Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[OH:14])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[O:18][N:17]=[C:16]([CH3:27])[C:15]=3[CH:13]([C:11]3[N:10]=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]=3)[OH:14])=[CH:21][CH:22]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccccc2)nn1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(O)c3cn(Cc4ccccc4)nn3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (1-benzyl-1H-[1,2,3]triazol-4-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:13][C:14]2[C:15]3[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:5][C:6]2[S:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([NH:13][C:14]2[C:15]3[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:5][C:6]2[S:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1
Reactant: CCOC(=O)c1cc2c(Nc3cc4sc(=O)[nH]c4cc3OC)ncnc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2[nH]c(=O)sc2cc1Nc1ncnc2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
A mixture of 15 mg (39 μmol) ethyl 4-[(5-methoxy-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (prepared according to example 25), 234 μL aqueous lithium hydroxide (1 molar), and 1.0 mL tetrahydrofuran was stirred at room temperature overnight. The mixture was then acidified by addition of aqueous hydrochloric acid (4 N). The precipitate was filtered, washed with water and diethyl ether and dried to give 10.1 mg (69%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.[C:32]1(=[O:42])[C:36]2([CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:35][C:34](=[O:41])[O:33]1.C(N(CC)CC)C>CN(C=O)C>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:34](=[O:41])[CH2:35][C:36]3([C:32]([OH:42])=[O:33])[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:29][CH2:30]2)=[CH:21][CH:20]=1)=[O:31]
Reactant: O=C1CC2(CCCC2)C(=O)O1
Reactant: O=C(Nc1nc2ccccc2s1)c1ccc(N2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccccc2s1)c1ccc(N2CCN(C(=O)CC3(C(=O)O)CCCC3)CC2)cc1
Reaction time: 5 h
Yield: 68.9 %

Procedure:
N-benzothiazol-2-yl-4-piperazin-1-yl-benzamide trifluoroacetate (40 mg) was mixed with 2-oxa-spiro[4,4]nonane-1,3-dione (30 mg) in DMF (5 mL) containing triethylamine (0.1 mL) and the mixture was stirred foe 5 hrs. Solvents were evaporated and the residue was treated with ethyl acetate and hydrochloric acid solution (0.1N). The precipitate from the organic layer was filtered to give 1-(2-{4-[4-(benzothiazol-2-ylcarbamoyl)-phenyl]-piperazin-1-yl}-2-oxo-ethyl)-cyclopentanecarboxylic acid as a white solid (30 mg). LCMS calc for C26H28N4O4S (m/e) 492, obsd 493.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:25]1([CH2:31][C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:36]([C:35]3[CH:34]=[CH:33][C:32]([CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:39][CH:38]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.047 g, 0.12 mmol) and EtOH (3.5 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.032 g, 0.16 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 ml, 0.48 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column, and elution of the column with a gradient of methanol (2 to 12%) in ethyl acetate/dichloromethane (v:v; 4:1) afforded a yellow solid which was triturated with diethyl ether. The precipitate was collected by filtration, and was successively washed with diethyl ether, water, and diethyl, then dried in vacuo (0.009 g, 14%). 1H-NMR (500 MHz, DMSO-d6) 2.38 (br t, 4H) and 3.59 (t, J=4.6 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.62 (br s, 4H, piperazine N(CH2)2), 3.67 (br s, 4H, piperazine N(CH2)2), 3.53 (s, 2H) and 3.62 (s, 2H) (NCH2-pyridyl and C6H4CH2), 7.39 (dd, J=5.3, 7.1 Hz, pyridine 5-H), 7.47 (d, J=7.7 Hz, 2H) and 8.14 (d, J=8.0 Hz, 2H) (3,5-C6H4 and 2,6-C6H4), 7.78 (d, J=7.5 Hz, 1H, pyridine 4-H), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=1.6, 4.7 Hz, 1H, pyridine 6-H), 8.56 (d, J=1.6 Hz, 1H, pyridine 6-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+].[C:30]([O:39][CH:40](Cl)[CH3:41])(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[I-].[Na+]>C1(C)C=CC=CC=1.CCCCCC.CC(C)=O>[C:30]([O:39][CH:40]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:41])(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: CCCCCCCC(=O)OC(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21
Reaction time: 72 h

Procedure:
To a round bottomed flask equipped with a reflux condenser and stirring bar were added piroxicam (3.00 g, 9.1 mmol), potassium carbonate (2.50 g, 18.1 mmol), alpha-chloroethyl octanoate (5.6 g, 27.0 mmol) and acetone (45 mL). The heterogenous reaction mixture was heated to reflux under a nitrogen atmosphere. After one hour sodium iodide (4.52 g, 30.2 mmol) was added and reflux continued an additional 72 hours. Chromatographed title product was isolated according to Example 5 as a white foam which oiled from toluene/hexane, but crystallized from the oil upon refrigeration. Collected were 2.19 g white crystals from two crops (4.4 mmol, 48.2%); mp 90°-91° C.; IR (KBr) 1766, 1675 cm-1 ; 1H NMR (CDCl3) delta 0.85 (t, J=7 Hz, 3H), 1.02-1.34 (m, 8H), 1.45 (d, br quintet, 2H), 1.73 (d, J=6 Hz, 3H), 2.08-2.33 (m, 2H), 3.12 (s, 3H), 6.40 (q, J=6 Hz, 1H), 7.06-7.17 (m, 1H), 7.63-7.95 (m, 5H), 8.30-8.42 (m, 2H), 9.56 (br s, 1H): precise mass calcd for C23H27N3O5S m/e (P+ --C2H4O) 457.1429, found 457.1700.
Reaction SMILES: [OH-].[Na+:2].CO.[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13]>ClCCl>[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[N-:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13].[Na+:2]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 29 °C

Procedure:
3.47 g of sodium hydroxide and 105 ml of methanol were taken into a round bottom flask and stirred at 29° C. A solution of 30 g of esomeprazole in 150 ml of dichloromethane was added to the above methanolic sodium hydroxide solution and stirred for 1 hour at 26° C. The mass was then distilled under a vacuum of 300 mm Hg at 38° C. The remaining residue was then co-distilled with 450 ml of dichloromethane in three equal lots. To the residue obtained, 60 ml of dichloromethane was added and stirred at 29° C. for 1.5 hours. The separated solid was filtered and washed with 30 ml of dichloromethane to give 32.2 g of Form J of esomeprazole sodium.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:12])[C:10](=[O:11])[C:5]2=[C:4]([O:13][CH3:14])[C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[Li]CCCC.CCCCCC.[N:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[C:37](OC)=[O:38].Cl>C1COCC1>[CH3:14][O:13][C:4]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([C:37]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][N:31]=2)=[O:38])[N:6]2[CH2:7][CH2:8][N:9]([CH3:12])[C:10](=[O:11])[C:5]=12
Reactant: COC(=O)c1cnccn1
Reactant: CCOC(=O)c1c(OC)c2n(c1Br)CCN(C)C2=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OC)c2n(c1C(=O)c1cnccn1)CCN(C)C2=O
Temperature: 25 °C

Procedure:
To a cold (−78° C.) solution of ethyl 6-bromo-8-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (0.5 g, 1.51 mmol; Example 7, steps 1 to 6, substituting benzyl bromide with iodomethane in step 5) in anhydrous THF (15 mL) under an atmosphere of dry nitrogen, a solution of n-BuLi in hexane (1.81 mL, 1.81 mmol, 1 M) was added. The resultant mixture was stirred at −78° C. for 15 minutes, and treated with methyl pyrazine-2-carboxylate (0.21 g, 1.51 mmol). The reaction mixture was allowed to warm up to room temperature, treated with dilute hydrochloric acid, and concentrated under vacuum. The residue was extracted with ethyl acetate. The organic extracts were combined, washed with aqueous sodium carbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 0 to 10% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([SH:12])[N:3]=1.[OH-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>C(O)C.O>[F:10][C:8]([F:9])([F:11])[C:6]1[N:5]=[C:4]([S:12][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[N:3]=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CSc2nc(O)cc(C(F)(F)F)n2)cc1

Procedure:
4-hydroxy-6-trifluoromethyl-2-pyrimidinethiol (Cpd #264; 4.90 g, 25.0 mmol) in ethanol (8 ml) is treated with 3.25 N NaOH (8 ml, 26.0 mmol) followed by 4-methoxybenzyl chloride (3.5 ml, 25.7 mmol). After refluxing for 1 hr, the reaction is diluted with water and filtered. The solid is recrystallized from ethanol: 4.63 g (14.6 mmol, 58%), mp 169-170° C.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=3[F:30])[N:17]=[CH:16][N:15]=2)=[O:12])[CH2:7][CH2:6]1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:18]2[CH:19]=[C:14]([NH:13][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:31])[CH3:1])[CH2:6][CH2:7]3)=[O:12])[N:15]=[CH:16][N:17]=2)=[C:22]([F:30])[CH:23]=1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reaction time: 8 h
Yield: 96.5 %

Procedure:
4-{[4-(2-Dimethylaminoethyl)piperazin-1-yl]carbonylamino}-6-(2-fluoro-4-nitrophenoxy)pyrimidine (167 mg) was dissolved in tetrahydrofuran (16 ml). After adding 20% palladium hydroxide-carbon (108 mg), the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered and washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated under reduced pressure, and the resultant residue was dried under reduced pressure to provide the title compound (150 mg, 97%) as pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].CN(C)CCN(C)C.[Li]CCCC.C([O:28][C:29]1[C:30](=[O:35])[CH2:31][CH2:32][CH2:33][CH:34]=1)C>C1COCC1>[OH:35][C:30]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:11][CH3:12])[C:5]=2[O:9][CH3:10])[CH2:31][CH2:32][CH2:33][CH2:34][C:29]1=[O:28]
Reactant: CCOC1=CCCCC1=O
Reactant: COc1cccc(OC)c1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCCCC2=O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
A stirred solution of 8.70 g (51.8 mmol) of 1,2,3-trimethoxybenzene and 8.25 mL (54.7 mmol) of tetramethylethylenediamine in 40 mL of THF was cooled in an ice bath and 24.0 mL of 2.5 molar n-BuLi in hexanes (60.0 mmol) was added dropwise over 20 min. The cooling bath was removed and the mixture was stirred at room temperature for 2 h. The mixture was cooled to -70° C. and a solution of 6.95 g (49.6 mmol) of 2-ethoxycyclohex-2-en-1-one in 30 mL of THF was added dropwise over 45 min. The cooling bath was removed and the mixture was stirred at room temperature for 2 days. The mixture was poured into 150 mL of 5% aqueous HCl and allowed to stand for 2 h. The mixture was extracted with two 80 mL portions of ether. The combined ether extracts were washed with 50 mL of saturated aqueous NaHCO3, and dried over MgSO4. Removal of the solvent left 13.56 g of an oil which was purified by flash chromatography on a column of 100 g of silica gel eluted successively with 250 mL portions of 0, 8, 16, 24, 40, 60, 80 and 100% ether in hexanes to furnish 7.08 g of 2-hydroxy-2-(2,3,4-trimethoxyphenyl)cyclohexanone as a solid, mp 88°-91° C. 1H-NMR (CDCl3) d 1.5-1.8 (4H), 2.0 (m, 1H), 2.5 (m, 2H), 2.9 (m, 1H), 3.7 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.6 (s, 1H), 6.75 (d, 1H), 7.25 (d, 1H).
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].CN(C)C=O.Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(OCC)C.O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a stirred solution containing 17.3 g (0.075 mole) of 3,5-ditrifluoromethylphenol, 5 g (0.075 mole) of 85% potassium hydroxide, 150 ml of dimethylformamide and 7 ml of water, 14.6 g (0.08 mole) of ethyl 2-bromopropionate was added in one portion. The stirred reaction mixture was heated at 80°-90° C. for 24 hours. After cooling to 25° C., 500 ml of water and 500 ml of ethyl ether were added and stirring was continued for 15 minutes. The separated ether layer was washed with water until neutral to litmus and dried over sodium sulfate. The ether was removed in vacuo at maximum temperature of 50°C. at 1-2 mm of Hg. The resulting product was obtained as an amber liquid, ND25 =1.4184 in 97% yield.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:15])[O:5][C:4](=O)[CH:3]=1.NC1C=CC=CN=1.Cl.[NH2:25][OH:26]>>[OH:26][N:25]1[C:6]([CH3:15])=[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: NO
Reactant: Cc1cc(=O)oc(C)c1Cc1ccccc1
Agent: Cl
Agent: Nc1ccccn1
Product: Cc1cc(=O)n(O)c(C)c1Cc1ccccc1
Yield: 41.6 %

Procedure:
2 g of 4,6-dimethyl-5-benzyl-2-pyrone, 4 g of 2-aminopyridine and 0.9 g of hydroxylamine hydrochloride were heated for 5 hours to 80° C. After the usual working up, there were obtained 0.89 g (42 %) of 1-hydroxy-4,6-dimethyl-5-benzyl-2-pyridone melting at 165° C (Calc.: 6.1 % N, found: 6.1 % N).
Reaction SMILES: C[O:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8](=[O:30])[CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=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>ClCCl>[OH:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8](=[O:30])[CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH:18]([C:21](=[O:29])[C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:19][CH2:20]3)[S:10][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)SC(CCCCN1CCC(C(=O)c3ccc(F)cc3)CC1)C(=O)N2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)C1CCN(CCCCC2Sc3cc(O)ccc3NC2=O)CC1
Reaction time: 0.5 h

Procedure:
675 mg (=0.0015 m) of 7-methoxy-2-(4-[4-(4-fluorobenzoyl)-piperidin-1-yl]-butyl)-2H-1,4benzothiazine-3(4H)-one (see Example 18) prepared analogously to Example 4 were placed in 5 ml of dichloromethane with exclusion of moisture. After cooling to -5° C. a solution of 1.10 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. 55 mg of 7-hydroxy-2-{4-[4-(4-fluorobenzoyl)-piperazin-1-yl]-butyl} -2H-1,4-benzothiazine-3(4H)-one were obtained.
Reaction SMILES: B(Br)(Br)Br.[CH:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[O:15]C)=[O:6].C(=O)(O)[O-].[Na+]>ClCCl>[CH:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[OH:15])=[O:6]
Reactant: COc1cc(C#N)ccc1C=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(C=O)c(O)c1
Temperature: 25 °C

Procedure:
100 ml of a boron tribromide solution in dichloromethane (1 M, 100 mmol) are added dropwise to a solution of 8 g (49.64 mmol) of 4-formyl-3-methoxybenzonitrile in 80 ml of anhydrous dichloromethane at −78° C. under an argon atmosphere. The reaction mixture is stirred at RT until the precursor has completely reacted (about 5 days). The reaction solution is then neutralized at 0° C. with saturated sodium bicarbonate solution. The phases are separated and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 3:1). 4.5 g (61% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[I-].CS[C:15]1[S:16][CH2:17][C@@H:18]2[CH2:27][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:20][N+:19]=12>N1C=CC=CC=1>[CH:7]1[C:8]2[C:3](=[C:2]([N:1]=[C:15]3[N:19]4[CH2:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=5[CH2:27][C@H:18]4[CH2:17][S:16]3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: Nc1cccc2cnccc12
Agent: [I-]
Solvent: c1ccncc1
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3cccc4cnccc34)N1C2
Temperature: 5 °C
Reaction time: 5 h
Yield: 78.3 %

Procedure:
5-Aminoisoquinoline (10.8 g.) is added to a solution of (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.2 g.) in pyridine (500 cc.). After 5 hours at a temperature of about 20° C., solution is complete and the reaction is allowed to continue for 10 hours. The solution is concentrated to dryness under reduced pressure (25 mm.Hg) at 60° C. The residue is dissolved in a mixture consisting of N sodium hydroxide solution (250 cc.) and methylene chloride (250 cc.). The organic phase is decanted, washed with water (2 × 100 cc.), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (50 mm.Hg) at 40° C. Isopropanol (150 cc.) is added to the residue obtained; the mixture is brought to the boil and is filtered hot. After cooling to 5° C., the crystals formed and filtered off and washed with isopropanol (3 × 10 cc.). After drying at 60° C., under reduced pressure (0.1 mm.Hg), (S)-3-(isoquinol-5-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b] isoquinoline (13.0 g.) is obtained in the form of white crystals melting at 164° C.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](OC)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].N1C=CN=C1>CO>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: CN(C)CCN
Reactant: COC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Agent: c1c[nH]cn1
Solvent: CO
Product: CN(C)CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A suspension of methyl 4-(4-biphenylylmethoxy)phenylacetate (1.00 g), N,N-dimethylethylenediamine (0.80 g), and imidazole (205 mg) in methanol (2.0 ml) was heated under reflux under nitrogen for 30 min and cooled until the temperature of the reaction mixture reached to 60±2° C. Methanol (4.0 ml) was added to the reaction mixture, which was heated under reflux for additional one hr and cooled to room temperature. The precipitate was collected by filtration and washed with methanol (2.0 ml) to obtain the titled compound (1.03 g).
Reaction SMILES: [CH2:1]([C:5]([CH3:22])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(N(CC)CC)C>[CH2:1]([C:5]([CH3:22])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C)(Cc1ccc(OCCO)cc1)C(=O)OCC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCC(C)(Cc1ccc(OCCOS(C)(=O)=O)cc1)C(=O)OCC

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 2-butyl-3-[4-(2-hydroxyethoxy)phenyl]-2-methylpropionate (2.73 g), which is the product of Reference example 10(d), triethylamine (1.85 ml) and methanesulfonyl chloride (0.75 ml) and the reaction mixture was treated to afford the desired compound (3.17 g) as a syrup.
Reaction SMILES: [F:1][C:2]([F:14])([C:7]1[CH:11]=[CH:10][N:9]([CH2:12]O)[N:8]=1)[C:3]([F:6])([F:5])[F:4].S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH2:12][N:9]1[CH:10]=[CH:11][C:7]([C:2]([F:14])([F:1])[C:3]([F:6])([F:5])[F:4])=[N:8]1
Reactant: O=S(Cl)Cl
Reactant: OCn1ccc(C(F)(F)C(F)(F)F)n1
Solvent: ClCCl
Product: FC(F)(F)C(F)(F)c1ccn(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.98 g of 3-(pentafluoroethyl)-1H-pyrazole-1-ylmethanol was dissolved to 20 ml of dichloromethane. 1.5 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 2.01 g of 1-(chloromethyl)-3-(pentafluoroethyl)-1H-pyrazole.