Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.S(=O)(=O)(O)O.O.[NH4+].[CH3:22]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH3:22])=[O:13])=[CH:2]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: COC(=O)CCc1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 93 %

Procedure:
2 g (10.57 mmol) of 3-indolepropionic acid were dissolved in 50 ml of methanol. The solution was cooled to 0° C. and 5 ml of sulfuric acid 96% were dropped under stirring. The solution was maintained at room temperature overnight and then poured onto ice-water, basified with 30% ammonium hydrate and finally extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give 2.3 g of an oily product (93% yield).
Reaction SMILES: S([N:11]=[N+:12]=[N-])(C1C=CC(C)=CC=1)(=O)=O.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]>C(Cl)Cl>[N+:11](=[C:15]([C:16](=[O:17])[CH3:18])[C:14]([O:20][CH2:21][CH3:22])=[O:19])=[N-:12]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: ClCCl
Product: CCOC(=O)C(=[N+]=[N-])C(C)=O
Temperature: 25 °C
Yield: 91.5 %

Procedure:
Polymer-bound tosylazide (11 g, 15.4 mmol) (typical loading 1.4 mmol/g, prepared according to Merz et al J. Org. Chem. 2001, 66, 2509-2511) was swollen in dry DCM (40 mL). Ethyl acetoacetate (1.0 g, 7.7 mmol, CAS 141-97-9) and TEA (3.2 mL, 23.1 mmol) were dissolved in DCM (10 mL) and added to the polymer containing solution. The resulting mixture was then shaken at RT under nitrogen until the reaction was judged completed by TLC, typically 6 h. The supernatant was filtered off, then the resin was washed with DCM (3×30 mL) to rinse out residual product. The reaction mixture was then evaporated to dryness to afford the title compound (1.1 g, 92%) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.O.[NH2:36][NH2:37]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:36][NH:37]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: C[C@@H]1CO[C@H](CNS(=O)(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: C[C@@H]1CO[C@H](CNS(=O)(=O)c2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 17 h
Yield: 41.1 %

Procedure:
A mixture of crude N-({(2S,5R)-4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl)benzenesulfonamide (0.29 mmol theoretical) and hydrazine monohydrate (0.28 mL, 5.78 mmol) in ethanol (3 mL) was stirred at 100° C. in a sealed tube for 17 hours. The mixture was concentrated in vacuo and the residue was purified on a Gilson reverse phase HPLC (CH3CN/water with 0.1% TFA). The product fractions were combined and concentrated in vacuo, taken up in EtOAc (15 mL) and a little CH3OH, washed with saturated aqueous NaHCO3 (2×10 mL) and brine (10 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (59 mg) as a pale yellow solid. LC-MS (ES) m/z=495 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.12 (d, J=6.3 Hz, 3H), 2.65-2.80 (m, 1H), 2.86-3.04 (m, 2H), 3.34-3.43 (m, 1H), 3.47-3.59 (m, 1H), 3.65-3.75 (m, 1H), 3.85-4.75 (bs, 2H), 5.39 (s, 2H), 6.13 (s, 2H), 6.52 (s, 1H), 7.56 (dd, J=8.6, 1.0 Hz, 1H), 7.58-7.68 (m, 3H), 7.69-7.74 (m, 1H), 7.85 (dd, J=7.6, 1.7 Hz, 2H), 7.88-7.97 (m, 2H), 11.53 (s, 1H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[C:11]([C:23]([F:26])([F:25])[F:24])[CH:10]=2)O1.[NH2:28][C:29]1[C:30]([C:38]#[N:39])=[N:31][C:32](Cl)=[CH:33][C:34]=1[NH:35][CH3:36].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[NH2:28][C:29]1[C:30]([C:38]#[N:39])=[N:31][C:32]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[C:11]([C:23]([F:24])([F:25])[F:26])[CH:10]=2)=[CH:33][C:34]=1[NH:35][CH3:36]
Reactant: CC1(C)OB(c2ccc(OCc3ccccn3)c(C(F)(F)F)c2)OC1(C)C
Reactant: CNc1cc(Cl)nc(C#N)c1N
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNc1cc(-c2ccc(OCc3ccccn3)c(C(F)(F)F)c2)nc(C#N)c1N
Temperature: 100 °C

Procedure:
The mixture of 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)methyl)pyridine (1.35 g), 3-amino-6-chloro-4-(methylamino)-picolinonitrile (0.5 g), tris(dibenzylideneacetone)dipalladium (125 mg), tricyclohexylphosphine (92 mg) in a mixed solvent of dioxane (15 ml) and water (10 ml) was heated under nitrogen at 100° C. for 3 hours. After cooling to room temperature, the mixture extracted with ethyl acetate (200 ml), organic layer dried over sodium sulphate, solvent removed under reduced pressure, residue was used for next step without further purification. MS m/z 400 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1(C)C=CC=CC=1.CCO.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:16]4[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=4[S:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1c(O)c2c(-c3ccc(Br)cc3)csc2[nH]c1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: N#Cc1c(O)c2c(-c3ccc(-c4ccc(F)cc4)cc3)csc2[nH]c1=O
Temperature: 60 °C

Procedure:
To an ambient slurry of 3-(4-bromophenyl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.030 g, 0.086 mmol), 4-fluorophenyl boronic acid (0.024 g, 0.173 mmol) and cesium carbonate (0.084 g, 0.26 mmol) in DME/PhCH3/EtOH/H2O (10/1/6/3 ratio, 2 mL) was added palladium tetrakis(triphenylphosphine) (0.001 g, 0.0009 mmol) in a single portion. The reaction was heated at 60° C. for 16 h, cooled to room temperature, filtered, concentrated and purified by RP-HPLC to afford the title compound. MS (DCI/NH3) m/e 362.2 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ ppm 12.51 (br s, 1H), 7.75 (dd, 2H), 7.64 (d, 2H), 7.52 (d, 2H), 7.31 (apparent t, 2H), 7.07 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C@H:11]1[CH2:15][C@H:14](O)[CH:13]=[CH:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N(CC)CC)C.[C:24]1(C)[C:25]([S:30](Cl)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][O:10][C@H:11]1[CH2:15][C@H:14]([S:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=2)=[O:31])[CH:13]=[CH:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CO[C@@H]1C=C[C@@H](O)C1)OCC
Reactant: Cc1ccccc1S(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CO[C@@H]1C=C[C@@H](S(=O)c2ccccc2)C1)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trans-1-diethylphosphonomethoxycyclopent-2-en-4-ol (0.4 g; 1.6 mmol) was dissolved in CH2Cl2 (6 mL) and cooled to 0° C. in an icebath under a nitrogen atmosphere. Triethylamine (0.3 g; 2.9 mmol) was then added followed by a solution of toluenesulfinyl chloride (0.4 g, 2.9 mmol)in CH2Cl2 (2 mL). The reaction mixture was stirred at 0° C. for 1 hr. The ice bath was removed and the reaction mixture concentrated in vacuo. The residual oil was purified by flash column chromotography with 2% methanol/98% dichloromethane as eluent. The product(0.54 g; 87%) was isolated as a colorless oil.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>CCOCC>[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12](=[O:13])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: [Li]CCCC
Solvent: CCOCC
Product: CCCCC(=O)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 99.5 %

Procedure:
To a suspension of copper bromide-dimethylsulfide complex (11.0 g, 53.5 mmol) in 200 mL ether at −78° C. was added 65 mL of n-BuLi (1.6M, 104.0 mmol) dropwise. The mixture was stirred at −78° C. for 45 min, warmed to −40° C. for 10 min and then re-cooled to −78° C. A solution of 4-trifluoromethylbenzoyl chloride (10.0 g, 48.0 mmol) in 50 mL ether was added dropwise at −78° C. After addition was complete, the reaction was stirred at −78° C. for 30 min, quenched with saturated (sat.) ammonium chloride and allowed to warm to room temperature (RT). The mixture was poured into ether containing ca 10 mL methanol and was washed with a mixture of ammonium chloride/ammonium hydroxide. The combined aqueous layers were extracted with ether. The combined ether layers were dried (MgSO4), filtered and concentrated to give 11.0 g of a solid. 1H NMR (CDCl3) δ 8.05 (d,2H), 7.72 (d,2H), 2.99 (t,2H), 1.80-1.67 (m,2H), 1.50-1.35 (m,2H), 0.96 (t,3H). 19F NMR (CDCl3) δ −63.13.
Reaction SMILES: [CH2:1]([Sn:5](CCCC)([C:12]1C=C[CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[I:22]I>CO>[CH2:1]([Sn:5]([I:22])([CH2:12][CH2:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(c1ccccc1)c1ccccc1
Reactant: II
Solvent: CO
Product: CCCC[Sn](I)(CCCC)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a three-necked flask protected from light, dibutyl diphenyltin (10 g, 25.9 mmol) was solubilized in 50 mL of dry methanol. A solution of iodine (6.04 g, 23.76 mmol) in methanol was then added slowly. After stirring at room temperature for 16 hours, methanol was eliminated under vacuum. The residue was dissolved in petroleum ether and washed with a saturated aqueous solution of sodium thiosulphate. Organic layers were washed with a saturated sodium chloride solution and dried over MgSO4. Solvent was evaporated and the crude product was distilled using a Kugelrohr apparatus (rotating glass oven for fractionating distillation of small sample volumes at 60° C. A colourless oil was obtained (10.5 g, 24.0 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][CH2:26][CH3:27].[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][CH2:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(=O)(=O)c1ccccc1
Yield: 99.9 %

Procedure:
Using the general method of Example 242, 1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.72 mmol) was reacted with benzenesulfonyl chloride (350 μL, 2.72 mmol) to provide 1.38 g of N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzenesulfonamide as an off white powder, m.p. 143–144° C. Analysis: Calculated for C28H37N5O2S: % C, 66.24; % H, 7.35; % N, 13.79. Found: % C, 66.08; % H, 7.25; % N, 13.72. Karl Fisher titration found 0.23% water.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([CH:45]([OH:47])[CH3:46])[CH:36]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[OH:47][CH:45]([C:37]1[CH:36]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[CH:20]2[NH:2][N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[C:18](=[O:17])[NH:19]2)[CH:40]=[C:39]([O:41][CH3:42])[C:38]=1[O:43][CH3:44])[CH3:46]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)c(C(C)O)c1
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C2NC(=O)N(c3ncccn3)N2)cc(C(C)O)c1OC
Temperature: 85 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
After adding 22 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 112 mg of {2-[3-(1-hydroxyethyl)-4,5-dimethoxyphenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{[3-(1-hydroxyethyl)-4,5-dimethoxyphenyl]-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-one (93 mg) as a light brown solid.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](OC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][CH:34]1[CH2:37][NH:36][CH2:35]1.C[Al](C)C.C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]([N:36]3[CH2:37][CH:34]([O:33][CH3:32])[CH2:35]3)=[O:29])[N:27]=2)[CH2:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1coc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: COC1CNC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC1CN(C(=O)c2coc(N3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C3)n2)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (1.57 g, 3.60 mmol) (obtained as described in Reference Example 70(8)) in toluene (80 ml) was added a solution of 0.67 M 3-methoxyazetidine (obtained as described in Reference Example 31(2))-trimethylaluminium in toluene (10.8 ml) at room temperature under an atmosphere of nitrogen and the mixture was stirred in an oil bath (60° C.) for 30 minutes. After checking the completion of the reaction, to the reaction mixture were added 10% aqueous acetic acid (100 ml) and ethyl acetate (200 ml) in an ice bath and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (1.50 g, yield 90%) as a pale brown solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][Si:8]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][NH2:12])[CH3:6].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][Si:8]([O:16][CH2:17][CH3:18])([O:7][CH2:5][CH3:6])[CH2:9][CH2:10][CH2:11][N:12]=[C:1]=[O:2])[CH3:15]
Reactant: O=C(Cl)Cl
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCO[Si](CCCN=C=O)(OCC)OCC
Yield: 64.8 %

Procedure:
In 150 ml of toluene was dissolved 9.9 g of carbonyl chloride, and a solution of 22.1 g of γ-triethoxysilylpropylamine and 23.3 g of triethylamine in 50 ml of toluene was dropped into the above solution at 0° C. to -5° C. over a period of 3 hours to effect reaction. After the reaction, the crystal of triethylamine hydrochloride was recovered by filtration and the filtrate was distilled to recover toluene, whereby 16.0 g of γ-triethoxysilylpropyl isocyanate was obtained at a fraction having a boiling point of 88° C. to 91° C. under 4.5 mmHg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[F:11][C:12]1([F:16])[CH2:15][NH:14][CH2:13]1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[Cl:9][C:4]1[CH:5]=[C:6]([I:8])[CH:7]=[C:2]([N:14]2[CH2:15][C:12]([F:16])([F:11])[CH2:13]2)[N:3]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC1(F)CN(c2cc(I)cc(Cl)n2)C1
Temperature: 90 °C
Yield: 49.7 %

Procedure:
To a suspension of 2,6-dichloro-4-iodopyridine (1 g, 3.65 mmol) and 3,3-difluoroazetidine hydrochloric acid salt (0.497 g, 3.83 mmol) in 25 mL tetrahydrofuran was added diisopropylethylamine (0.797 ml, 4.56 mmol). The reaction mixture was heated at 90° C. for 16 hours. Further addition of another equivalent of amine and base was performed, and the suspension was heated at 100° C. for several hours, and then cooled, diluted with ethyl acetate, washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel using flash chromatography (5% to 20% ethyl acetate/hexane) to afford 0.6 g of the title compound. MS (DCI+) m/z 331.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=O)=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH2:13][N:34]3[CH2:35][CH2:36][CH:31]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH:26]=4)[CH2:32][CH2:33]3)=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)oc1C=O
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)oc1CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure F and Scheme R using ethyl 5-(4-chlorophenyl)-2-formyl-3-furoate and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 509.0 (M+H)+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8](F)[CH:7]=1>C(O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:1][CH2:2][CH3:3])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
Sodium ethoxide (21% in ethanol, 8.6 mL, 26 mmol) was added dropwise to a solution of 4-chloro-2-fluoronitrobenzene (3 g, 17.1 mmol) in ethanol (20 mL), and once addition was complete the reaction was stirred for a further hour. The mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and the solution was washed with water (×2), then brine. The solution was dried over MgSO4 and evaporated under reduced pressure to afford the title compound as a solid, 3.45 g.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1)([OH:21])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1.[H-].[Na+].[CH3:35]I.[Cl-].[Na+]>CN(C)C=O.O.C(OCC)C.CCCCCC>[F:32][C:2]([F:1])([F:31])[C:3]([O:21][CH3:35])([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: CCOc1ccc(C(O)(COCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: CCOc1ccc(C(COCc2ccc(F)c(Oc3ccccc3)c2)(OC)C(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 97 %

Procedure:
1,1,1-Trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxy-4-fluorobenzyloxy)propan-2-ol (0.2 g) in dry N,N-dimethyl-formamide (2 cm3) was added to a suspension of sodium hydride (0.1 g of a 50% dispersion in oil - washed free of oil with n-hexane) in N,N-dimethylformamide (2 cm3) at the ambient temperature (ca. 22° C.) under an atmosphere of nitrogen. After stirring for 20 minutes a solution of methyl iodide (0.1 g) in N,N-dimethylformamide (3 cm3) was added in one portion. After 20 minutes no starting material could be detected by gas liquid chromatographic analysis. The mixture was carefully diluted with water (30 cm3) then solid sodium chloride was added and the mixture shaken with diethyl ether. The layers were separated and the aqueous layer extracted with a further three portions of diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulphate and the solvent removed by evaporation under reduced pressure. The resulting pale yellow oil was purified by chromatography on silica gel, eluting with n-hexane containing 10% by volume ethyl acetate to give 1,1,1-trifluoro-2-methoxy-2-(4-ethoxyphenyl)-3-(3-phenoxy-4-fluorobenzyloxy)propane as a colourless oil (0.2 g).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:23])=[C:12]([C:18](OCC)=[O:19])[C:13](=[O:17])[NH:14]3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:23])=[C:12]([C:18]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[O:19])[C:13](=[O:17])[NH:14]3)=[N:9][CH:8]=2)=[CH:24][CH:25]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Temperature: 120 °C

Procedure:
A mixture of ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (35 mg, 0.102 mmol) and 2-methoxyethylamine (384 mg, 5.11 mmol) was heated at 120° C. in a sealed tube for 18 h. The material was triturated with hot EtOH and filtered to give the product as a white solid: 1H NMR (d6-DMSO) δ 8.37 (1H, br), 7.39 (1H, br), 7.31 (2H, br t, J˜8 Hz), 7.15 (2H, br t, J˜9 Hz), 4.07 (2H, br), 3.47 (4H, br), 3.33 (3H, s); HRMS calcd for C19H18FN3O4+H+: 372.1360. Found: 372.1372.
Reaction SMILES: [Br:1][C:2]([N+:9]([O-:11])=[O:10])=[CH:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.C(=O)C1[O:17]C=CC=1.BrC[N+]([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:1][CH:2]([N+:9]([O-:11])=[O:10])[CH:3]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)[OH:17]
Reactant: O=Cc1ccco1
Reactant: O=[N+]([O-])C(Br)=Cc1ccco1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])CBr
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])C(Br)C(O)c1ccco1

Procedure:
The use of 2-(2-Bromo-2-nitroethenyl)furan as an antimicrobial with a broad spectrum of uses in water treatment, pulp and paper manufacturing, metal working fluids and various non-oxidizing biocide applications has been described. One process for producing BNEF comprises the reaction of furfural with bromonitromethane using a primary amine or primary amine salt and sodium carbonate as the catalytic agent at 10 mol% to produce an intermediate 2-Bromo-1-(2-furyl)-2-nitroethanol, which is dehydrated in the presence of acid to the desired product. The preferred solvent is ethanol. In a typical procedure, the reaction mixture is stirred for 25 hours at 5° C., and the acid is then added to effect the dehydration. The reaction mixture is extracted with methylene chloride and the crude product recovered as an oil which is steam-distilled. The solid product is filtered from the steam-distillate and recrystallized from ethanol, and the yield is reported to be in the range of 23%.