Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23](O)=[O:24])[S:22][C:15]=12)=[O:8].C1C[N:32]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(N)C.C1COCC1.Cl>CN(C=O)C.O>[CH2:31]([NH:32][C:23]([C:21]1[S:22][C:15]2[C:16](=[N:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]2[CH:26]=[CH:27][CH:28]=[C:10]([NH:9][C:7]([C:3]3[O:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[O:8])[CH:11]=2)[CH:20]=1)=[O:24])[CH3:30]
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc3cc(C(=O)O)sc23)c1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCNC(=O)c1cc2nccc(Oc3cccc(NC(=O)c4occc4C)c3)c2s1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred, cooled (0° C.) solution of 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.30 mmol) in anhydrous DMF (10 ml) were added PyBOP (171 mg, 0.33 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at 0° C. for 5 minutes, followed by addition of 2M ethylamine solution in THF (0.18 ml, 0.36 mmol). Stirring was continued at 0° C. for another 40 minutes. The mixture was poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried to give N-ethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide as light yellow solid. Yield: 115 mg, 90%.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].C([O-])(=O)C.[Na+].[Br:23]Br>C(O)(=O)C>[Br:23][C:15]1[S:14][C:13]([C:10]2[CH:11]=[CH:12][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:17][CH:16]=1
Reactant: BrBr
Reactant: CC(C)Oc1ccc(-c2nccs2)cc1C#N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1C#N
Temperature: 20 °C

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-(1,3-thiazol-2-yl)benzonitrile (D64) (215 mg) and sodium acetate (144 mg) in acetic acid (8 mL) stirred at room temperature was added a solution of Br2 (0.045 mL) in acetic acid (1 mL) dropwise. The reaction mixture was stirred at 20° C. until start material was consumed completely. The reaction mixture was basified with 2M NaOH, then diluted with ethyl acetate. The mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulphate. After concentration, the crude product 5-(5-bromo-1,3-thiazol-2-yl)-2-[(1-methylethyl)oxy]benzonitrile (D65) (320 mg) was used for next step without further purification. δH (CDCl3, 600 MHz): 1.36 (6H, d), 4.65 (1H, m), 6.95 (1H, d), 7.64 (1H, s), 7.92 (1H, d), 7.97 (1H, dd).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[C:16]([OH:21])(=O)[C:17]#[C:18][CH3:19].[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][C:39]([Br:42])=[C:38]([Br:43])[CH:37]=1>O1CCCC1>[Br:43][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:16](=[O:21])[C:17]#[C:18][CH3:19])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][C:39]=1[Br:42]
Reactant: CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)c(Br)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Br)c(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
Isobutyl chloroformate (0.984 g, 7.18 mmol) and N-methylmorpholine (0.725 g, 7.18 mmol) were added to an ice cold solution of 0.604 g (7.18 mmol) of 2-butynoic acid in 25 mL of tetrahydrofuran. After 10 min, a solution of 1.20 g (2.87 mmol) of 6-amino-4-[(3,4-dibromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran was added dropwise. After stirring overnight at 25° C., volatile material was removed and the residue was slurried in water and filtered. The crude product was washed with boiling EtOAC and ethanol and dried in vacuo(50° C.) to give 0.651 g of brown solid: mass spectrum (electrospray, m/e): M+H 485.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH2:14][CH2:15][CH3:16])=[C:9]([O:11][CH3:12])[CH:10]=1)(=O)C.[OH-].[Na+]>CO>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([OH:4])[CH:6]=[CH:7][C:8]=1[O:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCOc1ccc(OC(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(O)cc1OC
Reaction time: 1 h

Procedure:
5-Acetoxy-2-n-propoxyanisole (39.9 g, 0.178 M), 1.67 N sodium hydroxide solution (300 ml) and methanol (300 ml) were refluxed with stirring (1 hr). The methanol was then removed, the residue diluted with water and extracted with ether. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with ether. The combined extracts were washed with water, dried (sodium sulphate) and evaporated. The product was then passed through a short pad of florisil eluting with chloroform-methanol (95:5) and the filtrate evaporated to give 3-methoxy-4-n-propoxyphenol as an oil which solidified on standing. After trituration with 40/60 petrol and filtration the product had m.p. 54°-56° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:5]([CH2:11][CH:12]1[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH2:13]1)=[N:6]2.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].[OH-].[NH4+]>CC1C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:5]([CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([C:33]([O:34][CH2:35][CH3:36])=[O:37])[CH2:16][CH2:17]1)=[N:6]2
Reactant: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ncnc(Cl)c32)cc1
Reactant: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(Cc2nc3ncnc(Cl)c3n2Cc2ccc(F)cc2)CC1
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 16 parts of 6-chloro-7-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-7H-purine, 4.65 parts of ethyl carbonochloridate and 180 parts of methylbenzene was stirred for 2 hours at reflux temperature. After cooling, the reaction mixture was treated with ammonium hydroxide and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated, yielding 18.7 parts (100%) of ethyl 4-[[6-chloro-7-[(4-fluorophenyl)methyl]-7H-purin-8-yl]methyl]-1-piperidinecarboxylate as a residue (compound 28).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]>Br>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(OC)cc3)cc3sccc23)CC1
Agent: Br
Product: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3sccc23)CC1
Yield: 80.1 %

Procedure:
4-(4-Ethylpiperazin-1-yl)-6-(4-methoxyphenyl)thieno[3,2-c]pyridine (5.2 g) was dissolved in 48% hydrobromic acid (50 ml), and the mixture was reacted at 130° C. for 1.5 hr. The reaction solution was evaporated, basified with potassium carbonate and extracted with chloroform. The chloroform layer was washed with water, dried and evaporated. The resulting residue was purified by NH-silica gel column chromatography (ethyl acetate), to give the title compound as a pale brown powder (4.0 g, yield; 80%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]3C=N[C:25]([C:28]([OH:31])(C)[CH3:29])=[N:26][CH:27]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].Cl[C:33]1[N:34]=CC(C(=O)C)=NC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:28]([C:25]1[N:26]=[CH:27][C:22]([C:13]2[CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:9]3[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=3[CH:12]=2)=[N:34][CH:33]=1)(=[O:31])[CH3:29]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)cc(-c3ccccn3)c2s1
Reactant: CC(=O)c1cnc(Cl)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)=O)cn3)cc(-c3ccccn3)c2s1
Temperature: 100 °C

Procedure:
Intermediate 1 (171 mg, 0.5 mmol), 1-(5-chloropyrazin-2-yl)ethanone (94 mg, 0.60 mmol) and PdCl2(dppf) (41 mg, 0.05 mmol) were suspended in 1,4-dioxane (8 mL). A solution of Cs2CO3 (488 mg, 1.50 mmol) in H2O (2 mL) was added. The mixture was then heated under microwave irradiation at 100° C. for 30 min. The mixture was filtered, washed with H2O, EtOH, MeOH and Et2O to afford i (172 mg, 82%). MS: 419.06 [M+H]+.
Reaction SMILES: [C:1]([CH:6]1[C:11]2[NH:12][C:13](=[O:15])[S:14][C:10]=2[CH2:9][CH2:8][CH2:7]1)([O:3]CC)=[O:2].[OH-].[Na+].Cl>O>[C:1]([CH:6]1[C:11]2[NH:12][C:13](=[O:15])[S:14][C:10]=2[CH2:9][CH2:8][CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1CCCc2sc(=O)[nH]c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCc2sc(=O)[nH]c21
Temperature: 20 °C
Reaction time: 1 h
Yield: 8.4 %

Procedure:
A mixture of 6.8 g of 4-carbethoxy-2,3,4,5,6,7-hexahydrobenzothiazoline-2-one and 6 ml of 10 N sodium hydroxide in 100 ml of water was refluxed for 3 hours and then cooled to 20°C. 6 ml of 10 N hydrochloric acid were added thereto and the mixture was vacuum filtered. The precipiate was washed with acetone and 1 g of the raw product was taken up in a solution of 0.42 g of sodium bicarbonate in 40 ml of water. The mixture was stirred for 1 hour, was washed with ethyl acetate and was acidified with 1 N hydrochloric acid. The mixture was vacuum filtered and the precipitate was washed with water and dried to obtain 0.5 g of 4-carboxy-2,3,4,5,6,7-hexahydrobenzothiazole-2-one melting at 192°C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:13]([N:15]1[CH2:16][CH2:17][N:18]([CH:21]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:19][CH2:20]1)=[O:14]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 0.83 h
Yield: 101 %

Procedure:
(S)-(1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-carbamic acid tert-butyl ester (7.30 g, 14.6 mmol, Example 50) was dissolved in CH2Cl2 (50 mL) under nitrogen at ambient temperature. To this solution was added trifluoroacetic acid (12 mL). The resulting reaction mixture was stirred for 50 minutes, then concentrated in vacuo. The viscous pale-amber oil obtained was mixed with 50 mL of saturated aqueous NaHCO3 solution and stirred for 10 minutes, 50 mL of CH2Cl2 was then added. The resulting mixture was stirred until bubbling ceased. The two layers were separated, organic layer was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording 5.92 g (92%) of the pure titled compound as a off-white foam: mp 61-68° C. APCI-MS m/z 402.3 (MH+);
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=O>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:9]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH3:11])[C:8]([OH:13])=[O:12])=[CH:3][CH:2]=1
Reactant: CC(=O)C(=O)O
Reactant: Oc1ccccc1
Product: CC(C(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
reacting phenol with pyruvic acid in an acidic medium to obtain 2,2-bis-(4-hydroxyphenyl) propionic acid;
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[Br:11][C:12]1[C:13](Cl)=[N:14][CH:15]=[CH:16][CH:17]=1>CN(C=O)C>[Br:11][C:12]1[C:13]([O:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH2:1])[CH2:3][CH2:4]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@H](Oc2ncccc2Br)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) 150 mL reaction tube equipped with reflux condenser and under a nitrogen atmosphere, were added trans-4-aminocyclohexanol (2.0 g, 17 mmol), NaH (2.08 g, 60% dispersion in mineral oil, 52.1 mmol), and DMF (25 mL) to give a colorless solution. After stirring for 1 h, 3-bromo-2-chloropyridine (3.34 g, 17.4 mmol) was added to the mixture And the resulting mixture heated at 60° Celsius for 5 h. After the starting material was consumed, the reaction was cooled to room temperature and quenched with H2O (2 mL). The reaction mixture was concentrated to dryness and the resultant residue purified by FCC to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (dd, J=4.8, 1.6, 1H), 7.98 (dd, J=7.7, 1.6, 1H), 6.89 (dd, J=7.7, 4.8, 1H), 4.92 (dd, J=9.4, 5.2, 1H), 2.98 (s, 1H), 2.05 (m, 2H), 1.95 (m, 2H), 1.53-1.38 (m, 4H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C(CC(=O)C)(=O)C.[C:24]1(C)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:26]([CH3:27])=[CH:25][CH:24]=[C:29]2[CH3:28])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(N)c1
Reactant: Cc1ccccc1
Solvent: CC(=O)CC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cccc(-n2c(C)ccc2C)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
2-(3-Amino-phenoxy)-2-methyl-propionic acid ethyl ester (0.52 g, 2.36 mmol) was dissolved in Toluene (2 ml) and acetylacetone (0.53 m, 4.4 mmol) was added to the solution. The resulting mixture was refluxed for 6 h with a Dean-Stack apparatus. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material thus obtained was purified by flash column affording 2-[3-(2,5-Dimethyl-pyrrol-1-yl)-phenoxy]-2-methyl-propionic acid ethyl ester (0.5 g, 71%). 1H NMR (400 MHz, CDCl3): 1.): 1.24 (t, J=7.2 Hz, 3H), 1.57 (s, 6H), 2.02 (s, 6H), 4.23 (q, J=7.2 Hz, 2H), 5.88 (s, 2H), 6.71 (s, 1H), 6.83-6.91 (m, 2H), 7.26-7.33 (m, 1H); MS (EI) m/z: 302 (M+1).
Reaction SMILES: C(O)(=O)C.[Cl-].[NH4+:6].C[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:15]=[C:16]([C:17](=[NH:19])[O-])[C:9]=12>CO>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:14]1[C:10]2=[N:11][CH:12]=[CH:13][CH:8]=[C:9]2[C:16]([C:17]([NH2:19])=[NH:6])=[N:15]1
Reactant: Cc1ccnc2c1c(C(=N)[O-])nn2Cc1ccccc1F
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12

Procedure:
33.76 g (32.19 ml, 562 mmol) of glacial acetic acid and 9.28 g (173 mmol) of ammonium chloride are added to the solution of methyl(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidate in methanol obtained from example 2E), and the mixture is stirred under reflux overnight. The solvent is evaporated in vacuo, the residue is thoroughly triturated with acetone, and the precipitated solid is filtered off with suction.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6].[CH2:23]([N:26]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]1)[CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:23]([N:26]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6])[CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]
Reactant: O=C1Nc2cccnc2N(C(=O)NCCBr)c2ccccc21
Reactant: CCCN(CCC)CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
The darkened mixture of 1.806 g (0.005 mol) of 11-[[[2-bromo-ethyl]amino]carbonyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 0.992 g (0.005 mol) of 2-[(dipropylamino)-methyl]piperidine, 20 ml of anhydrous acetonitrile and 0.75 g (0.005 mol) of sodium iodide was refluxed for 4 hours with stirring under a nitrogen atmosphere. The mixture was left to cool, 50 ml of 10% aqueous potassium carbonate solution were added and the organic phase was separated off. The aqueous phase was extracted five times in all, with 10 ml aliquots of dichloromethane. The combined organic extracts were dried over sodium sulphate with the addition of animal charcoal and evaporated down in vacuo. The residue was purified by column chromatography on silica gel (30-60 microns) and using dichloromethane/cyclohexane/methanol/conc. ammonia 68/15/15/1 (v/v/v/v) as eluant. The corresponding eluates were evaporated down, the residue was recrystallised once from acetonitrile and dried in a vacuum dryer at 50° C. until a constant weight was obtained. 0.7 g (29% of theory) of colourless crystals were obtained, m.p. 163°-164° C., which were identical according to their mixed melting point, thin layer chromatogram and IR spectrum, to a preparation prepared according to Example 29.
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:21])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl:22][C:23]1[C:29]([CH3:30])=[C:28]([Cl:31])[CH:27]=[CH:26][C:24]=1[NH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[Cl:22][C:23]1[C:29]([CH3:30])=[C:28]([Cl:31])[CH:27]=[CH:26][C:24]=1[N:25]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:11](=[O:21])[C:2]([CH3:1])=[C:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1c(Cl)ccc(N)c1Cl
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: Cc1c(Cl)ccc(-n2c(-c3ccccc3)cc(=O)c(C)c2-c2ccccc2)c1Cl

Procedure:
In 170 ml of chlorobenzene were dissolved 3.4 g (0.012 mole) of 2-methyl-1,5-diphenyl-1,3,5-pentanetrione and 10.6 g (0.06 mole) of 2,4-dichloro-3-methylaniline, followed by further addition of 4.1 g (0.022 mole) of para-toluenesulfonic acid and 35.0 g of Molecular Sieves 5A to the solution. After heating the reaction mixture under reflux for 2 hours, solid matter was removed from the reaction mixture, followed by an addition of 200 ml of chloroform. The resultant mixture was washed first with 100 ml of 10% hydrochloric acid and then with 100 ml of a 10% aqueous solution of sodium hydroxide. The mixture was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate). Upon recrystallization of the resultant crystals from a 2:1 mixed solvent of acetone and hexane, 0.7 g of 1-(2,4-dichloro-3-methylphenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of 237°-238° C. was obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N+:9]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)([O-:11])=[O:10]>CN(C=O)C>[Br:1][C:17]1[CH:18]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: Nc1ccc([N+](=O)[O-])cc1Br
Temperature: 27.5 °C

Procedure:
N-Bromosuccinimide (26 g, 146 mmol) was added to a stirred solution of 4-nitro aniline (20 g, 145 mmol) in dry DMF (75 mL) in portions under stirring at temperature 25-30° C. Reaction mixture was stirred for 30 min. It was poured over crushed ice slowly under vigorous stirring, filtered and dried, to afford the title compound.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([O:9][C:10]1[CH:15]=[C:14](Br)[C:13]([F:17])=[CH:12][C:11]=1[Cl:18])[CH:7]=[CH2:8].[C:19](=[O:21])=[O:20].Cl>O1CCCC1>[CH2:6]([O:9][C:10]1[C:11]([Cl:18])=[CH:12][C:13]([F:17])=[C:14]([CH:15]=1)[C:19]([OH:21])=[O:20])[CH:7]=[CH2:8]
Reactant: C=CCOc1cc(Br)c(F)cc1Cl
Reactant: O=C=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: C=CCOc1cc(C(=O)O)c(F)cc1Cl
Reaction time: 0.5 h

Procedure:
At 20-25 C., 200 ml (0.4 mol) of a 2 M solution of isopropyl-magnesium chloride and tetrahydrofuran were added over a period of 30 minutes to a solution of 85 g (0.32 mol) of 1-allyloxy-5-bromo-2-chloro-4-fluorobenzene in 200 ml of tetrahydrofuran. The mixture was then stirred for 30 minutes and 50 g (1.1 mol) of dry ice were added with ice-cooling. The mixture was subsequently stirred for 16 hours, after which 250 ml of a 10% strength hydrochloric acid were added with ice-cooling. The aqueous phase was separated off and extracted with methyl tert-butyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and finally concentrated. The crude product was purified by trituration with a little n-hexane and the precipitated product of value was filtered off. Yield: 59.7 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[N+:27]([O-:29])=[O:28]>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:26][N+:27]([O-:29])=[O:28]
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Reactant: O=[N+]([O-])/C=C/c1ccccc1F
Solvent: Cc1ccccc1
Product: O=C(c1ccc2c(C(C[N+](=O)[O-])c3ccccc3F)c[nH]c2c1)N1CCOCC1
Temperature: 150 °C
Reaction time: 96 h
Yield: 18.5 %

Procedure:
A sealed tube containing (1H-indol-6-yl)(morpholino)methanone (0.6323 g, 2.75 mmol) and (E)-1-fluoro-2-(2-nitrovinyl)benzene (0.551 g, 3.30 mmol) in toluene (14 mL) was stirred at 150° C. for 4 days. The reaction was cooled and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 80 g column eluting with 0-100% EtOAc/hexanes. Appropriate fractions (100% elution) were collected and concentrated in vacuo to give the desired product (0.222 g, 0.508 mmol, 18.5% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:10][C:11]2[N:15]([CH3:16])[C:14]([CH2:17][O:18][CH:19]3OCCO3)=[N:13][C:12]=2[CH:24]([CH3:26])[CH3:25])[CH:6]=[C:7]([Cl:9])[CH:8]=1.[C:27](=O)([O-])[OH:28].[Na+]>CO>[Cl:9][C:7]1[CH:6]=[C:5]([S:10][C:11]2[N:15]([CH3:16])[C:14]([CH2:17][O:18][CH2:19][CH:27]=[O:28])=[N:13][C:12]=2[CH:24]([CH3:25])[CH3:26])[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: O=C([O-])O
Reactant: CC(C)c1nc(COC2OCCO2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nc(COCC=O)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
In a mixture of methanol (1 ml) and 6N-hydrochloric acid (1 ml) was dissolved 156 mg (0.37 mmol) of 5-(3,5-dichlorophenylthio)-2-(1,3-dioxolan-2-yloxymethyl)-4-isopropyl-1-methylimidazole (23a), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution to neutralize, and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was fractionated by silica gel chromatography (ethyl acetate) to obtain 39 mg of {[5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methoxy} acetaldehyde (24a) as oil (yield 28%).