Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]([C@H:4]([C:6]1C=CC(CC(C)C)=CC=1)C)=[O:3].C([Cl:20])(=O)CC.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26]>CO>[ClH:20].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH:26][C:2](=[O:3])[CH2:4][CH3:6]
Reactant: CN(C)CCCN
Reactant: CCC(=O)Cl
Reactant: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Solvent: CO
Product: CCC(=O)NCCCN(C)C
Product: Cl

Procedure:
Using the previous procedure, (S)(+) ibuprofen (Fluka reagent) is converted into its propionyl chloride, whose treatment with 3-dimethylaminopropylamine, in the procedure of the example 1, allows to obtain a sample of (S)2-(4-isobutylphenyl)]-N-(3-dimethylaminopropyl)-propionamide hydrochloride m.p. 97-98° C., [α]D=+27(c=1; CH3OH).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][C:5](=[O:7])[CH3:6])[CH3:16])=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Reaction time: 12 h

Procedure:
23.6 mL (250 mmol) acetic anhydride are added to 50.0 g (250 mmol) (S)-1-(4-bromophenyl)-ethylamine in 200 mL DCM while keeping the reaction temperature below 30° C. Stirring is continued for 12 h at rt. After that time, saturated NaHCO3-solution is added. The organic layer is separated, washed with water, dried over magnesium sulphate and the solvent is removed by evaporation.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[CH:2].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(N(CC)CC)C>CC(N(C)C)=O>[F:30][C:29]([F:32])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)=[N:7][CH:8]=2)=[N:24][CH:25]=1
Reactant: C#Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: FC(F)(F)c1ccc(Br)nc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#Cc3ccc(C(F)(F)F)cn3)cn2)CC1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a stirred solution of tert-butyl 4-(5-ethynylpyridin-2-yl)piperazine-1-carboxylate (509 mg, 1.77 mmol), 2-Bromo-5-trifluoromethylpyridine (400 mg, 1.77 mmol), triethylamine (0.74 mL, 5.31 mmol), and cuprous iodide (135 mg, 0.71 mmol) in DMA (20 mL) at 25° C. was added tetrakistriphenylphosphine palladium (0) (102 mg, 5 mol %). The reaction was then stirred for 1 hour. Volatiles were removed in vacuo, and the residue was azeotroped with toluene (2×10 mL). The residue was then dissolved in CH2Cl2 (10 mL) and washed with water (10 mL). The layers were then separated and the aqueous phase extracted with CH2Cl2 (2×100 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 25% EtOAc in hexanes) to give tert-butyl 4-(5-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridin-2-yl)piperazine-1-carboxylate as a yellow solid (729 mg, 1.68 mmol, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][N:9]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.I[CH3:34].[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:34])[C:13]3=[N:14][S:15](=[O:18])(=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][N:9]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN2CCS(=O)(=O)N=C2C1c1ccc(-c2ccccc2)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2CCS(=O)(=O)N=C2C1(C)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 8 h

Procedure:
A suspension of tert-butyl 9-(2-fluorobiphenyl-4-yl)-3,4,6,7-tetrahydropyrazino[2,1-c][1,2,4]thiadiazine-8(9H)-carboxylate 2,2-dioxide (0.71 g), iodomethane (0.115 mL) and NaH (60%, 93 mg) in DMF (16 mL) was stirred at 0° C. to room temperature overnight. The reaction mixture was added with water and extracted with EtOAc. The organic layer was washed with brine and water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane). The obtained material was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (150 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)#[N:2].C(C1C=CC=CN=1)#N.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22].[Cl:27]C1C=CC(C#N)=C(C)C=1>>[ClH:27].[NH2:22][C:21]1[C:20]2[C:19](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=2)[N:2]=1
Reactant: Cc1cc(Cl)ccc1C#N
Reactant: Cc1ccccc1C#N
Reactant: Cc1cccc(C#N)n1
Solvent: N#Cc1ccccn1
Product: Cc1cccc(-c2cc3ccccc3c(N)n2)n1
Product: Cl

Procedure:
Using the method of Example VII, but substituting 2-cyano-6-methylpyridine for the 2-cyanopyridine and 2-methylbenzonitrile for the 4-chloro-2-methylbenzonitrile, there was obtained 1-amino-3-(6-methyl-2-pyridyl)-isoquinoline hydrochloride. The compound was crystallized from isopropyl alcohol. Melting point 263.5°-264.5° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[N:15]=[C:14]([Cl:16])[N:13]=[C:12]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[CH:11]=1>CN(C)C=O>[ClH:16].[CH3:9][C:10]1[N:15]=[C:14]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])[N:13]=[C:12]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[CH:11]=1
Reactant: Cc1cc(N2CCc3ccccc3C2)nc(Cl)n1
Reactant: CNc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(N2CCc3ccccc3C2)nc(N(C)c2ccccc2)n1
Product: Cl
Yield: 52.3 %

Procedure:
After N-methylaniline(0.61 ml, 5.48 mmol) was added to a mixture solution of 6-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(0.95 g, 3.65 mmol) and dimethylformamide(10 ml), 0.7 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: C(C1C=CC(C(OC)=O)=C(O)C=1)=O.[F:14][C:15]1[CH:24]=[C:23]([CH:25]=[O:26])[CH:22]=[C:21]([O:27]C)[C:16]=1[C:17]([O:19][CH3:20])=[O:18].[Al+3].[Cl-].[Cl-].[Cl-]>>[F:14][C:15]1[CH:24]=[C:23]([CH:25]=[O:26])[CH:22]=[C:21]([OH:27])[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1c(F)cc(C=O)cc1OC
Agent: COC(=O)c1ccc(C=O)cc1O
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)c1c(O)cc(C=O)cc1F
Yield: 97.1 %

Procedure:
Followed procedure described in Intermediate 5, step 3 starting with methyl 2-fluoro-4-formyl-6-methoxybenzoate (280 mg, 1.3 mmol) and AlCl3 (350 mg, 2.6 mmol) where reaction was complete after refluxing 10 min. Isolated 250 mg of Intermediate 7, yield 96%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[O:7][N:6]=1.[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[ClH:1].[CH2:15]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=3[O:7][N:6]=2)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: Fc1ccc2c(CCCN3CCC(Cc4ccccc4)CC3)noc2c1
Yield: 30.8 %

Procedure:
A mixture of 5 g 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 5 g of 4-benzylpiperidine, 10 g of potassium carbonate and a few crystals potassium iodide in 50 ml of dimethylformamide was stirred at 70° for 4.5 hr. The mixture was cooled, filtered and concentrated to an oil. The oil was stirred with water and extracted with ether. The organic extracts were washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was treated with ethereal hydrogen chloride to give a salt. The salt was immediate rebasified to give an oil, which was purified by column chromatography (silica gel, tetrahydrofuran). The purified oil was treated with ethereal hydrogen chloride, and the resultant salt was recrystallized from ethyl acetate/methanol to give 2.8 g (31%) of product, mp 188°-189° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[N:31]=[C:30]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[N:31]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)n1

Procedure:
Example 66 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz; CDCl3) δ 8.06 (d, 1H, J=8.4 Hz), 7.79 (s, 1H), 7.64 (t, 1H, J=7.6 Hz), 7.38–7.34 (m, 2H), 7.01–6.97 (m, 2H), 6.88 (d, 1H, J=7.2 Hz), 6.53 (br s, 1H), 3.27 (dd, 2H, J=6.0, 12.4 Hz), 2.94 (d, 2H, J=14.0 Hz), 2.54–2.48 (m, 4H), 2.32 (t, 2H, J=6.4 Hz), 1.99–1.60 (m, 14H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 495.3 (M+H)+.
Reaction SMILES: CO[C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:19])[N:15]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[C:14]=2[CH:35]=1.[CH3:37][O:38][CH2:39][CH2:40][CH2:41][NH2:42]>>[CH3:37][O:38][CH2:39][CH2:40][CH2:41][NH:42][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)(=[O:19])=[O:20])[N:15]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[C:14]=2[CH:35]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(S(=O)(=O)Cc3ccccc3)n(-c3ccc(C)cc3)c2c1
Reactant: COCCCN
Product: COCCCNC(=O)CCCCCOc1ccc2nc(S(=O)(=O)Cc3ccccc3)n(-c3ccc(C)cc3)c2c1

Procedure:
100 mg of 6-[[1-(4-methylphenyl)-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with 3-methoxypropylamine according to general operating instructions 4. 22 mg was obtained.
Reaction SMILES: [C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([O:41]CC)=[O:40])[CH:34]=3)=[O:31])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:13][CH:12]([NH:29][C:30](=[O:31])[NH:32][C:33]3[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=3)[C:39]([OH:41])=[O:40])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)CC(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)CC(C)(C)C
Yield: 76.8 %

Procedure:
1-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (442 mg) was dissolved in methanol (20 ml), aqueous lithium hydroxide monohydrate (151 mg) solution (10 ml) and tetrahydrofuran (10 ml) were added, and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, extracted with methylene chloride. The solvent was evaporated under reduced pressure, diisopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 324 mg of the titled compound as colorless powder (Yield: 77.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:24]=1[CH2:25][O:26][NH2:27].CC([O-])=O.[Na+]>CCO>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:24]=1[CH2:25][O:26][N:27]=[C:16]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH2:17][CH3:18]
Reactant: NOCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NOCc1ccc(C(F)(F)F)cc1C(F)(F)F)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 65.3 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (3.21 mg, 10.17 mmol), O-(2,4-bistrifluoromethylbenzyl)hydroxylamine hydrochloride (3.16 mg, 10.68 mmol) and anhydrous NaOAc (876 mg, 10.68 mmol) in EtOH (120 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 2:3). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9) afforded a pale yellow solid which was recrystallized from CH2Cl2/PE to give N-{2-[1-(2,4-bistrifluoromethylbenzyloxyimino)propyl]-4-chlorophenyl}trifluoromethanesulfonamide 76 (3.70 g, 65%), as a pale yellow oil. 1H n.m.r. (200 MHz, CDCl3) δ 10.96, br s, 1H; 7.96, s, 1H; 7.85, d, J=8.4 Hz, 1H; 7.72, d, J=8.4 Hz, 1H; 7.61, d, J=8.8 Hz, 1H; 7.49, d, J=2.4 Hz, 1H; 7.33, dd, J=2.4 and 8.8 Hz, 1H; 5.45, s, 2H; 2.88, q, J=7.6 Hz, 2H; 1.21, t, J=7.6 Hz, 3H. HRMS (M+) 556.0254.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C[C:25]1(C)NC(=O)N[C:26]1=[O:31].[CH:33](O)=O.O>C(O)C>[CH2:26]([O:31][CH2:33][NH:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:25]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: O=CO
Reactant: Nc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Solvent: CCO
Solvent: O
Product: CCOCNc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Yield: 60.5 %

Procedure:
To a solution of the resulting 2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (602 mg, 1.85 mmol) in ethanol (40 mL) were added 5,5-dimethylhydantoin (260 mg, 2.04 mmol), 37% formic acid aqueous solution (3.00 mL, 23.6 mmol), and the solution was stirred under reflux for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate, the organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulfate, and then, evaporated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (430 mg, 1.12 mmol, 61%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](OCC)=[O:12])[N:8]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=O)[N:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:33].O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]2[C:11](=[O:12])[NH:33][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)=[CH:16][N:8]2[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)c2ccc(C(C)(C)C)cc2)n1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(=O)[nH]c(-c3ccc(C(C)(C)C)cc3)cn2n1
Temperature: 25 °C

Procedure:
A solution of 1.04 g (2.71 mmol) 1-[2-(4-tert-butyl-phenyl)-2-oxo-ethyl]-1H-pyrazole-3,5-dicarboxylic acid diethyl ester and 2.08 g (27.1 mmol) ammonium acetate in 20 ml acetic acid is stirred for 44 hours at 110° C. The reaction mixture is cooled to room temperature and excess water is added. The resulting precipitate is filtered off, and washed with water. The residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent to give 6-(4-tert-butyl-phenyl)-4-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester as colourless crystals; HPLC/MS 2.41 (A), [M+H] 340.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[C:8]2=[O:24])=[CH:4][CH:3]=1.[NH2:27][OH:28]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)/[C:19](/[NH2:20])=[N:27]/[OH:28])[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: COc1nn(-c2cccc(C#N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Reactant: NO
Solvent: O
Solvent: CCO
Product: COc1nn(-c2cccc(/C(N)=N/O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 80 °C
Yield: 99 %

Procedure:
According to Scheme 9 Step 1: To a stirred solution of 3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)benzonitrile (150 mg, 0.41 mmol) in ethanol (5 ml) was added hydroxylamine (0.100 ml of a 50% solution in water, 1.2 mmol) and the mixture was heated at 80° C. overnight. The reaction mixture was quenched with a saturated ammonium chloride solution and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water, with brine, dried over MgSO4, filtered and concentrated to afford (Z)-3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-N′-hydroxybenzamidine (150 mg, 99%) which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][CH2:12][C:13](=O)[C:3]1=2.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CCO.O>[OH:17][N:16]=[C:13]1[C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:11][CH2:12]1
Reactant: Cn1c2c(c3ccccc31)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c2c(c3ccccc31)CCC2=NO
Reaction time: 8 h

Procedure:
To a stirred solution of 1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (3.0 g) in 30 ml of 95% EtOH was added hydroxylamine hydrochloride (2.25 g) in 9 ml water followed by sodium acetate (4.4 g) in 9 ml water. The mixture was heated at reflux for 4 hours and thereafter an additional 1.1 gram of hydroxylamine hydrochloride in 5 ml water and 2.2 grams of sodium acetate in 5 ml i water were added. After an additional 2 hours of reflux, the mixture was allowed to stand at room temperature overnight. The material which precipitated was collected and recrystallized from 95% EtOH to give 1.9 grams of analytically pure material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:41])([F:42])[F:40])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(OC(F)(F)F)c1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC(F)(F)F)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (556 mg, 0.003 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (1.75 g, 0.014 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-trifluoromethoxy-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethoxy-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (290 mg, 23%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:18]=[C:17]([C:19](=O)[CH:20]([CH3:22])[CH3:21])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:18]=[C:17]([C:19](=[N:26][OH:27])[CH:20]([CH3:22])[CH3:21])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)C(=NO)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Temperature: 25 °C

Procedure:
To a mixture solution of 5-isobutyrylthiophene-3-sulfonic acid [2-(4-fluorophenyl)-ethyl]-methyl-amide (the compound of Preparation Example 88) (30 mg) in ethanol (2 mL) and water (1 mL) was added hydroxylamine.hydrochloride (11 mg) and sodium acetate (13 mg). After heating and refluxing for 12 hours, the reaction solution was cooled to room temperature. The solution was diluted with water and extracted with ethyl acetate. This solution was washed with saturated sodium chloride water. The crude product that was obtained after drying with anhydrous sodium sulfate and removing the solvent by evaporation was purified by silica gel column chromatography (ethyl acetate/hexane), the title compound (a pale yellow viscous oily substance) (29 mg) was obtained as a mixture where (E):(Z)=1:1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:37]=[CH:36][C:15]3[N:16]=[C:17]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH2:27][C@@H:28]5[CH2:32][O:31]C(C)(C)[O:29]5)=[CH:21][C:20]=4[CH3:35])[NH:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[OH-].[Na+].O>CO.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:37]=[CH:36][C:15]3[N:16]=[C:17]([C:19]4[C:20]([CH3:35])=[CH:21][C:22]([O:26][CH2:27][C@@H:28]([OH:29])[CH2:32][OH:31])=[CH:23][C:24]=4[CH3:25])[NH:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OC[C@@H]5COC(C)(C)O5)cc4C)[nH]c3c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OC[C@@H](O)CO)cc4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2,6-dimethylphenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethylphenyl)-amide (120 mg, 0.24 mmol) in MeOH (3 mL) was added 1N HCl (3 mL) and the solution was stirred at ambient temperature for 3 h. The solution was basified to pH 10 with 1N NaOH and the mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the organic layer was washed with water, brine, dried with MgSO4, filtered and concentrated. Purification by HPLC gave the title compound as a white solid. 1H NMR (Methanol-d4, 400 MHz): δ 8.22 (s, 1H), 7.90 (dd, 1H), 7.70 (d, 1H), 7.47 (s, 1H), 7.44 (dd, 1H), 7.13 (d, 1H), 6.80 (s, 2H), 4.11 (m, 1H), 4.03 (m, 2H), 3.72 (m, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 2.14 (s, 6H). MS (m/z) 460.1 (M+1); Retention time: 1.23 min (Method 10).