Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc(Sc2ccccc2)s1
Yield: 48 %

Procedure:
A suspension of 2-bromo-1,3-thiazole-5-carboxylic acid ethyl ester (1.5 g, 6.15 mmol, 1 eq) and K2CO3 (1.7 g, 12.3 mmol, 2 eq) in EtOH (60 mL) is cooled in an ice bath, and thiophenol (0.631 mL, 6.15 mmol, 1 eq) is added. The reaction is monitored by HPLC until the starting material is consumed. The reaction mixture is filtered (to remove a solid by-product), and the solvent is removed in vacuo. The crude mixture is purified by silica gel chromatography using a Biotage Flash 40S column using 2% EtOAc in hexanes to afford the product as an oil (0.784 g, 46%). MS (ESI) for C12H11NO2S2m/z 266.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([O:14][C:15](=[O:21])[CH:16]=[CH:17][N:18]([CH3:20])[CH3:19])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([C:16](=[CH:17][N:18]([CH3:20])[CH3:19])[C:15]([O:14][CH2:12][CH3:13])=[O:21])=[O:5]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CCOC(=O)C=CN(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)ccc1F
Temperature: 90 °C
Reaction time: 6.5 h
Yield: 11.3 %

Procedure:
A solution of 2,5-difluorobenzoyl chloride (5.26 g, 29.8 mmol) in toluene (100 mL) was treated with ethyl-3-(dimethylamino)-2-propenoate (5.27 g, 36.8 mmol), followed by triethylamine (5.9 mL, 42.5 mmol). The mixture was stirred at 90° C. for 6.5 h then allowed to cool, and the precipitate removed by filtration. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash chromatography (silica gel, 50-100% diethyl ether in petroleum ether [b.p. 40-60° C.]) to give the title compound as a yellow oil (0.95 g); ESMS m/z 284.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].Cl.[CH3:31][NH:32][CH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([N:32]([CH3:33])[CH3:31])=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CNC
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Agent: Cl
Product: CN(C)C(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(Cl)cc3Cl)cc1CCO2

Procedure:
2-[(2,4-Dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and dimethylamine hydrochloride salt were reacted in the general amide coupling procedure to give 288. NMR: (CDCl3): 2.73-3.04 (6H, br m), 2.95-3.00 (2H, m), 3.29 (3H, s, Me), 4.17-4.20 (2H, m), 6.79 (1H, s, Ar), 6.93 (1H, d, J 8.3, Ar), 7.19-7.29 (3H, m, Ar) and 7.47-7.48 (2H, m, Ar). MS: (ESI+) MH+=475.04
Reaction SMILES: CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C.[C:31]([O:35][C:36]([N:38]1[CH2:42][C@@H:41]([C:43](=[O:53])[NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]#[N:52])[CH:46]=2)[C@H:40]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([C:60](O)=[O:61])[CH:55]=2)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[CH3:63][N:64]1[CH2:69][CH2:68][C:67]2[N:70]=[C:71]([NH2:73])[S:72][C:66]=2[CH2:65]1>CC(N(C)C)=O.O>[C:31]([O:35][C:36]([N:38]1[CH2:39][C@@H:40]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([C:60](=[O:61])[NH:73][C:71]3[S:72][C:66]4[CH2:65][N:64]([CH3:63])[CH2:69][CH2:68][C:67]=4[N:70]=3)[CH:55]=2)[C@H:41]([C:43](=[O:53])[NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]#[N:52])[CH:46]=2)[CH2:42]1)=[O:37])([CH3:33])([CH3:34])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)Nc2cccc(C#N)c2)[C@H](c2cccc(C(=O)O)c2)C1
Reactant: CN1CCc2nc(N)sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1CCc2nc(NC(=O)c3cccc([C@@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C(=O)Nc4cccc(C#N)c4)c3)sc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
Add N-(-3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.10 g, 0.52 mmol), followed by hydroxybenzotriazole (0.07 g, 0.52 mmol) and N,N-diisopropylethyl amine (0.18 mL, 1.00 mmol) to a solution of trans-3-(3-carboxy-phenyl)-4-(3-cyano-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.17 g, 0.39 mmol) in dimethylacetamide (5 mL). Stir the mixture at room temperature for 1 h then add 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine (0.08 g, 0.50 mmol) and heat the mixture to 50° C. with stifling overnight. Cool the reaction to room temperature and dilute with water causing a solid to precipitate from solution. Collect the formed solid by filtration, wash with water and dry on the filter pad to provide 0.23 g (quant.) of trans-3-(3-cyano-phenylcarbamoyl)-4-[3-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[C:35]1(CO)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3)c2cc1OC
Yield: 89.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, phenylmethanol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (130 mg, yield 82%)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[NH3:26]>CO>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH2:26])[S:8]1(=[O:25])=[O:24]
Reactant: N
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccc(F)cc1F
Solvent: CO
Product: NCCOCCN1c2ccccc2N(c2ccc(F)cc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.53 g, 1.2 mmol) was treated with 7N ammonia in methanol to give 2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}ethanamine which was treated with 1N hydrochloric acid in ether to afford its hydrochloride salt as a white solid (0.042 g, 8.6%). MS (ES) m/z 369.9 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
To a solution of 4-hydroxybenzophenone (200 mg, 1 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (70 mg, 1.75 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (358 mg, 1 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (210 mg, 54%).
Reaction SMILES: [IH:1].[NH:2]1[CH2:6][CH2:5][N:4]=[C:3]1[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9]O.S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[IH:1].[Cl:15][CH2:9][C:8]([NH:7][C:3]1[NH:2][CH2:6][CH2:5][N:4]=1)([CH3:12])[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CO)NC1=NCCN1
Agent: I
Solvent: ClC(Cl)Cl
Product: CC(C)(CCl)NC1=NCCN1

Procedure:
In a 1 L three necked round bottom flask, 48.26 g (0.169 mol) of 2-(4,5-dihydro-1H-imidazol-2-ylamino)-2-methyl-propan-1-ol hydroiodide was dissolved in 400 mL of chloroform. To this, 15 mL (24.46 g, 0.206 mol) of thionyl chloride was added dropwise at room temperature. The reaction was then refluxed for 36 hours after which the solvent was removed by vacuum. The product retained too much solvent after this to afford a yield calculation. NMR 3.56 (s, 4H), 3.35 (m, 2H), 1.28 (d, 6H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:13][CH2:14][N:15](C(C)C)C(C)C.Cl.C(N)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:14]([NH:15][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[CH3:12])[CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C(=O)O)c1ccc(I)cc1
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCNC(=O)C(C)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.97 g (7.14 mmol) 2-(4-Iodo-phenyl)-propionic acid (111.1) and 1.25 mL (7.14 mmol) DIPEA are added to 582 mg (7.14 mmol) ethylamine hydrochloride in 70 mL DCM. 1.64 g (8.57 mmol) N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 194 mg (1.43 mmol) 1-hydroxy-7-azabenotriazole are added at 0° C. Subsequently, cooling is removed and the mixture is stirred for 20 h at rt. After that time, the mixture is washed with water and brine, dried over sodium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silica gel; heptane:EtOAc 50:50).
Reaction SMILES: [C:1]([O:4][CH:5]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[CH:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16](C(=O)C)[C:15]2=[O:26])[CH2:10][CH2:9]1)[CH3:7])(=[O:3])[CH3:2].Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.O>C(Cl)(Cl)Cl.CO>[C:1]([O:4][CH:5]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[CH:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:26])[CH2:10][CH2:9]1)[CH3:7])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(OC(C)=O)C(C)N2CCC(n3c(=O)n(C(C)=O)c4ccccc43)CC2)cc1OC
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(OC(C)=O)C(C)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1OC
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 85.9 %

Procedure:
In this Example, 0.7 g of 1-[3-acetoxy-3-(3,4-dimethoxyphenyl)-2-propyl]-4-(3-acetyl-2-keto-1-benzimidazolinyl)-piperidine is dissolved in a mixture of 2 ml of chloroform and 1 ml of methanol. To the solution is added 0.7 g of magnesium perchlorate and the mixture is stirred at room temperature for 2 minutes. Water is added to the reaction solution and the mixture is stirred. The chloroform layer is recovered and washed 2 times with water. The washed solution is dried and chloroform is distilled away. The resulting residue is recrystallized from dioxane to obtain 550 mg of 1-[3-acetoxy-3-(3,4-dimethoxyphenyl)-2-propyl]-4-(2-keto-1-benzimidazolinyl)-piperidine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([NH:12]C(=O)OC(C)(C)C)[CH:6]2[OH:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:12][CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[CH:6]1[OH:11]
Reactant: CC(C)(C)OC(=O)NC1Cc2c(F)cccc2C1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1Cc2c(F)cccc2C1O
Yield: 65.3 %

Procedure:
To a solution of 1,1-dimethylethyl (4-fluoro-1-hydroxy-2,3-dihydro-1H-inden-2-yl)carbamate (0.30 g, 1.1 mmol) in CH2Cl2 (10 mL) was added TFA (1 mL), and the solution was heated to reflux. The solution was immediately cooled and concentrated in vacuo. The residue was taken up in MeOH and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo to give 0.12 g (64% yield) of 2-amino-4-fluoro-2,3-dihydro-1H-inden-1-ol, which was used without further purification for the subsequent reductive amination.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[N:12][C:11]=3[C:4]=2[N:3]=1.S(=O)(=O)(O)O.O[Li].O.[N+:25]([O-])([OH:27])=[O:26]>C(#N)C>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]2[C:11](=[C:4]3[C:5](=[CH:8][C:9]=2[N+:25]([O-:27])=[O:26])[CH:6]=[CH:7][C:2]([CH3:1])=[N:3]3)[N:12]=1
Reactant: Cc1ccc2ccc3ccc(C)nc3c2n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Li]O
Solvent: O
Solvent: CC#N
Product: Cc1ccc2cc([N+](=O)[O-])c3ccc(C)nc3c2n1
Temperature: 0 °C
Reaction time: 192 h
Yield: 34 %

Procedure:
Neocuproine hydrochloride, hemihydrate (25.0 g, 99 mmol) was dissolved in 100 mL of concentrated nitric acid. 200 mL of concentrated sulfuric acid was added, and the reaction was heated at reflux for 2.5 hours, and then allowed to stand at room temperature for 8 days. The reaction mixture was then gradually added to a mixture of about 3 Kg of ice and 351 g (8.8 mole) of LiOH·H2O, while stirring with a glass rod. During the neutralization procedure, ice was added as necessary so that unmelted ice was always present during the neutralization, and the neutralization reaction was also simultaneously cooled by an acetone/ice bath. After the addition was completed, the pH of the reaction mixture was 12. The aqueous mixture was extracted two times with methylene chloride, first with 1000 mL, and then with 400 mL. The methylene chloride fractions were combined, and extracted once with 500 mL of distilled H2O. The methylene chloride phase was concentrated to a residue, and triturated with 500 mL of acetonitrile. The solid was filtered, washed with acetonitrile, and dried under vacuum to give 10.3 g of cream yellow solid, which was dissolved in 100 mL of refluxing acetonitrile, allowed to crystallize at room temperature, and was filtered to give 8.5 g (34%) of cream-yellow crystals, mp 184°-186° C. FDMS (m/e) 253M. Anal. calcd for C14H11N3O2 ·0.25 H2O: C, 65.23; H, 4.50; N, 16.30. Found: C, 65.57; H, 4.45; N, 16.27. The NMR and IR spectra were consistent with the assigned structure and the product was homogeneous by TLC.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10].C(O[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)CCCCCCC>C(Cl)(Cl)Cl.CCCCCC>[CH2:4]([C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:18][C:4]3[CH:5]=[CH:6][C:7]([C:8](=[O:17])[CH:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH3:10])=[C:2]([OH:1])[CH:3]=3)=[O:39])=[CH:41][CH:42]=2)=[CH:32][CH:33]=1)[CH2:3][CH2:2][CH2:7][CH2:8][CH2:9][CH2:11][CH3:12]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CC(C(=O)c1ccc(O)cc1O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)C(C)c4ccccc4)c(O)c3)cc2)cc1

Procedure:
600 mg (2.5 millimols) of the thus obtained 3-hydroxy-4-(1-oxo-2-phenylpropyl)phenol was reacted with 830 mg (2.4 millimols) of 4-(4'-octyloxyphenyl)benzoic acid chloride, similar to the procedure as described in Preparation Example 2, to obtain 960 mg of a crude product. The crude product was refined through silica gel column chromatography while using a mixed solvent of chloroform/hexane (50/50) as the eluent. The refined product was recrystallized from a mixed solvent of chloroform/ethanol (20/80) to obtain 153 mg of 3-hydroxy-4-(1-oxo-2-phenylpropyl)phenyl 4-(4'-octylphenyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@:11]12[CH2:28][CH2:27][C@H:26]3[C@@H:16]([CH2:17][CH2:18][C@@H:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20]4)[C@@H:15]1[CH2:14][CH2:13][C@@H:12]2[NH2:29].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:29][C@H:12]2[CH2:13][CH2:14][C@H:15]3[C@H:16]4[C@H:26]([CH2:27][CH2:28][C@:11]23[CH3:10])[C@:24]2([CH3:25])[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17]4)=[CH:4][CH:3]=1
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](N)CC[C@@H]12
Reactant: O=Cc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCc3ccc(Cl)cc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorobenzaldehyde (0.464 g) , 5α-androstan-17β-amine (4.40 g) , glacial acetic acid (0.99 g), sodium cyanoborohydride (0.21 g) and tetrahydrofuran (5 ml) were added to methanol (11 ml). The resulting mixture was warmed to dissolve the solid in solution and allowed to stir overnight at room temperature. Excess solvent was removed under reduced pressure. Water was added and made basic (pH 9) with 50% aqueous NaOH. The mixture was extracted with ether and the organic layer became cloudy. Celite was used to filter the organic layer. The aqueous layer was washed with ether and the combined organic layers were dried (NaSO4), filtered and concentrated. The crude solid was mixed with 10 g of flash silica gel and dissolved in ethyl acetate. The solvent was removed and the silica was poured on top of the chromatographic column. The compound was eluted with 50% ethyl acetate-hexane. The title compound was obtained as a solid which was recrystallized from acetone (0.364 g) mp 101°-102° C. (PLA2, diabetes)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH2:23].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH3:22][NH:23][C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:19]
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a crude solution of intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜666 mL, ˜121.5 mmol) was added 2.0 M methylamine (95 mL, 190 mmol, in THF) and T3P (50 wt % solution in EtOAc, 96.6 mL, 152 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 300 ml of 1N NaOH and 400 mL of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×500 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 75L Biotage™ column, eluting with gradients of 5%, 8%, 10%, 15% MeOH/CH2Cl2 with 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (18.9 g, 48% yield). Rf=0.35 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C17H23ClN2O2, 322.2, found, 323.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.47-7.45 (m, 2H), 7.33 (dd, J=7.9, 1.7 Hz, 1H) 5.94 (brs, 1H), 5.67 (brs, 1H), 3.75 (s, 3H), 2.85 (d, J=4.9 Hz, 3H), 2.86-2.73 (m, 3H), 2.62-2.56 (m, 4H), 2.54-2.47 (m, 2H), 1.84-1.76 (m 4H); 100 MHz 13C NMR (CDCl3) δ 177.6, 146.0, 135.5, 134.0, 130.8, 126.3, 123.6, 74.3, 56.8, 54.3, 41.1, 33.3, 26.9, 23.7.
Reaction SMILES: [C:1]([O:5][C:6](=[O:57])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28](=[O:39])[C@H:29]([O:31][CH2:32][C:33]4C=CC=CC=4)[CH3:30])[C@@H:24]([OH:40])[C@H:23]3[OH:41])=[C:15]([NH:42][CH2:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O:65][C@H](C)C(N[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3NCC(C2C=CC=CC=2)C2C=CC=CC=2)[C@H](O)[C@@H]1O)=O)C1C=CC=CC=1>>[C:1]([O:5][C:6]([NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28]([C@@H:29]([O:31][C:32](=[O:65])[CH3:33])[CH3:30])=[O:39])[C@@H:24]([OH:40])[C@H:23]3[OH:41])=[C:15]([NH:42][CH2:43][CH:44]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:14]=2)[CH2:9]1)=[O:57])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: CC(=O)O[C@@H](C)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to {(R)-1-[9-[(1R,2S,3R,4S)-4-((R)-2-benzyloxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Example 181, step 3), by substituting acetic acid (S)-1-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-ethyl ester (Example 182, step 2) for (R)-2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Example 181, step 2).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[OH:11][C:12]1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.[CH3:28][C:29]([CH3:32])([O-:31])[CH3:30].[K+].O>O1CCCC1.C(OCC)(=O)C>[C:29]([O:31][C:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1)=[O:11])([CH3:32])([CH3:30])[CH3:28]
Reactant: CC(C)(C)[O-]
Reactant: C=C(C)c1ccc(O)cc1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)c1ccc(OC(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A mixture of 5.64 g of p-hydroxy-α-methylstyrene, synthesized by base-catalyzed cleavage of 2,2-bis(p-hydroxyphenyl)propane, and 6.5 g of potassium tert-butoxide in 50 mL of dry tetrahydrofuran was stirred for 10 minutes, then a tetrahydrofuran solution of 12.7 g of di-tert-butyl dicarbonare was added. The resulting gelatinous mixture was mechanically stirred for 20 minutes, and then poured into cold water. After work-up, a crude product was obtained by evaporation of the extraction solvent (ethyl acetate). Purification was achieved by high pressure liquid chromatography with hexane as eluent to give 8.03 g (81%) of the pure p-tert-butoxycarbonyloxy-α-methylstyrene.