Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:13][C@@H:14](O)[CH2:15][CH:16]=[CH2:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:16]([CH2:15][CH:14]=[CH2:13])[CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1O
Reactant: C=CC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(C)Oc1ccc(F)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
To a solution of methyl 5-fluoro-2-hydroxybenzoate (1.0 g, 5.88 mmol), (R)-(−)-pent-4-en-2-ol (1.210 ml, 11.76 mmol) and triphenylphosphine (2.004 g, 7.64 mmol) in THF (14 ml) was added dropwise DIAD (1.486 ml, 7.64 mmol) and the resulting solution was stirred at rt. After 20 h, the reaction was diluted with Et2O and washed with 1N NaOH, water (3×'s) and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-40% EtOAc/hexane; 20 CV) to give methyl 5-fluoro-2-(pent-4-en-2-yloxy)benzoate (1.1331 g, 4.76 mmol, 81% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J=8.7, 3.3 Hz, 1H), 7.15 (ddd, J=8.9, 7.7, 3.4 Hz, 1H), 6.96 (dd, J=9.0, 4.2 Hz, 1H), 6.02-5.79 (m, 1H), 5.20-5.06 (m, 2H), 4.50-4.34 (m, 1H), 3.90 (s, 3H), 2.60-2.32 (m, 2H), 1.34 (d, J=6.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>>[NH2:1][C:2]1[C:11]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1ccccc1OCc1ccccc1
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2ccccc2OCc2ccccc2)c1N
Temperature: 110 °C
Yield: 70 %

Procedure:
A flask containing a mixture of methyl 3-amino-2,6-dibromoisonicotinate (3.00 g, 9.68 mmol), 2-benzyloxybenzeneboronic acid (2.52 g, 11.1 mmol), tetrakistriphenylphosphine palladium (0) (0.533 g, 0.461 mmol) and Na2CO3 (2.64 g, 24.9 mmol) was flushed with nitrogen. Toluene (24 mL) and methanol (8 mL) were added and the reaction was heated at 110° C. for 23 h. This was partitioned between EtOAc and aq. sat. sodium bicarbonate solution. The organic phase was washed with sat. aq. sodium bicarbonate solution and brine and then dried with sodium sulfate. Removal of the solvent followed by silica gel chromatography (step gradient elution with hexane containing 0 to 15% EtOAc afforded methyl 3-amino-2-(2-(benzyloxy)phenyl)-6-bromoisonicotinate (2.80 gm, 6.78 mmol, 74% yield) as a solid. This was quickly dissolved in TFA (40 mL) and the yellow solution cooled in an ice-bath. Sodium nitrite (0.935 g, 13.6 mmol) was added with stirring to give a dark red mixture. After 30 min, solid sodium azide (4.40 g, 67.8 mmol) was added over 5 min followed by Et2O (40 mL). This was stirred in the ice-bath for 30 min and then partitioned between H2O and EtOAc. The organic phase was separated and most of the solvent was removed. The residue was diluted with EtOAc, washed with aq. sat. NaHCO3 solution and brine and then dried over sodium sulfate. The solution was concentrated to about 50 ml volume and the solid was with EtOAc, to leave methyl 3-azido-2-(2-(benzyloxy)phenyl)-6-bromoisonicotinate (2.70 gm, 4.39 mmol, 65% yield) as a solid. 1,2-Dichloroethane (3 mL), rhodium octanoate dimer (0.171 g, 0.220 mmol), and crushed 4A° molecular sieves (2.70 g) were added and the mixture was heated at 80° C. for 48 h. It was diluted with a mixture of 25% MeOH in DCM and filtered. The solid was washed with additional 25% MeOH in DCM and the solvents removed from the combined filtrates. The residue was suspended in MeOH and filtration followed by washing with MeOH left methyl 9-(benzyloxy)-2-bromo-5H-pyrido[3,2-b]indole-4-carboxylate (1.84 g, 97% yield) as a solid. MS (ESI) m/z 411.0 (M+H). 1H NMR (500 MHz, chloroform-d) d ppm 9.63 (1H, br. s.), 7.98 (1H, s), 7.77 (2H, d, J=7.32 Hz), 7.48 (3H, m), 7.34 (1H, m), 7.16 (1H, d, J=7.93 Hz), 6.85 (1H, d, J=7.93 Hz), 5.48 (2H, s), 4.09 (3H, s).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]([CH:10]([O:23][CH3:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[C:8]#[N:9])[CH3:5])[CH3:2].[NH2:25][OH:26].Cl.C([O-])(O)=O.[Na+]>CO>[CH2:1]([O:3][CH:4]([O:6][CH:7]([CH:10]([O:23][CH3:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:13][CH:12]=1)/[C:8](=[N:25]/[OH:26])/[NH2:9])[CH3:5])[CH3:2]
Reactant: NO
Reactant: CCOC(C)OC(C#N)C(OC)c1ccc(N2CCOCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(C)OC(/C(N)=N/O)C(OC)c1ccc(N2CCOCC2)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(1-ethoxyethoxy)-3-methoxy-3-(4-morpholinophenyl)propanenitrile (0.60 g, 1.8 mmol) in anhydr MeOH (10 mL) under argon was added NH2OH.HCl (0.175 g, 2.5 mmol) and NaHCO3 (0.234 g, 2.8 mmol). The reaction was heated briefly at 75° C. then at 60° C. for 16 hrs. After cooling to room temp, the mixture was concentrated in vacuo to give (Z)-2-(1-ethoxyethoxy)-N′-hydroxy-3-methoxy-3-(4-morpholinophenyl)propanimidamide which was used in the next synthetic step without further purification (0.777 g).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:43][N:42]=[N:41][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(Cc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3cn(Cc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5](=[O:17])[CH2:6][CH2:7][CH:8]1[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][CH:10]=[C:9]1[CH3:16]>C(O)CO>[O:17]=[C:5]([CH2:6][CH2:7][CH:8]1[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][CH:10]=[C:9]1[CH3:16])[CH2:4][C:3]([O:2][CH2:1][CH2:1][O:2][C:3](=[O:18])[CH2:4][C:5](=[O:17])[CH2:6][CH2:7][CH:8]1[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][CH:10]=[C:9]1[CH3:16])=[O:18]
Reactant: COC(=O)CC(=O)CCC1C(C)=CCCC1(C)C
Solvent: OCCO
Product: CC1=CCCC(C)(C)C1CCC(=O)CC(=O)OCCOC(=O)CC(=O)CCC1C(C)=CCCC1(C)C
Temperature: 180 °C

Procedure:
A mixture of 25.2 g 3-oxo-5-(2,6,6-trimethyl-cyclohex-2-enyl)-pentanoic acid methyl ester and 4.3 g ethylene glycol was slowly heated to 180° C. while distilling off methanol. On completion, the reaction mixture was chromatographed over silica gel to yield a colourless liquid.
Reaction SMILES: [CH2:1]([NH:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:20](OCC)(=[O:24])[C:21]([O-])=[O:22].Cl>C1COCC1>[CH2:1]([N:3]1[C:21](=[O:22])[C:20]([OH:24])=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4]1(=[O:5])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: CCNS(=O)(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Temperature: 145 °C
Yield: 2754.6 %

Procedure:
N-Ethyl-1-phenylmethanesulfonamide (20 g) was divided into batches of 0.5 g each and taken in an 8 mL vial. To each vial was added potassium tert-butoxide (0.426 g, 3.8 mmol), ethyl oxalate (0.408 mL, 3.01 mmol) and dry THF (4 mL). Each vial was heated in a microwave reactor at 145° C. for 20 mins. Reaction mixture from all the vials were combined and treated with 1.5 N HCl (75 mL) and extracted with EtOAc. The organic layers were washed with water (3×25 mL) and brine, dried over Na2SO4 and evaporated. A small amount of the DCM was added to the solid residue and stirred well. Filtration gave nearly pure title compound (21 g, 82.6%) as off-white solid; 1H NMR (300 MHz, CDCl3) δ 1.47 (t, 3H, J=7.2 Hz), 3.8 (q, 2H, J=7.2 Hz), 7.3-7.5 (m, 3H), 7.9-8.0 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH3:20]>C1COCC1>[CH3:20][C:5]1([CH:9]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH2:4]1
Reactant: CI
Reactant: COc1cccc(C2CCCCC(=O)N2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1=CC=CC(C)(C2CCCCC(=O)N2)C1
Reaction time: 0.25 h

Procedure:
7-(3-Methoxyphenyl)-azepan-2-one, as described above in Step C, (0.13 g, 0.6 mmol) and NaH (60% dispersion in mineral oil) (0.03 g, 0.75 mmol) were dissolved in THF (5 mL) under Ar at ambient temperature. After 0.25 hours, iodomethane (0.064 mL, 1.0 mmol) was added and stirring was continued for 20 h. The reaction mixture was partitioned between EtOAc (100 mL)—H2O (100 mL), the organic layer separated, washed with H2O, dried (MgSO4), filtered and concentrated to give the title compound after SiO2 chromatography (CHCl3:MeOH, 100:1 to 50:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]1[O:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C[O-].[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:15])[CH2:14][O:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: COc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 51.8 %

Procedure:
(S)-1-(tert-Butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (10.0 g) was added to a mixed solution of p-methoxyphenol (11.64 g) and a solution of sodium methoxide in methanol (1M, 47 ml), and the mixture was stirred at 75° C. for 14 hours under heating. The reaction mixture was poured into water and extracted with toluene. The extract was washed with 10% sodium hydroxide and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (8.20 g).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][N:15]3C(=O)C4=CC=CC=C4[C:16]3=O)=[C:12]([CH3:26])[N:11]=[C:10]2[CH2:27][N:28]([CH3:30])[CH3:29])=[C:5](C(C2C=CC=CN=2)=O)[CH:4]=1.O.NN.[CH2:44](O)[CH3:45]>>[F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[CH:5][C:6]2[N:9]3[C:10]([CH2:27][N:28]([CH3:30])[CH3:29])=[N:11][C:12]([CH3:26])=[C:13]3[CH2:14][N:15]=[C:16]([C:45]3[CH:44]=[CH:4][CH:5]=[CH:6][N:9]=3)[C:7]=2[CH:8]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccc(C(F)(F)F)cc2C(=O)c2ccccn2)c1CN1C(=O)c2ccccc2C1=O
Reactant: CCO
Agent: NN
Solvent: O
Product: Cc1nc(CN(C)C)n2c1CN=C(c1ccccn1)c1cc(C(F)(F)F)ccc1-2

Procedure:
In the manner given in Example 4, N-[[1-[4-trifluoromethyl-2-(2-pyridylcarbonyl)phenyl]-2-[(dimethylamino)-methyl]-4-methylimidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 8-trifluoromethyl-6-(2-pyridyl)-1-[(dimethylamino)methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[C:14]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19]3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])[C:12]2=[O:34])[CH:5]=1.[Li+].[OH-]>C1COCC1.O>[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:14]2[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])[C:12](=[O:34])[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:35])=[O:2])[C:16](=[O:17])[CH:15]=2)[CH2:19]1
Reactant: COC(=O)c1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2cccc(C(=O)O)c2)c1=O

Procedure:
A crude mixture of compound 24 (˜50 mg) was treated with LiOH in THF-water (10:1) to give the title compound 25. 1H-NMR (400 MHz, CDCl3—CD3OD 10:1) δ 7.90 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.45 (d, J=7.3 Hz, 1H), 7.26-7.36 (m, 2H), 7.17 (d, J=8.1 Hz, 1H), 5.39 (s, 1H), 5.10-5.25 (ABq, J=36.9, 15.5 Hz, 2H), 5.03 (s, 2H), 3.31 (m, 2H), 2.95 (m, 1H), 2.81 (m, 1H), 2.64 (m, 1H), 2.07 (m, 1H), 1.82 (m, 1H), 1.51-1.68 (m, 2H). MS (ES) [m+H] calc'd for C25H26N5O4, 460.2; found 460.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[I:15])=[CH:5][CH:4]=1.[CH2:16]([C:20]1[NH:21][C:22]([CH:26]=[O:27])=[C:23]([Cl:25])[N:24]=1)[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:16]([C:20]1[N:21]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[I:15])=[CH:5][CH:4]=2)[C:22]([CH:26]=[O:27])=[C:23]([Cl:25])[N:24]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: BrCc1ccc(-c2ccccc2I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2I)cc1
Reaction time: 24 h

Procedure:
A solution of 4-(bromomethyl)-2'-iodobiphenyl (9.23 g; preparable as described in Example 2(b)) in dry dimethylformamide (50 ml) was added to a stirring mixture of 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (preparable as described in Drugs of the Future (1991), Vol. 16, p 305), anhydrous potassium carbonate (6.9 g) and dry dimethylformamide (100 ml), at ambient temperature. Stirring was continued at ambient temperature for 24 hours. Water (200 ml) was added and the resulting mixture was extracted with diethyl ether (500 ml then 200 ml). The combined extracts were washed with water (2×100 ml) and dried over magnesium sulphate. The organic solvent was evaporated and the residual orange oil was purified by flash chromatography on silica gel (eluting with 5% then 30% ethyl acetate in petroleum ether (b.p. 60°-80° C.)) to give the intermediate compound 2-butyl-4-chloro-1-(2'-iodobiphenyl-4-ylmethyl)-1H-imidazol-5-carboxaldehyde as a yellow oil (8.06 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CCC#N)=[O:16])=[C:13]([CH3:22])[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:11](=[S:33])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].N12CCCN=C1CCCCC2>O1CCOCC1.Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:22])[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:11](=[S:33])[NH:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1=C(C(=O)OCCC#N)C(c2ccc(C#N)cc2)NC(=S)N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)NC(=S)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Cyanoethyl 4-(4-cyanophenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 16; 47 mg, 0.1 mmol) is dissolved in 0.5 ml dioxane. After addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (15 μl, 15 mg, 0.1 mmol), the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with 1 N hydrochloric acid and extracted with ethyl acetate. After drying with magnesium sulfate and evaporating off the solvent, the residue is purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; flow rate: 25 ml/min; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:18]([CH:19]=O)[C:17]=1[OH:27]>>[OH:27][C:17]1[C:16]([O:15][CH3:14])=[CH:23][C:22]([N+:24]([O-:26])=[O:25])=[CH:21][C:18]=1[CH2:19][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: COc1cc([N+](=O)[O-])cc(C=O)c1O
Product: COc1cc([N+](=O)[O-])cc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(2-Hydroxy-3-methoxy-5-nitro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-methoxy-5-nitrosalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.65-2.70 (m, 4H), 3.59-3.66 (m, 4H), 3.85 (s, 2H), 3.99 (s, 3H), 5.40 (s, 1H), 7.67 (s, 1H), 7.72 (s, 1H), 7.85 (s, 1H), 12.20 (br s, 1H). Mass spectrum (ES) MH+=362.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[O:13][CH3:14].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C.C(Cl)Cl>[OH:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:10])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)C(C)C)ccc1O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)C(C)C)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
15.0 g of 4'-hydroxy-3'-methoxy-2-methylpropiophenone are dissolved in 300 ml of glacial acetic acid and 7.65 ml of 50.5 percent nitric acid (11.2N) in 40 ml of glacial-acetic acid are added dropwise thereto while stirring within 15 minutes. After 15 minutes the reaction mixture is poured into ice-water and the separated crystals are filtered under suction, washed with water and dissolved in methylene chloride. The solution is dried over sodium sulfate and evaporated. The crude product obtained is taken up in methylene chloride and filtered over 100 g of silica gel. The thus-obtained crystals are recrystallized from methylene chloride/n-hexane. There is obtained 4'-hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone in the form of yellow crystals of m.p. 85°-87°.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:13]([O-])=[CH:12][C:11]=2[N:10]=[CH:9]1)[CH3:7])(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:24])=O>ClCCl>[C:1]([O:4][CH2:5][CH:6]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([Cl:24])[C:11]=2[N:10]=[CH:9]1)[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)n1cnc2c[n+]([O-])c3ccccc3c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OCC(C)n1cnc2c(Cl)nc3ccccc3c21

Procedure:
To a stirred mixture of 10.2 g (0.036 mole) of 1-(2-acetoxy-1-methylethyl)-1H-imidazo[4,5-c]quinolin-5-oxide (prepared according to the method of Example 8) in 100 ml of dichloromethane was added in portions, 4.2 ml, 6.9 g (0.45 mole) of phosphorus oxychloride. After 4 hours the mixture was evaporated in vacuo. The residue was added to a saturated sodium bicarbonate solution, and that solution was extracted with chloroform. The chloroform layer was washed with both saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuo to yield light brown solid 1-(2-acetoxy-1-methylethyl)-4-chloro-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:8]=3[S:7](=[O:18])(=[O:17])[N:6]=[CH:5]2)[CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]2[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=[N:6][S:7](=[O:18])(=[O:17])[C:8]=2[CH:13]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=CN2C1CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)S(=O)(=O)N=CN2C1CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-cyclopropyl-7-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide (5 g; prepared in Step C of Example 41) in ethanol (180 mL) there is added 10 % palladium-on-carbon (500 mg). The suspension is placed in a hydrogenator under 10 atmospheres of H2 for 30 minutes at ambient temperature. The suspension is concentrated to dryness under reduced pressure and the residue is taken up in boiling acetone (300 mL). The insoluble material is removed by filtration in the hot state and is washed with boiling acetone. The filtrate is concentrated to dryness and the residue is recrystallised from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:13]([O:15][CH3:16])=[O:14].[F:22][N+]1C=C(C(F)(F)F)C=CC=1S([O-])(=O)=O.S([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:22])=[CH:5][C:4]=1[CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: O=S(=O)([O-])c1ccc(C(F)(F)F)c[n+]1F
Reactant: CCCCCC(CC(=O)OC)c1ccc(OC)cc1OC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCCC(CC(=O)OC)c1cc(F)c(OC)cc1OC
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 18 %

Procedure:
A solution of 943 mg (3.20 mmol) of methyl 3-(2,4-dimethoxyphenyl)octanoate [prepared as described in Preparation 32(i)] in 5 ml of 1,2-dichloroethane was added to a suspension of 864 mg (3.53 mmol) of 1-fluoro-5-trifluoromethylpyridinium-2-sulfonate in 10 ml of 1,2-dichloroethane, and the resulting mixture was stirred at 90° C. for 2.5 hours. The reaction mixture was then poured into a saturated aqueous solution of sodium sulfite, and the aqueous mixture was freed from the solvent by evaporation under reduced pressure, after which it was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 20 g of silica gel, using an 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give a mixture containing the title compound. This mixture was further purified by column chromatography through 40 g of silica gel, using a 7:1 by volume mixture of hexane and acetone as the eluent, to give the desired fluoride compound as an oily substance in a 18% yield.
Reaction SMILES: [H][H].[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][CH:5]=1.[ClH:14]>CO.[Pt](=O)=O>[ClH:14].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][NH:6][CH2:5]1
Reactant: Cc1cncc2ccccc12
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CC1CNCc2ccccc21
Reaction time: 4 h

Procedure:
In a hydrogen atmosphere 0.50 g (3.5 mmol) 4-methyl-isoquinoline, 50 mg platinum dioxide in 50 mL methanol and 3.5 mL 1M aqueous hydrochloric acid solution were hydrogenated at RT and 3 bar for 4 h. After removal of the catalyst by suction filtering the reaction mixture was evaporated down. A mixture of educt and product was obtained, which was reacted further without any further purification.