Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[N:13]2)=[N:6][CH:7]=1.[O:28]1CCC[CH2:30][CH:29]1OCCO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.C1COCC1>[OH:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[N:13]2)=[N:6][CH:7]=1
Reactant: OCCOC1CCCCO1
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCCO)cn4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
252 mg of 2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one (0.7 mmol) are suspended in abs. THF under a protective-gas atmosphere in a 25 ml three-necked flask, 0.19 ml of 2-(tetrahydropyran-2-yloxy)ethanol (1.4 mmol) and 367 mg of triphenylphosphine (1.4 mmol) are added, and the mixture is stirred at RT for 30 min. 275 μl of diisopropyl azodicarboxylate (1.4 mmol) are subsequently added dropwise, and the reaction mixture is stirred at RT for a further 2 h. For work-up, the reaction mixture is diluted with 20 ml of dichloromethane, washed with 10 ml of water, dried over sodium sulfate, evaporated to dryness and purified by chromatography. (silica gel: MTB ether→DCM→DCM:30% of MeOH). The THP-protected product is stirred at RT for 20 h in 5 ml of 4 N HCl in dioxane. The reaction solution is evaporated to dryness and crystallised from methanol/diethyl ether, giving “A294”; ESI 405; m.p. 182-3° C.
Reaction SMILES: CO.[CH:3]1([C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:13][CH:12]3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[C:20](O)=[O:21])[CH2:5][CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:3]1([C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:13][CH:12]3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[CH2:20][OH:21])[CH2:5][CH2:4]1
Reactant: O=C(O)c1c(C2CC2c2ccccc2)noc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1c(C2CC2c2ccccc2)noc1C1CC1
Temperature: 0 °C

Procedure:
(5-cyclopropyl-3-2-phenylcyclopropyl)isoxazol-4-yl)methanol (rac-I-6F). To a solution of 5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazole-4-carboxylic acid rac-I-6E (0.49 g, 1.82 mmol) in THF and cooled to 0°C. lithium aluminum hydride (4.5 mL, of a 1M solution in THF) was added dropwise. After stirring fo(12 h at rt, the reaction mixture was cooled back to 0°C. and quenched by dropwise addition of H2O (0.5 mL), 15% NaOH (0.5 mL), H2O (1 mL) followed by Na2SO4 and filtered through CELITE® under vacuum. The crude was purified by column chromatography on silica gel with DCM-EtOAc 0 to 5% gradient as eluent to give (5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methanol. 1H NMR (400 MHz, DMSO) δ 7.31-727 (m, 2H), 7.21-7.17 (m, 3H), 5.00 (t, J=5.2 Hz, 1H), 4.42-4.33 (m, 2H), 2.39-2.35 (m, 1H), 2.23-2.13 (m, 2H), 1.57-1.52 (m, 1H), 1.46-1.42 (m, 1H), 1.05-1.04 (m, 2H), 0.95-0.91 (M, 2H). MS m/z 256.1 (M+1).
Reaction SMILES: CI.[CH3:3][C:4]1([CH3:11])[NH:9][CH2:8][CH2:7][NH:6][C:5]1=[O:10].[C:12](=O)([O-])[O-].[K+].[K+]>COCCOC>[CH3:3][C:4]1([CH3:11])[N:9]([CH3:12])[CH2:8][CH2:7][NH:6][C:5]1=[O:10]
Reactant: CC1(C)NCCNC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CI
Product: CN1CCNC(=O)C1(C)C
Temperature: 45 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl-2-bromoisobutyrate (14.6 g, 74.9 mmol), ethylene diamine (33 mL, 487 mmol, 6.5 equiv) and potassium carbonate (11.4 g, 82.4 mmol, 1.1 equiv) in toluene (150 mL) was stirred for 22 h at reflux, cooled and filtered. The filtrate was concentrated and the residue triturated in Et2O to afford 6.3 g of 3,3-dimethyl-piperazin-2-one as a white solid. Methyl iodide (4 mL, 64.0 mmol, 1.3 equiv) was added dropwise to a suspension of 3,3-dimethyl-piperazin-2-one (6.3 g, 49.2 mmol) and potassium carbonate (8.8 g, 64.0 mmol, 1.3 equiv) in DME (20 mL). The reaction mixture was heated to 45° C., stirred for 3 h, cooled and filtered, washing the filter cake with DME. The filtrate was concentrated and the residue triturated in DME to afford 2.8 g (batch 1) of the title compound as a white solid. The filtrate from the trituration was concentrated and the residue purified by silica gel column chromatography (DCM/MeOH, 9:1) to afford 1.75 g (batch 2) of the title compound as a white solid. Title compound: ESI-MS: 143.1 [M+H]+; TLC: Rf=0.25 (DCM/MeOH, 9:1).
Reaction SMILES: C=O.C([Cl:11])(=O)C1C=CC=CC=1.[C:12]([O:15][CH2:16]C)(=[O:14])[CH3:13].[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22]C>[Cl-].[Zn+2].[Cl-]>[Cl:11][CH2:16][O:15][C:12](=[O:14])[C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(C)=O
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCC
Agent: C=O
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C(OCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Para-formaldehyde (4.5 g) and zinc chloride (catalytic amount) were mixed together at 0° C. Benzoyl chloride (0.142 mole, 20 g) was added dropwise over 1 hour. The reaction was warmed to ambient temperature, then was heated to 55° C. for 10 hours. The progress of the reaction was followed by TLC (silica gel, 5/95, ethyl acetate/hexane). Since the starting material was still seen, an additional 1 g para-formaldehyde was added. The reaction was continued stirring at 55° C. for an additional 10 hours, cooled and flash chromatographed on 500 g silica gel, eluting with a solvent mixture of 2% ethyl acetate and 98% hexane. The solvent was evaporated in vacuo. Since the product had a low boiling point, the rotovapor bath temperature was not above 35° C. The desired product, 11.82 g (49%) was obtained as clear oil. MS (ES+): m/e 171 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[C:25]1([CH3:34])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[C:2]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH3:34])=[N:3][N:4]=[CH:5]4)[CH:13]=2)[CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccccc3C)nncc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (100 mg, 296 μmol), o-tolylboronic acid (40 mg, 296 μmol) and tetrakis(triphenylphosphine)palladium (17 mg, 15 μmol) in 5 mL DME/EtOH (4:1) was treated with 2M potassium carbonate (444 μl, 888 μmol). The mixture was stirred at 90° C. for 2 h. The mixture was cooled to RT and purified directly without work-up, via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the title compound in (65 mg) as a pale yellow solid. Found MS (ES+): 394(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][C:9]=1[N:10]([S:19]([C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Cl:29])=[CH:24][C:23]=1[CH3:30])(=[O:21])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1)=[O:4].[O:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[CH:39]=[C:38]1B(O)O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][C:9]=1[N:10]([CH:11]([C:38]1[O:37][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[CH:39]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[S:19]([C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Cl:29])=[CH:24][C:23]=1[CH3:30])(=[O:21])=[O:20])=[O:4]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(Cc1cccc(I)c1)S(=O)(=O)c1cc(C)c(Cl)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(c1ccccc1)c1cc2ccccc2o1)S(=O)(=O)c1cc(C)c(Cl)cc1C
Yield: 98.6 %

Procedure:
To a degassed solution of 3-[(4-Chloro-2,5-dimethyl-benzenesulfonyl)-(3-iodo-benzyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (110 mg, 0.169 mmol) and benzofuran-2-boronic acid (55 mg, 0.185 mmol) in a mixture of DME (8 mL) and 2M aqueous Na2CO3 (4 mL), Pd(PPh3)4 (9 mg) was added and the reaction mixture was stirred at reflux conditions for 2 h under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, dried (Na2SO4) and concentrated. 3-[(3-Benzofuran-2-yl-benzyl)-(4-chloro-2,5-dimethyl-benzenesulfonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (107 mg, 100%) was isolated as a thick syrup and used for the next reaction without any further purification.
Reaction SMILES: [CH2:1]=C=O.C(OC([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([O:17]CC2C=CC=C(C#N)C=2)[C@H:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O)(C)(C)C.[BH4-].[Na+]>CO>[OH:17][CH:13]1[CH2:14][CH2:15][CH2:16][NH:11][C:12]1([CH3:1])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OCc2cccc(C#N)c2)[C@H]1c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(c2ccccc2)NCCCC1O
Reaction time: 0.5 h

Procedure:
The ketene of (a) above (3.2 g) was suspended in methanol under nitrogen and the temperature brought to -40° C. Sodium borohydride (0.3 g) was added portionwise. The mixture was stirred for 30 min and then concentrated in vacuo, azeotroping with tetrahydrofuran. Borane tetrahydrofuran complex (64 ml, 1.0M in tetrahydrofuran) was added and the mixture was heated at reflux overnight. The mixture was cooled and quenched carefully with methanol, and the mixture was then concentrated in vacuo. The resulting residue was dissolved in ethanol (100 ml) and potassium carbonate (4.2 g) was added. The mixture was heated at reflux for 12 h. The mixture was cooled and evaporated and the residue was extracted with ethyl acetate and water. The organic extract was washed with brine, dried (MgSO4) and evaporated to afford 3-hydroxy-2-methyl-2-phenylpiperidine as a white solid. 1H NMR (360 MHz, CDCl3) δ 7.79 (2H, d, ArH), 7.40 (2H, t, ArH), 7.15-7.19 (1H, m, ArH), 3.89 (1H, mc), 2.89-3.01 (2H, m), 1.67-1.91 (4H, m), 1.39 (3H, s, CH3).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]#[N:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1.S(=O)(=O)(O)[OH:24].O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([NH2:16])=[O:24])=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(C#N)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(C(N)=O)c12
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-4-carbonitrile (0.30 g, 1.1 mmol) and conc. sulfuric acid (1.0 mL) in acetic acid (6.0 mL) was heated under reflux for 31.5 hours. The solution was allowed to cool to room temperature, and poured into iced water. The resulting solution was neutralized with an aqueous sodium hydroxide solution, and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was recrystallized from methanol/isopropylether to give the title compound (0.14 g, 44% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH3:16])[N:10]=1.Cl.[OH-].[K+]>O>[C:2]1([NH:1][C:13]2[CH:12]=[C:11]([CH3:16])[N:10]=[C:9]([NH2:8])[N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Nc2ccccc2)nc(N)n1
Yield: 34.5 %

Procedure:
Compound No. 45. (CNI-4594) A mixture of aniline (0.93 g) and 2-amino-4-chloro-6-methylpyrimidine (1.44 g) in 36 mL water was treated with 0.84 mL conc HCl and heated at reflux for 1 hr. Addition of 20 mL 1N KOH gave a light buff solid, which was filtered out, dried, and recrystallized from ethyl acetate/2-methoxyethanol and ethyl acetate/hexane to give 0.69 g 4-phenylamino-2-amino-6-methylpyrimidine, mp 179-180° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH3:15][CH:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:17](=[O:18])[CH:16]([CH3:15])[CH2:20][CH2:21][CH3:22])=[CH:24]1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: CCCC(C)C(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Product: CCCC(C)C(=O)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
1-[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-2-methyl-pentan-1-one was prepared from phenanthridine, 2-methylvaleryl chloride, and indole according to GP 2.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]([S:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>O.C(OCC)(=O)C>[CH:13]([S:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:21][CH:22]=1)([CH3:15])[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(SC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(SC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A mixture of hydroxylammonium chloride (1.70 g), sodium hydrogen carbonate (2.46 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(isopropylthio)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.20 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (12 mL). N,N′-carbonyldiimidazole (0.48 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.44 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.90 g, 67%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([CH2:22]O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([CH2:22][O:9][C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:10])[CH:4]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OCC2CN(C(=O)OC(C)(C)C)C2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromo-3,5-dimethylphenol (3.7 g, 18.16 mmol), 3-hydroxymethylazetidine-1-carboxylic acid tert-butyl ester (commercially available, EP1889836 A1, 3.40 g, 18.16 mmol), di-tert-butylazodicarboxylate (4.6 g, 19.97 mmol) and triphenylphosphine (5.24 g, 19.97 mmol) are suspended in dichloromethane (100 mL) and stirred for 2 hours at room temperature. The solvent is removed under vacuum and the residue suspended in diethyl ether, cooled and the precipitate is filtered off. The solvent is removed under vacuum to give the title compound
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=[C:22]([C:24]3C=NC=C[N:25]=3)[CH:21]=[CH:20][N:19]=2)=[CH:12][CH:11]=1.[N:31]1C=CN=[CH:33][C:32]=1C(=O)C.N1NC(C(=O)C)=CC=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=[C:22]([C:24]3[NH:25][N:31]=[CH:32][CH:33]=3)[CH:21]=[CH:20][N:19]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)c1cnccn1
Reactant: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Agent: CC(=O)c1ccn[nH]1
Product: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3ccn[nH]3)n2)cc1

Procedure:
Title compound was obtained according to the scheme 6 similarly to the compound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone as the starting material 1-(2H-pyrazol-3-yl)-ethanone (Table 11). Characterization of the title compound is provided in the Table 12.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:29]1(=[O:35])[NH:33][C:32](=[O:34])[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CC(O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:13]2[C:14]([CH3:17])([CH3:18])[C:15](=[O:16])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:33]4[C:29](=[O:35])[CH2:30][CH2:31][C:32]4=[O:34])[CH2:6][CH2:7]3)[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: O=C1CCC(=O)N1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
7.4 g 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A1) and 3.6 g succinimide are suspended in 50 ml of 2-propanol and heated to 50° C. 5.1 g potassium carbonate are added in portions during 1 h. After adding potassium carbonate the reaction mixture is stirred for 30 min at 50° C., then 3-4 h at 75° C. until the reaction is complete. After stirring for 3-4 h at 75° C., the heating is turned off and the mixture is allowed to cool down slowly to RT. 100 ml of water is added, the mixture is stirred for 0.5 h at RT and the crystallized product is filtered. The product is dried at 50° C. in a vacuum dryer.
Reaction SMILES: [C:1]([C:3]1([CH3:6])[CH2:5][CH2:4]1)#[CH:2].Cl/[C:8](=[N:14]\[OH:15])/[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C>C(OCC)C>[CH2:12]([O:11][C:9]([C:8]1[CH:2]=[C:1]([C:3]2([CH3:6])[CH2:5][CH2:4]2)[O:15][N:14]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)/C(Cl)=N/O
Reactant: C#CC1(C)CC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C2(C)CC2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a mixture of 1-ethynyl-1-methylcyclopropane (Preparation 4B, 5.0 g, 62.4 mmol) and (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (4.73 g, 31.2 mmol) in diethyl ether (80 mL) was added a solution of triethylamine (8.67 mL, 62.4 mmol) in diethyl ether (20 mL) dropwise over 75 min. After complete addition, the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography using a 10% mixture of ethyl acetate in hexane to give ethyl-5-(1-methylcyclopropyl)isoxazole-3-carboxylate (3.54 g, 65% yield) as a yellow liquid. The product had an HPLC ret. time=2.23 min.-(condition B); LC/MS M+1=196.07. 1H NMR (400 MHz, CDCl3) δ ppm 0.79 (m, 2H), 1.13 (m, 2H), 1.26 (t, J=7.15 Hz, 3H), 1.35 (s, 3H), 4.31 (q, J=7.12 Hz, 2H), and 6.23 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.Br[CH2:20][C:21]1[C:22]([CH3:32])=[N+:23]([O-:31])[C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[CH:6]=[CH:5][N:4]3[C:15](=[O:18])[N:16]([CH2:20][C:21]4[C:22]([CH3:32])=[N+:23]([O-:31])[C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[N:17]=[C:3]3[C:2]=2[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=2)=[CH:9][CH:10]=1
Reactant: O=c1[nH]nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Reactant: Cc1c(CBr)ccc(C(F)(F)F)[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)ccc(C(F)(F)F)[n+]1[O-]

Procedure:
The title compound was also prepared from 8-bromo-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one by treatment with 3-(bromomethyl)-2-methyl-6-(trifluoromethyl)pyridine 1-oxide and potassium carbonate in N,N-dimethylformamide at 70° C., followed by treatment with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and aqueous potassium carbonate solution in toluene under (Ph3P)4Pd catalysis at 100° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][O:6][C:7]1([CH3:25])[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([O:17][C:18]3[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:9]=2[O:8]1.C1(C)C=CC=CC=1>CCCCCC>[CH3:1][NH:2][C:3]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([O:17][C:14]2[CH:15]=[CH:16][C:9]3[O:8][C:7]([O:6][CH3:5])([CH3:25])[CH2:12][CH2:11][C:10]=3[CH:13]=2)=[CH:19][CH:20]=1)=[O:4]
Reactant: CN=C=O
Reactant: COC1(C)CCc2cc(Oc3ccc(N)cc3)ccc2O1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(C)(OC)O3)cc1
Reaction time: 6 h
Yield: 97 %

Procedure:
Methyl isocyanate (0.16 g) was added at room temperature to a solution composed of 0.4 g of 4-(2-methoxy-2-methyl-2,3-dihydro-6-benzopyranyloxy)aniline and 3.0 ml of toluene, and the mixture was stirred for 6 hours. Addition of n-hexane to the mixture yielded crystals which were collected by filtration to give the desired product as white crystals (yield not less than 97%).