Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1.C([O-])(O)=O.[Na+]>C(O)C.O>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([O:9][CH2:13][CH3:14])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(O)c1ccc(O)cc1
Temperature: 50 °C
Yield: 288 %

Procedure:
A mixture of 5 g of 4-hydroxymandelic acid and 1.28 g of p-toluenesulfonic acid in 200 ml of ethanol is heated at 50° C. for 4 hours. The mixture is poured into saturated aqueous NaHCO3 solution, and a white precipitate is formed. The mixture is diluted with water until the precipitate disintegrates, and then is extracted with diethyl ether. The organic phases are dried over sodium sulfate. Filtration and evaporation of the solvent give ethyl 4-hydroxymandelate (4.2 g, 82%) as a pale yellowish solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:35]Br)[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][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])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].C(OCC(C[C:70]#[N:71])COCCCCCCCCCCCCCCCC)(=O)C1C=CC=CC=1>CS(C)=O>[C:1]([O:9][CH2:10][CH:11]([CH2:35][C:70]#[N:71])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][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])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CBr)COC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCOCC(CC#N)COC(=O)c1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CC#N)COC(=O)c1ccccc1
Yield: 95.5 %

Procedure:
A mixture of 1.76 g (3.10 mM) of 2-bromomethyl-3-n-octadecylcarbamoyloxypropyl benzoate, 185 mg (3.26 mM) of 95% sodium cyanide in 30 ml of dimethylsulfoxide is allowed to react by the same procedure as described in the (136) and 1.49 g (95.5% yield) of the titled compound n5' is obtained.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:27][C:28](=[O:38])[NH:29][O:30]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[N+:19]=3[O-:26])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:27][C:28]([NH:29][OH:30])=[O:38])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[N+:19]=3[O-:26])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cccc(NC(=O)[C@@H]2CC=NN2C(=O)[C@@H](CC(=O)NOCc2ccccc2)CC2CCCC2)[n+]1[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCc1cccc(NC(=O)[C@@H]2CC=NN2C(=O)[C@@H](CC(=O)NO)CC2CCCC2)[n+]1[O-]
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
(5S)-1-((2R)-2-(Cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(6-ethyl-1-oxido-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (61 mg, 0.12 mmol) was dissolved in methanol (8 mL), and Pearlman's catalyst (16 mg, 0.02 mmol) was added. The resulting mixture was stirred under 1 atm of H2 for 30 min. After 30 min, the mixture was filtered, concentrated, and purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-[(2R)-2-(cyclopentylmethyl)-4-(hydroxyamino)-4-oxobutanoyl]-N-(6-ethyl-1-oxido-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (35 mg, 0.08 mmol, 68% yield) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.01-1.23 (m, 2H) 1.34 (s, 3H) 1.43-1.65 (m, 5H) 1.70-1.77 (m, 1H) 1.79-1.92 (m, 3H) 2.21-2.37 (m, 1H) 2.42-2.57 (m, 1H) 2.87-3.04 (m, 2H) 3.81-3.96 (m, 1H) 5.11-5.20 (m, 1H) 7.10-7.24 (m, 2H) 7.45-7.56 (m, 1H) 8.30-8.40 (m, 1H). MS: 432 ([M+H]+).
Reaction SMILES: [CH:1]1([CH:7]([O:35][CH3:36])[C:8]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:9]=2[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:43](Cl)(=[O:45])[CH3:44]>ClCCl>[F:24][C:23]([F:26])([F:25])[C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=1)[CH2:12][N:11]([CH2:10][C:9]1[CH:27]=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:29]=[CH:30][C:8]=1[CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:35][CH3:36])[C:43](=[O:45])[CH3:44]
Reactant: COC(c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O)C1CCCCC1
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-amine (Example 41, STEP E, 20 mg, 0.038 mmol) in dichloromethane (1 ml) was added pyridine (9.0 mg, 0.114 mmol) followed by acetyl chloride (2.98 mg, 0.038 mmol) at room temperature and stirred for overnight. Reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulphate and concentrated in vacuo. The product was purified on Biotage column (12+S), eluting with 2% ethyl acetate in heptane (1 CV), 2-20% (10CV), 20% (2CV) to yield the title compound (8 mg, 37%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (m, 6H) 1.2 (m, 3H) 1.7 (m, 1H) 1.9 (m, 1H) 2.2 (s, 3H) 3.1 (s, 3H) 3.9 (m, 1H) 4.6 (m, 4H) 7.4 (m, 1H) 7.5 (m, 2H) 7.6 (m, 2H) 7.8 (s, 1H). MS (ES+) Calc: 569.2, Found: 614.2 (M+45).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][O:24][NH:25][CH3:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([C:19](=[O:21])[N:25]([O:24][CH3:23])[CH3:26])[CH2:17][CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
A 1 L flask was charged with 25.02 g (85.9 mmol) trans-4-(benzyloxycarbonylamino-methyl)-cyclohexanecarboxylic acid, 9,21 g (94.5 mmol) O,N-dimethylhydroxyl amine HCl, 41.8 g (94.5 mmol) BOP, 750 mL methylene chloride and 75 mL diisopropylethyl amine. The reaction mixture was then stirred under nitrogen overnight. The solution was then washed with water, 5% citric acid (2×300 mL), saturated sodium bicarbonate (2×300 mL), brine (1×300 mL) and dried over Na2SO4 and concentrated to an oil. The oil was chromatographed on silica gel eluted with 50% ethyl acetate/50% hexanes to give 27.2 g of a clear oil that solidified on standing.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([Cl:12])[CH:6]=2.[F:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:15]=1[NH2:16].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:18]3[C:19]([CH3:21])=[CH:20][C:14]([F:13])=[C:15]([CH:17]=3)[NH2:16])[CH:3]=[N:4]2)=[CH:9][N:8]=1
Reactant: Clc1cc2ncc(Br)cc2cn1
Reactant: Cc1cc(F)c(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(F)c(N)cc1-c1cnc2cc(Cl)ncc2c1
Temperature: 75 °C
Yield: 79.6 %

Procedure:
Sparge a solution of 3-bromo-7-chloro-1,6-naphthyridine (0.5 g, 2.053 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.516 g, 2.053 mmol) in dioxane (15 mL) with Ar, add a solution of K2CO3 (0.568 g, 4.11 mmol) in H2O (3 mL), followed by Pd(PPh3)4 (0.237 g, 0.205 mmol), heat at 75° C. for 8 h, then cool to RT. Add H2O, extract with EtOAc (2×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (470 mg, 80%) as an off-white solid. MS(ESI) m/z: 288.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([NH:13][C:14]2[N:19]=[CH:18][C:17]3[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[N:21][NH:22][C:16]=3[CH:15]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:37])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC#N>[Br:37][C:15]1[C:16]2[NH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)[C:17]=2[CH:18]=[N:19][C:14]=1[NH:13][C:11]([NH:10][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:9])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-c2n[nH]c3cc(NC(=O)N[C@H](C)c4ccc(Cl)cc4)ncc23)ccn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(-c2n[nH]c3c(Br)c(NC(=O)N[C@H](C)c4ccc(Cl)cc4)ncc23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a stirred solution of 1-[(1R)-1-(4-chlorophenyl)ethyl]-3-[3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]urea (Example 19; 82 mg, 0.202 mmol) in MeCN (2 mL) was added NBS (47 mg, 0.262 mmol). The mixture was left to stir for 1 h at room temperature and then treated with 1N Na2S2O3, and extracted with chloroform:iPrOH (3:1, x3). The combined organics were dried (Na2SO4), concentrated in vacuo and purified by column chromatography on silica gel to yield 1-[7-bromo-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-3-[(1R)-1-(4-chlorophenyl)ethyl]urea (42 mg, 0.086 mmol, 43%). MS ESI calc'd. for C21H19BrClN6O [M+1]+ 485, found 485.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Br>>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:5]([CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Br:13])[C:4]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: BrCc1ccccc1Br
Product: COc1ccc([N+](=O)[O-])cc1N(Cc1ccccc1Br)Cc1ccccc1Br

Procedure:
2-Methoxy-5-nitroaniline and 1-bromo-2-(bromomethyl)benzene were processed as described in Example 2A to provide the title compound.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][O:7][C@@H:6]2[C@@H:9]([N:12]=[N+]=[N-])[CH2:10][O:11][C@H:5]12)=[N+]=[N-]>CO.[Pd]>[O:7]1[CH2:8][C@@H:4]([NH2:1])[C@H:5]2[O:11][CH2:10][C@H:9]([NH2:12])[C@@H:6]12
Reactant: [N-]=[N+]=N[C@H]1CO[C@H]2[C@@H]1OC[C@H]2N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2N
Reaction time: 8 h

Procedure:
A mixture of (3R,3aR,6S,6aR)-3,6-diazidohexahydrofuro[3,2-b]furan (2.5 g, 12.74 mmol) and 5% palladium on active carbon (0.25 g) in methanol (300 mL) was hydrogenated under 40 psi in an autoclave overnight. The catalyst was removed by filtration and the solvent was evaporated to give the desired product, which was used in the next step without further purification.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[S:9](N)(N)(=[O:11])=[O:10].O.Cl>COCCOCCOC>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][S:9]1(=[O:11])=[O:10]
Reactant: Nc1ccccc1N
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: O
Solvent: COCCOCCOC
Product: O=S1(=O)Nc2ccccc2N1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
A solution of orthophenylenediamine (20 g) and sulfamide (20.4 g) in diglyme (200 ml) was stirred at 160° C. for 2 hours, the reaction mixture was cooled to room temperature, water (200 g) was poured thereto, hydrochloric acid was added until pH 1, extracted with ethyl acetate, and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a reddish brown solid (14.2 g). Further recrystallization from ethanol-diethyl ether afforded the title compound as colorless crystals (13.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([Cl:18])=[C:16]([C:19]#[N:20])[C:15]([S:21][C:22]([F:25])([F:24])[F:23])=[C:14]1[CH:26]=[CH:27][C:28]#[N:29].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([Cl:18])=[C:16]([C:19]#[N:20])[C:15]([S:21][C:22]([F:25])([F:24])[F:23])=[C:14]1[CH2:26][CH2:27][C:28]#[N:29]
Reactant: N#CC=Cc1c(SC(F)(F)F)c(C#N)c(Cl)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CCCc1c(SC(F)(F)F)c(C#N)c(Cl)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 50 %

Procedure:
A 3.03 g (6.18 mmoles) portion of the 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-(2-cyanoethenyl)-3-trifluoromethylthio-4-cyano-5-chloropyrrole prepared above was treated with 467 mg (12.4 mmoles) of sodium borohydride in 250 mL of ethanol at room temperature for 16 hours. An additional 234 mg (6.18 mmoles) of sodium borohydride was then added in two equal portions over a two hour period to complete the reaction. The solvent was then removed under reduced pressure and the residue poured into 25 mL of ice water. The mixture was acidified with aqueous 6N HCl, extracted with dichloromethane (2×50 mL) and the organic extracts were partitioned with saturated aqueous NaHCO3 solution, dried over anhydrous MgSO4 and concentrated. The residue was chromatographed on silica gel eluting with 70/30 v/v dichloromethane-hexane to furnish 1.52 g (50%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-(2-cyanoethyl)-3-trifluoromethylthio-4-cyano-5-chloropyrrole (ASE 196) as a white solid of melting point 150° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH2:18][C:17]2=O.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C.O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH2:18][C:17]2=[N:26][OH:27]
Reactant: CCN1CCC(=O)c2cccc(CSc3nc4ccccc4[nH]3)c21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN1CCC(=NO)c2cccc(CSc3nc4ccccc4[nH]3)c21
Yield: 60 %

Procedure:
8-(2-Benzimidazolyl)thiomethyl-1-ethyl-4-oxo-1,2,3,4-tetrahydroquinoline (1.5 g), hydroxylamine hydrochloride (458 mg) and sodium acetate (1.7 g) were dissolved in a mixed solvent (23 ml) of ethanol-water (20:3), and the solution was refluxed for 3 hours. After completion of the reaction, the solvent was distilled off and the resulting residue was poured into water. The precipitated crystals were collected by filtration and recrystallized from methanol to give 8-(2-benzimidazolyl)thiomethyl-1-ethyl-4-hydroxyimino-1,2,3,4-tetrahydroquinoline (0.94 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5](F)=[O:6].[NH3:16]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([NH2:16])=[O:6]
Reactant: N
Reactant: O=C(F)c1ccc(OC(F)(F)F)c(Cl)c1
Product: NC(=O)c1ccc(OC(F)(F)F)c(Cl)c1
Reaction time: 0.5 h

Procedure:
242.5 g (1 mol) of 3-chloro-4-trifluoromethoxybenzoyl fluoride were allowed to drop into 500 ml of 25% strength by weight aqueous ammonia solution with ice cooling, then the mixture was stirred for 30 minutes and the precipitate which deposited was filtered off with suction. 227 g of product having a melting point of 98° C. were obtained. This corresponds to a crude yield of 95% of theory.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH:15]1[C:19]([C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])=[N:18][N:17]=[N:16]1>CC(O)C>[NH:18]1[C:19]([C:20]2[CH:21]=[C:22]([NH:23][C:2]3[O:3][C:4]([C:7]4[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=4)=[CH:5][N:6]=3)[CH:24]=[CH:25][CH:26]=2)=[N:15][N:16]=[N:17]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Solvent: CC(C)O
Product: N#Cc1ccc(-c2cnc(Nc3cccc(-c4nnn[nH]4)c3)o2)cc1
Temperature: 80 °C
Yield: 100.6 %

Procedure:
A mixture of 4-(2-chlorooxazol-5-yl)benzonitrile 2 (0.216 g, 1.05 mmol) and commercially available 3-(1H-tetrazol-5-yl)aniline 35 (0.17 g, 1.05 mmol) in 2-propanol (20 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, a white solid precipitated out which was filtered off, washed with 2-propanol, and dried. This was further purified by dissolving into DMSO and re-precipitated with addition of water. Resulting solid was filtered, washed with water, methanol and dried under high vacuum to yield 4-(2-((3-(1H-tetrazol-5-yl)phenyl)amino)oxazol-5-yl)benzonitrile 36 as a white solid (0.348 g, 100%). MS (ES) m/z 330 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=[O:9])=[CH:6][CH:5]=1)[CH3:2].[CH2:28]([O:30][C:31]1[CH:43]=[CH:42][C:34]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:33][CH:32]=1)[CH3:29]>>[CH2:1]([N:3]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:4]1[CH:5]=[CH:6][C:7]([C:8]2([N:35]([C:34]3[CH:42]=[CH:43][C:31]([O:30][CH2:28][CH3:29])=[CH:32][CH:33]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=[O:13])[O:9]2)=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOc1ccc(Nc2ccccc2)cc1
Reactant: CCN(Cc1ccccc1)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Product: CCOc1ccc(N(c2ccccc2)C2(c3ccc(N(CC)Cc4ccccc4)cc3)OC(=O)c3ccccc32)cc1
Yield: 93 %

Procedure:
Following a procedure similar to that described in Example 2 but employing 5.4 g of 2-[4-(ethylbenzylamino)benzoyl]benzoic acid and 3.1 g of 4-ethoxy-N-phenylaniline there was obtained 7.5 g of 3-[4-(ethylbenzylamino)phenyl]-3-[(4-ethoxyphenyl)phenylamino]phthalide, m.p. 163°-173° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed an orange-colored image.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)[C:6]([N+:19]([O-])=O)=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:19][C:6]1[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N)c(Nc2ccc(CCO)cc2)n1

Procedure:
A mixture of 2-{4-[(6-methoxy-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1, 3.52 g, 12.17 mmol), iron powder (3.4 g, 60.84 mmol) and ammonium chloride (325 mg, 6.08 mmol) in ethanol/water (v/v, 2:1, 90 mL) was heated at reflux temperature for 1 h. After cooling, the catalyst was removed and the filtrate was concentrated. The residue was extracted with ethyl acetate (100 mL) and washed with water. The organic layer was dried (MgSO4), and concentrated to give 3.41 g (quant.) of the title compound as a black oil: 1H-NMR (CDCl3) δ 7.48 (2H, d, J=8.4 Hz), 7.14 (2H, d, J=8.4 Hz), 7.04 (1H, d, J=8.2 Hz), 6.75 (1H, br.s), 6.13 (1H, d, J=8.2 Hz), 3.87 (3H, s), 3.83 (2H, t, J=6.6 Hz), 2.81 (2H, t, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19]C)=O)[CH2:13][CH2:12]1.[NH2:21][NH2:22].O>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]([NH:21][NH2:22])=[O:19])[CH2:13][CH2:12]1
Reactant: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Yield: 90.9 %

Procedure:
To a stirred solution of 3,4-difluoro nitrobenzene (1b, 3.5 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(2-fluoro-4-nitrophenyl)-4-piperidine carboxylate (3b, 5.33 g, 86%). To a stirred solution of ester (3b, 5.0 g, 18 mmol) in ethanol, NH2NH2.H2O (2.25 g, 45 mmol) is added and refluxed for 12 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(2-fluoro-4-nitro phenyl)-4-piperidinecarbohydrazide (4b, 4.62 g, 91%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4b, 3.38 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.47 g, 40%). Nitro compound (5b, 1.23 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 920 mg, 83%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodi imide)) (0.19 g, 1 mmol) and amine compound (7e, 0.28 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-3-fluoro-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8e, 333 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[N:9])[CH:5]=[N:6][CH:7]=1.[CH:10](=O)[CH3:11].C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.C(O)(=O)C>[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([NH:1][CH2:10][CH3:11])[CH:3]=1)#[N:9]
Reactant: CC=O
Reactant: N#Cc1cncc(N)c1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNc1cncc(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To a solution of 5-amino-3-cyanopyridine (300 mg, 2.52 mmol) in methanol (10 ml) was added acetaldehyde (1.42 ml, 25.1 mmol), and the mixture was stirred at room temperature for 10 minutes. Next, sodium cyanoborohydride (950 mg, 15.1 mmol) was added, and acetic acid was further added to adjust the pH of thereaction mixture to about 6. The mixture was stirred for 5 hours. After the reaction was completed, the reaction mixture was neutralized with an aqueous sodium carbonate solution and extracted with diethyl ether (30 ml×3). The diethyl ether layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (Wako Gel C-200, 20 g; eluted with chloroform:methanol=200:1) to give 3-cyano-5-ethylaminopyridine (200 mg, 1.36 mmol, yield 54%).