Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[N+](C1C=CC(C[O:14][C:15]([C@@H:17]2[N:21]3[C:22](=[O:35])[C@@H:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:20]3[S:19][C@:18]2([CH2:37][O:38][C:39](=[O:44])[NH:40][C:41](=[O:43])[CH3:42])[CH3:36])=[O:16])=CC=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[C:41]([NH:40][C:39]([O:38][CH2:37][C@@:18]1([CH3:36])[C@H:17]([C:15]([OH:16])=[O:14])[N:21]2[C:22](=[O:35])[C@@H:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:20]2[S:19]1)=[O:44])(=[O:43])[CH3:42]
Reactant: [H][H]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Yield: 87 %

Procedure:
A suspension of 10% palladium on charcoal (400 mg) in ethyl acetate (40 ml) and aqueous 0.5% sodium bicarbonate was prehydrogenated and charged with (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylic acid p-nitrobenzyl ester (400 mg 0.68 mmol). The whole was shaken at 50 psi hydrogen pressure for 30 minutes and polish filtered. The aqueous was washed with ethyl acetate (20 ml), combined with a back extract of H2O (20 ml), overlayed with ethyl acetate (25 ml) and adjusted to pH 2.9 with 35% sulfuric acid. The layers were separated and the rich organic phase was washed with water (20 ml), combined with a back extract (EtOAc, 20 ml), dried (4A sieves), polish filtered and concentrated in vacuo to a colorless foam (270 mg) in 87% yield; nmr 100 MHz (CDCl3 -D2O) ppm 7.32 (2, m, m-phenyl H's) 6.96 (3, m, o,p-phenyl H's), 5.59 (2, br s, mag. equiv. C5,C6 -H's), 4.79 (1, s, C3 -H), 4.59 ##STR66## 4.08 (m, AB of C2 -CH2O), 2.25 ##STR67## and 1.58 (3, s, C3 -Me) with small ethyl acetate impurity.
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(Cl)(Cl)Cl.[F:11][C:12]([F:33])([F:32])[C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH:23]([CH3:27])[C:24](Cl)=[O:25])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.C(N(CC)CC)C>O>[F:11][C:12]([F:32])([F:33])[C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH:23]([CH3:27])[C:24]([N:3]3[CH2:4][CH2:5][CH2:6][O:2]3)=[O:25])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1
Reactant: C1CNOC1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)N1CCCO1
Yield: 97.7 %

Procedure:
To a mixture of isoxazolidine hydrochloride (11.0 g) and chloroform (200 ml), under stirring and ice-cooling, was added (±)-2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride (34.5 g) and then added dropwise triethylamine (22.2 g). After the completion of addition, the reaction mixture was stirred for further 30 minutes at room temperature, to which water was added to form two layers. The organic layer so separated was washed with 1 N hydrochloric acid and then with 1 N aqueous sodium hydroxide and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl]isoxazolidine (37.3 g) as a white crystalline solid. After recrystallization from a mixture of n-hexane/acetone, the resulting white crystalline solid showed the melting point of 105°-107° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>C1COCC1>[CH3:15][N:16]([CH3:20])[C:17]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:18]
Reactant: OC1CCNCC1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-hydroxypiperidine (5.0 g, 49 mmol) in THF (70 mL) was added triethylamine (14.4 mL, 103 mmol) and dimethylcarbamyl chloride (9.0 mL, 98 mmol) slowly. The mixture was stirred at room temperature for 1.5 hours. The white precipitate was filtered off, washed with THF. The THF solution was concentrated to dryness then purified with column chromatography (SiO2, MeOH/CH2Cl2=1:19) to afford 4-hydroxypiperidine-1-carboxylic acid dimethylamide as colorless oil. Yield: 7.8 g (94%).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:26][CH2:27][CH2:28][CH2:29][S:30]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Yield: 66.5 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (140 mg, 0.437 mmol) was reacted with 3-chloropropane sulfonyl chloride (58 uL, 0.480 mmol) in the presence of diisopropylethyl amine (305 uL, 1.75 mmol) and DMAP (53 mg, 0.437 mmol) in dichloromethane (5 mL) to give the title compound (134 mg, 77%)
Reaction SMILES: [C:1]([C:3]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#N.[OH-:20].[K+].C(O)C[OH:24]>O>[C:1]([C:3]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([OH:24])=[O:20]
Reactant: OCCO
Reactant: N#CC1(c2cccc3ccccc23)CCC(=O)CC1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C1CCC(C(=O)O)(c2cccc3ccccc23)CC1
Yield: 31.5 %

Procedure:
A mixture of 11.21 g. (0.039 mole) of 4-cyano-4-(1-naphthyl)cyclohexanone, ethylene ketal (prepared in Example 23) and 12 g. of potassium hydroxide in 60 ml. of ethylene glycol is heated at reflux for about 16 hours. The resulting solution is allowed to cool, diluted with water and washed with ether. The aqueous layer is covered with ether and then cautiously acidified. The aqueous layer is extracted with two additional portions of ether and the extracts combined. The extracts are evaporated to dryness and the solid remaining is recrystallized from a mixture of ethyl acetate and cyclohexane to give 3.84 g. (31.5% yield) of 4-carboxy-4-(1-naphthyl)cyclohexanone, ethylene ketal, having a melting point of 174° to 177°C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[C:10]([C:19]([F:22])([F:21])[F:20])=[N:11][N:12]([CH3:18])[C:13]=2[O:14][CH:15]([F:17])[F:16])=[N:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([S:7]([CH2:8][C:9]2[C:10]([C:19]([F:22])([F:20])[F:21])=[N:11][N:12]([CH3:18])[C:13]=2[O:14][CH:15]([F:17])[F:16])=[O:31])=[N:4][CH:3]=1
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncc(Br)s2)c1OC(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)(F)F)c(CS(=O)c2ncc(Br)s2)c1OC(F)F

Procedure:
The 5-bromo-2-({[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-thiazole obtained in this manner (4.0 g, 9.429 mmol) is initially charged in 100 ml of toluene. With stirring, 3-chloroperbenzoic acid (1.976 g, 8.015 mmol, 77% pure) is then added a little at a time, and the mixture is stirred at room temperature for a further 4 hours. For work-up, the reaction mixture is washed successively with water, aqueous NaHSO3 solution, aqueous NaHCO3 solution and finally with NaCl solution. The organic phase is dried over magnesium sulfate, filtered off and concentrated. The residue is triturated with n-heptane, filtered off and dried. The racemic 5-bromo-2-({[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfinyl)-1,3-thiazole obtained (3.75 g) is purified by preparative chiral HPLC (column: Chiralcel® OD; mobile phase: n-hexane/2-propanol 90:10; flow rate: 0.6 ml/min; column temperature: 25° C.) and separated into the enantiomers. This gives 1.505 g (36.2% of theory) of 5-bromo-2-[(S)-{[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfinyl]-1,3-thiazole (Rt=10.258 min) and 1.305 g (31.4% of theory) of 5-bromo-2-[(R)-{[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfinyl]-1,3-thiazole (Rt=12.557 min).
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13]>CO>[NH:12]([C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#[N:5])[NH2:13]
Reactant: N#Cc1c(I)ccnc1F
Reactant: NN
Solvent: CO
Solvent: O
Product: N#Cc1c(I)ccnc1NN
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.2 g of 2-fluoro-4-iodonicotinonitrile in 20 mL of MeOH at 20° C. are added 2.4 mL of hydrazine hydrate. The yellow suspension is stirred for 20 minutes at 20° C. and is then filtered. The precipitate is washed with methanol to give, after drying under vacuum, 947 mg of a white powder of 2-hydrazino-4-iodonicotinonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@H:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:2].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C@H:5]1[CH2:9][CH:8]([O:10][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:7][N:6]1[S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:12])=[O:13])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@H]1CC(O)CN1S(=O)(=O)c1ccc(C)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC(OS(=O)(=O)c2ccc(C)cc2)CN1S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a cold solution of 11.85 g (38 mmoles) 1-(4-toluenesulfonyl)-4-hydroxy-D-proline ethyl ester in 37 mL pyridine at 0° C. was added 8.0 g (41 mmoles) of 4-toluenesulfonyl chloride portionwise in 15 minutes. The cold solution was stirred one hour at 0° C. and then 48 h at room temperature. Water (100 mL) was added dropwise in the solution cooled at 0° C. which was stirred 30 minutes at 0° C. The precipitate was filtered and washed with cold water and ether to give 15.55 g of titled compound. MP 122° C. [α]20 =+26.36° (c=2, chloroform)
Reaction SMILES: [I-].[K+].[CH2:3]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH3:4].[CH3:12][CH:13]([CH3:16])[CH2:14]O>O.ClCCl>[CH2:3]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][CH2:12][CH:13]([CH3:16])[CH3:14])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CC(C)CO
Reactant: CCc1ccc(N)cc1
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(NCC(C)C)cc1
Temperature: 150 °C
Reaction time: 0.05 h

Procedure:
To potassium iodide (5342 mg, 32.2 mmol), [Cp*IrCl2]2 (128 mg, 0.161 mmol) and 4-ethylaniline (2 mL, 16.09 mmol) at room temperature, was added 2-methylpropan-1-ol (5.94 mL, 64.4 mmol), followed by water (10 mL). The reaction vessel was sealed and heated by microwaves (Biotage Initiator) to 150° C. for 90 minutes. After cooling the reaction mixture was diluted with water (10 mL) and dichloromethane (20 mL) then stirred vigorously for 3 minutes. The organic phase was separated by hydrophobic frit. The aqueous phase was diluted with further dichloromethane (10 mL) and again stirred vigorously for 2 minutes, then the organics separated by hydrophobic frit. The combined organic fractions were evaporated in vacuo to give the crude product as a brown oil. The crude was purified by silica (Si) chromatography (0-50% dichloromethane-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the required product, 2.612 g, as a pale yellow oil. LCMS [LCMS1] Rt 0.96 min, m/z (ES+) 178 (M+H).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:30][C:31]1[C:36]([Pb+3])=[C:35]([CH3:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][C:31]1[C:36]([CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][CH:1]([CH2:7][CH2:6]3)[C:2]2=[O:10])=[C:35]([CH3:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]=1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C

Procedure:
To a mixture of bicyclo[3.2.1]octane-2,4-dione (0.553 g, 4 mmol) in dry chloroform (12 ml) is added 4-dimethylaminopyridine (2.44 g, 20 mmol), and the mixture is stirred at room temperature until all the solid is dissolved. To this solution is then added dry toluene (8 ml), and 3,5-dimethylbiphen-4-yllead triacetate (0.5 M solution in dry chloroform, 10 ml, 5 mmol), and the mixture is heated under reflux for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH=1 with 2N aqueous hydrochloric acid, filtered and the filtrate is extracted with dichloromethane. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel to give 3-(3,5-dimethylbiphen-4-yl)bicyclo[3.2.1]octane-2,4-dione as a white powder.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](Cl)(=[O:11])[CH3:10].Cl>N1C=CC=CC=1>[CH3:8][C:3]1[CH:2]=[CH:1][C:6]([O:7][C:9]([CH3:10])=[O:11])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C)cc1
Yield: 92.9 %

Procedure:
A mixture of 65.0 g (0.60 mol) of p-cresol, 51.8 g (0.66 mol) of acetyl chloride, and 6 mL of anhydrous pyridine was refluxed for 1.5 hr and then added to 600 mL of 2% hydrochloric acid. The product was extracted with 2×100 mL of ether, the combined extract was washed with 2% NaOH, then dried over Na2SO4, and finally evaporated to dryness. Drying the residue in vacuum gave 83.7 g (93%) of p-tolyl acetate (bp 104-105° C./25 mm Hg). A mixture of 40.0 g (0.27 mol) of p-tolyl acetate and 45.0 (0.34 mol) of AlCl3 was slowly (for ca. 0.5 hr) heated to 120-125° C. This mixture was stirred at this temperature for 1 hr, and then 500 mL of 2M HCl was added at 0° C. The product was extracted with 3×100 mL of diethyl ether, the combined extract was dried over Na2SO4 and then evaporated to dryness. This procedure gave 39.7 g (99%) of the title product which was further used without an additional purification.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[C:21](#[N:24])[CH2:22][OH:23].O>C(#N)C>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[O:23][CH2:22][C:21]#[N:24])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Reactant: N#CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#CCOc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a suspension of 1,5-difluoro-2,4-dinitrobenzene (3.8 g) and anhydrous potassium carbonate (3.1 g) in acetonitrile (50 ml) kept at room temperature, a solution of glycolonitrile (1.5 g) in acetonitrile (10 ml) was dropwise added, followed by stirring at room temperature for 1 hour. The reaction mixture was heated and allowed to reflux for 30 minutes (inner temperature, 83° C.). After cooling, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and concentrated to give crystalline 2,4-dinitro-5-fluorophenoxyacetonitrile (4.0 g; yield, 89.1%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=1)=[O:5])[CH3:2].[I:16]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:14]([O:13][C:11]([C:9]1[C:10]([I:16])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:7][N:8]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1I
Temperature: 25 °C

Procedure:
To a solution of 10 g 1H-Pyrazole-3,5-dicarboxylic acid diethyl ester in 400 ml acetonitrile 13 g ammonium cerium(iv) nitrate (CAN) and 7.17 g iodine were added and the mixture was heated to reflux for 5 h. Then, after cooling to RT, 30 ml sat. sodium thiosulfate solution were added. The mixture was extracted with ethyl acetate (3×100 ml), the combined organic layers were washed with water and then dried over MgSO4, filtered and the solvents were removed under reduced pressure. The residue was filtered through a pad of silica gel eluting with heptane/ethyl acetate 1:1.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[CH3:19][O:20][C:21]1[C:22](=[O:41])[C:23]([C:37](OC)=[O:38])=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH:26]=1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:37]([C:23]1[C:22](=[O:41])[C:21]([O:20][CH3:19])=[CH:26][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=2)[N:24]=1)=[O:38]
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(OC)c1=O
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (2.63 g, 27 mmol) and iPr2NEt (4.70 mL, 27 mmol) in CH2Cl2 (30 mL) was added AlMe3 (1.8 M solution in toluene, 15 mL, 27 mmol) dropwise at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 5-methoxy-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (2.95 g, 9 mmol) in CH2Cl2 (30 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give the title compound (2.15 g, 67% yield) as off-white crystals: mp 170-171° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.41 (3H, s), 3.71 (3H, s), 3.98 (3H, s), 7.63-7.71 (2H, m), 7.80-7.86 (1H, m), 7.88 (1H, s), 7.98 (1H, s). Anal. Calcd for C15H14F3N3O4: C, 50.42; H, 3.95; N, 11.76. Found: C, 50.48; H, 4.07; N, 11.66.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][C:5]#[C:6][C:7]([OH:28])([CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][CH2:24][CH3:25])[CH:18]=[N:17][C:16]=2[N:15]([CH3:26])[C:13]1=[O:14])[CH3:2].[CH3:31][I:32]>C(OCC)C>[I-:32].[CH2:29]([N+:3]([CH2:1][CH3:2])([CH2:4][C:5]#[C:6][C:7]([OH:28])([CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][CH2:24][CH3:25])[CH:18]=[N:17][C:16]=2[N:15]([CH3:26])[C:13]1=[O:14])[CH3:31])[CH3:30]
Reactant: CCCn1cnc2c1c(=O)n(CCCCC(C)(O)C#CCN(CC)CC)c(=O)n2C
Reactant: CI
Solvent: CCOCC
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(O)C#CC[N+](C)(CC)CC)c(=O)n2C
Product: [I-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1 g (2.4 mmol) of 1-(8-diethylamino-5-hydroxy-5-methyl-6-octynyl)-3-methyl-7-propylxanthine--prepared as in Example 1A2), 1C2) or 1D2)--was introduced into 30 ml of diethyl ether, 425 mg (3.0 mmol) of methyl iodide were added, and the mixture was stirred at room temperature for 20 hours. Then a further 212 mg (1.5 mmol) of methyl iodide were added and the mixture was stirred under reflux for 2 hours. The resulting crystals were filtered off with suction, washed with diethyl ether and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[C:33](=[O:35])[CH3:34])[CH2:23][CH2:24]2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3ccccc32)cc1
Solvent: CC(=O)O
Product: CC(=O)N(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1nccs1
Yield: 66.3 %

Procedure:
A mixture of 6.76 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[2-thiazolylamino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine, 15 parts of acetic acid anhydride and 40 parts of acetic acid was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was taken up in water. The whole was alkalized with ammonium hydroxide and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4.9 parts (66.3%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-amino]-1-piperidinyl]ethyl]-N-(2-thiazolyl)acetamide; mp. 185.5°-193.0° C. (compound 102).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([N:31]2[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]2)=[O:26])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(O)CC1
Reaction time: 4 h
Yield: 96.4 %

Procedure:
A solution of the carbonate(45 g, 0.13 mol) produced in Example 1 in 250 mL of methylene chloride was added dropwise under nitrogen over three hours to a solution of 4-hydroxypiperidine (14.3 g, 0.14 mol) and triethylamine (19.7 mL, 0.14 mol) in 250 mL of methylene chloride at ice bath temperature. After the addition the reaction was stirred at ice bath temperature for 4 hours and at room temperature overnight. The reaction was extracted one time with 1N HCl and then multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 39.27 g of a light yellow solid. Recrystallization from diisopropyl ether-methanol gave 31.78 g (79%) of the title compound as an off-white crystalline solid, mp 130-133° C.