Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([O:29]C)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>CN1CCOCC1.C(OCC)(=O)C.O>[Si:5]([O:18][C@H:19]1[CH2:20][C:21]2[C:22]([OH:29])=[CH:23][CH:24]=[CH:25][C:26]=2[CH2:27][CH2:28]1)([C:1]([CH3:3])([CH3:4])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc2c1C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC2
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)[Si](O[C@@H]1CCc2cccc(O)c2C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of Example 26B (0.9 g, 2.2 mmol) in N-methylmorpholine (7 mL) was treated with potassium carbonate (0.3 g, 2.2 mmol) and thiophenol (0.23 mL, 2.24 mmol), and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate, and the combined organic extract was washed three times with water and once with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel (5 to 20% ethyl acetate-hexane, eluant) to afford 0.45 g (52% yield) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 9.11 (br, 1H), 7.64 (m, 4H), 7.41 (m, 6H), 6.85 (t, J=7.6 Hz, 1H), 6.45-6.56 (m, 2H), 4.06 (m, 1H), 2.70-2.86 (m, 2H), 2.45-2.54 (m, 2H), 1.73 (m, 2H), 0.97 (s, 9H). MS (DCI+) m/z 403 (M+H)+, 420 (M+NH4)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])C=O)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:15].OO>CO>[CH:1]([C:4]1[CH:5]=[C:6]([OH:15])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C=O)cc1C(C)C
Agent: OO
Solvent: CO
Product: COc1ccc(O)cc1C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-isopropyl-4-methoxybenzaldehyde (12.5 g, 70 mmol) in MeOH(140 mL) was added concentrated sulfuric acid (1.2 mL) followed by dropwise addition of 30% by wt aqueous hydrogen peroxide(6 g, 20 mL, 176 mmol). The mixture was left to stir at ambient room temperature. After 3 hours, the mixture was concentrated in vacuo to about ⅓ of the reaction volume. The concentrate was partitioned between EtOAc (100 mL) and brine (50 mL). The EtOAc extract was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give 13.5 g of dark oil as crude product. The crude product was purified by chromatography (250 g silica gel, 10% EtOAc in hexane) to afford 10.1 g (86%) of compound 1c as a thick oil that eventually solidified.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([NH:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])=[O:22])=[CH:15]2>C(OCC)(=O)C>[N:5]1([CH2:4][CH2:3][CH2:2][NH:1][C:25]([CH:24]([NH:23][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=3)=[O:22])[CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NCCCN1CCOCC1
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccccc1)C(=O)NCCCN1CCOCC1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h

Procedure:
4-(3Aminopropyl)morpholine (0.34 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.30 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) substituting the following workup: the reaction was diluted with ethyl acetate, the resulting solution washed three times with 2 N NaOH and once with brine, dried over Na2SO4, and concentrated. The residue was stirred under ether for 1 hour, the solid filtered and dried: Yield 125 mg, 87%; HPLC (60/40) 2.85 minutes (98%); PBMS 469/471 (MH+, 100/90%);
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[N:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C=O)C.O>[Cl:24][CH2:23][CH2:22][CH2:21][N:10]1[CH2:9][CH2:8][N:7]2[C:3]([C:2]([F:12])([F:1])[F:13])=[N:4][N:5]=[C:6]2[CH2:11]1
Reactant: ClCCCBr
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2n1CCN(CCCCl)C2
Temperature: 80 °C
Yield: 30 %

Procedure:
To a solution of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (1.90 g) in DMF (10 mL) was added K2CO3 (2.35 g) and 1-bromo-3-chloropropane (1.70 mL) at rt. The reaction mixture was heated at 80° C. for 3 h, diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4 for 1 h, and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as transparent liquid (0.68 g, 30.00%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[C:5]#N.[OH2:13].S(=O)(=O)(O)[OH:15]>>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[C:5]([OH:15])=[O:13]
Reactant: O
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(F)c(F)c(Br)c1Cl
Product: O=C(O)c1cc(F)c(F)c(Br)c1Cl
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A solution of 3-bromo-2-chloro-4,5-difluorobenzonitrile (9.8 g) in concentrated sulfuric acid (10 ml) was stirred at 100° C. for 35 minutes. After cooling, 18N sulfuric acid (50 ml) and water (10 ml) were added to the reaction mixture. The reaction mixture was stirred at 100° C. for 4 hours and then poured into ice water (300 ml). The resulting precipitate was collected by filtration, washed with water sufficiently and recrystallized from dichloromethane-n-hexane to give the title compound (9.24 g) as colorless prisms, mp 137.5°-139.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[N:4]=[C:5]([S:29][CH3:30])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([OH:28])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:39][CH3:40].O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[N:4]=[C:5]([S:29][CH3:30])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:39][CH3:40])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OC)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OC
Temperature: 25 °C
Reaction time: 21 h

Procedure:
After dissolving 1.0 g of {2-(3-hydroxy-4-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 10 ml of DMF, 473 mg of potassium carbonate and 219 μl of iodoethane were added and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (983 mg, isomeric mixture) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2](=[NH:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1CCN2C(=NCCC2)CC1.C(O[CH:24]=[CH:25][C:26](=O)[C:27]([F:30])([F:29])[F:28])C>C(#N)C>[NH2:9][C:2]1[N:1]=[C:26]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:24][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: CCOC(=O)CC(=N)N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1ccc(C(F)(F)F)nc1N
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
19.5 g (0.12 mol) of ethyl 3-amino-3-iminopropanoate (described in Chemical and Pharmaceutical Bulletin, vol. 43, No. 5, p. 793 (1995)) was added to 100 mL of acetonitrile, and 18.6 g (0.12 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto at room temperature. The resulting mixture was stirred for 5 minutes. 20.6 g (0.12 mol) of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one was added to the above mixture, and 18.6 g (0.12 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto. The resulting mixture was stirred for 3 hours at 80° C. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was concentrated to half the original volume. Ice water was added thereto. Crystals precipitated therefrom were separated by filtration, and were dissolved in ethyl acetate. The filtrate was extracted with ethyl acetate. The solution having the crystals dissolved therein and the organic phase extracted were combined, and the resultant was washed with brine, and then was dried and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:9 to 1:4), and thus 17.8 g of the title compound was obtained as colorless crystals (yield: 62%).
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:6]([NH:8][C@H:9]([C:14](OC)=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])[CH2:3][CH2:4][CH3:5].[NH3:25]>CO>[C:21]([O:20][C:18]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:25])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])[CH2:3][CH2:4][CH3:5])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: N
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)OC
Solvent: CO
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(N)=O
Reaction time: 8 h

Procedure:
1.81 g (5 mmoles) of BOC-Nva-Met-OMe are dissolved in 20 ml of methanol, and gaseous ammonia is introduced into the solution for 0.5 hours under ice cooling. The reaction mixture is allowed to stand at room temperature overnight, and then stored in a cold place for some hours. The separated crystalline product is filtered off to obtain 1.27 g of the desired product. The filtrate is evaporated, and the residue is recrystallized from 5 ml of ethanol to obtain further 0.35 g of the product. Thus 1.62 g (93%) of BOC-Nva-Met-NH2 are obtained; m.p.: 166°-167° C., Rf2 =0.57, [α]D25 =-40.9° (c=1%, in methanol).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:15][C:12]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([N:20]4[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]4)[C:3]2=[N:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: Cc1cnc2c(Cl)nc3ccccc3n12
Reactant: CN1CCNCC1
Product: Cc1cnc2c(N3CCN(C)CC3)nc3ccccc3n12

Procedure:
By reaction of 4-chloro-1-methylimidazo[1,2-a]quinoxaline (example 2) with N-methylpiperazine, according to a procedure that is similar to that followed in example 3, there is obtained 1-methyl-4(N'-methylpiperazinyl)imidazo[1,2-a]quinoxaline. m.p. (DSC)=108.0° C.(onset); IR (KBr): 2928, 1535, 1510 cm-1 ; 1H-NMR (CDCl3): δ8.1 (1H,dd), 7.7 (1H,dd), 7.4÷7.0 (3H,m), 4.35 (4H,t), 2.85 (3H,s), 2.6 (4H,t), 2.3 (3H,s); UV (EtOH): λmax =228, 248, 279, 309, 325 nm. Elementary analysis for C16H19N5 (m.w. 281.36): calcd. C 68.30, H 6.81, N 24.89%; found C 68.37, H 7.15, N 25.05%.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][C:19]=1[CH3:27].Cl>C(OC)(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:25][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)=[C:19]([CH3:27])[CH:20]=1)=[O:26]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(-c2ccco2)c(C)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1ccco1
Reaction time: 20 h

Procedure:
To a stirred solution of ethyl trifluoroacetate (0.66 g, 4.67 mmol) in t-butylmethylether (15 mL) was added sodium methoxide (28 wt. % solution in methanol; 1.2 mL, 4.98 mmol) over 2 min. A solution of 1-[4-(2-furyl)-3-methylphenyl]ethanone in t-butylmethylether (4 mL) was added dropwise over 5 minutes, and the mixture was stirred for 20 hours. 2N HCl (10 mL) was added, and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give 1.12 g of brown oil. The compound was used for next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]#[N:20])[S:8][C@H:7]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:31]=1.C[Sn]([N:36]=[N+:37]=[N-:38])(C)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]3[NH:38][N:37]=[N:36][N:20]=3)[S:8][C@H:7]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:31]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC#N)S[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)CN1C(=O)[C@@H](Cc2nnn[nH]2)S[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Yield: 71.2 %

Procedure:
A heterogeneous mixture of trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetonitrile (75 mg, 167 μmol), trimethyltin azide (70 mg, 334 μmol) and toluene (2 mL) was heated at reflux for 18 hours. Reaction mixture concentrated under reduced pressure and purified by flash column chromatography (80:15:1 chloroform/methanol/ammonium hydroxide) to yield a clear oil which was taken up in ethyl acetate, washed with 0.5 N hydrochloric acid, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 58.5 mg (71 %) of the title compound as a white powder.
Reaction SMILES: O.[Br:2][C:3]1[CH2:4][CH:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]([C:16]([C:18](OCC)=[O:19])=[O:17])[CH:8]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:7][CH2:6]2>CC(C)=O.[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:2][C:3]1[CH:4]=[C:5]2[CH2:6][CH2:7][CH:8]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:9]3[C:16](=[O:17])[C:18](=[O:19])[NH:13][C:11]([CH:12]=1)=[C:10]23
Reactant: CCOC(=O)C(=O)N1C2=C([N+](=O)[O-])C=C(Br)CC2CCC1CC(=O)OC
Agent: [Ti+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a mixture of 20% aqueous titanium trichloride (670 g, 0.867 mol), water (500 mL), and acetone (500 mL) was added dropwise a solution of 6-bromo-2-methoxycarbonylmethyl-8-nitro-N-ethoxalyltetrahydroquinoline (52.0 g, 0.121 mol) in acetone (600 mL) at 0° C. The mixture was stirred overnight at room temperature, concentrated to ca. 1 L and diluted with water (1 L). The precipitates formed were collected by filtration, washed with water, and dried in vacuo to give 35.2 g of the title compound. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate to give 6.0 g of the title compound (total 89%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=[S:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15]1([CH:21]2[O:23][C:22]2(C#N)C#N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[OH-:2].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[C:11]1[S:14][C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:22]([OH:23])[N+:10]1=[N:9][CH:8]=2)([O-:3])=[O:2]
Reactant: N#CC1(C#N)OC1c1ccccc1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c(=S)c2c1
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc2cn[n+]3c(O)c(-c4ccccc4)sc3c2c1
Product: [OH-]

Procedure:
0.41 g of 7-nitro-1(2H)-phthalazinethione and 0.37 g of 3-phenyl-2,2-oxiranedicarbonitrile in 10 ml of acetone are heated under reflux for 30 hours. After cooling in an ice-bath, the violet crystals obtained are removed by filtration under suction, washed with ether and dried in vacuo. There is obtained 9-nitro-3-hydroxy-2-phenylthiazolo[2,3-a]-phthalazin-4-ium hydroxide (internal salt) of m.p. 303°-305°.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:30])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3cc(Cl)ccc3Cl)c2O1

Procedure:
The title compound was prepared (0.034 g, 27%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dichlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.16 g, 0.34 mmol) and methylamine (0.107 g, 3.4 mmol). mp 158-160° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:8][CH2:9][C:10](=[O:13])[NH:11][N:12]=2)=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24][Br:25])=[O:23])=[CH:18][CH:17]=1>C(O)C>[Br-:25].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24][N+:1]2[CH:6]=[CH:5][C:4]([C:7]3[CH2:8][CH2:9][C:10](=[O:13])[NH:11][N:12]=3)=[CH:3][CH:2]=2)=[O:23])=[CH:18][CH:17]=1
Reactant: O=C1CCC(c2ccncc2)=NN1
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)CC3)cc2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
4,5-Dihydro-6-(4-pyridyl)-pyridazin-3(2H)-one (175 mg, 1 mmol) and 4'-methoxyphenacyl bromide (252 mg, 1.1 mmol) were dissolved in absolute ethanol (5 ml), refluxed for two hours and then stirred at room temperature overnight. The resulting precipitate was collected by filtration and washed with absolute ethanol to obtain the titled compound (350 mg) as brown columns.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[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>>[F:19][C:18]([F:20])([F:21])[CH2:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:31])=[O:30])=[CH:9][CH:10]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:37]2[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Product: O=C(O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 552.2[M−H]−.
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)(O)=[O:2].C(Cl)(=O)C(Cl)=O.[NH2:41][C:42]1[NH:46][N:45]=[N:44][N:43]=1.N1C=CC=CC=1>ClCCl>[NH:43]1[C:42]([NH:41][C:1]([C:4]2[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([O:18][CH:19]([C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:14][CH2:13]3)=[CH:6][CH:5]=2)=[O:2])=[N:46][N:45]=[N:44]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc(OCCCN2CCC(OC(c3ccc(Cl)cc3)c3ccccn3)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1nnn[nH]1)c1ccc(OCCCN2CCC(OC(c3ccc(Cl)cc3)c3ccccn3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To 0.84 g (1.75 mmol) of 1-[3-(4-carboxyphenoxy)propyl]-4[(4-chlorophenyl)-2-pyridylmethoxy]piperidine dissolved in 8 ml of dichloromethane was added dropwise 1.5 ml of oxalyl chloride under cooling in an ice bath. The mixture was stirred at 0° C. for 0.5 hour and then at room temperature for 0.5 hour, and concentrated under reduced pressure. The residue was added dropwise to a mixed solution of 0.15 g (1.76 mmol) of 5-amino-1,2,3,4-tetrazole dissolved in 10 ml of dichloromethane and 5 ml of pyridine under cooling in an ice bath. After completion of the dropwise addition, the mixture was stirred at 0° C. for 2 hours and then at room temperature for 2 hours, and concentrated under reduced pressure. The residue was applied to silica gel column chromatography using a mixed solvent of chloroform and methanol in a volume ratio of 20:1 and then using a mixed solvent of chloroform, methanol and 28% aqueous ammonia in a volume ratio of 100:10:1 as eluents to obtain 0.54 g (yield: 57%) of 1-{3-{4-[N-(1,2,3,4-tetrazol-5-yl)carbamoyl]phenoxy}propyl}-4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine as an orange foamy product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])[C:7]2=[O:12].CN(C)C=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:34])[C:31](O)=[O:32])=[CH:26][C:25]=1[C:35]([F:38])([F:37])[F:36].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CCOC(C)=O>[NH2:16][C:14](=[O:15])[C@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:31](=[O:32])[CH:30]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([C:35]([F:36])([F:37])[F:38])[CH:26]=2)[CH3:34])[C:7]1=[O:12])[CH3:17]
Reactant: CC(C(=O)O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[C@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C(=O)Nc1cccc2c(=O)n([C@H](C)C(N)=O)ccc12)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)propanamide (183.1 mg, 0.0007522 mol) in N,N-dimethylformamide (6 mL, 0.08 mol) was added 2-(4-chloro-3-(trifluoromethyl)phenyl)propanoic acid (110.0 mg, 0.0004137 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (360 mg, 0.00095 mol) and N,N-diisopropylethylamine (305 μL, 0.00175 mol). The reaction mixture was stirred at 50° C. overnight. LC/MS was checked, and the reaction was complete. In the work up, EtOAc (100 mL) was added to the reaction solution, and the solution was washed with water (2×100 mL), Sat. NaHCO3, H2O, and brine. The mixture was dried with MgSO4 and was rotovaped. The residue was purified by HPLC. The product was recovered as a solid. MS m/z=466.1 (M+1). 1H NMR (400 MHz; DMSO-d6) δ 10.08(s, 1 H), 8.07(d, J=7.9 Hz, 1 H), 7.92(s, 1 H), 7.80-70(m, 3 H), 7.63(s, 1 H), 7.50-7.40(m, 2 H), 7.23 (s, 1 H), 6.51(dd, J=7.6, 4.8 Hz, 1 H), 5.47(q, J=7.2 Hz, 1 H), 4.16(q, J=7.0 Hz, 1 H), 1.58-1.45(m, 6H).