Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[CH3:13][N:14]1[CH:18]=[C:17]([NH:19][C:20]([C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)=[O:21])[N:16]=[C:15]1[C:28](O)=[O:29].[CH3:31][O:32][C:33]([C:35]1[N:36]([CH3:50])[CH:37]=[C:38]([NH:40][C:41]([C:43]2[N:44]([CH3:49])[CH:45]=[C:46]([NH2:48])[N:47]=2)=[O:42])[CH:39]=1)=[O:34].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(Cl)(Cl)Cl.O>[CH3:31][O:32][C:33]([C:35]1[N:36]([CH3:50])[CH:37]=[C:38]([NH:40][C:41]([C:43]2[N:44]([CH3:49])[CH:45]=[C:46]([NH:48][C:28]([C:15]3[N:14]([CH3:13])[CH:18]=[C:17]([NH:19][C:20]([C:22]4[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=4)=[O:21])[N:16]=3)=[O:29])[N:47]=2)=[O:42])[CH:39]=1)=[O:34]
Reactant: COC(=O)c1cc(NC(=O)c2nc(N)cn2C)cn1C
Reactant: Cn1cc(NC(=O)c2nccn2C)nc1C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(NC(=O)c2nc(NC(=O)c3nc(NC(=O)c4nccn4C)cn3C)cn2C)cn1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
Trimethylsilyl triflate (150 μL, 0.81 mmol) was added in a single portion to a mixture of 1-methyl-4-[(1-methyl-1H-imidazole-2-carbonyl)-amino]-1H-imidazole-2-carboxylic acid (200 mg, 0.80 mmol) in anhydrous acetonitrile (8.00 mL). The solution which formed within a few moments was transferred to solid N-(1-chloro-2-methylprop-1-enyl)-N-methyl aminomethylpolystyrene (1.55 mequiv/g, 1.04 g, 1.61 mequiv). After stirring at ambient temperature for 10 minutes, an equal volume of anhydrous CHCl3 (stabilized with amylenes) was added and the mixture was filtered in an inert atmosphere. The resin was washed with an additional 10 mL of anhydrous CHCl3 (stabilized with amylenes), and the combined filtrates containing the 1-methyl-4-[(1-methyl-1H-imidazole-2-carbonyl)-amino]-1H-imidazole-2-carbonyl chloride were added dropwise to a vigorously stirred 2-phase mixture of a solution of 4-[(4-amino-1-methyl-1H-imidazole-2-carbonyl)-amino]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (171 mg, 0.62 mmol) in CHCl3 (10 mL), and a solution of Na2CO3 (170 mg, 1.60 mmol) in H2O (5 mL). The resulting reaction mixture was stirred for 5 minutes, and then was diluted with CHCl3 and H2O. The CHCl3 solution was isolated, dried (MgSO4), and concentrated to afford a 59% yield (240 mg) of 1-methyl-4-{[1-methyl-4-({1-methyl-4-[(1-methyl-1H-imidazole-2-carbonyl)-amino]-1H-imidazole-2-carbonyl}-amino)-1H-imidazole-2-carbonyl]-amino}-1H-pyrrole-2-carboxylic acid methyl ester as a very pure off-white solid. Reverse phase HPLC of this material was carried out on an Agilent 1100 system using a Vydac 4.6×250 mm Protein & Peptide C18 column eluted at 1.2 mL/min with a linear gradient of 20% MeCN:80% H2O to 40% MeCN:60% H2O over a 15 minute period. Both solvents contained 0.1% TFA. A single 304 nm HPLC peak eluted at 10.847 minutes. 1H NMR (CD3CN plus TFA): δ 10.90 (s, 1H), 10.71 (s, 1H), 9.49 (s, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.65 (m, 2H), 7.46 (d, J=1.8 Hz, 1H), 6.92 (d, J=1.9 Hz, 1H), 4.15 (s, 3H), 4.12 (s, 3H), 4.11 (s, 3H), 3.92 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14]([Cl:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)O)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(-c2noc(C)n2)c(C(=O)Cl)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoic acid (reference example 5-1) (817 mg), thionyl chloride (0.53 mL), N,N-dimethylformamide (1 drop) and toluene (10 mL) was stirred at 80° C. for 30 minutes. The mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure to give 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoyl chloride.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[OH:16][CH2:17][CH2:18][N:19]([CH2:32][CH2:33]O)[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])(=[O:22])=[O:21].N1C(C)=CC(C)=CC=1C>C(Cl)Cl.C(Cl)(Cl)Cl>[F:13][C:12]([F:15])([F:14])[S:9]([O:16][CH2:17][CH2:18][N:19]([CH2:32][CH2:33][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])(=[O:22])=[O:21])(=[O:10])=[O:8]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCO)CCO
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCOS(=O)(=O)C(F)(F)F)CCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triflic anhydride (13.6 g, 48.3 mmol) was added dropwise with stirring to a 0° C. solution of N,N-bis-(2-hydroxyethyl)-2-nitrobenzenesulfonamide (7.00 g, 24.1 mmol) from Example 16A and 2,4,6-collidine (5.85 g, 48.3 mmol) in anhydrous methylene chloride (50 mL) (J. A. Kozlowski, et al., Bioorg. Med. Chem. Lett. 12: 791-794, 2002). Reaction stirred two hours at 0° C. and then overnight at room temperature. Reaction diluted with chloroform, washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column cluting with 3:1 hexane:ethyl acetate to afford the title compound. MS (ESI) m/z 555 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32])[CH:25]=[CH:24]2>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]([N:37]2[CH2:36][CH2:35][N:34]([S:31]([C:26]3[CH:25]=[CH:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([Cl:20])[CH:22]=4)[CH:27]=3)(=[O:33])=[O:32])[CH2:39][CH2:38]2)=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1

Procedure:
In the same manner as in Referential Example 12, a reaction was conducted using 3-(1-tert-butoxycarbonylpiperidin-4-yl)propionic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]-piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=N[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])C.Cl.[CH:28]1[CH:29]=[CH:30][C:31]2N(O)N=[N:34][C:32]=2C=1>C(Cl)(Cl)Cl>[CH3:1][O:5][C:6](=[O:7])[C:29]1[CH:30]=[CH:31][C:32]([NH:34][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[C:26]([NH:24][CH2:23][CH2:22][CH3:21])[CH:28]=1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCNc1cc(C(=O)OC)ccc1NC(=O)CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
In chloroform (10 ml), 5-t-butoxycarbonylaminovaleric acid (574 mg), WSCI hydrochloride (690 mg), and HOBt (487 mg) were dissolved. Then, the resulting solution was stirred at room temperature for 30 minutes. The solution was added with 4-amino-3-propylaminobenzoic acid methyl (503 mg) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. After having been washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and saturated saline solution, the solution was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (540 mg) as a colorless viscous substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=1.N1C=CC=CC=1CC(C)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)=[C:16]([CH3:21])[CH:15]=1
Reactant: O=C1CCCc2cc(Br)ccc21
Reactant: Cc1cc(F)ccc1O
Agent: CC(=O)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(F)ccc1Oc1ccc2c(c1)CCCC2=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a suspension of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (2.0 g, 8.9 mmol), 4-fluoro-2-methylphenol (1.7 g, 13.3 mmol), 1-pyridin-2-ylacetone (240 mg, 1.8 mmol) and Cs2CO3 (5.8 g, 17.8 mmol) in DMSO (40 mL) was added CuBr (127 mg, 0.9 mmol) at rt under N2. The reaction was stirred at 100° C. overnight. The reaction was cooled, diluted with water (50 mL), and extracted with EtOAc (3×50 mL). Organics were washed with water (3×50 mL) and brine (50 mL), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (PE:EtOAc=30:1) gave 2.3 g (95%) of the title compound as a colorless oil. [M+H] Calc'd for C17H15FO2, 271. Found, 271.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1([CH:14]=[O:15])[C:13]2[N:9]([N:10]=[CH:11][CH:12]=2)[CH2:8][CH2:7]1.[C:16](OCC)(=[O:18])C.O>CN(C)C=O>[N:6]1([CH:14]=[O:15])[C:13]2[N:9]([N:10]=[CH:11][C:12]=2[CH:16]=[O:18])[CH2:8][CH2:7]1
Reactant: CCOC(C)=O
Reactant: O=CN1CCn2nccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c1N(C=O)CC2

Procedure:
To phosphoric trichloride (136 ml) was added N,N-dimethylformamide (339 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the mixture was added a solution of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-carbaldehyde (100 g) in N,N-dimethylformamide (200 ml), and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was carefully added to a mixture of ethyl acetate and water under ice-cooling, and the mixture was adjusted to pH 6. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give 2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1,7-dicarbaldehyde (102 g).
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[CH3:7].C(N(CC)C(C)C)(C)C.Cl[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:20]([O:19][CH2:18][N:6]1[C:2]([I:1])=[C:3]([CH3:7])[CH:4]=[N:5]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cn[nH]c1I
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnn(COCc2ccccc2)c1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-iodo-4-methyl-1H-pyrazole (0.5 g, 2.4 mmol, CAS RN 24086-18-8) in CH2Cl2 (5 mL) was added N,N-diisopropylethylamine (342 mg, 450 μL, 2.64 mmol) and benzyl chloromethyl ether (460 mg, 407 μL, 2.64 mmol, CAS RN 3587-60-8) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes and then poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL CH2Cl2. The layers were separated and the aqueous layer was extracted a second time with 30 mL CH2Cl2. The organic layers were washed with 30 mL brine, dried with MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30). Colorless oil (610 mg, 77%). MS (ESI): m/z=329.014 [M+H]+.
Reaction SMILES: Cl.CN.[N:4]1([C:9](=[O:29])[CH2:10][C@H:11]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C=CN=[CH:5]1.O>C(O)(C)C>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:18]([C@H:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][C:9]([NH:4][CH3:5])=[O:29])=[CH:19][NH:20]2
Reactant: COc1cccc2[nH]cc([C@@H](CC(=O)n3ccnc3)c3ccccc3)c12
Agent: CN
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CNC(=O)C[C@@H](c1ccccc1)c1c[nH]c2cccc(OC)c12
Temperature: 22 °C
Yield: 98 %

Procedure:
Methylamine hydrochloride (2.04 kg) was added, and the reactor contents were stirred at 22 degrees C. overnight. A 10 mL aliquot of the reactor contents was taken, from which HPLC indicated completion (<1% of (S)-1-Imidazol-1-yl-3-(4-methoxy-1H-indol-3-yl)-3-phenyl-propan-1-one) of the reaction. Cold tap water (64 L) was added, followed by isopropyl alcohol (8.2 kg). The reactor was set up for atmospheric distillation, and the reactor jacket was heated at 85 degrees C. and methylene chloride was removed by distillation until the reactor temperature reached 70 degrees C. The reactor was gradually cooled to 22 degrees C. and the resulting slurry was stirred for one hour. The product was filtered on a Nutsche filter, and the collected solid was washed with water-isopropyl alcohol (1:1) and dried at 70 degrees C. to afford (S)-3-(4-methoxy-1H-indol-3-yl)-N-methyl-3-phenyl-propionamide as an off-white crystalline solid, (7.094 kg, 98% yield). 1H nmr (DMSO-d6): 2.48 (d, 3H, J=4.56 Hz), 2.60-2.90 (m, 2H), 3.69 (s, 3H), 5.05 (t, 1H, J=7.95 Hz), 6.34 (m, 1H), 6.90 (m, 2H), 7.08 (m, 2H), 7.20 (m, 4H), 7.75 (bq, 1H, J=4.56 Hz), 10.8 (bs, 1H). Mp=178-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.N>C(O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(O)cc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: N
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1cc(Cl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g 3-chloro-5-nitrophenol are dissolved in 250 ml of ethanol. 11.9 g potassium carbonate and 6 ml dimethylsulphate are added and the mixture is stirred for 12 hours at ambient temperature. Then 3 ml of a 33% ammonia solution are added and then the ethanol is eliminated in vacuo. The residue is taken up in water and the precipitated solid is suction filtered and dried.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:6](=O)[C:5](NC=O)=[N:4][CH:3]=1.C([N:14]([CH2:17]C)CC)C.O=P(Cl)(Cl)[Cl:21]>>[C:17]([C:5]1[C:6]([Cl:21])=[N:8][C:2]([CH3:1])=[CH:3][N:4]=1)#[N:14]
Reactant: Cc1cnc(NC=O)c(=O)[nH]1
Reactant: CCN(CC)CC
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cnc(C#N)c(Cl)n1
Yield: 77 %

Procedure:
3-Carboxamido-2-hydroxy-6-methylpyrazine (4.09 g, 26.70 mmol), prepared by the method of Dick and Wood, J. Chem. Soc.,1379 (1955), was treated as described in Example 91A with triethylamine (5.41 g, 53.41 mmol) and 70 ml POCl3 to yield the title compound (3.16 g, 77%) as a fluffy yellow solid. mp: 63°-65° C. 1H NMR (300 MHz, CDCl3) δ2.70 (s, 3H), 8.50 (s, 1H). MS (DCI/NH3) m/e 171 (M+NH4)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH2:7])[C:4]([SH:8])=[CH:3][CH:2]=1.[C:9](O)(=O)[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11]>C1(C)C(C)=CC=CC=1>[OH:11][CH:10]([C:9]1[S:8][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[N:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: Nc1ccccc1S
Solvent: Cc1ccccc1C
Product: OC(c1ccccc1)c1nc2ccccc2s1

Procedure:
A mixture of O-aminothiophenol (23.5 g.) and dl-mandelic acid (25 g.) was refluxed in xylene with a Dean-Stark tube for two days.
Reaction SMILES: [ClH:1].[CH2:2]([CH:9]1[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N.[CH2:20]=O.Cl>C(O)=O>[ClH:1].[CH2:2]([CH:9]1[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:11]([CH3:20])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CC1CCNCC1Cc1ccccc1
Reactant: C=O
Agent: Cl
Agent: N
Solvent: O=CO
Product: CN1CCC(CC(=O)O)C(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 95 g of 3-benzyl-4-piperidine-acetic acid hydrochloride (isomeric mixture), 30 ml of concentrated ammonia solution, 900 ml of 33% formaldehyde solution and 140 ml of 90% formic acid is heated for 18 hours at boiling temperature. After cooling to room temperature and adding 120 ml of concentrated hydrochloric acid, the mixture is evaporated to dryness under reduced pressure and the residue is dried under high vacuum for 5 hours at 100°. The crude 3-benzyl-1-methyl-4-piperidine-acetic acid hydrochloride (isomeric mixture) obtained is further reacted without purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:10])=[C:7]([O:21][CH3:22])[CH:6]=1)(=[O:3])[CH3:2].[C:23](=O)([O-])[O-].[Cs+].[Cs+].[I:29]C>CN(C)C=O>[I-:29].[C:1]([NH:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N+:14]([CH2:15][CH3:16])([CH2:17][CH3:18])[CH3:23])=[O:10])=[C:7]([O:21][CH3:22])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)CCNC(=O)c1ccc(NC(C)=O)cc1OC
Reactant: CI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC[N+](C)(CC)CCNC(=O)c1ccc(NC(C)=O)cc1OC
Product: [I-]
Temperature: 80 °C

Procedure:
307 mg (1, mmol) of 4-acetylamino-N-(2-diethylamino-ethyl)-2-methoxy-benzamide is mixed in 8 ml of dimethylformamide with 358 mg (1.1 mmol) of cesium carbonate and 312 mg (2.2 mmol) of iodomethane, and it is heated under argon in a pressure vessel for 2.5 hours to a bath temperature of 80° C. After concentration by evaporation under vacuum, it is taken up in 25 ml of saturated sodium bicarbonate solution and extracted three times with 25 ml each of methylene chloride. The collected organic phase is dried, filtered and concentrated by evaporation, and 145 mg (32% of theory) of [2-(4-acetylamino-2-methoxy-benzoylamino)-ethyl]-diethyl-methyl-ammonium iodide with a melting point >300° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[F:11].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[F:11].[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1N1CCN(C)CC1
Product: COC(=O)c1ccc(N2CCN(C)CC2)cc1F
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 2,4-difluoro-benzoic acid methyl ester (4.5 g, 26.2 mmol), 1-methyl-piperazine (4.36 mL, 39.2 mmol, 1.5 eq.) and K2CO3 (3.62 g, 26.2 mmol, 1 eq.) in N,N-dimethylformamide (10 mL) was stirred at 100° C. for 4 hours. The mixture was then poured into 200 mL of water and extracted with 150 mL of EtOAc. The organic layer was separated, washed with water (100 mL) dried over sodium sulphate and evaporated to dryness. The crude was purified by flash chromatography on silica gel, using a mixture dichloromethane-MeOH-30% NH4OH 95:5:0.5 as eluant, affording 1.65 g of 2-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (first eluting, pale yellow solid) and 3.04 g of 4-fluoro-2-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (second eluting, yellow oil).
Reaction SMILES: [CH2:1]([CH:3]([CH2:31][CH3:32])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:20](O)=[O:21])[CH2:15][CH2:14]2)=[C:9]([F:30])[CH:8]=1)=[O:5])[CH3:2].CO[C:35](=O)[CH:36]([N:44]1CCN(C2C=CC(NC(=O)C(CC)CC)=CC=2F)[CH2:46][CH2:45]1)C1C=CC=C(F)C=1.[OH-].[K+].CC(O)=O>O.CO.O>[CH2:36]([N:44]([CH2:45][CH3:46])[C:20]([CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:31][CH3:32])=[CH:8][C:9]=2[F:30])[CH2:18][CH2:17]1)=[O:21])[CH3:35]
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)OC)c3cccc(F)c3)CC2)c(F)c1
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)O)c3cccc(F)c3)CC2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3cccc(F)c3)CC2)c(F)c1
Temperature: 25 °C

Procedure:
{4-[4-(2-Ethyl-butyrylamino)-2-fluoro-phenyl]-piperazin-1-yl}-(3-fluoro-phenyl)-acetic acid. A mixture of {4-[4-(2-ethyl-butyrylamino)-2-fluoro-phenyl]-piperazin-1-yl}-(3-fluoro-phenyl)-acetic acid methyl ester (0.22 g, 0.47 mmol) in water/MeOH (1:4, 5 mL) was treated with KOH (0.095 g, 1.70 mmol) and the resulting mixture was heated at reflux for 24 h. The mixture was cooled to rt and acidified to pH 6.5 with AcOH. The mixture was diluted with water and extracted with DCM. The organic layer was dried (Na2SO4) and concentrated to yield the title compound (0.24 g), which was carried forward to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH2:33].[Cl-].C(N(CC)CCCN=C=NCC)C.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:33][CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[O:18])=[CH:20][CH:21]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Reactant: NCc1ccccn1
Agent: CCN=C=NCCCN(CC)CC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(C(=O)NCc2ccccn2)cc1
Reaction time: 72 h
Yield: 27.6 %

Procedure:
To a solution of 0.5 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)benzoic acid that was synthesized under Synthetic Example 4 and 0.21 g of 2-picolylamine in 6 mL of N,N-dimethylformamide, 0.32 g of 1-(3-(diethylamino)propyl)-3-ethylcarbodiimide chloride was added at room temperature and the mixture was stirred for 72 hours. After the completion of reaction, 20 mL of ethyl acetate and 15 mL of saturated saline were added to the reaction solution, the mixture was separated to extract an aqueous layer with 10 mL of ethyl acetate whereto an organic layer was added, the resulting mixture was washed with 10 mL of water and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After purification of the resulting residue using silica gel column chromatography that was eluted with ethyl acetate-hexane (5:1) to obtain 0.17 g of aimed product as resinous matter.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH2:5][CH2:4][NH:3]1.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(N(C(C)C)C)(C)C.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:13]([O:20][NH:21][C:10](=[O:12])[CH2:9][CH2:8][C:7]1[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)CCC1=CCCNC1=O
Agent: CC(C)N(C)C(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(CCC1=CCCNC1=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 268 %

Procedure:
29 mg of 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid (g) was dissolved in 0.5 ml of DMF solution (0.171 mM). 30 mg of BnONH2.HCl (0.188 mmol), 0.033 ml of diisopropyl methylamine (0.189 mmol), 43 mg of EDC (0.224 mmol) and 5 mg of DMAP (0.041 mmol) were added thereto and the mixture was stirred for overnight at room temperature. The mixture was diluted with 7 ml of ethyl acetate and washed with 5% HCl (1 ml) and 1 ml of sat. NaHCO3 solution. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with methanol/chloroform (1:20) solvent mixture as an eluant to give 126 mg (yield: 55%) of the title compound (h).