Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][C:31]1=[O:36].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:33]2[CH2:34][CH2:35][NH:30][C:31](=[O:36])[CH2:32]2)=[O:18])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: O=C1CNCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N2CCNC(=O)C2)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 84.9 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (114 mg, 0.271 mmol) obtained in Example 12 in methylene chloride (3 ml), piperazin-2-one (33 mg, 0.325 mmol), 1-hydroxybenzotriazole (37 mg, 0.271 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (62 mg, 0.325 mmol) and 4-methylmorpholine (35 μl, 0.325 mmol) were added. The reaction mixture was stirred for 4 days at room temperature, and was concentrated under reduced pressure. Ethyl acetate was added to the resulting concentration residue, and the mixture was washed sequentially with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:30) was concentrated under reduced pressure. The resulting solid was washed with ether, and then was collected by filtration, to obtain the title compound (116 mg, 0.230 mmol, 85%) as a white powder.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: COc1ccccc1B(O)O
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccccc1-c1nn(C2CCCCO2)c2ccc(C#N)cc12
Yield: 82.5 %

Procedure:
To a solution of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.600 g, 1.96 mmol), in ethylene glycol dimethyl ether (20 mL) was added 2-methoxyphenyl boronic acid (0.447 g, 2.94 mmol), [1,1′-bis(diphenylphosphino)-ferrocene] complex with dichloromethane (1:1) (0.226 g, 0.196 mmol) and potassium phosphate (2.07 g, 9.8 mmol). The reaction mixture was heated to reflux temperature for 12 hours. The solvent was then evaporated to dryness and the residue was dissolved in 20 mL of ethyl acetate. The heterogeneous solution was washed 3 times with 10 mL of water and once with 10 mL of brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The resulting brown solid was adsorbed on silica gel and purified by column chromatography (85:15 hexanes/ethyl acetate) to provide the title compound (0.539 g, 82.5% yield): ES-MS (m/z) 334 [M+1]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[OH:34])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:45][O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCOCC>C(Cl)Cl>[CH2:47]([O:46][CH2:45][C@@:23]1([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[O:24][C@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:21]([OH:34])[CH2:22]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reaction time: 14 h
Yield: 88 %

Procedure:
To a stirred solution of 2 (117.0 g, 243.8 mmol) and Hunig's base (diisopropylethylamine, 63.0 g, 487.5 mmol) in CH2Cl2 (400 mL) at 23° C. was added a solution of benzyl chloromethyl ether (40.7 g, 260.0 mmol) over a 15 min. period. The resultant mixture was maintained at 23° C. and stirred for 14 h. Ether (1 L) was added to the mixture and the ethereal solution was washed with 10% aqueous HCl (2×100 mL) and H2O (200 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 /AcOEt 40:1 then 10:1) to yield 128.9 g (88%) of 3 as a white solid. Rf (CH2Cl2 /AcOEt 10:1) 0.31.
Reaction SMILES: C=O.[P:3](=[O:7])([OH:6])([OH:5])[OH:4].NC(N)=O.[OH-].[Ca+2:13].[OH-]>O>[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[Ca+2:13].[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[Ca+2:13].[Ca+2:13]
Reactant: O=P(O)(O)O
Agent: C=O
Agent: NC(N)=O
Agent: [Ca+2]
Solvent: O
Product: O=P([O-])([O-])[O-]
Temperature: 45 °C

Procedure:
were initially heated with intensive stirring to 80° C. with 100 g of 30% formalin (1 mole) and 25 g of 85% phosphoric acid in a ground glass flask. The cell walls of the bacteria were thus ruptured and the plant protection agents present deactivated and hydrolyzed by reaction of the NH2 - or NH-functions thereof with formaldehyde by N-methylolation (>N--CH2 --O---H2 -N>) or methylene linkage (>N--CH2 --N<). After this primary reaction, samples were taken and centrifuged. By titrating the formaldehyde in the filtrates, it was analytically determined that 0.05 mole of formaldehyde has been consumed. A solution of 60 g of urea (1 mole) in 100 g of water and 10 g of 30% formalin (0.1 mole) were then added to the reaction mixture. After condensation for 15 minutes at 70° C., the mixture was cooled over a period of 30 minutes to a temperature of 45° C. and a readily filterable, powder-form biomass mixed condensate was obtained. This biomass mixed condensate was neutralized with calcium hydroxide, as a result of which substantially insoluble calcium phosphate precipitated in very finely divided form in the biomass condensate dispersion. The powder-form product was filtered off and washed with a 2% aqueous ammonia solution. The product was then dried under reduced pressure at 70° C., giving a substantially odorless powder in an amount of 176 g. The nitrogen content amounted to 13.4%.
Reaction SMILES: [OH-].[K+].O.[OH:4][CH:5]([CH3:12])[CH2:6][C:7]([O:10][OH:11])([CH3:9])[CH3:8].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:13]([O:11][O:10][C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:4])[CH3:12])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(O)CC(C)(C)OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(O)CC(C)(C)OOC(=O)C(C)(C)C
Yield: 81.3 %

Procedure:
A jacketed reactor equipped with a mechanical stirrer, a thermometer and a dropping funnel was charged with 19.9 g (0.160 mole) of 45% KOH, 9.9 g of water, 21.5 g (0.150 mole) of 93.7% 3-hydroxy-1,1-dimethyl butyl hydroperoxide (also known as 4-hydroxy-2-methyl-2-hydroperoxypentane), 25 g of methylene chloride and 0.65 g (0.002 mole) of tetrabutylammonium bromide, a phase transfer catalyst (PTC). The resulting vigorously stirred mixture was cooled to -5° to -2° C. and to it was slowly added 12.6 g (0.100 mole) of 95.4% pivaloyl chloride over a period of about 30 minutes. The resulting product mixture was then stirred for 2 hours at -5° to -2° C. after which 25 g of 10% KOH and an additional 50 g of methylene chloride were added to the reaction mixture. The reaction mass was allowed to separate into two liquid phases at 10° C. and the lower organic layer was removed, dried over about 5% by weight of anhydrous MgSO4 and after the spent desiccant was separated by filtration the methylene chloride was removed in vacuo at 0° to 10° C. Obtained was 24.5 g of liquid product which had an assay of 72.3% according to peroxyester active oxygen content. The corrected yield was 81.3%. An infrared spectrum of the product showed a large broad OH band centered at 3450 to 3550 cm-1.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C@@H:25]1[N:33]([C:34](=[O:53])[C@@H:35]([NH:39][C:40](=[O:52])[C@@H:41]([N:43](C)[C:44](=O)OC(C)(C)C)[CH3:42])[CH:36]([CH3:38])[CH3:37])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH2:26]1)=[O:24])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C@@H:25]1[N:33]([C:34](=[O:53])[C@@H:35]([NH:39][C:40](=[O:52])[C@@H:41]([NH:43][CH3:44])[CH3:42])[CH:36]([CH3:38])[CH3:37])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH2:26]1)=[O:24])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@@H]1C(=O)Nc1ccccc1C(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@@H]1C(=O)Nc1ccccc1C(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
TFA (0.5 mL, 6.49 mmol, Eq: 127) was added to a solution of tert-butyl (R)-(2S)-1-((2S)-1-(2-(2-benzoylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (32 mg, 51.0 μmol, Eq: 1.00) in DCM (0.5 mL) and the resulting solution was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue treated with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (1×10 mL) and the organic layer was concentrated in vacuo. The crude residue was treated with MeOH/DCM/ether to give (R)-1-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-benzoyl-phenyl)-amide as an off-white solid (24 mg), m/z=528 (M+H).
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]=[CH2:4].[CH3:6][C:7]1([CH3:16])[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]1=[O:15].Cl>O.C(OCC)C>[CH2:4]([C:8]1([OH:15])[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][CH2:12][C:7]1([CH3:16])[CH3:6])[CH:3]=[CH2:2]
Reactant: CC1(C)CCCC(C)(C)C1=O
Reactant: C=CCBr
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: C=CCC1(O)C(C)(C)CCCC1(C)C
Temperature: 25 °C
Yield: 68 %

Procedure:
Magnesium (11.5 g, 0.48 moles) and dried diethyl ether (300 ml) were added, in this order, to one liter four-necked flask equipped with a mechanical stirrer, a dropping funnel, a thermometer, a reflux condenser and a nitrogen gas inlet tube and stirred at room temperature. While stirring at room temperature, a mixed solution of allyl bromide (57.7 g, 0.48 moles)/dried diethyl ether (100 ml) was dropped to the mixture in 2 hours. The resulting mixture was heated under reflux for 30 minutes. Into the mixture was dropped a mixed solution of 2,2,6,6-tetramethylcyclohexanone (49 g, 0.32 moles)/dried diethyl ether (100 ml) in about 40 minutes while stirring under heating and refluxing conditions. The mixture was further stirred for 2 hours under refluxing conditions. The resultant reaction mixture was poured into iced water, followed by adding a 1N hydrochloric acid aqueous solution to render the mixture weakly acidic and separating it into two layers. The organic layer was washed with a saturated sodium bicarbonate aqueous solution (50 ml) and then with water (50 ml) three times. The organic layer was dried over anhydrous magnesium sulfate and separated by filtration, followed by concentration and fractionation to obtain 42.7 g (yield 68%) of the captioned compound. This compound was a colorless transparent liquid having a woody, green, earthy and patchuli oil-like odor.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C@H:26]1[CH2:32][CH2:31][S:30][C@H:29]2[CH2:33][CH2:34][CH2:35][C@@H:36]([C:37]([O:39][CH3:40])=[O:38])[N:28]2[C:27]1=[O:41]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:15]([NH:25][C@H:26]1[CH2:32][CH2:31][S:30][C@H:29]2[CH2:33][CH2:34][CH2:35][C@@H:36]([C:37]([O:39][CH3:40])=[O:38])[N:28]2[C:27]1=[O:41])=[O:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)O)Cc1ccccc1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21

Procedure:
(2R,5R)-2,5-Dibenzyl-6-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)-6-oxohexanoic acid was synthesized as described in General Procedure G using (2R,5R)-2,5-dibenzylhexanedioic acid (200 mg, 0.613 mmol) and (4S,7S,10aS)-methyl 4-amino-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (249 mg, 0.643 mmol) to give a white solid (278 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.31-7.09 (10H, m), 6.88 (1H, d, J=6.6 Hz), 5.30 (1H, t, J=4.7 Hz), 5.17-5.11 (1H, m), 5.07-4.98 (1H, m), 3.68 (3H, s), 3.22-3.11 (1H, m), 3.02-2.92 (1H, m), 2.90-2.81 (1H, m), 2.80-2.63 (4H, m), 2.46-2.37 (2H, m), 2.06-1.96 (2H, m), 1.86-1.75 (2H, m), 1.72-1.47 (7H, m).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[NH:56][CH2:55][CH2:54][N:53](C(OC(C)(C)C)=O)[CH2:52]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:56]6[CH2:55][CH2:54][NH:53][CH2:52][C@@H:51]6[CH3:50])[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)n1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4CCNC[C@@H]4C)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (39.0 mg. 0.059 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (0.177 mmol, 3.0 eq) and acetic acid (3.55 mg, 0.059 mmol) and fitted magnetic stir bar. The result solution was stirring at room temperature for 4 h. MP-B(OAc)3H (0.591 mmol, 138 mg, 10.0 eq) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and MeOH (2.0 mL) and 1 drop of concentrated HCl was added to the solution. The solution was heated at 60° C.° for 12 h. Purification was completed via a Gilson HPLC (acidic conditions). The product was dissolved in 3 mL of MeOH and passed through 0.5 g amine columns (washed with 8 mL MeOH) to afford 14.5 mg (33.03%) of the title compound. LC-MS m/z 744 (M+H)+, 1.43 min (ret time).
Reaction SMILES: Cl.[CH3:2][CH:3]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[C:17]1[O:18][C:19]2[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:20]=2[N:21]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:26][C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:17]([N:9]3[CH2:8][CH2:7][CH:6]([CH2:5][CH2:4][CH:3]([NH:12][C:13](=[O:15])[CH3:14])[CH3:2])[CH2:11][CH2:10]3)[O:18][C:19]=2[CH:25]=1
Reactant: Oc1ccc2nc(Cl)oc2c1
Reactant: CC(=O)NC(C)CCC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NC(C)CCC1CCN(c2nc3ccc(O)cc3o2)CC1
Yield: 77 %

Procedure:
A solution of N-[1-methyl-3-(piperidin-4-yl)propyl]acetamide hydrochloride (500 mg), 2-chloro-1,3-benzoxazol-6-ol (361 mg) and N,N-diisopropylethylamine (826 mg) in DMF (15 mL) was stirred at 100° C. for 10 hr. The reaction mixture was allowed to cool, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate/THF mixed solvent (10/1), and the solution was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (543 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6]1)=[O:4].[Na+].[Br-:21].OOS([O-])=O.[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.O.CCOC(C)=O>[Br:21][C:14]1[CH:13]=[CH:12][C:11]([O:16][CH3:17])=[C:10]([CH:15]=1)[CH2:9][CH:7]1[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH2:8]1
Reactant: [Br-]
Reactant: COc1ccccc1CC1CN(C(=O)C(F)(F)F)C1
Agent: O=S([O-])OO
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(Br)cc1CC1CN(C(=O)C(F)(F)F)C1
Reaction time: 5 h
Yield: 53.5 %

Procedure:
To a solution of 2,2,2-trifluoro-1-[3-(2-methoxy-benzyl)-azetidin-1-yl]-ethanone (95 mg, 0.35 mmol) in acetone (2 mL) and water (2 mL) was added NaBr (143 mg, 1.40 mmol) followed by Oxone (210 mg, 0.35 mmol). After 5 h, 10% sodium metabisulfite solution was added. After 1 h, EtOAc was added and the aqueous portion extracted twice with EtOAc. The combined organics were dried (Na2SO4) and concentrated. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (66 mg, 53%). MS (ESI): mass calcd. for C13H13BrF3NO2, 352.1; m/z found, 354.1 [M+H]+. 1H NMR (CDCl3): 7.32 (dd, J=8.7, 2.5 Hz, 1H), 7.17 (d, J=2.5 Hz, 1H), 6.75 (t, J=10.2 Hz, 1H), 4.43 (dd, J=9.6, 8.4 Hz, 1H), 4.26-4.14 (m, 1H), 4.09 (dd, J=9.6, 5.7 Hz, 1H), 3.89 (dd, J=10.7, 5.7 Hz, 1H), 3.81 (s, 3H), 3.14-2.96 (m, 1H), 2.90 (d, J=7.8 Hz, 2H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([OH:9])[C:5](C)=[CH:6][CH:7]=1.CO[C:12]1[C:13](=[NH:21])[CH:14]=[C:15](OC)[C:16](=[NH:18])[CH:17]=1>O.N>[CH:2]1[C:7](=[N:18][C:16]2[CH:17]=[CH:12][C:13]([NH2:21])=[CH:14][CH:15]=2)[CH:6]=[CH:5][C:4](=[O:9])[CH:3]=1
Reactant: COC1=CC(=N)C(OC)=CC1=N
Reactant: Cc1ccc(N)cc1O
Agent: N
Solvent: O
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Reaction time: 0.33 h
Yield: 3.2 %

Procedure:
0.02 mole (0.246 g) 3-amino-6-methyl phenol is dissolved in 30 cc water to which 5 cc ammonia 22° Be' were added. To this solution there is added 0.02 mole (0.332 g) 2,5-dimethoxy benzoquinone diimine from the first stage in solution in 60 cc water. The mixture is agitated for 20 minutes. Thereafter the reaction mixture is filtered off, yielding 0.125 g of said indoaniline which exhibits a melting point of 104°.
Reaction SMILES: Cl[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:19]([CH3:20])[C:10]2=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]2[N:8]=1.Br[C:22]1C=C[S:24][C:23]=1C1N(C)C2=NC=C(C(F)(F)F)C=C2N=1.[Na].C(S)C.CN(C=O)C>O>[CH2:23]([S:24][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:19]([CH3:20])[C:10]2=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]2[N:8]=1)[CH3:22]
Reactant: Cn1c(-c2sccc2Br)nc2cc(C(F)(F)F)cnc21
Reactant: Cn1c(-c2sccc2Cl)nc2cc(C(F)(F)F)cnc21
Agent: [Na]
Solvent: CCS
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccsc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 188 %

Procedure:
A mixture of 0.22 g of 2-(3-chlorothiophen-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine, 0.23 g of 2-(3-bromothiophen-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine, 0.21 g of ethyl mercaptan sodium salt (80%) and 4 ml of DMF was stirred at 100° C. for 30 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.41 g of 2-(3-ethylthiothiophen-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (15)).
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][C:6](O)=[O:7])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:30][O:31][C:32](=[O:41])[CH2:33][NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[CH3:30][O:31][C:32](=[O:41])[CH2:33][N:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:6](=[O:7])[CH2:5][N:4]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N(CC(=O)O)c1ccccc1
Reactant: COC(=O)CNc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: COC(=O)CN(C(=O)CN(C(C)=O)c1ccccc1)c1ccccc1

Procedure:
To 20 parts by volume of chloroform was added 0.96 part by weight of N-acetylphenylglycine. With ice cooling, 1.03 parts by weight of dicyclohexylcarbodiimide was added, and the mixture was stirred. Furthermore, 0.83 part by weight of phenylglycine methyl ester was added, and about 3 hours later, the temperature was returned to room temperature. The mixture was then stirred overnight. After the reaction, the precipitate was collected by filtration, and washed with chloroform. The filtrate was concentrated to dryness. The resulting solid was washed with ethyl acetate, and extracted with a mixture of chloroform and petroleum ether to give 1.2 parts by weight of the captioned compound having a melting point of 198° to 200° C.
Reaction SMILES: P([O-])(O)(O)=O.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2([NH:18]C(OCC(Cl)(Cl)Cl)=O)[CH2:17][CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1>C1COCC1.[Zn]>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2([NH2:18])[CH2:17][CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC1(c2cccc(Cl)c2)CCC1)OCC(Cl)(Cl)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: NC1(c2cccc(Cl)c2)CCC1
Reaction time: 0.17 h
Yield: 92 %

Procedure:
According to the procedure of Just and Grozinger (Just, G. and K. Grozinger, Synthesis 457 (1976)), a rapidly stirring mixture of 1.0 ml of 1M potassium dihydrogenphosphate and Zn powder (1.0 g) was treated dropwise during 1 minute with a solution of the product from Step 3 in 5 ml of THF. After 10 minutes, an exotherm to 28° C. was produced and the two-phase system gave way to a slurry. This mixture was stirred for 1 hour when it was filtered through celite; the filter cake was washed alternately with THF and H2O (twice each). The pooled filtrate was concentrated in vacuo and the aqueous residue was cooled and brought to pH 12-13 with 8% aqueous NaOH. This was extracted 3 times with CHCl3 ; the extracts were washed with H2O and then with brine. The pooled extract was dried (MgSO4) and concentrated to give 0.23 g (92%) of the titled product.