Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:42](=[O:43])[N:6]2[C:7]([C:29]([O:31]CC3C=CC([N+]([O-])=O)=CC=3)=[O:30])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)=[O:22])[N:17]=[C:18]([S:19][CH3:20])[N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+](C1C=CC(COC([NH:55][S:56]([NH:59][CH2:60][CH2:61][CH2:62]O)(=[O:58])=[O:57])=O)=CC=1)([O-])=O>>[OH:1][C@@H:2]([C@H:4]1[C:42](=[O:43])[N:6]2[C:7]([C:29]([O-:31])=[O:30])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:21]([C:23]5[CH:24]=[N+:25]([CH2:62][CH2:61][CH2:60][NH:59][S:56](=[O:58])(=[O:57])[NH2:55])[CH:26]=[CH:27][CH:28]=5)=[O:22])[N:17]=[C:18]([S:19][CH3:20])[N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C(NS(=O)(=O)NCCCO)OCc1ccc([N+](=O)[O-])cc1
Reactant: CSc1nc(C(=O)c2cccnc2)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Product: CSc1nc(C(=O)c2ccc[n+](CCCNS(N)(=O)=O)c2)c2sc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Yield: 18.4 %

Procedure:
The title compound (41 mg) was prepared in the same manner as in steps a) and b) of Example 4, except that 222 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-methylthio-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate and 166 mg of 3-(4-nitrobenzyloxycarbonylaminosulfonyl)aminopropanol were used as the starting compounds.
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CN([CH:23]=[O:24])C.Cl>C1COCC1>[CH2:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH:23]=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCc1ccsc1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccsc1C=O
Temperature: 0 °C
Yield: 54.6 %

Procedure:
Magnesium (0.63 g; 25.8 mmol) and anhydrous THF (25 ml) were put into a flask, and 2-bromo-3-dodecylthiophene (7.78 g; 23.5 mmol) was added dropwise thereto. After starting Grignard reaction, the solution was refluxed until magnesium was almost removed. The purified DMF (3.65 g; ˜4 ml; 50 mmol) was slowly added dropwise to the reaction solution. The reaction solution was refluxed for one day, and cooled to 0° C., and 5% HCl (100 ml) was added thereto to terminate the reaction. An organic material layer was extracted from ethyl ether, and the obtained organic material layer was washed sequentially with NaHCO3, a saturated NaCl solution, and water. The residual moisture was removed over anhydrous magnesium sulfate. After removing the solvent, the residue was column separated using silica gel (ethyl acetate/hexane=1/9) to obtain 3-dodecylthiophene-2-carboaldehyde (3.6 g; 55%).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CCC(Oc1ccccc1C#N)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccccc1C#N)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 53.6 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.08 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-cyanophenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 94, above] and 29.4 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.40 g of the title compound as white crystals, melting at between 95° and 97° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([O:6][C:7]1[C:12](C=O)=[C:11]([CH3:15])[N:10]=[C:9]2[N:16]([CH3:19])[CH2:17][CH2:18][C:8]=12)(=[O:5])=[O:4].OO.[C:24]([O-])([OH:26])=[O:25].[Na+]>ClCCl>[CH:24]([O:26][C:12]1[C:7]([O:6][S:3]([C:2]([F:21])([F:1])[F:20])(=[O:5])=[O:4])=[C:8]2[CH2:18][CH2:17][N:16]([CH3:19])[C:9]2=[N:10][C:11]=1[CH3:15])=[O:25]
Reactant: O=C([O-])O
Reactant: Cc1nc2c(c(OS(=O)(=O)C(F)(F)F)c1C=O)CCN2C
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2c(c(OS(=O)(=O)C(F)(F)F)c1OC=O)CCN2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 80 mg (0.24 mmol) of aldehyde 31 in 3 mL of dichloromethane was added 1 mg (0.09 mmol) of SeO2 and 1.5 mL of H2O2 (30% in H2O). The reaction mixture was stirred at room temperature for 16 h then cooled to 0° C., 12 mL of 5% of NaHCO3 was added slowly. The mixture was stirred for additional 20 min then extracted with three portions of 15 mL of ethyl acetate. The combined organic layer was washed with brine and dried over Na2SO4. After solvent was removed, the residue was purified by flash chromatography on a silica gel column (15×2 cm). Elution with 1:10 EtOAc-hexanes gave product 32 as light yellow solid: yield 47.6 mg (57%). Silica gel TLC Rf 0.28 (4:1 EtOAc-hexanes); 1H NMR (CDCl3, ppm): δ 2.25 (s, 3H), 2.94 (s, 3H), 3.08 (t, J=8.4 Hz, 2H), 3.57 (t, J=8.4 Hz, 2H), 8.23 (s, 1H). 13C NMR (CDCl3, ppm): δ 19.21, 23.69, 32.36, 52.10, 113.38, 116.76, 119.95, 126.71, 150.24, 158.20, 162.82; 19F NMR (CDCl3, ppm): δ−73.77 (s, 3F); HRMS (ESI+) calculated for C11H11N2O5SF3 (M+H+) 340.0414. found 340.0413.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:18]>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][C:15]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:16]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NC(=O)c2cccc(C)c2N)cc1
Product: COc1ccc(NC(=O)c2cccc(C)c2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 45 %

Procedure:
Using the procedure described in Example 93, Part A, 4-tert-butylbenzoyl chloride (1.76 mmol) and 2-amino-N-(4-methoxyphenyl)-3-methylbenzamide (1.6 mmol) yielded 0.30 g (45%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCCCNc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Aminobenzophenone (25 g.) is heated with octadecyl bromide (70 g.) in dry hexamethylphosphoramide (100 ml.) containing anhydrous potassium carbonate (30 g.) for 16 hours at 100° C. The solution is cooled to room temperature, filtered to remove solids, and the filtrate is diluted with cold water (10 ml.). The solid so obtained is collected and washed with water. Recrystallization from ethanol followed by dichloromethance provides the product of the Example.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[CH:19]=[N:18][C:17](S)=[N:16]1.[F:21][C:22]([F:26])=[C:23]([F:25])[F:24].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[CH:19]=[N:18][C:17]([C:23]([F:25])([F:24])[CH:22]([F:26])[F:21])=[N:16]1
Reactant: FC(F)(F)c1cc(Cl)c(-n2cnc(S)n2)c(Cl)c1
Reactant: FC(F)=C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)C(F)(F)c1ncn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sixty percent oily sodium hydride (40 mg, 1 mmol) was added to a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-mercapto-1,2,4-triazole 0.31 g, 1 mmol) in N,N-dimethylformamide (10 ml) at room temperature in a nitrogen atmosphere. After stirring at room temperature for 15 minutes, the atmosphere in the reaction vessel (20 ml volume) was replaced with tetrafluoroethylene gas, and the mixture was heated at 80° C. for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oily product was subjected to silica gel chromatography to give 0.21 g of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1,1,2,2-tetrafluoroethyl)-1,2,4-triazole.
Reaction SMILES: [C:1](=O)([O:4]C)[O:2][CH3:3].C[O-].[Na+].[CH2:10]=[C:11]([OH:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[C:1](=[O:4])([O:2][CH3:3])[O:19][CH:11]([CH3:10])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)OC
Reactant: C=C(O)Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)OC(C)Cc1ccccc1
Temperature: 78 °C

Procedure:
Into a 2 liter reaction flask equipped with stirrer, thermometer, reflux condenser, heating mantle and Bidwell addition funnel is placed 222 grams of dimethyl carbonate and 24 grams of a solution of sodium methoxide in methanol. The resulting mixture is heated to reflux. Over a 30 minute period 268 grams of alpha-methylene phenylethyl alcohol having the structure: ##STR161## is added over a period of 20 minutes after bringing the mixture to reflux at 72°-76° C. At the end of the addition of the alpha-methylene phenylethyl alcohol the reaction mass is continued to be refluxed at 78° C. for a period of two hours. At the end of the two hour period, the excess methyl alcohol is taken off at 100° C. The reaction mass is then cooled and 200 ml wter is added thereto. The organic phase is then distilled on a 12" Goodloe column yielding the following fractions:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].OO.O.S([O-])(O)=[O:18].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1ccc(B(O)O)cc1F
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
22.3 g of the crude 3-fluoro-4-ethoxyphenyl boronic acid obtained in the first step was dissolved in 200 ml of tetrahydrofuran, and 23.6 g (208 mmol) of aqueous 30% hydrogen peroxide was added while being kept at about 35° C. in a warm bath. After addition and after stirring the reaction solution at a room temperature for 24 hours, the reaction solution was poured into 300 ml of water, then sodium hydrogen sulfite was added and stirred at a room temperature for one hour. The reaction solution was extracted with 300 ml of ethyl acetate and the extracted layer was washed with water and then with an aqueous saturated sodium chloride solution successively and, after dying over anhydrous magnesium sulfate, concentrated under a reduced pressure. The concentrated residue was purified by silica gel column chromatography using a ethyl acetate/heptane mixed solvent as an eluent to obtain 17.6 g (113 mmol) of 3-fluoro-4-ethoxyphenol.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][CH2:14][CH2:13][CH2:12][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: ClCCCBr
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CCCCl
Temperature: 25 °C
Reaction time: 96 h
Yield: 59 %

Procedure:
A mixture of adenine (4.05 g, 30 mM), 1-bromo-3-chloropropane (21.3 g, 13.4 mM), and potassium carbonate (10.4 g, 75 mM) in DMF (200 mL) was stirred at room temperature under argon for 4 days, filtrated, and evaporated to dryness. The crude product was washed with water and dried. Recrystallization from ethanol gave 9-(3-chloropropyl)adenine in 59% yield.
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@@H:3]1C(O)=O.[N:15](C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[OH:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@@H:3]1[NH2:15]
Reactant: O=C(O)[C@H]1CCc2ccccc2[C@H]1O
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N[C@H]1CCc2ccccc2[C@@H]1O

Procedure:
One gram of the hydroxamic acid of (1S,2S)-1-hydroxy-2-carboxyteralin is reacted with equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in tetrahydrofuran at room temperature using the procedure of Bittner, Grinberg and Kartoon (Tet. Lett. 23, 1965-8 (1974)). The product is isolated by acidification and extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (1S,2S)-1-hydroxy-2-aminotetralin is isolated as a light yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9](C(OC(C)(C)C)=O)[C:8]=2[C:19]([O:21][CH3:22])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:11]=[CH:10][NH:9][C:8]=2[C:19]([O:21][CH3:22])=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(-c2ccccc2)ccn1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1[nH]ccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 62.4 %

Procedure:
1-tert-Butyl 2-methyl 3-phenyl-1H-pyrrole-1,2-dicarboxylate (18.0 g, 59.7 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to 0° C. TFA (23.0 mL, 0.299 mmol) was added to the reaction mixture and the solution stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure to remove excess of TFA. To the resulting residue was added 10% sodium bicarbonate solution (50 mL) and the aqueous portion extracted with CH2Cl2. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 30% EtOAc/hexanes) to obtain methyl 3-phenyl-1H-pyrrole-2-carboxylate (7.50 g, 62.4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.69 (s, 3H), 6.29 (t, J=2.8 Hz, 1H), 7.02 (d, J=2.8 Hz, 1H), 7.03 (m, 5H), 12.0 (s, 1H).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:20](=[O:22])=[O:21]>C1COCC1>[CH:1]1[C:14]2[CH:13]([C:20]([OH:22])=[O:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=O
Reactant: c1ccc2c(c1)Cc1ccccc1S2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thioxanthene, 9.1 g, was dissolved in 100 mL of dry THF. The solution was cooled in an ice bath and n-BuLi (24 mL of 2.5M solution) was added dropwise. The red solution was stirred at room temperature for one hour. Powdered CO2 was added (ca. 150 g) causing formation of a white precipitate. After stirring an additional hour the mixture was evaporated and the residue dissolved in water. The aqueous solution was extracted with CH2Cl2, and neutralized with HCl. The precipitated product was dissolved in ether, dried and evaporated producing thioxanthene-9-carboxylic acid as a white solid (8.8 g): 1H NMR (DMSO-d6) δ 5.25 (s, 1H), 7.30 (m, 4H), 7.49 (m, 4H), 12.60 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][C:12]([NH2:15])=[N:11]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.Cl>O1CCOCC1>[F:17][C:3]([F:2])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(3-trifluoromethyl-phenyl)-4,5-dihydro-1H-pyrazol-3-ylamine hydrochloride salt (200 mg, 0.88 mmol) (Example 3A) in dioxane (50 mL) was added triethylamine (0.069 mL, 0.88 mmol) followed by 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (200 mg, 0.88 mmol). The mixture was stirred at room temperature for 24 h and then poured onto dichloromethane. 2N hydrochloric acid was added and the organics extracted with 2N hydrochloric acid (3×50 mL). The acid layer was basified with 10N potassium hydroxide and extracted with dichloromethane (3×50 mL). The combined organics were dried (Na2SO4), filtered and evaporated to dryness. The residue dissolved in diethyl ether and 1M hydrochloric acid in diethyl ether was added to form a brown solid which was collected and dried (171 mg, 86%). MS (ES) m/z: 228.1 [M+H].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:8]2)[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCC2(CC1)CNc1ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC2(CC1)CN(S(C)(=O)=O)c1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
Dissolve 1,2-dihydro-1'-methyl-spiro[3H-indole-3,4'-piperidine] (3.0 g, 14.8 mmoles) in dry CH2Cl2 (25 ml) and cool under N2 in an ice bath. Add, dropwise, methane sulfonyl chloride (1.5 ml, 19.3 mmoles), followed by ethyl diisopropyl amine (5.0 ml, 28.7 mmoles). Warm to room temperature and stir overnight. Dilute the solution to 100 ml with CH2Cl2. Wash the solution with saturated aqueous NaHCO3 (4×25 ml), then with water. Dry solution with anhydrous Na2SO4, then remove the solvent using reduced pressure. Purify the resulting reaction mixture by flash chromatography (SiO2) using 5% MeOH(NH3)/EtOAc as eluent. Yield: 3.37 g (81%) of the title compound.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8])[CH:2]([CH3:4])[CH3:3].[Br:15][CH2:16][C:17](Br)=[O:18]>C1COCC1>[Br:15][CH2:16][C:17]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8])=[O:18]
Reactant: O=C(Br)CBr
Reactant: CC(C)CNCC(=O)N1CCOCC1
Solvent: C1CCOC1
Product: CC(C)CN(CC(=O)N1CCOCC1)C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
2-Isobutylamino-1 -morpholin-4-yl-ethanone (1.43 g, 7.13 mmol) was dissolved in 15 mL of THF. To this solution at −78° C. was added a solution of bromoacetyl bromide (1.24 mL, 14.3 mmol) in 15 mL of THF. The mixture was warmed to room temperature and stirred for 2 h. Solvent was removed in vacuo. The residue was dissolved in 30 mL of methylene chloride, washed with saturated sodium bicarbonate, and brine, then dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography eluting with 2% MeOH in methylene chloride to give 2-bromo-N-isobutyl-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide (1.37 g, 60%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH:12](OC)(OC)OC>CO>[O:11]1[C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=[CH:12]1
Reactant: COC(OC)OC
Reactant: Nc1ccc(C(=O)O)cc1O
Solvent: CO
Product: O=C(O)c1ccc2ncoc2c1
Temperature: 100 °C
Yield: 89.1 %

Procedure:
A mixture of 4-amino-3-hydroxybenzoic acid (250 mg, 1.63 mmol) and trimethyl orthoformate (500 μL, 4.57 mmol) are heated in an oil bath at 100° C. for 2 h. The mixture is cooled to rt and diluted with MeOH. The resulting solution is filtered through a pad of Celite, and the filtrate is concentrated in vacuo to give 1,3-benzoxazole-6-carboxylic acid as a brown solid (237 mg, 89%): 1H NMR (DMSO-d6) δ 13.2, 8.9, 8.3, 8.0, 7.9.
Reaction SMILES: Cl[CH:2]([C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4].[CH3:10][OH:11].C[O-].[Na+]>>[CH3:10][O:11][CH:2]([C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4]
Reactant: CO
Reactant: CCCC(=O)C(Cl)CC
Agent: C[O-]
Agent: [Na+]
Product: CCCC(=O)C(CC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.5 grams of 3-chloro-4-heptanone in 3 ml anhydrous methanol (0.01 moles 3-chloro-4-heptanone) is placed into a 25 ml, three-necked, round bottom flask equipped with magnetic stirrer, pot thermometer, reflux condenser (with drying tube), 10 ml addition funnel with nitrogen inlet at top, an ice water-salt bath, and nitrogen bubbler. The 3-chloro-4-heptanone solution is cooled to a temperature of between 0° and 1° C. Into the 10 ml addition funnel is placed a solution of 0.54 grams of sodium methoxide dissolved in 7 ml anhydrous methanol (0.01 moles sodium methoxide). Over a period of one hour, while maintaining the reaction mass at a temperature of between 0° and 1° C, the sodium methoxide solution is added to the 3-chloro-4-heptanone. The reaction mass is then permitted to warm up to room temperature. It is then vacuum filtered thereby separating the white precipitate from the filtrate. The white solid precipitate is washed with 25 ml methylene chloride, and the washings are combined with the filtrate prior to concentration. After concentration of the filtrate, the concentrate is dried over anhydrous sodium sulfate and further concentrated to a weight of 1.0 grams (white oil). The major peak is isolated by GLC trapping (8 feet × 1/4 inch SE-30 column). NMR, IR and mass spectral analyses confirm that the resulting material has the structure: ##STR89##
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N+:3]=1[O-]>C(OC(=O)C)(=O)C>[C:6]([O:8][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)(=[O:7])[CH3:5]
Reactant: COC(=O)c1ccc(C)[n+]([O-])c1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(COC(C)=O)nc1
Yield: 121.2 %

Procedure:
To a solution of methyl 6-methylnicotinate (6.05 g) in methylene chloride (100 mL) was added m-chloroperbenzoic acid (77%, 13.5 g). The reaction mixture was stirred at room temperature for 2 h and then diluted with chloroform (100 mL). The mixture was washed successively with aqueous sodium sulfite, saturated sodium bicarbonate, and brine. The organic later was then dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide 6.21 g of methyl 6-methylnicotinate 1-oxide. A solution of methyl 6-methylnicotinate 1-oxide (4.35 g) in acetic anhydride (50 mL) was heated at 120° C. for 2 h and then concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 1:2 to 3:5 ethyl acetate/hexanes) provided 3.3 g of the title compound: 1H NMR (300 MHz, CDCl3) δ 9.18, 8.31, 7.44, 5.29, 3.96, 2.19.