Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[C:16]3([CH:31]=[CH:30][C:29](=[O:32])[CH:28]=[CH:27]3)[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[C:16]3([CH:31]=[CH:30][C:29](=[O:32])[CH:28]=[CH:27]3)[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=CC(N3CCN(Cc4ccccc4)CC3)=NC23C=CC(=O)C=C3)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C1C=CC2(C=C1)N=C(N1CCN(Cc3ccccc3)CC1)C=C2c1ccc(O)cc1
Temperature: 20 °C
Yield: 62.4 %

Procedure:
2-(4-Benzyl-1-piperazinyl)-4-(4-hydroxyphenyl)-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one can be obtained in the following manner: 2-(4-benzyl-1-piperazinyl)-4-(4-methoxyphenyl)-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (6.3 g) dissolved in acetic acid (150 cc) and a 48% strength solution of hydrobromic acid (100 cc) are heated for 12 hours to a temperature of about 100° C. After being cooled to a temperature of about 20° C., the solution is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. Crushed ice (200 g) is added to the residue, followed by 11N aqueous ammonia solution (500 cc). The aqueous solution is washed with chloroform (2×300 cc). The organic fractions are combined, washed with distilled water (200 cc), dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in chloroform (200 cc) and the solution is poured into silica (120 g) contained in a column 3.2 cm in diameter. Elution is performed first with chloroform (1 liter) and the corresponding eluate is rejected. Elution is then performed with a mixture of chloroform and methanol (95:5 volume) (1 liter) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. 2-(4-Benzyl-1-piperazinyl)-4-(4-hydroxyphenyl)-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (3.8 g) is thereby obtained in the form of a brown cake.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:3]=1.[CH3:15]C1C(C2C=CC=CN=2)=NC(C)=CC=1.CC1C(C2C=CC=CN=2)=NC=C(C)C=1.[CH2:43]([OH:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C)P(=O)(N(C)C)N(C)C>[CH2:43]([OH:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[CH:1]([C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:3]=1)=[CH2:15]
Reactant: Cc1cc(C)nc(-c2ccccn2)c1
Reactant: Cc1ccc(C)c(-c2ccccn2)n1
Agent: Cc1cnc(-c2ccccn2)c(C)c1
Solvent: OCc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=Cc1cc(C)nc(-c2ccccn2)c1
Reaction time: 0.75 h
Yield: 61 %

Procedure:
500 g (2.75 mols) of a mixture of isomers, consisting of 4,6-dimethyl-2,2'-bipyridine (45% by weight), 3,6-dimethyl-2,2'-bipyridine (45% by weight) and 3,5-dimethyl-2,2'-bipyridine (10% by weight), are reacted in accordance with the procedure of Example 1(a). The crude product formed is heated under 133 to 400 Pa for 2 hours at 120° to 125° C. and then for 45 minutes at 170° C. (bath temperature). 299 g of a distillate are thus obtained which has a boiling range of 65°-107° C. and which is composed of 65% by weight of 3,6-dimethyl-2,2'-bipyridine, 7% by weight of 3,5-dimethyl-2,2'-bipyridine as well as 17% by weight of benzyl alcohol and 10% by weight of hexamethylphosphoric acid triamide. The residue is heated under 0.1 Pa and, in a boiling range of 48° -170° C., a mixture distils off which is subjected to a fractional redistillation after di-tert.-butyl-p-cresol has been added as a polymerisation inhibitor. Thus, 51 g of (4-(2-benxyloxy)-ethyl)-6-methyl-2,2'-bipyridine, 11 g of 3,6- and 3,5-dimethyl-2,2'-bipyridine, 105 g of benzyl alcohol and 147 g of 4-vinyl-6-methyl-2,2'-bipyridine (61% of theory) are obtained.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:18]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:19]=1[C:20]#[N:21].O>CS(C)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:18]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:19]=2[C:20]#[N:21])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Oc2ccccc2)cc1
Temperature: 75 °C
Yield: 87.2 %

Procedure:
To a solution of 5.71 g (0.0307 moles) of 4-phenoxyphenol dissolved in 150 ml of DMSO was added 1.23 g (0.0307 moles) of NaOH. The slurry was heated at 75° C. for 15 minutes and 5.04 g (0.0276 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 75° C. for 4 hrs. The reaction mixture was cooled and poured into water. The product was collected by filtration, washed well with water and dried. The crude product was dissolved in CH2CL2 and washed with 10% aqueous NaOH, water and dried (Na2SO4). Removal of solvent in vacuo afforded 8.0 g (87% yield) of product. Recrystallization from ethanol gave purified 2-(4-phenoxyphenoxy)-5-nitrobenzonitrile, mp 150°-151.5° C.
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C1(C)C=CC=CC=1>O>[CH3:2][C:1]1[O:16][C:11]([C:12]([F:13])([F:14])[F:15])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(CC(=O)C(F)(F)F)C(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(C(F)(F)F)oc1C
Yield: 57.6 %

Procedure:
To a mixture of ethyl 2-acetyl-5,5,5-trifluoro-4-oxopentanoate (1.37 g) and toluene (5 mL) was added TsOH monohydrate (0.109 g) at room temperature, and the mixture was refluxed with azeotropic removal of water by Dean-Stark apparatus for 14 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (0.730 g).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:19][CH:18]=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]12([CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH3:16])[C:27](=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)CCCCc1ccncc1
Reactant: CCCNCCC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)CCCCc1ccncc1
Temperature: 25 °C
Yield: 32.3 %

Procedure:
N,N-Dimethylformamide (8.4 ml) was added to a mixture of 2-(1-adamantyl)-N-propylethylamine (Intermediate No. 1-6) (0.37 g, 1.7 mmol) and 5-(4-pyridyl)valeric acid (Intermediate No. 5-1) (0.30 g, 1.7 mmol), and the whole was stirred at room temperature. N-Methylmorpholine (0.27 ml, 2.5 mmol) and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 g, 2.0 mmol) were added thereto, and the whole was stirred overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate (20 ml) was added to the residue, and the whole was washed with a saturated aqueous sodium hydrogencarbonate solution (20 ml) and saturated brine (5 ml) successively. The organic layer was dried over sodium sulfate, and ethyl acetate was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography to give 0.21 g (33%) of the titled compound as a colorless oily matter.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][OH:10].C(N(CC)CC)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[CH2:9][OH:10])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: N[C@@H]1CCCC[C@H]1CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a suspension of trans-2-aminocyclohexylmethanol hydrochloride (4.50 g, 27.3 mmol) and triethylamine (11 mL, 81 mmol) in 200 mL dichloromethane at 0° C. was added dropwise a solution of 4-chlorobenzenesulfonyl chloride (5.69 g, 27.1 mmol) in 25 mL dichloromethane. The reaction was stirred at 0° C. for 1 h, then washed with aqueous sodium bicarbonate and water. The organic layer was concentrated and purified by flash chromatography on a 40 g silica gel column using a gradient of 0 to 100% ethyl acetate in hexane to give 4-chloro-N-(trans-2-hydroxymethylcyclohexyl)benzenesulfonamide (6.5 g, 78%). 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (m, 2H), 7.48 (m, 2H), 5.21 (d, J=7.81 Hz, 1H), 3.76-3.95 (m, 1H), 3.37 (ddd, J=11.14, 7.11, 3.40 Hz, 1H), 2.87-3.10 (m, 1H), 2.34-2.55 (m, 1 H), 1.47-1.70 (m, 4H), 1.19-1.40 (m, 2H), 0.94-1.19 (m, 3H). LC/MS R.T.=2.73 min; [M+H]+=304. HRMS [M+H]+ calc'd 304.0774, found 304.0768.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].[Cl:11][C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17](Cl)[C:13]=1[C:14]([OH:16])=[O:15].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:11][C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CCOc1ccc(N)cc1
Reactant: O=C(O)c1c(Cl)c([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Nc2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 10.5 g of 4-ethoxyaniline in 250 ml acetonitrile was added over a 1.5 hour period to a solution of 20 g of 2,6-dichloro-3,5-dinitrobenzoic acid and 11 g of N,N-diisopropylethylamine in 400 ml of acetonitrile and stirred at room temperature for five hours. After the solvent was removed in vacuo, the residue was dissolved in 500 ml of chloroform and extracted with several portions of 5% ammonium hydroxide. The aqueous extracts were washed with chloroform and acidified with dilute acid. The resulting solid was collected by filtration and was washed with water to provide 2-chloro-6-[(4-ethoxyphenyl)amino]-3,5-dinitrobenzoic acid, mp 202°-206° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(Cl)Cl.[OH:8][C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1>C(OCC)C>[N+:1]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:18]([OH:19])[C:9]=1[OH:8])([O-:4])=[O:2]
Reactant: Oc1cc2ccccc2cc1O
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CCOCC
Product: O=[N+]([O-])c1c(O)c(O)cc2ccccc12

Procedure:
Fuming nitric acid (4.2 ml) was added to methylene chloride (50 ml) and the resulting solution diluted with diethyl ether (100 ml): Then 3-methylbuthylnitrite (1.9 ml) was added and this final solution added at 25-30° C. to a solution of 2,3-dihydroxynaphthalene (16.0 g) in ether (100 ml).The reaction mixture was washed with water, extracted into potassium bicarbonate (1 M), acidified and finally extracted into ether. After column chromatography (SiO2, toluene-ethyl acetate-acetic acid 18:1:1) the product was crystallized from toluene. Yield: 1.5 g, melting point 141-143° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([C:20](=[O:22])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:23][Li]>>[OH:22][C:20]([CH3:23])([CH3:21])[CH:18]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[C:2]1[CH3:1])[CH3:19]
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Reactant: [Li]C
Product: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(C)C(C)(C)O
Temperature: -78 °C

Procedure:
A 50 mL round bottom flask was charged with (±)-tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-indole-3-carboxylate (0.2441 g, 0.810 mmol), vac/purged with N2, diluted with THF (5 mL) and cooled to −78° C. Methyllithium (0.648 ml, 0.972 mmol) was then added slowly, drop-wise, and the solution was allowed to slowly warm to ambient temperature. The reaction was then quenched with 1N HCl, extracted with EtOAc. The org layer was washed with water then brine, dried over Na2SO4, filtered, concentrated, purified by column chromatography using 10% EtOAc in Hex (10CV), 15% (10CV) to elute (±)-tert-butyl 1-(3-hydroxy-3-methylbutan-2-yl)-2-methyl-1H-indole-3-carboxylate (157.2 mg, 61.1%). LRMS (M+H+) m/z: calcd 318.42. found 318.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.Cl[C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:13](=[O:14])[O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(Cl)ccc2n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1cn2nc(Cl)ccc2n1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine-2-amine (561 g, 3.3 mmol) in dimethylacetamide (11 ml) was added 2,2,2-trichloroethyl chloroformate (0.506 ml, 3.66 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction solution, and a solid was separated by filtration, which was washed with water to give 724 mg (63.3%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([CH2:13][C:14](OCC)=[O:15])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[C:6]1([C:5]2[NH:4][CH2:1][CH2:2][NH:3][C:14](=[O:15])[CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NCCN
Solvent: c1ccncc1
Product: O=C1C=C(c2ccccc2)NCCN1
Temperature: 180 °C
Yield: 23.1 %

Procedure:
30 g ethylenediamine were added to 96 g ethyl benzoylacetate in 200 ml pyridine and the mixture was boiled under reflux for five hours. Then the pyridine was distilled off and the residue was heated to 180° C. for one hour. After cooling, 500 ml of dichloromethane were added, and the reaction mixture was heated to 40° C. until dissolution occurred. Precipitation with acetone yielded 21.7 g 7-phenyl-1,2,3,4-tetrahydro-1,4-diazepin-5-one having a melting point of 206-214° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH:11]1(OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:11]1([O:10][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1cc(F)ccc1O
Reactant: CS(=O)(=O)OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(F)ccc1OC1CCCC1

Procedure:
In a manner similar to the method described in Example 4a, 5-fluoro salicylaldehyde (Aldrich) reacted with methanesulfonic acid cyclopentyl ester prepared in Example 133a and potassium carbonate in dimethylformamide to give a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH:20](N)([CH3:22])[CH3:21]>>[CH:20]([NH:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([CH3:22])[CH3:21]
Reactant: CC(C)N
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Product: CC(C)Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 70 %

Procedure:
The use of polar solvents as reaction media results in only very poor yields and lengthy reaction times are required. For example, the reaction of 1-nitroanthraquinone with a 300% excess of isopropylamine at 75° C after 100 hours gives a yield of only 70% of 1-isopropylaminoanthraquinone.
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:34]1([CH2:39][CH:40]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[CH2:49][C:50](O)=[O:51])[CH3:41])[CH2:38][CH2:37][CH2:36][CH2:35]1.Cl.CN(C)CCCN=C=NCC>ClCCl>[N:34]1([CH2:39][CH:40]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[CH2:49][C:50]([N:24]2[CH2:25][CH:26]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:19][CH2:20][S:21](=[O:27])[CH:22]3[CH2:23]2)=[O:51])[CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: CC(CN1CCCC1)Oc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: CC(CN1CCCC1)Oc1ccccc1CC(=O)N1CC2C(C1)C(c1ccccc1)(c1ccccc1)CCS2=O
Temperature: 20 °C
Reaction time: 20 h
Yield: 36.5 %

Procedure:
0.03 g of hydroxybenzotriazole hydrate is added to a solution, cooled to +5° C., of 0.69 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide and 0.68 g of {[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetic acid in 25 cm3 of dry dichloromethane, followed by a solution of 0.5 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 20 cm3 of dry dichloromethane. After stirring for 2 hours at +5° C. and 20 hours at 20° C., the reaction mixture is washed twice with 50 cm3 of distilled water and dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 32 cm), eluting under a nitrogen pressure of 0.8 bar with an ethyl acetate, acetic acid and water mixture (80/20/20 by volume) and collecting fractions of 25 cm3. Fractions 21 to 50 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 8 cm3 of ethyl acetate, the crystals are washed with ethyl acetate and diisopropyl oxide and then dried. 0.45 g of (1RS,4aRS,7aRS)-6-{{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]-pyrrole 1-oxide is obtained in the form of beige crystals; melting point 126° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
Cis-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.46 g, 6.42 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.257 g, 6.42 mmol) dissolved in water (2 mL) was added over 5 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.4 mL, 6.53 mmol) was added over 1 min and stirring continued at −40° C. for 1 h 15 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 35 min. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. The residue was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-60% Acetonitrile in H2O/MeCN/Acetic Acid 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.62 g, 72%) was isolated as a colorless foam. 1H NMR (400 MHz, cd3od) δ 1.90-2.10 (m, 4H), 2.65-2.80 (m, 2H), 3.04 (p, 1H), 3.19-3.34 (m, 1H), 3.44 (s, 3H), 3.94 (ddd, 1H), 4.32-4.44 (m, 1H), 5.85 (s, 1H), 6.78-6.90 (m, 2H), 7.09-7.20 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[NH2:26][O:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>>[OH:30][CH2:29][C:28]([O:27]/[N:26]=[C:22](/[C:19]1[N:20]=[C:21]2[N:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[F:1])[N:9]=[CH:8][CH:7]=[CH:6]4)[N:14]=[N:15][C:16]2=[N:17][CH:18]=1)\[CH3:23])([CH3:32])[CH3:31]
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Reactant: CC(C)(CO)ON
Agent: Cl
Product: C/C(=N\OC(C)(C)CO)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 97.7 %

Procedure:
The title compound (12.0 mg, 89%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (10.0 mg, 0.03 mmol) and 2-aminooxy-2-methyl-propan-1-ol hydrochloride (8.8 mg, 0.06 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, CDCl3) δ ppm 9.41 (s, 1H), 8.94 (d, 1H), 8.18 (d, 1H), 7.94 (d, 1H), 7.83 (s, 1H), 7.46 (dd, 1H), 6.17 (s, 2H), 3.75 (d, 2H), 2.36 (s, 3H), 1.95 (1, 1H), 1.41 (s, 6H). LCMS (method A): [MH]+=410, tR=5.39 min.
Reaction SMILES: [CH:1](=[C:8]1[C:12]2=[N:13][C:14]3[CH:15]=[C:16]([NH:22][C:23]([C:25]4[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([O:30][CH3:31])=[O:29])=[O:24])[CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:39](O)(=O)C>CN(C)C=O>[CH3:39][N:22]([C:16]1[CH:17]=[CH:18][C:19]2[C:20](=[O:21])[N:11]3[CH2:10][CH2:9][C:8](=[CH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]3=[N:13][C:14]=2[CH:15]=1)[C:23]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29])=[O:24]
Reactant: CC(=O)O
Reactant: COC(=O)c1cccc(C(=O)Nc2ccc3c(=O)n4c(nc3c2)C(=Cc2ccccc2)CC4)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc(C(=O)N(C)c2ccc3c(=O)n4c(nc3c2)C(=Cc2ccccc2)CC4)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, methyl ester (0.85 g) dissolved in dimethylformamide (40 ml) was added to a suspension of 50% NaH (0.18 g) in dimethylformamide (5 ml) and the mixture was stirred at room temperature for 1 hour and then reacted with methyl iodide (0.54 g) at room temperature for 17 hours. The reaction mixture was diluted with ice water and then acidified with acetic acid: the precipitate was filtered and purified over a flash column using chloroform-ethyl acetate 3:1 as eluant. A further purification from isopropyl ether gave 3-[N-methyl-N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, methyl ester, m.p. 200°-202° C. (0.42 g), which was dissolved in dimethylformamide (20 ml) and treated with 5% aqueous NaOH (3.6 ml) at room temperature for 2 hours. The precipitate, 3-[N-methyl-N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, sodium salt, m.p. >300° C., was filtered and then dissolved in formic acid: the solution was diluted with water to give a precipitate which was filtered and washed with water until neutral. Crystallization from dichloromethane-methanol gave 0.2 g of 3-[N-methyl-N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, m.p. 302°-304° C., NMR (CDCl3) δ ppm.: 3.38 (m) (2H, C- 2 protons), 3.61 (s) (3H, CH3), 4.32 (t) (2H, C-1 protons), 7.14 (dd) (1H, C-7 proton), 7.32 (t) (1H, C-5 benzoyl proton), 7.35-7.85 (m) (7H, C-4 and C-6 benzoyl protons and phenyl protons), 7.88 (bs) (1H, --CH=), 8.00 (bd) (1H, C-5 proton), 8.13 (d) (1H, C-8 proton), 8.15 (bs) (1H, C-2 benzoyl proton).