Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:15][CH2:16][CH2:17][C:18]([OH:20])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)([Cl:23])=O>>[CH2:1]([S:15][CH2:16][CH2:17][C:18]([Cl:23])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCSCCC(=O)O
Product: CCCCCCCCCCCCCCSCCC(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 3-(tetradecylthio)propionic acid (3.02 g) and thionyl chloride (20 ml) was stirred for 30 minutes at room temperature and then evaporated under a reduced pressure to obtain 3-(tetradecylthio)propionyl chloride. The thus obtained 3-(tetradecylthio)propionyl chloride was dissolved in toluene (5 ml) and added dropwise to a mixture consisting of 2,6-diisopropylaniline (1.77 g), triethylamine (2.1 ml) and toluene (20 ml), followed by 1 hour of stirring at room temperature. The reaction mixture was washed with 3% hydrochloric acid, 10% sodium hydroxide solution and saturated brine successively and then dried on anhydrous magnesium sulfate. After removing the solvent by distillation under a reduced pressure, the resulting residue was subjected to a silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:5) and then to crystallization using isopropyl ether, thereby obtaining the title compound (2.55 g) in the form of colorless needle crystals.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:6][CH2:7][C:8]12O[CH:12]1[CH2:11][CH2:10][C:9]2=[O:14])(=[O:3])[CH3:2]>C(O)(=O)C>[C:1]([O:4][CH:10]1[C:9](=[O:14])[C:8]([CH2:7][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH2:11]1)(=[O:3])[CH3:2]
Reactant: CCCCCC(CCC12OC1CCC2=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCCC(CCC1=CCC(OC(C)=O)C1=O)OC(C)=O
Yield: 159.4 %

Procedure:
A solution of 2-(3-acetoxyoctyl)-2,3-epoxycyclopentanone (26.8 g.) [prepared as described in (g) above] in glacial acetic acid (500 ml.) was heated at reflux for 12 hours. The excess acetic acid was then removed in vacuo and the residue distilled under reduced pressure to give 5-acetoxy-2-(3-acetoxyoctyl)cyclopent-2-enone (24.7 g.), b.p. 164°-175° C./0.2 mm.Hg.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[F:22].CN(C=O)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[O:18])=[CH:15][C:14]=1[F:22]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-tert-butyl-phenylamine was added 4-bromo-3-fluoro-benzoic acid, DMF (21 mL) and EDCI and were stirred at room temperature overnight. The reaction was diluted with DCM (8 mL) and was washed with HCl (1 M, 8 mL), NaOH (1 M, 8 mL), and brine (5 mL), dried over Na2SO4, and concentrated by stream of nitrogen. The resulting viscous oil was purified by flash chromatography with increasing concentration ethyl acetate in hexanes to afford the product. LCMS calcd for C17H17FNO (m/e) 349, obsd 350 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[CH3:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4]([OH:5])=[N:14][CH:12]=[N:1][C:2]=2[N:10]=1
Reactant: NC=O
Reactant: Cc1ccc(C(=O)O)c(N)n1
Product: Cc1ccc2c(O)ncnc2n1
Temperature: 170 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of 2-Amino-6-methyl-nicotinic acid (1.44 g, 9.46 mmol) and formamide (8.0 g, 178 mmol) was stirred at 170° C. for 2 hours. After cooling, the mixture was quenched with water (4 mL). The precipitate was filtered, washed with water and dried to afford 7-Methyl-pyrido[2,3-d]pyrimidin-4-ol (0.79 g, 51%). 1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J=8.4 Hz, 1H), 8.22 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 2.75 (s, 3H). MS (APCI+) [M+H]+162.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:22][C:23](=O)[C:24]#[C:25][CH2:26][O:27][CH2:28][CH3:29]>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:23](=[O:22])[CH:24]=[C:25]([CH2:26][O:27][CH2:28][CH3:29])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOCC#CC(=O)OC
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Solvent: ClC(Cl)Cl
Product: CCOCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 4-ethoxy-but-2-ynoic acid methyl ester employing the procedure described in Example 94. [α]D25 −9.80 (c 0.5, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:22].CC1C=CC(S(O[CH2:34][C@H:35]2[CH2:37][O:36]2)(=O)=O)=CC=1>>[NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:34][C@H:35]4[CH2:37][O:36]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:22]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Product: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OC[C@H]1CO1
Yield: 16.8 %

Procedure:
The title compound (198 mg, 0.538 mmol, 16.8%) was obtained as light brown crystals from an 4-(4-amino-3-chlorophenoxy)-6-cyano-7-hydroxyquinoline crude product (1.00 g, 3.21 mmol) and (2R)-oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate, by the same procedure as in Example 7.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][N:7]=1
Reactant: Cc1cc(Cl)ncc1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ncc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a mixture of 6-chloro-4-methylpyridin-3-ol (2.00 g, 13.9 mmol) and cesium carbonate (6.81 g, 20.9 mmol) in DMF (40 mL) is added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.56 g, 15.3 mmol) at 0° C. After stirring at rt for 1 hour, the mixture is poured onto water (300 mL). The aqueous layer is extracted with EtOAc (300 mL). The separated organic layer is washed with water (200 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (9:1) to give 3.00 g (95% yield) of the title compound as white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:46]([O:48][CH3:49])=[O:47])[CH2:41][CH2:42][C:43](O)=[O:44])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:46]([O:48][CH3:49])=[O:47])[CH2:41][CH2:42][C:43]([NH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:44])=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCCNC(=O)CC[C@H](NC(=O)OCc2ccccc2)C(=O)OC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 74 %

Procedure:
A mixture of 2-[2-aminoethoxymethyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (1.61 g), ("amlodipine"), (S)-4-benzyloxycarbonylamino-4-methoxycarbonylbutanoic acid (1.28 g) [see G. H. L. Nefkens and J. F. Nivard, Rec. Trav. Chim. Pays Bas, 199, 83, 1964], 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.83 g), 1-hydroxybenzotriazole (0.59 g) and triethylamine (0.44 g) in dichloromethane (25 ml) were reacted together as described in Example 5 part (a) to give the title compound (2.0 g) as an essentially pure solid foam which was used directly in Example 1 and Preparation 2 without further purification.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([NH:31][CH3:32])(=[O:30])=[O:29])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH:31][CH3:32])(=[O:30])=[O:29])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:9]2)=[N:16][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(S(C)(=O)=O)C2)ncc1Cl

Procedure:
2-[5-Chloro-2-(10-methanesulfonyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide was prepared from 2-[2-(10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide and methanesulfonyl chloride in an analogous manner to Example 278. Product isolated as a white solid (29 mg, 83%). m.p.=135-139° C.; LCMS (m/e) 563 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.12 (s, 1H), 8.48 (d, 1H, J=8.3 Hz), 8.15 (s, 1H), 7.97 (dd, 1H, J=1.5 and 7.8 Hz), 7.61-7.55 (m, 1H), 2.65 (d, 1H, J=2.3 Hz), 7.35-7.22 (m, 2H), 7.05 (d, 1H, J=8.1 Hz), 6.94 (bs, 1H), 3.87 (m, 2H), 3.20-3.12 (m, 1H), 3.10-3.00 (m, 3H), 2.65 (d, 3H, J=5.3 Hz), 2.52 (s, 3H), 2.25-1.90 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[C:6]([N+:29]([O-:31])=[O:30])[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[N+:29]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1)[C:3]([OH:32])=[O:2])([O-:31])=[O:30]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1
Yield: 61.9 %

Procedure:
A solution of 4.5 g of 3-nitro-5-(octadecyloxy)benzoic acid methyl ester and 4 ml of 6N NaOH in 200 ml of methanol and 50 ml of dioxane was stirred at reflux for 2.5 hours. The solvents were removed at reduced pressure and the residue was acidified with 1N HCl. The solid was filtered and recrystallized from methanol-water to give 2.7 g (62% yield, mp 101°-103°) of 3-nitro-5-(octadecyloxy) benzoic acid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([CH3:26])[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([CH3:18])[N:17]=2)=[C:9]([O:34][CH2:35][CH3:36])[CH:8]=1.[CH3:37][C:38]([CH3:40])=[O:39]>O1CCCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@@:16]2([CH3:18])[C@:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([CH3:26])[NH:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:38]([OH:39])([CH3:40])[CH3:37])=[CH:8][C:9]=3[O:34][CH2:35][CH3:36])=[N:17]2)=[CH:20][CH:21]=1
Reactant: CCOc1cc(Br)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.8 %

Procedure:
To a solution of n-butyllithium (11.6 mL, 28.95 mmol, 2.5 M solution in hexane, Aldrich) in tetrahydrofuran (50 mL) at −78° C. was added dropwise a solution of rac-(4S*,5R*)-2-(4-bromo-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (1.5 g, 2.894 mmol, example 74) in tetrahydrofuran (50 mL). The brown reaction mixture was stirred at −78° C. for 15 min then acetone (2.12 mL, 28.94 mmol) was added dropwise. The color turned yellow at the end of addition. The reaction mixture was stirred at −78° C. for 30 min then quenched with water. The ice bath was removed to let the reaction warmed up to room temperature. The reaction was worked up with water and ethyl acetate. The organic layers were washed with brine and dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated to give a yellow residue. Purification of the crude residue by flash chromatography (120 g of silica gel, eluting with 100% ethyl acetate, 2-5% methanol in ethyl acetate) to give the title compound (702 mg, 49%). HR-MS (ES, m/z) calculated for C28H31N2O2Cl2 [(M+H)+] 497.1757, observed 497.1758.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=2)[N:5]=[C:4]([CH3:24])[N:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=2)[N:5]=[C:4]([CH3:24])[N:3]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(Cl)nc(C)nc1Cn1ccnc1-c1cccc(F)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)nc(C)nc1N=[N+]=[N-]

Procedure:
A solution of 124 (2.25 mmol) and NaN3 (731 mg, 11.25 mmol) in DMF (15 ml) is heated at 70° C. in a sealed tube overnight. The solvent is removed in vacuo and water (10 ml) and EtOAc (10 ml) are added to the residue. The layers are separated and the aqueous layer is extracted with EtOAc (2×10 ml). The combined extracts are washed with brine (15 ml) and dried with Na2SO4. The solvent is removed in vacuo and the resulting yellow oil (125) is used in the next step without further purification.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:8]=1[CH2:9][NH:10][C:11](=[O:17])[CH:12](OC)OC.[OH-].[Na+]>>[CH3:22][C:19]1[CH:20]=[CH:21][C:7]([CH3:6])=[C:8]2[C:18]=1[CH:12]=[C:11]([OH:17])[N:10]=[CH:9]2
Reactant: COC(OC)C(=O)NCc1cc(C)ccc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C)c2cc(O)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sulfuric acid (18 M; 3.8 mL, 68 mmol) was added to N-(2,5-dimethylbenzyl)-2,2-dimethoxyacetamide (1.17 g, 4.92 mmol) at rt, and the solution was stirred at rt overnight. The solution was poured into ice, basified with NaOH (10 N) until pH>13, extracted with Et2O (3×30 ml), and the extracts were back-extracted with water (20 ml). The aqueous layer was neutralized with HCl until pH=7-8 and extracted with EtOAc (3×30 ml). The EtOAc extracts were washed with water (2×20 ml), brine (20 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a brown solid. It was purified by prep. TLC eluting with 4% MeOH in DCM to give the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): δ=2.46 (s, 3H), 2.55 (s, 3H), 6.84 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 7.16 (d, J=7.2 Hz, 1H), 8.61 (s, 1H). MS(ES+): m/z=173.43 (100) [MH+]. HPLC: tR=2.35 min (polar—5 min, ZQ3).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:21]([N:23]([CH2:39][CH3:40])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=O)[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:22]>C(O)C.N1CCCCC1>[CH2:39]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:40]
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide as a yellow solid (72.6 mg, 54%).
Reaction SMILES: C[O:2][C:3](=[O:44])[C@@H:4]([NH:20][C:21]([C:23]1[N:24]=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1)=[CH:28][CH:27]=2)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>>[Cl:19][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:20][C:21]([C:23]3[N:24]=[CH:25][C:26]4[C:31]([CH:32]=3)=[CH:30][C:29]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][CH:35]=3)=[CH:28][CH:27]=4)=[O:22])[C:3]([OH:44])=[O:2])=[CH:7][CH:8]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc2cc(Oc3ccc(C(F)(F)F)cc3)ccc2cn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(N[C@@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)O)c1cc2cc(Oc3ccc(C(F)(F)F)cc3)ccc2cn1
Yield: 76.7 %

Procedure:
A solution of 3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-(2S)-{[6-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-propionic acid methyl ester (20 mg, 0.0321 mmol) was treated with LiOH (5 mg, 0.128 mmol) by the General Procedure to give 15 mg of 3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-(2S)-{[6-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-propionic acid as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4].CO.[Na].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28]>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:28][CH2:27][N:29]([CH2:33][CH3:34])[CH2:30][CH3:31])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(O)cc1
Reactant: CCN(CC)CCCl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(OCCN(CC)CC)cc1

Procedure:
To a solution of 1.4 g. (0.0042 mol.) of 2-n-butyl-3-(4-hydroxyphenylsulfonyl)benzofuran in 20 ml. of methanol was added 25 ml. of methanol containing 110 mg. (0.0048 g.-atom) of sodium. The reaction mixture was heated on a steam bath for 30 minutes then evaporated to dryness. The residue was dissolved in 25 ml. of toluene and ca. 1 ml. of methanol, a suspension of 0.615 g. (0.0048 mol.) of distilled 2-diethylaminoethyl chloride in 15 ml. of toluene was added and the resulting mixture was heated on a steam bath for 3 hours. The solution was filtered through MgSO4 and chromatographed on silica gel with 50:50 ether-acetone to give the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH:24]1([C:27]#[C:28][CH2:29][NH:30][C:31]2[CH2:35][S:34][C:33](=[O:36])[N:32]=2)[CH2:26][CH2:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:35]2/[C:31]([NH:30][CH2:29][C:28]#[C:27][CH:24]3[CH2:26][CH2:25]3)=[N:32][C:33](=[O:36])[S:34]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(NCC#CC2CC2)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCC#CC2CC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.5 g) in 2-propanol (20 mL) were added 4-[(3-cyclopropylprop-2-yn-1-yl)amino]-1,3-thiazol-2(5H)-one (1.29 g) and piperidinium acetate (0.64 g). The reaction mixture was stirred at 80° C. for 1 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.56 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([NH2:22])[CH:16]=2)=[O:12])([CH3:4])([CH3:3])[CH3:2].FC1C([O:31][C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][C:39]([C:43](=[O:55])[NH:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:38][CH:37]=3)=O)=C(F)C(F)=C(F)C=1F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:51]([O:50][C:48](=[O:49])[NH:47][CH2:46][CH2:45][NH:44][C:43]([C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:32](=[O:31])[NH:22][C:17]1[CH:16]=[C:15]3[C:20]([CH:21]=[C:13]([C:11](=[O:12])[NH:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:23])[NH:14]3)=[CH:19][CH:18]=1)=[CH:42]2)=[O:55])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc2ccc(N)cc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)Nc3ccc4cc(C(=O)NCCNC(=O)OC(C)(C)C)[nH]c4c3)cc2c1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
A mixture of above amine 36 and compound 33 (0.226 g, 0.44 mmol) in dry DMF (6 ml) in the presence of DIEA (77 μl, 0.44 mmol) was stirred at 55° C. for 2 days. After removal of solvent, the residue was recrystalized from MeOH-ether to give compound 37 in a quantitative yield.