Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[CH:15]=[C:14]([O:16]C)[CH:13]=[CH:12][C:11]=2[O:18]C)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3]>C1C=CC=CC=1>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[OH:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(OC)c(Oc2ccc(C(C)(C)C)cc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc(Oc2cc(O)ccc2O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A separable flask was charged with 140 g of the thus-obtained 2-(4-t-butylphenoxy)-1,4-dimethoxybenzene, 1000 g of aluminum trichloride and 500 cc of benzene. The mixture was stirred at 100° C. for 2 hours and was thrown into ice-hydrochloric acid. The formed precipitate was recovered by filtration, washed with water and dried to obtain about 100 g of 2-(4-t-butylphenoxy)hydroquinone.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:19])[CH:10]=1.[CH3:20]O>C1C=CC=CC=1>[Br:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13]([O:15][CH3:20])=[O:14])=[C:11]([F:19])[CH:10]=1
Reactant: Cc1cc(C(=O)O)c(F)cc1Br
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Product: COC(=O)c1cc(C)c(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
(Trimethylsilyl)diazomethane (4.0 ml, 8.0 mmol, 2 M in Et2O) was added dropwise to a solution of 4-bromo-2-fluoro-5-methyl-benzoic acid (1.88 g, 8.05 mmol) in benzene (7.5 ml)-MeOH (5.6 ml) at 10±2° C. over 10 minutes. The mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/1) to give methyl 4-bromo-2-fluoro-5-methyl-benzoate (1.62 g, 82%).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([O:11][CH2:12][CH3:13])[C:7]=1[C:14]#[N:15])=[O:4].S(=O)(=O)(O)[OH:17]>>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([O:11][CH2:12][CH3:13])[C:7]=1[C:14](=[O:17])[NH2:15])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: CCOc1nsc(NC(=O)NC)c1C#N
Product: CCOc1nsc(NC(=O)NC)c1C(N)=O
Temperature: 0 °C

Procedure:
A solution of 5.6 g of 1-methyl-3-(4-cyano-3-ethoxy-5-isothiazolyl)urea (from Example I) in 10 ml of concentrated sulfuric acid was heated at 50° during 1.5 hours. The reaction mixture was poured into 200 ml of ice-water and stirred for one half hour. The resultant precipitate was collected by filtration and was allowed to air-dry overnight. The solid was slurried with 50 ml of saturated sodium bicarbonate solution. The resulting white solid was collected by filtration and recrystallized from ethanol to give 4.3 g of 1-methyl-3-(4-carbamoyl-3-ethoxy-5-isothiazolyl)urea, m.p. 240°-241°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[O:20][CH3:21])=[CH:3][C:2]=1[Cl:1]
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of 3,4-dichlorophenol (38 g, 233.13 mmol, 1.00 equiv), 1-fluoro-2-methoxy-4-nitrobenzene (40 g, 233.75 mmol, 1.00 equiv) and potassium carbonate (64 g, 463.77 mmol, 1.99 equiv) N,N-dimethylformamide (250 mL) was stirred overnight at 60° C. The resulting solution was diluted with 1000 mL of water, extracted with 3×200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 60 g (82%) of 1,2-dichloro-4-(2-methoxy-4-nitrophenoxy)benzene as a brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl>CS(C)=O>[CH:2]([C:3]1([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:27][CH:28]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4]1)=[O:1]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(CO)CCC3)CC2)c2ncnn12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C=O)CCC3)CC2)c2ncnn12
Reaction time: 3 h

Procedure:
To a mixture of 4′-{[4-(trans-4-{[1-(hydroxymethyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.7 g), triethylamine (0.86 mL) and dimethyl sulfoxide (10 mL) was added a solution (5 mL) of sulfur trioxide-pyridine complex (0.59 g) in dimethyl sulfoxide at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.7 g, 100%).
Reaction SMILES: C([O:8][NH:9][C:10]([CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH2:31][CH3:32])=[N:22][N:23]2[CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:19][CH:18]=1)=[O:16])=[O:11])C1C=CC=CC=1>[OH-].[OH-].[Pd+2]>[OH:8][NH:9][C:10]([CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH2:31][CH3:32])=[N:22][N:23]2[CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:19][CH:18]=1)=[O:16])=[O:11]
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)NCCC(=O)NOCc3ccccc3)ccc12
Agent: [Pd+2]
Agent: [OH-]
Product: CCc1nn(C2CCCC2)c2cc(C(=O)NCCC(=O)NO)ccc12
Yield: 91.4 %

Procedure:
This compound was prepared according to the method of Example 38, using 203 mg (0.467 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (2-benzyloxycarbamoyl-ethyl)-amide as starting material and 50 mg of Pd(OH)2/C (Pearlman's catalyst) as catalyst, to give 147 mg (91%) of a white powder: mp 166-169° C.; Anal. calcd for C18H24N4O3: C, 62.77;H, 7.02; N, 16.27. Found: C, 62.58; H, 7.12; N, 16.27.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].CS(O[C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1)(=O)=O>CN(C)C=O.O>[NH2:1][C@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Temperature: 25 °C

Procedure:
Sodium azide (4.4 g, 67.4 mmol) was added to a solution of 1,1-dimethylethyl (3R)-3-[(methylsulfonyl)oxy]-pyrrolidine-1-carboxylate (14.3 g, 54 mmol) in dry dimethylformamide (75 mL) and the resultant suspension heated at 65° C. for 8 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted into diethyl ether. The organic phase was washed two further times with water, then brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with diethyl ether/cyclohexane (20:80 to 40:60), to give the title compound as an oil.
Reaction SMILES: C[C:2]1([C:5]([C:7]2[C:12]3[N:13]4[CH2:19][CH2:18][CH2:17][N:16]([C:20]5[C:21]([CH3:28])=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)[C:14]4=[N:15][C:11]=3[C:10]([Cl:29])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3]1.O1[CH2:34][CH2:33][CH2:32]C1>>[Cl:29][C:10]1[C:11]2[N:15]=[C:14]3[N:16]([C:20]4[C:21]([CH3:28])=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:17][CH2:18][CH2:19][N:13]3[C:12]=2[C:7]([C:5]([CH:2]2[CH2:3][CH2:4]2)([CH:32]2[CH2:33][CH2:34]2)[OH:6])=[CH:8][CH:9]=1
Reactant: C1CCOC1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(=O)C4(C)CC4)c23)c(C)n1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)(C4CC4)C4CC4)c23)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of methyl [9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanone (145.7 mg, 0.365 mmol) in tetrahydrofuran (2.0 mL) was added c-propylmagnesium bromide (1.0 M solution in tetrahydrofuran, 3.42 mL, 3.420 mmol). The reaction mixture was stirred at room temperature for 2 hrs. After cooling, the mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-55% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from hexane to give the title compound as a solid (105.5 mg, 0.240 mmol, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14]([NH2:15])=[N:13][C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]4[O:33][C:32]5[CH:31]=CC=CC=5O[CH2:25]4)=[O:23])[CH2:18][CH2:17]3)=[N:11][C:6]2=[CH:7][C:8]=1[O:9][CH3:10].NC1C2C(=CC(OC)=C(OC)C=2)N=C(Cl)N=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14]([NH2:15])=[N:13][C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]4[O:33][CH2:32][CH2:31][CH2:25]4)=[O:23])[CH2:18][CH2:17]3)=[N:11][C:6]2=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc2nc(N3CCN(C(=O)C4COc5ccccc5O4)CC3)nc(N)c2cc1OC
Agent: COc1cc2nc(Cl)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Yield: 73 %

Procedure:
The procedures were the same as described for Doxazosin, except that compound 3 (3.0 g, 16.3 mmol) prepared from Example 5 was reacted with 4-amino-2-chloro-6,7-dimethoxyquinazoline (3.8 g, 16.1 mmol) to provide 5.0 g of hydrochloride salt of Terazosin (73% yield), which is then converted to Terazosin (4.7 g, white solid) by alkalizing.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[Br:1][C:2]1[C:7]2[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(Br)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
To a solution of ethyl 4-{7-bromo-2-[(2,4-dichlorophenyl)amino]-1H-benzimidazol-1-yl}butanoate (Reference Example 78; 1.61 g, 3.42 mmol) in tetrahydrofuran (15 mL) was added lithium tetrahydroborate (372 mg, 17.1 mmol) at 0° C. The mixture was stirred at room temperature for 16 hr, and the reaction was quenched by methanol. The mixture was concentrated in vacuo, neutralized with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the crude product of 4-{7-bromo-2-[(2,4-dichlorophenyl)amino]-1H-benzimidazol-1-yl}butan-1-ol (945 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][C:6]=1[O:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])([CH3:3])[CH3:2]>CO.[Pd]>[CH2:25]([C:22]1[CH:23]=[CH:24][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([CH:21]=1)[O:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[CH3:26]
Reactant: C=Cc1ccc(OC(C)C)c(OCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(OC(C)C)c(OCCN2C(=O)c3ccccc3C2=O)c1
Reaction time: 2 h

Procedure:
0.15 g of 10% palladium-on-charcoal is added to a solution of 0.53 g of 2-[2-(isopropoxy-5-vinylphenoxy)ethyl]isoindole-1,3-dione (1.51 mmol) in 8 ml of methanol. The suspension is stirred under a hydrogen atmosphere for 2 hours, the solid is then removed by filtration on a silica filter, and the solvent is evaporated off. The title product is isolated by crystallization from a cyclohexane/ethyl acetate mixture. 0.53 g of a white solid is obtained:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17]OC(OC)N(C)C.N1CCCC1.C([O-])(=O)C.[NH4+]>CN(C=O)C.CC(C)=O.Cl.[Cl-].[Ti+3].[Cl-].[Cl-].O>[C:1]1([C:7]2[CH:8]=[C:9]3[C:10]([CH:13]=[CH:17][NH:14]3)=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCNC1
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2ccc3cc[nH]c3c2)cc1
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
A mixture of 4-phenyl-2-nitrotoluene (1.8 g, 8.5 mmol), N,N-dimethylformamide dimethyl acetal (4.4 ml, 33 mmol) and pyrrolidine (0.78 ml, 9.3 mmol) was heated in DMF (20 ml) at 110° C. for 16 hours. The resulting deep red solution was poured into water (100 ml) and extracted with ether (2×100 ml). These extracts were concentrated to give a deep red oil which was dissolved in acetone (5 ml) and then added to a mixture of titanium(III) chloride (40.4 g of a 20% solution in aqueous hydrochloric acid, 52 mmol) and ammonium acetate (80 ml of a 3.9M aqueous solution). The resulting mixture was shaken for 10 minutes and then extracted with ether (3×100 ml). The extracts were washed with brine, dried and concentrated to give a dark solid, which was crystallised from a mixture of petrol (60°-80° C.) and dichloromethane to give 6-phenylindole (1.16 g, 71% yield) as a dark crystalline solid melting at 154° C. (Literature m.p. 160°-1° C., O.Sus et al, Justus Liebigs Ann. Chem., 1955, 593, 91).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.Br[CH:18]([CH3:27])[C:19]([O:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:18]([CH3:27])[C:19]([O:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: Oc1ccc(Oc2ccc(Br)cc2F)cc1
Reactant: COC(=O)C=C(OC)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Yield: 58.2 %

Procedure:
A mixture of 12.0 g (42.4 mmol) 4-(4-bromo-2-fluorophenoxy)phenol, 9.5 g (42.4 mmol) methyl 4-bromo-3-methoxy-2-pentenoate, 6.45 g (46.6 mmol) potassium carbonate and 180 ml acetonitrile was heated at reflux for 16 hours. The mixture was poured into water and extracted with ether. The combined ether extracts were washed with dilute aqueous NaOH, washed with water, dried over MgSO4 and the solvent was removed by rotary evaporation. The residue was purified by HPLC eluting with 95:5 hexane:acetone, to give 10.5 g (58 percent) of the product as a clear colorless oil. Calc: C, 53.66; H, 4.27. Found: C, 53.28, H, 4.40. Structure was established on the basis of IR and NMR analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:16][CH2:15][CH:14]([N:17]([CH2:25][CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH:12]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I.CS[C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[NH:31]>CCO>[CH2:25]([N:17]([CH:14]1[CH2:15][CH2:16][C:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][C:30]([C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)=[NH:31])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)=[CH:12][CH2:13]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH3:26]
Reactant: CCN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3cc(N)ccc23)CC1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3cc(NC(=N)c4cccs4)ccc23)CC1
Reaction time: 24 h
Yield: 75 %

Procedure:
A solution of above compound 130 in dry EtOH (5 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.29 g, 1.037 mmol) at room temperature and stirred for 24 h. Solvent was evaporated and crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layer washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 131 (0.18 g, 75%, over two steps) as a yellow solid. mp 110-112° C.; 1H NMR (DMSO-d6) δ 1.09 (t, 3H, J=6.6 Hz), 1.42 (s, 9H), 1.82-1.93 (m, 2H), 2.22-2.64 (m, 4H), 3.12-3.18 (m, 2H), 4.06 (brs, 1H), 6.10 (s, 1H), 6.32 (s, 2H), 6.60 (d, 1H, J=8.4 Hz), 6.82 (s, 1H), 7.09 (t, 1H, J=4.5 Hz), 7.23 (s, 1H), 7.59 (d, 1H, J=4.8 Hz), 7.68-7.73 (m, 2H), 10.84 (s, 1H); ESI-MS (m/z, %) 465 (MH+, 100).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:16]=1)=[N:13][O:14][N:15]=2)=[O:7].[OH-].[K+].Cl>CO>[N:15]1[O:14][N:13]=[C:12]2[CH:16]=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:17])=[O:2])=[O:7])[CH:9]=[CH:10][C:11]=12
Reactant: COC(=O)CNC(=O)c1ccc2nonc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNC(=O)c1ccc2nonc2c1

Procedure:
500 mg (2.13 mmol) [(benzo[1,2,5]oxadiazole-5-carbonyl)-amino]-acetic acid methyl ester are treated in 50 mL methanol with 6 mL (3 eq.) 1N KOH in methanol containing 10% water at room temperature for two hours, then cooled below 5° C. and neutralized with 6 mL 1 N aqueous HCl. The reaction mixture is extracted with ethyl acetate, the combined organic phases are washed with brine and dried with sodium sulfate, then evaporated to dryness to yield the desired product as a beige-pinkish powder. MS (ES−): 220 (M−1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Al+3:10].[Cl-].[Cl-].[Cl-]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Al:10]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: [Al+3]
Agent: [Cl-]
Product: Cc1ccc([Al](c2ccc(C)cc2)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.9 %

Procedure:
To a solution of 4-methylphenylmagnesium bromide (9 mL, 9 mmol, 1.0 M in THF) was added a solution of AlCl3 (6 mL, 3 mmol, 0.5 M in THF) at 0° C. The mixture was stirred at room temperature for 15 hours. The solution was removed from the solids by cannula and the solvent was evaporated under a strong stream of dry nitrogen gas. The residue was washed twice with n-hexane (10 mL each) and filtered in an enclosed system (Schlenk filtration) to avoid exposure of the moisture sensitive organometallic product to the atmosphere. The filtered solid was dried under reduced pressure affording the title product (0.81 g, 72%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][CH:10]=1)=[O:4].[BH4-].[Na+].[OH-].[Na+]>C1COCC1>[CH3:17][C:12]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([CH:3]3[CH2:2][O:4]3)=[CH:6][N:7]=2)[C:15]([CH3:16])=[CH:14][CH:13]=1
Reactant: Cc1ccc(C)n1-c1ccc(C(=O)CCl)cn1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ccc(C2CO2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To the ketone from example 39 (1.34 g, 5.4 mmol) dissolved in dry THF (20 ml), cooled to 0° C., was added sodium borohydride (308 mg, 8.1 mmol) portionwise. The reaction mixture was stirred for 2 hours then 3M NaOH (aq) (10 ml) was added and stirring continued for a further 16 hours. The reaction mixture was extracted with ethyl acetate (2×20 ml) and the combined organic extracts washed with brine (5 ml), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate:pentane (1:5) to give the title compound as a colourless oil (900 mg, 4.2 mmol, 78%). 1H NMR (CDCl3, 400 MHz) δ: 2.13 (s, 6H), 2.91 (dd, 1H), 3.25 (t, 1H), 3.98 (t, 1H), 5.90 (s, 2H) 7.20 (d, 1H), 7.62 (dd, 1K), 8.58 (s, 1H). LRMS: m/z 215 (M-H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[Cl-].[NH4+:10]>C(Cl)(Cl)Cl>[CH:3]1[C:4]2[N:10]([C:2]3[CH:7]=[CH:6][C:5]([N:10]4[C:7]5[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=5[C:5]5[C:4]4=[CH:3][CH:2]=[CH:7][CH:6]=5)=[CH:4][CH:3]=3)[C:7]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:5]=2[CH:6]=[CH:7][CH:2]=1
Reactant: [NH4+]
Reactant: Clc1ccc(Cl)cc1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reaction time: 0.17 h

Procedure:
The reaction was conducted for 10 minutes in the same experimental procedures as in Example 16 except for using 1,4-dichlorobenzene (4.6 g, 31.6 mmol, 1.0 equivalent) as an aryl halide. To the reaction mixture was added an aqueous solution of ammonium chloride, and the mixture was poured into chloroform (800 mL). The aqueous layer was separated off, and the organic layer was passed through a silica gel pad and concentrated to remove the excess chloroform under reduced pressure. To the thus-obtained suspension was added methanol (130 mL), and the crystal was collected from the suspension by suction filtration, washed with methanol and dried under reduced pressure to afford 12.6 g of pCP as a white powder.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:30]([F:33])([F:32])[F:31])=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]([O:36][C:37]([CH:39]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1)=[O:38])[CH3:35]>>[CH2:34]([O:36][C:37]([CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]4[N:11]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[O:8][C:9]=4[C:30]([F:32])([F:31])[F:33])=[O:13])=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)=[O:28])[CH2:40]1)=[O:38])[CH3:35]
Reactant: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(C(=O)C2CCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)C1

Procedure:
This compound was prepared from 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid and piperidine-3-carboxylic acid ethyl ester using the same method describer in earlier example. LC-MS showed a single peak with a retention time of 3.62 min. LRMS calcd for C31H33F3N4O5 (M+H) 599.24, obsd 599.2
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C([O-])(=O)C.[NH2+]1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH:16][C:14](=[O:15])[CH2:13][C:12]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1)=[O:17])([O-:3])=[O:2]
Reactant: CC(=O)CC(=O)OCCNC(=O)c1cccnc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: O=C(C=Cc1cccc([N+](=O)[O-])c1)CC(=O)OCCNC(=O)c1cccnc1
Yield: 86.2 %

Procedure:
A solution of 9.07 g (0.06 mole) of m-nitrobenzaldehyde, 15.0 g (0.06 mole) of 2-nicotinoylaminoethyl acetoacetate and 1.74 g (0.012 mole) of piperidinium acetate in 100 ml of benzene was heated at reflux under azeotropic dehydration conditions for 2 hours. After the reaction, the mixture was extracted with benzene, and the extract was washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 19.82 g of 2-nicotinoylaminoethyl 3-nitrobenzilideneacetoacetate as white crystals.