Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)CC)C.[NH2:33][C:34]1[C:35]([CH3:40])=[CH:36][CH:37]=[CH:38][CH:39]=1.C(P(C#N)(CC)=O)C>ClCCl>[CH3:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[NH:33][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1ccccc1N
Agent: CCP(=O)(C#N)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 54.6 %

Procedure:
A mixture of 0.332 g of 4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid, 0.111 g of triethylamine, 0.107 g of o-toluidine, and 0.15 ml of diethylphosphoryl cyanide in 20 ml of dichloromethane is heated on a steam bath overnight. The mixture is washed with water, 1M NaHCO3, 1N HCl, brine and dried (Na2SO4). The dichloromethane solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is crystallized from dichloromethane-hexane to give 0.23 g of white crystals, m.p. 228°-231° C.
Reaction SMILES: C(OC([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[CH:10]([C:15]1[CH:16]=[N:17][C:18]([F:31])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:20]=1)[CH2:11]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[NH4+].[OH-]>C(Cl)Cl.O>[CH3:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([C:19]2[CH:20]=[C:15]([CH:10]3[CH2:11][CH:12]4[NH:8][CH:9]3[CH2:14][CH2:13]4)[CH:16]=[N:17][C:18]=2[F:31])=[CH:26][CH:25]=1)(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(c1cnc(F)c(-c3ccc(S(C)(=O)=O)cc3)c1)C2
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(C3CC4CCC3N4)cnc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Compound 17 (312 mg, 0.7 mmol) was dissolved in anhydrous CH2Cl2 (3 mL) and cooled in an ice-water bath. TFA (3 mL) was added in 30 min. After stirring at room temperature for 1 hr, the mixture was poured into a cold solution of NH4OH in water (1:1). The mixture was then extracted with CH2Cl2. The organic phase was washed with brine, then dried over anhydrous Na2SO4 and evaporated to dryness. After flash chromatography on a silica gel column with CH2Cl2-MeOH, the free base was isolated as a clear oil (242 mg, 99%). 1H NMR (CDCl3): δ (ppm) 1.5-1.7 (m, 5H), 1.8-1.9 (m, 1H), 2.87 (dd, 1H, J=5.1, 9.0 Hz), 3.11 (s, 3H), 3.65 (br s, 1H), 3.84 (m, 1H), 7.7-7.8 (m, 2H), 8.0-8.05 (m, 2H), 8.09 (dd, 1H, J=2.4, 3.6 Hz), 8.15 (m, 1H). 13C NMR (CDCl3): δ (ppm) 29.6, 30.5, 31.7, 40.8, 44.6, 44.9, 56.8, 63.2, 121.6 (d, J=112.5 Hz), 128.0, 130.2 (d, J=12.3 Hz), 140.3 (d, J=14.7 Hz), 141.3 (d, J=18.6 Hz), 146.6 (d, J=57.6 Hz), 157.6, 160.8.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:20][CH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[Br:20][CH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=4[N:7]=[CH:8]3)=[CH:34][CH:35]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(CBr)cc3)cc2)n(C)c1=O
Yield: 40.1 %

Procedure:
A solution of 1,3-dimethylxanthine (990 mg), potassium carbonate (1348 mg) and 4-(4-bromomethylbenzoyl)benzyl bromide (2007 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:5) and recrystallized from ethyl acetate-isopropyl ether to provide the title compound as colorless solid (1021 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]([OH:15])=[O:14].C(=O)(O)[O-].[Na+]>O1CCOCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)CNc1ccc([N+](=O)[O-])cc1

Procedure:
From 1-fluoro-4-nitrobenzene by heating with glycine at reflux in a mixture of aqueous sodium bicarbonate and dioxane to give (4-nitro-phenylamino)-acetic acid, followed by treatment with formaldehyde and formic acid at reflux to give [methyl-(4-nitro-phenyl)-amino]-acetic acid. Treatment with thionyl chloride and catalytic DMF to give the acid chloride followed by amide formation with 2-amino-4,6-dimethylpyridine in triethylamine and chloroform gives N-(4,6-dimethyl-pyridin-2-yl)-2-(4-nitro-phenylamino)-acetamide. The amide is the reduced with borane-dimethylsulfide in THF at reflux then catalytic hydrogenation over Raney nickel in methanol gives the required aniline.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl>C(Cl)Cl.O1CCOCC1.CCOC(C)=O>[F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[C:18]([F:21])([F:19])[F:20])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)[C@H](F)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(O[C@@H]2CCNC[C@H]2F)c(C(F)(F)F)c1
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of tert-butyl (3R,4R)-3-fluoro-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (1.6 g, 1.0 eq, 3.9 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. while stirring. 4N HCl in dioxane (10 mL) was added to the above solution and stirred at 0° C. for 30 minutes and brought to room temperature for 3 hours. The volatiles were removed under vacuum to leave a crude solid. The crude mixture was dissolved in EtOAc (100 mL) and partitioned with 1N aqueous NaOH solution (50 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give the desired product in 95% yield.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1.[C:33]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([C:37]1[CH:42]=[CH:41][C:40]([C:25]2[C:26]([CH3:28])=[CH:27][C:22]([S:21][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:9][CH:10]=3)[CH2:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[CH:23][C:24]=2[CH3:30])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cc1cc(SC(CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 367 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1 MS: 570.2 [M−H]−; Isomer 2 MS: 570.2 [M−H]−.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:44]=[CH:43][C:16]([CH2:17][N:18]([C:30]3[CH:42]=[CH:41][C:33]4[O:34]C(C)(C)[O:36][C:37](=[O:38])[C:32]=4[CH:31]=3)[C:19]([C:21]3[CH:29]=[CH:28][C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CCO>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([C:19]([N:18]([CH2:17][C:16]3[CH:43]=[CH:44][C:13]([C:12]#[C:11][C:8]4[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=4)=[CH:14][CH:15]=3)[C:30]3[CH:42]=[CH:41][C:33]([OH:34])=[C:32]([CH:31]=3)[C:37]([OH:38])=[O:36])=[O:20])=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc4c(c3)OCO4)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc4c(c3)OCO4)c3ccc(O)c(C(=O)O)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)-1,3-benzodioxole-5-carboxamide and NaOH 5M aq. in the presence of EtOH as a pale yellow powder (55%). 1H NMR (CDCl3, 300 MHz) δ 10.47 (s, 1H), 7.44 (m, 5H), 7.26 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 6.97 (m, 1H), 6.86 (m, 2H), 6.80 (d, J=9.1 Hz, 1H), 6.62 (d, J=8.6 Hz, 1H), 5.93 (s, 2H), 5.07 (s, 2H), 2.62 (t, J=7.8 Hz, 2H), 1.61 (m, 2H), 1.36 (m, 2H), 0.93 (t, J=7.2 Hz, 3H). M− (ESI): 546.2; M+ (ESI): 548: HPLC, Rt: 5.23 min (Purity: 98.3%)
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)=[CH:23][CH:24]=1
Reactant: NCc1ccncc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: c1ccc2c(c1)ncn2-c1ccnc(NCc2ccncc2)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 4-(aminomethyl)pyridine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): 303.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.61 (d, J=5.8 Hz, 2H); 8.57 (br s, 1H); 8.44 (d, J=5.5 Hz, 1H); 7.85 (d, J=8.0 Hz, 1H); 6.89 (d, J=5.5 Hz, 1H); 5.96 (br s, 1H); 4.78 (d, J=6.4 Hz, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3]1([CH3:25])[CH:7]([C:8]([OH:10])=[O:9])[N:6]2[C:11](=[O:24])[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:5]2[S:4]1.[OH:26]O>C(O)(=O)C.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Br:1][CH2:2][C:3]1([CH3:25])[CH:7]([C:8]([OH:10])=[O:9])[N:6]2[C:11](=[O:24])[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:5]2[S:4]1=[O:26]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(CBr)C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S1=O

Procedure:
Sodium tungstate (0.02 g) was added to a solution of 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylic acid (3.1 g) in acetic acid (8 ml) at 7° ~ 10°C under stirring and then to the mixture was added 30% aqueous hydrogen peroxide (1.2 ml). The mixture was stirred at 7° ~ 10°C for 1 hour. After the reaction, icewater (50 ml) was added to the reaction mixture and then extracted with ethyl acetate. The extract was washed with water and back-extracted with 5% sodium bicarbonate aqueous solution. The aqueouos layer was washed with ethyl acetate twice, acidified with 5% hydrochloric acid to pH2 and then extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give powder of 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylic acid-1-oxide (2 g). Infrared Absorption Spectrum (CHCl3). 3350, 1795, 1740, 1688 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:24](O)([CH3:27])([CH3:26])[CH3:25].N12CCCN=C1CCCCC2>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([O:9][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1cc(Br)ccc1Cl
Temperature: 40 °C
Yield: 86.1 %

Procedure:
To a solution of 5-bromo-2-chlorobenzoic acid (11.75 g) in N,N-dimethylformamide (50 ml) was added 1,1′-carbonyldiimidazole (8.10 g), and the mixture was stirred under heating at 40° C. for one hour. Thereto were added t-butanol (7.40 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.60 g), and the mixture was further stirred under heating at 40° C. overnight. The mixture was diluted with diethyl ether, and washed successively with water (3 times), 2% aqueous hydrochloric acid solution (twice), a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give t-butyl 5-bromo-2-chlorobenzoate (12.53 g) as pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[CH:4][C:3]=1[CH3:11].[CH3:12][N:13]1[C:17]([C:18]#[N:19])=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Br-]>C1COCC1>[C:18]([C:17]1[N:13]([CH3:12])[C:14]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[CH:4][C:3]=2[CH3:11])=[CH:15][CH:16]=1)#[N:19]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: Cc1cc(NC#N)ccc1Br
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cc(NC#N)ccc1-c1ccc(C#N)n1C
Yield: 12.7 %

Procedure:
(4-bromo-3-methylphenyl)cyanamide (0.104 g, 0.5 mmol) tris (dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol) were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous flow of nitrogen and THF (2 mL) was added with stirring. Tri-tert-butylphosphine (10 wt % in hexane) (0.0486 mL, 0.0252 mmol) was added to the mixture and allowed to stir until the starting bromide was consumed. The mixture was then diluted with 1/1 hexane/ethylacetate, filtered through a plug of silica gel, the solvent evaporated and the residue was flash chromatographed on silica gel using 4/1 Hexane/THF to give [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-methylphenyl]cyanamide (0.015 g, 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15]C)=[O:14])=[CH:10][CH:9]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ccccc2Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2Cl)s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
289 mg (1.14 mmol) of the compound from Example 46A were dissolved in 2 ml of THF/methanol (1:1), and 1.14 ml (2.29 mmol) of 2 M aqueous sodium hydroxide solution were added. The reaction mixture was stirred at 80° C. for 2 h. After cooling to RT, the solvent was removed on a rotary evaporator and the residue was taken up in 5 ml of water and washed with 5 ml of ethyl acetate. The aqueous phase was acidified with 1 N hydrochloric acid and extracted twice with in each case 5 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. This gave, in a purity of 91%, 218 mg (73% of theory) of the target compound.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[C:23]#[N:24].N(OC(C)(C)C)=O>O1CCCC1>[C:23]([C:3]1[C:4]([C:19]([F:22])([F:20])[F:21])=[N:5][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:11][C:12]=2[Cl:13])[CH:2]=1)#[N:24]
Reactant: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (2.33 g) in dry tetrahydrofuran (30 ml) was added with stirring at room temperature, a solution of tert-butyl nitrite (1.36 ml) in dry tetrahydrofuran (5 ml) during 2 minutes. The solution was then heated under reflux for 1 hour and cooled, and additional tert-butyl nitrite (2.72 ml) was added. The solution was heated under reflux for 30 minutes, and left to cool overnight. Evaporation in vacuo gave an orange oil, which was purified by chromatography on silica (Merck, 40-230 mesh, 0.7 kg cm-2) eluting with dichloromethane-hexane (1:1). The product was finally recrystallized from hexane to give 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole, m.p. 121°-123° C., as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[C@@H:16]([NH:17][C:18](=O)[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([NH:26][S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:20]=3)[CH2:15][CH2:14][N:13]([CH3:38])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>O=P(Cl)(Cl)Cl>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C@H:11]3[C@H:16]([CH2:15][CH2:14][N:13]([CH3:38])[CH2:12]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([NH:26][S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:20]=3)[C:6]=2[CH:7]=1
Reactant: COc1ccc([C@@H]2CN(C)CC[C@@H]2NC(=O)c2ccc(C)c(NS(=O)(=O)c3ccc(C)cc3)c2)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(C)c(NS(=O)(=O)c2ccc(C)cc2)c1
Yield: 69 %

Procedure:
3.9 g rac-cis-3-(3,4-dimethoxyphenyl)-1-methyl-4-[4-methyl-3-(p-toluene-sulphonamido)-benzamido]-piperidine are heated at the boiling point under reflux in 50 ml phosphorus oxytrichloride for 3 h. After the excess phosphorus oxytrichloride has been distilled off, the residue is partitioned between methylene chloride and 2 N sodium hydroxide solution, and the organic phase is washed with water and dried over sodium sulphate. After the methylene chloride has been distilled off, the residue is purified by silica gel chromatography. The main product fraction which has been separated off is concentrated and the solid residue is recrystallized from ethyl acetate/petroleum ether. 2.6 g of the title compound are obtained as yellowish crystals of m.p. 206°-210° C. (decomp.).
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13]OS(C)(=O)=O)[O:11][CH:12]=1)=[O:7])[CH3:4].Cl.[NH:20]1[C:24]([C:25](=[O:27])[CH3:26])=[CH:23][CH:22]=[N:21]1.C([O-])([O-])=O.[K+].[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CC(C)=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][N:21]2[CH:22]=[CH:23][C:24]([C:25](=[O:27])[CH3:26])=[N:20]2)[O:11][CH:12]=1)=[O:7])[CH3:4]
Reactant: CC(=O)c1ccn[nH]1
Reactant: CCOC(=O)c1coc(COS(C)(=O)=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: N#N
Solvent: CC(C)=O
Product: CCOC(=O)c1coc(Cn2ccc(C(C)=O)n2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methanesulfonyloxymethyl-oxazole-4-carboxylic acid ethyl ester (160 mg, 0.64 mmol) and TBAB (41 mg, 0.13 mmol) in dry acetone (9.0 mL) was treated at rt with a solution of 1-(1H-pyrazol-5-yl)ethan-1-one hydrochloride (99 mg, 0.64 mmol) and K2CO3 (448 mg, 3.21 mmol) in acetone (4.0 mL). After stirring at rt for 2 days, the solvent was removed under reduced pressure. The residue was partitioned between water and EA, the two layers were separated and the aq. layer was extracted twice with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:2 hept-EA)=0.33. LC-MS-conditions 02: tR=0.80 min, [M+H]+=263.97.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Si:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]([N:6]2[C:22](=[O:23])[C:21]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]3[C:19]2=[O:24])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A mixture of 2-nitro-4-(tert-butyldimethylsilyloxy)aniline (10.3 g, 38.5 mmol) and phthalic anhydride (6.50 g, 41.5 mmol) in toluene (30 mL) was refluxed for 18 h. A Dean-Stark apparatus was fitted to the flask, diisopropylethylamine (0.1 mL) was added and water was removed azeotropically over the next 24 h. About 20 mL of solvent was removed by distillation and the resultant solution allowed to cool to room temperature. The residue was diluted with methylene chloride and passed through a plug of silica gel eluting with methylene chloride. The desired fractions were combined and concentrated in vacuo. Recrystallization from methylene chloride-hexane provided 12.2 g (80%) of the title compound in two crops.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.S(O[Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])(OC(F)(F)F)(=O)=O.O>ClCCl>[O:1]1[C:5]2([CH2:6][CH2:7][C:8]([O:11][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])=[CH:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)[Si](OS(=O)(=O)OC(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC1=CCC2(CC1)OCCO2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-one (11.6 g) in dichloromethane (200 mL) were added dropwise triethylamine (20.7 mL) and trifluoromethyl tri(propan-2-yl)silyl sulfate (25.0 g). The reaction mixture was stirred at room temperature so for 1 hr, and ice-cooled water was added. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (22.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=1)[C:5](O)=[O:6].C1C=CC(P([N:33]=[N+:34]=[N-:35])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=1)[C:5]([N:33]=[N+:34]=[N-:35])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(/C=C/c2ccccc2)n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N=[N+]=[N-])cc(/C=C/c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-6-(E)-styryl-isonicotinic acid (214 mg, 0.89 mmol) in DMF (5 mL) is added at 0° C. TEA (0.21 mL, 1.5 mmol) and slowly (30 min) DPPA (366 mg, 1.33 mmol). The reaction mixture is stirred for 0.5 h at 0° C. and 0.5 h at r.t. The reaction is quenched with ice (20 g) and extracted with Et2O (6×30 mL). The combined organic extracts are washed successively with saturated NaHCO3 (2×15 mL) and water (2×10 mL), and are evaporated in vacuo without heating. The residue is purified by FC (SiO2, EtOAc-heptane) to provide the title compound.