Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CCN(C[C@@H]2CCCNC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the (S)-tert-butyl 3-(piperidin-1-ylmethyl)piperidine-1-carboxylate isolated above in 200 μL DCM was slowly added 2 mL TFA and the resulting solution stirred for 30 min at 25° C. The solvent was evaporated and the crude product was used directly in the next reaction without further purification. (For example, reaction with Intermediate A5 in Specific Scheme 5)
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)C(C)C)C.[CH2:35]([NH:39][NH2:40])[CH:36]([CH3:38])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CN(C=O)C>[CH2:35]([N:39]1[C:2]2[C:3](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:4](=[O:6])[NH:40]1)[CH:36]([CH3:38])[CH3:37]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)CNN
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Cn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid (1.5 g) in DMF (50 mL) was added EDCI.HCl (1.71 g) followed by N-ethyldiisopropylamine (5.51 mL). After 10 minutes isobutylhydrazine.p-toluenesulfonicacid salt (2.32 g) was added. The reaction mixture was stirred at ambient temperature for 22 hours and the reaction was poured onto aqueous 1N HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification via ISCO combiflash chromatography afforded pure desired 1-isobutyl-5-nitro-1,2-dihydro-indazol-3-one (0.9 g) as a yellow solid. MS (ESI−):234.1 ([M−H]−).
Reaction SMILES: Cl[CH2:2][C@@:3]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([OH:7])[C@H:4]([OH:6])[CH3:5].[OH-].[Na+].O.C(#N)C>CO>[O:7]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])([CH:4]([OH:6])[CH3:5])[CH2:2]1
Reactant: C[C@@H](O)[C@](O)(CCl)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CC(O)C1(c2ccc(F)cc2F)CO1
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A solution of 0.28 g (1.2 mmol) of (2S,3R)-1-chloro-2-(2,4-difluorophenyl)butane-2,3-diol ((2S,3R)/(2R,3R)=88/12) in 3 mL of methanol was cooled in ice, and 1.4 mL of a 1 M aqueous solution of NaOH was added thereto. Reaction was performed for 1.5 hours, and 10 mL of water was added to stop the reaction. Extraction was performed with ethylacetate (20 mL). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting crude product was quantitatively analyzed by HPLC. Thereby, the title compound was obtained in a yield of 95% ((2R,3R)/(2S,3R)=88/12) (HPLC, column: CAPCELL PAK C18 TYPE MG, mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=2/8, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 28 minutes (2S,3R), 30 minutes (2R,3R)) 1H-NMR (400 MHz, CDCl3) (2R,3R) δ: 1.16 (d, 3H, J=6.1 Hz), 2.80 (d, 1H, J=4.4 Hz), 3.30 (d, 1H, J=4.4 Hz), 4.09 (q, 1H, J=6.1 Hz), 6.80-6.93 (m, 2H), 7.32-7.37 (m, 1H)).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2([CH2:14][C:13](=[O:15])[C:12]3[C:16]([OH:23])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=3[O:10]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([N:4]1[CH2:5][CH2:6][C:7]2([CH2:14][C:13](=[O:15])[C:12]3[C:16]([O:23][CH3:24])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=3[O:10]2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(CC1)CC(=O)c1c(ccc([N+](=O)[O-])c1O)O2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c([N+](=O)[O-])ccc2c1C(=O)CC1(CCN(C(C)=O)CC1)O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.7 %

Procedure:
A mixture of 1'-acetyl-3,4-dihydro-5-hydroxy-6-nitro-spiro[2H-1-benzopyran-2,4'-piperidine]-4-one (3.84 g, 12 mmol), potassium carbonate (1.66 g, 12 mmol) and methyl iodide (3.74 ml, 8.51 g, 60 mmol) in DMF (30 ml) was stirred in a sealed vessel at room temperature for 3 days, adding further portions of methyl iodide (1 ml) after 24 and 48 h. The solvent was evaporated under reduced pressure, water (60 ml) was added, the pH was adjusted to 6.5 with HCl-H2O (2M) and the mixture was extracted with methylene chloride (3×60 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The crude product was re-subjected to the above procedure, the solvent was evaporated under reduced pressure, water (60 ml) was added and the mixture was extracted with methylene chloride (3×60 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure to give the ketone (4.08 g) as a yellow solid, m.p. 160°-165° C.
Reaction SMILES: [Mg].[CH:2](Cl)([CH3:4])[CH3:3].II.[CH3:8][CH:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][CH:11]=[O:12]>CCOCC>[CH3:3][CH:2]([CH:11]([OH:12])[CH2:10][CH:9]([CH3:8])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:4]
Reactant: CC(C)Cl
Reactant: CC(C)CC(C)CC=O
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CC(C)CC(O)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
26.4 g (1.1 gram atom) of magnesium shavings and 100 ml of dry ether are added to a round flask which is provided with a stirrer, condenser, thermometer and dropping funnel. There is now slowly added thereto a solution of 86.4 g (1.1 mol) of isopropyl chloride in 150 ml of anhydrous ether and the mixture is held at reflux temperature. The reaction is initiated by the addition of a small amount of iodine to the magnesium. After completion of the addition of the isopropyl chloride, the mixture is held for a further 1 hour at reflux temperature. There are now slowly added thereto at 5° C. 128.2 g (1 mol) of 3,5-dimethylhexanal dissolved in 250 ml of anhydrous ether. The mixture is again held for 3 hours at reflux temperature. The mixture is then cooled down to 0° C. and the product is decomposed by the addition of 340 ml of ice-cold 10% hydrochloric acid. The ethereal solution is washed neutral with water and dried, and the solvent is evaporated. There are thus obtained 176 g (70%) of crude product, fractional distillation of which yields 121.4 g of 2,5,7-trimethyl-octan-3-ol of boiling point 79° C./5 mmHg; nD20 =1.4362.
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[N:6]([C@@H:10]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]3[OH:12])[C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.[OH-].[NH4+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)Cl.CO>O>[CH2:24]([S:9][C:7]1[N:6]([C@@H:10]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]2[OH:12])[C:5]2[CH:19]=[C:20]([Cl:21])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OC[C@H]1O[C@@H](n2c(=S)[nH]c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reactant: ClCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](n2c(SCc3ccccc3)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reaction time: 5 h

Procedure:
Compound 53 (0.5 g) was dissolved in cold water (10 ml) containing concentrated ammonium hydroxide (2.5 ml). Benzyl chloride (0.5 ml) was added to this solution with stirring and the stirring continued at room temperature for 5 hours. The white solid (0.41 g) which had separated from solution was collected by filtration, washed with cold water. The solid was extracted with ethyl acetate (100 ml) and the ethyl acetate phase was dried over anhydrous Na2SO4 and then evaporated by aspirator to give a syrup. The syrup was subjected to a flash column of silica gel with CH2Cl2 --MeOH (15:1) as eluant. Fractions were collected (25 ml each) and fractions containing the desired compound were combined and evaporated to afford 54 which was crystallized from CH2C12 --MeOH (15:1), mp. 149° C., Yield 0.223 g (35.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=O.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].C1COCC1>C(O[Ti](OCC)(OCC)OCC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])/[CH:5]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20]
Reactant: O=Cc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 65 °C
Yield: 96.6 %

Procedure:
To a solution of 3-chloro-4-(trifluoromethoxy)benzaldehyde (2.8 g, 12 mmol) and (R)-2-methylpropane-2-sulfinamide (2.7 g, 22 mmol) and THF (25 mL) at RT was added tetraethoxytitanium (9.3 mL, 45 mmol) and the reaction was heated to 65° C. for 12 h. The reaction was cooled to RT, water (100 mL) was added and the solids were filtered and discarded. The filtrate was extracted with EtOAc, the organic fraction was dried, filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:10) to afford 3.8 g (98%) of (R,E)-N-(3-chloro-4-(trifluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (218).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[CH2:23]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+]>>[CH2:23]([N:30]([S:31]([C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)(=[O:33])=[O:32])[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccc2)c1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccc2)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Following the procedure of Example 49, the product of Example 65 is reacted with benzyl-(4-methoxybenzenesulfonyl)amine and sodium hydride to provide ethyl 4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 164°-166° C.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[CH3:28])[N:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[O:30][CH3:29])=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[C@H:14]2[CH2:15][CH2:16][C@H:17]([OH:20])[CH2:18][CH2:19]2)=[C:22]([CH3:28])[CH:23]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1cc(Cl)ccc1C1c2c(cc(Br)n2C(C)C)C(=O)N1[C@H]1CC[C@H](O)CC1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N([C@H]1CC[C@H](O)CC1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-2-methyl-phenyl)-5-(trans-4-hydroxy-cyclohexyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate AJ) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 7.15 min (HPLC 2); ESI-MS: tR=1.18 min, [M+H]+ 494/495 (LC-MS 1); TLC: Rf=0.18 (EtOAc).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH2:27])[C:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])([OH:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH2:35][NH:36][C:37]([NH2:39])=[S:38].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CN(C)C=O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:11]([OH:18])([C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:35][NH:36][C:37]([NH2:39])=[S:38])=[O:2])=[CH:9][CH:8]=1)=[CH2:27])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: C=C(c1ccc(C(=O)OC)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: NNC(N)=S
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(c1ccc(C(=O)NNC(N)=S)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A sample of the product from part (i) (370 mg, 1 mmol) was suspended in dichloromethane (15 ml), and was treated with dimethylformamide (1 drop) and oxalyl chloride (0.1 ml, 1.1 mmol). The solution was stirred at room temperature for1 hour and was evaporated under reduced pressure. The residue. was dissolved in dichloromethane (15 ml) and treated with thiosemicarbazide (0.1 g, 1 mmol) and sodium carbonate (0.1 g, 1 mmol). The mixture was stirred at room temperature for 24 hours then filtered. The filtrate was absorbed onto silica and chromatographed by gradient elution with ethyl acetate/methanol (97:3, 95:5, 94:6). Fractions containing the desired product were combined and evaporated under reduced pressure. The crude product was triturated with ether to give 4-{2-[2,4-difluorophenyl]-2-hydroxy-1-[1,2,4-triazol-1-yl]-3-buten-3-yl}benzoylthiosemicarbazide (0.21 g, 47%) as a colourless solid which was characterised by 1H-N.M.R. spectroscopy (300 MHz, DMSO). δ=4.83 (Abq, 2H), 5.32 (s,1H), 5.58 (s,1H), 6.57 (s,1H), 6.77 (m,1H), 6.98 (m,1H), 7.11 (m, 1H), 7.30 (d,2H), 7.58 (brs, 1H), 7.60 (s,1H), 7.62 (d,2H), 7.78 (brs, 1H), 8.19 (s, 1H), 9.22 (brs, 1H), 10.22 (brs,1H) ppm.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.S(=O)(O)[O-].[Na+].[N+:15]([CH2:18][CH2:19][CH3:20])([O-:17])=[O:16].[OH-].[Na+]>C(O)C.O>[N+:15]([CH:18]([CH2:19][CH3:20])[CH:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[OH:8])([O-:17])=[O:16]
Reactant: Cc1ccc(C=O)cc1
Reactant: CCC[N+](=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C(O)c1ccc(C)cc1)[N+](=O)[O-]

Procedure:
The procedure of Example 1 was followed for the reaction of 120 g of p-tolualdehyde and 114 g of sodium bisulfite with 178 g of 1-nitropropane and 80 g of sodium hydroxide. Water and ethanol were the solvents. The product obtained was a clear, yellow liquid weighing 100 g; ir (film) 2.8 (s), 3.4 (m), 6.5 (s), 7.3 (m), 9.7 (m), 12.2 (s) microns.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16](I)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(I)c1OC
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(Cc2cnc(N)nc2N)cc(C=Cc2ccccc2)c1OC
Temperature: 0 °C
Yield: 53.7 %

Procedure:
A mixture of 500 mg of 5-(3,4-dimethoxy-5-iodo-benzyl)pyrimidine-2,4-diamine, 1.53 g of styrene, 1.46 g of triethylamine and 31 mg of palladium-(II) acetate in 25 ml of dioxan is held at reflux under argon for 14 hrs. The mixture is poured on to ice-water, adjusted to pH 5 to 7 with 3N aqueous hydrochloric acid and extracted with methylene chloride. The organic phase is dried over magnesium sulphate, concentrated and the residue is chromatographed on silica gel with methylene chloride/methanol 97:3. 252 mg (53%) of 5-(3,4-dimethoxy-5-styryl-benzyl)pyrimidine-2,4-diamine are isolated as an orange solid. M.p.226°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:11]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][CH2:20][C:13](=[CH:14]3)C2=O)[CH:7]=[CH:8][C:9]=1[Cl:10])[CH3:2].[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23].C[C:28](C)=[O:29]>>[CH2:22]([N:24]([CH2:25][CH3:26])[C:28](=[O:29])[C:18]1[CH2:19][CH2:20][CH2:13][CH2:14][C:15]=1[C:16]([NH:11][C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:17])[CH3:23]
Reactant: CCNCC
Reactant: CCOc1cc(N2C(=O)C3=CC(CCC3)C2=O)ccc1Cl
Reactant: CC(C)=O
Product: CCOc1cc(NC(=O)C2=C(C(=O)N(CC)CC)CCCC2)ccc1Cl
Temperature: 25 °C

Procedure:
To 50 ml of acetone is added 3.0 g of N-(3-ethoxy-4-chlorophenyl)-3,4,5,6-tetrahydroisophthalimide and a solution of 0.8 g of diethylamine in 5 ml of acetone is dropwise added to the solution over the period of about 3 minutes under stirring at room temperature. The solution is stirred at room temperature for a further 4 hours and the solvent is distilled off under reduced pressure for concentration, and recrystallization of the resultant residue from n-hexane yields 2.2 g of the subject compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14]([CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:25](C([Sn])=C(CCCC)CCCC)[CH2:26]CC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl-].[Li+]>CN1CCCC1=O.C(OCC)(=O)C.CCCCCC>[CH2:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH:16]1[C:14]([NH:13][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:25]=[CH2:26])=[CH:3][CH:4]=2)[NH:12][N:11]=1)=[O:15]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: O=C(Nc1cc(-c2ccc(Br)cc2)[nH]n1)C1Cc2ccccc2C1
Agent: [Cl-]
Agent: [Li+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Product: C=Cc1ccc(-c2cc(NC(=O)C3Cc4ccccc4C3)n[nH]2)cc1

Procedure:
5-(4-Bromophenyl)-3-(2-indanyl)carbonylaminopyrazole (106.5 mg), tributylvinyltin (0.25 ml), a tris(dibenzylideneacetone)dipalladium chloroform complex (17.1 mg), tri-2-furylphosphine (34.4 mg) and lithium chloride (34.0 mg) were dissolved in N-methylpyrrolidone (2 ml) with heating, and the resultant mixture was heated at 80° C. overnight. After allowing to cool, the reaction solution was diluted with ethyl acetate-hexane (1:1, 100 ml), washed with saturated aqueous potassium fluoride solution (100 ml×2) and then dried over anhydrous magnesium sulfate. The solvent was distilled away under a reduced pressure. The resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) and then crystallized from chloroform to obtain the title compound (70.2 mg) as white crystals (melting point: 193-195° C.).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][S:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])=[O:26]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH2:31][CH2:32][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[C:29]4=[O:33])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CS(=O)(=O)N1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(S(C)(=O)=O)C4=O)nc3)CC2)c(C)c1
Yield: 74.2 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 127 and 1-methanesulfonylimidazolidin-2-one (82 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (170 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:9]2[CH2:14][CH:13]([CH3:15])[NH:12][CH2:11][CH:10]2[CH3:16])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:36])[CH2:34]Cl)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:14][CH:13]([CH3:15])[N:12]([CH2:34][C:33](=[O:36])[NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH2:11][CH:10]2[CH3:16])=[CH:22][CH:21]=1
Reactant: COc1ccc(NC(=O)CCl)cc1
Reactant: CC1CN(C(c2ccc(F)cc2)c2ccc(F)cc2)C(C)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)CN2CC(C)N(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2C)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 416 mg of 1-[bis(4-fluorophenyl)methyl]-2,5-dimethylpiperazine and 316 mg of N-(4-methoxyphenyl)chloroacetamide was dissolved in 5 ml of a 1:1 by volume mixture of tetrahydrofuran and N,N-dimethylformamide. 365 mg of anhydrous potassium carbonate were then added to the solution, and the reaction mixture was stirred at 80° C. for 5 hours. At the end of this time, ethyl acetate was added to the mixture, and the organic layer was separated. The organic layer was washed three times with water, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel thin layer chromatography using a 2:1 by volume mixture of cyclohexane and ethyl acetate as the developing solvent, to afford a purified 1-[bis(4-fluorophenyl)methyl]-4-[(4-methoxyphenyl) carbamoylmethyl]-2,5-dimethylpiperazine, melting at 131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[CH3:20])=[O:12]>C(N(CC)CC)C.C(O)C.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])=[O:12])[CH:7]=1
Reactant: Cc1ccc(C(=O)CBr)c(C)c1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Cn2cc(Cl)cnc2=O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloropyrimidin-2-one (425 mg) and 2-bromo-2',4'-dimethylacetophenone (682 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and the solid filtered off.
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10](=[O:19])[CH:9]([NH:20][C:21]([O:23]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:8]=2)CCCCC1.C(N([CH2:38][CH3:39])CC)C.[CH3:40][S:41]([NH:44][C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([N+:53]([O-])=O)[CH:48]=1)=[O:46])(=[O:43])=[O:42]>CN(C)C=O>[CH2:39]1[CH2:38][CH:7]([C:9]2([NH:20][C:21]([NH:53][C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([C:45]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:46])[CH:48]=3)=[O:23])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10]2=[O:19])[CH2:13][CH2:12][CH2:17]1
Reactant: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Reactant: CS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)Nc2cccc(C(=O)NS(C)(=O)=O)c2)(C2CCCCC2)N=Cc2ccccc21
Yield: 48.9 %

Procedure:
The rifle compound was prepared in the same way as that described in Example 11, Step 4, using 5-cyclohexyl-1,3-dihydro- 1-methyl-3(R,S)-[(4-nitrophenyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (0.5 g, 1.2 mmol), triethylamine (0.16 ml, 1.2 mmol), dimethylformamide (10 ml) and 1-(methylsulphonylaminocarbonyl)-3-nitrobenzene (0.25 g, 1.2 mmol). After recrystallisation from ethanol, the compound (0.15 g, 26%) was afforded as a pale beige solid. mp 175° C (dec.). 1H NMR (360 MHz, D6 -DMSO) δ 0.88 (1H, m), 1.10-1.67 (7H, m), 1.72-1.81 (1H, m), 1.91 (1H, m), 2.95 (1H, m), 3.32 (3H, s), 3.34 (3H, s) 5.08 (1H, d, J=8.2 Hz), 7.37 (3H,m), 7.47 (1H, d, J=7.9 Hz), 7.56 (2H, m), 7.64 (1H, dd, J=7.0 and 7.0 Hz), 7.75 (1H, d, J=7.9 Hz), 7.91 (1H, s), 9.21 (1H, s), 12.07 (1H, brs).