Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C@@H:10]([OH:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:7]=2[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[O:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])(=O)=O.Cl>C1(C)C=CC=CC=1>[Si:52]([O:18][C@@H:10]1[C:9]2[C:14](=[CH:15][C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[C:7]([C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)=[O:27])[C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:13][C:12]([CH3:16])([CH3:17])[CH2:11]1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)C[C@H](O)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)O1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CC1(C)C[C@H](O[Si](C)(C)C(C)(C)C)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)O1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Under argon, 200 mg (0.39 mmol) of [(4S)-7-cyclopentyl-5-(4-fluorophenyl)-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl][4-(trifluoromethyl)phenyl]methanone (Example 12A) and 180 μl (1.56 mmol) of 2,6-dimethylpyridine are dissolved in 1.25 ml of toluene and cooled to −20° C. A solution of 0.18 ml (0.78 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate in 1.25 ml of toluene is added dropwise, and the mixture is stirred at −20° C. for 15 min, then warmed to 0° C. and stirred for 1 hour. Another 18 μl (0.078 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate are added, and stirring is continued for another 1.5 h. 5 ml of 0.1 N hydrochloric acid are added, and the mixture is extracted repeatedly with ethyl acetate. The organic phases are washed with a 1:1 mixture of saturated sodium bicarbonate solution and saturated sodium chloride solution and with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 15:1). This gives 227 mg (93% of theory) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.[NH2:20][CH2:21][C@@H:22]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C.[I-].[K+]>CN(C=O)C>[Si:24]([O:23][C@H:22]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[CH2:21][NH:20][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: O=C(Nc1ccc(C#CCCCBr)cc1)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 55 °C
Yield: 90.2 %

Procedure:
A mixture of Intermediate 26 (0.33 g, 1.0 mmol) and Intermediate 2 (0.40 g, 1.2 mmol) in DMF (5 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.25 mL, 1.5 mmol) and catalytic potassium iodide. The mixture was heated overnight in a 55° C. oil bath. The mixture was concentrated under reduced pressure and purified via automated flash silica gel chromatography, using a 12 g Isco RediSep flash column (dichloromethane/methanol/ammonium hydroxide). Concentration of the desired fractions under reduced pressure provided the title compound (0.53 g, 90%). ES/MS calcd. for C30H37F3N3O4Si+588.3. found m/z=588.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:38])[CH:9]([NH:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[C:17]([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29](OC(F)(F)F)[CH:28]=3)[N:24]=[CH:23]2)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2].[F:39][C:40]([F:46])([F:45])[CH2:41][CH2:42][CH2:43][OH:44].[H-].[Na+].[OH2:49]>CS(C)=O>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:38])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([O:44][CH2:43][CH2:42][CH2:41][C:40]([F:46])([F:45])[F:39])[N:18]=[C:17]([N:22]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([O:49][C:40]([F:46])([F:45])[F:39])=[CH:31][CH:32]=3)[N:24]=[CH:23]2)[N:16]=1)[CH2:10][CH:11]([CH3:12])[CH3:13])[CH3:2]
Reactant: CCOCCCNC(=O)C(CC(C)C)Nc1cc(Cl)nc(-n2cnc(-c3cccc(OC(F)(F)F)c3)c2)n1
Reactant: O
Reactant: OCCCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOCCCNC(=O)C(CC(C)C)Nc1cc(OCCCC(F)(F)F)nc(-n2cnc(-c3ccc(OC(F)(F)F)cc3)c2)n1

Procedure:
A solution of 4-methyl-2-{6-chloro-2-[4-(3-trifluoromethoxyphenyl)-imidazol-1-yl]-pyrimidin-4-ylamino}pentanoic acid (3-ethoxypropyl)amide (145 mg), 4,4,4-trifluoro-1-butanol (135 mg) and NaH (37 mg, 60%) in dimethylsulfoxide (10 ml) was stirred at room temperature for 17 hours. The solution was taken up in water, and extracted three times with ethyl acetate. The etyl acetate layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Semi-preparative HPLC purification provided 16.2 mg of 4-methyl-2-{6-(4,4,4-trifluorobutoxy)-2-[4-(4-trifluoromethoxyphenyl)-imidazol-1-yl]pyrimidin-4-ylamino}pentanoic acid (3-ethoxypropyl) amide. ESI-MS(m/z)647[M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=1)[CH:13]=[CH:12]2)C1C=CC=CC=1.CO.C(O)=O>C1COCC1.[Pd]>[NH:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17]2
Reactant: c1ccc(COc2ccc3cc(-c4nc5ccccc5[nH]4)ccc3c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: O=CO
Product: Oc1ccc2cc(-c3nc4ccccc4[nH]3)ccc2c1
Temperature: 100 °C
Yield: 109.8 %

Procedure:
T470 To a solution of 2-(6-(benzyloxy)naphthalen-2-yl)-1H-benzo[d]imidazole (73 mg, 0.21 mmol) in THF (2 mL) was added MeOH (2 mL), Pd—C (10%, 30 mg), and formic acid (0.30 mL). The mixture was flushed with argon and sealed in a microwave vial. The mixture was heated at 100° C. for 5 minutes in a microwave synthesizer. The mixture was filtered off Pd—C and the filtrate was concentrated to give T470 as a white solid (60 mg, 94%). 1H NMR (400 MHz, CD3OD): δ 8.46 (t, J=1.0 Hz, 1H), 8.12 (s, 1H), 8.05 (dd, J=8.8, 2.0 Hz, 1H), 7.85 (d, J=9.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.62 (m, 2H), 7.29 (m, 2H), 7.16 (m, 2H); MS (ESI): 261 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[CH2:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[OH:1][C:2]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([CH3:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C=C1CC[C@H]2[C@@H]3CCc4cc(O)c(C=O)cc4[C@H]3CC[C@]12C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)c(C=O)cc4[C@H]3CC[C@]12C
Yield: 76.2 %

Procedure:
To a solution of 3-hydroxy-17-methyleneestra-1,3,5(10)-triene-2-carboxaldehyde (23, 0.401 g, 1.35 mmol) in EtOAc (10 mL) was added 10% palladium on carbon (0.060 g). The reaction mixture was stirred for 4 h under the hydrogen atmosphere at room temperature. After the catalyst was filtered, the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (10:1→2:1, v/v) to afford 0.307 g of 27 (76% yield).
Reaction SMILES: [C:1](=[O:3])=[O:2].[OH-:4].[CH3:5][N+:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1(C)C=CC=CC=1>[C:1](=[O:4])([OH:3])[O-:2].[CH3:5][N+:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C=O
Reactant: [OH-]
Agent: C[N+]1(C)CCCCC1
Solvent: Cc1ccccc1
Product: O=C([O-])O

Procedure:
Carbon dioxide was passed for 1 hour into 553 g of a 15.56% strength aqueous N,N-dimethylpiperidinium hydroxide solution. The solution heated up from 20° C. to 38° C. within °minutes, and then cooled down again. 300 ml of toluene was added to 100 ml of the solution. The resultant mixture was refluxed and the water was distilled off azeotropically over a period of 11 hours.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11].[Sb](Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][CH:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O[C@@H]1[C@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1C1COC2(CCCCC2)O1
Temperature: 68 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a mixed solution consisting of 150 ml of cyclohexanone and 120 ml of dichloromethane were added 10.0 g of D-glucose and 299 mg of antimony pentachloride, and the mixture was refluxed with stirring in a water bath of 68° C. for 8 hours. During this reaction, the refluxing solvent was dried with 35 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. After completion of the reaction, 1.71 g of the starting sugar was recovered by filtration, and the reaction solution was diluted with chloroform, washed with aqueous sodium bicarbonate and water, and subsequently dried over anhydrous magnesium sulfate. The solvents including cyclohexanone were distilled off under reduced pressure, and the residue was recrystallized from ligroin to give 12.6 g (66.4%) of 1,2:5,6-di-O-cyclohexylidene-α-D-glucofuranose, m.p. 133°-136° C.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2([CH2:17][C:16]3[C:11](=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[CH:14][CH:15]=3)[C:10]2=[O:21])[CH2:6][CH2:5]1)(=O)C.[ClH:22]>C(O)C>[ClH:22].[N+:18]([C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][C:7]3([C:10]2=[O:21])[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=1)([O-:20])=[O:19]
Reactant: CC(=O)N1CCC2(CC1)Cc1ccc([N+](=O)[O-])cc1C2=O
Agent: Cl
Solvent: CCO
Product: O=C1c2cc([N+](=O)[O-])ccc2CC12CCNCC2
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of 0.216 g (0.75 mmol) 1'-acetyl-1,3-dihydro-1-oxo-6-nitrospiro[2H-indene-2,4'-piperidine] and 2 ml (6 mmol) 3N hydrochloric acid in 6 ml ethanol was heated at reflux for 18 hours. Another 0.2 ml (0.6 mmol) 3N hydrochloric acid was added and the solution was heated at reflux for 4 hours, then cooled to room temperature to give a white precipitate. The precipitate was filtered off, washed with ethanol, and dried to give 0.158 g (74%) product; 1H NMR (DMSO-d6): δ1.60 (d, 2H), 1.96 (m, 2H), 3.06 (m, 2H), 3.3 (m, 4H), 7.88 (d, 1H), 8.35 (d, 1H), 8.55 (d of d, 1H), 8.9 (broad s, 2H).
Reaction SMILES: C1(CCO)CC1.[CH3:7][C@H:8]1[C@H:13]([OH:14])[CH2:12][C@@H:11]2[CH2:15][C@H:9]1[C:10]2([CH3:17])[CH3:16].FC1C=C(F)C(F)=CC=1C(NS(C)(=O)=O)=O.[Cl:34][C:35]1[C:36](F)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=1)[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[O:41]>>[Cl:34][C:35]1[C:36]([O:14][C@@H:13]2[CH2:12][C@@H:11]3[CH2:15][C@@H:9]([C:10]3([CH3:16])[CH3:17])[C@H:8]2[CH3:7])=[CH:37][C:38]([F:48])=[C:39]([CH:47]=1)[C:40]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])=[O:41]
Reactant: C[C@H]1[C@H](O)C[C@@H]2C[C@H]1C2(C)C
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: OCCC1CC1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Oc1cc(F)c(C(=O)NS(C)(=O)=O)cc1Cl)C2(C)C

Procedure:
Following the procedure as described in Example 1 and making variations as required to replace 2-cyclopropylethanol with (1R,2R,3R,5S)-2,6,6-trimethylbicyclo-[3.1.1]heptan-3-ol and 2,4,5-trifluoro-N-(methylsulfonyl)benzamide with 5-chloro-2,4-difluoro-N-(methylsulfonyl)-benzamide, the title compound was obtained as a colorless solid (0.06 g, 5%): 1H NMR (300 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.33 (d, JC-F=12.6 Hz, 1H), 4.79-4.74 (m, 1H), 3.31 (s, 3H), 2.71-2.64 (m, 1H), 2.37-2.26 (m, 2H), 1.91-1.80 (m, 2H), 1.59-1.52 (m, 1H), 1.19 (s, 3H), 1.10-1.06 (m, 4H), 0.95 (s, 3H); MS (ES−) m/z 402.1, 404.1 (M−1).
Reaction SMILES: C(O)=O.[C:4]1([CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:26]=O.[ClH:28]>C(O)C>[ClH:28].[ClH:28].[CH3:26][N:12]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14]1)[CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=O
Reactant: c1ccc(CCNC2CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Solvent: O=CO
Solvent: CCO
Product: CN(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
136 ml of formic acid was added to 210 g of 4-(2-phenylethylamino)-1-benzylpiperidine. Since the temperature of the mixture increased to about 90° C., the mixture was ice-cooled. To the reaction mixture was added 64 ml of 37% formalin at 50°-60° C.; the ice bath was removed; and the mixture was stirred for 1 hour. To the resulting reaction mixture were added 1 liter of ethanol and 120 ml of concentrated hydrochloric acid, followed by concentration under reduced pressure. To the residue was added 1 liter of ethanol. The resulting insolubles were collected by filtration and then washed with ethanol to obtain 251.7 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-benzylpiperidine dihydrochloride as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:26]=[CH:25][C:12]([C:13]([NH:15][C:16]3[S:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][N:20]=3)=[O:14])=[CH:11][C:10]=2[N+:27]([O-:29])=[O:28])=[CH:4][CH:3]=1.[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45](Cl)=[O:46])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45](=[O:46])[NH:1][C:2]3[CH:3]=[CH:4][C:5]([S:8][C:9]4[CH:26]=[CH:25][C:12]([C:13](=[O:14])[NH:15][C:16]5[S:17][C:18]([C:21]([CH3:24])([CH3:22])[CH3:23])=[CH:19][N:20]=5)=[CH:11][C:10]=4[N+:27]([O-:29])=[O:28])=[CH:6][CH:7]=3)[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)c1cnc(NC(=O)c2ccc(Sc3ccc(N)cc3)c([N+](=O)[O-])c2)s1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1cnc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c([N+](=O)[O-])c2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A suspension of the product of Example 161B (226 mg, 0.5274 mmol) in anhydrous methylene chloride (5 mL) was treated with 9-fluorenylmethoxycarbonyl chloride (164 mg, 0.6329 mmol) and dry pyridine (0.085 mL, 1.055 mmol), and the resulting yellow solution stirred under a nitrogen atmosphere at ambient temperature for 3 hours. The reaction was diluted with ethyl acetate (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to provide the title compound as a yellow solid (338 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.Cl.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:10]([C:7]1[CH:6]=[C:5]([CH2:4][C:3]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: NCCc1c[nH]c2ccc(Br)cc12
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Br)cc12)c1cc(Cc2cc(F)ccc2F)on1
Yield: 59.9 %

Procedure:
A solution of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.104 g, 0.435 mmol), 2-(5-bromo-1H-indol-3-yl)ethanamine hydrochloride (0.120 g; 0.435 mmol), HATU (0.166 g; 0.435 mmol) and N,N diisopropylethylamine (0.201 mL; 1.09 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.120 g (60%) of N-(2-(5-bromo-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [Br-].[C:2]([C:4]1[CH:5]=[N:6][N:7]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=2)[C:8]=1[CH2:9][N+]1C=CC=CC=1)#[N:3].[CH3:27][N:28]([CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([N:35]=[O:36])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH3:27][N:28]([CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:36])=[CH:9][C:8]2[N:7]([C:16]3[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[N:6]=[CH:5][C:4]=2[C:2]#[N:3])=[CH:31][CH:30]=1
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C[n+]1ccccc1
Reactant: CN(C)c1ccc(N=O)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc([N+]([O-])=Cc2c(C#N)cnn2-c2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
To a stirred suspension of 9.0 grams (0.020 mole) of 1-[[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]methyl]pyridinium bromide and 3.5 grams (0.023 mole) of N,N-dimethyl-4-nitrosoaniline in 95 mL of ethanol was added a solution of 16 grams (0.12 mole) of potassium carbonate in 59 mL of water. When the addition was complete, the reaction mixture was stirred at ambient temperature for four hours. After this time, the reaction mixture was filtered. The filter cake was washed in succession with water, ethanol, and diethyl ether, yielding 7.6 grams of N-[4-(dimethylamino)phenyl]-a-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]nitrone. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: CO[NH:3][CH3:4].[N:5]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[CH:18][C:17]=3[CH:21]=2)=[CH:10][CH:9]=1)=[C:6]=[O:7].C([O:26][CH2:27]C)C>>[CH3:27][O:26][N:5]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[CH:18][C:17]=3[CH:21]=2)=[CH:10][CH:9]=1)[C:6]([NH:3][CH3:4])=[O:7]
Reactant: CCOCC
Reactant: CNOC
Reactant: O=C=Nc1ccc(Oc2ccc3sncc3c2)cc1
Product: CNC(=O)N(OC)c1ccc(Oc2ccc3sncc3c2)cc1
Reaction time: 12 h
Yield: 82 %

Procedure:
6.1 parts of N-methoxy-N-methylamine were added to a solution of 26.8 parts of 5-(4'-isocyanatophenoxy)-benzisothiazole in 300 parts of diethyl ether at from 20° to 30° C., the mixture was stirred for 12 hours at this temperature and then evaporated down, and the residue was triturated in about 50 parts of diethyl ether, isolated and dried. 26 g (82% of theory) of 5-(4'-(N-methoxy-N-methylaminocarbonylamino)-phenoxy)-benzisothiazole of melting point 108° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].[C:32](Cl)(=[O:36])[O:33][CH2:34][CH3:35]>CN(C)C=O>[C:20]1([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:26][C:32]([O:33][CH2:34][CH3:35])=[O:36])=[CH:3][CH:4]=2)=[CH:9][C:10](=[O:11])[NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(C=C(c1ccccc1)c1ccc(O)cc1)NCc1cccnc1
Reactant: CCOC(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=CC(=O)NCc2cccnc2)c2ccccc2)cc1
Yield: 100 %

Procedure:
95 mg of 3-(4-hydroxyphenyl)-3-phenyl-N-(3-pyridylmethyl)acrylamide was reacted with 2 ml of dimethylformamide, 48 mg of anhydrous potassium carbonate and 0.04 ml of ethyl chlorocarbonate for 4 hours under a stream of argon. The reaction mixture was extracted with ethyl acetate three times, washed twice with water and once with brine, and then dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was evaporated and purified via column chromatography on silica gel (chloroform:methanol=20:1) to give ethyl [4-[1-phenyl-2-[N-(3-pyridylmethyl)carbamoyl]ethenyl]phenoxy]acetate (140 mg, yield: 100%) as an oil.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-])=O)[CH:14]=1.CC(O)=O>C(O)C.O.[Fe]>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH:14]=1)[NH2:20]
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(Br)n2n1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(C)c(N)c3)c(Br)n2n1
Temperature: 80 °C
Yield: 97.6 %

Procedure:
To a stirred solution of 3-bromo-6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.190 g, 0.523 mmol) in ethanol (15 mL) and water (5 mL) containing AcOH (3.13 mmol) is added iron (0.146 g, 2.61 mmol). The reaction mixture is heated at 80° C. for 2 hours, cooled, concentrated under reduced pressure and sat. aqueous NaHCO3 (50 mL) is added. The mixture is extracted with EtOAc (3×25 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography using a gradient of hexanes to EtOAc to afford the title compound (0.170 g, 89%) as an off-white solid: Rf 0.18 (1:1 EtOAc:hexanes); LCMS (m/z)=333.2, 335.2 [M+H]+, tR=2.22 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([CH2:13][C:14](O)=[O:15])=[N:9]2)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([CH2:13][C:14]([Cl:21])=[O:15])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nnc(CC(=O)O)n2)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(Cn2nnc(CC(=O)Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
The 2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]acetic acid (262.0 mg, 1.05 mmol) obtained in (B) was added dropwise with thionyl chloride (615.9 μl, 8.44 mmol) under ice cooling and stirred at room temperature for 30 minutes. Excessive regents were evaporated to obtain the title compound (0.27 g, quantitative) as pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5]O[C:3]=1[CH3:9].[CH2:10]([O:12][C:13](=[O:16])[CH2:14][NH2:15])[CH3:11].[OH-].[Na+].C(OCC)C>C(O)C.CC(C)=O>[CH2:10]([O:12][C:13]([CH2:14][N:15]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:9])=[O:16])[CH3:11]
Reactant: CCOC(=O)CN
Reactant: Cc1occc(=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)Cn1ccc(=O)c(O)c1C
Temperature: 25 °C

Procedure:
3-hydroxy-2-methyl-4-pyrone (15 g) in ethanol (250 ml) has added to it glycine-ethyl ester (14 g) and concentrated aqueous sodium hydroxide to adjust pH to 10.0, the mixture is stirred at room temperature for several days, then rotary evaporated to dryness, resulting in white residue. Dissolution in acetone followed by di-ethyl ether treatment yields white precipitate of 1-ethoxycarbonylmethyl-3-Hydroxy-2-methyl-pyrid-4-one. The molecular ion mass M+=266.7. The compound dissolved in ethanol/water mixture with added iron forms the purple coloured complex. TLC showed a single, purple band separate and of lower rf than the 3-hydroxy-2-methyl-4-pyrone control (orange-red).