Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[CH:26])=[CH:19][C:16]=1[CH:17]=[O:18])([O-:14])=[O:13].[Cl-].[NH4+]>C1COCC1>[N+:12]([C:15]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[CH:26])=[CH:19][C:16]=1[CH:17]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)[OH:18])([O-:14])=[O:13]
Reactant: C#CCOc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: Brc1ccc(C2CC2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCOc1ccc([N+](=O)[O-])c(C(O)c2ccc(C3CC3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 407 mg (16.7 mmol) magnesium turnings in 5 ml anhydrous THF is treated with a solution of 1-bromo-4-cyclopropyl-benzene in 20 ml THF at such a rate to maintain gentle reflux. Stirring is continued for another ½ h after complete addition. The resulting Grignard reagent is then slowly added to a solution of 2-nitro-5-propargyloxy-benzaldehyde in 30 ml THF at −75° C. The reaction is kept between −75° C. and −65° C. throughout the addition, followed by slow warming to rt. The mixture is then poured into saturated aqueous ammonium chloride solution and extracted with diethyl ether. Purification of the crude product by flash chromatography (hexane/dichloromethane) yields a yellow brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:26]>>[ClH:26].[ClH:26].[ClH:26].[N:19]1([CH2:18][C:14]2[N:13]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH:17]=[CH:16][CH:15]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1=NS(=O)N=C1NCCCOc1cccc(CN2CCCCC2)n1
Agent: Cl
Product: N=C(N)C(=N)NCCCOc1cccc(CN2CCCCC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A methanolic solution of the product prepared in Step A was diluted to 100 ml and 12.4 ml of concentrated HCl was added. The solution was stirred at ambient temperature for 18 hours, concentrated, and the residue was dissolved in 80 ml of water and extracted twice with CH2Cl2. The aqueous layer was concentrated, treated with n-propanol and concentrated under high vacuum to give the title compound as a foam.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:23])[C:5]2[C:10]([CH3:12])([CH3:11])[C:9](=O)[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[N:7]=1.B#B.CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([Cl:23])[C:5]2[C:10]([CH3:12])([CH3:11])[CH2:9][N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[N:7]=1
Reactant: COc1ccc(CN2C(=O)C(C)(C)c3c(Cl)nc(Cl)nc32)cc1
Agent: B#B
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(C)(C)c3c(Cl)nc(Cl)nc32)cc1

Procedure:
To a solution of 2,4-dichloro-7-(4-methoxybenzyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (270 mg, 0.77 mol) in tetrahydrofuran (10 mL) was added diborane (1 M in tetrahydrofuran, 3.85 mL, 3.85 mmol) dropwise under nitrogen. The mixture was refluxed overnight. After cooling, methanol (2 mL) was added dropwise to decompose the excessive diborane. The solvent was removed and the residue was purified by silica gel column chromatography to afford the product
Reaction SMILES: [OH:1][CH:2]1[C:6]([C:7](=[O:9])[CH3:8])=[CH:5][S:4][CH2:3]1.S(Cl)(Cl)(=O)=O.Cl>C(Cl)Cl>[OH:1][C:2]1[C:6]([C:7](=[O:9])[CH3:8])=[CH:5][S:4][CH:3]=1
Reactant: CC(=O)C1=CSCC1O
Agent: Cl
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)c1cscc1O
Reaction time: 0.5 h
Yield: 77 %

Procedure:
2.88 parts of 3-hydroxy-4-acetyldihydrothiophene are introduced into 20 parts by volume of dried methylene chloride; a solution of 1.7 parts by volume of sulfuryl chloride in 20 parts by volume of dried methylene chloride is added in the course of 10 minutes at 0° C. During the reaction, nitrogen is passed in, in order to expel the hydrochloric acid formed. After 30 minutes, the reaction mixture is worked up. The end product is isolated from the reaction mixture by the method described in Example 1c. 2.22 parts (77% of theory) of 3-hydroxy-4-acetylthiophene of melting point 44°-47° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([O:10][CH3:9])[CH:16]=2)=[CH:4][N:3]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1cnc(Br)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cnc(N)cn2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 102.5 %

Procedure:
To a solution of 2-amino-5-bromopyrazine (642 mg) in dimethoxyethane (40 mL) was added 3-methoxyphenylboronic acid (560 mg), 1.5N aqueous sodium carbonate solution (4 mL) and tetrakis(triphenylphosphine) palladium (0) (86 mg). The mixture was stirred at 80° C. for 6 hours. To the reaction mixture was added water (20 mL) and the whole was extracted with ethylacetate (50 mL×3). The extract was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with ethyl ether (10 mL) to give the subject compound (760 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([F:21])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CCOC(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>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:15][C:16]=1[F:21]
Reactant: Nc1ccc(Br)cc1F
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
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: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cccc([N+](=O)[O-])c2)cc1F
Temperature: 95 °C

Procedure:
A mixture of 3-nitrobenzeneboronic acid (0.70 g, 4.2 mmol), 4-bromo-2-fluoroaniline (730 mg, 4.0 mmol), (PPh3)4Pd (93 mg, 0.08 mmol), and K2CO3 (0.69 g, 5.0 mmol) in toluene (20 mL) and water (2 mL) was heated at 95° C. for 16 h and the mixture was diluted with EtOAc (20 mL). The mixture was washed with water (10 mL) and brine (10 mL), concentrated and purified by silica gel chromatography to afford the 4-amino-3-fluoro-3'-nitrobiphenyl (structure 82 of Scheme XXI, where R1 =R3-7 =H, R8 =F) (0.4 g, 41%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:32][CH2:33][N:28]([C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: Cc1cccc(C)c1N1CCNCC1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2c(C)cccc2C)CC1
Yield: 76 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 76%). 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 6H), 3.18-3.21 (m, 4H), 3.69-3.72 (m, 4H), 4.15 (s, 3H), 6.97-7.04 (m, 3H), 7.22-7.42 (m, 4H), 7.82-7.87 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[O:13]CCO1.C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>O1CCCC1.CCCCCC.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:24])[OH:20])=[C:3]([CH:9]=[O:13])[CH:4]=1
Reactant: Fc1ccc(Br)c(C2OCCO2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=Cc1cc(F)ccc1B(O)O
Temperature: -74 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of 2.30 g (9.31 mmol) 2-(2-bromo-5-fluoro-phenyl)-[1,3]dioxolane in 15 ml tetrahydrofuran was added dropwise at −70° C. 6.11 ml (9.77 mmol) of a 1.6 M solution of n-butyllithium in hexane. The reaction mixture was stirred at −74° C. for 1 h. After dropwise addition of 2.65 ml (11.2 mmol) triisopropyl borate at −70° C. the reaction mixture was allowed to warm to 15° C. during a period of 2 h. Water (7 ml) was added, and the mixture was acidified to pH 1 by addition of 37% hydrochloric acid solution. After heating at 60° C. for 1 h, the mixture was cooled to room temperature and extracted with three 50-ml portions of diethyl ether. The combined organic layers were washed with 50 ml brine, dried over sodium sulfate and concentrated. Flash chromatography gave 1.2 g (77%) of the title compound as a light yellow liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2C)=[O:9])[CH:3]=1.[CH2:19]([NH:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21]>>[CH2:19]([N:22]([CH2:23][CH2:24][CH3:25])[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[O:9])[CH:3]=1)[CH2:20][CH3:21]
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CCCNCCC
Product: CCCN(CCC)c1cc(C(=O)Nc2ccc(O)cc2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 7) and dipropylamine (Aldrich), the title compound was obtained as a brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([NH:16][CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:30])=[O:15])[CH2:9]1)=O)(C)(C)C>Cl.CO>[ClH:29].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[S:22][C:18]([CH2:17][NH:16][C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[O:15])=[C:19]([CH3:30])[N:20]=2)=[CH:24][CH:25]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CNC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: Cc1nc(-c2ccc(Cl)cc2)sc1CNC(=O)C1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 195.1 %

Procedure:
1-tert-Butoxycarbonyl-N-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methyl]piperidine-3-carboxamide (916 mg, 2.04 mmol) was dissolved in a 10% hydrogen chloride/methanol solution (20 mL) and the mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture was concentrated and the residue was air-dried to give 769 mg (98%) of the desired compound as a colorless amorphous product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:15][C:14](=[O:16])[C@H:13]([NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH:17]([CH3:19])[CH3:18])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OCc2ccccc2)C(C)C)cc1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid (40 g, 139.2 mmol) and cesium carbonate (85.7 g, 444 mmol) in dimethylformamide was added benzyl bromide (16.1 g, 135 mmol). The reaction mixture was stirred overnight. The dimethylformamide was removed on the rotoevaporator and the residue was dissolved in ethyl acetate (200 ml) and partitioned with an equal volume of water. The organic phase was collected and washed with an equal volume of brine. The aqueous phases were back extracted with ethyl acetate (2×150 ml), combined and dried over magnesium sulfate and condensed to provide 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid benzyl ester (42.6 g) as a white crystalline solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[Cl-].[Na+]>O.C(O)C>[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([N:1]=[N+:2]=[N-:3])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 45 °C

Procedure:
A solution of 35 g. (0.5 moles) of sodium azide in 200 ml of water was placed in a 2 litre Erlenmeyer flask and diluted with 400 ml of 90% aqueous ethanol. To this solution was added with stirring a warm (45° C.) solution of 96 g. (0.50 mole) of p-toluenesulfonyl chloride in 1 litre of 99% ethanol. During the addition, sodium chloride separated. The reaction mixture was stirred at room temperature for 2.5 hours. Most of the solvent is removed at 35° C. (15 mm) with a rotary evaporator. The residue was mixed with 1.2 liters of water in a separatory funnel, and the oily p-toluenesulfonyl azide separated. This oil was washed with two 100 ml portions of water and dried over anhydrous sodium sulfate. Filtration with suction gave 50 g (60%, based on p-toluenesulfonyl chloride) of pure, colorless p-toluenesulfonyl azide which completely crystallised on standing at 5°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(N(CC)CC)C.C(OC(Cl)=O)C.[BH4-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: OCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
5-Bromonicotinic acid (1.00 g; 4.95 mmol) is dissolved in 30 mL anhydrous THF and triethylamine (0.76 mL; 5.44 mmol) is added by syringe, the flask is flushed with argon and cooled to 0° C. Ethylchloroformate (0.52 mL; 5.44 mmol) is then added dropwise by syringe and the mixture is stirred at RT for 60 min. The crude mixture is filtered and the residue is washed twice with 5 mL THF, the filtrate is transferred to a 100 mL RBF and cooled to 0° C. Sodium borohydride (468 mg: 12.4 mmol) is added in portions, followed by 5 mL H2O which is added dropwise via a syringe. The mixture is stirred at RT overnight and then concentrated in vacuo. The crude product is extracted 6 times with EtOAc, the organic layers are combined and dried over anhydrous sodium sulfate, concentrated in vacuo and deposited on silica. Purification by column chromatography on silica gel (pre washed with 1% NEt3 in hexanes) using a solvent gradient from hexanes to EtOAc and then to 50% MeOH in EtOAc, led to the isolation of the product as a clear, colorless oil (426 mg, 46% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15]CC)=[O:14])[N:9]=2)=[N:3]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([OH:15])=[O:14])[N:9]=2)=[N:3]1
Reactant: CCOC(=O)c1noc(-c2cc(C)n(C)n2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2nc(C(=O)O)no2)nn1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 133.8 %

Procedure:
Ethyl 5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxylate (1.206 mmol, 0.285 g) was dissolved in ethanol (7 ml) and cooled to 0° C. with an ice bath. NaOH 1 M solution (3 ml) was added, the ice bath was removed and the mixture was heated to 60° C. for 1.5 h. Ethanol was evaporated and the residue was diluted with MTBE. The mixture was again cooled with an ice bath and acidified with 2 M HCl. The mixture was warmed to RT and stirred overnight. Water, MTBE and DCM were added, but the precipitate did not dissolve. The organic phase and the water phase were combined and evaporated. 0.336 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 2.27 (s, 3H), 4.16 (s, 3H), 7.01 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)[C:14]([C:15]([NH2:17])=[O:16])=[C:10]3[NH:9][C:8](=[O:31])[CH2:7][C:6]=2[CH:32]=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)[C:14]([C:15]([NH2:17])=[O:16])=[C:10]3[NH:9][C:8](=[O:31])[CH2:7][C:6]=2[CH:32]=1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)Cc1cc(N)ccc1-2
Product: C=CC(=O)Nc1ccc2c(c1)CC(=O)Nc1c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn1-2

Procedure:
Compound 75 was prepared from 8-amino-5-oxo-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide and acryloyl chloride according to the procedure similar to that for compound 8. 1H NMR (400 MHz, CD3OD-d4) δ 7.85-7.79 (m, 3H), 7.75-7.71 (m, 2H), 7.43-7.37 (m, 2H), 7.20-7.14 (m, 1H), 7.12-7.06 (m, 4H), 6.50-6.35 (m, 2H), 5.81 (dd, J=2.6, 9.0 Hz, 1H), 3.75 (s, 2H). MS (ESI) m/e [M+1]+ 480.1.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[C:19]([O:16][CH:11]1[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13]([CH3:14])([CH3:15])[CH2:12]1)(=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Product: CC1(C)CC(OC(=O)CCC(=O)O)CC(C)(C)N1OC1CCCCC1
Yield: 90.6 %

Procedure:
A mixture of 12.8 grams (50.0 mmol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, 5.0 grams (50.0 mmol) of succinic anhydride and 15 ml of toluene is heated at reflux for five minutes. Solvent is evaporated and the residue is dissolved in hexane. Water is added and the resulting precipitate is washed with hexane to afford 16.1 grams (90% yield) of the title compound as the monohydrate as a white solid melting at 56°-60° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([NH:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH:9]1[C:21]1[N:26]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)NNc2ccc(F)cn2)C1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2nnc3ccc(F)cn23)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Intermediate 86a (550 mg, 1.25 mmol), Et3N (0.69 mL, 5 mmol) and Ph3P (657 mg, 2.5 mmol) in THF (20 mL) at 0° C. was added hexachloroethane (590 mg, 2.5 mmol) and the mixture stirred for 10 min. The solution was allowed to warm to RT, stirred for 1 h, then partitioned between EtOAc/water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, to give crude 2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester, contaminated with triphenylphosphine oxide, as a pale brown solid (500 mg). The solid (500 mg) was treated with a 4M HCl solution in dioxane (30 mL) and the mixture stirred at RT for 2 h. The suspension was diluted with MeOH, then applied onto an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound as a pale yellow solid (100 mg, 23% over 2 steps). LCMS (Method 4): Rt 0.26, m/z 222 [MH+].
Reaction SMILES: [C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:10]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]1=[O:34])[C:5]([CH3:7])=[CH2:6])([OH:3])=[O:2].[N+](=[CH2:37])=[N-]>C(OCC)C>[CH3:37][O:2][C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[CH:10]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9]1=[O:34])[C:5]([CH3:7])=[CH2:6])=[O:3]
Reactant: C=[N+]=[N-]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Solvent: CCOCC
Product: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Yield: 62 %

Procedure:
14 g (purity 70%; 20 mmoles) of 1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one was treated with a diazomethane solution in diethyl ether. After evaporation of the reaction mixture to dryness, benzene was added. After filtering off the phthalimide, the filtrate was concentrated and chromatographed [silica gel; toluene - ethyl acetate 4:1(v/v] to obtain 6.24 g (62% yield) of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[CH3:21][CH2:22][O:23][C:24]([C:26]([CH2:28][C:29]([CH3:31])=O)=O)=[O:25]>>[CH2:22]([O:23][C:24]([C:26]1[CH:28]=[C:29]([CH3:31])[N:18]([C:16]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH3:20])=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:17]=2)[N:19]=1)=[O:25])[CH3:21]
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Reactant: CCOC(=O)C(=O)CC(C)=O
Product: CCOC(=O)c1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and ethyl acetopyruvate.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(N([Li])C(C)C)(C)C.[CH3:21][CH:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:21][CH:22]1[CH2:27][CH2:26][C:25]([O:28][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:24][CH2:23]1
Reactant: C[Si](C)(C)Cl
Reactant: CC1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Li]N(C(C)C)C(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1CC=C(O[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a 20 ml THF solution of 7 ml of N,N-diisopropylamine, 35.4 ml of a 1.4M n-butyl lithium solution was added dropwise at −78° C., followed by stirring at 0° C. for 30 minutes. The resulting diisopropylamino lithium (LDA) solution was then added dropwise to a 10 ml THF solution of 4 ml of 4-methylcyclohexan-1-one at −78° C. After stirring at −78° C. for 1 hour, 6.5 ml of trimethylsilyl chloride was added dropwise. After stirring at room temperature for 1 hour, the reaction mixture was poured into an aqueous sodium bicarbonate solution. The resulting mixture was extracted with ether. The organic layer was washed with saturated saline, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. Distillation under reduced pressure yielded 5.83 g of 4-methyl-1-(trimethylsilyloxy)-1-cyclohexene (yield: 96%).