Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][CH2:12][CH2:11][CH2:10][C:7]2([CH2:9][CH2:8]2)[CH:6]1[OH:14])=[O:4].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][CH2:12][CH2:11][CH2:10][C:7]2([CH2:9][CH2:8]2)[CH:6]1[O:14][C:22](=[O:24])[CH3:23])=[O:4]
Reactant: COC(=O)C1CCCCC2(CC2)C1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCCC2(CC2)C1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-hydroxy-spiro[2.6]nonane-5-carboxylic acid methyl ester (0.899 g) obtained in Step 2 in chloroform (18 mL) were added successively triethylamine (6.33 mL), 4-dimethylaminopyridine (0.11 g) and acetic anhydride (2.15 mL) under argon atmosphere and ice-cooling, followed by stirring the mixture at room temperature for 3.5 hours. After ice-cooling the reaction mixture and adding saturated aqueous sodium bicarbonate solution thereto, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (diethyl ether:hexane (volume ratio)=1:9) to give 4-acetoxy-spiro[2.6]nonane-5-carboxylic acid methyl ester (1.06 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[H-].[Na+].Br[CH:24]1[CH2:27][CH2:26][CH2:25]1.CO>CN(C=O)C>[CH:24]1([N:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:20])[C:5]([C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][CH:10]=3)=[N:6]2)[CH2:27][CH2:26][CH2:25]1
Reactant: BrC1CCC1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cn(C2CCC2)nc(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 1.5 h

Procedure:
Under an argon atmosphere, to a solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (2.0 g) in DMF (40 mL) was added under ice-cooling 60% sodium hydride (596 mg), and the mixture was stirred for 1.5 hr. Then, bromocyclobutane (1.05 mL) was added, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added methanol, and the mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol) and further purified by HPLC to give the title compound (0.92 g).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][CH2:16][C:17](=[O:39])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([C:33](=[O:37])[CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([CH2:26][C@@H:27]([OH:38])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)(=[O:14])[CH3:13].O>N1C=CC=CC=1>[C:12]([O:15][CH2:16][C:17](=[O:39])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([C:33](=[O:37])[CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([CH2:26][C@@H:27]([O:38][S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)(=[O:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
Acetyl chloride (9.71 ml) was added to a stirred solution of (3β,5α)-3-hydroxypregnane-11,20-dione (97.1 g) [prepared as described by Cameron et al., J. Chem. Soc., 1955, 2807] in methanol (2.4 l) and a solution of bromine (18.5 ml) in methanol (1 l) was then added over 30 min at room temperature. The reaction mixture was poured into water (30 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure to give crude (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g). δ (CDCl3) 0.61 (s,3H), 1.02 (s,3H), 3.00-3.20 (m,1H), 3.49-3.62 (m,2H) and 3.85 (s,2H). Potassium acetate (240 g), potassium iodide (6 g) and glacial acetic acid (250 ml) were added to a solution of (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g) in acetone (4.8 l) and the mixture was heated under reflux for 3 h. The reaction mixture was poured into water (50 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. The residue was chromatographed over silica gel and the purified product was crystallised from diethyl ether to give (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) m.p. 163°-165° C.; [α]D +103.3° (c 0.97). 4-Toluenesulfonyl chloride (52 g) was added to a solution of (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) in pyridine (260 ml) and the solution was stirred for 4 h at room temperature. The reaction mixture was poured into water (2.6 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. Crystallisation of the residue from methanol gave (3β,5α)-21-(acetyloxy)-3-{[(4-methylphenyl)sulfonyl]oxy}pregnane-11,20-dione (35 g). m.p. 155°-156° C.; [α]D +62.4° (c 1.11).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1>>[C:19]1([CH3:23])[CH:20]=[CH:21][C:22]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:11][CH:10]3[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=2)=[CH:17][CH:18]=1
Reactant: Cc1cccc(I)c1
Reactant: C#Cc1ccc(C2CC2C(=O)OC)cc1
Product: COC(=O)C1CC1c1ccc(C#Cc2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from methyl 2-(4-ethynylphenyl)cyclopropanecarboxylate (80 mg, 0.40 mmol) and 1-iodo-3-methylbenzene (97 mg, 0.44 mmol) according to the general procedure IF to give 57 mg (49%) of a white after purification by flash chromatography (SiO2, EtOAc:PE, 1:9): Rf=0.43 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 7.46-7.38 (m, 4H), 7.14 (d, J=7.9 Hz, 2H), 7.06 (d, J=8.2 Hz, 2H), 3.72 (s, 3H), 2.59-2.47 (m, 1H), 2.36 (s, 3H), 1.92 (ddd, J=8.5, 5.3, 4.2 Hz, 1H), 1.63 (dt, J=9.9, 5.0 Hz, 1H), 1.33 (ddd, J=8.4, 6.5, 4.7 Hz, 1H); 13C NMR (CDCl3) δ 173.6, 140.2, 138.4, 131.6, 131.5, 129.1, 126.1, 121.6, 120.2, 89.6, 88.5, 52.0, 26.2, 24.2, 21.5, 17.2; ESI-MS m/z 313.1 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][N:15]([CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCN1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]ncc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nn(CCN3CCCC3)cc2C1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
1,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.8 g, 8.06 mmol)(EP1057814, Example 2c) was added to 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1.65 g, 9.67 mmol) and potassium carbonate (3.34 g, 24.2 mmol) in N,N-dimethylformamide (35 ml) and the mixture was heated at 65° C. for 26 hours, then cooled to room temperature and stirred for 72 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in 2N sodium hydroxide solution. The aqueous mixture was extracted with ethyl acetate (×2) and the combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ammonium hydroxide, methanol and ethyl acetate in dichloromethane as eluant (gradient from 0:0:50:50 to 0:0.1:50:50 to 0.5:5:0:95) to give the title compounds from preparation 228-A and preparation 228-B as a mixture of isomers (300 mg). LRMS: m/z ES+ 321 [MH+]
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:29][C:30](=[O:33])[NH:31][CH3:32])[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:61])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([O:29][C:30](=[O:33])[NH:31][CH3:32])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:61])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC(=O)NC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC(=O)NC

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-methylcarbamoyloxypropan IIIc1 is allowed to react and worked up by the same procedure as described in (5). The summary of the experimental condition and the physical data of the prodcut are listed in the Table 8.
Reaction SMILES: [OH-].[Na+].C1COCC1.[N:8]1([C:13]2[CH:14]=[C:15]([CH:20]=[C:21]([C:23]3[N:27]=[CH:26][NH:25][N:24]=3)[CH:22]=2)[C:16]([O:18]C)=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl>CO>[N:8]1([C:13]2[CH:14]=[C:15]([CH:20]=[C:21]([C:23]3[N:27]=[CH:26][NH:25][N:24]=3)[CH:22]=2)[C:16]([OH:18])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)c1cc(-c2nc[nH]n2)cc(N2CCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(-c2nc[nH]n2)cc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aqueous 5 N sodium hydroxide solution (0.21 mL, 1.05 mmol) was added to a THF (0.7 mL)-methanol (0.7 mL) suspension of methyl 3-(1-pyrrolidinyl)-5-(1,2,4-triazol-3-yl)benzoate (95.8 mg, 0.35 mmol), and stirred at room temperature for 18 hours. 5 N hydrochloric acid (0.21 mL, 1.05 mmol) was added to the reaction mixture and concentrated under reduced pressure. 40% methanol/chloroform was added to the residue, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, the formed insoluble matter was taken out through filtration, washed and dried to obtain the title compound as a pale yellow solid.
Reaction SMILES: [Na].[C:2]1([CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1)[OH:3].Cl[CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14].[Cl-].[NH4+]>O.CN(C)C=O>[CH3:14][O:13][CH:12]([O:15][CH3:16])[CH2:11][O:3][C:2]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: COC(CCl)OC
Reactant: Oc1ccc(O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1ccc(O)cc1)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The monosodium salt of hydroquinone prepared in Example 1 and dimethyl formamide (100 ml) were charged under nitrogen gas into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel and were warmed to effect dissolution. The resulting solution was then allowed to warm to room temperature, and 1-chloro-2,2-dimethoxyethane was added dropwise over a period of about 20 minutes. After the addition was completed, the reaction mixture was heated at about 85° to 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) was added, and the reaction mixture was neutralized with ammonium chloride. The reaction mixture was then extracted with chloroform, and the organic phase was separated from the aqueous phase. The organic phase was then stripped of solvent, leaving a red oil. This oil was distilled to yield the desired product 4-(2,2-dimethoxyethoxy)phenol as a pink oil boiling at 116° to 120° C. at 0.008 mm of Hg pressure.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2)[CH3:2].S(Cl)(Cl)=O.[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([O:15][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14])=[CH:6]2)[CH3:2]
Reactant: CCc1ccc2nnc(C(=O)O)cc2c1
Reactant: Oc1ccccc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCc1ccc2nnc(C(=O)Oc3ccccc3)cc2c1

Procedure:
A mixture of 6-ethylcinnolin-3-yl carboxylic acid (0.606 g.) and thionyl chloride (30 ml.) was heated under reflux on a steam bath for 20 minutes. The resulting solution was evaporated under reduced pressure to give a yellow crystalline solid, to which was added a solution of phenol (1.13 g.) in dry tetrahydrofuran (20 ml.). The mixture was heated under reflux on a steam bath for 2 hours. The resulting solution was evaporated and the residue was washed by decantation with ether (2× 50 ml.). The residual brown oil was dissolved in ethyl acetate (50 ml.) and washed successively with 5% w/v aqueous sodium bicarbonate (10 ml.) and water (2× 10 ml.). The ethyl acetate solution was dried (MgSO4), filtered and evaporated, and the residual oil was applied to the top of a silica column (30 g. Kieselgel 60). Elution with a 50% v/v mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.), and evaporation of the appropriate fractions, gave crude phenyl 6-ethylcinnolin-3-yl carboxylate. The product was recrystallised from aqueous ethanol, and then had m.p. 143°-145° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][O:14][CH2:15][CH2:16][NH2:17]>>[CH3:13][O:14][CH2:15][CH2:16][NH:17][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: COCCN
Product: COCCNc1ccc([N+](=O)[O-])cc1OC

Procedure:
0.3 mol (56.2 g) of 4-chloro-3-methoxynitrobenzene in 170 ml of 2-methoxyethylamine is heated to reflux for 18 hours. The excess 2-methoxyethylamine is distilled off. The reaction medium is diluted with 300 g of ice-cold water.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO>[CH3:13][O:9][C:8](=[O:10])[C:7]1[C:2]([I:1])=[CH:3][CH:4]=[N:5][C:6]=1[O:11][CH3:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1nccc(I)c1C(=O)O
Solvent: CO
Product: COC(=O)c1c(I)ccnc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-iodo-2-methoxy-nicotinic acid (1.7 g, 6.1 mmol) in 50 mL of methanol (50 ml) was added trimethylsilyldiazomethane (15 mL of a 2M solution in hexanes, 30 mmol). The mixture was stirred at ambient temperature overnight, then concentrated. The crude product was purified by flash column chromatography on silica (eluent: hexanes-ethyl acetate-triethylamine 100-10-1, then 70-30-1). 1.685 g colorless solid were isolated (94%). 1H NMR (500 MHz, acetone-d6) δ 7.93 (d, J=5.4 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H);
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][N:12]1[CH2:33][CH2:32][N:15]2[C:16]3[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=3[CH2:18][N:19]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:21]=[C:20]3[CH:14]2[CH2:13]1>C(Cl)Cl>[CH3:11][N:12]1[CH2:33][CH2:32][N:15]2[C:16]3[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=3[CH2:18][N:19]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:21]([CH:3]=[O:4])=[C:20]3[CH:14]2[CH2:13]1
Reactant: CN(C)C=O
Reactant: CN1CCN2c3ccccc3Cn3c(cc4ccccc43)C2C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN1CCN2c3ccccc3Cn3c(c(C=O)c4ccccc43)C2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the reagent made from 0.56 ml of dimethylformamide in 5 ml methylene chloride and 1.03 g of phosphorous oxychloride is added a solution of 1.88 g of 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]-benzodiazepine in 5 ml methylene chloride in a dropwise manner maintaining the temperature of the reaction below 10°. The reaction is allowed to stir at room temperature for 30 minutes. The reaction mixture is quenched with 10 ml of a saturated solution of sodium acetate and heated at reflux temperature for 1 hour. On cooling to room temperature the reaction is extracted with 3×50 ml methylene chloride. The organic extracts are combined and dried over anhydrous sodium sulfate and the solvent removed by evaporation under reduced pressure to yield 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxaldehyde which is converted to the hydrochloride salt, mp 260°-266°.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH:10]([O:12]C2CCCCO2)[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH:10]([OH:12])[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(OC2CCCCO2)CCN1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(=O)OCC1CC(O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of the product of step G (710 mg, 2.3 mmol) in methanol (20 mL) was added p-toluenesulfonic acid monohydrate (20 mg, 0.1 mmol). After stirring at ambient temperature for 4 h the solution was concentrated in vacuo to afford the crude product. Purification by flash column chromatography (SiO2, 19:1 to 7:3, hexanes/ethyl acetate) afforded tert-butyl 2-(acetoxymethyl)-4-hydroxypiperidine-1-carboxylate (506 mg, 83%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 4.49-4.41 (m, 2H), 4.33-4.05 (m, 3H), 3.94-3.88 (m, 1H), 3.29-3.21 (s, 1H), 2.05 (s, 3H), 1.89-1.80 (m, 1H), 1.76-1.69 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([O:10][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:7]=[N:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1cncc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cncc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
0.31 g (2 mmol) of 5-hydroxy-nicotinic acid methyl ester and 3.1 g (4 mmol) of polymer-supported triphenylphosphine were combined in a flask charged with 45 mL of THF and 0.31 mL (3 mmol) of benzyl alcohol, and shaken at r.t. until the starting materials dissolved. The reaction mixture was then cooled to 0° C. with a water/brine bath, 0.58 mL (3 mmol) of DIAD was added and the reaction slurry then stirred overnight at r.t. The reaction mixture was filtered and the resin was washed 3 times with DCM/MeOH=1:1. The organic layer was then evaporated and flashed (EtOAc/hexanes=1:2) to give the desired 5-benzyloxy-nicotinic acid methyl ester, which was subsequently hydrolyzed according to general procedure B to give 5-benzyloxy-nicotinic acid which was used in the next step without further purification. LCMS: 230 (M+1)+.
Reaction SMILES: C(O[C:5]1([CH3:14])[CH:9]=[CH:8][C:7](=[O:10])[CH:6]1[CH2:11][CH:12]=[CH2:13])(=O)C.[OH2:15]>C(O)(=O)C>[CH2:11]([C:6]1[C:7](=[O:10])[CH2:8][CH:9]([OH:15])[C:5]=1[CH3:14])[CH:12]=[CH2:13]
Reactant: O
Reactant: C=CCC1C(=O)C=CC1(C)OC(C)=O
Solvent: CC(=O)O
Product: C=CCC1=C(C)C(O)CC1=O
Yield: 83 %

Procedure:
In the same flask as in Example 1, there were charged 3-acetoxy-2-allyl-3-methyl-4-cyclopentenone (3.0 g), water (10 g) and acetic acid (5 g), and the resultant mixture was stirred under reflux for 10 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and extracted three times with methyl isobutyl ketone (60 ml). The organic layers were combined together, washed with water and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography to give 1.95 g of 2-allyl-4-hydroxy-3-methyl-2-cyclopentenone. Yield, 83%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A suspension of 4-iodophenol (3 g, 13.64 mmol), 1-bromopropane (1.845 g, 15.00 mmol), and sodium carbonate (7.54 g, 54.5 mmol) in DMF (30 mL) was stirred at 80° C. for 4 hrs. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with 0.5M NaOH (2×50 mL), and water (2×50 mL), and then dried over MgSO4. The solvent was removed. The crude product (3.11 g) was obtained, which was directly used for the next reaction without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.61-7.53 (m, 2H), 6.74-6.67 (m, 2H), 3.90 (t, J=6.5 Hz, 2H), 1.88-1.76 (m, 2H), 1.05 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].F[C:10](F)(F)C(F)=C(F)F>>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][CH:10]=1
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: Nc1ccccc1N
Product: c1ccc2[nH]cnc2c1

Procedure:
The first step (a) illustrated on FIG. 15 is a reaction between ortho phenylene diamine 23 and hexafluoropropene 24 in autoclave for 24 hours and the resulting derived product is obtained with a good output (75%). This reaction does not make it possible to obtain a fluorinated vinyl monomer with benzimidazole functionality 21b, but to obtain 2-(1,1,1,2-tetrafluoroethyl)benzimidazole 10, after recrystallization in a water/ethanol mixture and with an output of 75%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)C(C)C)(C)C>CCCCO>[C:17]([C@H:16]([NH:21][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:14]([N:12]1[CH2:13][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:10][C@H:11]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[C@H](N)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C(C)(C)C

Procedure:
A solution of (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylamine (6-1, 325 mg, 0.877 mmol, 1 equiv), ethyl bromoacetate (0.195 mL, 1.76 mmol, 2.00 equiv), and N,N-diisopropylethylamine (0.613 mL, 3.51 mmol, 4.00 equiv) in n-BuOH (4.0 mL) was heated under microwave irradiation at 150° C. for 15 min. The reaction mixture was concentrated and the residue was partitioned between a ethyl acetate (100 mL) and a 1:1 mixture of saturated aqueous potassium bisulfate solution and brine (100 mL). The organic layer was then washed with saturated aqueous sodium bicarbonate solution (100 mL) followed by brine (100 mL), then dried over magnesium sulfate and concentrated to give ethyl ({(1S)-1-tert-butyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amino)acetate (7-1) as an off-white solid. LRMS m/z (M+H) 457.5 found, 457.2 required.