Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O.[C:63]([O:68][C:69]1([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[CH2:72][NH:71][CH2:70]1)(=[O:67])[CH2:64][CH2:65][CH3:66]>ClCCl.CN(C)C=O>[C:63]([O:68][C:69]1([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[CH2:70][N:71]([C:12](=[O:14])[CH:11]([NH:10][C:9]([NH:8][CH2:7][CH2:6][C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:24])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:72]1)(=[O:67])[CH2:64][CH2:65][CH3:66]
Reactant: CCCC(=O)OC1(c2ccccc2)CNC1
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(=O)OC1(c2ccccc2)CN(C(=O)C(Cc2ccc(OC)cc2)NC(=O)NCCc2c[nH]cn2)C1
Reaction time: 2 h
Yield: 4.2 %

Procedure:
To 80 mg (0.24 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)-propanoic acid (cf. preparation 2-3) dissolved in 2.75 mL of dichloromethane and 1.25 mL of dimethylformamide are added 0.08 mL (0.48 mmol) of diisopropylethylamine, 84 mg (0.26 mmol) of TBTU and 88 mg (0.26 mmol) of 3-phenylazetidin-3-yl butyrate trifluoroacetate. After 2 hours, the solution is washed with 1N sodium hydroxide solution and the organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product obtained is chromatographed by preparative TLC (eluent: 9/1 dichloromethane/methanol). 5.4 mg of 1-[2-{3-[2-(1H-imidazol-4-yl)ethyl]-ureido}-3-(4-methoxyphenyl)propionyl]-3-phenylazetidin-3-yl butyrate are obtained in a yield of 2%.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2[NH:27][C:26]([CH3:28])=[N:25][N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:15][C:16]1[CH:17]=[C:18]([C:23]2[NH:27][C:26]([CH3:28])=[N:25][N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22])=[O:8])=[O:5]
Reactant: Cc1nnc(-c2ccc(Cl)c(N)c2)[nH]1
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Product: Cc1nnc(-c2ccc(Cl)c(NC(=O)NC(=O)c3cc(F)c(F)cc3Cl)c2)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 85 mg of 3-(3-amino-4-chlorophenyl)-5-methyl-4H-1,2,4-triazole in 8 ml of acetonitrile and the mixture was stirred at room temperature for 2 hours. The solid formed is then filtered off with suction and dried under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)[CH2:15][CH3:16]>>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:19][C:18]([S:17][CH2:14][CH2:15][CH3:16])([CH3:22])[CH3:21]
Reactant: CCCSC(C)(C)C=O
Reactant: CC(C)(S)CNc1ccccc1N
Product: CCCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Yield: 35.5 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.40 g, 2.06×10-3 mol) and 0.452 g (3.09×10-3 mol, 150 M %) of 2-propylthio-2-methylpropanal were reacted by the method of Example 2 to give 0.239 g (40% yield) of 2-(2-mercapto-2-methylpropylamino)-1-[2-propylthio-2-methylpropylamino]benzene as a colorless oil after purification by radial chromatography on a 4 mm silica gel plate eluting with 200 ml 5% diethyl ether/petroleum ether and 100 ml 7% diethyl ether/petroleum ether.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[C:26]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:27]
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1Cl
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccccc2Cl)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-phenyl)-acrylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([C@@:8]2([CH3:29])[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[C:15](=[O:28])[C:11]3([CH2:14][CH2:13][CH2:12]3)S[CH2:9]2)[CH:7]=1.O[O:32][S:33]([O-:35])=O.[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([C@@:8]2([CH3:9])[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[C:15](=[O:28])[C:11]3([CH2:14][CH2:13][CH2:12]3)[S:33](=[O:35])(=[O:32])[CH2:29]2)[CH:7]=1
Reactant: COc1ccc(CN2C(=O)C3(CCC3)SC[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: COc1ccc(CN2C(=O)C3(CCC3)S(=O)(=O)C[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
To a solution of (R)-7-(5-bromo-2-fluorophenyl)-8-(2,4-dimethoxybenzyl)-7-methyl-5-thia-8-azaspiro[3.5]nonan-9-one (1.7 g, 3.44 mmol, Eq: 1.00) in methanol (50 ml) was added at 23° C. Oxone® (4.23 g, 6.88 mmol, Eq: 2.00). The reaction mixture was stirred at 23° C. for 24 hours. The reaction mixture was carefully quenched by addition of water at 0° C., 10 ml of a diluted NaHSO3 solution, sat. NaHCO3 solution and ethyl acetate were added. Vigorous stirring was continued for 10 min. The organic layer was separated and washed with water, then dried over Na2SO4, filtered and evaporated to give (R)-7-(5-bromo-2-fluoro-phenyl)-8-(2,4-dimethoxy-benzyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]nonan-9-one (1.9 g, 3.25 mmol, 94.5% yield) as an off-white foam. MS (ISP): m/z=526.4 [M+H]+ and 528.3 [M+2+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1.Cl[C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:19]3[CH:29]=[C:23]4[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]4[C:21](=[O:30])[N:20]=3)=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(Cl)nc2)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(Cl)nc3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-((6-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7])[CH3:2]>CO.[Ni]>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(=O)OC
Agent: [Ni]
Solvent: CO
Product: CCOc1cc(N)ccc1C(=O)O
Reaction time: 16 h
Yield: 108 %

Procedure:
4.05 g (21.7 mmol, 1 eq) 2-hydroxy-4-nitro-benzoic acid are dissolved in 40 mL MeOH and 1.8 mL (24.8 mmol, 1.14 eq) thionyl chloride are slowly added dropwise. The mixture is refluxed for 2 h at 50° C. and stirred for another 2 h. After cooling the volatile constituents are eliminated in vacuo and 4.36 g of the crude methyl 2-hydroxy-4-nitro-benzoate are obtained, which are reacted without further purification. 1 g (5.1 mmol, 1 eq) of the methyl ester are dissolved in 25 mL DMF, 2.1 g (15.3 mmol, 3 eq) potassium carbonate are added and then 1.4 mL (18.8 mmol, 3.7 eq) bromoethane are added dropwise. The reaction mixture is stirred for 16 h at RT, then poured into 100 mL water and the pH is adjusted with concentrated aqueous hydrochloric acid to pH 3. It is extracted twice with 100 mL EE, dried on MgSO4 and after the elimination of all the volatile constituents in vacuo 1.28 g of methyl 2-ethoxy-4-nitro-benzoate are obtained. 1.28 g (5.06 mmol, 1 eq) of the nitro compound are dissolved in 50 mL MeOH, a spatula tip of Raney nickel is added and the reaction mixture is stirred in the autoclave under a hydrogen pressure of 4 bar for 16 h. The catalyst is filtered off through Celite® and the filtrate is freed in vacuo of all the volatile constituents. 0.99 g of the aniline are obtained [MS-ESI+: 351 (M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: COc1ccc(CC(=O)O)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: COc1ccc(CCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a solution of (4-methoxy-2-nitrophenyl)acetic acid (400 mg; 1.9 mmol; 1 eq) in THF (10 mL) at 0° C. is added slowly under nitrogen borane-tetrahydrofuran complex (4.74 mL; 1 M; 4.7 mmol; 2.5 eq) and the reaction is stirred overnight at room temperature. No conversion is observed. The reaction mixture is heated at 70° C. for 2 h. The reaction is quenched by addition of water and the expected product is extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent removed under reduced pressure. The residue obtained is purified by the flash chromatography using cyclohexane/EtOAc (7/3) as eluent to afford 350 mg (94%) of the title compound as a yellow oil. 1H NMR (CDCl3) δ 7.20 (d, J=3.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.85 (dd, J=8.0, 3.0 Hz, 1H), 3.66 (t, J=9.0 Hz, 2H), 3.61 (s, 3H), 2.86 (t, J=9.0 Hz, 2H), 1.88 (br s, 1H). HPLC (max plot) 100%; Rt 2.48 min.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.O=[CH:10][CH2:11][NH:12][C:13]([C:15]1[S:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)=[O:14].O>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[S:16][C:15]3[C:13](=[O:14])[NH:12][CH:11]=[CH:10][C:19]=3[CH:18]=2)=[CH:21][CH:22]=1
Reactant: O=CCNC(=O)c1ccc(-c2ccc(Cl)cc2)s1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: O=c1[nH]ccc2cc(-c3ccc(Cl)cc3)sc12
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Add trifluoromethane sulfonic acid (3 mL, 0.03 mol) and 5-(4-chlorophenyl)-thiophene-2-carboxylic acid (2-oxoethyl) amide (1 g, 0.004 mol) to a 25 mL three-necked round bottom flask equipped with a stir bar, Dean-Stark trap, nitrogen inlet/outlet, and thermocouple. Heat the reaction mixture to 95° C. for 2 h, then cool to 40° C., and pour onto cold water (20 mL, 1.11 mol). Stir the mixture for 10 min. Filter the resulting slurry and rinse the solids with water (100 mL). Dry to afford crude 2-(4-chlorophenyl)-6H-thieno[2,3-c]pyridine-7-one (0.95 g, 0.004 mol) as a brown solid. LC-MS/ES m/z (35Cl) 262 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])=[N+:2]=[N-:3].S(Cl)([Cl:16])=O>>[N:1]([C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:5]=1[C:6]([Cl:16])=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc(F)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: [N-]=[N+]=Nc1cc(F)ccc1C(=O)Cl
Temperature: 80 °C

Procedure:
2-Azido-4-fluoro-benzoic acid (3.01 g, 17 mmol; Barral, Karine; Moorhouse, Adam D.; Moses, John E. Organic Letters (2007), 9(9), 1809-1811) was dissolved at ambient temperature in thionyl chloride (27.3 ml) under an argon atmosphere. The reaction mixture was heated to 80° C. for 1.5 h and brought to dryness under reduced pressure to give 2-azido-4-fluoro-benzoyl chloride as orange oil. 2-Azido-4-fluoro-benzoyl chloride was dissolved at ambient temperature in CH2Cl2 (23 ml) under an argon atmosphere. 4-Chloro-phenylamine (2.12 g, 17 mmol; [106-47-8]) was added and the reaction mixture was stirred at ambient temperature for 14 h. Saturated aqueous NaHCO3 solution was added until a pH of 8 was adjusted, the layers were separated and the aqueous layer was extracted two more times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a brown solid which was crystallized from heptane/CH2Cl2 to give the title compound (3.08 g, 11 mmol; 64%) as off-white crystals. MS: m/e=291.0 [M+H+].
Reaction SMILES: [CH:1]1([C:4]2[CH:48]=[CH:47][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18]([C:20]([C:22]5[CH:27]=[C:26]([CH2:28][O:29][CH2:30][C:31]6([CH2:43][OH:44])[CH2:36][O:35]C(C7C=CC=CC=7)[O:33][CH2:32]6)[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:17]4)=[CH:12][C:11]=3[O:45][CH3:46])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+].C([O-])(O)=O.[Na+]>O1CCCC1>[CH:1]1([C:4]2[CH:48]=[CH:47][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:17][N:18]([C:20]([C:22]5[CH:27]=[C:26]([CH2:28][O:29][CH2:30][C:31]([CH2:32][OH:33])([CH2:36][OH:35])[CH2:43][OH:44])[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:19]4)=[CH:12][C:11]=3[O:45][CH3:46])=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(C2CN(C(=O)c3cc(COCC4(CO)COC(c5ccccc5)OC4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C2CN(C(=O)c3cc(COCC(CO)(CO)CO)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
To a solution of the crude {3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidin-1-yl}-[4-(5-hydroxymethyl-2-phenyl-[1,3]dioxan-5-ylmethoxymethyl)-pyridin-2-yl]-methanone prepared in (1) in THF (10 mL) was added 1 N hydrochloric acid (5.0 mL). The reaction mixture was stirred at RT for 24 hr. To the reaction mixture were added aqueous 1 N NaOH and saturated aqueous NaHCO3 and then the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: chloroform/methanol=5/1) to give the title compound (0.33 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[O:15][CH2:16][C:17]([NH2:19])=[O:18])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:33][C:34]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[C:35]=1[C:36](Cl)=[O:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[O:15][CH2:16][C:17]([NH2:19])=[O:18])[N:10]([C:36](=[O:37])[C:35]3[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:34]=3[F:33])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: NC(=O)COc1ccccc1C1NN=C(c2ccc(Cl)cc2)S1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)COc1ccccc1C1SC(c2ccc(Cl)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 2-(2-(5-(4-chlorophenyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)phenoxy)acetamide is added DIEA (2.0 mmol) and 2,4,6-tri-fluorobenzoyl chloride (2.0 mmol) and the reaction mixture is stirred for 12 hours at room temperature. After evaporation of the solvent, the residue is purified by automated chromatography (hexane/EtOAc) to give 2-{2-[5-(4-chloro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-acetamide: 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 7.27 (d, J=8.8, 2H), 7.15 (m, 2H), 7.14 (d, J=8.4 Hz, 2H) 6.99 (bs, 1H), 6.84 (t, J=6.4 Hz, 3H), 6.66 (d, J=8.4 Hz, 1H), 6.53 (t, J=8.0 Hz, 2H), 5.29 (bs, 1H), 4.47 (d, J=1.6 Hz, 2H); LC/MS: (ES+) 506.2 (M+1)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])O.[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[C:16]([C:22]#[N:23])[N:15]=1.O>C(#N)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:16]([C:22]#[N:23])[N:15]=1
Reactant: N#Cc1nc(Cl)ccc1CCl
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1nc(Cl)ccc1COc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution (10 ml) of 1.50 g (5.70 mmol) of the resulting N-oxide substance in phosphorus oxychloride was stirred at 80° C. for 1 hour. The reaction solution was concentrated in vacuo, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue followed by extracting with chloroform and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous saline solution. After drying and concentrating, the resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=2:1) to give 625 mg (yield: 58%) of 2-chloro-5-chloromethyl-6-cyanopyridine as a white solid. Phenol (30 mg; 0.32 mmol) and 44 mg (0.32 mmol) of sodium hydrogen carbonate were added to a solution (5 ml) of 50 mg (0.27 mmol) of 2-chloro-5-chloromethyl-6-cyanopyridine in acetonitrile followed by stirring at room temperature for 8 hours and 30 minutes. Water was added to the reaction solution followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, dried and concentrated in vacuo and the resulting residue was purified by a thin-layer column chromatography (hexane:ethyl acetate=6:1) to give 61 mg (yield: 93%) of 2-chloro-6-cyano-5-phenoxymethylpyridine as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=1.[C:27]1([CH:33]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:34][NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[C:38]=2[Cl:47])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:47][C:38]1[C:39]([C:43]([F:44])([F:45])[F:46])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:35]([CH2:34][CH:33]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:14][CH2:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:26])[CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1cccc(CNCC(c2ccccc2)c2ccccc2)c1Cl
Reactant: COC(=O)Cc1cccc(CCCCOS(=O)(=O)c2ccc(C)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)Cc1cccc(CCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 50 °C
Yield: 31 %

Procedure:
A mixture of {3-[4-(toluene-4-sulfonyloxy)butyl]phenyl}acetic acid methyl ester, (2,2-diphenylethyl)-(2-chloro-3-trifluoromethylbenzyl)amine (73 mg, 0.19 mmol), and potassium carbonate (26 mg, 0.21 mmol) in acetonitrile (5 ml) was stirred and heated to 50° C. for 5 hr. The reaction was cooled, diluted with water, and extracted with diethyl ether. The organic extracts were washed with water, dried, and the solvent removed. The residue was chromatographed over silica gel (hexane/methylene chloride/Diethyl ether:60/40/5) to give the title compound as an oil (35 mg, 31%). MS (ESI) 594.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH2:19][CH2:20][CH3:21])[N:17]=[C:16]([C:22]([NH2:24])=O)[CH:15]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>ClCCl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH2:19][CH2:20][CH3:21])[N:17]=[C:16]([C:22]#[N:24])[CH:15]=1
Reactant: CCCn1nc(C(N)=O)cc1CCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCn1nc(C#N)cc1CCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxamide (16.3 g, 50.0 mmol) and pyridine (20.9 mL, 150 mmol) in dichloromethane (100 mL) at 0° C. was added a solution of trifluoroacetic anhydride (9.89 mL, 70.0 mmol) in dichloromethane (100 mL) over ten minutes. The solution was stirred at 0° C. for about 15 minutes, then was allowed to warm to ambient temperature. After 45 minutes, saturated aqueous sodium bicarbonate (200 mL) was added and the dichloromethane was removed under reduced pressure. A white solid was isolated by filtration, washed with water, and dried. The solid was recrystallized from 1:1 heptane/ethyl acetate to yield 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carbonitrile.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:19]=1[CH2:20][C:21](Cl)=[O:22]>>[CH3:17][C:13]1[CH:12]=[C:11]([CH:2]([NH:1][C:21]([CH2:20][C:19]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:18]=2)=[O:22])[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccc2ccccc2n1
Reactant: Cc1cccc(C(N)CCN2CCCCC2)c1
Product: Cc1cccc(C(CCN2CCCCC2)NC(=O)Cc2ccc3ccccc3n2)c1
Yield: 62.7 %

Procedure:
The procedure of Example 1 was repeated using 697 mg (3.0 mmol.) of 1-[3-amino-3-(3-methylphenyl)propyl]piperidine and 575 mg (3.0 mmol.) of quinaldinoyl chloride, to obtain 755 mg (yield: 65%) of the subject compound as a pale yellow solid product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15].[OH-].[Na+]>>[CH3:9][C:4]1[CH:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[NH:8][C:14](=[O:15])[C:13](=[O:17])[NH:1]2
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 518.2 %

Procedure:
To a stirred solution of 3,4-diaminotoluene (0.302 g, 0.247 mmol, Aldrich) in 2 N HCl (4 mL, 8 mmol), oxalic acid dihydrate (0.330 g, 0.261 mmol, Fisher) was added in one portion. The resulting deep purple solution was refluxed for 13 h, to give a purple suspension. This was cooled to 25° C., filtered, washed with water (5 mL), and dried in vacuo (0.1 mm Hg) to give a blue-grey powder. This was taken up in 2 N NaOH (34 mL, 68 mmol), giving a brown solution, which was filtered. The brown filtrate was acidified to pH 1.0 by addition of 2 N HCl (42 mL, 84 mmol), resulting in a tan suspension. Filtration of the suspension and washing of the filter cake with water (mL) gave the title compound as a grey powder (225.5 mg, 43%); mp 318° C. (the block was preheated to 300° C.); 1H NMR (DMSO-d6) δ 2.32 (s, 3 H), 6.90-6.99 (m, 3H), 11.22 (s, 1H), 11.90 (s, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]nnc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 19 %

Procedure:
The title compound is prepared from 1H-benzotriazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 19% of theory; LC (method 4): tR=1.87 min; Mass spectrum (ESI+): m/z=319 [M+H]+.