Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[K+].CO.[H][H].[O:10]([CH2:17][C:18]([NH:20][CH:21]1[C:41](=[O:42])[N:23]2[CH:24]([C:29]3[N:33](CC4C=CC=CC=4)[N:32]=[N:31][N:30]=3)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]12)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Pd].C(OCC)(=O)C.O>[O:10]([CH2:17][C:18]([NH:20][CH:21]1[C:41](=[O:42])[N:23]2[CH:24]([C:29]3[NH:33][N:32]=[N:31][N:30]=3)[C:25]([CH3:27])([CH3:28])[S:26][C@H:22]12)=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1c1nnnn1Cc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 5 h
Yield: 51 %

Procedure:
A mixture of 100 mg. (1 mmole) of potassium bicarbonate and 2.3 g. of 10% palladium-on-carbon, in a mixture of 12 ml. of methanol and 3 ml. of water, is stirred under an atmosphere of hydrogen until hydrogen uptake ceases. A solution of 464 mg. of 6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1-benzyltetrazol-5-yl)penam in 10 ml. of ethyl acetate is then added, and stirring under an atmosphere of hydrogen is continued for an additional 5 hours. At this point the reaction mixture is filtered, and the residue is washed with aqueous methanol. The washings and the filtrate are combined and evaporated in vacuo. To this latter residue is added chloroform and water and the pH is adjusted to 8.0. The chloroform is removed and discarded, and fresh chloroform is added to the aqueous phase. The pH is lowered to 2.5 and the chloroform layer is separated. The dried chloroform is evaporated in vacuo, leaving 190 mg. (51% yield) of 6-(2-phenoxyacetamido)-2,2-dimethyl-3 -(5-tetrazolyl)penam.
Reaction SMILES: [O:1]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[N+:2]([O-:4])=[O:3].O.CO.[O-:14][C:15]#[N:16].[K+]>C(O)(=O)C>[NH2:16][C:15]([N:8]1[CH2:9][CH2:10][CH:5]([O:1][N+:2]([O-:4])=[O:3])[CH2:6][CH2:7]1)=[O:14]
Reactant: N#C[O-]
Reactant: O=[N+]([O-])OC1CCNCC1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)N1CCC(O[N+](=O)[O-])CC1
Reaction time: 4 h

Procedure:
7.1 g. 4-Nitroxypiperidine are dissolved in 60 ml. water and 30 ml. methanol and mixed with 16.2 g. potassium cyanate. After the dropwise addition of 12 ml. glacial acetic acid, stirring is continued at ambient temperature for 4 hours. The inorganic salts are precipitated out by the addition of 100 ml. ethyl acetate. After suction filtration, the aqueous phase is separated off and the organic phase is dried with anhydrous sodium sulphate. After suction filtration, the filtrate is evaporated in a vacuum. The residue is triturated with diethyl ether and the crystals are filtered off with suction. There are obtained 8.3 g. of the title compound, i.e. 89% of theory; m.p. 110°-111° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]2[N:15]([CH2:27][C:28]([O:30]CC)=[O:29])[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>CO.O.C(OCC)(=O)C.O>[CH2:1]([S:8][C:9]1[N:14]=[C:13]2[N:15]([CH2:27][C:28]([OH:30])=[O:29])[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1C(=O)N(c2ccccc2Cl)Cc2cnc(SCc3ccccc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CN1C(=O)N(c2ccccc2Cl)Cc2cnc(SCc3ccccc3)nc21
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 7-benzylthio-3-(2-chlorophenyl)-1-(ethoxycarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.435 g, 3.36 mmol) and lithium hydroxide monohydrate (481 mg, 11.5 mmol) in methanol (10 mL) and water (30 mL) were refluxed for 48 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate/water. The aqueous layer was adjusted to pH 4 and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated in vacuo to give 1.2 g of 7-benzylthio-3-(2-chlorophenyl)-1-(hydroxycarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)(=O)=O.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[C:24]#[CH:25].C([O-])(=O)C.[Na+]>CN(C)C=O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:19][CH3:20])[CH:8]=[C:7]([C:25]#[C:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][CH2:15]2
Reactant: C#CC(=O)OCC
Reactant: COc1cc2c(cc1OC)CCC(OS(=O)(=O)C(F)(F)F)=C2
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C#CC1=Cc2cc(OC)c(OC)cc2CC1

Procedure:
To a solution of 178 mg (0.53 mmol) of (3,4-dihydro-6,7-dimethoxy-2-naphthyl) trifluoromethane-sulfonate in dimethylformamide (2 ml) were added 0.39 ml (3.9 mmol) of ethyl 2-propynoate, 84.8 mg (1.0 mmol) of sodium acetate and 14.8 mg (0.020 mmol) of bis(triphenylphosphine)palladium (II) acetate with stirring under nitrogen, and the mixture was stirred for 1 hour and 30 minutes at 60° C. A saturated saline solution was added to the reaction mixture to conduct extraction with benzene-hexane (1:2). An organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel to obtain 76.5 mg (yield: 51%) of crude crystals of the title compound. The crude crystals were recrystallized from diethyl ether-hexane, thereby obtaining a pale yellow crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)[CH:7]=[CH:6]2.[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[C:17]=1[C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH:7]=[CH:6]2
Reactant: CC(C)CC(=O)Cl
Reactant: COc1ccc2cc(-c3cc4ccccc4o3)ccc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc(-c3oc4ccccc4c3C(=O)CC(C)C)ccc2c1

Procedure:
Following the procedure described in Step 2 of Example 1, 2-(6-methoxy-2-naphthyl)-1-benzofuran (3.00 g, 10.9 mmol), was acylated with isovaleryl chloride (1.9 mL, 16 mmol), in presence of tin (IV) chloride (1.7 mL, 14 mmol) in chloroform (60 mL). Purification by flash chromatography using 15-100% chloroform in hexane as an eluant then by using the Biotage apparatus using 1.5% ethyl acetate in hexane as an eluant yielded the title compound as a yellow wax (1.34 g); 1HNMR (200 MHz, DMSO-d6): δ8.35 (s, 1H), 8.0 (d, 3H, J=8.2 Hz), 7.8 (d, 1H, J=10.2 Hz), 7.7 (d, 1H, J=7.7 Hz), 7.35-7.55 (m, 3H), 7.3 (d, 1H, J=8.7 Hz), 3.95 (s, 3H), 2.6 (d, 2H, J=7.7 Hz), 2.0-2.1 (m, 1H), and 0.75 ppm (d, 6H, J=7.7 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:22]([OH:24])=O)[C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[CH:11][CH:12]=1)=[O:4].S(Cl)(Cl)=O.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(Cl)Cl.CN(C=O)C>[CH3:25][C:2]([CH3:1])([CH3:26])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([C:22]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:24])[CH:8]=1)=[O:4]
Reactant: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2C(=O)O)c1
Reactant: CC(C)N
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2C(=O)NC(C)C)c1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a room temperature solution of 29.2 (432 mg, 1199 μmol) in DCM (6.0 mL) was added two drops of DMF followed by thionyl chloride (0.26 mL, 3596 μmol). The mixture was refluxed under N2 for 1.5 hours, cooled to room temperature, and the organic solvent was removed under reduced pressure. The residue was treated with neat isopropylamine (2.0 mL, 23515 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA), and the mixture was heated at 50° C. for 45 minutes. The reaction was then quenched with water (5 mL) and extracted with (3×5 mL) EtOAc. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0-50% EtOAc/hexanes for elution gave 29.3 as white solid (378 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[N:1]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccccn1
Solvent: CCO
Product: CCOC(=O)c1cn2ccccc2n1
Yield: 62.8 %

Procedure:
A solution of 2-amino-pyridine (2 g, 21 mmol) and ethyl bromopyruvate (4.14 g, 21 mmol) in ethanol (31 mL) was stirred under reflux for 24 h. The solvent was evaporated, and the residue was dissolved in a minimum volume of water. The solution was neutralized (pH=8) with saturated NaHCO3. The aqueous layer was extracted with AcOEt and the organic layer was washed with saturated NaCl. The solvent was removed under pressure to afford 2.51 g of ethyl imidazo[1,2-a]pyridine-2-carboxylate (Yield: 62%) as an orange oil which can be used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]([CH3:12])([CH3:11])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[H][H].[OH-].[Na+]>C(O)(=O)C.[Pt](=O)=O>[CH3:13][N:2]([CH3:1])[CH2:3][C:4]([CH3:11])([CH3:12])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: CN(C)CC(C)(C)c1ccncc1
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)CC(C)(C)C1CCNCC1
Yield: 93.7 %

Procedure:
A solution of 2 g (1.1×10-2 mole ) of N,N,β,β-tetramethyl-4-pyridineethanamine in 400 ml of acetic acid was hydrogenated in a Parr's apparatus at 50° C. at a hydrogen pressure of 3.106Pa in the presence of platinum dioxide. After eliminating the catalyst by filtering, the solvents were evaporated off under reduced pressure. The residue obtained was taken up in an aqueous 30% sodium hydroxide solution and extracted with methylene chloride. The organic phase was washed, dried over magnesium sulphate and filtered and the solvents were evaporated off under reduced pressure. 1.9 g (yield: 92%) of the desired compound was obtained as an oil. B Pt=60°-64° C. under 0.02 mm Hg (i.e. about 2.66 Pa)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+]([O-])=O)[CH:3]=1.O.O.O.O.O.O.O.O.O.[S-2:22].[Na+].[Na+].Br[CH2:26][N+:27]([O-:29])=[O:28]>CN(C=O)C.O>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=2[S:22][C:26]=1[N+:27]([O-:29])=[O:28]
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])CBr
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c([N+](=O)[O-])sc2cc(Cl)ccc12
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
A solution of 4-chloro-2-nitrobenzonitrile (2.19 g, 12 mmol) (EP 110,559; cf. Chem. Abstr., 101 130431 f (1984)) in 40 ml of DMF was stirred under cooling (ice bath), and a solution of sodium sulfide nonahydrate (3.47 g, 14.4 mmol) in 8 ml of water was added dropwise. When the addition was complete (0.5 h) the mixture was stirred for 15 min. and bromonitromethane (2.02 g, 14.4 mmol) was added dropwise. The ice bath was removed and stirring was continued for 16 h. The reaction mixture was poured into icewater and the yellow precipitate was filtered off and dried to afford 1.05 g (38%) of 3-amino-6-chloro-2-nitrobenzo[b]thiophene M.p. 243°-245° C. 1H-NMR (DMSO-d67): δ 7.55 (dd, 1H), 8.11 (d, 1H), 8.36 (d, 1H), 8.97 (br. s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][CH2:6][N:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1.[CH3:20]COCC.[N+](=C)=[N-].C(O)(=O)C>C(O)C>[CH3:20][O:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][CH2:6][N:7]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15]1
Reactant: CCOCC
Reactant: Oc1ccccc1C=CCN1Cc2ccccc2C1
Agent: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccccc1C=CCN1Cc2ccccc2C1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
The process for the preparation of this compound and its physical properties will be given below. 236.2 milligrams of the N-(o-hydroxycinnamyl)-isoindoline of the hereinafter-given Example 24 is dissolved in 10 milliliters of ethanol. After adding an ether solution of diazomethane thereto, the resulting mixture is left standing overnight at room temperature. The excess diazomethane is then decomposed with acetic acid, the solvent is distilled off, and the residue is recrystallized from acetone as a maleic acid salt to obtain 220.2 milligrams (yield 61.2%) of N-(o-methoxycinnamyl)-isoindoline.maleic acid salt as crystals having a melting point of 147°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[CH:11][O:10][C:9]=2[C:20]([NH:22][NH2:23])=[O:21])=[CH:4][CH:3]=1.CN([CH:27]=[O:28])C>C(OCC)(=O)C>[C:20]([C:9]1[CH:8]=[C:12]([CH:13]=[CH:14][C:27]=1[OH:28])[C:11]([NH:23][NH:22][C:20]([C:9]1[O:10][CH:11]=[C:12]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:21])=[O:10])#[N:22]
Reactant: CN(C)C=O
Reactant: NNC(=O)c1occ(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccc(Cl)cc3)c2-c2ccc(Cl)cc2)ccc1O

Procedure:
A mixture of 3,4-bis(4-chlorophenyl)-2-furancarboxylic acid hydrazide (compound of Reference Example 36, 0.092 g) and the compound of Reference Example 63 (0.11 g) in DMF (5 ml) was stirred overnight at 70° C. The reaction solution was diluted with ethyl acetate, washed with water, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 1:20 methanol/chloroform), and recrystallized from ethyl acetate/hexane, thereby giving 0.054 g of the desired compound. Melting point: 190-191° C. (Recrystallized from ethyl acetate)
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5](=[O:13])[O:4][CH2:3]1>C(Cl)Cl>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:13])[O:4][CH:3]=[CH:2]2
Reactant: O=C1OCC(Br)c2cc(Br)ccc21
Solvent: ClCCl
Product: O=c1occc2cc(Br)ccc12

Procedure:
4,6-Dibromo-3,4-dihydro-1H-isochromen-1-one (1.8 g, 5.8 mmol) was dissolved in DCM (15 ml) then added TEA (20 mL, 143 mmol) and stirred at room temperature for 72 hours. The mixture was concentrated then took up the residue with DCM and washed with 1N HCl. Repeated the wash with brine then dried over Na2SO4 and evaporated to dryness. The residue was purified by MPLC with 0-100% EtOAc/hexane to yield 6-Bromo-1H-isochromen-1-one. LC-MS (IE, m/z): 227 [M+2]+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C(OP([CH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32]P(OCC)(OCC)=O)=[CH:27][C:26]=1[CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])(OCC)=O)C.[C:51](O[K])([CH3:54])([CH3:53])[CH3:52].S(=O)(=O)(O)O>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:15]=[CH:53][C:51]([C:54]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:24][C:25]2[CH:30]=[C:29]([CH3:31])[C:28]([CH:32]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]3[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=3)=[CH:27][C:26]=2[CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:48])[CH3:49])=[CH:52][CH:3]=1
Reactant: CCOP(=O)(Cc1cc(CCC(C)CCCC(C)C)c(CP(=O)(OCC)OCC)cc1C)OCC
Reactant: CC(C)(C)O[K]
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C=C(c2ccccc2)c2ccc(Br)cc2)c(CCC(C)CCCC(C)C)cc1C=C(c1ccccc1)c1ccc(Br)cc1
Reaction time: 3.5 h

Procedure:
Under an inert atmosphere, 4-bromobenzophenone (2.611 g, 10 mmol), and 1,4-bis(diethylphosphonomethyl)-2-(3,7-dimethyloctyl)-5-methyl benzene (2.184 g, 4.10 mmol) were dissolved in tetrahydrofuran (30 g). At room temperature, tetrahydrofuran (10.92 g) solution of tert-butoxy potassium (1.380 g, 12.30 mmol) was added dropwise for 5 minutes, and successively stirred for 3.5 hours. The reaction mixture was charged into water (200 ml) and neutralized with 5% sulfuric acid. After neutralization, ethyl acetate (250 ml) was added and the organic layer was partitioned. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant raw product was purified by silica gel chromatography to give the desired product. (Yield: 1.34 g, 44%)
Reaction SMILES: C[O:2][C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8](=[O:28])[CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)[S:10][C:5]=2[CH:4]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8](=[O:28])[CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)[S:10][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)SC(CCCCN1CCN(c3cc(C)ccn3)CC1)C(=O)N2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccnc(N2CCN(CCCCC3Sc4cc(O)ccc4NC3=O)CC2)c1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
360 mg of 7-methoxy-2-{4-[4-(4-methylpyridin-2-yl)-piperazin-1-yl]-butyl}-2H-1,4-benzothiazine-3(4H)-one (see Example 19) prepared analogously to Example 1 were added to 5 ml of dichloromethane with exclusion of moisture. After cooling to -5° C., a solution of 0.73 g of boron tribromide in 1 ml of methylene chloride was added dropwise with stirring. Stirring was then continued for a further 30 minutes at room temperature. The reaction mixture was worked up by adding it with stirring to a mixture of ice and aqueous sodium hydrogen carbonate solution. 200 ml of chloroform were then added. The resulting organic solution was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained from the remaining residue by fractional column chromatography. The fractions containing the title compound were concentrated and treated with ether. 30 mg of 7-hydroxy-2-{4-[4-(4-methylpyridin-2-yl)-piperazin-1-yl]butyl}-2H-1,4-benzothiazine-3(4H)-one were obtained as white crystals having a melting point of 212° C.
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[OH-].[Na+].O.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>CO>[CH3:8][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[N:1][C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:19][CH:18]=1)=[O:22]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CN1CCCCC1=N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCCCC1=NC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.60 g.; 0.068 mole) is converted to free base by adding 7 ml. of NaOH (50%) to an aqueous slurry (using a minimal amount of water) of the salt and then extracting with benzene. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth. A benzene solution of 12.73 g. (0.068 mole) of p-trifluoromethylphenylisocyanate [prepared according to Inukai and Maki, Kogyo Kagaku Zasshi, 67 (5) 807-9 (1964] is added to the above solution slowly. After 4 hours of stirring at room temperature, the benzene is evaporated in vacuo to give a solid residue. Repeated recrystallizatons of the solid from methanol yields the pure product, 1-(1-methyl-2-piperidylidene)-3-(4-trifluoromethylphenyl)urea, m.p. = 154°-155° C.
Reaction SMILES: C([Al]([CH2:6][CH3:7])CC)C.CNCCNC.C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[N:19][C:18]=1[O:25][CH3:26].Cl>C1(C)C=CC=CC=1.CCCCCC>[CH3:26][O:25][C:18]1[C:17]([C:16](=[O:15])[CH2:6][CH3:7])=[CH:22][CH:21]=[C:20]([O:23][CH3:24])[N:19]=1
Reactant: COC(=O)c1ccc(OC)nc1OC
Reactant: CC[Al](CC)CC
Agent: CNCCNC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCC(=O)c1ccc(OC)nc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, 15% hexane solution of triethyl aluminium was dropped at 0° C. to 26 m solution of toluene with 0.6 ml of N,N′-dimethyl-ethan-1,2-diamine, and the mixture was stirred at room temperature for 1 hour. Then, 5 ml solution of toluene with 1 g of 2,6-dimethoxy-nicotinic acid methylester was dropped at room temperature, and the mixture was stirred at 130° C. for 1 hour. The reaction solution was cooled down under ice temperature, 1M of hydrochloric acid was added, and extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure to obtain 156 mg of the above compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH:15]([OH:28])[CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-:31].[K+]>C(O)(C)(C)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH:15]([OH:28])[CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([NH2:27])=[O:31])=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: [OH-]
Reactant: CCCCCCCOc1ccc(OCC(O)Cn2ccc3cc(C#N)ccc32)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCCCCCCOc1ccc(OCC(O)Cn2ccc3cc(C(N)=O)ccc32)cc1

Procedure:
455 mg (1.12 mmol) 1-[3-(4-Heptyloxyphenoxy)-2-hydroxypropyl]indole-5-carbonitrile are dissolved in 10 ml tert-butanol. Having added 1.10 g (22.4 mmol) pulverized, 88% potassium hydroxide, the batch is heated to 100° C. for 3 hours. After cooling the reaction solution, hydrolysis using 50 ml distilled water and neutralization with 1 N hydrochloric acid are carried out. The aqueous phase is extracted three times with ethyl acetate and the combined organic phases are washed once with water and then twice with saturated sodium chloride solution. Following drying on sodium sulfate, the solvent is removed on the rotary evaporator. The residue is purified on silica gel by means of column chromatography (flow agent: ethyl acetate), the product accruing as a solid.