Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:26]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:20]2[CH:21]=[N:22][CH:23]=[N:24][CH:25]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:39][CH:40]1[CH2:44][CH2:43][O:42][CH2:41]1)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>CN(C=O)C.CCOC(C)=O>[N:22]1[CH:21]=[C:20]([C:8]2[CH:9]=[CH:10][C:11]3[O:12][C:13]4[C:18](=[CH:17][C:16]([O:19][CH2:39][CH:40]5[CH2:44][CH2:43][O:42][CH2:41]5)=[CH:15][CH:14]=4)[C@:5]4([CH2:4][O:3][C:2]([NH2:1])=[N:26]4)[C:6]=3[CH:7]=2)[CH:25]=[N:24][CH:23]=1
Reactant: O=S(=O)(OCC1CCOC1)C(F)(F)F
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC1=N[C@]2(CO1)c1cc(OCC3CCOC3)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(S)-2-Amino-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (0.075 g, 0.217 mmol) and cesium carbonate (0.106 g, 0.325 mmol) were dissolved in DMF (0.7 mL) and stirred for five minutes before being cooled in an ice bath. (Tetrahydrofuran-3-yl)methyl trifluoromethanesulfonate (0.056 g, 0.238 mmol) was dissolved in DMF (0.15 mL) and added dropwise to the reaction, which was stirred for one hour. An additional equivalent of triflate was added and the reaction was stirred for five days. The reaction was cooled to 0° C. and 0.5 eq. of triflate was dissolved in 0.1 mL of DMF and added dropwise to the reaction. The reaction was stirred for two days. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep 40 g, gradient elution 0-10% MeOH:DCM) but the material was impure so the material was repurified via Gilson HPLC (10-90% MeCN:H2O). The product fractions were partitioned between DCM and saturated sodium bicarbonate solution. The aqueous layer was extracted with DCM, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford (S)-2′-(pyrimidin-5-yl)-7′-((tetrahydrofuran-3-yl)methoxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white solid. LC-MS MH+ 431.4
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[C:32]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)(=[O:35])[CH2:33][CH3:34]
Reactant: CCC(=O)Cl
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A181) and propionyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5]2.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5]3)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)c1cc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(C(=O)Nc2ccc3[nH]c(C(=O)OC(C)(C)C)cc3c2)cc1
Reaction time: 0.67 h
Yield: 98.4 %

Procedure:
A solution of tert-butyl 5-amino-1H-indole-2-carboxylate (220 mg, 0.94 mmol), 4-acetylbenzoic acid (155 mg, 0.94 mmol) and TBTU (303 mg, 0.94 mmol) in DMF (6 mL) at 4° C. was treated with diisopropylethylamine (329 uL, 1.89 mmol) and stirred 40 min at 0˜5° C. The solvent was removed under vacuo. The crude product was chromatographed on silica gel eluted with 1% MeOH in CH2Cl2 to give 2 (350 mg, 98%). 1HNMR DMSO-d6) δ11.66 (bs, 1H), 10.34 (s, 1H), 8.09 (d, 1H, J=8.8 Hz), 8.07 (s, 4H), 7.55 (d, 1H, J=8.8 Hz), 7.41 (d, 1H, J=8.8 Hz), 7.03 (s, 1H), 2.63 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:30](=[O:32])[CH3:31])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([F:16])=[CH:18][CH:19]=1)[CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCn1c2ccc(C(C)=O)cc2c2cc(C(=O)c3ccc(F)cc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
To N-ethylcarbazole (5.00 g; 25.60 mmol) in CH2Cl2 (40 ml) is added 4-fluorobenzoyl chloride (4.06 g; 25.60 mmol) and AlCl3 (3.41 g; 25.6 mmol) at 0° C. After stirring for 4 h at room temperature, acetyl chloride (2.01 g; 25.60 mmol) and AlCl3 (3.41 g; 25.6 mmol) are added at 0° C. This reaction mixture is stirred at room temperature for overnight. After the reaction is completed, the reaction mixture is poured into ice-water. Then, the product is extracted with CH2Cl2. The organic layer is washed with H2O, saturated NaHCO3 aq. solution and brine, followed by drying over anhydrous MgSO4. Condensation under reduced pressure and washing with tert-Butyl methyl ether (TBME) affords a gray solid as crude product (7.20 g). The compound is used for the next reaction without further purification. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 1.50 (t, 3H), 2.73 (s, 3H), 4.45 (q, 2H), 7.21 (d, 2H), 7.49 (dd, 2H), 7.89 (dd, 2H), 8.05 (dd, 1H), 8.19 (dd, 1H), 8.59 (d, 1H), 8.78 (d, 1H).
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:28]([OH:30])=[O:29])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:27])[NH:8][S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10].C([O-])(O)=O.[Na+]>ClC(Cl)C>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C@H:2]([C:28]([O:30][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:29])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:27])[NH:8][S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:19])([CH3:20])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)c(C)c2c1OC(C)(C)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c(C)c2c1OC(C)(C)CC2
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 89.8 %

Procedure:
A] A slurry of 6.9 g (12 mmoles) of Z-Arg(Pmc)-OH in 60 ml of dichloroethane was added with 8.64 ml (36 mmoles) of N,N-dimethylformamide-di-tert.-butyl-acetale, in 60 minutes at 50° C. At the end of the addition, the reaction mixture was kept under stirring for 40 minutes at 50° C., then it was added with 20 ml of an aqueous solution of 5% sodium hydrocarbonate. The dichloroethane was evaporated under vacuum and the aqueous phase was diluted with 100 ml of ethyl acetate. The organic phase was separated and washed with an aqueous solution of 5% sodium hydrocarbonate and with a saturated aqueous solution of sodium chloride. The organic phase was then anhydrified and evaporated under vacuum, and the resulting crude was purified on a silica gel column (eluent: ethyl acetate/n-hexane 6:4). There were obtained 3.4 g of Z-Arg(Pmc)-OtBu (HPLC, gradient (I): R.t. 32 min.; purity 99%).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:5][CH2:4][CH2:3][C:2]([OH:7])([CH3:6])[CH3:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(C)(O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-methylbutane-1,3-diol (2.13 mL, 20 mmol) in pyridine (20 mL) at 0° C. was added para-toluenesulfonyl chloride (3.8 g, 20 mmol) in pyridine (10 mL) drop-wise over 15 minutes. This mixture stirred at ambient temperature for 3 hours and 35 mL H2O was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organics were washed with H2O (2×50 mL), dried over MgSO4, filtered, concentrated tinder reduced pressure and dried under vacuum (˜1 mm Hg) to afford the title compound. MS (ESI) m/z 276 (M+18)+.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([Br:7])[NH:4][N:3]=1.[H-].[Na+].CS(O[CH2:15][CH3:16])(=O)=O>CN(C)C=O.O>[Br:1][C:2]1[N:6]=[C:5]([Br:7])[N:4]([CH2:15][CH3:16])[N:3]=1
Reactant: CCOS(C)(=O)=O
Reactant: Brc1n[nH]c(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(Br)nc1Br
Temperature: 100 °C
Yield: 90.6 %

Procedure:
3,5-Dibromo-1H-1,2,4-triazole (2.5 g, 11.0 mmol, Eq: 1.00) was dissolved in dimethylformamide (31.8 ml) and sodium hydride (529 mg, 60% dispersion in mineral oil, 13.2 mmol, Eq: 1.2) was added slowly. Ethyl methanesulfonate (2.74 g, 2.27 ml, 22.0 mmol, Eq: 2) was added to the reaction and the mixture was heated in a microwave oven for 60 minutes at 100° C. The mixture was diluted with water and extracted 3× with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated to give 3,5-dibromo-1-ethyl-1H-[1,2,4]triazole (2.54 g, 90.4%) as a white powder. MS: m/z=255.9 (M+H+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Br:15])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(O)C>[BrH:15].[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C1CNCCN1
Solvent: CCO
Product: Br
Product: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
Following the procedure of Example 6, but replacing 1-benzylpiperazine with 1-[4-nitrobenzyl]piperazine, provided the desired compound. To a solution of piperazine (2 g, 0.023 mol) in 10 mL of ethanol added a solution of 4-nitrobenzyl bromide (5 g, 0.023 mol) in 20 mL of warm ethanol. It was gently refluxed for 1 hour and stirred at room temperature for one over night. The resulting white precipitate was filtered, washed with a small amount of cold ethanol, and dried to yield 1-[4-nitrobenzyl]piperazine hydrobromide (3 g). MS m/z M+H=222, H1 --NMR (in MeOH-d4) δ=2.7 (t, 4H, piperazine), 3.25 (t, 4H, piperazine), 3.75 (s, 2H, benzyl), 7.62 (d, 2H, aromatic), 8.20 (d, 2H, aromatic). The obtained 1-[4-nitrobenzyl]piperazine hydrobromide (3 g, 9.93 mmol) was dissolved in 60 mL of 3N sodium hydroxide aqueous solution and stirred at room temperature for 30 minutes. The product was extracted with ethyl acetate (50 mL×3), and the combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate. Solvent was removed to obtain 1.7 g of 1-[4-nitrobenzyl]piperazine in 78% yield. MS m/z M+H=222, H1 -NMR (in MeOH-d4) δ=2.45 (t, 4H, piperazine), 2.90 (t, 4H, piperazine), 3.55 (s, 2H, benzyl), 7.52 (d, 2H, aromatic), 8.50 (d, 2H, aromatic).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[OH:16])[CH2:2][C:3]([CH3:5])=[CH2:4].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:16][C:7]1[CH:8]=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:6]=1[CH2:1][CH2:2][C:3]([CH3:5])=[CH2:4])(=[O:19])[CH3:18]
Reactant: C=C(C)CCc1cc(OC)c(OC)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=C(C)CCc1cc(OC)c(OC)cc1OC(C)=O

Procedure:
100 mg. of the phenol of Example 1 was combined with 2 ml. of pyridine and 1 ml. of acetic anhydride for one hour. The reaction mixture was extracted with ether and the ether extract washed sequentially with water, 1NHCl, water and saturated salt solution then dried over sodium sulfate. Upon evaporation 0.11 grams of the acetate was recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6](/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:7]([NH2:9])[CH3:8].[CH3:26][CH:27]1[CH2:33][C:32](=[O:34])[O:31][C:29](=[O:30])[CH2:28]1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6](/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:7]([NH:9][C:32]([CH2:33][CH:27]([CH3:26])[CH2:28][C:29]([OH:31])=[O:30])=[O:34])[CH3:8]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CC(N)C(/C=C/c1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CC(=O)O)CC(=O)NC(C)C(/C=C/c1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
20 mg of (1RS,2RS,3E)-2-(3,4-dichlorobenzyl)-1-methyl-4-(2-naphthyl)-3-butenylamine was dissolved in 1 ml of methylene chloride, and 10 mg of 3-methylglutaric anhydride and 4 μl of triethylamine were added thereto. The mixture was stirred at room temperature for 3 hours. A saturated sodium carbonate aqueous solution and methylene chloride were added to the reaction solution, and the mixture was stirred for 30 minutes. Then, the organic layer was collected by separation, washed with 1N hydrochloric acid and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-200, 2 g; chloroform/methanol=20/1) to obtain 16 mg (yield: 74%) of the above-identified compound as colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:5].[CH3:20][O:21]C1C=C(OC)C=CC=1C(C1C=CC=CC=1O)=O.COC1C=CC=CC=1C(O)=O.COC1C=C(OC)C=C(OC)C=1.COC1C(OC)=C(OC)C=CC=1C(C1C=CC=CC=1O)=O>>[CH3:20][O:21][C:17]1[C:2]([OH:1])=[C:3]([CH:14]=[CH:15][C:16]=1[O:18][CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:5]
Reactant: COc1ccc(C(=O)c2ccccc2O)c(OC)c1
Reactant: COc1ccc(C(=O)c2ccccc2OC)c(O)c1
Agent: COc1cc(OC)cc(OC)c1
Agent: COc1ccc(C(=O)c2ccccc2O)c(OC)c1OC
Agent: COc1ccccc1C(=O)O
Product: COc1ccccc1C(=O)c1ccc(OC)c(OC)c1O

Procedure:
According to the method of production of 2-hydroxy-4-methoxy-2'-methoxybenzphenone (4a) and 2,4 -dimethoxy-2'-hydroxybenzophenone (4b), 2.00 g 13.14 mmol) of 2-methoxybenzoic acid was reacted with 2.19 g (13.04 mmol) of 1,3,5-trimethoxy benzene to give 2.20 g (7.75 mmol) of 3, 4-dimethoxy-2-hydroxy-2'-methoxybenzophenone and 2,3,4-trimethoxy-2'-hydroxybenzophenone Then, described in example 3, 1.35 g (5.92 m mol) of 3,4-dihydroxybenzophenone as pale yellow powder was produced. The physical properties were measured and are listed below.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][C@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[CH3:19]I.[H-].[Na+].Cl>CN(C)C=O>[CH3:19][C:4]1([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:2](=[O:1])[N:6]([C@@H:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH2:5]1
Reactant: COC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (3R)-5-oxo-1-[(R)-1-phenylethyl]pyrrolidin-3-yl-carboxylate (49.5 g, 200 mmol) and methyl iodide (37.4 mL, 600 mmol) in dimethylformamide (1 L), sodium hydride (in oil; content, 55%; 11.35 g: 260 mmol) was gradually added in 5 minutes at room temperature. After stirring at room temperature for 2 hours, methyl iodide (24.9 mL, 400 mmol) and sodium hydride (in oil; content, 55%; 6.11 g; 140 mmol) were further added, and the mixture was stirred for another 4 hours. The reaction mixture was added to 0.5N hydrochloric acid (1 L) in an ice bath, and extracted with ethyl acetate (2 L+1 L). The organic layers were combined and washed with water (1 L×2) and saturated aqueous solution of sodium chloride (1 L), and dried with anhydrous sodium sulfate. After removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure. The thus obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate, 80:20→67:33→50:50→33:67) to obtain stereoisomers at position 3 of the title compound (stereoisomer A: 19.86 g (76.0 mmol, 38%) as a pale yellow oil, stereoisomer B: 20.22 g (77.4 mmol, 39%) as a pale yellow solid, and a mixture of stereoisomers A and B: 9.69 g (37.1 mmol, 19%) as a pale yellow oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:38](O)(=[O:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:38](=[O:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCCCC(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCCCCC(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 31.2 %

Procedure:
A procedure similar to that described in Example 3, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 423 mg (3.6 mmol) of hexanoic acid, to provide 364 mg of the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1O.[OH-].[K+].Cl>C(O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C:9]1[CH2:10][CH2:11][C:12](=[O:13])[C:14]=1[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC[C@H](O)/C=C/C1=C(C/C=C\CCCC(=O)O)C(=O)CC1
Temperature: 10 °C

Procedure:
A solution of racemic PGE2 (200 mg.) in 100 ml. of 50% aqueous ethanol containing 10 grams of potassium hydroxide is kept at 25° C. for 10 hours under nitrogen. Then, the solution is cooled to 10° C. and neutralized by addition of 3 normal hydrochloric acid at 10° C. The resulting solution is extracted repeatedly with ethyl acetate, and the combined ethyl acetate extracts are washed with water and then with saturated aqueous sodium chloride solution, dried, evaporated to give racemic PGB2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH2:19])=[O:12])=[CH:6][CH:5]=1)[CH3:2].[C:20]([NH:27][C@@H:28]([C:30](O)=[O:31])[CH3:29])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[C:23]([O:22][C:20](=[O:21])[NH:27][C@@H:28]([C:30](=[O:31])[NH:19][C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=1[C:11](=[O:12])[NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=1)[CH3:29])([CH3:24])([CH3:25])[CH3:26]
Reactant: CCOc1ccc(NC(=O)C2=C(N)CCCC2)cc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOc1ccc(NC(=O)C2=C(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)CCCC2)cc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 63.3 %

Procedure:
A mixture of 2-amino-cyclohex-1-enecarboxylic acid (4-ethoxy-phenyl)-amide (1.46 g, 5.60 mmol), N-Boc-D-alanine (1.06 g, 5.60 mmol), EDC (1.60 g, 8.4 mmol), HOBT (151 mg, 1.12 mmol) and 1.0 mL of N-methylmorpholine in 30 mL of methylene chloride was allowed to stir at room temperature for 28 h. Upon completion, the mixture was concentrated and 30 mL of saturated aqueous sodium bicarbonate was added. The resulting mixture was extracted with ethyl acetate (30 mL×3). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The material was purified by chromatography on a silica gel column using 30% ethyl acetate/hexane successively as the eluents to give 1.53 g of product H4. 1H NMR (400 MHz, CDCl3) δ: 12.95 (s, 1H), 7.36 (d, J=8.86 Hz, 2H), 7.25 (br s, 1H), 8.87 (d, J=8.95 Hz, 2H), 5.23 (br s, 1H), 4.13 (br s, 1H), 4.02 (q, J=7.0 Hz, 2H), 3.01 (br s, 2H), 2.37 (br s, 2H), 1.70 (m, 4H), 1.43 (s, 9H), 1.41 (dd, J=7.0, 7.0 Hz, 3H), 1.40 (obscured d, J=7.07 Hz, 3H). MS (ESI+) 432 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C:16]23[C:24](=[O:25])[N:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)[C:22](=[O:34])[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=1)=[O:4]>C1COCC1.O>[OH:4][CH2:3][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]23[C:24](=[O:25])[N:23]([C:26]4[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=4)[C:22](=[O:34])[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:35][CH:36]=1
Reactant: O=Cc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4ccccc4CO)cc3)CCCCN12
Reaction time: 0.5 h
Yield: 93438.5 %

Procedure:
NaBH4 (13.7 mg) was added to a solution of 6-[4-(2-formyl-phenyl)benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]-nonane-7,9-dione (0.178 mg) in THF (5 mL) at 0° C. After stirring for 30 minutes, the reaction mixture was diluted with water and extracted with EtOAc. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/2, Chromatotron) afforded the titled compound (167 mg). MS (m/z) 477 (M+-OH).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][NH2:10])=[S:8].[N+:12]([C:15]1[O:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13].[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].C(O)(C)C>C(O)C>[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].[N+:12]([C:15]1[O:19][C:18]([CH:20]=[N:10][NH:9][C:7](=[S:8])[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:11])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CN(C)CCCNC(=S)NN
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: CN(C)CCCNC(=S)NN=Cc1ccc([N+](=O)[O-])o1

Procedure:
N-(3-dimethylaminopropyl)hydrazinecarbothioamide (0.12 g) was reacted with 5-nitro-2-furaldehyde (0.15 g) in 5 ml ethanol at reflux for 15 minutes. The mixture was cooled and treated with methanesulfonic acid (0.055 ml) and isopropanol and stored at 4° C. to give 0.15 g of the title compound as orange needles, mp 184°-187° C.