonitrile (50 ml) was added. The mixture was stirred at room temperature whilst pyridine (12.1 ml) was added rapidly dropwise. When the reaction was complete the bulk of the solvents was removed by evaporation in vacuo and the residue partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulphate, and evaporated to afford the desired thioester as a pale yellow solid (41.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.ClCCCl.C(=O)([O-])[O-].[K+].[K+].[C:38](Cl)(=[O:43])[O:39][CH2:40][CH:41]=[CH2:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([NH:16][C:38](=[O:43])[O:39][CH2:40][CH:41]=[CH2:42])([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: N[C@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: C=CCOC(=O)N[C@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(R)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine was dissolved in DCE (400 uL, 0.1 M in DCE, 40 umol) and potassium carbonate added (100 mg, 723 umol, 18 eq), followed by allyl carbonochloridate (400 uL, 0.2 M in DCE, 80 umol, 2.0 eq). The reaction mixture was agitated at room temperature for 18 h and then filtered and rinsed with DCE (2×250 uL). The combined filtrate was evaporated and the residue was redissolved in 1 mL of MeOH and purified by reverse phase preparative HPLC using MeOH:water:TFA system. (R)-allyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylcarbamate was obtained as a colorless oil (13.2 umol, 33% yield). LCMS: M+calc=478.11; found=479.35.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH2:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[N+:27]([O-:28])=[N:26][C:25]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[N:24][C:23]=2[CH:35]=1)[CH3:17].FC(F)(F)C(O)=O>C(Cl)Cl.N>[CH2:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[N+:27]([O-:28])=[N:26][C:25]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[N+:24]([O-:6])[C:23]=2[CH:35]=1)[CH3:17]
Reactant: CCOc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc2c(c1)[n+]([O-])c(NCCN(C)C)n[n+]2[O-]
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 30.4 %

Procedure:
Hydrogen peroxide (70%, 0.7 mL, ca. 13.9 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (2.0 mL, 13.9 mmol) in DCM (20 mL) at 5° C. The mixture was stirred at 5° C. for 5 min, warmed to 20° C., stirred for 10 min, and cooled to 5° C. The mixture was added to a stirred solution of 1-oxide 18 (385 mg, 1.4 mmol) and trifluoroacetic acid (0.53 mL, 6.9 mmol) in DCM (20 mL) at 5° C. and the mixture stirred at 20° C. for 6 h. The solution was carefully diluted with dil. aq. NH3 solution (20 mL) and the mixture extracted with CHCl3 (5×50 mL). The organic fraction was dried and the solvent evaporated. The residue was chromatographed, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 19 (125 mg, 31%) as a red solid, mp (MeOH/EtOAc) 150-152° C.; 1H NMR 8.23 (d, J=9.6 Hz, 1 H, H-8), 7.48 (d, J=2.6 Hz, 1 H, H-5), 7.46 (brs, 1 H, NH), 7.03 (dd, J=9.6, 2.6 Hz, 1 H, H-7), 4.25 (q, J=7.0 Hz, 2 H, CH2O), 3.64 (br dd, J=6.0, 5.9 Hz, 2 H, CH2N), 2.61 (t, J=6.0 Hz, 2 H, CH2N), 2.30 [s, 6 H, (CH3)2], 1.49 (t, J=7.0 Hz, 3 H, CH3); 13C NMR δ 165.5, 150.2, 140.3, 125.6, 123.5, 120.6, 95.4, 65.4, 57.5, 45.2 (2), 35.9, 14.3; MS (FAB+) m/z 294 (MH+, 100%), 278 (30), 276 (20); HRMS (FAB+) calcd for C13H19N5O3 (MH+) m/z 294.1566, found 294.1568. Anal. Calcd for C13H19N5O3: C, 53.2; H, 6.5; N, 23.9. Found: C, 53.1; H, 6.3; N, 23.6%.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1CCO[CH:9]1[CH2:13][N:14]1[C:23]2[C:18](=[C:19]([O:24][CH3:25])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]1=[O:26]>>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][C:15](=[O:26])[N:14]2[CH2:13][CH:9]=[O:8]
Reactant: COc1cccc2c1ccc(=O)n2CC1OCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1ccc(=O)n2CC=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 15 mL of 80% aqueous trifluoroacetic acid solution, 0.44 g of 1-(1,3-dioxolan-2-ylmethyl)-5-methoxyquinolin-2(1H)-one was added, and stirred at room temperature for 5 hours. The solvent was removed under reduced pressure, ethyl acetate and water were added, the organic layer was separated, and sodium chloride was added to the aqueous layer, and extracted twice with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (5-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.CO[CH:17](OC)[CH2:18][CH2:19][C:20]#[N:21]>>[CH3:14][O:13][C:9]1[CH:8]=[C:7]2[C:4](=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12])[CH:5]=[C:19]([C:20]#[N:21])[CH:18]=[CH:17]2
Reactant: COC(CCC#N)OC
Reactant: COc1ccc(C=O)c(OC)c1OC
Product: COc1cc2ccc(C#N)cc2c(OC)c1OC

Procedure:
2,3,4-Trimethoxybenzaldehyde (9.8 g) and 3-cyano-propionaldehyde dimethylacetal (6.35 mL) were treated under the same conditions as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]1)=[O:9].[NH2:28][C:29]1[C:38]([CH3:39])=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([CH3:40])[CH:30]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl.C(N(C(C)C)CC)(C)C>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]([NH:28][C:29]2[C:38]([CH3:39])=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([CH3:40])[CH:30]=2)=[O:20])[CH2:15][CH2:16]1)=[O:9]
Reactant: COC(=O)c1cc(C)c(N)cc1C
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a stirred solution of 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (670 mg, 1.82 mmol) and methyl 4-amino-2,5-dimethylbenzoate (390 mg, 2.18 mmol) in dichloromethane (3.6 mL) and diisopropylethylamine (0.413 mL) was added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (829 mg, 2.18 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane containing from 3% to 5% methanol to provide methyl 4-{3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionylamino}-2,5-dimethylbenzoate (568 mg, 59% yield). LCMS (10-70) Rt=4.55; [M+H+] found 530.4.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]([C:10]3[C:11]([CH3:21])=[CH:12][C:13](C)=[C:14]([CH:19]=3)[C:15]([O:17][CH3:18])=[O:16])=[C:7]([CH3:9])[N:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][CH:24]1CCC(C=O)[CH2:26][CH2:25]1.CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.CC1C=C(C)C(B2OC(C)(C)C(C)(C)O2)=CC=1C(OC)=O>>[CH3:22][O:23][CH:24]1[CH2:25][CH2:26][CH:1]([C:4]2[NH:5][C:6]([C:10]3[CH:19]=[C:14]([CH:13]=[CH:12][C:11]=3[CH3:21])[C:15]([O:17][CH3:18])=[O:16])=[C:7]([CH3:9])[N:8]=2)[CH2:2][CH2:3]1
Reactant: COC1CCC(C=O)CC1
Reactant: COC(=O)c1cc(-c2[nH]c(C3CC3)nc2C)c(C)cc1C
Agent: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C3CCC(OC)CC3)nc2C)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 160.3, except 4-methoxycyclohexanecarbaldehyde (compound 300.2) was used instead of cyclopropanecarbaldehyde and methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) was used instead of except methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1).
Reaction SMILES: C([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16]([CH3:18])=[CH2:17])=[N:11]2)CCC.S(=O)(=O)(O)O.[OH-].[Na+]>O.CCOC(C)=O>[F:23][C:21]1[CH:20]=[CH:19][C:9]2[C:10]([C:16]([CH3:18])=[CH2:17])=[N:11][C:12]3[CH:13]=[CH:14][NH:15][C:6](=[O:5])[C:7]=3[C:8]=2[CH:22]=1
Reactant: C=C(C)c1nc2ccnc(OCCCC)c2c2cc(F)ccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)c1nc2cc[nH]c(=O)c2c2cc(F)ccc12
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a stirred suspension of 1-butoxy-9-fluoro-6-isopropenylbenzo[c]-1,6-naphthyridine (30 mg, 0.097 mmol) in water (0.5 ml) was added sulfuric acid (0.5 ml) (CAUTION: EXOTHERM). The reaction mixture was stirred for 15 h at 100° C. The reaction was diluted with EtOAc (30 mL) and water (30 mL). To the resulting biphasic mixture was added NaOH (0.85 g, 21 mmol) portionwise to make the aqueous layer basic. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude residue was dissolved in 3 ml DMF and 100 uL of TFA, and purified by preparative reverse phase HPLC eluting with an acetonitrile/water+(with 0.05% TFA as a modified) gradient, to afford 9-fluoro-6-isopropenylbenzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (500 MHz, DMSO-D6) δ 11.92 (br s, 1H), 9.74 (dd, 1H), 8.41 (dd, 1H), 7.64-7.60 (overlapping m, 2H), 6.78 (d, 1H), 5.70 (s, 1H), 5.22 (s, 1H), 2.25 (s, 3H). LRMS (ESI) calc'd for (C15H11FN2O) [M+H]+, 255.1; found 255.0.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH2:9]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15])[CH:10]=[CH2:11].C>O1CCOCC1>[N-:15]=[C:4]=[O:3].[CH2:9]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15])[CH:10]=[CH2:11]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: C=CCOC(=O)[C@H](C)N
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of alanine allyl ester, prepared as described by H. Waldmann and H. Kunz in Liebigs Ann. Chem., 1983, 1712-1725, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give alanine allyl ester isocyanate.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[Na+].COC1C=CC(O)=CC=1>O1CCOCC1.O>[C:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCCCCCCCCCCC(=O)O
Agent: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)C(=O)NCCCCCCCCCCCC(=O)O

Procedure:
The same procedure as described above is utilized with 5.4 g (0.052 mol) of methacryloyl chloride, 10 g (0.047 mol) of 12-aminododecanoic acid, 4.4 g (0.01 mol) of sodium hydroxide, and p-methoxyphenol in a mixed solvent (H2O:Dioxane=50:50) at 0°-5° C. Yield after recrystallized from ethyl acetate is 10 g (75%). Melting point 70.8°-72.4° C. NMR (DMSO-d6), 7.8 gamma (br s, 1H, NH), 5.5 gamma (br s, 1H, =CH2), 5.2 gamma (br s, 1H, =CH2), 3.0 gamma (t, 2H, NCH2), 2.1 gamma (t, 2H, CH2COOH), 1.7 gamma (s, 3H, CH3), 1.2 gamma (br s, 18H, (CH2)9).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[CH3:28][C:29]([CH3:42])([CH3:41])[CH2:30][O:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH3:28][C:29]([CH3:42])([CH3:41])[CH2:30][O:31][C:32]1[N:37]=[CH:36][C:35]([N:4]2[C:5](=[O:27])[C:6]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]2[CH2:1][CH3:2])=[CH:34][CH:33]=1
Reactant: CC(C)(C)COc1ccc(B(O)O)cn1
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)C)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.8 %

Procedure:
A mixture of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.7 g), [6-(2,2-dimethylpropoxy)pyridin-3-yl]boronic acid (0.61 g), copper acetate (0.71 g), pyridine (0.8 mL), triethylamine (1.4 mL), molecular sieves 4 A (1.4 g) and methylene chloride (10 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.12 g, 12%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:39]=[CH:40][CH:41]=1)[CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:38])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])[CH:22]=1>O1CCCC1.CO>[F:3][C:4]1[CH:5]=[C:6]([CH:39]=[CH:40][CH:41]=1)[CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:38])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])[CH:22]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCc2cccc(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCc2cccc(F)c2)c1
Yield: 68 %

Procedure:
In a manner similar to that of Example 19g, by reaction of 400 mg (10 mmol, 10 eq) of sodium hydroxide and methyl 3-[2-(3-fluorobenzyloxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 305 mg of 3-[2-(3-fluorobenzyloxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=73° C.). Yield=68% over the two steps.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20]OS(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:36]4[CH2:35][CH2:34][N:33]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[Cl:26])[CH2:38][CH2:37]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Reactant: Clc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(CN2CCN(c3ccccc3Cl)CC2)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 41.9 %

Procedure:
Compound 7 was prepared using the method of described in Example 3, starting with compound 2 (1.0 g, 2.60 mmol), 1-(2-chlorophenyl)piperazine (0.56 g, 2.86 mmol), and cesium carbonate (1.27 g, 3.90 mmol) to give 7 (0.53 g, 42%); C27H33Cl2N3O, LRMS (m/z)=487 (MH+).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[O:26]([C:33]1[CH:43]=[CH:42][C:36]([CH:37]=[CH:38][C:39](O)=[O:40])=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH:8][C:39](=[O:40])[CH:38]=[CH:37][C:36]2[CH:42]=[CH:43][C:33]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:34][CH:35]=2)=[CH:4]1
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Reactant: O=C(O)C=Cc1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccc(Oc2ccccc2)cc1
Yield: 55 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (1.0 g), triethylamine (0.54 mL), 4-phenoxycinnamic acid (0.94 g), WSC.HCl (0.75 g), and methylene chloride (40 mL), to give the captioned compound (0.93 g, 55%) as an oily product.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:23]>>[NH2:23]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1

Procedure:
When 2-benzoyl-benzo[b]thiophen-3-ol was reacted with the following reagents instead of with ammonium acetate under the conditions of Example 31, the title compound, m.p. 121°-122° C. (petroleum ether/ethyl acetate 2:1), was obtained with the yields given to the right below:
Reaction SMILES: [CH2:1]([C:5]1([CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7](C(OCC)=O)[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4].Cl>O1CCOCC1>[CH2:1]([C:5]1([CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[CH:7][C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CCCCC1(C)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 36 %

Procedure:
A solution of Example 27D (1.92 g, 6.35 mmol) in 1,4-dioxane (25 mL) was treated with aqueous 1N hydrochloric acid solution (25 mL) and refluxed for 3 hours. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in hot hexane and filtered. The precipitate was dried to give the title compound (0.527 g, 36%). 1H NMR (300 MHz, CDCl3) δ ppm 0.56 (m, 0.5 H) 0.70 (t, 1.5 H) 0.81 (t, 1.5 H) 0.92 (m, 1 H) 1.16 (m, 2.5 H) 1.53 (s, 1.5 H) 1.56 (s, 1.5 H) 1.85 (m, 1 H) 2.03 (m, 0.5 H) 2.26 (m, 0.5 H) 3.74 (s, 0.5 H) 3.75 (s, 0.5 H) 6.22 (s, 0.55 H) 7.44 (m, 2 H) 7.62 (m, 1 H) 8.08 (0.5, 1 H) 8.14 (m, 0.5 H). MS (DCI NH3+) m/z 248 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:4][CH:3]=1.Cl.[N:33]1([C:39](=[O:47])[CH2:40][N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:44]3[CH2:43][CH2:42][N:41]([CH2:40][C:39]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[O:47])[CH2:46][CH2:45]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Agent: Cl
Product: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 7) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone hydrochloride (Oakwood Chemicals) in an analogous manner as described in example 8. HR-MS (ES, m/z) calculated for C34H38N5O4Cl2 [(M+H)+] 650.2296, observed 650.2299.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=[C:2]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)[CH:7]=1
Reactant: Cc1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-c1cc(Cl)cc(Nc2ccc(C)cc2)n1
Temperature: 70 °C
Reaction time: 5 h
Yield: 21.1 %

Procedure:
To a mixture of 2,4-dichloro-6-(5-chloro-2-methoxy-phenyl)-pyridine (25 mg, 0.087 mmol), p-tolylamine (10.2 mg, 0.1 mmol), sodium tert-butoxide (26 mg, 0.26 mmol), and tetrahydrofuran (15 ml), degassed with argon, was added palladium acetate (15 mg, 0.066 mmol) followed by 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (30 mg, 0.048 mmol). The mixture was stirred at 70° C. for 5 hours and filtered through a pad of celite under suction. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with ethyl acetate-hexane (1:9) to provide the title compound (6.6 mg, 21% yield). 1H NMR (acetone-d6) δ 2.32 (s, 3H, CH3), 3.95 (s, 3H, CH3), 6.83–6.84 (m, 1H, Ar), 7.15 (d, 2H, J=8.2 Hz, Ar), 7.20 (d, 1H, J=8.9 Hz, Ar), 7.43 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.46 (d, 1H, J=1.5 Hz, Ar), 7.57–7.60 (m, 2H, Ar), 8.10 (d, 1H, J=2.7 Hz, Ar), 8.43 (s, 1H, NH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10](OS(C)(=O)=O)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([OH:20])(=[S:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([S:19][C:17](=[O:20])[CH3:18])[CH3:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC(C)CNC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 11.9 g (47.0 mmol) crude methanesulfonic acid 2-tert-butoxycarbonylamino-1-methyl-ethyl ester in 100 ml DMF was added to a mixture of 5.0 g (1.4 equiv.) thioacetic acid and 15.3 g (1.0 equiv.) Cs2CO3 in 150 ml DMF. The reaction mixture was stirred for 4 h at 80° C. under argon and light protection. The mixture was poured into 300 ml water and extracted twice with 300 ml ethyl acetate each. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: CH2Cl2) gave pure thioacetic acid S-(2-tert-butoxycarbonylamino-1-methyl-ethyl) ester as brown oil.