Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([O-:31])(=[O:30])[CH:22]([C:24]1C=CC=CC=1)[OH:23].[OH-].[Na+]>O.C(OCC)(=O)C>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([O-:31])(=[O:30])[C@H:22]([CH3:24])[OH:23]
Reactant: O=C([O-])C(O)c1ccccc1
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](O)C(=O)[O-]
Temperature: 15 °C
Reaction time: 20 h

Procedure:
Sertraline mandelate (750 grams) was slurried in a mixture of water (3.9 L) and ethyl acetate (3.9 L). The slurry was cooled to 15° C. NaOH (25% aqueous, 250 mL) was added, resulting in a solution with pH 9.6. The free base of sertraline was partitioned into the ethyl acetate layer which was separated. The aqueous layer was extracted with an additional 3.4 liters of ethyl acetate. The combined ethyl acetate layers were washed with 3.9 liters of water. The ethyl acetate layer containing sertraline base was concentrated under vacuum and filtered to clarify the solution. To this solution was added L-lactic acid (155 g). The reaction mixture was granulated hr 20 hours at room temperature. The solids were filtered, washed 4 times with ethyl acetate(400 mL each time). The crystals were dried overnight under vacuum at 40° C. The yield was calculated to be 84%. mp 153° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH3:7])(=[O:6])=[O:5].[CH3:8][N:9]([CH3:23])[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:19]=1)[C:13](OC)=[O:14]>CS(C)=O>[CH3:21][N:20]([CH3:22])[C:18]1[CH:17]=[C:12]([C:13](=[O:14])[CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])[CH:11]=[C:10]([N:9]([CH3:8])[CH3:23])[CH:19]=1
Reactant: CS(C)(=O)=O
Reactant: COC(=O)c1cc(N(C)C)cc(N(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(C(=O)CS(C)(=O)=O)cc(N(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 3.6 g. of sodium hydride (50% dispersion in oil) and 9.4 g. of dimethylsulfone in 50 ml. of absolute dimethylsulfoxide was stirred with the exclusion of moisture for 2.5 hours at 50° C. and then treated with 11.1 g. of methyl 3,5-bis(dimethylamino)benzoate. The mixture was stirred for 18 hours at room temperature, diluted with 500 ml. of water and extracted with 600 ml. of ethyl acetate. The ethyl acetate phases were washed with 300 ml. of water, dried over magnesium sulfate and evaporated to dryness in vacuo. Recrystallization of the residue from ethyl acetate yielded 3',5'-bis-(dimethylamino)-2-methylsulfonylacetophenone, having a melting point of 151°-153° C.
Reaction SMILES: O[C:2]1(C2C=CC=CC=2OC)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].Br[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.[Mg].COC1C=CC([Mg]Br)=CC=1.C1OC2C=CC(C3C4C(=CC=CC=4)C(=O)C=3C(OCC)=O)=CC=2O1>CCOCC.C1COCC1>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([CH:2]2[C:6]3[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:4]([C:11]3[CH:12]=[CH:13][C:14]4[O:17][CH2:18][O:19][C:15]=4[CH:16]=3)[CH:3]2[C:20]([OH:22])=[O:21])=[CH:35][CH:36]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Reactant: COc1ccc(Br)cc1
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Ethyl (1RS) 1-Hydroxy-1-(methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate, A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9:1 Et2O/THF (10 ml) was added to magnesium turnings (0.105 g, 5.0 mmol), and the resulting mixture was allowed to stir for 30 min. The resultant 4-methoxyphenyl magnesium bromide was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)1-oxoindene-2-carboxylate (0.77 g, 2.4 mmol) in 10: 1 Et2O/ THF (55 ml) at 0° C. The resulting mixture was stirred at 0° C. for 1 h and was then partitioned between EtOAc and 1M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow glassy solid (0.80 g, 80%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH2:5][NH:6][CH3:7].C(N(CC)CC)C.[C:16]1([CH:26]=[C:27]2[CH2:32][C:31](=[O:33])[O:30][C:28]2=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>ClCCl>[C:16]1([CH:26]=[C:27]([CH2:32][C:31](=[O:33])[N:6]([CH3:7])[CH2:5][C:4]([O:3][CH3:2])=[O:8])[C:28]([OH:30])=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CNCC(=O)OC
Reactant: O=C1CC(=Cc2cccc3ccccc23)C(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)CC(=Cc1cccc2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of 1.40 g of sarcosine methyl ester hydrochloride in 50 ml of dichloromethane were added 1.54 ml of triethylamine and 1.70 g of the 2-(1-naphthylmethylene)succinic anhydride obtained, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was washed successively, with diluted hydrochloric acid, and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform) to obtain 2.37 g of 2-(1-naphthylmethylene)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionic acid as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C:13]1[C:14]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:15]([CH2:38][CH2:39][CH3:40])[N:16]2[C:21]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][C:18]([N:28]1[CH2:37][CH2:36][C:31]3(OCC[O:32]3)[CH2:30][CH2:29]1)=[N:17]2)=[O:12])[CH3:9].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH2:8]([O:10][C:11]([C:13]1[C:14]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:15]([CH2:38][CH2:39][CH3:40])[N:16]2[C:21]=1[C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:19][C:18]([N:28]1[CH2:29][CH2:30][C:31](=[O:32])[CH2:36][CH2:37]1)=[N:17]2)=[O:12])[CH3:9]
Reactant: CCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCC4(CC3)OCCO4)nn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCC(=O)CC3)nn12
Temperature: 50 °C

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of 2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-phenyl-7-propyl-pyrrolo[1,2-b]pyridazine-5,6-dicarboxylic acid diethyl ester (99) (245 mg, 0.47 mmol) in THF (10 mL) and water (1 mL). The reaction mixture was heated to 50° C. for 4 h, poured into aqueous NaHCO3 solution. The mixture was extracted with EtOAc and the organic layer was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 35% EtOAc/hexane) provided the title compound. 1H NMR (DMSO-d6) δ 1.05-1.11 (m, 6H), 1.38 (t, 2H, J=7.0 Hz), 1.83-1.89 (m, 2H), 2.63-2.67 (m, 4H), 3.34 (t, 2H, J=7.8 Hz), 3.71 (q, 2H, J=7.2 Hz), 4.08-4.11 (m, 4H), 4.35 (q, 2H, J=7.2 Hz), 7.05 (s, 1H), 7.60-7.66 (m, 5H). Mass Spectrum (ES+) m/e=478.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([O:34]C)=[O:33]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)[C:11]([F:13])([F:14])[F:12])[O:8][C:28]1[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[C:26]([F:25])[CH:27]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(c1ccc(Oc2ccc(C(=O)O)c(F)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 151, step 7) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine. The product of this reaction was hydrolyzed in analogy to Example 141 to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=498.1 [M−H+].
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([OH:19])=[C:14]([O:20][CH3:21])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([O:19][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[C:14]([O:20][CH3:21])[CH:13]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: COc1cc(Cl)c(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Cl)cc1Oc1ncccc1C(=O)O

Procedure:
2-Chloronicotinic acid and 4,5-dichloro-2-methoxyphenol are reacted in the presence of potassium carbonate in dimethylformamide to give 2-(4,5-dichloro-2-methoxyphenoxy)nicotinic acid, which is reacted with thionyl chloride in dichloroethane to be converted into the acid chloride. This acid chloride is reacted with ethoxymagnesium.diethyl malonate in a mixed solvent of chlorobenzene and ethanol, followed by treatment with conc. hydrochloric acid and acetic acid to obtain the acetyl compound. This acetyl compound is reacted with benzaldehyde in the presence of a small amount of sodium hydroxide in ethanol to give 2-(4,5-dichloro-2-methoxyphenoxy)-3-cinnamoylpyridine. This compound is treated with aluminium chloride to give 2-(4,5-dichloro-2-hydroxyphenoxy)-3-cinnamoylpyridine.
Reaction SMILES: [N:1](=[C:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1)[OH:2].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C(Cl)Cl>[N:1]1[O:2][C:10](=[O:11])[N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:3]=12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: ON=C1CCCCCN1
Solvent: ClCCl
Product: O=c1onc2n1CCCCC2
Temperature: 25 °C
Reaction time: 144 h
Yield: 89.2 %

Procedure:
To a solution of 2 g (16 mmol) of 2-hydroximinohomopiperidine (Maybridge) in 20 mL of methylene chloride (CH2Cl2) was added 2.5 g (16 mmol) of 1,1′-carbonyldiimidazole (CDI). This was stirred at 25° C. for six days. This solution was diluted with CH2Cl2, washed with water, dried (MgSO4), filtered and concentrated to afford 2.2 g (89% yield) of the title compound as a white semi-solid.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[C:5](=[O:8])[NH:4][C:3]2[S:9][CH:10]=[CH:11][C:2]1=2.[N+:12]([O-])([OH:14])=[O:13]>C(OC(=O)C)(=O)C>[N+:12]([C:10]1[S:9][C:3]2[NH:4][C:5](=[O:8])[C:6](=[O:7])[NH:1][C:2]=2[CH:11]=1)([O-:14])=[O:13]
Reactant: O=c1[nH]c2ccsc2[nH]c1=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]c2cc([N+](=O)[O-])sc2[nH]c1=O
Yield: 25.6 %

Procedure:
Thieno[2,3-b]pyrazine-2,3(1H,4H)-dione (1.00 g, 5.95 mmol) was reacted with fuming nitric acid (0.374 ml, 8.9 mmol) in acetic anhydride following the procedure outlined in example 4 (Method F). The crude product (655 mg) was recrystallized from acetic acid to afford 325 mg (26%) of the title compound. M.p.>300° C. 1H-NMR (DMSO-d6, δ): 7.58 (s, 1H), 12.1 (s, 1H), 12.62 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:8][C:3]=1[C:4](OC)=[O:5].CC(O)=O.[CH:23]([NH2:25])=O>>[CH3:13][O:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:5])[NH:25][CH:23]=[N:1]2)=[CH:8][C:9]=1[O:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCOc1cc(C(=O)OC)c(N)cc1OC
Reactant: NC=O
Solvent: CC(=O)O
Product: COCCOc1cc2c(=O)[nH]cnc2cc1OC
Temperature: 140 °C
Yield: 69 %

Procedure:
According to the procedure described in Example 6A Step 4, a mixture of methyl 2-amino-4-methoxy-5-(2-methoxyethoxyl)benzoate (3.05 g, 11.9 mmol) and AcOH (5.4 mL) in formamide (15.25 mL) was heated at at 140° C. overnight, to afford 7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-one as a solid (2.07 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 12.0 (br, 1H), 7.99 (s, 1H), 7.45 (s, 1H), 7.14 (s, 1H), 4.19 (t, 2H), 3.91 (s, 3H), 3.71 (t, 2H), 3.32 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:20][C:21]1[C:22]([CH2:55][CH2:56][N:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)=[CH:23][C:24]([O:53][CH3:54])=[C:25]([NH:27][C:28]2[N:33]=[C:32]([C:34]3[N:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]4=[N:36][C:35]=3[C:43]3[CH:44]=[C:45]([CH:50]=[CH:51][CH:52]=3)[C:46](OC)=[O:47])[CH:31]=[CH:30][N:29]=2)[CH:26]=1.CO>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:46](=[O:47])[C:45]1[CH:50]=[CH:51][CH:52]=[C:43]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:34]=2[C:32]2[CH:31]=[CH:30][N:29]=[C:28]([NH:27][C:25]3[CH:26]=[C:21]([F:20])[C:22]([CH2:55][CH2:56][N:57]4[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]4)=[CH:23][C:24]=3[O:53][CH3:54])[N:33]=2)[CH:44]=1
Reactant: Nc1c(F)cccc1F
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(F)c(CCN4CCCCC4)cc3OC)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CCN2CCCCC2)c(F)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
To 2,6-difluoroaniline (133 mg, 1 mmol) was added 1N NaHMDS in THF (1 mL, 1 mmol). The mixture stirred for 15 min at rt. Methyl 3-{3-[2-({5-fluoro-2-(methyloxy)-4-[2-(1-piperidinyl)ethyl]phenyl}amino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-2-yl}benzoate (120 mg, 0.206 mmol) in 3 mL of dry THF was added. The mixture stirred at rt for 30 min. 1 mL of MeOH was added followed by 1 g of silica gel. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (52 mg, 0.0767 mmol, 37%). 1H NMR (400 MHz, CDCl3) δ ppm 9.46 (d, J=7.33 Hz, 1H), 8.21-8.29 (m, 3H), 8.11 (s, 1H), 8.02 (d, J=7.70 Hz, 1H), 7.74-7.83 (m, 2H), 7.66 (d, J=8.80 Hz, 1H), 7.47-7.56 (m, 1H), 7.32-7.40 (m, 1H), 7.22 (dd, J=8.43, 5.87 Hz, 1H), 6.91-7.01 (m, 3H), 6.76 (d, J=6.60 Hz, 1H), 6.63 (dd, J=5.32, 3.12 Hz, 1H), 3.92 (s, 3H), 2.79-2.87 (m, 2H), 2.54-2.61 (m, 2H), 2.45-2.54 (m, 4H), 1.59-1.68 (m, 4H), 1.42-1.52 (m, 2H). MS (ESI): 678 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13](=[C:16]([CH2:18][CH3:19])[CH3:17])[O:12][C:11]1=[O:20].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]#[CH:29]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([O:9][CH2:29][C:28]#[CH:27])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13](=[C:16]([CH2:18][CH3:19])[CH3:17])[O:12][C:11]1=[O:20]
Reactant: CCC(C)=C1OC(=O)N(c2cc(O)c(Br)cc2F)C1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(N2C(=O)OC(=C(C)CC)C2=O)c(F)cc1Br
Yield: 76.6 %

Procedure:
To an acetonitrile solution (25 ml) of 3-(2'-fluoro-4'-bromo-5'-hydroxyphenyl)-5-(sec-butylidene)-1,3-oxazolidine-2,4-dione (0.26 g, 0.82 mmol) was added potassium carbonate (0.11 g) and the mixture was heated at reflux for 1 hour. After the addition of propargyl bromide (0.1 g, 0.83 mmol), the reaction mixture was further refluxed for 1 hour. 3-(2'-fluoro-4'-bromo-5'-propargyloxyphenyl)-5-(sec-butylidene)-1,3-oxazolidine-2,4-dione (0.24 g, 77% yield) was obtained by an operation similar to that of Example 1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([CH:11]=O)=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([CH:11]=[N:14][OH:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)c2nsnc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: ON=Cc1ccc(Br)c2nsnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
To a solution of 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde (16.65 g) (Example I3) in ethanol (150 ml) were added hydroxylamine hydrochloride (9.52 g), sodium hydrogen carbonate (11.51 g) and water (15 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (1500 ml) and water (400 ml). After separation of the phases, the aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layers were washed with water (200 ml) and brine (200 ml), dried over sodium sulfate and concentrated to give 7-bromo-benzo[1,2,5]-thiadiazole-4-carbaldehyde oxime (16.65 g) as a brown solid. 1H-NMR (DMSO-d6, 400 MHz): 11.94 (s, 1H), 8.66 (s, 1H), 8.09-9.90 (m, 2H) ppm.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: C1COCCN1
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Temperature: 110 °C
Yield: 58 %

Procedure:
A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) in 8 ml morpholine was heated at 110° C. for 15 h. After evaporation of all volatiles the residue was acidified by addition of 1 N HCl and extracted three times with ethyl acetate. The combined organic extracts were washed sequentially with 1 N HCl and saturated brine, dried over sodium sulphate, and concentrated in vacuo to afford the title compound as a light yellow amorphous solid (58%). MS (m/e): 284.1 ([M−H]−, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[N:44]1([CH2:50][CH2:51]O)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:51][CH2:50][N:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: OCCN1CCCCC1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCCCC3)cc21
Reaction time: 3 h
Yield: 37 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 61 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(piperidin-1-yl)ethanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 3 h, and being purified by silica gel column chromatography (CH2Cl2/EtOAc=1:4) to obtain the title compound (37%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[O:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1nc2ccccc2o1
Product: c1ccc2oc(COc3ccc(CCCn4ccnc4)cc3)nc2c1
Yield: 28 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-chloromethylbenzoxazole to give 2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]benzoxazole. The yield was 28%. Recrystallization from ethyl acetate-hexane gave pale brown prisms, mp 81-82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH:5]=[N:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Oc1cnc(C(F)(F)F)c(Cl)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2cnc(C(F)(F)F)c(Cl)c2)cc1
Temperature: 85 °C
Reaction time: 18 h
Yield: 7.3 %

Procedure:
5-Chloro-6-(trifluoromethyl)pyridin-3-ol (Preparation 83, 250 mg, 1.266 mmol) was added to a solution of 4-fluorobenzaldehyde (150 mg, 1.209 mmol) and potassium carbonate (260 mg, 1.881 mmol) in DMSO (5 mL). The mixture was stirred at 85° C. for 18 hours, then at 125° C. for 72 hours. The mixture was diluted with EtOAc (15 mL) and washed with water (2×10 mL). The organic layer was dried over sodium sulfate, filtrated and concentration in vacuo. The crude oil was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane to yield the title compound as a yellow oil (26.5 mg, 70%):
Reaction SMILES: Cl[C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([Cl:18])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>C1COCC1>[Cl:18][C:11]1[C:3]([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[C:2]([NH:33][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CN2CCCCC2)c1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2c([N+](=O)[O-])ccc(Cl)c2CN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(2,6-dichloro-3-nitro-benzyl)-piperidine (21) (0.894 g, 3.09 mmol) and triethylamine (0.606 g, 6 mmol) in anhydrous THF (5 mL), p-methoxy benzylamine (0.823 g, 6 mmol) was added at 0° C. under stirring. The reaction mixture was allowed to warm to room temperature and stirred for additional 12 hours and evaporated to dryness. The product was extracted with EtOAc (100 mL) and washed with water (2×50 mL) and dried (MgSO4). The product was purified by column chromatography (SiO2, hexanes:EtOAc, 95:5 to 9:1) as a yellow oil. Yield: 0.81 g, 67%. 1H-NMR (CDCl3) δ 1.23-1.26 (m, 6H), 2.23 (m, 4H), 3.63 (s, 2H), 3.76 (s, 3H), 3.92 (d, 2H, J=4.4 Hz), 6.65 (d, 1H, J=9.04 Hz), 6.82 (d, 2H, J=8.6 Hz), 7.18 (d, 2H, J=8.6 Hz), 7.18 (d, 2H, J=8.6 Hz) 7.57 (d, 1H, J=9 Hz), 8.29 (bs, 1H). NOE's were observed from H4 to H3, H5, H6. No NOE was observed from H4 to H1, which would have been expected if the other regioisomer was formed. MS (CI) m/z 390 (M+1), 392 (M+2).