Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.S(Cl)(Cl)=O.[CH3:15][NH:16][CH3:17].Cl[S:19](O)(=[O:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([C:8]([S:19](=[O:21])(=[O:20])[N:16]([CH3:17])[CH3:15])=[CH:9][N:10]=2)[CH:7]=1
Reactant: Clc1cn2ccnc2cn1
Reactant: O=S(=O)(O)Cl
Reactant: CNC
Solvent: O=S(Cl)Cl
Product: CN(C)S(=O)(=O)c1cnc2cnc(Cl)cn12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
6-Chloroimidazo[1,2-a]pyrazine (3.07 g, 0.020 mole) is added in portions with stirring to 20 ml chlorosulfonic acid, and the mixture heated 2 hours at 100° C. and then cooled to room temperature. Thionyl chloride (2 g) is added and the mixture reheated to 100° C. for 2 hours. After cooling to room temperature, the mixture is quenched on crushed ice and extracted with ether. The ether layer is dried over sodium sulfate, filtered and concentrated under vacuum to give an oil which is stirred with a mixture of crushed ice and aqueous dimethylamine for one hour. The crude 6-chloro-3-(N,N-dimethylsulfamoyl)imidazo[1,2-a]pyrazine is collected by filtration.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Solvent: CO
Product: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Reaction time: 72 h
Yield: 1243.2 %

Procedure:
A solution of 15.1 g (47.1 mmol) of (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid (mycophenolic acid) and 0.7 g (3.7 mmol) of p-toluenesulfonic acid in 400 ml of methanol was allowed to stand at room temperature for 3 days. The mixture was concentrated under reduced pressure to approximately 75 ml and then partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic phase was further washed with brine and then dried over sodium sulfate. Concentration of the organic phase under reduced pressure gave 15.4 g (46.0 mmol, 98%) of methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as a white solid, mp 104°-105° C.
Reaction SMILES: C([C:3]1[C:29]([CH2:30][CH3:31])=[CH:28][C:6]2N(C(=O)CN3CCCC3)C3N=CC=CC=3C3N(C(=O)NN=3)[C:5]=2[CH:4]=1)C.[H-].[Na+].[N:34]1(CCCCl)CCCC1.C[N:44](C)[CH:45]=[O:46]>C1(C)C(C)=CC=CC=1>[N:34]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:28][C:29]=2[CH:30]=[CH:31][C:45](=[O:46])[N:44]=1
Reactant: ClCCCN1CCCC1
Reactant: CCc1cc2c(cc1CC)-n1c(n[nH]c1=O)-c1cccnc1N2C(=O)CN1CCCC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=c1ccc2ccccc2nn1
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 6,7-diethyl-2,9-dihydro-9-(pyrrolidinoacetyl)-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling (3-pyrrolidinopropyl)chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 6,7-diethyl-2,9-dihydro-2-(3-pyrrolidinopropyl)-9-(pyrrolidinoacetyl)-3H-pyrido[3,2-c]-s-triazolo[4,3-a]]1,5]benzodiazepin-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH3:16][OH:17]>>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:14][CH3:15])[N:4]=[CH:3][C:2]([NH:1][CH2:9][C:10]([CH3:11])([CH3:5])[CH2:16][OH:17])=[CH:11]2
Reactant: COc1cc2cc(N)cnc2cc1OC
Reactant: CO
Product: COc1cc2cc(NCC(C)(C)CO)cnc2cc1OC

Procedure:
The reaction is run similar to the preparation in Example 7. To a MeOH solution of 4 Å powdered molecular sieves (0.35 g) under argon is added 3-amino-6,7-dimethoxyquinoline (0.32 g, 1.6 mmol) and 2.2-dimethyl-3-hydroxypropionaldelhyde (0.19 g, 1.9 mmol). The product mixture is chromatographed (3% MeOH/CHCl3) to afford 0.10 g of material which is partitioned between CH2Cl2/10% NaOH. The organic layer is washed with 10% NaOH, H2O, and brine, then dried (MgSO4), and recrystallized from EtOAc/hexanes to provide a light-orange solid (m.p. 170-173.5° C.). Anal. Calcd. for C16H22N2O3: C, 66.18; H, 7.64; N, 9.65; Found: C. 66.11; H, 7.49; N, 9.33.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]2[OH:16].[C:18]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:8]=[C:7]2[O:16][CH3:18]
Reactant: Oc1cc(C(F)(F)F)nc2c(Cl)ccc(F)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C(F)(F)F)nc2c(Cl)ccc(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 8-Chloro-5-fluoro-2-(trifluoromethyl)quinolin-4-ol (Step 1, 3.54 g, 13.3 mmol, 1 eq.) in acetone (75 mL) was added anhydrous K2CO3 (3.88 g, 28.0 mmol, 2.1 eq.), followed by iodomethane (1.8 mL, 28.9 mmol, 2.17 eq.). The resulting mixture was stirred at reflux for 1.5 hours. An additional aliquot of iodomethane (1.8 mL, 28.9 mmol, 2.17 eq.) was added and reflux was continued for an additional 1 hour. The reaction was cooled to room temperature, poured onto ice and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator to give 3.72 g (100% yield) of the desired product as a yellow solid, which was used in subsequent reactions without further purification. An analytical sample was prepared by recrystallization from hexane/ethyl acetate; MP=198-200° C.; MS (ES) m/z (relative intensity): 280 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7]CC1C=CC=CC=1>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[OH:7]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
To 4.5 g of ([2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene were added 230 ml of ethyl acetate and 0.46 g of 10% palladium-on-carbon, and the mixture was stirred under hydrogen atmosphere at room temperature for 5 hours. After replacing the reaction system by nitrogen, the reaction solution was filtered over celite and the filtrate was concentrated to give 3.57 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:38]=[CH:37][C:19]([CH2:20][N:21]2[CH:25]=[C:24]([C:26]([O:28]CC)=[O:27])[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:22]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:22]2)=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (2.42 g), ethyl 1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-carboxylate (3.40 g), potassium carbonate (2.51 g) and N,N-dimethylformamide (50 ml) was stirred overnight at 80° C. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. A mixture of the residue, potassium hydroxide (1.78 g) and ethanol (50 ml) was refluxed for 5 hours. After the reaction solvent was removed under reduced pressure, water was added to the reaction mixture, then the mixture was acidified with 1N hydrochloric acid. The crystals obtained were collected by filtration to yield 1-[4-(5-methyl-2 phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-carboxylic acid (3.66 g, yield: 75%). This was recrystallized from acetone-hexane. Melting point: 165–166° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O.[C:10](O)(=[O:12])[CH3:11]>Br>[OH:2][C:1]1[CH:8]=[CH:7][C:6]([C:10](=[O:12])[CH3:11])=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: CC(=O)O
Agent: Br
Solvent: O
Product: CC(=O)c1ccc(O)cc1O
Temperature: 80 °C
Yield: 53 %

Procedure:
Resorcinol (0.55 g, 5.0 mmol) was dissolved in 5% hydrobromic acid in glacial acetic acid (155 ml, made by bubbling hydrogen bromide gas through glacial acetic acid). The reaction mixture was heated to 80° C. for 4.5 hours. The reaction solution was cooled to room temperature, added to water (500 ml) and the aqueous solution was extracted with ether (500 ml, 2X). The ether phases combined and washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue was recrystallized from an ether/hexane mixture to give 0.40 g, 53% of the title product:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:10]2[C:11](=[O:15])[NH:12][CH:13]=[CH:14][C:9]=2[S:8][C:7]=1[CH3:16]>S(=O)(=O)(O)O.C1N(COCCO)C2NC(N)=NC(=O)C=2N=1>[Br:5][C:6]1[C:10]2[C:11](=[O:15])[NH:12][CH:13]=[C:14]([N+:1]([O-:4])=[O:2])[C:9]=2[S:8][C:7]=1[CH3:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1sc2cc[nH]c(=O)c2c1Br
Agent: Nc1nc(=O)c2ncn(COCCO)c2[nH]1
Agent: O=S(=O)(O)O
Product: Cc1sc2c([N+](=O)[O-])c[nH]c(=O)c2c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A solution of nitric acid (1.68 mL, 70%, 26.8 mmol) in sulfuric acid (5 mL) was added dropwise to a 0° C. solution of Example 66A (3.27 g, 13.4 mmol) in sulfuric acic (15 mL). The resulting mixture was stirred at 0° C. for 1 hour, warmed to room temperature overnight, and poured into ice water. The resulting precipitate was collected by filtration, washed with water, and dried in a vacuum oven to provide 2.47 g (64% yield) of the desired product. MS (ESI(+)) m/e 290 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C=O)C.[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[N:12]=1>C1(C)C=CC=CC=1>[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([Cl:3])=[O:21])=[CH:18][CH:17]=2)[N:12]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)no1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(C(=O)Cl)cc2)no1

Procedure:
46 ml of thionyl chloride and 1 ml of DMF are added to a solution of 10.0 g of 4-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid in 150 ml of toluene. The solution is heated under reflux for 5 hours. The solvent is removed, giving 4-(5-methyl-1,2,4-oxadiazol-3-yl)-benzoyl chloride, EI 222. Subsequent reaction with 9.3 g of 1-tert-butoxycarbonylpiperazine in 150 ml of dichloromethane and 48 ml of triethylamine gives, after customary work-up, tert-butyl 4-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoyl]piperazine-1-carboxylate, FAB 373.
Reaction SMILES: [O:1]([C:8]1[CH:44]=[CH:43][CH:42]=[CH:41][C:9]=1[CH2:10][O:11][CH2:12][CH:13]1[CH2:40][CH2:39][C:16]2[N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=[N:19][C:15]=2[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C1C=CC=CC=1COCC1CCC2N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2C1)C1C=CC=CC=1>C(O)(=O)C.O>[O:1]([C:8]1[CH:44]=[CH:43][CH:42]=[CH:41][C:9]=1[CH2:10][O:11][CH2:12][CH:13]1[CH2:40][CH2:39][C:16]2[NH:17][CH:18]=[N:19][C:15]=2[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccccc2COCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Agent: c1ccc(Oc2ccccc2COCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)cc1
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(Oc2ccccc2COCC2CCc3[nH]cnc3C2)cc1
Temperature: 90 °C

Procedure:
A mixture of 5-((2-phenoxybenzyloxy)methyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-((2-phenoxybenzyloxy)methyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (1.20 g, 2.1 mmol) was dissolved in a mixture of acetic acid (9 ml) and water (1 ml). The mixture was heated to 90° C. for 2 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (10 ml). a 3.5 M solution of hydrogen chloride in ethyl acetate (0.60 ml) was added. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (first: 100:10:1, then 100:20:2) as eluent to give 74 mg of the title compound. For biological testing, the title compound was transferred into its hydrochloride salt by lyophilization of its solution in 0.1 N hydrochloric acid (40 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]([C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[C:8]([C:10]([F:13])([F:12])[F:11])=[N:9][C:5]=2[CH:4]=1.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](O)=[O:27].CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([N:7]2[C:6]3[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=[C:8]2[C:10]([F:13])([F:11])[F:12])=[CH:19][N:18]=1)=[O:27]
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1ccc(N)nc1
Reactant: O=C(O)c1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1ccc(NC(=O)c2c(F)cccc2F)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.3 %

Procedure:
To a solution of 5-(5-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)pyridin-2-amine (80 mg, 0.25 mmol) in CHCl3 (10 ml) was added 2,6-difluorobenzoic acid (90 mg, 0.57 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (240 mg, 1.25 mmol) and 4-dimethylaminopyridine (DMAP) (160 mg, 1.31 mmol). The resultant solution was allowed to stir for 24 hours at room temperature. The reaction progress was monitored by TLC (EtOAc/petroleum ether=1:1). After the completion, the resultant solution was diluted with 30 ml of CHCl3 and washed with 30 ml of H2O. The mixture was dried and concentrated by evaporation under reduced pressure on a rotary evaporator. The crude product was purified by SGC using 1:5 EtOAc/petroleum ether as eluent to afford 90 mg (81%) of 2,6-difluoro-N-(5-(5-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)benzamide (Compound 163) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[NH2:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]3[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:19][C:13]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH2:1]([O:3][C:4]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]3[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:19][C:13]=2[N:12]=1)=[O:5])[CH3:2]
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCN)nc2c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)NCCCc1nc2cc(C3=NNC(=O)CC3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
0.45 ml (4 7 mmol) of ethylchloroformate are added dropwise over a period of 10 minutes to a solution of 1 00 g (3.5 mmol) of 6-[2-(3-aminopropyl)-1H-benzimidazol-5-yl]-4,5-dihydro -5-methyl-3(2H)-pyridazinone and 1 25 g (9.0 mmol) of potassium carbonate in 10 ml of acetone and 10 ml of water with cooling in an ice bath. After 3 hours' stirring at room temperature, the reaction mixture is filtered and the filtrate is diluted with 20 ml of water and extracted three times with 20 ml portions of dichloromethane. The combined organic phases are dried and concentrated by evaporation under vacuum and the residue is chromatographed on silica gel with dichloromethane/methanol (9:1) as solvent. The polar main fraction (Rf 0 46) yields 0.65 g (52%) of the title compound in the form of a yellowish, amorphous solid after concentration by evaporation under vacuum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:10]2[CH:11]=[CH:12][C:13]3[C:18]([C:9]2=[N:8][C:7]=1[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19].C(N(CC)CC)C.Cl[C:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[S:31](=[O:39])(=[O:38])[N:30]=1>C(O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]1[C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[S:31](=[O:38])(=[O:39])[N:30]=3)=[C:7]([CH3:20])[N:8]=[C:9]12
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1CSCCN
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc2c3cccc(Cl)c3ccn2c1CSCCNC1=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a mixture of 3-(2-aminoethyl)thiomethyl-7- chloro-2-methylimidazo[2,1-a]isoquinoline (1.5 g) and triethylamine (0.5 g) in ethyl alcohol (35 ml) was added portionwise 3-chloro-1,2-benzisothiazole-1,1dioxide (1.0 g). After being stirred at ambient temperature for 1 hour, the resulting precipitate was collected by filtration and washed several times with ethyl alcohol to give 3-[2-[(7-chloro-2-methylimidazo[2,1-a]isoquinolin-3-yl)methylthio]ethylamino]-1,2-benzisothiazole-1,1-dioxide (2.2 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH3:11][NH2:12]>>[CH3:11][NH:12][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: CN
Reactant: N#Cc1cccc(CBr)c1
Product: CNCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a stirred solution of methylamine (40% in water) (200 mL) under N2, was added 3-(bromomethyl)benzonitrile (10 g, 0.051 mol) slowly in small portions over a period of 10 min at 0° C. After being stirred at RT for 3 h, the reaction mixture was extracted with DCM. Then the organic layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The obtained crude was purified using column chromatography on silica gel (pet ether/ethyl acetate) to afford the title compound as a pale yellow liquid (6.1 g, 82%). 1H NMR (DMSO-d6, 400 MHz) δ 7.74 (s, 1H), 7.63-7.68 (m, 2H), 7.48-7.52 (m, 1H) 3.66 (s, 2H), 2.22 (s, 3H).
Reaction SMILES: [NH:1]([C:25]([O:27][CH:28]1[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:30]([CH3:46])([CH3:45])[CH2:29]1)=[O:26])[NH:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([CH3:24])([CH3:23])[CH2:7]1)=[O:4].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>>[N:2]([C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([CH3:23])([CH3:24])[CH2:7]1)=[O:4])=[N:1][C:25]([O:27][CH:28]1[CH2:29][C:30]([CH3:46])([CH3:45])[N:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:32]([CH3:34])([CH3:35])[CH2:33]1)=[O:26]
Reactant: CCCCCCCCON1C(C)(C)CC(OC(=O)NNC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)N=NC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C

Procedure:
The procedure of Example 4 is repeated using 4.6 g of bis(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl) hydrazine-1,2-dicarboxylate and 2.3 g of iodobenzene diacetate to afford 3.3 gg of the title compound as a pale yellow oil. NMR, IR and mass spectra analyses are consistent with the desired structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:14][C:15](=[O:26])[C:16]4[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[C:19]([CH3:25])[C:17]=4[N:18]=3)=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:32]1([NH2:38])([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCCC1>[C:32]1([NH:38][C:15]([C:16]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[C:19]([CH3:25])[C:17]=2[NH:18][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:27]([F:30])([F:29])[F:28])[CH:11]=2)=[O:14])=[O:26])([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH2:33]1
Reactant: NC1(C2CC2)CC1
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C#N)cc(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 60 °C
Yield: 57.4 %

Procedure:
To a solution of 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-8-methyl-4-oxo-4H-benzo[d][1,3]oxazine-6-carbonitrile (1.2 g, 2,8 mmol) (prepared according to WO 04/067528) in tetrahydrofuran (40 ml), is added bicyclopropyl-1-ylamine hydrochloride (0.6 g, 4.2 mmol) and 1.2 ml (8.4 mmol) triethylamine, and the solution is heated at a temperature of 60° C. for 8 h. The solution is cooled down to ambient temperature and the solvent is evaporated. Then the mixture is triturated in 100 ml water and the crystals are washed with water and ether to afford 0.85 g of the title compound. The mother liquor is evaporated and a second crop of crystals is obtained by crystallisation in diisopropylether to afford 0.46 g of the title compound (F: 270-272° C.).
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:9]1([O:19][CH3:20])[C:10](=[CH:12][CH:13]=[C:14]([CH:18]=1)[CH2:15][CH:16]=[CH2:17])[OH:11].C(N(CC)CC)C.O>ClCCl>[CH2:1]([S:5]([O:11][C:10]1[CH:12]=[CH:13][C:14]([CH2:15][CH:16]=[CH2:17])=[CH:18][C:9]=1[O:19][CH3:20])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCc1ccc(OS(=O)(=O)CCCC)c(OC)c1
Temperature: -20 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
13 ml (100 mmol) of butanesulfonyl chloride is added dropwise to a solution of 15 g (90 mmol) of eugenol and 16 ml (110 mmol) of triethylamine in 150 ml of dichloromethane previously cooled to −20° C., then the reaction mixture is stirred for 4 hours at room temperature. After adding 50 ml of water and extracting with dichloromethane, the organic phase is dried over sodium sulfate, filtered and evaporated. The raw residue is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 90/10. 24.3 g (74%) of 4-allyl-2-methoxy-phenyl 1-butane sulfonate is obtained in the form of a yellow oil.
Reaction SMILES: ClCCl.[NH2:4][C@H:5]([CH2:10][OH:11])[CH2:6][CH:7]([CH3:9])[CH3:8].C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.O>[Si:19]([O:11][CH2:10][C@@H:5]([NH2:4])[CH2:6][CH:7]([CH3:9])[CH3:8])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)C[C@H](N)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a room temperature dichloromethane (100 mL) solution of L-leucinol (6.0 g) was added triethylamine (11 mL), DMAP (0.1 g) and t-butyldimethylsilyl chloride (8.5 g). The mixture was stirred at room temperature for 2 hours and then water was added. The organic layer was separated and the aqueous further extracted with dichloromethane. The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield the title compound, a residue which was used as such in the next reaction. 1H NMR (CD3COCD3) δ 3.48 (m, 2H), 3.32 (m, 1H), 2.76 (m, 1H), 1.78 (m, 1H), 1.22-1.02 (m, 2H), 0.88 (m, 15H), 0.06 (s, 6H).