Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:5][C:6]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1.[CH:31](=O)[CH2:32][CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:5][C:6]([CH:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:21])([CH3:22])[CH2:20]2)=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14]2)[CH:8]=1
Reactant: COc1cc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)cc1N1CCCCC1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN1CCN(c2cc(OC)c(N3CCCCC3)cc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1-[5-methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (5 mg, 0.0121 mmol) produced in Example (72b), propionaldehyde (1.4 mg, 0.0242 mmol) and tetrahydrofuran (0.3 mL) was added sodium triacetoxyborohydride (5 mg, 0.0242 mmol), followed by stirring for 1 hour and 10 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The solvent was distilled off nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-[5-methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solvent was distilled of by nitrogen stream. Heptane was added to the obtained residue to produce a solid, which was then triturated by sonication. The supernatant heptane solution was removed and the resulting solid was dried to give 6.1 mg of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=2.[Cl-].[CH:15](=[N+:22]([CH3:24])[CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:23][N:22]([CH3:24])[CH:15]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1C(c1ccccc1)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-5-nitro-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc([N+](=O)[O-])cc2)c1N
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc(-c2ccc([N+](=O)[O-])cc2)c1N
Yield: 45.5 %

Procedure:
A flask containing a mixture of methyl 3-amino-6-bromo-2-(4-nitrophenyl)isonicotinate (1.70 g, 4.83 mmol), 3-(trifluoromethyl)phenylboronic acid (1.83 g, 9.66 mmol), powdered potassium phosphate tribasic (3.38 g, 15 9 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (0.460 g, 0.966 mmol), and Pd(OAc)2 (0.108 g, 0.483 mmol) was flushed with nitrogen. THF (20 mL) was added and the mixture was heated at reflux under nitrogen for 2 hr. The mixture was diluted with EtOAc and washed with water and brine. After drying with Na2SO4), the solvents removed and the residue was suspended in a mixture of 20% EtOAc in hexane. Filtration afforded methyl 3-amino-2-(4-nitrophenyl)-6-(3-(trifluoromethyl)phenyl)-isonicotinate (1.0 g, 2.2 mmol, 46% yield). MS (ESI) m/z 417.99 (M+H). 1H NMR (400 MHz, chloroform-d) δ ppm 8.39-8.47 (2H, m), 8.22-8.27 (2H, m), 8.19 (1H, d, J=7.55 Hz), 7.93-8.03 (2H, m), 7.54-7.65 (2H, m), 6.13 (2H, br. s.), 4.04 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:17][OH:18])=[C:10]([C:13]([F:16])([F:15])[F:14])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:12][S:11][C:10]=1[C:13]([F:14])([F:15])[F:16])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1c(-c2ccc(Cl)cc2)csc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)csc1C(F)(F)F
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed [4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methanol (500 mg, 1.71 mmol, 1.00 equiv), triethylamine (521 mg, 5.15 mmol, 3.01 equiv), dichloromethane (10.0 mL). This was followed by the addition of MsCl (390 mg, 3.42 mmol, 2.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 0.5 h at 25° C. The reaction progress was monitored by TLC(ethyl acetate/petroleum ether=1:6). The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 675 mg of [4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate as a light yellow solid. The crude could be used for the next step directly. Mass spectrum (ESI, m/z): Calcd. for C13H10C1F3O3S2, 371.0 (M+H). found 371.0.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:28])[CH2:23][C:24]([F:27])([F:26])[F:25])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:28])[CH2:23][C:24]([F:27])([F:25])[F:26])=[O:19]
Reactant: O=C(CC(F)(F)F)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(CC(F)(F)F)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 94.3 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-7-oxo-N′-(3,3,3-trifluoropropanoyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 229 (0.26 g, 0.65 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)-6-hydroxy-7-oxo-N′-(3,3,3-trifluoropropanoyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 230 (0.19 g, 93.6%) as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccc(Cl)cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-chlorobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-chlorobenzoyl chloride in a similar manner as described above to give a tan solid (69% yield). 1H-NMR (CDCl3): δ 8.89 (s, 1H), 7.71 (d, 2H), 7.60 (m, 1H), 7.40 (d, 2H), 7.23 (dd, 1H), 7.17 (dd, 1H), 6.36 (d, 1H), 5.30 (m, 1H), 2.69 (m, 2H), 2.29 (m, 1H), 1.96 (m, 3H); MS m/z 403 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:19][CH:20]=[CH2:21])[C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])[CH3:24].[H-].[Na+]>FC(F)(F)C1C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:19][CH:20]=[CH2:21])[C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:35][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH:23]([CH3:25])[CH3:24])=[CH:27][CH:28]=3)(=[O:33])=[O:34])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(Br)ccc2C1
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: FC(F)(F)c1ccccc1
Product: C=CCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2C1
Reaction time: 0.08 h
Yield: 177.4 %

Procedure:
In an inert atmosphere (argon), allyl-((S)-6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (1.94 g, 5.3 mmol) was dissolved in trifluortoluol (10 ml) at room temperature. Tris(dibenzylideneacetone)dipalladium (230 mg, 0.25 mmol) and tri-tert-butyl-phosphane (152 mg, 0.75 mmol) were added to the reaction mixture. In a separate flask, 4-Isopropyl-benzenesulfonamide (996 mg, 5 mmol) was dissolved in trifluortoluol (20 ml) at 65° C. Sodium hydride (50% in oil) (240 mg, 5 mmol) was added, stirred for 5 minutes and added to the reaction mixture. The reaction mixture was dispensed into 8 vials and stirred for 1 hour at 150° C. in the microwave (CEM). The combined reaction mixture was evaporated to dryness. H20 (50 ml) was added and extracted three times with 50 ml diethylether. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield 4.3 g of crude product. The crude product was purified with silica gel chromatography with cyclohexane/ethyl acetate (85:15) as eluent, yielding the product (1.5 g, 50% purity, 31% yield).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH2:7]([NH:14][C:15]([C:17]1[S:21][C:20]([NH2:22])=[N:19][C:18]=1[CH3:23])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([NH:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[N:19][C:18]=1[CH3:23])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)C2CC2)sc1C(=O)NCc1ccccc1
Yield: 87 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use cyclopropanecarbonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 87% yield; m. p. 241-243° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.5 (s, 1H), 8.49 (t, J=6.0 Hz, 1H), 7.31-7.17 (m, 5H), 4.34 (d, J=6.0 Hz, 2H), 1.94-1.84 (m, 1H), 1.15-1.08 (m, 4H); 13C NMR (DMSO-d6, 75 MHz) δ 172.7, 162.2, 157.3, 151.0, 140.1, 128.7, 127.6, 127.1, 118.8, 43.0, 17.4, 14.1, 9.0; MS (ES+) m/z 316.3 (M+1).
Reaction SMILES: [C:1]([NH:11][C:12]([CH3:17])([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:18][C@@H:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:4]([O:3][C:1]([NH:11][C:12]([CH3:13])([CH3:17])[C:14]([NH:18][C@@H:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:33])=[O:16])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H]1CCc2cc([N+](=O)[O-])ccc2NC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
Prepared from N-carbobenzyloxy-2-methylalanine and 3(R)-amino-7-nitro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step A) substituting benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate for benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate according to the procedure described in Example 1, Step I. 1H NMR (400 MHz, CDCl3): δ 1.48 (s, 3H), 1.49 (s, 3H), 2.00 (m, 1H), 2.73 (m, 2H), 2.92 (m, 1H), 4.45 (m, 1H), 5.07 (s, 2H), 5.30 (s, 1H), 7.05 (d, 8 Hz, 1H), 7.30 (m, 6H), 8.06 (dd; 8, 6 Hz; 1H), 8.13 (d, 2.5 Hz, 1H), 8.35 (s, 1H). FAB-MS: calculated for C22 H24N4O6 424; found 425 (M+H, 100%).
Reaction SMILES: [OH-:1].[K+].C(P(C(C)(C)C)C1C=CC=CC=1[C:14]1[C:19](C(C)C)=[CH:18][C:17](C(C)C)=[CH:16][C:15]=1[CH:26](C)C)(C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:26]([O:1][CH2:26][C:15]1[CH:14]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1
Reactant: [OH-]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1.25 h

Procedure:
Method C) Compound 28 was dissolved in toluene (8 mml/mmol) and to the solution was added potassium hydroxide (2 eq, 11.7N) and the solution was degassed. To the solution was added properly substituted benzyl bromide (1.1 eq), 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.06 eq) and tris-(dibenzylideneaceton)-dipalladium(0) (0.03 eq). The mixture was stirred at 60° C. for 1.25 hrs. The mixture was cooled to room temperature, diluted with EtOAc and washed with 5% NaHCO3 solution (10 ml/mmol). The organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give compound pure 30 in yields varying from 30-80%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20]([C:23]1[N:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[O:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[N:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cn1
Temperature: 90 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
A mixture of 2-(benzyloxy)-4-fluoro-1-nitrobenzene (21.0 g), 6-(methylsulfonyl)pyridin-3-ol (14.7 g) and potassium carbonate (12.2 g) in N,N-dimethylformamide (130 mL) was stirred at 90° C. for 5 h and then at 60° C. for 15 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed successively with water and brine, dried (MgSO4), filtered, and concentrated to give light yellow crystals, which were washed with ethyl acetate-hexane to give the title compound (28.0 g, 82%) as pale yellow crystals. MS 401 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]([OH:8])[CH2:6][C:5]([CH3:10])([CH3:9])[C:4](=[O:11])[C:3]=1[CH3:12].[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1.C(OC=C)C.[OH-].[Na+]>C(Cl)Cl>[CH3:13][CH:14]1[O:8][CH:7]2[CH2:6][C:5]([CH3:9])([CH3:10])[C:4](=[O:11])[C:3]([CH3:12])=[C:2]2[O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=C(O)C(O)CC(C)(C)C1=O
Agent: C=COCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1=C2OC(C)OC2CC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Preparation of the C9 unit 170 g (1.0 mol) of crystalline 3,4-dihydroxy-2,6,6-trimethyl-2-cyclohexen-1-one were suspended in 500 ml of methylene chloride. First 500 mg (2.9 mmol) of p-toluenesulfonic acid were added to the suspension and then 144 g (2.0 mol) of vinyl ethyl ether were run in at room temperature (RT) over the course of 2 hours (h). The mixture was then stirred at RT for 4 h and subsequently 100 ml of 5% strength sodium hydroxide solution were run in. The lower organic phase was separated off, and the aqueous phase was extracted once with 100 ml of methylene chloride. The combined organic phases were washed with 200 ml of water and concentrated in a rotary evaporator. The residue was dried under greatly reduced pressure (oil pump) to give 2,4,6,6-tetramethyl-7,7a-dihydro-6H-benzo[1,3]dioxol-5-one as a yellow oil which was pure by thin-layer chromatography (TLC) and almost pure by gas chromatography (GC).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)Cl.C1(C)C=CC([Mg]Br)=CC=1.COC(C(=O)C1C=CC=CC=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:47]1[CH:51]=[CH:50][N:49]=[CH:48]1>C(#N)C>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[C:48]1[NH:47][CH:51]=[CH:50][N:49]=1
Reactant: c1c[nH]cn1
Reactant: COC(=O)C(Cl)(c1ccccc1)c1ccc(C)cc1
Agent: COC(=O)C(=O)c1ccccc1
Agent: Cc1ccc([Mg]Br)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)C(c1ccccc1)(c1ccc(C)cc1)c1ncc[nH]1

Procedure:
13.7 g phenyl-p-tolyl-chloroacetic acid methyl ester (prepared from p-tolyl-magnesium bromide and benzoyl-formic acid methyl ester and treatment with PCl5 ; (b.p. 150°C./0.3 mm Hg) are heated with 10 g imidazole in 100 ml acetonitrile at boiling temperature for 16 hours. The acetonitrile is distilled off in a vacuum. The residue is treated with 50 ml of water and then extracted with methylene chloride. The methylene chloride solution is distilled off in a vacuum and the residue recrystallized from a little ethyl acetate. The phenyl-p-tolyl-imidazolyl-acetic acid methyl ester i.e. phenyl-4-methylphenyl-imidazolyl-acetic acid methyl ester of m.p. 146°C. is thus obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:21][CH:22]1[O:25][CH:23]1[CH3:24]>>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]([CH2:24][CH:23]4[O:25][CH:22]4[CH3:21])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1OC1CBr
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13
Product: Cc1ccc2c(=O)n3c4ccccc4n(CC4OC4C)c3nc2c1

Procedure:
3-Methyl-6-(2,3-epoxybutyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-methylbenzimidazo[2,1-b]quinazolin-12(6H)one and 1-bromo-2,3-epoxybutane.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[C:5](I)=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:24]#[N:25])=[C:19](B(O)O)[CH:20]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:24]#[N:25])=[C:19]([C:5]2[C:4]([O:3][CH:2]([F:13])[F:1])=[CH:9][N:8]=[C:7]([O:10][CH3:11])[CH:6]=2)[CH:20]=1
Reactant: COc1cc(I)c(OC(F)F)cn1
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(OC(F)F)cn1

Procedure:
460 mg (purity 90%, 1.38 mmol) of 5-(difluoromethoxy)-4-iodo-2-methoxypyridine and 299 mg (1.65 mmol, 1.2 eq.) of 5-chloro-2-cyanophenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. The crude product was purified by flash chromatography (IR-50SI, petroleum ether/ethyl acetate 10-15%). Yield: 230 mg (purity 80%, 43% of theory)
Reaction SMILES: BrCCBr.[Cl:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[CH2:8]Br.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[N:23]1[C:28](=[O:29])[CH:27]=[CH:26][C:25]([C:30](Cl)=[O:31])=[CH:24]1.Cl>[Zn].[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.C(OCC)(=O)C.COCCOC>[Cl:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[CH2:8][C:30]([C:25]1[CH:26]=[CH:27][C:28](=[O:29])[N:23]([C:17]2[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])[CH:24]=1)=[O:31]
Reactant: O=C(Cl)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: [Pd]
Agent: Cl
Agent: [Zn]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: BrCCBr
Product: O=C(Cc1ccc(F)cc1Cl)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a mixture of zinc powder (208 mg) and ethylene glycol dimethyl ether (10 mL) were added 1,2-dibromoethane (20 mg) and 2-chloro-4-fluorobenzyl bromide (473 mg) and the mixture was stirred at 75° C. for 1 hour. The compound prepared in Example 5 and tetrakis(triphenylphosphine)-palladium (123 mg) were added hereto and the reaction mixture was stirred at same temperature for 15 minutes. The reaction mixture was added by hydrochloric acid (1 mol/L) and ethyl acetate, then the water layer was extracted with ethyl acetate. The obtained extract was dried with anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the title compound (171 mg) having the following physical data.
Reaction SMILES: ClCl.S1C2C=CC=CC=2N=[C:4]1[S:12][S:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.S[CH2:24][CH:25]([OH:27])C>ClC1C=CC=CC=1>[OH:27][CH:25]([CH3:24])[CH2:4][S:12][S:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: CC(O)CS
Reactant: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1
Agent: ClCl
Solvent: Clc1ccccc1
Product: CC(O)CSSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 7 h
Yield: 146.1 %

Procedure:
Chlorine gas (17.5 g/0.25 mole) was passed at 0 to 5° C. into a suspension of 2,2'-dithiobisbenzthiazole (83 g/0.25 mole) in chlorobenzene (600 ml). 1-mercapto-2-propanol (46 g/0.5 mole) was then added drop-wise to this solution, followed by stirring for 7 hours at room temperature. The precipitated product was filtered off and mixed with methylene chloride (500 ml) and 5% NaHCO3 solution (500 ml). The organic phase was then washed twice with water and concentrated by evaporation. A yellowish-brown oil (94 g) was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21]C)[N:12]2[CH2:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O.C(=O)(O)[O-].[Na+]>CO.O1CCOCC1>[NH2:23][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:21])[N:12]2[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1

Procedure:
2-Butoxy-8-methoxy-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-6-amine (Isomer 2, 178 mg) was suspended in methanol (2 ml) and 4N HCl in dioxan (1 ml) added. The resulting clear solution was stripped and the residue treated with water and basified with saturated aqueous sodium bicarbonate. The solid obtained was filtered, washed with water and dried to give the title compound (isomer 2), yield 72 mg (low due to mechanical losses).