Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[CH:26][CH:27]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:28](=[O:29])[C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: Cc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and p-toluic acid.
Reaction SMILES: C([BH3-])#[N:2].[Na+].O=[C:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][S:14][C:15]2[NH:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH2:8][CH2:7]1.C([O-])(=O)C.[NH4+]>CO>[NH2:2][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][S:14][C:15]2[NH:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH2:8][CH2:7]1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(CCSc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCN(CCSc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 49.9 %

Procedure:
Step 4): Sodium cyanoborohydride (0.06 g, 9.5 mmol) was added to solution of 2-[2-(4-oxopiperidin-1-yl)ethyl]thio-4,5-diphenylimidazole (0.34 g, 0.91 mmol), powdered 3A molecular sieves (0.268 g) and ammonium acetate (0.73 g, 9.5 mmol) in methanol (10 ml). The mixture was stirred at room temperature under nitrogen atmosphere for 65 hours and then filtered and washed with methanol. The filtrate was concentrated. The residue was dissolved in 10% NaOH solution and ethyl acetate. The organic layer was washed with water and saturated NaCl solution, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (0.8% NH4OH in chloroform/methanol) to give 2-[2-(4-aminopiperidin-1-yl)ethyl]thio-4,5-diphenylimidazole (172 mg, 49.9%) as a pale yellow oil.
Reaction SMILES: CS(O[C@H:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)=O.[C:13]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[F-].[Cs+].O>CN(C=O)C>[CH:14]([C:13]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:12]
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](C)OS(C)(=O)=O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](C)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of (R)-ethyl 2-(methylsulfonyloxy)propanoate (15 g, 0.076 mol) in DMF (300 ml) was added dibenzyl malonate (21.5 g, 0.076 mol) and CsF (11.5 g, 0.076 mol). The mixture was heated to 50° C. for 2 days. After cooled to room temperature, the mixture was poured into water and then extracted with EtOAc. The organic phase was washed with brine, water and dried. Concentrated to afford (R)-1,1-dibenzyl 2-ethyl propane-1,1,2-tricarboxylate, which was purified by silica gel chromatography (11 g, 40%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:28]1(=O)[CH2:31][CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[CH2:18][CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC3CCNCC3)ccc2n1-c1cncnc1
Reactant: O=C1CCC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C4CCC4)CC3)ccc2n1-c1cncnc1

Procedure:
In analogy to the procedure described for the synthesis of example 43, step 7, the title compound was synthesized from 5-(piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indole-2-carboxylic acid ethyl ester (example 44, step 2) and cyclobutanone. The title compound was obtained in 58% yield as light yellow solid. MS (m/e): 421.1 (MH+, 100%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH2:38])=[O:37])=[C:32]([F:39])[CH:31]=2)[CH2:25]1)=[N+]=[N-].O>C1COCC1>[NH2:20][CH2:23][C@@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH2:38])=[O:37])=[C:32]([F:39])[CH:31]=2)[CH2:25]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(N)=O)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CN(c2ccc(C(N)=O)c(F)c2)C(=O)O1
Temperature: 40 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
Triphenylphosphine (2.9 g, 11.0 mmol) was added portionwise to a solution of 5-(S)-azidomethyl-3-[4′-aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one (2.8 g, 10.0 mmol) in THF (75 ml) under nitrogen atmosphere. The solution was stirred at 40° C. for 2 h, water (2.0 ml) added, and the reaction mixture was stirred at 40° C. overnight. Solvent was removed under vacuum, and the resulting solid was triturated with ether. Precipitated material was filtered, washed with ether and ethanol and dried under vacuum to afford the product as white crystals (1.7 g, 69%). HPLC Rt=5.0 min. MS (m/z): [M+H]+=254.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1>>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([C:5]34[CH:8]=[CH:9][CH:10]=[CH:11][CH:4]3[C:3]([NH:2][C:6]4=[O:7])=[O:12])=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: O=C1NC(=O)C2(c3ccnc4cc(Cl)ccc34)C=CC=CC12

Procedure:
N-hydroxy-phthalimide and 4,7-dichloro-quinoline were reacted to form 0-(7-chloro-4-quinolyl)-phthalimide melting at 225° C. and the latter is reacted to obtain 0-(7-chloro-4- quinolyl)-hydroxylamine melting at 175° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:42]1[N:43]=[C:44]([NH:47][CH:48]=[O:49])[S:45][CH:46]=1)[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:12]([CH:16]=[CH:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][S:14](=O)[C@H:9]12)=[O:6].P(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:42]1[N:43]=[C:44]([NH:47][CH:48]=[O:49])[S:45][CH:46]=1)[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:25])=[C:12]([CH:16]=[CH:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnn3)CS(=O)[C@H]12)c1csc(NC=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnn3)CS[C@H]12)c1csc(NC=O)n1
Temperature: 0 °C
Yield: 51.2 %

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[2-(3-pyridazinyl)vinyl]-3-cephem-4-carboxylate-1-oxide (syn isomer) (trans isomer) (1.8 g) in N,N-dimethylformamide (18 ml) was added phosphorus trichloride (0.45 ml) at -30° C. with stirring. The reaction mixture was stirred at -15° to -10° C. for 30 minutes and added dropwise to ice-water (100 ml). The suspension was adjusted to pH 7.5 with saturated aqueous sodium bicarbonate. The precipitate was collected by filtration, washed with water, dried under reduced pressure, and subjected to column chromatography on silica gel to give benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)-acetamido]-3-[2-(3-pyridazinyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (0.9 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][NH:6][N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12].F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:20])[N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C[O+](C)C
Reactant: COC(=O)c1c(F)ccc2n[nH]cc12
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(F)ccc2nn(C)cc12
Reaction time: 5 h
Yield: 84.9 %

Procedure:
To a solution of methyl 5-fluoro-2H-indazole-4-carboxylate (4.50 g, 23.2 mmol) in ethyl acetate (93 mL) was 25 added trimethyloxonium tetrafluoroborate (4.46 g, 30.1 mmol) at room temperature, and the mixture was stirred for 5 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (4.10 g, yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:24]3[CH2:26][CH2:25]3)[CH2:22]O)[C:11](=[O:27])[C@:10]([C:29]3([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30]3)([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:24]3[CH2:26][CH2:25]3)[CH2:22][NH:42][S:39]([CH:36]3[CH2:38][CH2:37]3)(=[O:41])=[O:40])[C:11](=[O:27])[C@:10]([C:29]3([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30]3)([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COC(=O)C1([C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N([C@H](CO)C3CC3)C2=O)CC1
Product: COC(=O)C1([C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N([C@H](CNS(=O)(=O)C3CC3)C3CC3)C2=O)CC1

Procedure:
The tile compound was prepared from methyl 143R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate (35 mg, 0.068 mmol; Example 270, Step D) and cyclopropanesulfonamide (25 mg, 0.20 mmol) by a procedure similar to the one described in Example 202, Step C. Purification of the residue by chromatography on silica gel (4 g SiO2, 45% and 60% EtOAc/Hex) provided the title compound as a pale yellow.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:13]1)=[O:11].[H-].[Na+].[F:25][C:26]([F:30])([F:29])[CH2:27]I>CN(C=O)C>[Cl:22][C:21]1[C:16]([CH:14]2[CH2:13][N:12]([C:10]([C:2]3[N:3]([CH2:27][C:26]([F:30])([F:29])[F:25])[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)=[O:11])[CH2:15]2)=[N:17][CH:18]=[CH:19][N:20]=1
Reactant: FC(F)(F)CI
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2Cl)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1nc2ccccc2n1CC(F)(F)F)N1CC(c2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of (1H-benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methanone (84), as prepared in Preparation 36 below, (314 mg, 1.0 mmol) in dry DMF (10 mL) was added sodium hydride (applied as 60% dispersion in oil, 62 mg, 1.5 mmol)) at 0° C. under N2 atmosphere. After 0.5 h, 1,1,1-Trifluoro-2-iodo-ethane (418 mg, 2.0 mmol) was added slowly. The reaction mixture was stirred at RT for 4 h. The reaction was quenched with water (10 mL) at 0° C. and extracted with EtOAc (3×20 mL). The combined organics were washed with water (2×15 mL), brine (20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography to provide (85) (355 mg, 0.90 mmol, 90% yield) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC2CCCCO2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirred solution of 66.6E (38 g, 164 mmol) and 3,4-dihydro-2H-pyran (45 mL, 493 mmol) in DCM (355 mL,) was added 4-methylbenzenesulfonic acid hydrate (0.63 g, 3.30 mmol). The mixture was stirred at room temperature and monitored by TLC. After 2 hours, the solution was washed with a mixed aqueous solution of saturated aqueous sodium bicarbonate/brine/water (1:1:2). The aqueous layer was extracted three times with ether. After drying over anhydrous sodium sulfate and then filtering, the organic solvent was removed under reduced pressure. The crude material was purified on silica gel (0-10% EtOAc in hexanes) to yield a white solid. The product was recrystallized from MeOH to provide 66.6F (yield 90%). 1H NMR (400 MHz, CDCl3) δ ppm 8.24 (1H, d, J=2.0 Hz), 7.93 (1H, dd, J=8.6, 2.0 Hz), 7.17 (1H, d, J=8.6 Hz), 5.62 (1H, t, J=2.5 Hz), 3.90 (3H, s), 3.83 (1H, td, J=11.1, 2.9 Hz), 3.66 (1H, m), 2.18 (1H, m), 2.04 (1H, m), 1.94 (1H, m), 1.79 (2H, m), 1.67 (1H, m).)
Reaction SMILES: C[O:2][C:3](=[O:11])[CH:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH3:5].[OH-].[K+]>O.C(O)C>[S:8]1[CH:9]=[CH:10][C:6]([CH:4]([CH3:5])[C:3]([OH:11])=[O:2])=[CH:7]1
Reactant: COC(=O)C(C)c1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccsc1
Yield: 93.8 %

Procedure:
2-(3-thienyl)propionic acid methyl ester (26.6 g) was added to a water:ethanol (1:4) solution of potassium hydroxide, followed by one-hour refluxing. The reaction was carried out in a similar manner to the foregoing Example 8 to obtain 22.9 g 2-(3-thienyl) propionic acid nD20 1.5361.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]=O)=[CH:19][C:14]=2[N:13]=[CH:12]1>N1CCCCC1.CCO>[NH:11]1[C:15]2[CH:16]=[CH:17][C:18](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: O=Cc1ccc2[nH]cnc2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]cnc2c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 9.9 %

Procedure:
Indolin-2-one (80 mg, 0.60 mmol), 1H-benzo[d]imidazole-5-carbaldehyde (97 mg, 0.66 mmol) and piperidine (2 drops) in EtOH (2 mL) were heated with stirring in a sealed tube under microwave irradiation at 90° C. for 15 min. A yellow precipitate was filtered and rinsed with EtOH. Recrystallization from EtOH afforded the title compound as a yellow powder (15.5 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.71 (br. s., 1H), 10.59 (s, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 7.65-7.75 (m, 2H), 7.59 (d, J=8.34 Hz, 1H), 7.22 (t, J=7.58 Hz, 1H), 6.82-6.91 (m, 2H); MS ESI [M+H]+ 262.0, calcd for [C16H11N3O+H]+ 262.3.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:24].C(=O)([O-])[O-].[K+].[K+]>CCCCCC>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:24])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [NH4+]
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Product: CCCCN(CCCC)CCCOc1ccc(C(N)=O)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
6.5 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.02 mol) is dissolved in 60 mL of n-hexane. 2.50 g of ammonium hydroxide (0.02 mol, 1 eq) and 2.76 g of potassium carbonate (0.02 mol, 1 eq) are added. The reaction mixture is heated to 50° C. and stirred for 3 hours. After the reaction the solid inorganic salt is filtered, washed with 2×5 mL of n-hexane and the filtrate is concentrated. The residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 5.34 g of the title compound (VIa) (87%) as a yellowish solid.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[OH:11][C:12]1[C:21]2[C:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][C:17]([CH3:25])([CH3:24])[C:16]=2[CH:15]=[C:14]([CH3:26])[CH:13]=1.[C:27](O)(=[O:29])C.Cl>C(OCC)C.O>[CH:27]([C:13]1[C:14]([CH3:26])=[CH:15][C:16]2[C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][C:20]([CH3:22])([CH3:23])[C:21]=2[C:12]=1[OH:11])=[O:29]
Reactant: CC(=O)O
Reactant: Cc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: Cc1cc2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Temperature: 20 °C

Procedure:
Formylation. Hexamethylenetetramine (21 g, 0.15 mol) and 1-hydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene were added in one portion with stirring to acetic acid (250 mL) and the mixture was heated at 95°-100° C. for 2 h. After cooling to 80°-85° C., water (250 mL) and concentrated hydrochloric acid (60 mL) were added and the mixture was heated at 95°-100° C. for a further 2 h. The reaction product was then cooled to 20° C., diethyl ether (150 mL) was added and the mixture was stirred vigorously. The organic layer was separated, washed with brine (2×50 mL), neutralized with 5% sodium bicarbonate solution (100 mL), and dried (Na2SO4). The solvent was removed by distillation and the residue was distilled to yield 2-formyl-1-hydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (4a) (18 g), mp 91°-92° C., GLC purity 99%+. 1H-NMR (CDCl3) δ12.92 (1H, s), 10.21 (1H, s), 6.73 (1H, s), 1.68 (3H, s), 1.67 (4H, s), 1.48 (6H, s), 1.32 (6H, s). 13C-NMR (CDCl3)67194.4 (1C, d), 163.5 (1C, s), 156.5 (1C, s), 138.0 (1C, s), 130.8 (1C, s), 120.1 (1C, d), 116.2 (1C, s), 37.7 (1C, t), 35.3 (1C, s), 34.6 (1C, t), 33.9 (1C, s), 31.0 (2C, q), 27.7 (2C, q), 17.8 (1C, q). IR (KBr) 1615, 1628 cm-1, MS (m/e) 246.2 (M+, 23.9) 231.2 (100.0), 189.1 (19.9), 161.2 (19.2).
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.C(OCC)(=O)C>CN(C=O)C>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:6]2[C:2]([CH3:1])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:3](=[O:20])[N:4]([C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)=[O:9])[C:5]2=[O:7])=[CH:32][CH:31]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine -2,4-dione (43 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 4-fluorobenzyl bromide (24 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 38 mg of white crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][C:4]1([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]([CH3:26])[CH2:3][C:4]1([CH2:18][C:19]([OH:21])=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17]
Reactant: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC1(CC(=O)O)CCN(CCc2ccccc2)C1=O
Yield: 92 %

Procedure:
A solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (659 mg, 1.83 mmol), trifluoroacetic acid (6.5 mL) and CH2Cl2 (6.5 mL) is stirred at room temperature for 1 hour. The solution is concentrated from CH2Cl2 (3×50 mL), dissolved in 1N NaOH (10 ml), and the basic layer is extracted with Et2O (2×25 mL). The pH of the basic layer is adjusted to pH 1 with 6N HCl. The acidic layer is extracted with CH2Cl2 (2×25 mL), the combined CH2 Cl2 layers dried (MgSO4), filtered and concentrated to give 511 mg (92%) of the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:10][C:11]1[N:15]2[N:16]=[C:17](Cl)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1.O>O1CCCC1>[Cl:10][C:11]1[N:15]2[N:16]=[C:17]([O:9][CH:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1
Reactant: OC1CCCCC1
Reactant: Clc1ccc2nnc(Cl)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1nnc2ccc(OC3CCCCC3)nn12
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
106 mg of sodium hydride at 60% in oil are added to a solution of 530 mg of cyclohexanol in 5 cm3 of tetrahydrofuran at 0° C. under argon. After stirring for 15 min, 500 mg of 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine (commercial) are added. The brown suspension is stirred, allowing the temperature to return gradually to 20° C. for 24 h. The reaction medium is poured into water and the mixture is extracted with ethyl acetate. After concentration to dryness under vacuum, a brown powder is obtained, which is washed with ether. The filtrate is concentrated to dryness and the oily yellow residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 μm), elution being carried out with a gradient of 100% dichloromethane to 95:5 dichloromethane/methanol. 184 mg of 3-chloro-6-(cyclohexyloxy)[1,2,4]-triazolo[4,3-b]pyridazine are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[S:12][C:13]([Cl:22])=[CH:14][C:15]=1[S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17]>C(Cl)Cl>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:20]([NH:19][S:16]([C:15]2[CH:14]=[C:13]([Cl:22])[S:12][C:11]=2[Cl:10])(=[O:17])=[O:18])=[O:21])[N:3]=1
Reactant: O=C=NS(=O)(=O)c1cc(Cl)sc1Cl
Reactant: Cc1cc(C)nc(N)n1
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2cc(Cl)sc2Cl)n1
Reaction time: 16 h

Procedure:
To a suspension of 12 g of 2-amino-4,6-dimethylpyrimidine in 300 ml of methylene chloride was added at ambient temperature 26 g of 2,5-dichloro-3-thiophenesulfonyl isocyanate. After stirring for 16 hours, the resulting solution was evaporated to dryness and the desired product, obtained as a solid residue, was triturated with ethyl ether and filtered. The solid product thus obtained melted at 192°-194° and showed infrared absorption peaks at 1550 cm-1, 1605 cm-1, and 1690 cm-1.