Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH3:17])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:23]([S:26](Cl)(=[O:28])=[O:27])([CH3:25])[CH3:24].Cl>O.CCCCCC.O1CCCC1>[CH2:1]([S:8][C:9]1[N:10]=[C:11]([N:15]([CH2:16][CH3:17])[S:26]([CH:23]([CH3:25])[CH3:24])(=[O:28])=[O:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1cccc(SCc2ccccc2)n1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(c1cccc(SCc2ccccc2)n1)S(=O)(=O)C(C)C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a mixture of 3.16 g of the 2-benzylthio-6-ethylaminopyridine obtained in 1) above and 30 ml of tetrahydrofuran was added dropwise 9.4 ml of a 1.65 mol/l hexane solution of n-butyl lithium at -10° to 0° C. in a nitrogen stream. To the reaction mixture was added 1.84 g of isopropylsulfonyl chloride at 0° to 15° C., followed by reacting for 0.5 hour. After completion of the reaction, the reaction mixture was poured into water, made weakly acidic with hydrochloric acid, and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/19 by volume) to obtain 0.77 g of N-(6-benzylthiopyridin-2-yl)-N-ethylisopropylsulfonamide as an oily substance.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO[CH2:12][CH2:13][O:14][CH3:15]>C([O-])(O)=O.[Na+].CCOCC>[CH3:6][C:3]1[CH:4]=[CH:12][C:13]2[O:14][C:15]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])=[CH:8][C:9]=2[CH:2]=1
Reactant: COCCOC
Reactant: N#Cc1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 25 °C

Procedure:
Intermediate 1 (20 g) was added to a stirred solution of 2-bromobenzonitrile (10.34 g) and tetrakistriphenylphosphine palladium (0) (1.5 g) in DME (200 ml) and 8% NaHCO3 solution (50 ml) at reflux under nitrogen. Further catalyst (1.5 g) was added and the reaction continued overnight. The reaction was cooled to room temperature and diluted with ether (200 ml). The organic layer was separated, washed with water (3×100 ml) and dried. Filtration and evaporation gave a white solid which was purified by chromatography eluting with system A (1:9) to give the title compound (10.58 g) as a white solid.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH2:19][CH3:20].[F:30][C:31]1[C:36]([F:37])=[C:35]([C:38]#[N:39])[CH:34]=[CH:33][C:32]=1O.C(O)(=O)C(O)=O>C1(C)C=CC=CC=1>[C:16]1([C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][C:32]3[CH:33]=[CH:34][C:35]([C:38]#[N:39])=[C:36]([F:37])[C:31]=3[F:30])=[O:26])=[CH:28][CH:29]=2)[CH:1]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(O)c(F)c1F
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCCc1ccc(C(=O)O)cc1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OC(=O)c2ccc(-c3ccccc3)cc2)c(F)c1F
Reaction time: 0.5 h

Procedure:
A mixture of 0.11 mole of dicyclohexylcarbodimide and 20 ml of toluene is added to a mixture of 0.1 mole of p-pentylbenzoic acid, 0.1 mole of 2,3-difluoro-4-cyanophenol (prepared as in Example 1), 1.5 g of 4-N,N-dimethylaminopyridine and 200 ml of toluene. After stirring for 4 hours at room temperature 0.4 g of oxalic acid is added to the mixture and stirring is continued for 30 minutes. Working up i the customary manner gives 4-(4-penylbenzoyloxy)-2,3-difluorobenzonitrile.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH2:3][CH2:4][CH3:5].C1CCC(NC2CCCCC2)CC1.[NH2:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33].Cl.C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)(Cl)Cl>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OC
Reaction time: 8 h
Yield: 75 %

Procedure:
BOC-Nva-OH, liberated from 8.0 g (20 mmoles) of the DCHA salt as described in Step 1 of Example 4, and 3.82 g (21 mmoles) of H-Leu-OMe.HCl are dissolved in 60 ml of chloroform, and 2.94 ml (21 mmoles) of triethylamine are added. The solution is cooled with ice, and a solution of 4.33 g (21 mmoles) of DCC in 40 ml of chloroform is added with stirring. The reaction mixture is allowed to stand at 5° C. overnight, the separated DCU is removed by filtration, the filtrate is washed thrice with 30 ml of n hydrochloric acid, each, thrice with 30 ml of n sodium hydrocarbonate solution, each, and finally with 30 ml of water, dried over anhydrous sodium sulfate, and then evaporated. The crystalline residue is triturated with n-hexane, filtered off, and the resulting 6.65 g of crude product is recrystallized from a mixture of 5 ml of ethyl acetate and 20 ml of petroleum ether. 5.20 g (75%) of BOC-Nva-Leu-OMe are obtained; m.p.: 100°-101° C., Rf2 =0.84, [α]D25 =-47.5° (c=1%, in methanol).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:7])[CH3:6]>S(=O)(=O)(O)O>[C:5]([NH:8][C:9]1[CH:18]=[C:17]([F:19])[C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:7])[CH3:6]
Reactant: COC(=O)c1ccc(F)cc1NC(C)=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(F)cc1NC(C)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a three-neck flask (2,000 ml) was added concentrated nitric acid (500 ml). The mixture was cooled in an ice-water bath. Concentrated sulfuric acid (500 ml) was dropwise added to the mixture under mechanical stirring. After addition, the temperature of the resulting mixture was maintained below 15° C. Methyl 2-acetylamino-4-fluoro-benzoate (105.5 g, 0.5 mol) was slowly added. The resultant mixture was kept in an ice-water bath for 40 min with stirring. Then the mixture was poured into ice water (8 L). A large number of yellow solids precipitated. The mixture was stood for 10 min and filtered in vacuo. The filter cake was washed with lots of water and then transferred in water (2 L). The pH of the solution was adjusted to 7 with ammonia liquor under stirring and filtered in vacuo. The filter cake was dried by baking and recrystallized with ethyl acetate.
Reaction SMILES: ClC(Cl)(Cl)[NH:3][C:4](=[O:17])[NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=1.C(=O)(O)[O-].[Na+]>CO.O>[NH:5]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=1)[C:4]([NH2:3])=[O:17]
Reactant: CCOC(=O)Cc1csc(NC(=O)NC(Cl)(Cl)Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)Cc1csc(NC(N)=O)n1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A solution of ethyl 2-(3-trichloromethylureido)thiazol-4-ylacetate (6.32 g.) in a mixture of methanol (400 ml.) and water (150 ml.) was adjusted to pH 7 to 7.6 with sodium bicarbonate aqueous solution with stirring at room temperature, and then the solution was stirred for 70 minutes at the same temperature. The methanol was distilled off from the reaction mixture under reduced pressure, and the precipitates were collected by filtration, washed with water and then dried to give colorless crystals of ethyl 2-ureidothiazol-4-ylacetate (3.45 g.), mp 173° to 174° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[C:2]=1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(N(CC)CC)C.[BH4-].[Na+].CO.Cl>O1CCCC1>[OH:8][CH2:7][C:3]1[C:2]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccnc1-c1cccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: OCc1cccnc1-c1cccnc1
Temperature: 20 °C
Yield: 84.4 %

Procedure:
To a continually stirred, ice-cold solution of 2,3′-bipyridine-3-carboxylic acid (0.28 g, 1.40 mmole) in dry tetrahydrofuran (10 ml) and triethylamine (0.20 ml, 1.43 mmole) ethyl chloroformate (0.14 ml, 1.46 mmole) was added drop-by-drop over a 30 minute period. The precipitated product was then filtered and washed several times with tetrahyrofuran (3×2 ml). The THF phases were combined, cooled to +10° C., and while stirring under an argon atmosphere, sodium borohydride (0.185 g, 4.9 mmole) was added and then methanol (0.90 ml, 22.2 mmole) was added drop-by-drop over a 1 hour period during which time the temperature increased to 20° C. (Soai et al., 1987). The material was stirred for an additional 1 hour at room temperature. Then, 1N hydrochloric acid was carefully added, the solvent was evaporated under vacuum to 5 ml and washed with dichloromethane (3×5 ml). Sodium carbonate (0.85 g) was added to the aqueous phase, which was then extracted with dichloromethane. The combined fractions were dried with magnesium sulfate and evaporated under vacuum (2 Hg mm, 45° C.) giving a pure product (0.22 g, 84%). 1H-NMR, δ, ppm, 8.71 (1H, dd, J=2.1, 0.6 Hz, C2′-H), 8.55 (1H, dd, J=4.8, 1.5 Hz, C6-H), 8.52 (1H, dd, J=4.8, 1.8 Hz, C6′-H), 7.95 (1H, dd, J=7.8, 1.5 Hz, C4-H), 7.91 (1H, ddd, J=7.8, 2.1, 1.8 Hz, C4′-H), 7.35 (1H, ddd, J=7.8, 4.8, 0.6 Hz, C5′-H), 7.31 (1H, dd, J=7.8, 4.8 Hz, C5-H), 4.58 (2H, s, CH2—O).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl-].[In+3].[Cl-].[Cl-].O[C:13]([CH:25]1[CH2:27][CH:26]1[C:28]#[N:29])([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH3:14].[CH3:30][S:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[CH:38]2>ClCCl>[CH3:30][S:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[C:38]2[C:13]([CH:25]1[CH2:27][CH:26]1[C:28]#[N:29])([C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=1)[CH3:14]
Reactant: CC(O)(c1ccc(C(F)(F)F)cc1)C1CC1C#N
Reactant: CSCc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc(C(F)(F)F)cc3)C3CC3C#N)c[nH]c12

Procedure:
0.02 ml (0.24 mmol) of trifluoroacetic acid and 43.3 mg (0.20 mmol) of indium(III) chloride were added to 50.0 mg (0.20 mmol) of the compound from Example 132A and 69.5 mg (0.39 mmol) of the compound from Example 8A in 2 ml of dichloromethane at RT, and the mixture was heated under reflux overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 9.0 mg (11% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: CC1(C)OC2C=CC([C@H]3OC(=O)[N:14](CCC4C=CC(OCCOCC5C=CC=C(S(C(C)C)=O)C=5)=CC=4)C3)=CC=2C[O:3]1.[CH3:43][C:44]1(C)[O:49][C:48]2[CH:50]=[CH:51][C:52]([C@@H:54]([OH:81])[CH2:55][NH:56][CH2:57][CH2:58][C:59]3[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][O:68][CH2:69][C:70]4[CH:75]=[CH:74][CH:73]=[C:72]([S:76]([CH:78]([CH3:80])[CH3:79])=[O:77])[CH:71]=4)=[CH:61][CH:60]=3)=[CH:53][C:47]=2[CH2:46][O:45]1.C[Si](C)(C)[O-].[K+]>C1COCC1.ClCCl>[NH3:14].[C:44]([O:49][C:48]1[CH:50]=[CH:51][C:52]([C@@H:54]([OH:81])[CH2:55][NH:56][CH2:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][O:68][CH2:69][C:70]3[CH:75]=[CH:74][CH:73]=[C:72]([S:76]([CH:78]([CH3:80])[CH3:79])=[O:77])[CH:71]=3)=[CH:61][CH:60]=2)=[CH:53][C:47]=1[CH2:46][OH:3])(=[O:45])[CH3:43]
Reactant: CC(C)S(=O)c1cccc(COCCOc2ccc(CCNC[C@H](O)c3ccc4c(c3)COC(C)(C)O4)cc2)c1
Reactant: CC(C)S(=O)c1cccc(COCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)c1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc([C@@H](O)CNCCc2ccc(OCCOCc3cccc(S(=O)C(C)C)c3)cc2)cc1CO
Product: N
Yield: 90.3 %

Procedure:
(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-({2-[4-(2-{[3-(isopropylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)ethanol (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-{2-[4-(2-{[3-(isopropylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}-1,3-oxazolidin-2-one (0.07 g) was stirred with potassium trimethylsilanolate (0.14 g) in THF (5 ml) under reflux for 2.5 h. After cooling the mixture was diluted with dichloromethane and poured onto a 10 g Bond Elut silica cartridge which was eluted successively with dichloromethane, then dichloromethane:ethanol:0.880 ammonia solution (100:8:1 and then 50:8:1) to give the title compound (0.031 g). LCMS RT=2.61 min. vi) 4-[(1R)-1-Hydroxy-2-({2-[4-(2-{[3-(isopropylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)ethyl]-2-(hydroxymethyl)phenol acetate
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:28]=[CH:27][C:16]2[N:17]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:18](=[O:20])[NH:19][C:15]=2[CH:14]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:12][C:13]1[CH:28]=[CH:27][C:16]2[N:17]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:11][CH2:10][CH2:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:25][CH2:26]3)[C:18](=[O:20])[NH:19][C:15]=2[CH:14]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: CCCCc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 5 parts of 1-chloro-4,4-bis(p-fluorophenyl-butane 3.8 parts of 5-chloro-1-(4-piperidyl)-2-benzimidazolinone, 1.4 parts of sodium bicarbonate and 80 parts of absolute ethanol is stirred and refluxed for 24 hours. The reaction mixture is evaporated. Water and toluene are added to the residue and the whole is shaken vigorously. The layers are separated and the toluene layer is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel, using a mixture of chloroform and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is triturated in diisopropylether. The solid product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 5-chloro-1{1-[4,4-bis(p-fluorophenyl)butyl]-4-piperidyl}-2-benzimidazolinone; mp. 185.8° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:14]([O:17][CH2:18][CH3:19])(=[O:16])[CH3:15]>C(O)C>[OH:3][N:2]=[C:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:8][CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(C)=O
Reactant: CCCCCC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCC1CCCC1=NO
Temperature: 25 °C
Yield: 84 %

Procedure:
Namely, to a solution of 50 ml (0.35 mol) of ethyl cyclopentanone-2-carboxylate in 130 ml of dioxane was added 3.8 ml of Triton B. Then, to the solution was added 27.1 ml (0.242 mol) of acrylonitrile in 50 ml of dioxane. The solution was stirred at room temperature for 12 hours, and extracted with ether after 100 ml of 10% hydrochloride acid was added thereto. An organic layer was dried over anhydrous magnesium sulfate. After removing the solvent, 300 ml of conc. hydrochloric acid was added to the residue and the mixture was heated under reflux for 24 hours. After cooling, the mixture was extracted with ether and 5% aqueous solution of sodium hydroxide was added to the ether layer and the mixture was stirred. An aqueous layer was made acidic with addition of 10% hydrochloric acid, and then the mixture was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate. After removing the solvent, the residue was dissolved in 150 ml of ethanol and 10 ml of conc. sulfuric acid was added thereto. The mixture was heated under reflux for 14 hours, and then ethanol was removed therefrom after cooling, and ethyl acetate was added thereto. The mixture was washed with 10% aqueous solution of sodium hydroxide and dried over anhydrous magnesium sulfate. After removing the solvent, the resulting residue was chromatographed over silica gel to obtain 45 g (yield 70% of ethyl 2-oxocyclopentanepropionate from hexane-ethyl acetate (4:1) eluate. In 150 ml 80% ethanol was dissolved 5.5 g (30 mmol) of this compound. To the solution were added 4.17 g (60 mmol) of hydroxylamine hydrochloride and 2.7 g (33 mmol) of sodim acetate and the mixture was stirred at room temperature over night. After removing ethanol, the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After removing the solvent, the resulting residue was chromatographed over silica gel to obtain 5 g (yield 84%) of ethyl 2-hydroxyiminocyclopentanepropionate from hexane-ethyl acetate (6:1) eluate. In 15 ml of anhydrous ethanol was dissolved 4.4 g of this compound and the solution was stirred at 50° C. for 4 hours under a hydrogen pressure of 120 atm. with use of Raney nickel (W2) as a catalyst. After removing Raney nickel by filtration and removing the solvent, the resulting residue was chromatographed over silica gel to obtain 0.95 g (yield 31%) of 2-azabicyclo-[4.3.0]-nonane-3-one from ethyl acetate eluate.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:43]=[CH:44][CH:45]=1)[CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11]1)([CH3:3])[CH3:2].[CH3:46][O:47][CH2:48][CH2:49][C:50](Cl)=[O:51]>>[CH:1]([N:4]([C:50](=[O:51])[CH2:49][CH2:48][O:47][CH3:46])[C:5]1[CH:6]=[C:7]([CH:43]=[CH:44][CH:45]=1)[CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:20][CH:21]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:11]1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(NC(C)C)c2)cc1
Reactant: COCCC(=O)Cl
Product: COCCC(=O)N(c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1)C(C)C

Procedure:
Analogously to Example 116b, 0.400 g of tert-butyl 3-(3-isopropylaminobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.270 g of 3-methoxypropionyl chloride are reacted. The title compound is obtained as a colourless oil. Rf=0.27 (1:1 EtOAc-heptane); Rt=5.97.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.Cl[C:7]1[N:16]=[C:15]2[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13][N:14]2[CH:17]2[CH2:19][CH2:18]2)=[CH:9][C:8]=1[F:24]>C(#N)C>[CH:17]1([N:14]2[C:15]3[C:10](=[CH:9][C:8]([F:24])=[C:7]([N:1]4[CH2:5][CH:4]=[CH:3][CH2:2]4)[N:16]=3)[C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13]2)[CH2:18][CH2:19]1
Reactant: C1=CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2nc(N3CC=CC3)c(F)cc2c1=O

Procedure:
3-Pyrroline (1.0 g; 14.5 mmol) and acid 51 (2.0 g; 7.1 mmol) in acetonitrile (50 mL) were heated at reflux temperature overnight. The volatiles were evaporated and water added to the residue. The resulting solid was filtered, washed with water and ether to yield 109 as a beige solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O.N1C2C=CC=CC=2N=N1>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1coc(-c2ccc(CO)cc2)n1
Reactant: O=S(Cl)Cl
Agent: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1coc(-c2ccc(CCl)cc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
A solution of ethyl 2-[4-(hydroxymethyl)phenyl]-1,3-oxazole-4-carboxylate (0.467 g, 1.89 mmol) in CH2Cl2 was treated with a solution of thionyl chloride (0.281 g, 2.36 mmol) and benzotriazole (0.281 g, 2.36 mmol) in CH2Cl2, and stirred 6 hours at room temperature. The reaction was diluted with CHCl3, filtered over Celite and concentrated under vacuum. The resultant residue was purified by flash chromatography (silica, MeOH:CH2Cl2 5%) to give the title product in 82% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 266 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([NH:11]C(C)=O)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Cl.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([NH2:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(=O)Nc1c(C)cc(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(F)cc([N+](=O)[O-])c1N
Temperature: 0 °C
Yield: 94.3 %

Procedure:
A stirred solution of 22.4 grams (0.106 mole) of 5-fluoro-2-methylcarbonylamino-3-methylnitrobenzene, 100 mL of concentrated hydrochloric acid, and 100 mL of ethanol was heated at reflux for about 17 hours. The reaction mixture was cooled and poured into 500 grams of ice. The mixture was made basic with aqueous 50% sodium hydroxide. The resultant solid was collected by filtration and was thoroughly washed with water. The solid was dried at about 60° C. under vacuum, yielding 17.0 grams of 4-fluoro-2-nitro-6-methylaniline, mp 111°-113° C. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain more product.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[C:10]([Cl:16])[CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]#[N:25].N1CCCC[CH2:27]1.C(O)C>C(OCC)C>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[CH:27]/[C:14]1[C:13]2[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][C:12]=2[Cl:15])[NH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2])/[C:24]#[N:25]
Reactant: C1CCNCC1
Reactant: N#CCc1ccccn1
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1/C=C(\C#N)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Combine 2-carboethoxy-4,6-dichloroindole (1.43 g, 5.0 mmol), pyrid-2-ylacetonitrile (0.59 g, 5.0 mmol), piperidine (0.2 mL), and ethanol (30 mL). Heat to reflux. After 16 hours, cool to ambient temperature. Add diethyl ether to give a solid. Filter, rinse with diethyl ether, dry, recrystallize from acetone/water, filter, and dry to give the title compound: mp; 250-254° C. (dec). 1H NMR (DMSO-d6) δ 12.9 (br s, 1H), 8.86 (s, 1H), 8.70 (d, 1H, J=1 Hz), 8.00 (m, 1H), 7.82 (d, 1H, J=7.2 Hz), 7.55 (s, 1H), 7.48 (m, 1H), 7.48 (m, 1H), 7.34 (s, 1H), 4.35 (q, 2H, J=7.1 Hz), 1.25 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13](OS(C)(=O)=O)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:26]1([N:29]2[C:33]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[N:32][NH:31][C:30]2=[S:40])[CH2:28][CH2:27]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([S:40][C:30]3[N:29]([CH:26]4[CH2:28][CH2:27]4)[C:33]([C:34]4[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=4)=[N:32][N:31]=3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: S=c1[nH]nc(-c2ccncc2)n1C1CC1
Reactant: CC(OS(C)(=O)=O)c1nnn(-c2cccc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Sc1nnc(-c2ccncc2)n1C1CC1)c1nnn(-c2cccc(Cl)c2)n1
Yield: 68.2 %

Procedure:
The title compound (25.2 mg, 68%, white solid) was prepared from methanesulfonic acid 1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (26.4 mg, 0.087 mmol) using potassium carbonate (13.3 mg, 0.096 mmol) and 4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione (19.0 mg, 0.087 mmol) in acetonitrile (3 mL) at room temperature overnight. The reaction mixture was purified by chromatography using a silica SPE tube (2% methanol in dichloromethane). 1H NMR (CDCl3) δ (ppm): 8.78 (d, 2H), 8.16 (s, 1H), 8.04 (m, 1H), 7.75 (d, 2H), 7.49 (m, 2H), 5.67 (q, 1H), 3.24 (m, 1H), 2.08 (d, 3H), 1.16 (m, 2H), 0.82 (m, 2H).