Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)O)=[O:5])[CH3:2].[NH2:23][CH:24]1[CH2:29][N:28]([CH3:30])[C:27](=[O:31])[CH2:26][CH2:25]1.Cl.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O.ClC1C=C(C=CC=1F)N>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[NH:23][CH:24]1[CH2:25][CH2:26][C:27](=[O:31])[N:28]([CH3:30])[CH2:29]1)=[O:5])[CH3:2]
Reactant: CN1CC(N)CCC1=O
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cl
Agent: Nc1ccc(F)c(Cl)c1
Product: CCOC(=O)c1ccn(C(C)C)c1C(NC1CCC(=O)N(C)C1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Step D2, but 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step E4) and 5-amino-1-methylpiperidin-2-one [1228838-10-5] (free base was made from the purchased HCl salt) were used instead of 5-bromo-2-[(4-chloro-phenyl)hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 3-chloro-4-fluoroaniline respectively to afford the title compound (diastereomeric mixture) as an off-white solid. tR: 4.31 min (HPLC 1); ESI-MS: tR=1.13/1.15 min, [M+H]+ 432/434 (LC-MS 1); TLC: Rf=0.25 (EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:40]([CH3:42])[CH3:41])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(F)cc3)c(=O)c12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(F)cc3)c(OC(C)C)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of [8-chloro-3-(4-fluorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.020 g), N,N-dimethylformamide (1.0 mL), potassium carbonate (0.020 g) and 2-iodopropane (0.050 g) was stirred at room temperature for 2 days. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 by volume) to afford title compound as a light brown oil, 0.024 g.
Reaction SMILES: C[O:2][CH:3](OC)[C@@H:4]1[O:19][CH2:18][C@H:7]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C@H:5]1[OH:6].FC(F)(F)C(O)=O.O>C(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][S:8][C@H:7]2[CH2:18][O:19][C@@H:4]([CH:3]=[O:2])[C@@H:5]2[OH:6])=[CH:11][CH:12]=1
Reactant: COc1ccc(CS[C@H]2CO[C@@H](C(OC)OC)[C@@H]2O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CS[C@H]2CO[C@@H](C=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a 0° C. solution of 0.340 g of product from Example 321 in 4 ml of methylene chloride is added a solution of 1 ml of trifluoroacetic acid and 0.266 ml of water. The reaction is stirred at room temperature for 1 hour, concentrated in vacuo, extracted with methylene chloride, neutralized with 1 g of sodium bicarbonate, filtered and concentrated in vacuo to give after chromatography (Silica gel: 50-60% ethyl acetate/hexane) 0.222 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][O-].[Na+].[C:17](OC(=O)CC)(=O)[CH2:18]C>CO>[CH3:14][O:9][C:7](=[O:8])[C:6]1[CH:13]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=1[NH:11][C:10](=[O:12])[CH2:17][CH3:18]
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Reactant: CCC(=O)OC(=O)CC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)Nc1ccc(O)cc1C(=O)OC
Yield: 680 %

Procedure:
5-Hydroxy isatoic anhydride (17.9 g, 0.1 mol) was heated to reflux with sodium methoxide (0.5 g, 0.01 mol) in methanol (600 mL) for 1 h. The reaction mixture was cooled on icebath, propionic anhydride (15.0 g, 0.115 mol) was added and then the mixture was heated to reflux for 0.5 h The mixture was then concentrated under reduced pressure to app. one-half of its original volume and left over night in a refrigerator. The resulting precipitate was collected, washed with methanol and dried to give the title compound as pure white crystals (15.2 g, 0.068 mol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:19])[CH2:17]Br)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CC(=O)CC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:17][C:16]([C:15]1[CH:20]=[CH:21][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)=[O:19]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)COc2cccc(OC)c2)cc1
Temperature: 80 °C

Procedure:
In a one liter round-bottom flask, fitted with a condenser and nitrogen inlet, were added 3-methoxyphenol (12.4 g, 0.1 mole), 4-methoxyphenacyl bromide (22.9 g, 0.1 mole), potassium carbonate (17.3 g, 0.125 mole) in 100 ml of 2-butanone. This mixture was heated to 80° C. and was maintained at this temperature for about four hours. The progress of the reaction was monitored by thin layer chromatography (silica gel, 9:1 toluene:ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(OCC)(=O)C.[N:15]#[C:16]Br.[OH-].[Na+]>O>[NH2:15][C:16]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1O
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc2ccccc2o1
Temperature: 45 °C
Reaction time: 12 h
Yield: 88.2 %

Procedure:
A mixture of 2.5 g 2-aminophenol (6-1) and 20 ml ethyl acetate was heated to 45° C. 3 g of cyanogen bromide was added to the mixture. The mixture was stirred at 45-50° C. for 12 hours. After cooling to room temperature, 1.5 g of sodium hydroxide in 15 ml of water was added. The organic layer was separated and washed with brine until neutral pH. Toluene (5 ml) was added and the solvent was removed to yield 2.71 g (88%) 2-aminobenzoxazol (6-2).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:6][CH:5]=1.[K].[OH-]>C(O)C.O>[CH2:14]([S:13][CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][CH:6]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCSCCOc1ccc(C(=O)OC)cc1
Agent: [K]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCSCCOc1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 94.1 %

Procedure:
A solution of 4-[2-(dodecylthio)ethoxy]benzoic acid methyl ester (11.29 g, 29.7 mmol) in 80% aqueous ethanol (100 ml) was treated with a solution of potassium, hydroxide, (6.0 g, 0.107 mol) in water (15 ml) and the resulting mixture was heated at 80° C. for 2 h. The solvent was then concentrated in vacuo and the residue was treated with 150 ml of 1N aqueous hydrochloric acid. The aqueous phase was extracted three times with dichloromethane and the combined organic extracts were washed with brine, dried (magnesium sulfate) and evaporated. The residue was recrystallized from dichloromethane to give 10.24 g (94%) of the title material as white needles: mp 97-98° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([Cl:48])[C:39]=1[C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([Cl:48])[C:39]=1[C:40]([N:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:18]=1)=[O:41]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: c1cc(CNc2ccc(OCCN3CCCC3)cc2)cc(OC2CCCCO2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1c(Cl)cc(Cl)cc1Cl)N(Cc1cccc(OC2CCCCO2)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.050 g, 0.13 mmol) in 0.5 mL methylene chloride was added triethylamine (0.035 mL, 0.25 mmol), 2,4,6-trichlorobenzoyl chloride (0.061 g, 0.25 mmol), and catalytic N,N-dimethylaminopyridine (DMAP). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated to give the title compound of Step A which was used in Step B without further purification. MS 605.4 (M+1)+
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]2[N:7]=[CH:8][N:9]([C:42]=2[N:43]=[CH:44][N:45]=1)[C@@H:10]1[O:41][C@H:15]([CH2:16][O:17][C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C@@H:13]([OH:14])[C@H:11]1[OH:12])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:55]([CH2:57][CH2:58][O:59][CH2:60]Cl)#[N:56].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([NH:4][C:5]1[C:6]2[N:7]=[CH:8][N:9]([C:42]=2[N:43]=[CH:44][N:45]=1)[C@@H:10]1[O:41][C@H:15]([CH2:16][O:17][C:18]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C@@H:13]([OH:14])[C@H:11]1[O:12][CH2:60][O:59][CH2:58][CH2:57][C:55]#[N:56])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(C)=O)ncnc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(C)=O)ncnc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
N6-Acetyl-5′-O-(4,4′-dimethoxytrityl)adenosine (22.0 g, 36.0 mmol) was dissolved in 170 mL of 1,2-dichloroethane, and 16.3 g of diisopropylethylamine (126 mmol) was added, and 12.1 g of dibutylstannyl dichloride (39.7 mmol) was added subsequently. Then, the reaction was performed at room temperature for 1 hour. Then, the reaction solution was heated up to 80° C., and 4.30 g of chloromethyl 2-cyanoethyl ether (36.0 mmol) was added dropwise, and the solution was stirred for 30 minutes. After the reaction completed, the reaction solution was added to an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by silica gel column chromatography to obtain N6-acetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl) adenosine (7.47 g, yield 33%).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:27][CH2:26]4)[N:23]=[CH:24][C:10]=13)[CH2:2]2.C(N(CC)CC)C.ClC(Cl)(O[C:47](=[O:53])OC(Cl)(Cl)Cl)Cl.[CH:55]1([NH2:58])[CH2:57][CH2:56]1>ClCCl>[CH:55]1([NH:58][C:47]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:13]3[N:12]=[C:11]4[N:22]([CH:25]5[CH2:26][CH2:27][N:28]([CH2:31][C:32]([F:34])([F:35])[F:33])[CH2:29][CH2:30]5)[N:23]=[CH:24][C:10]4=[C:9]([N:3]4[CH2:4][CH:5]5[O:8][CH:1]([CH2:7][CH2:6]5)[CH2:2]4)[N:14]=3)=[CH:16][CH:17]=2)=[O:53])[CH2:57][CH2:56]1
Reactant: NC1CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(CC(F)(F)F)CC4)c3n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(CC(F)(F)F)CC4)c3n2)cc1)NC1CC1

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (47 mg, 0.097 mmol) in dichloromethane (3 mL) was treated with triethylamine (0.13 mL), followed by triphosgene (14 mg, 0.048 mmol). After the passage of five minutes, cyclopropylamine (0.14 mL) was added. The mixture was concentrated to dryness under reduced pressure. The resultant residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Gemini 21 mm×100 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 75% acetonitrile over 30 minutes. After the concentration of fractions under reduced pressure, 1-cyclopropyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)urea (67 mg) was obtained. MS (ES+): 571.5, 572.5 (M+H)+
Reaction SMILES: C1(COC([N:11]2[CH2:16][CH2:15][C:14]([F:36])([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28]OS(C)(=O)=O)[O:25][C:24]4=[O:34])=[CH:19][C:18]=3[F:35])[CH2:13][CH2:12]2)=O)C=CC=CC=1.[OH-].[NH4+].[N:39]1C=CC=[CH:41][CH:40]=1.C(OC(=O)C)(=[O:47])C>C(O)(C)C.C(#N)C.C(Cl)Cl>[O:34]=[C:24]1[N:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3([F:36])[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)=[C:18]([F:35])[CH:19]=2)[CH2:27][C@H:26]([CH2:28][NH:39][C:40](=[O:47])[CH3:41])[O:25]1
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3(F)CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3(F)CCNCC3)c(F)c2)C(=O)O1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-4-fluoro-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step 4, 0.190 g) and concentrated aqueous ammonium hydroxide (2 mL) in isopropanol (1 mL) and acetonitrile (2 mL) is placed in a sealed tube and immersed in an oil bath maintained at 95° C. for 18 hrs. The mixture is then diluted with methylene chloride (20 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude 5-aminomethyl-2-oxazolidinone intermediate (Rf=0.13 by TLC, methanol/chloroform, 5/95). A solution of this intermediate and pyridine (0.088 mL) in dry methylene chloride (3.6 mL) under N2 is treated with acetic anhydride (0.051 mL), and the resulting solution is stirred at ambient temperature for 18 hrs. The mixture is then diluted with methylene chloride (10 mL), washed with water (5 mL), saturated aqueous sodium bicarbonate (5 mL) and saline (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude acetamide intermediate which, after being combined with approx. 1.5 g of crude product from previous reaction workups, is chromatographed on silica gel (230-400 mesh, 150 g), eluting with a gradient of methanol/methylene chloride (1/9/90-1/4/95), and those fractions having an Rf=0.19 by TLC (triethylamine/methanol/chloroform, 1/9/90) are pooled and concentrated to give the title compound, mp 163-165° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][O:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH3:12][N+:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH3:1].[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([OH:16])(=[O:15])=[O:13])=[CH:18][CH:19]=1
Reactant: Cc1ccc2ccccc2n1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1ccc2ccccc2[n+]1C

Procedure:
2-Methyl-quinoline (71.5 pbw) and methyl-p-toluenesulfonate (102.3 pbw) are heated for about 10 minutes at 100° C. An exothermic reaction sets in, in which the mixture is heated to 180.C. After another 10 minutes the mixture is poured onto acetone, filtered with suction, washed with acetone and dried.
Reaction SMILES: C([SiH](CC)CC)C.[C:8]1([C:14]2[CH:28]=[CH:27][C:17]([C:18]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=O)=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>FC(F)(F)C(O)=O.O>[C:8]1([C:14]2[CH:28]=[CH:27][C:17]([CH2:18][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(-c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)CCCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
Triethylsilane (32.62 ml) was added in one portion to a stirred solution of ethyl 3-(4-phenylbenzoyl)propanoate [(2), 25.06 g] in trifluoroacetic acid (71.5 ml) and the resulting mixture was stirred at room temperature for about 20 hours. The resulting clear dark orange solution was diluted with water and extracted with ether. The extracts were washed with aqueous sodium bicarbonate (x2) and then water (x2), dried and concentrated to give a mobile brown liquid. Triethylsilane remaining in this liquid was removed by Kugelrohr evaporative distillation at 110° C. and a pressure of ca. 1 mmHg to leave crude ethyl 4-(4-phenylphenyl)butanoate (21.20 g) as a brown oil. (Compare method of C. T. West, S. J. Donnelly, D. A. Kooistra and M. P. Doyle, J. Org. Chem., 1973, 38, 2675).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][CH:8]([CH3:15])[CH2:9][CH2:10][P+](C)(C)C.[Cl:16][CH2:17][CH2:18][C@H:19]([CH3:22])[CH:20]=O.CN(C)C=O>CCOCC>[Cl:16][CH2:17][CH2:18][C@H:19]([CH3:22])/[CH:20]=[CH:10]\[CH2:9][CH:8]([CH3:15])[CH3:7]
Reactant: CC(C)CC[P+](C)(C)C
Reactant: C[C@H](C=O)CCCl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)C/C=C\[C@@H](C)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
23.5 ml of n-butyllithium (about 2-M in n-hexane) are added dropwise under argon to a suspension of 20.4 g of 3-methylbutyl-trimethylphosphonium bromide in 80 ml of dry ether, a reaction temperature of about 20° being adhered to by slight cooling. Thereafter, the mixture is stirred at room temperature for a further 2 hours. The mixture is cooled to -10° and a solution of 5.4 g of (S)-4-chloro-2-methylbutyraldehyde in 5 ml of dry ether is added thereto. The separated precipitate is stirred for one hour without cooling bath, whereupon 100 ml of dimethylformamide are added dropwise at room temperature. The mixture is stirred at room temperature for 16 hours, hydrolysed on ice and extracted with ether. The ether phase is washed with water, dried and concentrated under reduced pressure. The residue is purified by adsorption on silicagel as well as on neutral aluminium oxide of the activities III and II (elution agent: n-hexane). After distillation under reduced pressure (13 mm Torr/90°), there are obtained 4.13 g (53%) of (S)-cis-1-chloro-3,7--dimethyl-4-octene. [α]D20 =+32.6° (2.15% in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH:29]=[C:28]([CH2:40][CH3:41])[N:27]=1.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:29]=[C:28]([CH2:40][CH3:41])[N:27]=1
Reactant: CCc1cc(NCCCCCCO)nc(Cl)n1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)OCCCCCCNc1cc(CC)nc(Cl)n1
Yield: 38.2 %

Procedure:
In 10 ml of dichloromethane were dissolved 0.70 g of dl-5-chloro-6-ethyl-4-(6-hydroxyhexyl)aminopyrimidine and 0.30 g of ethyl chloroformate, and under stirring, 0.40 g of triethylamine and a catalytic amount of 4-dimethylaminopyridine were added to the solution and the mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane and washed with water. Then, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; toluene:ethyl acetate=4:1) to give 0.30 g of the title compound as pale yellow oily product. nD18.7 1.5138.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C@@H:9]2[CH2:19][CH2:20][C@@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[OH:22])=[N:6][CH:7]=1.[OH:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C@@H:21]([OH:22])[CH2:20][CH2:19][C@@H:9]2[C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([OH:30])[CH:36]=4)=[CH:7][N:6]=3)[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]2=[O:18])=[CH:24][CH:25]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(Br)cn2)N1c1ccccc1
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(O)c3)cn2)N1c1ccccc1
Yield: 86.6 %

Procedure:
(3R,4S)-4-(5-Bromopyridin-2-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (23 mg, 0.051 mmol) was coupled with 3-hydroxyphenyl boronic acid (9.2 mg, 0.067 mmol) under standard Suzuki conditions illustrated by Example 42. Purification by chromatography (4 g silica gel, 15% to 100% ethyl acetate-hexane) afforded (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)pyridin-2-yl]-1-phenylazetidin-2-one (20.7 mg, 87% yield) as a clear film; Rf 0.14 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 8.88 (d, J=2.2 Hz, 1H), 7.88 (dd, J=8.2, 2.3 Hz, 1H), 7.86-7.80 (m, 1H), 7.39-7.22 (m, 7H), 7.12-7.02 (m, 3H), 6.96 (t, J=8.7 Hz, 2H), 6.96-6.91 (m, 1H), 4.97 (d, J=2.3 Hz, 1H), 4.76-4.72 (m, 1H), 3.28-3.22 (m, 1H), 3.20 (br s, 1H), 2.17-1.90 (m, 4H), 1.80 (br s, 1H) ppm; MS [M+H]+ 469.0.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([CH3:19])[N:14]1[CH2:20][C:21]([NH:23][CH:24]([CH3:28])[C:25]([OH:27])=[O:26])=[O:22].O[N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.ClCCl.O>[O:36]=[C:31]1[CH2:32][CH2:33][C:34](=[O:35])[N:30]1[O:26][C:25](=[O:27])[CH:24]([NH:23][C:21](=[O:22])[CH2:20][N:14]1[CH:15]([CH3:19])[CH2:16][CH2:17][CH2:18][CH:13]1[CH3:12])[CH3:28]
Reactant: CC(NC(=O)CN1C(C)CCCC1C)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(NC(=O)CN1C(C)CCCC1C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.75 g (25 mMol) p-toluenesulphonic acid were heated under reflux for 1 h in 20 ml toluene using a water separator. After having evaporating the solvent, 6.30 g (25 mMol) 2-[2-(2,6-Dimethyl-piperidin-1-yl) acetylamino]-propanoic acid (27), 2.88 g (25 mMol) N-Hydroxysuccinimide and 5.15 g (25 mMol) N,N′-Dicyclohexylcarbodiimide were added to the residue dissolved in 100 ml dichloromethane. The reaction mixture was stirred for 16 h at room temperature. The solution was filtered and the filtrate was evaporated in vacuo to dryness. The product was recrystallised from diisopropylether.