Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[C:23](O)=[O:24])([CH3:19])([CH3:18])[CH3:17].C(NC1CCCCC1)(NC1CCCCC1)=O.ON1C2C=CC=CC=2N=N1.[CH3:60][CH:61]1[NH:65][CH2:64][C:63]2([CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]2)[S:62]1>ClCCl.O>[C:30]([C:27]1[CH:26]=[C:22]([C:23]([N:65]2[CH2:64][C:63]3([CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]3)[S:62][CH:61]2[CH3:60])=[O:24])[CH:21]=[C:20]([C:16]([CH3:19])([CH3:17])[CH3:18])[C:28]=1[OH:29])([CH3:31])([CH3:33])[CH3:32]
Reactant: CC1NCC2(CCN(C)CC2)S1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC1SC2(CCN(C)CC2)CN1C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of dicyclohexylcarbodiimide (985 mg, 4.77 mmol) in dry and distilled dichloromethane (10 ml) was added to a stirred solution of 3,5-di-tert-butyl-4-hydroxybenzoic acid (1.14 g, 4.55 mmol) in dichloromethane (15 ml) at room temperature under an argon atmosphere. Dicyclohexylurea began to precipitate as a white solid. 1-Hydroxybenzotriazole (645 mg, 4.77 mmol) was added and the resulting solution was stirred at room temperature for 5 min. 2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (846 mg, 4.55 mmol) in dichloromethane (5 ml) was then added and the resulting mixture was kept at room temperature overnight. The next day mixture was heated at 30° C. (temperature of water bath) for 5 hrs and then kept at room temperature for another 4 days. The resulting suspension was filtered and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 140/10/1) to give two fractions: AF723 (224 mg, 99.16% chemical purity) and a mixture of AF723 with a by-product (943 mg). The mixture of AF723 with by-product was purified by flash chromatography in a COMBI-flash system using linear gradient (silica, CH2Cl2/EtOH/NH4OH 220/10/1 to 140/10/1). After evaporation and drying under vacuum, AF723 (516 mg, 100% chemical purity) was obtained as a white solid. 1H NMR (CDCl3, 500 MHz) δ 7.27 (s, 2H, arom CH), 5.55 (m, 1H, CH—S), 5.44 (s, 1H, OH), 4.10 (m, 1H, CHH—N—CO), 3.40 (m, 1H, CHH—N—CO), 2.60 (m, 2H, CH2—NCH3), 2.28 (m, 1H, CHH—NCH3), 2.25 (s, 3H, NCH3), 2.11 (m, 1H, CHH—NCH3), 1.95-1.66 (m, 4H, two CH2—CS), 1.60 (d, J=6.15 Hz, 3H, CH3—CH), 1.44 (s, 18H, t-butyl) ppm; 13C NMR (CDCl3, 500 MHz) δ 170.78 (C═O), 155.52 (C), 135.93 (two C), 127.39 (C), 124.30 (two CH), 59.56 (C), 58.00 (CH), 56.40 (CH2), 54.23 (CH2), 52.82 (CH2), 45.88 (CH3), 37.68 (CH2), 36.50 (CH2), 34.28 (C), 30.21 (CH3), 23.99 (CH3) ppm; FTIR (HATR) 2943.89, 1619.92, 1388.67 cm−1; GC-MS (EI) 7.31 min m/z: 419 (M+1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[N:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:33][N:34](C)[CH:35]=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[N:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29]([N:34]([CH3:35])[CH3:33])=[O:30])[CH2:24][CH2:23]5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCN(CC(=O)O)CC3)cc1OCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCN(CC(=O)N(C)C)CC3)cc1OCC2
Temperature: 25 °C

Procedure:
2-(4-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetic acid (0.050 g, 0.00011 mol;) dissolved in N,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine (0.119 mL, 0.000686 mol) Dimethylamine hydrochloride (0.0373 g, 0.000457 mol) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.0521 g, 0.000137 mol). Stir at r.t. 2 h. Add sat. sodium bicarbonate, extract with ethyl acetate. Dry organics over sodium sulfate and concentrate to give 331, analyzed by rHPLC. MS: (ESI+)=466.2. 1H NMR (400 MHz, DMSO) δ 9.10 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H), 6.34 (s, 1H), 6.01-5.79 (m, 1H), 4.50 (d, J=10.0 Hz, 4H), 3.53 (s, 4H), 3.18 (s, 2H), 3.03 (s, 3H), 2.82 (s, 3H), 1.47 (d, J=6.5 Hz, 6H).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[C:27]1([CH:33]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:34]([OH:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N:42]12[CH2:49][CH2:48][CH:45]([CH2:46][CH2:47]1)[C@@H:44](O)[CH2:43]2>C1COCC1>[C:27]1([CH:33]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:34]([O:36][C@@H:44]2[CH:45]3[CH2:48][CH2:49][N:42]([CH2:47][CH2:46]3)[CH2:43]2)=[O:35])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)C(c1ccccc1)N1CCCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCC1
Reaction time: 8 h
Yield: 27.2 %

Procedure:
PS-DCC (loading: 1.25 mmol/g; 0.99 g, 1.24 mmol) was suspended in dry THF (12 ml). HOBT (0.19 g, 1.24 mmol), 2-phenyl-2-(pyrrolidin-1-yl)acetic acid hydrochloride (0.15 g, 0.62 mmol) and (R)-quinuclidin-3-ol (0.24 g, 1.86 mmol) were sequentially added. The mixture was shaken overnight and then PS-DCC was filtered washing with EtOAc and THF. The solution was evaporated and the residue was dissolved in EtOAc (30 ml) and washed with water (15 ml) and with a sat. NaHCO3 (20 ml). The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=92/8 to 85/15) to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(pyrrolidin-1-yl)acetate (53 mg, 27.2% yield) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].[OH-].[Na+]>O1CCCC1.O>[CH3:22][S:23]([NH:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])(=[O:25])=[O:24]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-amino-4-nitrobenzoate (600 mg) and triethylamine (2.9 mL) were dissolved in tetrahydrofuran (11 mL), methanesulfonyl chloride (0.51 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. Methanol (18 mL) and 1N aqueous sodium hydroxide solution (9.1 mL) were added to the obtained residue, and the mixture was stirred at 50° C.-60° C. After completion of the reaction, to the reaction mixture was added aqueous sodium hydroxide solution, and the mixture was partitioned with ethyl acetate. The aqueous layer was neutralized with diluted hydrochloric acid, and the precipitated solid was collected by filtration to give 2-methanesulfonylamino-4-nitrobenzoic acid (358 mg). Using the obtained 2-methanesulfonylamino-4-nitrobenzoic acid (358 mg) and 1-(2,4-dimethylphenyl)piperazine (262 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, N-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-nitrophenyl}methanesulfonamide (330 mg) was obtained. Then, to a solution of ethanol (5.4 mL) and water (1.8 mL) were added ammonium chloride (528 mg) and iron (379 mg), and the obtained N-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-nitrophenyl}methanesulfonamide (267 mg) was added while stirring at 60° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (268 mg).
Reaction SMILES: [CH3:1][CH2:2][O:3]C1C=CC2N(C)[C@H]3N(C)CC[C@@]3(C)C=2C=1.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=2)[CH:22]([CH3:30])[C:21]1=[O:31]>>[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][C:25]([O:29][C:2](=[O:3])[CH3:1])=[CH:26][CH:27]=2)[CH:22]([CH3:30])[C:21]1=[O:31]
Reactant: CC1C(=O)N(C)c2ccc(O)cc21
Reactant: CCOc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Product: CC(=O)Oc1ccc2c(c1)C(C)C(=O)N2C

Procedure:
A process for the preparation of eserethole of formula ##STR7## which comprises the steps of: a) acylating the compound II 1,3-dimethyl-5-hydroxy-oxindole to obtain 1,3-dimethyl-5-acyloxy-oxindole (III);
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([OH:9])[C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[CH3:14].[C:15]1([CH2:21][C:22](O)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:21]([C:22]1[NH:8][C:7]2[C:6]([OH:9])=[C:5]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:4]=[C:3]([CH3:14])[C:2]=2[N:1]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(N)c1N
Reactant: O=C(O)Cc1ccccc1
Product: Cc1cc(C(C)(C)C)c(O)c2[nH]c(Cc3ccccc3)nc12
Yield: 51.1 %

Procedure:
A mixture of 2,3-diamino-4-hydroxy-5-tert-butyltoluene (Description 11) (prepared from 12 g of 2,3-dinitro-4-hydroxy-5-tert-butyltoluene) and phenylacetic acid (30 g) was heated for 1 h at 120°-130° C. under nitrogen. The reaction product was extracted with chloroform, washed with 10% sodium carbonate, water, and dried (Na2SO4). The chloroform solution was evaporated to dryness in vacuo, and recrystallised from chloroformethylacetate-pentane to afford the title compound (9.3 g), m.p. 226°-228° C.
Reaction SMILES: CC[N:3]([C:9]1[CH:14]=[CH:13][C:12]2[C:15]([NH:17][NH:18][C:19](=[O:20])[C:11]=2[CH:10]=1)=[O:16])CCCCN>C(Cl)Cl>[CH:14]1[C:9]([NH2:3])=[CH:10][C:11]2[C:19]([NH:18][NH:17][C:15](=[O:16])[C:12]=2[CH:13]=1)=[O:20]
Reactant: CCN(CCCCN)c1ccc2c(=O)[nH][nH]c(=O)c2c1
Solvent: ClCCl
Product: Nc1ccc2c(=O)[nH][nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 100 mg activated ester-terminated dendrimer (e.g., PAMAM-CONHS) in 15 ml CH2Cl2 with 0.1ml triethylamine is added N-(4-aminobutyl)-N-ethylisoluminol (ABEI, 1.01 eq isoluminol per activated ester end group). The reaction is stirred overnight at room temperature, diluted with CH2Cl2 to 75 ml and washed with water (3×30 ml) and saturated Na2CO3 (3×30 ml). The organic layer is dried over Na2SO4and stripped of solvent to yield the dendritic isoluminol conjugate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([NH2:22])[C:20]([CH2:23][O:24][CH2:25][CH3:26])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:29](OC)([CH3:31])[CH3:30].C(O)(=O)C>C(#N)C.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([N:22]=[C:29]([CH3:31])[CH3:30])[C:20]([CH2:23][O:24][CH2:25][CH3:26])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1N
Solvent: CC(=O)O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1N=C(C)C
Temperature: 100 °C
Reaction time: 22 h
Yield: 100 %

Procedure:
A suspension of 7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (6.91 g, 19.8 mmol) in 55 mL of acetonitrile was treated with 2,2-dimethoxypropane (12.2 mL, 99.2 mmol) and 14 mL of glacial acetic acid. The reaction mixture was heated to 100° C. under an atmosphere of nitrogen. After 22 h, the reaction was cooled to ambient temperature and concentrated under reduced pressure to yield a brown oil. The oil was dissolved in 125 mL of CHCl3 and washed with saturated NaHCO3 solution (2×30 mL) and water (30 mL). The combined aqueous washes were back-extracted with CHCl3 (25 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 7.69 g of N-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine as a brown solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:10][CH:9]=1)[NH2:6].[C:23]1([C@H:29]([CH3:33])[C:30](O)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:10][CH:9]=1)[NH:6][C:30](=[O:31])[C@H:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:33]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2OC)cc1
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
A mixture of 4-(2-methoxyphenyl)-L-phenylalanine methyl ester hydrochloride (0.03 g), (S)-2-phenylpropionic acid (0.014 g), EDC (0.02 g), HOBT (0.021 g) and DIEA (0.034 mL) in DMF (5 mL) was stirred at room temperature for 18 h. DMF was removed and the residue was partitioned between EtOAc and water. The organic layer was evaporated and washed sequentially with 10% citric acid, satd. NaHCO3 and brine. The resulting organic layer was dried (MgSO4), evaporated and the residue was purified by flash column chromatography (silica gel; eluent: CH2Cl2/EtOAc 9:1) to yield N-[(S)-2-phenylpropionyl]-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (0.031 g). ESMS: m/z 417 (MH+).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:19])[NH:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20]=[O:21].C(N(CC)CC)C.O>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:19])[N:16]2[CH2:20][OH:21])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)NC(=O)CC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)N(CO)C(=O)CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
7-(tert-Butyl-dimethylsilanyloxy)-3,4-dihydro-1H-quinolin-2-one (830 mg) was suspended in DMF (13 ml), formaldehyde (4.3 ml) and triethylamine (0.083 ml) were added, and the mixture was stirred at 80° C. overnight. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=2:1) to give the title compound (36 mg) as white crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([SH:19])[N:14]=[C:13]([O:20][CH3:21])[C:12]=2[C:22]#[N:23])=[CH:7][CH:6]=1.Cl[CH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30].C(=O)(O)[O-].[Na+].O>CN(C=O)C>[C:17]([C:16]1[C:15]([S:19][CH2:25][C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([OH:31])=[O:30])=[N:14][C:13]([O:20][CH3:21])=[C:12]([C:22]#[N:23])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=1)#[N:18]
Reactant: COc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: O=C(O)c1cccc(CCl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(SCc2cccc(C(=O)O)c2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
50 mg (0.153 mmol) of the compound from Example 10A together with 29 mg (0.168 mmol) of 3-(chloromethyl)benzoic acid and 38.5 mg (0.458 mmol) of sodium bicarbonate are stirred in 0.6 ml of DMF at room temperature for 2 h. Water is added and the reaction mixture is purified by preparative HPLC (with 0.15% hydrochloric acid added).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH3:9])[CH:7]=O.[Cl:10][C:11]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl.CCCCCC>[Cl:10][C:11]1[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][CH2:7][CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: CC(C=O)c1cccs1
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(CNCc1cccc(C(F)(F)F)c1Cl)c1cccs1
Yield: 107 %

Procedure:
To a solution of 2-thiophen-2-yl-propionaldehyde (100 mg, 0.7 mmol) in dry dichloromethane (20 ml) was added 2-chloro-3-trifluoromethyl-benzylamine (30 mg, 0.14 mmol) followed by the addition of sodium triacetoxyborohydride (60.5 mg, 0.28 mmol). After the resulting mixture was stirred at room temperature overnight water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate. The combined organic layers was washed with brine, dried over sodium sulfate and concentrated in vacco. The crude mixture was purified by silica gel column chromatograph using EtOAc:Hexane/25:75 as the eluent to give 50 mg (40% yield) of the title compound as an oil. MS m/e 334.4 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[C:22]1=[O:37].[N:38]1([C:43]2[CH:44]=[CH:45][C:46](/[CH:51]=[CH:52]/[C:53](O)=[O:54])=[N:47][C:48]=2[O:49][CH3:50])[CH:42]=[CH:41][N:40]=[CH:39]1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(Cl)CCl>[N:38]1([C:43]2[CH:44]=[CH:45][C:46](/[CH:51]=[CH:52]/[C:53]([NH:20][N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:34])([F:35])[F:36])[C:22]3=[O:37])=[O:54])=[N:47][C:48]=2[O:49][CH3:50])[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: COc1nc(/C=C/C(=O)O)ccc1-n1ccnc1
Reactant: NN1CCCC(c2ccccc2C(F)(F)F)C1=O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1nc(/C=C/C(=O)NN2CCCC(c3ccccc3C(F)(F)F)C2=O)ccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 130.3 %

Procedure:
IPEA (742 μL), EDC (206 mg) and HOBT (146 mg) were added to a mixture of 1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (185 mg), (E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]acrylic acid (340 mg) and DMF (5 mL), and the reaction solution was stirred at room temperature for 14 hours. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate→ethyl acetate:methanol=9:1) to obtain the title compound (453 mg). The property value of the compound is as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.O[CH2:13][CH:14]([CH2:16]O)O.[CH3:18][CH2:19][OH:20].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH2:18]([O:7][C:6]([C:5]1[C:4]([F:11])=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:16][CH:14]=[CH:13]2)=[O:8])[CH3:19].[CH2:19]([O:20][C:6]([C:5]1[CH:9]=[C:10]2[C:2](=[CH:3][C:4]=1[F:11])[N:1]=[CH:16][CH:14]=[CH:13]2)=[O:8])[CH3:18]
Reactant: CCO
Reactant: OCC(O)CO
Reactant: Nc1ccc(C(=O)O)c(F)c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)c1cc2cccnc2cc1F
Product: CCOC(=O)c1ccc2ncccc2c1F
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a suspension of 4-amino-2-fluoro-benzoic acid (1 g, 6.38 mmol) in sulfuric acid 75% (15 mL) were added glycerol anhydrous (2.108 mL, 28.72 mmol) and sodium 3-nitrosulfonate (2.93 g, 12.8 mmol). The mixture was stirred at 100° C. for 4 h. It was then cooled down to 60° C. and EtOH was added. The mixture was then stirred at 60° C. for 45 h. The solution was poured into ice-water mixture and then basified with saturated aqueous ammonium hydroxide. It was extracted twice with EtOAc. The organic phases were joined and washed with brine, dried over Na2SO4 and concentrated. The residue was purified by MPLC eluting with a DCM/MeOH gradient to afford a yellow oil as a mixture (1:1) of 5-fluoro-quinoline-6-carboxylic acid ethyl ester and 7-fluoro-quinoline-6-carboxylic acid ethyl ester (tR 1.3 min and tR 1.1 min (conditions 6), MH+=220).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClC1C=CC=CC=1>[N+:15]([C:3]1[CH:4]=[C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[F:18])([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1[N+](=O)[O-]
Solvent: Clc1ccccc1
Product: O=C1CCC(c2ccc(NC(=O)c3ccccc3F)c([N+](=O)[O-])c2)=NN1

Procedure:
11.7 gm of 6-(4'-amino-3'-nitro-phenyl)-4,5-dihydro-3(2H)-pyridazinone wereadded in small portions to a boiling solution of 15.8 gm of o-fluoro-benzoyl chloride in 350 ml of chlorobenzene, and the resulting mixture was heated for 15 hours more. After cooling, the reaction product was suction-filtered off and boiled with ethanol for purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH3:20][C:21]1([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([N:24]3[CH2:25][CH2:26][C:21]([OH:27])([CH3:20])[CH2:22][CH2:23]3)=[O:17])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C(=O)O)cn2)c1=O
Reactant: CC1(O)CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCC(C)(O)CC3)cn2)c1=O
Temperature: 100 °C
Reaction time: 24 h
Yield: 12.6 %

Procedure:
In a 250 mL round-bottomed flask, 6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinic acid (195 mg, 695 μmol), 4-methylpiperidin-4-ol (80.0 mg, 695 μmol), HOBT (138 mg, 903 μmol) and Hunig's base (269 mg, 364 μl, 2.08 mmol) were combined with DMF (13 ml) to give a light yellow suspension. EDC (173 mg, 903 μmol) was added and the reaction mixture was heated to 100° C. and stirred for 24 h. Additional 4-methylpiperidin-4-ol (80.0 mg, 695 μmol), HOBT (106 mg, 695 μmol) and EDC (133 mg, 695 μmol) were added with 2 ml DMF. The reaction mixture was heated to 100° C. and stirred for 24 h. The reaction was cooled to 25° C. and quenched with water. The aqueous layer was back-extracted with EtOAc (3×75 mL). The organic layers were combined, washed with sat NaCl (1×50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was taken up in DCM/MeOH 9:1 and filtered. The filtrate was conc. in vacuo to give a light yellow solid. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to afford 0.033 g (13%) of the title compound as a yellow solid. (M+H)+=378/380 m/e.