Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:70]=[CH:69][C:53]2[NH:54][C:55]([CH:57]([NH2:68])[CH2:58][C:59]3[C:64]([CH3:65])=[CH:63][C:62]([OH:66])=[CH:61][C:60]=3[CH3:67])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:70]=[CH:69][C:53]2[NH:54][C:55]([CH:57]([NH:68][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[C:64]([CH3:65])=[CH:63][C:62]([OH:66])=[CH:61][C:60]=3[CH3:67])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(O)cc(C)c1CC(N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C(=O)NC(Cc2c(C)cc(O)cc2C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-1-(5-chloro-1H-benzimidazol-2-yl)-2-(4-hydroxy-2,6-dimethylphenyl)ethylamine in tetrahydrofuran. Yield: %; Rf value: 0.39 (silica gel: dichloromethane/ethanol=9:1); C30H31ClN4O3 (531.06); mass spectrum: (M+H)+=531/533 (chlorine isotope).
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[NH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH3:27])[CH2:21]1>C1(C)C=CC=CC=1>[CH2:26]([N:22]1[CH2:23][CH2:24][CH2:25][CH:20]([NH:19][CH:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[O:12][C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:21]1)[CH3:27]
Reactant: CCN1CCCC(N)C1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: CCN1CCCC(NC2c3ccccc3Oc3ccccc32)C1

Procedure:
A solution of 4.0 g. of 9-acetoxyxanthene and 2.36 g. of 3-amino-1-ethylpiperidine in 175 ml. of dry toluene was refluxed for 24 hours. The cooled solution was then concentrated in vacuo. The residue was chromatographed on activated magnesium silicate, eluting with ether and acetone. Concentration of the acetone fraction in vacuo and then chromatographing on silica gel with acetone, then concentrating the eluate in vacuo gave N-(N-ethyl-3-piperidinyl)-9-xanthenylamine, m.p. 47.5°-48.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[C:5]([O:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Reactant: CCOC(=O)CCc1cc(O)ccc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.65 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (0.46 g), anhydrous potassium carbonate (0.30 g) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over, anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (0.89 g, 95%) of 3-[2-ethoxy-5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 136-137° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=3[N:17]=2)=[CH:12][CH:11]=1.[C:28]1([CH3:36])[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C=O)C>[CH3:36][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=4[N:17]=3)=[CH:14][CH:15]=2)=[CH:30][CH:29]=1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CCCCC2CCOc2ccc(-c3nc4cc(C(N)=O)ccc4[nH]3)cc2)cc1
Reaction time: 16 h
Yield: 47.4 %

Procedure:
To a solution of 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide (0.10 g, 0.27 mmol) in DMF (1 mL) was added p-tolualdehyde (70 μL, 0.59 mmol), activated 4 Å molecular sieves, and NaB(OAc)3H (0.175 g, 0.82 mmol). The solution was stirred for 16 h and additional portions of aldehyde (1 equiv.) and NaB(OAc)3H (3 equiv.) were added. When HPLC monitoring indicated reaction completion, the solution was quenched with 1 N NaOH and purified by reverse phase HPLC (C18; H2O/CH3CN/0.01% TFA), providing 60 mg (48%) of product. HPLC (Method C): Rt=4.60. MS (ESI+): mass calcd. for C29H32N4O2, 468.25; m/z found, 469.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.18 (s, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.34-7.32 (m, 2H), 7.23-7.20 (m, 2H), 7.15-7.13 (m, 2H), 4.33-4.10 (m, 3H), 3.45-3.39 (m, 1H), 3.15-3.07 (m, 1H), 2.90-2.85 (m, 1H), 2.72-2.67 (m, 1H), 2.42-2.37 (m, 1H), 2.20-2.10 (m, 1H), 1.93 (br s, 1H), 1.88-1.73 (m, 2H), 1.73-1.45(m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:36]1[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(C)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 4-methylphenylboronic acid. Colorless crystals (24 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1.[Cl:17][C:18]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.CCO.[OH-].[Na+]>CO>[Cl:17][C:18]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[CH:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)=[O:16]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)c1ccc(OC2CCCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: O=C(C=Cc1cccc(Cl)c1Cl)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
4′-Tetrahydropyranyloxy-acetophenone (1.98 g, 9.0 mmol),ii 2,3-dichlorobenzaldehyde (1.93 g, 11.0 mmol), EtOH (15 mL), and MeOH (15 mL) were combined in a 100 mL round bottom flask with a stir bar. After all of the reactants were dissolved, 50% (w/v) aq. NaOH (1.0 mL, 19 mmol) was added. The flask was stoppered and stirred at room temperature for 8 h. The resulting white precipitate was filtered, washed with EtOH (1 mL, 3×), and allowed to air dry to afford 2.95 g of THP-4Al as a white powder (87% yield). The product was used without further purification. TLC: Rf=0.40 (hexane/EtOAc 4:1); Melting point: 116-118° C.; 1H NMR: (300 MHz, Acetone-d6) δ 8.15, 7.18 (AA′XX′ peak, Jaa′=Jxx′=2.5, Jax=8.4, Jax′=0.4 Hz, 2H), 8.13 (d, J=16 Hz, 1H), 8.04 (dd, J=7.9, 1.4 Hz, 1H), 7.89 (d, J=16 Hz, 1H), 7.64 (dd, J=7.9, 1.4 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 5.61 (t, J=3.0 Hz, 1H), 3.82 (ddd, J=11.5, 8.4, 2.6 Hz, 1H), 3.61 (dtd, J=11.5, 4.0, 1.3 Hz, 1H), 1.86 (m, 3H), 1.66 (m, 3H); 13C NMR: (75 MHz, DMSO-d6) δ 187.23, 161.54, 138.27, 136.06, 133.45, 132.73, 131.77, 131.48, 130.95, 128.36, 126.93, 126.31, 116.38, 96.22, 61.89, 30.14, 25.13, 18.67; IR (ATR): 2964, 1656, 1608, 1595, 1573, 1556, 1507, 1455, 1425, 1411, 1372, 1326, 1314, 1248, 1222, 1205, 1173, 1155, 1121, 1106, 1035, 1020, 961 cm−1; ESI-MS: expected, 376.1; observed, m/z 376.9 [M+H+].
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([OH:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1.CCCCCC>[O:5]1[CH:3]([CH2:1][O:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:4]1
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: ClCC1CO1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCOCC1CO1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Epichlorohydrin (74.0 g), stearyl alcohol (54.2 g) and cetyltrimethylammonium chloride (3.2 g) were dissolved in toluene (120 ml). To this solution, a 50% aqueous solution of sodium hydroxide (80 g) was added, followed by stirring at 65° C. for 30 minutes. To this mixture, hexane (80 ml) was added, followed by stirring at 65° C. for 3.5 hours. The reaction mixture was then diluted with hexane (700 ml), followed by filtration to remove the insoluble material. The resulting filtrate was concentrated under reduced pressure to yield crude 1,2-epoxy-3-octadecyloxypropane. The entire amount of this crude product and diethylene glycol (235 g) were dissolved in dioxane (350 ml). To this solution, 60% oily sodium hydride (1.20 g) was added, followed by stirring at room temperature for 30 minutes. The reaction mixture was then heated at 110° C. for 13 hours. After cooling, acetic acid (1.8 g) was added and the dioxane was distilled off under reduced pressure. The resulting residue was dissolved in a mixture of hexane-ether-water. After the organic layer was collected and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to yield crude 2-[2-[(2-hydroxy-3-octadecyloxy)propoxy]ethoxy]ethanol. This crude product was dissolved in pyridine (300 ml). To this solution, trityl chloride (82 g) was added, followed by stirring at 80° C. for 2 hours. Methanol (10 ml) was then added, followed by stirring under the same conditions as above for 30 minutes. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier 1.7 kg; developing solvent, hexane:ethyl acetate=6:1→3:1) to yield the desired compound (80.0 g).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH:7]1[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)C.[OH-].[K+]>C(O)C>[CH:14]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]([CH2:9]3)[CH:7]1[CH2:6][CH2:5][C:4]([OH:17])=[O:3])[CH2:13]2
Reactant: CCOC(=O)CCC1C2CC3CC(C2)CC1C3
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of tricyclo[3.3.1.1-3,7]decane-2-propanoic acid ethyl ester (0.011 mol, 2.68 g) in anhydrous ethanol (135 mL) was added potassium hydroxide (0.057 mol, 3.18 g) in several portions. The clear solution was heated at reflux for 1 h, cooled to ambient temperature, and concentrated. The yellow residue was partitioned with CH2Cl2 (100 mL) and water (50 mL), and the basic, aqueous phase extracted with CH2Cl2 (100 mL). The aqueous phase was re-acidified (pH 2) by the addition of 10% aqueous hydrochloric acid, and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated to provide tricyclo[3.3.1.1-3,7]decane-2-propanoic acid as a white solid (96%, 2.27 g). mp 115.5°-116° C.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:36]2[C:37]([CH:42]3CCCC3)=[N:38]OC=2C)=NC=1>>[CH:37]([NH:38][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:42])[CH3:36]
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(C3CCCC3)noc2C)nc1
Product: Cc1onc(C2CCCCC2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 4 %

Procedure:
As described for example 30d, 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (708 mg, 1.5 mmol), instead of 6-(3-cyclopentyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, was converted to the title compound (19 mg, 4%) which was obtained as a white solid after purification by chromatography (silica, 0 to 5% methanol in dichloromethane) and trituration with diisopropyl ether. MS: m/e=358.5 [M+H]+.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:50]([O:57][C:58]([N:60]1[CH2:64][CH:63]([CH2:65][O:66][C:67]2[CH:72]=[CH:71][C:70]([F:73])=[C:69]([F:74])[CH:68]=2)[CH:62]2[NH:75][CH2:76][CH2:77][CH:61]12)=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:50]([O:57][C:58]([N:60]1[CH2:64][CH:63]([CH2:65][O:66][C:67]2[CH:72]=[CH:71][C:70]([F:73])=[C:69]([F:74])[CH:68]=2)[CH:62]2[N:75]([C:7](=[O:9])[CH:2]([NH:1][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([CH3:4])([CH3:5])[CH3:6])[CH2:76][CH2:77][CH:61]12)=[O:59])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: O=C(OCc1ccccc1)N1CC(COc2ccc(F)c(F)c2)C2NCCC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.4 %

Procedure:
A solution of Boc-Tle-OH (463 mg, 2.0 mmol) in NMP (6 mL) was cooled to 0° C. and treated with HATU (758 mg, 2.0 mmol) and DIPEA (0.45 mL, 2.5 mmol). After 10 min, amine 80 (772 mg, 2.0 mmol) in NMP (6 mL) was added. The reaction mixture was allowed to warm to ambient temperature. After 16 h, the solution was diluted with EtOAc, washed successively with 1M HCl, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was diluted with ACN/water and purified by RP-HPLC (2″ Dynamax® C18, 20% ACN/water to 100% ACN over 30 min; Flow: 40 mL/min). The product-containing fractions were combined, concentrated, and extracted with EtOAc. The organic extract was washed successively with saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, and filtered. The aqueous phase was back-extracted with DCM and the combined organic extracts were concentrated to afford 81 (269 mg) as an off-white foam. 1H NMR (CDCl3, 300 MHz): δ7.37-7.28 (m, 5H), 7.02 (app q, J=9.0 Hz, 1H), 6.66 (m, 1H), 6.52 (m, 1H), 5.28 (d, J=9.6 Hz, 1H), 5.19-5.13 (m, 2H), 4.46 (m, 2H), 4.31 (d, J=9.9 Hz, 1H), 4.01-3.98 (m, 2H), 3.85-3.76 (m, 2H), 3.46-3.37 (m, 2H), 2.81 (app q, J=5.7 Hz, 1H), 2.43 (m, 1H), 2.26 (m, 1H), 1.43 (s, 9H), 0.99 (s, 9H) ppm. Mass spectrum, m/z [602.8] (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35]O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:35][C:31]3[N:30]([CH3:29])[CH:34]=[CH:33][CH:32]=3)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cccc1CO
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cn1cccc1COc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and (1-methyl-1H-pyrrol-2-yl)-methanol according to the procedure of Example 69. MS (ESI) m/z 473.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O1CCOCC1>[CH2:1]([NH:13][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CCCCCCCCCCCCN
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCNCCCCCCCCCCCC
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 35 %

Procedure:
18.54 g (100 mmol) dodecylamine (laurylamine), 6.36 g (60 mmol) Na2CO3 and 50 mg tetrabutyl ammonium iodide (TBAI) were suspended in 100 ml anhydrous DMF in a 500 ml 3-neck flask having a reflux condenser and a dropping funnel. A solution of 16.4 ml (60 mmol) 1-bromo tetradecane in 100 ml anhydrous dioxane were added dropwise at 100° C. over a period of 110 minutes and the mixture was stirred for another 3.5 hours at 100° C. (FIG. 6). The solution was filtered at a temperature as hot as possible. The crystalline solid which precipitated at 4° C. overnight, was removed and was washed with a little of cold methanol. Subsequently, the solid was re-crystallised from 200 ml methanol. 9 g of colourless leaf-like crystals were obtained which are re-crystallised from 100 ml MtBE. The crystals which precipitated at −18° C., were sucked off from a cooled frit and washed with cold MtBE. 7.94 g (21 mmol) of a colourless crystalline solid were obtained, corresponding to a yield of 35%.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[Br:13]Br>C(O)(=O)C>[Br:13][C:11]1[CH:10]=[CH:9][C:5]2[NH:6][C:7](=[O:8])[CH:2]([CH3:1])[O:3][C:4]=2[CH:12]=1
Reactant: BrBr
Reactant: CC1Oc2ccccc2NC1=O
Solvent: CC(=O)O
Product: CC1Oc2cc(Br)ccc2NC1=O
Reaction time: 8 h

Procedure:
In 56 ml of glacial acetic acid, 6 g of 2-methyl-1,4-benzoxazin-3-(4H)-one is precooled at 0° C. and mixed drop by drop with 1.9 ml of bromine in 19 ml of glacial acetic acid. It is allowed to reach room temperature and stirred for another 8 hours. The mixture is poured onto ice water, the crystals are suctioned off and washed with water. 9.3 g of crude product results, which is recrystallized from ethanol/water. 7-Bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is obtained as a by-product. As an alternative, 4-bromo-2-aminophenol can also be reacted according to the described processes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[N:9]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[OH-].[K+]>Cl.O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1)[NH2:9]
Reactant: Cc1ccc(N)cn1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: O
Product: Cc1ccc(NN)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
5-Amino-2-methyl-pyridine (9.90 g, 91.6 mmol) was dissolved in 6 N HCl (100 mL), cooled to 0° C., and vigorously stirred throughout the procedure. Sodium nitrite (6.32 g, 91.6 mmol) was dissolved in water (50 mL), this solution was added to the reaction solution. After 30 min, tin (II) chloride dihydrate (52.0 g, 230 mmol) in 6 N HCl (100 mL) was added, and the reaction slurry was stirred at 0° C. for 3 h. The pH was adjusted to pH 14 with 40% aqueous potassium hydroxide solution. EtOAc extractions (6×250 mL), drying the organics over solid magnesium sulfate, and concentration afforded 5-hydrazino-2-methyl-pyridine as a tan solid (8.0 g). This material was used directly without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH2:13][CH2:14][CH:15]2[N:20]3[CH2:21][CH2:22][CH:17]([C:18](=[O:23])[CH2:19]3)[CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C.C1COCC1>[C:7]1([CH2:13][CH2:14][CH:15]2[N:20]3[CH2:21][CH2:22][CH:17]([CH:18]([OH:23])[CH2:19]3)[CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CN2CCC1CC2CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1CN2CCC1CC2CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of LAH in diethyl ether was added a solution of 6-(2-phenylethyl)quinuclidin-3-one in THF, followed by heating under reflux for 4 hours. To the reaction mixture was added Na2SO4.10H2O, followed by stirring at room temperature for overnight. The reaction mixture was filtered, and the filtrate was then concentrated under reduced pressure to obtain 6-(2-phenylethyl)quinuclidin-3-ol as a colorless oil.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:18][CH:17]([NH:19][C:20](=[O:39])[CH2:21][NH:22][C:23](=[O:38])[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[CH2:16]1)=O)(C)(C)C>>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:21][NH:22][C:23](=[O:38])[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:35])([F:37])[F:36])[CH:25]=2)=[O:39])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CNC1

Procedure:
The title compound was prepared as colorless oil from TFA de-protection of 3-[2-(3,5-bis-trifluoromethyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butylester, as prepared in the previous step, using the procedure described in Step D of Example 1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:15])([F:14])[F:1])=[CH:6][CH:7]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)(F)F)cc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)F)cc1
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (0.73 g, colorless oil) from 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanone (0.65 g, 2.99 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][CH:6]=[N:5]1.[OH-].[Na+]>CO>[F:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=[N:5]1
Reactant: CCOC(=O)c1ccnn1CCF
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccnn1CCF
Temperature: 20 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To a solution of ethyl 1-(2-fluoroethyl)-1H-pyrazole-5-carboxylate (0.2 g) in methanol (5 ml) was added 2M sodium hydroxide (5 ml) and the mixture stirred at 20° C. for 18 h. The solvent was removed in vacuo and the residue dissolved in water (20 ml) and acidified to pH-4 using 2M hydrochloric acid then extracted with ethyl acetate (20 ml), dried over sodium sulphate and evaporated to give the title compound (0.132 g) as a white solid.