Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C(O)C.[C:6]([NH:14][C:15]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:16]=1[C:17]([O:19]C)=[O:18])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C(OCC)(=O)C>[C:6]([NH:14][C:15]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:16]=1[C:17]([OH:19])=[O:18])(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(Sc2ccccc2)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(Nc1cc(Sc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
0.4 mL of 10% aqueous sodium hydroxide was added to 6 ml of ethanol suspension containing 0.30 g of methyl 2-(benzamido)-4-(phenylthio)benzoate at room temperature, and the resulting mixture was heated to reflux for 1 hour. After one reaction mixture was cooled to room temperature, 1.0 mol/b hydrochloric acid and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue and a solid substance was separated, by filtration to obtain 0.28 g of 2-(benzamido)-4-(phenylthio)benzoic acid as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4](F)[CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.CCCCCC.C(OCC)C>[C:31]1([CH2:37][C:38]([NH:40][C:41](=[O:42])[NH:1][C:2]2[CH:29]=[CH:28][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:21][CH2:20][CH:19]([CH2:22][N:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[CH2:18][CH2:17]4)=[O:15])[CH:8]=3)=[CH:4][CH:3]=2)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)c(F)c1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)cc1
Reaction time: 64.5 h

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (50 mg) was dissolved in N,N-dimethylformamide (1.5 ml) under a nitrogen atmosphere, and then 0.25 M 2-phenylacetyl isocyanate in hexane (1.45 ml) was added, followed by stirring for 64.5 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (3 ml) and hexane (3 ml). The solid was filtered off, and dried under aeration to provide the titled compound (49.1 mg) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([NH:7][CH2:8][CH2:9][C:10](=[O:12])[NH2:11])=[O:6].CN(C)C=O.[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22].[N:33](=[C:35]([C:37]1[C:41]([OH:42])=[C:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[N:39]([CH3:53])[N:38]=1)[CH3:36])[NH2:34]>O>[C:10]([CH2:9][CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:13]=[CH:14][CH:15]=[C:2]([NH:1][C:21]([NH:34][N:33]=[C:35]([C:37]2[C:41]([OH:42])=[C:40]([C:43]3[CH:44]=[CH:45][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:47][CH:48]=3)[N:39]([CH3:53])[N:38]=2)[CH3:36])=[S:22])[CH:3]=1)(=[O:12])[NH2:11]
Reactant: CC(=NN)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: NC(=O)CCNC(=O)c1cccc(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1cccc(C(=O)NCCC(N)=O)c1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
3-Amino-N-(2-carbamoylethyl)benzamide (56 mg, 0.27 mmol) was stirred with a dimethylformamide solution of thiocarbonyldiimidazole (0.1 M, 2.25 mL, 0.225 mmol) at room temperature for 1.5 hours, and then with a dimethylformamide solution of 3-(1-hydrazonoethyl)-1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-ol prepared in Reference Synthetic Example 14 (0.1 M, 1.8 mL, 0.18 mmol) at 40° C. for 1 hour, and then stirred at room temperature for 17 hours. After addition of water and saturated aqueous sodium chlorides the solution was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and chloroform and hexane were added to the residue. The precipitated solid was collected by filtration, washed with hexane and dried to give 102.7 mg of the desired product (yield 100%).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]1([C:14]#[C:15][C:16]2[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:8]1([C:14]#[C:15][C:16]2[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([NH:30][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])(=[O:31])=[O:32])=[O:21])=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
In a stream of nitrogen and at 0° C., 0.16 ml (1.31 mmol) of pivaloyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (1.06 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and 260 mg (2.12 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 360 mg (yield: 73.0%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:15]2([OH:14])[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:18]2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ncc(Br)cn2)C1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A solution of 5-bromo-2-iodopyrimidine (2 g, 7.02 mmol) in anhydrous toluene (25 mL) was cooled to −78° C. with stirring under nitrogen, forming a thick paste. n-Butyllithium (2.5M solution in hexanes, 2.83 mL) was then added dropwise over 10 minutes. The reaction mixture was stirred at −78° C. for 30 minutes, then solid tert-butyl 3-oxoazetidine-1-carboxylate (1.33 g, 7.74 mmol) was added portionwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and further diluted with water (20 mL). The crude material was extracted into ethyl acetate (2×30 mL). The combined organic phases were dried over sodium sulphate, filtered and concentrated under vacuum. The resulting brown oil (2.66 g) was loaded onto a 50 g KP-silica cartridge, and eluted from a 0-90% ethyl acetate in heptane gradient using a Biotage isolera 4, to afford the title compound (1.083 g, 46%) as a yellow solid. δH (500 MHz, CDCl3) 8.84 (s, 2H), 4.91 (s, 1H), 4.35 (d, J 9.0 Hz, 2H), 4.22 (d, J 9.1 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[C:2]([CH:7]=1)[NH2:1]
Reactant: Nc1cc(F)ccc1S
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(F)ccc1SCc1cccc([N+](=O)[O-])c1
Yield: 63.1 %

Procedure:
Following General Procedure A, the title compound (460 mg, 97%) was prepared from 2-amino-4-fluorobenzenethiol (562 g, 3.93 mmol), 1-(bromomethyl)-3-nitrobenzene (566 mg, 2.62 mmol), K2CO3 (1.8 g, 13.10 mmol) in DMF (10 ml).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:7]#[N:8])([O-:3])=[O:2].[H-].[Na+].I[CH2:16][CH2:17][CH3:18]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:16][CH2:17][CH3:18])[C:7]#[N:8])([O-:3])=[O:2]
Reactant: CCCI
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In DMF (20 ml), 3-nitro-4-aminobenzonitrile (1.12 g) was dissolved, and the solution was added with 60% sodium hydride (411 mg), followed by stirring at room temperature for 30 minutes. The solution was added with 1-iodopropane (805 μl) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in ethyl acetate. The resultant was washed with water and then subjected to extraction with ethyl acetate. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate.
Reaction SMILES: [CH2:1]([O:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:15](Cl)(=[O:19])[C:16](Cl)=O.[CH3:21][N:22]([CH3:25])C=O>ClCCl>[CH3:6][CH2:5][CH2:4][CH:3]([CH3:8])[CH3:2].[CH2:1]([O:9][CH:10]([O:19][CH2:15][CH3:16])[CH2:25][N:22]([C:21]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1)[C:12](=[O:14])[CH2:11][CH2:10][O:9][CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCOCCc1ccccc1
Solvent: ClCCl
Product: CCCC(C)C
Product: CCOC(CN(C(=O)CCOCCc1ccccc1)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Phenethyloxypropanoic acid (0.25 g) was dissolved in dichloromethane (8 mL) and treated with oxalyl chloride (0.22 g) and a drop of dimethylformamide at ambient temperature. The resultant solution was stirred at ambient temperature for 1 hour. The solution was then concentrated and azeotroped with dichloromethane (3×8 mL). The collected residue was dissolved in dichloromethane (8 mL) and added to a stirred solution of N-(2,2-diethoxyethyl)aniline (0.27 g) and N-ethyl-N-isopropyl-propan-2-amine (0.4 mL), dissolved in dichloromethane (4 mL), at ambient temperature. The resultant solution was stirred at ambient temperature for 1 hour. The mixture was then poured into ethyl acetate (25 mL), washed with water (2×25 mL), washed with brine (25 mL), dried over anhydrous magnesium sulphate, filtered and concentrated. The collected residue was purified by flash chromatography eluting with 1:6 ethylacetate:iso-hexane to yield the sub-titled compound (0.18 g) as an oil.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([OH:15])([CH3:14])[C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])C.[OH-].[Li+]>O1CCCC1.O>[OH:15][C:5]([CH3:14])([C:6]([NH:8][CH2:9][C:10]([F:11])([F:12])[F:13])=[O:7])[C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)C(C)(O)C(=O)NCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(C(=O)O)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of 3.60 g (15.0 mmol) (S or R)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid ethyl ester, entity A, in 50 ml of tetrahydrofurane were added 0.65 g (16 mmol) of lithium hydroxide in 25 ml of water and the mixture was stirred for 18 hours at room temperature. After removal of the organic solvent by distillation the mixture was acidified to pH 1. Extraction with ethylacetate gave 2.70 g (85%) of the title compound as an oil, MS m/e (%): 214.3 (M−H, 100).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1)=[O:4]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccc1C1Cc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccccc1C1Cc2ccccc2N1
Temperature: 25 °C

Procedure:
Trimethylacetyl chloride (3.6 ml) was added dropwise to a solution of 5.8 g 2-(2-aminophenyl)-2,3-dihydro-1H-indole and 4.3 ml Et3N in 75 ml CH2Cl2 with ice bath cooling. The resulting mixture was stirred at room temperature for thirty minutes and then quenched with water. The organic extract was washed with water, saturated NaHCO3 solution and saturated NaCl solution and dried (MgSO4). Concentration gave 7.7 g crude product which was flash chromatographed using CH2Cl2 as eluent to give 4.9 g solid, m.p. 175°-178° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH2:16][OH:17])[CH:15]=1>C1COCC1.C(Cl)Cl.O=[Mn]=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:15]=1)[CH:16]=[O:17]
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1C=O
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To a solution of [5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]methanol (Ex-57C, 5.8 g, 20 mmol) in 250 ml of THF and 250 ml of CH2Cl2, was added MnO2 (1.8 g, 20 mmol). The mixture was heated to reflux. The reaction was pushed to completion by adding two more portions of MnO2 (1.8 g each ) within 48 h. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated and the residue was recrystallized from EtOAc/Hexane to give 5.1 g (88%) of 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde. 1H-NMR (300 MHz, DMSO-d6) δ 11.29 (br s, 1H), 10 24 (s, 1H), 8.10 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.37 (d, J=7 Hz, 1H), 7.01–7.05 (m, 1H), 6.91–6.95 (m, 1H), 6.85–6.86 (m, 2H), 4.06 (s, 3H), 3.99 (s, 3H). HRMS (EI) Calcd. for C17H15NO3: 281.1052 (M+); Found: 281.1046.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([SH:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].CS(O[CH:18]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])(=O)=O>CO>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([S:12][CH:18]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COC(=O)C(C)(C)C(CCCCc1ccccc1)OS(C)(=O)=O
Reactant: COc1ccc(S)cc1OC
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C)(C)C(CCCCc1ccccc1)Sc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
Sodium (0.5 g, 2.2 mmol) is added to MeOH (10 mL) cooled in ice. When the reaction is complete a solution of 3,4-dimethoxybenzenethiol (6 g, 3.5 mmol) in MeOH (5 mL) is added. After 2 minutes a solution of methyl 3-methanesulfonyloxy-2,2-dimethyl-7-phenylheptanoate (3 g, 8.8 mmol) in MeOH (5 mL) is added. The cooling bath is removed and the reaction is stirred at room temperature overnight. The solvent is removed in vacuo, CH2Cl2 (50 mL) added and the solution washed with NaHCO3 (50 mL), 1 N HCl (50 mL) and brine (50 mL). The solution is dried over MgSO4 and the solvent removed in vacuo. The product is purified by column chromatography (silica, 20% ether in petroleum ether) to yield methyl 3-(3,4-dimethoxyphenylsulfanyl)-2,2-dimethyl-7-phenylheptanoate (0.65 g, 18%): 1H NMR (300 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.19-7.11 (m, 3H), 7.02-6.91 (m, 2H), 6.77 (d, J=8.2 Hz, 1H), 3,87 (s, 3H), 3.85 (s, 3H), 3.57 (s, 3H), 3.22 (dd, J=10.0, 3.2 Hz, 1H), 2.64-2.51 (m, 3H), 1.81-1.74 (m, 1H), 1.66-1.42 (m, 4H), 1.27 (s, 3H), 1.22 (s, 3H); MS (FAB) m/e 416 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[O:9][CH2:10][CH3:11].[CH3:12][S-:13].[Na+].C(I)C.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:13][CH3:12])=[CH:4][C:3]=1[O:9][CH2:10][CH3:11]
Reactant: C[S-]
Reactant: CCOc1cc(F)ccc1Br
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(SC)ccc1Br
Temperature: 65 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a stirred solution of 1-bromo-2-ethoxy-4-fluorobenzene (2.0 g) in DMF (20 mL) was added sodium methanethiolate (1.66 g). The mixture was stirred for 2 h at 65° C. The mixture was cooled to room temperature and ethyl iodide (1.3 mL) was added. The mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.65 g of the title compound.
Reaction SMILES: BrBr.[S-:3][C:4]#[N:5].[K+].[F:7][C:8]([F:22])([F:21])[O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14][C:13]2=[O:20]>C(O)(=O)C>[NH:5]=[C:4]1[N:16]2[C:17]3[C:12]([C:13](=[O:20])[CH2:14][CH2:15]2)=[CH:11][C:10]([O:9][C:8]([F:21])([F:7])[F:22])=[CH:19][C:18]=3[S:3]1
Reactant: N#C[S-]
Reactant: O=C1CCNc2ccc(OC(F)(F)F)cc21
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N=c1sc2cc(OC(F)(F)F)cc3c2n1CCC3=O
Yield: 6.3 %

Procedure:
The procedure is carried out as in Example 1, but starting with 2.2 g of bromine in 10 ml of acetic acid, 3.09 g of potassium thiocyanate and 3.2 g of 6-trifluoromethoxy-2,3-dihydro-(1H)-quinolin-4-one in 35 ml of acetic acid. The organic phase is extracted with 170 ml of an approximately 0.1 N aqueous hydrochloric acid solution. The aqueous hydrochloric phase is alkalinized with 4 ml of a 10 N sodium hydroxide solution and extracted with three times 100 ml of ethyl acetate. The organic extracts are combined, washed with 100 ml of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa) at 40° C. The crude io product obtained is chromatographed on silica gel, eluting with a mixture of ethyl acetate and petroleum ether (80-20 by volume). The yellow solid isolated (0.3 g) is washed with a cold solution of petroleum ether and of isopropyl ether (60-40 by volume), and is then dried under reduced pressure (70 Pa) at 40° C. 0.25 g of 2-imino-8-trifluoromethoxy-2H,4H-thiazolo-[5,4,3-ij]quinolin-6-one is thus obtained in the form of a yellow powder melting at 192° C. [Analysis C11H7F3N2O2S, % calculated C: 45.84, H: 2.45, F: 19.77, N: 9.72, O: 11.1, S: 11.12, % found C: 45.5, H: 2.1, F: 19.4, N: 9.3, S: 11.1].
Reaction SMILES: [CH3:1][C:2](=[CH:7][CH2:8][CH2:9][CH:10]([CH3:13])[CH:11]=[CH2:12])[CH2:3][CH2:4][CH:5]=O.[NH2:14][OH:15]>>[CH3:1][C:2](=[CH:7][CH2:8][CH2:9][CH:10]([CH3:13])[CH:11]=[CH2:12])[CH2:3][CH2:4][CH:5]=[N:14][OH:15]
Reactant: NO
Reactant: C=CC(C)CCC=C(C)CCC=O
Product: C=CC(C)CCC=C(C)CCC=NO

Procedure:
As described above, for example, the oximation reaction can be carried out using 4,8-dimethyl-4,9-decadienal and hydroxylamine to yield 4,8-dimethyl-4,9-decadienal oxime (an oxime intermediate).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.O.[NH3:22]>C(Cl)(Cl)Cl>[NH2:22][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1OCC(C)C
Reactant: N
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc(N)nn2)cc1OCC(C)C
Yield: 53.8 %

Procedure:
7.0 g (24 mmol) of 3-chloro-6-[4-methoxy-3-(2-methylpropoxy)phenyl]pyridazine are reacted as described in Example 1 in 40 ml of ammonia-saturated ethylene glycol. The crude product obtained by precipitation with water is dissolved in chloroform, the solution is dried with potassium carbonate, and the product is precipitated with petroleum ether (b.p. 50°-70° C.). 3.5 g (53.8%) of the title compound of m.p. 187° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:17]([CH3:19])[CH3:18])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:8])=[O:4].CCN(CC)CC.ClC(OCC(C)C)=O.[N+:35](=[CH2:37])=[N-:36]>O1CCCC1.CCOCC>[N+:35](=[CH:37][C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:9]1[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:17]([CH3:19])[CH3:18])=[O:16])=[N-:36]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Reactant: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)C=[N+]=[N-])C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A mixture of Example 37B (100 mg, 0.367 mmol) and Et3N (154 μL, 1.102 mmol) in tetrahydrofuran (4 mL) at 0° C. was added Isobutyl chloroformate (50 μL, 0.386 mmol). Mixture was then stirred at 0° C. for 30 minutes followed by addition of excess diazomethane in Et2O. Mixture was allowed to slowly come to ambient temperature over 3 hours. Mixture was then concentrated and diluted with EtOAc. Organic was then washed with saturated aqueous NaHCO3 and brine. Organic was dried (MgSO4), filtered and concentrated. Purification by chromatography (silica gel, 100% EtOAc) afforded 82 mg (75%) of the title compound. MS (ESI) m/z 297 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccccc1N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1ccccc1N1CCOCC1)C(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
2.78 ml (16.4 mmol) of trifluoromethanesulphonic anhydride are slowly added dropwise to a solution, cooled to −10° C., of 2 g (10.9 mmol) of 2-(4-morpholinyl)-phenol and 4.57 ml (32.8 mmol) of triethylamine in 15 ml of dichloromethane. The mixture is stirred at −10° C. for 30 min and then at 0° C. for 30 min. It is washed successively with 10% strength sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo, and the residue is dried under high vacuum. 3.48 g (87.6% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[CH:7][C:6]([O:13]C)=[CH:5]2>Br.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:8]([CH3:12])=[CH:7][C:6]([OH:13])=[CH:5]2)=[CH:10][CH:11]=1
Reactant: COc1cc(C)c2ccc(Br)cc2c1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(O)cc2cc(Br)ccc12

Procedure:
The suspension of 6-bromo-3-methoxy-1-methyl-naphthalene (3.7 g, 0.015 mol), from Step 4, in 38% HBr-acetic acid (20 mL) was refluxed for 16 h. The mixture was then extracted in ethyl acetate and the extract was basified with 10% sodium hydroxide solution and the layers were separated. The aqueous layer was acidified with dil. HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 7-bromo-4-methyl-naphthalen-2-ol, 1.9 g which was used as such in next step.