Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]=[CH:5][N:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH:14]1[CH:18]=[N:17][C-:16]=[N:15]1.[Na+]>O1CCCC1>[CH:1]([CH:4]=[CH:5][N:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)=[O:8])([CH3:3])[CH3:2]
Reactant: [c-]1nc[nH]n1
Reactant: CC(C)C=CN(C(=O)Cl)C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C=CN(C(=O)n1cncn1)C(C)(C)C
Temperature: 65 °C
Reaction time: 6 h
Yield: 55.9 %

Procedure:
21 g (0.103 mole) of N-(2-isopropylvinyl)-N-tert.-butylcarbamyl chloride are added dropwise to a suspension of 10.5 g (0.115 mole) of sodium 1,2,4-triazolide in 100 ml of dry tetrahydrofuran at 20° C. The mixture is stirred for 6 hours at 65° C., after which it is cooled to 20° C., the resulting precipitate is filtered off under suction, the filtrate is evaporated down and the oil which remains is distilled under reduced pressure. 13.6 g of 1-(N-(2-isopropylvinyl)-N-tert.-butylcarbamoyl)-1,2,4-triazole are obtained as a colorless liquid of boiling point 95°-97° C./0.15 mbar and nD 1.4815 (Compound No. 2)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH3:9][C@H:10]1[CH2:15][N:14]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:13][CH2:12][N:11]1[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:27])([F:26])[F:28])=[N:23][N:24]=2)[N:21]=1
Reactant: C[C@H]1CNCCN1c1ccc2nnc(C(F)(F)F)n2n1
Reactant: O=Cc1cccnc1
Product: C[C@H]1CN(Cc2cccnc2)CCN1c1ccc2nnc(C(F)(F)F)n2n1
Yield: 76 %

Procedure:
A mixture of pyridine-3-carboxaldehyde and 6-[(2S)-2-methylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 358, preparation of starting materials) was allowed to react by General Synthetic Method 5, to give 6-[(2S)-2-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 76% yield.
Reaction SMILES: [OH-].[K+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=O)/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12].[NH2:15][NH2:16]>CO>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH2:9][CH:10]([C:11]([OH:13])=[O:12])[NH:16][N:15]=1
Reactant: NN
Reactant: O=C(O)/C=C/C(=O)c1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC(c2cccs2)=NN1
Yield: 82.6 %

Procedure:
Potassium hydroxide (3.3 g) is dissolved in 100 cc of methanol and 9.1 g of 4-(2-thienyl)-4-oxocrotonic acid is added. To the resulting solution is added 2 g of hydrazine and the solution is refluxed for 2 hours. The methanol is removed and the viscous residue dissolved in 80 cc of water. The solution is made strongly acid with 20% HCl and a precipitate forms. It is filtered and air-dried to yield 8.1 g of the title compound, melting point 163°-165° C., dec. After recrystallization from ethanol the compound is constant melting at 171°-173° C., dec.
Reaction SMILES: C(=O)([O-])O.[Na+].[NH2:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])[C:10]([CH:21]=[O:22])=[C:9]([SH:23])[N:8]=1.Br[CH2:25][S:26]([NH:29][CH:30]1[CH2:32][CH2:31]1)(=[O:28])=[O:27].C(OCC)(=O)C>CN(C=O)C>[NH2:6][C:7]1[N:8]=[C:9]([S:23][CH2:25][S:26]([NH:29][CH:30]2[CH2:32][CH2:31]2)(=[O:28])=[O:27])[C:10]([CH:21]=[O:22])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])[N:12]=1
Reactant: Cc1ccc(-c2nc(N)nc(S)c2C=O)c(C)c1
Reactant: O=S(=O)(CBr)NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(N)nc(SCS(=O)(=O)NC3CC3)c2C=O)c(C)c1
Temperature: 85 °C

Procedure:
Sodium hydrogen carbonate was added to a solution of 2-Amino-4-(2,4-dimethylphenyl)-6-mercapto-pyrimidine-5-carbaldehyde in DMF and the suspension stirred. C-bromo-N-cyclopropyl-methane sulphonamide was added, and the mixture heated, ˜85° C., for ˜3 hrs. The resulting suspension was allowed to cool and ethyl acetate added, the mixture was washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a pale yellow solid. The crude solid was purified by column chromatography on silica eluting with mixtures of ethyl acetate and hexane.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[N:6]1[CH:13]=[CH:17][CH:16]=[CH:15]1)([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1-n1cccc1
Yield: 96.6 %

Procedure:
1.37 g (9.9 mmol) 2-nitro-anilin and 1.3 ml (11 mmol) of 2,5-dimethoxy-tetrahydrofuran was refluxed for 1 hour in 20 ml acetic acid. The reaction mixture was evaporated and the residue was diluted in EtOAc and washed with water, NaHCO3 (sat.), water, and then dried over Na2SO4. The solvent was evaporated and 1.8 g (96%) of 1a was obtained as an oil.
Reaction SMILES: [OH:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7](S)[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([OH:18])[N:3]=1>[OH-].[Na+].[Ni]>[OH:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([OH:18])[N:3]=1
Reactant: Oc1nc(O)c2nc(S)n(-c3ccccc3)c2n1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: Oc1nc(O)c2ncn(-c3ccccc3)c2n1
Temperature: 120 °C
Yield: 37.6 %

Procedure:
10 g of 2,6-dihydroxy-9-phenyl-8-purinethiol was dissolved in about 100 ml 1N sodium hydroxide followed by addition of about 30 g Raney nickel. Slight foaming occurred. The reaction was slowly heated to reflux (oil bath about 120° C.). After 1.5 hours the reaction was filtered. The filtrate was cooled to about 4° C. and filtered. The white solid was dissolved in hot water treated with charcoal, filtered and treated with concentrated hydrochloric acid to produce a white precipitate. This was filtered, dried under vacuum at 80° C. for three hours to yield 3.3 g of 2,6-dihydroxy-9-phenylpurine (38% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:6]([C:7]([NH:9][CH2:10][CH:11](OC)[O:12]C)=[O:8])[CH:5]=1.C(OCC)(=O)C>C1COCC1.Cl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:6]([C:7]([NH:9][CH2:10][CH:11]=[O:12])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(C(=O)NCC(OC)OC)cc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)NCC=O)cc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A mixture of 29.7 g (95.1 mmol) of N-(2,2-dimethoxy-ethyl)-5-nitro-isophthalamic acid methyl ester in 300 ml of THF and 300 ml of 2N HCl is stirred overnight. Ethyl acetate is added, and the mixture is washed twice with brine. The organic phase is dried over sodium sulfate and evaporated to yield the product in the form of a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]=[CH:10][S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[C:20](Cl)[N:19]=[C:18]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[N:17]=1.Cl>CN(C)C=O>[Cl:15][C:16]1[N:17]=[C:18]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[N:19]=[C:20]([NH:14][S:11]([CH:10]=[CH:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:13])[C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30]
Reactant: NS(=O)(=O)C=Cc1ccccc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
Sodium hydride (60%) (480 mg) was added to a solution of 1.00 g of 2-phenylethenesulfonamide in 10 ml of dimethylformamide with ice cooling followed by stirring at room temperature for 15 minutes. To this reaction solution was added 1.91 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine with stirring. The reaction mixture was stirred at room temperature for 2.5 hours and poured into a mixture of 1N hydrochloric acid and ice. The resulting crystals were collected by filtration and pulverized in hot ethanol. After allowing to cool, the crystals were collected by filtration to give 1.91 g of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9](=[O:10])[NH:8][C:7]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[C:6]([CH3:17])[CH:5]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C)C=O>[Br:3][C:4]1[C:9](=[O:10])[N:8]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:7]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[C:6]([CH3:17])[CH:5]=1
Reactant: CON(C)C(=O)c1[nH]c(=O)c(Br)cc1C
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(C(=O)N(C)OC)c(C)cc(Br)c2=O)cc1

Procedure:
Add sodium hydride (2.5 mmol, 2.5 eq) to a cooled solution of 5-bromo-N-methoxy-N,3-dimethyl-6-oxo-1,6-dihydropyridine-2-carboxamide (2, 1.0 mmol, 1 eq) in dimethylformamide (25 mL) and stir the reaction for 20 min. Add 4-methoxybenzyl chloride (1.2 mmol, 1.2 eq) and stir the reaction for 16 h. After completion, quench the reaction with water and extract with ethyl acetate. Remove the solvent and purify the crude by column chromatography to afford 5-bromo-N-methoxy-1-(4-methoxybenzyl)-N,3-dimethyl-6-oxo-1,6-dihydropyridine-2-carboxamide (3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([CH3:10])=[N:9][C:5]=2[CH:4]=1.S(Cl)([Cl:16])(=O)=O.O>C(O)(=O)C>[Cl:16][C:4]1[C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc2[nH]c(C)nc2c1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(C)nc2c1Cl
Reaction time: 2 h

Procedure:
1.30 g (8.02 mmol) 5-methoxy-2-methyl-1H-benzo[d]imidazole and 0.70 mL (8.56 mmol) sulphuryl chloride in 30.0 mL acetic acid were stirred for 2 h. Another 0.3 mL sulphuryl chloride were added and the mixture was stirred for a further 2 h. The reaction mixture was mixed with water and evaporated down i.vac. The residue was stirred with DIPE and isopropanol, suction filtered and dried.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:12]=[CH:11][C:9]([OH:10])=[C:5]([O:6][CH2:7][CH3:8])[CH:4]=1.CN(CC1C=CC=CC=1)C.C[O:24]C(C)(C)C.C(Cl)(=O)C(C)C>O>[C:2]([OH:24])(=[O:1])[CH:3]([CH3:12])[CH3:4].[O:1]=[CH:2][C:3]1[CH:12]=[CH:11][C:9]([OH:10])=[C:5]([O:6][CH2:7][CH3:8])[CH:4]=1
Reactant: COC(C)(C)C
Agent: CC(C)C(=O)Cl
Agent: CCOc1cc(C=O)ccc1O
Agent: CN(C)Cc1ccccc1
Solvent: O
Product: CC(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
166 g (1 mol) of ethylvanillin and 160 g (1.33 mol) of N,N-dimethylbenzylamine are introduced into 800 ml of tert-butyl methyl ether in a stirred apparatus with the exclusion of moisture. 128 g (1.2 mol) of isobutyroyl chloride are added over the course of 1.5 h, during which the reaction temperature rises to about 38° C. The reaction mixture is stirred overnight at room temperature and then poured into about 1 l of water. The organic phase is separated off, washed with hydrochloric acid, 5% sodium hydroxide solution and water, dried and evaporated, giving a residue of 238 g of crude ethylvanillin isobutyrate, which is recrystallized from 240 ml of isopropanol. Yield 215 g of ethylvanillin isobutyrate; m.p. 57° C.
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6]C)=[O:5].[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+]>C(Cl)Cl.C1COCC1.O>[CH:9]1([NH:15][C:2](=[O:8])[CH2:3][C:4]([OH:6])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)CC(=O)Cl
Reactant: NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
To a solution of methyl 3-chloro-3-oxopropanoate (2.2 g, 16.1 mmol) in dry DCM (30 ml) at 0° C. was added cyclohexylamine (4.0 g, 40.3 mmol). The reaction mixture was stirred for 1 hr at room temperature. The reaction mixture was washed with diluted HCl, saturated NaHCO3 then brine well. The organic phase was collected, dried over anhydrous sodium sulfate then filtered and concentrated. The resultant crude amide was used directly in the next step with no additional purification (3.2 g, 100%). To a solution of this material (500 mg, 2.51 mmol) in THF/water (1:1, 20 ml) was added NaOH (200 mg, 5.02 mmol) and the mixture was stirred for 3 hrs at room temperature. The mixture was extracted with Et2O then the aqueous phase was acidified to pH 1 and extracted with EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate then filtered and concentrated to afford the title compound 58 as a beige solid (450 mg, 97% yield). MS (m/z): 186.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[O:18][CH3:19])[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[O:18][CH3:19])[CH:3]=1
Reactant: CO[C@@H]1CCCC[C@H]1Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CCCC[C@H]1Oc1cc(F)ccc1N

Procedure:
(R,R)-4-fluoro-2-(2-methoxycyclohexyloxy)-nitrobenzene (0.18 g) in methanol (20.0 ml) was hydrogenated under 50 psi hydrogen for 20 h at rt using palladium on charcoal (5%) (40 mg) as catalyst. The catalyst was filtered off; the resulting solution was evaporated to dryness to yield an oil.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])[NH2:2].Cl>O>[CH3:13][O:12][C:10]1[CH:11]=[C:3]2[C:4]([C:5]([OH:6])=[N:2][NH:1]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C(=O)O)c(NN)c1
Agent: Cl
Solvent: O
Product: COc1ccc2c(O)n[nH]c2c1
Yield: 86.3 %

Procedure:
A mixture of the product from Step A (10.5 g, 48 mmol), water (250 mL), and conc HCl (2.5 mL) was refluxed for 30 min. The volume of the reaction mixture was reduced by evaporation (ca 100 mL) and the pH adjusted to 7 by the slow addition of a saturated aqueous solution of sodium carbonate at room temperature. The solid that formed upon standing was collected and dried to give a gray solid (6.8 g): APCl/LCMS m/z 165 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:42][CH3:43])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH:29]=2)[N:24]=[CH:23][N:22]=1.Cl.C(=O)([O-])O.[Na+]>C(O)CCC>[CH3:43][O:42][C:27]1[CH:26]=[C:25]2[C:30]([C:21]([NH:1][C:2]3[CH:19]=[CH:18][C:5]4[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[S:8][C:4]=4[CH:3]=3)=[N:22][CH:23]=[N:24]2)=[CH:29][C:28]=1[O:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCN(C)CC1
Reactant: Nc1ccc2nc(NC(=O)c3ccccc3)sc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: COc1cc2ncnc(Nc3ccc4nc(NC(=O)c5ccccc5)sc4c3)c2cc1OCCCN1CCN(C)CC1
Reaction time: 8 h

Procedure:
N-(6-{7-Methoxy-6-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4yl-amino}benzothiazol-2-yl)benzamide was prepared by heating a mixture of N-(6-amino-benzothiazol-2-yl)benzamide (Intermediate 2, 40 mg. 0.148 μmol), 4-chloro-7-methoxy-6-[3-(4methylpiperazin-1-yl)propoxy]quinazoline (IM 8, 52 mg, 0.148 mmol), and HCl (112 μL, 4 M solution in dioxane, 0.444 mmol) in n-butanol (6 mL) to 110° C. for 5 h. Saturated sodium hydrogencarbonate solution was added and the product was extracted with ethyl acetate. After washing with water and drying over Na2SO4, the solvent was removed. The residue was taken up in little methanol, then water was slowly added. After stirring the mixture overnight, a grey solid was obtained (39 mg, 66 μmol, 45%). LC(ESI-MS: m/z=584 [M+H]+; m/z=582 [M−H]−; Rt=2.26 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccnc1Cl

Procedure:
A solution 2-Chloro-nicotinic acid (3.0 grams, 19.0 mmole), potassium carbonate (6.5 grams, 48.0 mmole) and benzyl bromide (2.8 ml, 24.0 mmole) in dimethylformamide (20 ml) was stirred at room temperature over night. The mixture was poured into 200 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 10% ethyl acetate/hexane as eluent (2.8 g). MW 247.69; MS (m/e) 247 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([N:24]=[C:25]=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C=NC1CCCCC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)NC4CCCCC4)cc23)CC1
Yield: 86.6 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 16.37 mg (0.131 mMol) cyclohexyl isocyanate, 20.1 mg (87%) of the title compound were recovered.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(C(OCC)=O)[CH2:9][C:8](=[O:10])[N:7]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])=[O:5])[CH3:2].[Cl-].[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:9][C:8](=[O:10])[N:7]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=O)N1Cc1ccc(OC)cc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 6 h
Yield: 90.2 %

Procedure:
A mixture of 66.2 g (0.18 mole) of diethyl[1-(2,4-dimethoxy-benzyl)-4-oxo-2,2-azetidine-dicarboxylate] prepared according to the preceding paragraph, 70 ml of dimethyl sulfoxide, 12.7 g (0.22 mole) of sodium chloride and 6.5 ml (0.36 mole) of water is stirred on an oil bath (temperature 170°-180° C. for 6 hours. The reaction mixture is poured into 500 ml of a saturated aqueous sodium chloride solution, extracted five times with 100 ml ethyl acetate each, the organic phase is dried over anhydrous magnesium sulfate, filtered and from the filtrate the ethyl acetate is distilled off. Thus 47.6 g of ethyl-[1-(2,4-dimethoxy-benzyl)-4-oxo-2-azetidine-carboxylate] are obtained. B.p.: 170°-176° C./0.15 Hgmm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13](Br)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH3:19][C:20]1([CH3:29])[CH2:25][CH2:24][C:23](B(O)O)=[CH:22][CH2:21]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:23]3[CH2:24][CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21][CH:22]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(N)c(Br)c2)CCOCC1
Reactant: CC1(C)CC=C(B(O)O)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccc(N)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a mixture of 4-(4-amino-3-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 1.45 g, 4.61 mmol), 4,4-dimethylcyclohexen-1-ylboronic acid (782 mg, 5.08 mmol) and dichloro(1,1-bisdiphenylphosphino-ferrocene palladium (II) (Pd(dppf)Cl2) dichloromethane adduct (337 mg, 0.461 mmol) in 40 mL of DMF was added K3PO4 (3.91 g, 18.4 mmol). The resulting mixture was stirred at 70° C. for 18 h under Ar. After cooling to RT, the mixture was treated with 150 mL of EtOAc, washed with H2O (3×30 mL) and brine (30 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-2% EtOAc/DCM) to afford 1.14 g (72%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C21H29NO3, 344.2 (M+H). found 344.4.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)=[NH:4].[CH2:15]([N:17]([CH2:28][CH3:29])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21](O)=O)[CH3:16]>>[CH2:28]([N:17]([CH2:15][CH3:16])[C:18]1[CH:19]=[C:20]([C:21]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=3)[N:4]=2)[CH:24]=[C:25]([CH3:27])[N:26]=1)[CH3:29]
Reactant: N=C(NO)c1ccc(CC(=O)O)cc1
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Product: CCN(CC)c1cc(-c2nc(-c3ccc(CC(=O)O)cc3)no2)cc(C)n1

Procedure:
The title compound is prepared in analogy to Example 5 starting from [4-(N-hydroxycarbamimidoyl)-phenyl]-acetic acid and 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=0.78 min; [M+1]+=367.13.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.Br[CH2:23]CCCC(C)(C1C=CC(C)=CC=1)CO.O1C=CCCC1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:16]=[CH:17][C:18]([CH3:23])=[CH:19][CH:20]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(C)(CCCCBr)COC2CCCCO2)cc1
Yield: 93 %

Procedure:
According to the method described for the synthesis of 207d, 206e (18.2 g, 63.8 mmol) was reacted with 3,4-dihydro-2H-pyran (6.4 g, 76.0 mmol) and p-toluenesulfonic acid hydrate (0.43 g, 2.3 mmol) in CH2Cl2 (300 mL) to give 207e (22.0 g, 93%) as an oil, which was used without further purification. 1H NMR (CDCl3): δ 7.25-7.05 (m, 4H), 4.60-4.48 (m, 1H), 3.82 (m, 2H), 3.48-3.37 (m, 2H), 3.35-3.26 (m, 2H), 2.30 (s, 3H), 1.90-1.40 (m, 11H), 1.34 (s, 3H), 1.40-1.08 (m, 1H). 13C NMR (CDCl3): δ 142.78, 135.22, 128.81, 126.39, 99.09, 99.01, 61.93, 61.85, 41.67, 41.56, 38.12, 37.87, 33.68, 33.64, 30.62, 25.96, 22.89, 20.97, 19.41, 19.37. HRMS (LSIMS, nba): Calcd for C19H30O2Br (MH+): 369.1429. found: 369.1451.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:5][CH:4]=1.[N:22](OC)=[O:23].OS(O)(=O)=O.N([O-])=O.[Na+]>CO.O.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[O:21])[C:14](=[N:22][OH:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:5][CH:4]=1
Reactant: CON=O
Reactant: CCCCCCCC(=O)c1ccc(OC)c2ccccc12
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CCCCCCC(=NO)C(=O)c1ccc(OC)c2ccccc12

Procedure:
10.0 g (35.2 mmol) of 1-(4-methoxynaphthyl)-octan-1-one are dissolved in 35 mL of t-butyl methyl ether. HCl-gas is introduced into this solution under cooling in an ice bath, and methyl nitrite-gas, which is genarated by adding H2SO4 aq. solution (3.5 mL of conc. H2SO4 and 7 mL of H2O ) into NaNO2 (3.65 g, 52.7 mmol) in methanol (3 mL) and H2O (3 mL), is introduced for 10 min at an ice-bath temperature. Then, the reaction solution is poured into ice, and the crude product is extracted with t-butyl methyl ether. This ether layer is washed with saturated NaHCO3 aq. solution and brine, dried over anhydrous MgSO4, and then condensed. The residue is applied to column chromatography on silica gel with ethyl acetate-hexane (10:90) as eluent. 2.02 g of yellow solid are obtained (18%). M.p. 92-93° C. 1H-NMR spectrum (CDCl3). δ [ppm]: 0.90 (t, 3H), 1.31-1.55 (m, 6H), 1.59-1.65 (m , 2H), 2.79 (t,2H), 4.06 (s, 3H), 6.80 (d, 1H), 7.51 (t, 1H), 7.58 (t, 1H), 7.72 (d, 1H), 7.75 (d, 1H), 8.33 (d, 1H), 8.44 (d, 1H).