Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]23[CH2:15][CH:13]([CH2:14]2)[CH2:12]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.N1([C:21](N2C=NC=N2)=[O:22])C=NC=N1.[CH3:28][O:29][CH:30]([O:50][CH3:51])[C:31]1[C:40]([CH2:41][N:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][C:43]2=[O:49])=[CH:39][C:38]2[CH2:37][CH2:36][CH2:35][NH:34][C:33]=2[N:32]=1>CN(C=O)C>[C:11]12([NH:10][C:8]3[C:5]([C:6]#[N:7])=[CH:4][N:3]=[C:2]([NH:1][C:21]([N:34]4[C:33]5[C:38](=[CH:39][C:40]([CH2:41][N:42]6[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][C:43]6=[O:49])=[C:31]([CH:30]([O:50][CH3:51])[O:29][CH3:28])[N:32]=5)[CH2:37][CH2:36][CH2:35]4)=[O:22])[CH:9]=3)[CH2:14][CH:13]([CH2:15]1)[CH2:12]2
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2
Reactant: O=C(n1cncn1)n1cncn1
Reactant: N#Cc1cnc(N)cc1NC12CC(C1)C2
Solvent: CN(C)C=O
Product: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2C(=O)Nc1cc(NC23CC(C2)C3)c(C#N)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-amino-4-(bicyclo[1.1.1]pentan-1-ylamino)nicotinonitrile (intermediate 277, 61 mg, 0.305 mmol) in anhydrous DMF (1.5 ml) was added to a solution of di(1H-1,2,4-triazol-1-yl)methanone (50 mg, 0.305 mmol) in DMF (1.5 ml) at 0° C. After stirring for 1.5 h at room temperature a solution of 1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one (intermediate 81, 60 mg, 0.179 mmol) in DMF (1.5 ml) was added. The reaction mixture was stirred for 18 h at room temperature, then evaporated directly onto isolate and purified by normal phase chromatography: 12 g RediSep® silica column; eluting with EtOAc then a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as a yellow solid. (UPLC-MS 6) tR 1.00; ESI-MS 561.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:19]([N:21]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:22][CH3:23])[CH3:20]>CN(C)C=O.C1(C)C=CC=CC=1>[ClH:27].[CH2:19]([N:21]([CH2:22][CH3:23])[CH:24]([C:14]1[C:13]([CH3:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N:8][NH:9]2)[CH2:25][CH3:26])[CH3:20]
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: CCN(CC)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCC(c1c(C)ccc2[nH]nc(-c3ccccc3)c12)N(CC)CC
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
3-Phenyl-5-methylindazole (4.17 g) was dissolved in dimethylformamide (70 ml) and sodium hydride 50% pure (1.15 g) was added to the solution, followed by stirring it at room temperature for 10 min. To the resulting solution was added dropwise a solution of diethylaminopropyl chloride (3.59 g) in 30 ml of toluene. The mixture was stirred at 70° C for 1 hour and poured into ice-water, and extracted with chloroform. The extract was washed with water, dried over sodium sulfate and concentrated by evaporation. The residue was treated with ether-hydrochloric acid to obtain 4.5 g of 1-diethylaminopropyl-3-phenyl-5-methylindazole hydrochloride (m.p. 127°-129° C).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:10]#[N:11])[C:6]([O:12][CH3:13])=[CH:5][N:4]=1.Cl.NO.C([N:19](CC)CC)C.ClC(OC)=O>O.C(#N)C>[NH2:11][C:10]1[N:9]=[C:7]2[N:8]([C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]2[O:12][CH3:13])[N:19]=1
Reactant: COc1ncc(OC)c(NC#N)n1
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Agent: Cl
Agent: NO
Solvent: CC#N
Solvent: O
Product: COc1cnc(OC)n2nc(N)nc12
Temperature: 45 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a 25 mL three-neck round bottom flask were added 1.11 g (5.55 mmol) of 90 wt % 2,5-dimethoxy-4-cyanoaminopyrimidine (2), 463 mg (6.66 mmol) of hydroxylamine hydrochloride, and 9.8 g of acetonitrile. To this mixture was added 681 mg (6.72 mmol) of triethylamine in one portion. The reaction mixture was heated to a gentle reflux (˜45° C.) for 2 h. The reaction mixture was cooled in an ice water bath to about 5.8° C. at which time an additional 716 mg (7.08 mmol) of triethylamine was added in one portion. To this mixture was added 662 mg (7.01 mmol) of methyl chloroformate in one portion at which time the internal reaction temperature rose from 5.8° C. to 12.1° C. The ice water bath was removed and the mixture was stirred at ambient temperature for 1 h and then at reflux (˜76° C.) for about 3 h. The reaction mixture was cooled to ambient temperature and an additional 100 μL of triethylamine was added to adjust the reaction pH to about 7-8. To this mixture was added 11.3 g of water; the mixture was transferred to a 100 mL round bottom flask; and the acetonitrile was removed in vacuo at 60 mm Hg and 30° C. The aqueous slurry was then suction filtered over a medium glass frit and the residue from the flask was transferred with ˜2 g of water. After the cake de-liquored, another 1 g displacement water wash was passed through the cake. After suction air drying the cake for 30 min, the mixture was allowed to dry over a nitrogen pad overnight. This afforded 588 mg (˜97% pure by liquid chromatography (LC) analysis) of 2-amino-5,8-dimethoxy-[1,2,4]-triazolo[1,5-c]pyrimidine (I) as a light yellow solid in 52.8% yield from starting 2,5-dimethoxy-4-cyanoaminopyrimidine (2). 1H NMR (DMSO-d6, 400 MHz) δ 3.90 (s, 3H), 4.06 (s, 3H), 6.28 (br s, 2H), 7.48 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 55.37, 57.04, 123.07, 138.60, 143.73, 148.50, 166.02.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:24])[CH2:18][NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:7][CH:8]=1.O.[NH2:26][NH2:27]>ClCCl>[ClH:2].[ClH:1].[C:20]([NH:19][CH2:18][CH:17]([OH:24])[CH2:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[N:5]=[N:4][C:3]([NH:26][NH2:27])=[CH:8][CH:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(Cl)nn1
Reactant: NN
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(NN)nn1

Procedure:
A stirred mixture of 3-chloro-6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]pyridazine hydrochloride (0.3 g.) and hydrazine hydrate (3 ml.) was heated under reflux for 50 minutes. After cooling, dichloromethane was added and this mixture was extracted with water, the dichloromethane was removed by evaporation and the residue was treated with a mixture of n-propanol (1.2 ml.) and concentrated hydrochloric acid (0.13 ml.) to give 3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine dihydrochloride, m.p. 163°-168°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.O.Cl>C(O)C.[Fe]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(Br)nc1N
Yield: 47.9 %

Procedure:
To a suspension of 2-amino-6-bromo-3-nitropyridine (21.8 g) in ethanol (220 ml)-water (22 ml) was added iron powder (39.0 g) at room temperature. Conc. hydrochloric acid (0.8 ml) was added and the mixture was gradually heated with stirring to start the reaction. The mixture was refluxed under heating for 2 hr, and an insoluble matter was removed by filtration while hot. The solvent was evaporated under reduced pressure, and water (200 ml) and active charcoal were added to the resulting solid, which was followed by heating. The insoluble matter was removed by filtration while hot, and water was evaporated under reduced pressure from the filtrate to give 2,3-diamino-6-bromopyridine (9.00 g) as a green brown powder. To the resulting solid from the above reaction were added ethanol (100 ml)-water (100 ml) and the mixture was heated for dissolution. The insoluble matter was removed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/3) to further give the objective compound (8.25 g) as a black powder.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH2:28][CH3:29])=[N:17][N:18]3[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)=[O:5])C.O1CCCC1.[OH-].[Na+]>CO>[CH2:28]([C:16]1[C:15]2[C:19](=[CH:20][C:12]([C:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH:8]=3)=[CH:13][CH:14]=2)[N:18]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[N:17]=1)[CH3:29]
Reactant: CCOC(=O)C1CC=C(c2ccc3c(CC)nn(-c4ccc(F)cc4)c3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nn(-c2ccc(F)cc2)c2cc(C3=CCC(C(=O)O)CC3)ccc12
Reaction time: 3 h
Yield: 29.6 %

Procedure:
To a stirred solution of 1.13 g (2.87 mmol) of 4-(3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl)-cyclohex-3-ene-carboxylic acid ethyl ester dissolved in 50 mL of methanol and 15 mL of tetrahydrofuran was added 8.62 mL (8.61 mmol) of 1N sodium hydroxide and reaction mixture heated to reflux for 3 hr. After 3 hr, the reaction mixture was concentrated on a rotary evaporator, diluted with 200 mL of H2O, acidified to pH 1 with 1N HCl and extracted 2×200 mL ethyl acetate. The organic extracts were combined, washed with water, brine and dried over Na2SO4. Filtration, concentration and drying gave crude product. Recrystallization from ethyl acetate/hexane gave 0.31 grams of white crystalline product mp=214-216° C.; MS, m/z 365 (M+H+, base).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][OH:12].[H-].[Na+].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](F)[N:21]=1.C(Cl)Cl.CO>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][O:12][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[N:21]=1
Reactant: OCc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: Fc1cccc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
[1-(3,5-Dichloro-benzyl)-1H-imidazol-2-yl]-methanol (300 mg, 1.17 mmol) was dissolved in DMF and NaH (46 mg, 1.17 mmol) was added under N2 atmosphere. After 20 minutes, 2,6-di-fluoropyridine (0.11 mL, 1.17 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction was partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×75 mL). The combined organic extracts were washed with water (2×70 mL) and brine, dried over MgSO4, filtered and concentrated to yield a yellow solid. Chromatography (silica, 40:1 CH2Cl2/MeOH) afforded 2-[1-(3,5-dichlorobenzyl)-1H-imidazol-2-ylmethoxy]-6-fluoro-pyridine (270 mg, 66%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:27]=[CH:26][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][N:15]3[CH:23]=[CH:24][CH:25]=[C:14]3[CH2:13]2)=[O:11])=[CH:8][CH:7]=1)CCC.[F:36][C:37]1[CH:38]=[C:39](Br)[CH:40]=[C:41]([F:43])[CH:42]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:36][C:37]1[CH:38]=[C:39]([C:6]2[CH:7]=[CH:8][C:9]([C:10]([N:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[CH2:16][N:15]4[CH:23]=[CH:24][CH:25]=[C:14]4[CH2:13]3)=[O:11])=[CH:26][CH:27]=2)[CH:40]=[C:41]([F:43])[CH:42]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2cc(F)cc(F)c2)cc1)N1Cc2cccn2Cc2ccccc21

Procedure:
A mixture of 1.5 g of 10,11-dihydro-10-[4-(tributylstannyl)benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 1 ml of 3,5-difluoro-1-bromobenzene and 200 mg of tetrakis(triphenylphosphine)palladium(O) in 200 ml of toluene is refluxed for 16 hours. The reaction mixture is filtered and the filtrate evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 700 mg of the desired product as a solid. Mass spectrum: M+H:401.
Reaction SMILES: [N:1]1([C:7]2[C:8]([C:15]([F:18])([F:17])[F:16])=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH3:28].Cl>C(#N)C>[CH2:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:8]([C:15]([F:16])([F:18])[F:17])=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[CH2:2][CH2:3]1)[CH2:27][CH3:28]
Reactant: CCCI
Reactant: N#Cc1cccc(N2CCNCC2)c1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2cccc(C#N)c2C(F)(F)F)CC1

Procedure:
Preparation according to Example 1: 3-Piperazin-1-yl-2-(trifluoromethyl)benzonitrile (0.83 g, 3.25 mmol), acetonitrile (40 ml), potassium carbonate (0.88 g, 8.1 mmol) and 1-iodopropane (0.255 ml, 3.25 mmol). Yield: 0.74 g (77%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 234-236° C. MS m/z (relative intensity, 70 eV) 297 (M+, 15), 269 (14), 268 (bp), 225 (26), 177 (8).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:14])=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2.[C-:15]#[N:16].[K+].[OH2:18]>>[OH:14][C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:15]([NH2:16])=[O:18])=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:13])[NH:11]2
Reactant: O
Reactant: [C-]#N
Reactant: Nc1ccc(O)c2c1NC(=O)CC2
Agent: Cl
Agent: [K+]
Product: NC(=O)Nc1ccc(O)c2c1NC(=O)CC2
Temperature: 50 °C

Procedure:
10.7 g of 8-amino-5-hydroxy-3,4-dihydrocarbostyril hydrochloride was dissolved in 300 ml of water, and a solution of 4.06 g of potassium cyanide dissolved in 100 ml of water was added thereto while stirring at a temperature of 50° C. After stirring the mixture for one hour at 50° C., the precipitated crystals were recovered by filtration, washed successively with 1 l of water and methanol to obtain 8.75 g of 5-hydroxy-8-ureido-3,4-dihydrocarbostyril as colorless amorphous crystals having a melting point of 209.0°-211.2° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH3:19])=[C:11]([O:20][CH3:21])[CH:10]=1)=[O:8].[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]2[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH3:19])=[C:11]([O:20][CH3:21])[CH:10]=2)=[O:8])=[C:27]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:35]
Reactant: COc1cc(C(=O)CCCCCBr)cc(C(C)C)c1OC
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCC(=O)c2cc(OC)c(OC)c(C(C)C)c2)ccc(C(=O)OC)c1O
Yield: 98.9 %

Procedure:
A mixture of 6.0 g (0.017 mol) of 6-bromo-1-[3,4-dimethoxy-5-(1-methylethyl)phenyl]-1-hexanone, 3.39 g (0.016 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 7.0 g (0.051 mol) of potassium carbonate in 120 mL of acetone and 12 mL of DMF was stirred at reflux for 19 hours. After workup as in Example 16, the crude product was purified by HPLC using 16% ethyl acetate-hexane to give 7.7 g (98% yield) of 4-[[6-[3,4-dimethoxy-5-(1-methylethyl)phenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid methyl ester as an oil. The nmr spectrum was consistent with the structure.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[CH3:10][C:11](O)=[O:12].C(OC(=O)C)(=O)C.O>CCO>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:11](=[O:12])[CH3:10])[CH3:2]
Reactant: CC(=O)O
Reactant: CCc1ccccc1N
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCO
Product: CCc1ccccc1NC(C)=O
Temperature: 120 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
2-Ethylaniline (9.70 g, 80.0 mmol) was added to a mixture of glacial AcOH (30 mL) and acetic anhydride (20 mL), and the resulting mixture was refluxed at 120° C. for 3 h. The reaction mixture was then cooled to room temperature and poured into a boiling mixture of water and EtOH (20 mL each). The mixture was stirred at rt for 1 h and then cooled (0-5° C.) overnight. EtOH was evaporated and the remainder of the mixture was diluted with water (100 mL). The obtained mixture was neutralized with Na2CO3 and extracted with EtOAc. The combined extract was washed with brine, dried with anhydrous MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 5% MeOH in CH2Cl2, to afford 5.50 g (42%) of the title compound as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (broad s, 1H), 7.05-7.40 (m, 4H), 2.55 (q, J=7.6 Hz, 2H), 2.02 (s, 3H), 1.09 (t, J=7.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1.C(=O)(O)[O-].[K+]>CN(C=O)C>[Br:7][C:6]1[C:2]([N:12]2[N:13]=[CH:14][CH:15]=[N:11]2)=[C:3]([N+:8]([O-:10])=[O:9])[S:4][CH:5]=1
Reactant: c1c[nH]nn1
Reactant: O=[N+]([O-])c1scc(Br)c1Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1scc(Br)c1-n1nccn1
Reaction time: 1 h

Procedure:
A mixture of 3,4-dibromo-2-nitrothiophene (1.5 g, 5.23 mmol), 1H-1,2,3-triazole (0.30 mL, 5.18 mmol) and potassium bicarbonate (0.54 g, 5.36 mmol) in DMF (13 mL) were stirred in an oil bath set at 110° C. under condenser with N2 (g) inlet for 1 h. The reaction mixture was quenched with H2O and extracted with ethyl acetate. The organic phase was collected, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash chromatography (silica, 30:70 ethyl acetate/hexane) gave the regio-isomer nitro intermediate of interest (0.518 g, 36%). Retention time (min)=1.950, method [4], MS(ESI) 276.9 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[F:6][C:7]([F:17])([F:16])[C:8]([F:15])([F:14])[C:9]([F:13])([F:12])[CH:10]=O>O1CCCC1>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:10]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[C:9]([F:13])([F:12])[C:8]([F:15])([F:14])[C:7]([F:17])([F:16])[F:6]
Reactant: O=CC(F)(F)C(F)(F)C(F)(F)F
Reactant: c1cc[nH]c1
Solvent: C1CCOC1
Product: FC(F)(F)C(F)(F)C(F)(F)C(c1ccc[nH]1)c1ccc[nH]1

Procedure:
Pyrrole (2; 50 mmol) and heptafluorobutyraldehyde (7; R=CF3CF2, as the hydrate, 25 mmol ) were condensed in tetrahydrofuran in the presence of acid catalyst as described above to give bis-(pyrrol-2-yl) hepta-fluoroprop-1-ylmethane (8; R=CF3CF2) in >50% isolated yield. GCMS m/z; 314 (M+, 22%), 145 (100%); 1H NMR (δ, CDCl3 at 7.24); 4.92 (t, 1H), 6.22 (d, 4H), 6.75 (s, 2H), 8.07 (bs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][C:54]=1[F:60]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:52][C:53]3[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][C:54]=3[F:60])=[O:16])[CH2:12][CH2:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)cc1F
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.9 %

Procedure:
To a solution of 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.02 g) in N,N-dimethylformamide (5.0 ml) were added triethylamine (1.28 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.03 g), followed by stirring at room temperature for 5 min. To this was added 4-amino-3-fluorophenol hydrochloride (500 mg), followed by stirring at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with a 1N aqueous solution of sodium hydroxide. To the aqueous layer was added 5N hydrochloric acid to make it acidic, this was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as a pale red solid (395 mg, 39%).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:7]([CH3:9])[N:8]=1)=[N+:2]=[N-:3].[C:20]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:21][C:22]([CH3:24])=O.C(N(CC)CC)C>CN(C)C=O.ClCCl>[CH2:13]([NH:12][C:10]([C:6]1[S:5][C:4]([N:1]2[C:22]([CH3:24])=[C:21]([C:20]([O:26][CH2:27][CH3:28])=[O:25])[N:3]=[N:2]2)=[N:8][C:7]=1[CH3:9])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnn(-c2nc(C)c(C(=O)NCc3ccccc3)s2)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
To a solution of 2-azido-N-benzyl-4-methylthiazole-5-carboxamide (0.53 g, 1.92 mmol) and ethyl acetoacetate (0.50 g, 3.85 mmol) in N,N-dimethylformamide (2 mL) was added triethylamine (0.54 mL, 3.85 mmol). The reaction mixture was stirred at ambient temperature for 24 hours, diluted with dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white solid in 49% yield (0.36 g): 1H NMR (300 MHz, DMSO-d6) δ 9.03 (t, J=6.0 Hz, 1H), 7.36-7.34 (m, 5H), 4.46 (d, J=6.0 Hz, 2H), 4.35 (q, J=6.0 Hz, 2H), 2.89 (s, 3H), 2.64 (s, 3H), 1.34 (t, J=6.0 Hz, 3H); MS (ES+) m/z 386.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: C1COCCN1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCOCC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and morpholine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=373.