Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]C)=O)=[CH:19][CH:18]=3)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:28].[NH4+:29].N>CO>[ClH:28].[CH:1]1([O:6][C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:29])=[O:26])=[CH:19][CH:18]=3)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [Cl-]
Reactant: COC(=O)Cc1ccc(Cc2cc(OC3CCCC3)nc3c2CCC3)cc1
Reactant: [NH4+]
Agent: N
Solvent: CO
Product: Cl
Product: NC(=O)Cc1ccc(Cc2cc(OC3CCCC3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 42 h
Yield: 49.1 %

Procedure:
A 20-mL vial was charged with methyl 2-(4-((2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetate (0.038 g, 0.10 mmol) and ammonium chloride (0.017 g, 0.31 mmol). To this was added methanol (3 mL) followed by NH3 (4.0 mL, 7N in methanol, 28 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 42 hr. The crude reaction solution concentrated under reduced pressure. The residue was adsorbed onto silica then purified by chromatography on silica using dichloromethane/methanol (10:0 to 1:1) as eluent, followed by preparative HPLC (water/acetonitrile with 0.05% TFA), to afford the title compound (0.019 g, 54%) as a yellow solid. MW=386.91. M.p. 78-80° C. 1H NMR (DMSO-d6, 500 MHz) δ 7.43 (br s, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 6.83 (br s, 1H), 6.51 (br s, 1H), 5.31-5.25 (m, 1H), 3.86 (s, 2H), 3.32 (s, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.02 (quin, J=7.5 Hz, 2H), 1.96-1.86 (m, 2H), 1.73-1.63 (m, 4H), 1.62-1.53 (m, 2H); APCI MS m/z 351 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([S:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]2[CH:30]=[CH:29][C:20]([CH:21]=[C:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH3:3].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:3][CH:2]([S:4]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=2)=[CH:12][CH:13]=1)(=[O:6])=[O:5])[CH3:1]
Reactant: CC(C)S(=O)(=O)Oc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)Oc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Reaction time: 12 h
Yield: 45.9 %

Procedure:
1.2 g (2.7 mmole) 5-(4-[2-(4-(2-propanesulfonyloxy)phenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was dissolved in 250 ml ethyl acetate by heating. 6 ml acetic acid and 1 g Pd/C (5%) were added and the hydrogenation was started while the solution was warm. After 12 hours at room temperature, more of the catalyst was added. After 60 hours the reaction mixture was filtered through celite and the solvent was evaporated in vacuo. The hydrogenation was restarted with more Pd/C (10%) and ethyl acetate. After 6 hours the reaction mixture was filtered through celite and the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica gel using dichloromethane:methanol (95:5) as eluent to give 0.557 g (yield 45.9%) of the desired product.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]3([C:15]([O:17]CC)=[O:16])[CH2:14][CH2:13]3)=[O:10])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([O:4][C:5]2[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]3([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]3)=[O:10])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OC3CC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC1(C(=O)O)CC1)c1ccc(OC2CC2)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 1766 %

Procedure:
To a solution of ethyl 1-(4-cyclopropoxybenzamido)cyclopropanecarboxylate (33.7 g, 6.48 mmol) in ethanol (380 mL), add sodium hydroxide (174.7 mL, 174.7 mmol) and stir the mixture at 65° C. for 3 hours. Cool the material to ambient temperature and concentrate under reduced pressure to remove the ethanol. Acidify the residue with 10% NaHSO4. Filter the resulting solid and wash with water (3×) and diethyl ether (2×). Dry the material in a vacuum oven to give the title compound (29.9 g, 98%) as a white solid: MS (m/z): 262 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([OH:16])=O.Cl.[CH3:22][O:23][C:24](=[O:30])[C@H:25]([C@@H:27]([CH3:29])[OH:28])[NH2:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH3:22][O:23][C:24](=[O:30])[C@@H:25]([NH:26][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:19]([F:20])=[C:11]([Br:10])[CH:12]=1)[C@H:27]([OH:28])[CH3:29]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ccc(F)c(Br)c1)[C@@H](C)O
Temperature: 0 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
Diisopropylethylamine (6.8 mL, 39.0 mmol) was added to a stirred solution of 3-bromo-4-fluorobenzoic acid 1 (2.152 g, 9.83 mmol), L-threonine methyl ester hydrochloride (1.968 g, 11.6 mmol), EDCI (2218 g, 11.6 mmol) and HOBt (1.410 g, 10.4 mmol) in anhydrous DMF (60 ml) at 0° C. under N2. The solution was stirred at 0° C. for 1 h and at room temperature for 20 h. The solution was diluted with EtOAc (300 mL) and washed with 1.0 M HCl (2×80 mL), saturated NaHCO3 (2×80 mL), H2O (4×80 mL), dried over MgSO4, filtered and concentrated in vacuo to give a colorless syrup which solidified on standing to afford 3.280 g (100%) of (2S,3R)-2-(3-bromo-4-fluoro-benzoylamino)-3-hydroxy-butyric acid methyl ester 2 as a white solid, mp 73-74° C. MS (ES+) m/z 333.9 (C12H13BrFNO4+H requires 334.00).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:19][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:19][C:9]2[N:10]([CH3:22])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C1Cc2[nH]c3ccc(OC)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1Cc2c(n(C)c3ccc(OC)cc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-7-methoxycyclopent[b]indole-2-carboxylic acid ethyl ester (10 g, 0.04 mole) in 75 ml of dimethylformamide, was added sodium hydride (1.7 g, 60% in oil, 0.043 mole). After stirring at ambient temperature for two hours, a solution of methyl iodide (2.7 ml, 0.043 mole) in dimethylformamide (10 ml) was added, and the mixture was stirred at 70° C. for five hours. After cooling, the mixture was poured into 200 ml of water, stirred for five minutes, and extracted with ethyl acetate. The organic layer was washed successively with water (2×) and a saturated NaCl solution, and then dried over anhydrous MgSO4. After filtering, the solvent was evaporated to afford a dark oil (~10 g) which was eluted on a silica gel column with dichloromethane via HPLC. The desired fractions were combined and concentrated to give the product as a thick yellow oil, 6.8 g.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([NH:10][C@@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:34].[N:35]1([C:40](N)=[NH:41])C=CC=N1.C(N(CC)CC)C.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:34].[C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([NH:10][C@@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH:15][C:40](=[NH:35])[NH2:41])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC(=O)[C@@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=N)N)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Yield: 63.6 %

Procedure:
Prepared according to the method described in Example 2(f) above from (R)-N2 -(diphenylacetyl)-(R)-N-[1-(4-bromophenyl)ethyl]ornithine amide (free base, 0.42 g; 0.83 mmol; from step (d) above), 1H-pyrazole-1-carboxamidine mono hydrochloride (0.13 g; 0.83 mmol), triethylamine (0.17 g; 1.66 mmol; instead of DiPEA) and DMF (4 mL), 18 hours reaction time. The solution was concentrated under vacuum and the crude product chromatographed on silica gel using MeOH:CHCl3 :ammonium hydroxide (3:6:1). Conversion to the hydrochloride salt afforded the title compound as a white solid (0.31 g).
Reaction SMILES: C([O:5]O)(C)(C)C.[C:7]([O:11][C:12]([NH:14][C@@H:15]1[C@@H:20]([C:21]2[C:22]([C:38]([O:40][CH3:41])=[O:39])=[C:23]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:24]3[O:28][CH2:27][O:26][C:25]=3[CH:29]=2)[CH:19]=[CH:18][C@@H:17]([OH:42])[C@H:16]1[OH:43])=[O:13])([CH3:10])([CH3:9])[CH3:8]>CCCCCCCCCC.C1C=CC=CC=1.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[C:7]([O:11][C:12]([NH:14][C@H:15]1[C@H:16]([OH:43])[C@H:17]([OH:42])[C@@H:18]2[O:5][C@@H:19]2[C@@H:20]1[C:21]1[C:22]([C:38]([O:40][CH3:41])=[O:39])=[C:23]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]2[O:28][CH2:27][O:26][C:25]=2[CH:29]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OO
Reactant: COC(=O)c1c([C@H]2C=C[C@@H](O)[C@@H](O)[C@@H]2NC(=O)OC(C)(C)C)cc2c(c1OCc1ccccc1)OCO2
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: CCCCCCCCCC
Solvent: c1ccccc1
Product: COC(=O)c1c([C@@H]2[C@@H](NC(=O)OC(C)(C)C)[C@H](O)[C@H](O)[C@@H]3O[C@@H]32)cc2c(c1OCc1ccccc1)OCO2
Temperature: 60 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
t-Butylhydroperoxide in decane (5M, 0.45 ml) was added to a solution of methyl 6-[(1R,4R,5S,6R)-6-(tert-butyloxycarbonylamino)-4,5-dihydroxy-2-cyclohexen-1-yl]-4-(phenylmethoxy)-1,3-benzodioxole-5-carboxylate (280 mg, 0.55 mmol) and vanadyl acetylacetonate (7 mg, 0.026 mmol) in benzene (10 ml). After stirring for 2 h at 60° C, the reaction mixture was concentrated under reduced pressure and subjected to chromatography (hexane/ethyl acetate, 1:5) to afford 129 mg (53%) of epoxide 16 and 42 mg of recovered starting material. 1H NMR (270 MHz, CDCl3) ε 7.27~7.40 (m, 5H), 7.04 (s, 1H), 5.99 (d, J=2.3 Hz, 2H), 5.68 (bd, J=7.3 Hz, 1H), 5.24 (AB, J=11.3 Hz, Δν=16.5 Hz, 2H), 4.28 (t, J=4.99 Hz, 1H), 3.83 (m, 4H), 3.35~3.46 (m, 3H), 3.07 (d, J=10.9 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:37]2[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=2)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C(F)(F)F)cc1
Yield: 56.9 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 4-(trifluoromethyl)phenylboronic acid (0.095 g; 0.5 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.061 g (57%) of the title compound.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9](OCC)[CH3:10]>>[CH2:1]=[CH2:2].[CH2:9]=[CH:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOCC
Product: C=C
Product: C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
3,5,6,7-Tetrahydro-s-Hydrindacen-1(2H)-one (12.00 g, 0.06967 moles) was stirred in diethylether (200 mL) at 0° C. as PhMgBr (0.105 moles, 35.00 mL of 3.0 M solution in diethylether) was added slowly. This mixture was then allowed to stir overnight at room temperature. After the reaction period the mixture was quenched by pouring over ice. The mixture was then acidified (pH=1) with HCl and stirred vigorously for 2 hours. The organic layer was then separated and washed with H2O (2×100 mL) and then dried over MgSO4. Filtration followed by the removal of the volatiles resulted in the isolation of the desired product as a dark oil (14.68 g, 90.3% yield).
Reaction SMILES: Cl.[NH2:2][C:3](=[N:15][OH:16])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[O-]CC.[Na+].[NH2:21][C:22]1[C:27]2[CH2:28][CH2:29][O:30][C:26]=2[C:25]([C:31](OC)=O)=[CH:24][C:23]=1[Cl:35]>C(O)C>[NH2:21][C:22]1[C:27]2[CH2:28][CH2:29][O:30][C:26]=2[C:25]([C:31]2[O:16][N:15]=[C:3]([CH:4]3[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]3)[N:2]=2)=[CH:24][C:23]=1[Cl:35]
Reactant: CCOC(=O)N1CCC(C(N)=NO)CC1
Reactant: COC(=O)c1cc(Cl)c(N)c2c1OCC2
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1CCC(c2noc(-c3cc(Cl)c(N)c4c3OCC4)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
A mixture of intermediate 2 (10.07 g), sodium ethoxide (5.42 g) and molecular sieves (45 g) in ethanol (150 ml) was stirred for 30 minutes at RT. Intermediate 1 (9.1 g) was added and the reaction mixture was stirred and refluxed for 10 hours. The reaction mixture was cooled, filtered and the filtrate evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent evaporated, yielding 11.6 g (74%) of ethyl 4- [5-(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)- 1,2,4-oxadiazol-3-yl]-1-piperidinecarboxylate (intermediate 3; mp. 162.4° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[Li]CCCC.[CH:18](=[O:22])[CH:19]([CH3:21])[CH3:20].[Cl-].[NH4+]>C1COCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([CH:18]([OH:22])[CH:19]([CH3:21])[CH3:20])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: CC(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 106.7 %

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (2.03 g, 8.93 mmol) in dry THF (10 mL) at −78° C., under argon, was added dropwise n-BuLi (1.6 M in hexane, 13.4 mmol, 8.38 mL). The mixture was stirred for 5 minutes then isobutyraldehyde (1.22 mL, 8.38 mmol) was added and the mixture was slowly warmed up to room temperature and stirred overnight at room temperature. Aqueous ammonium chloride was added and the solution extracted with ethylacetate and the organic extract was dried (Mg2SO4), filtered and evaporated. The residue was purified on silica gel (0% to 20% ethyl acetate in hexane) to give 1.97 g of 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-2-methyl-propan-1-ol (100%). 1H NMR (300 MHz; CDCl3): δ 0.77 (d, J=6.6 Hz, 3 H), 0.90 (d, J=6.6 Hz, 3 H), 1.33 (s, 6 H), 1.95 (m, 1 H), 4.23 (s, 2 H), 4.28 (d, J=7.2 Hz, 2 H), 6.72 (d, J=8.4 Hz, 1 H), 7.03 (dd, J=8.1 Hz and 1.8 Hz, 1 H), 7.06 (d, J=1.5 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH2:30][C:31]([OH:33])=O)[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:36]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:41]=[CH:40][CH:39]=[C:38](NC)[CH:37]=1.C1C=CC2N(O)N=[N:56][C:54]=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:36]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:41]=[CH:40][CH:39]=[C:38]([CH2:54][NH:56][C:31]([CH2:30][N:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:22]=[CH:23][C:18]([NH:17][C:15]([C:10]4[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:34])([F:1])[F:35])=[CH:4][CH:5]=5)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:16])=[CH:19][CH:20]=3)[CH2:29][CH2:28]2)=[O:33])[CH:37]=1
Reactant: On1nnc2ccccc21
Reactant: CNc1cccc(-c2ccccc2)c1
Reactant: O=C(O)CN1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1)NCc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
To a stirred solution of (4-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-acetic acid (241 mg), biphenyl-3-yl-methylamine (95 mg), HOBt (87 mg), and Et3N (202 mg) in CH2Cl2 (20 mL) was added EDCl (125 mg) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3 and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with CH2Cl2/MeOH (97/3) and the solid obtained was recrystallized from EtOH to give the title compound (180 mg) as white crystals.
Reaction SMILES: [O:1]=[C:2]([N:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]>CCOC(C)=O>[O:1]=[C:2]([N:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCCCCOc1ccc(C#Cc2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)O)cc2)cc1
Solvent: CCOC(C)=O
Product: CCCCCOc1ccc(CCc2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)O)cc2)cc1
Yield: 49 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step c) but using oxo{(4-{[4-(pentyloxy)phenyl]ethynyl}benzyl)[4-(trifluoromethyl)benzyl]amino}acetic acid in EtOAc gave the title compound as a yellow oil (49%). M−(LC/MS(ESI)): 526. HPLC (Condition A), Rt: 5.62 min (HPLC purity: 74.1%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:11](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@@](=O)/N=C/c1cc2cccc(Cl)c2nc1Cl
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
To a solution of 2,8-dichloroquinoline-3-carboxaldehyde (43.0 g, 0.19 mol) in anhydrous THF (500 mL) was added titanium(IV) isopropoxide (114 mL, 0.38 mol) at r.t. After stirring for 15 minutes, (R)-(−)-2-methyl-2-propanesulfinamide (23.0 g, 0.19 mol) was added and stirring was continued for 17 h at r.t. Water (1 L) was added to the reaction mixture and the precipitate obtained was filtered and washed with DCM. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound (61 g, 97%) as a pale yellow solid. δH (CDCl3) 9.11 (1H, s), 8.83 (1H, s), 7.93 (1H, dd, J 7.54, 1.31 Hz), 7.88 (1H, dd, J 8.22, 1.31 Hz), 7.55 (1H, t, J 7.88 Hz), 1.33 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.[CH3:17][O:18][CH:19]([SiH2:22]Cl)[O:20][CH3:21]>>[CH3:17][O:18][CH:19]([SiH2:22][CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)[O:20][CH3:21]
Reactant: COC(OC)[SiH2]Cl
Reactant: Cc1cnc2c(c1)CCCC2
Agent: [Li]CCCC
Product: COC(OC)[SiH2]C1CCCc2cc(C)cnc21

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 5,6,7,8-tetrahydro-3-methylquinoline (0.01 M), butyl lithium (0.01 M) and dimethoxymethylsilyl chloride (0.015 M). The sample was distilled twice using a kugelrohr apparatus to give the title compound (0.25 g) bp 110°-120° C./0.5 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[CH:15]1([CH2:20][CH2:21][C:22]([NH:24][C:25]2[NH:26][CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=3)[C:29]=2[C:30]([NH2:32])=[O:31])=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[CH:15]1([CH2:20][CH2:21][C:22]([NH:24][C:25]2[NH:26][CH:27]=[C:28]([C:33]3[CH:34]=[CH:35][C:36]([NH:39][C:13]([NH:12][C:3]4[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=4[F:1])=[O:14])=[CH:37][CH:38]=3)[C:29]=2[C:30]([NH2:32])=[O:31])=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)c[nH]c1NC(=O)CCC1CCCC1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c[nH]c1NC(=O)CCC1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.6 %

Procedure:
0.072 cm3 (0.50 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate is added at a temperature in the region of 25° C. to 0.170 g (0.50 mmol) of 2-(3-cyclo-pentylpropionylamino)-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide in solution in 20 cm3 of tetrahydrofuran. After stirring for 48 hours at a temperature in the region of 25° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is then diluted in 50 cm3 of ethyl acetate and then washed with 50 cm3 of water and 50 cm3 of a saturated aqueous sodium chloride solution. The organic solution is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography [eluent; dichloromethane/methanol/acetonitrile (95/2.5/2.5 by volume)]. After concentrating the fractions under reduced pressure, 0.048 g of 2-(3-cyclopentylpropionylamino)-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrole-3-carboxamide is obtained in the form of a yellow powder melting at 222° C. IR (KBr), 3470; 3389; 1717; 1633; 1594; 1546; 1443; 1341; 1312; 1194; 1167; 1119; 1070 & 614 cm−1. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 1.11 (m, 2H); from 1.42 to 1.68 (m, 6H); from 1.71 to 1.85 (m, 3H); 2.40 (t, J=8.0 Hz, 2H); 5.56 (broad m, 1H); 6.39 (d, J=2.5 Hz, 1H); 7.09 (broad m, 1H); 7.30 (d, J=9.0 Hz, 2H); 7.38 (m, 1H); 7.49 (m partially masked, 1H); 7.51 (d, J=9.0 Hz, 2H); 8.62 (dd, J=2.5 and 7.5 Hz, 1H); 9.00 (broad s, 1H); 9.32 (broad s, 1H); 10.8 (broad s, 1H); 11.4 (broad s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([CH2:16][CH3:17])=[C:14]([O:18]C)[N:13]=[C:12]([O:20]C)[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:22](Br)(=[O:24])[CH3:23]>>[CH3:8][C:6]1[CH:5]=[C:4]([N:9]([C:10]2[NH:11][C:12](=[O:20])[NH:13][C:14](=[O:18])[C:15]=2[CH2:16][CH3:17])[C:22](=[O:24])[CH3:23])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CCc1c(Nc2cc(C)cc(C)c2)nc(OC)nc1OC
Reactant: CC(=O)Br
Product: CCc1c(N(C(C)=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 86 %

Procedure:
(3,5-Dimethyl-phenyl)-(5-ethyl-2,6-dimethoxy-pyrimidin-4-yl)-amine (5 g, 17.4 mmol) was refluxed with acetyl bromide (50 mL) for 18 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (2:1)) to afford 4.5 g (86%) of a white solid. m.p. 238-239° C.; 1H-NMR (200 MHz, CDCl3) δ 0.93 (3H, t, J=7.5 Hz), 2.05-2.15 (3H, m), 2.24-2.40 (8H, m), 6.94-6.99 (3H, m); m/z (EI) 301(M+).