Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:15]([CH2:16][C:17]([O:19]C)=[O:18])[C@@H:14]([O:21]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:30][O:31]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[O:40][CH2:41][C@H:42]([NH:77][C:78](=[O:96])[CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH3:95])[C@H:43]([O:59][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)/[CH:44]=[CH:45]/[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])(=O)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>ClCCl>[C:17]([CH2:16][C@H:15]1[C@@H:14]([OH:21])[C@@H:13]([CH2:30][OH:31])[O:12][C@@H:11]([O:40][CH2:41][C@H:42]([NH:77][C:78](=[O:96])[CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH3:95])[C@H:43]([OH:59])/[CH:44]=[CH:45]/[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C@@H:10]1[OH:9])([OH:19])=[O:18]
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](CO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](CC(=O)OC)[C@H]1OC(=O)c1ccccc1)NC(=O)CCCCCCCCCCCCCCCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@H](O)[C@H](CC(=O)O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 24 h
Yield: 77.9 %

Procedure:
The compound (6) (176 mg, 130 μmol) was dissolved in dichloromethane (3 ml), followed by cooling to 0° C. Tetrabutylammonium fluoride (TBAF, 188 μl) was added and the mixture was stirred at room temperature for 24 hours. After confirming the completion of the reaction using TLC (AcOEt/Hex=1/2), the reaction mixture was concentrated under reduced pressure and the residue was dissolved in methanol (5 ml). A catalytic amount of sodium methoxide was added and the mixture was stirred at 40° C. for 24 hours. Further, water was added, followed by stirring for 24 hours. After confirming the completion of the reaction using TLC (CHCl3/MeOH/H2O=5/4/1), the reaction mixture was neutralized with an ion-exchange resin Amberlite IR-120 (H+), followed by removing the resin by filtration. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting syrup was purified by gel filtration (Sephadex LH-20, CHCl3/MeOH/H2O=5/4/0.7) to give a compound (1a) (78 mg, 90%).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:22][O:21]3)=[CH:16][C:15]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(#N)C>O>[C:1]([C:5]([N:7]1[C:8]([NH2:9])=[CH:13][CH:12]=[CH:11][CH:10]1[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:21])[CH2:22][N:38]2[CH2:39][CH2:40][N:35]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[CH:16][C:15]=1[O:23][CH:24]([CH3:25])[CH3:26])=[O:6])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)Oc1cc(C2CO2)ccc1-c1cccc(NC(=O)C(C)(C)C)n1
Reactant: c1ccc(CCN2CCNCC2)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cc(C(O)CN2CCN(CCc3ccccc3)CC2)ccc1C1C=CC=C(N)N1C(=O)C(C)(C)C
Temperature: 80 °C
Yield: 61.1 %

Procedure:
To a 25 mL round-bottomed flask equipped with condenser and N2 inlet were added 300 mg (0.847 mmol) N-t-butylcarbonyl-6-(2-isopropoxy-4-oxiranylphenyl)-pyridin-2-ylamine, 193 mg (1.017 mmol) N-phenethylpiperazine, 9 mL acetonitrile, and 0.85 mL water. The reaction was heated to 80° C. for 20 hours, cooled, and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride/ammonium hydroxide as eluant to afford 283 mg (62%) of an off-white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7](=[O:14])[C:6]=2[CH:15]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([N+:21]([O-:23])=[O:22])=[CH:13][C:8]=3[S:7](=[O:14])[C:6]=2[CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: O=S1c2ccccc2-c2ccc(Br)cc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)c1cc(Br)ccc1-2
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A flask equipped with a stirrer and a thermometer was charged with 69.8 g of glacial acetic acid and 27.9 g of 3-bromodibenzothiophene-5-oxide prepared in Example 1-1 in a nitrogen atmosphere, and cooled to 10° C. 239.8 g of concentrated sulfuric acid was added dropwise, and the resulting mixture was cooled to −2° C. Then 72.0 g of 70 wt % nitric acid was added dropwise at −2 to 8° C., and the resulting mixture was stirred at or below 5° C. for 2 hours. The reaction mass was poured into 1200 g of ice water to terminate the reaction, and stirred further. The reactant was filtered, washed with water, and dried. The resulting dry cake was washed with ethanol to obtain 31.9 g of 3-bromo-7-nitrodibenzothiophene-5-oxide. The product was subjected to elemental analysis, the results of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:13].[Cl:14]N1C(=O)CCC1=O.C(Cl)Cl.CCCCCCC>CN(C)C=O>[NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])([CH3:12])[O:7][C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[F:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)Oc2ccc(F)c(N)c2O1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CC1(C)Oc2c(Cl)cc(F)c(N)c2O1
Yield: 72.7 %

Procedure:
In a flask were placed 2.23 g (0.0122 mole) of 4-amino-2,2-dimethyl-5-fluoro-1,3-benzodioxole and 40 mL of N,N-dimethylformamide. To this solution was added in a dropwise manner a solution of 1.79 g (0.0134 mole) of N-chlorosuccinimide in N,N-dimethylformamide while maintaining the temperature at ambient conditions. The solvent was evaporated under reduced pressure, leaving a residue which was passed through a column of silica gel eluting with methylene chloride/heptane (1:1 ). Product-containing fractions were combined and the solvent evaporated, yielding 1.93 g of 4-amino-7-chloro-2,2-dimethyl-5-fluoro-1,3-benzodioxole as the residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](I)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[CH2:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>ClCCl.O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]/[C:18](=[CH:26]\[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])/[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)I)cc1
Reactant: C=C(COCCOC)C(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC/C(=C\S(=O)(=O)c1ccc(C)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of p-toluenesulphonyl iodide (19.39 g, 68.7 mmol) in dichloromethane (50 mL) at room temperature under a nitrogen atmosphere was added tert-butyl 2-(2-methoxyethoxymethyl)acrylate (9.91 g, 45.8 mmol). The mixture was stirred at room temperature for 16 hours, cooled to 0° C. and triethylamine (12.7 mL, 91.6 mmol) added dropwise. The reaction was stirred at 0° C. for 0.5 hours and at room temperature for 4 hours, diluted with distilled water (100 mL) and the layers separated. The aqueous layer was further extracted with dichloromethane (25 mL) and the combined organic extracts were washed with 1.0M aqueous hydrochloric acid solution (100 mL), 5% aqueous sodium thiosulphate solution (25 mL) and distilled water (50 mL). The dichloromethane phase was concentrated under reduced pressure to give a brown oil (17.48 g, quantitative). The crude product was purified by chromatography on silica by gradient elution with hexane/ethyl acetate mixtues to give, after combination and evaporation of appropriate fractions, the title compound as a pale yellow oil (16.2 g, 95%) which crystallised on standing, m.pt.=40°-41° C., Rf =0.3 (silica; hexane/ethyl acetate, 2:1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2]
Reactant: [H][H]
Reactant: CCNCc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCNCc1ccccc1N
Reaction time: 2 h
Yield: 99.9 %

Procedure:
N-Ethyl-N-(2-nitrobenzyl)amine (4 g, 22 mmol) in ethanol (100 ml) was treated with 10% palladium-on-carbon (180 mg) and hydrogenated at N.T.P. for 2 hours. When uptake of hydrogen had ceased the reaction was filtered through Celite and evaporated to give N-ethyl-N-(2-aminobenzyl)amine (3.3 g, 100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH3:37][N:38]([CH3:43])[C:39](=[O:42])[CH:40]=[CH2:41]>CO>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][CH2:41][CH2:40][C:39]([N:38]([CH3:43])[CH3:37])=[O:42])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C=CC(=O)N(C)C
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: CO
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCCC(=O)N(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 120 h
Yield: 43.5 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (200 mg, 0.39 mmol) was dissolved in stirred methanol (10 ml) and N,N-dimethylacrylamide (40 mg, 0.39 mmol) added. The reaction mixture was stirred for 120 hr at room temperature and then 50° C. for a further 24 hr. More N,N-dimethylacrylamide (9 mg, 0.1 mmol) was added and the reaction mixture was heated at 50° C. for 30 hr. A further portion of N,N-dimethylacrylamide (10 mg, 0.1 mmol) was added and the reaction mixture heated to 50° C. for a further 24 hr. The solvent was then removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (94:4:0.2) increasing in polarity to (93:7:0.3) to give the title compound (100 mg) as a foam. MS: 590 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[C:8]([C:17]#[C:18][Si](C)(C)C)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)C.[OH-].[Na+]>C1COCC1.CO.O>[C:17]([C:8]1[C:7]([CH:6]=[CH:5][C:4]([OH:23])=[O:3])=[CH:12][CH:11]=[C:10]([C:13]([F:16])([F:14])[F:15])[N:9]=1)#[CH:18]
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1nc(C(F)(F)F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 117.8 %

Procedure:
To a suspension of 3-(6-trifluoromethyl-2-trimethylsilanylethynyl-pyridin-3-yl)-acrylic acid ethyl ester (68 mg, 0.169 mmol) in THF (1 ml) and CH3OH (0.5 ml) was added a solution of 1N-NaOH (0.5 ml) and the mixture was stirred for 50 min at room temperature. The resulting residue was dissolved in H2O and then washed three times with EtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na2SO4 and concentrated in vacuo to give 3-(2-ethynyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (48 mg, 99%). To a suspension of N-(4-aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (83 mg, 0.298 mmol) in THF (3 mL) was added N-methylmorpholine (0.066 ml, 0.597 mmol). The mixture was stirred for 5 minutes, to which were added 3-(2-ethynyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (48 mg, 0.065 mmol) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 71.4 mg, 0.258 mmol). The mixture was stirred overnight at room temperature and was concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, 1N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by recrystallization from CH2Cl2 to give N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-ethynyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (30 mg, 32%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH:11](NC)[CH2:10]2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([CH2:33][C:34]([OH:36])=O)[CH:30]([CH3:32])[CH3:31])(=[O:28])=[O:27])=[CH:22][CH:21]=1.[CH3:37][N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.OS([O-])(=O)=O.[K+]>ClCCl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([CH:30]([CH3:32])[CH3:31])[CH2:33][C:34]([NH:38][CH2:37][CH:11]2[CH2:12][CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][CH:7]=3)[CH2:10]2)=[O:36])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)N(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Reactant: CNC1CCCN(c2ccc(C(F)(F)F)cc2)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(CC(=O)NCC1CCCN(c2ccc(C(F)(F)F)cc2)C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 53.9 %

Procedure:
A solution of crude [1-(4-trifluoromethyl-phenyl)-piperidin-3-yl]-methylamine (47.0 mg, 0.18 mmol, crude) and [(4-fluoro-benzenesulfonyl)-isopropyl-amino]-acetic acid (50.0 mg, 0.18 mmol) in dichloromethane (5 mL) at 25° C. was treated with HATU (69.1 mg, 0.18 mmol). N,N-Diisopropylethylamine (46.9 mg, 0.36 mmol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2 M aqueous KHSO4 and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (50/50 hexanes/ethyl acetate) afforded 2-[(4-fluoro-benzenesulfonyl)-isopropyl-amino]-N-[1-(4-trifluoromethyl-phenyl)-piperidin-3-ylmethyl]-acetamide (50.0 mg, 53%) as a white solid. [MH]+=516.2.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([Br:30])[CH:29]=2)(=[O:23])=[O:22])[CH:11]=1)C)(C)(C)C.C(OCC)(=O)C.[ClH:38]>C(O)C>[ClH:38].[Br:30][C:28]1[CH:29]=[C:24]([S:21]([N:12]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:10]([CH2:9][NH:7][CH3:6])=[CH:11]2)(=[O:22])=[O:23])[CH:25]=[N:26][CH:27]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(Br)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
tert-Butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrr-ol-3-yl}methyl)methylcarbamate (120 mg) was dissolved in ethanol (3 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 4 hr, the mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a solid (yield 51.3 mg, 49%).
Reaction SMILES: [CH3:1][CH:2]1CC2C(=CC=C(C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)C=2)N1.C(C1C=C(C2OC(C)=C(CCl)N=2)C=CC=1)C.C([C:46]1[CH:47]=[C:48]([C:52]2[O:53][C:54]([CH3:78])=[C:55]([CH2:57][N:58]3[C:66]4[C:61](=[CH:62][C:63]([C:67]([OH:76])([C:72]([F:75])([F:74])[F:73])[C:68]([F:71])([F:70])[F:69])=[CH:64][CH:65]=4)[CH2:60][CH:59]3[CH3:77])[N:56]=2)[CH:49]=[CH:50][CH:51]=1)C>>[CH2:1]([C:51]1[CH:46]=[CH:47][C:48]([C:52]2[O:53][C:54]([CH3:78])=[C:55]([CH2:57][N:58]3[C:66]4[C:61](=[CH:62][C:63]([C:67]([OH:76])([C:68]([F:69])([F:71])[F:70])[C:72]([F:74])([F:75])[F:73])=[CH:64][CH:65]=4)[CH2:60][CH:59]3[CH3:77])[N:56]=2)=[CH:49][CH:50]=1)[CH3:2]
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2)(C(F)(F)F)C(F)(F)F
Reactant: CCc1cccc(-c2nc(CN3c4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4CC3C)c(C)o2)c1
Agent: CCc1cccc(-c2nc(CCl)c(C)o2)c1
Product: CCc1ccc(-c2nc(CN3c4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4CC3C)c(C)o2)cc1

Procedure:
In analogy to example 51.3, from 2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole (example 51.2) and 2-(3-ethyl-phenyl)-4-chloromethyl-5-methyl-oxazole was prepared 2-{1-[2-(3-ethyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-2,3-dihydro-1H-indol-5-yl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, orange gum, MS: 499 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23].Br.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.BrCC1CCCCO1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCCO3
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(pyridin-2-ylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (90%) as a colorless solid: mp 122-123° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.59 (d, J=4.8 Hz, 1H), 7.71 (ddd, J=7.8, 7.5, 1.2 Hz, 1H), 7.31-7.15 (m, 4H), 7.03 (dd, J=7.5, 7.5 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 5.24 (d, J=15.9 Hz, 1H), 5.04 (d, J=15.9 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.28-4.20 (m, 1H), 4.14-4.05 (m, 2H), 4.02-3.94 (m, 1H), 2.22-2.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.5, 156.8, 155.4, 153.1, 149.1, 146.3, 142.1, 137.7, 132.2, 129.0, 124.0, 123.7, 123.1, 123.0, 121.9, 116.2, 109.6, 103.6, 80.5, 70.87, 70.85, 58.1, 45.9, 32.2; MS (ES+) m/z 401.0 (M+1).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]([C:14]([O:16]C)=O)[CH2:10][CH:11]([CH3:13])[CH3:12].Cl.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C1CCC(N=C=NC2CCCCC2)CC1.[NH2:39][CH2:40][C:41]([O:43]CC)=[O:42].Cl>C(Cl)(Cl)Cl>[CH3:19][S:20]([NH:8][C@@H:9]([C:14]([NH:39][CH2:40][C:41]([OH:43])=[O:42])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])(=[O:22])=[O:21]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@@H](NS(C)(=O)=O)C(=O)NCC(=O)O
Temperature: 20 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
To 13.9 ml (0.1 mol) of triethylamine in 100 ml of dry chloroform at 0° C. was added 9.1 g (0.05 mol) of D-Leu-OCH3.HCl. To this solution 4.5 ml (0.055 mol) of methanesulfonyl chloride was added at 0° C. while maintaining the reaction mixture above pH 8. After stirring at 20° C. for about 3 hours, the precipitated triethylamine hydrochloride was filtered and washed with chloroform. The filtrate was washed as follows: 1× with 50 ml 5% NaHCO3, 1× with 50 ml 10% KHSO4, 2× with 50 ml H2O. The organic layer was dried over anhydrous MgSO4, and the chloroform was evaporated under vacuum. The residual oil (Mes-D-Leu-OCH3, 10 g, 0.0446 mol) was dissolved at 10° C. in 50 ml of dry methanol containing 1.5 g of sodium. To this solution was added 3 ml of H2O and this reaction mixture was left for 72 hours at 20° C. The precipitate, Mes-D-Leu-ONa, was filtered, dried and dissolved in 50 ml of H2O. The solution was acidified to pH 2 with concentrated HCl. The solution was then extracted with chloroform, and the organic layer was dried over anhydrous MgSO4 and evaporated under vacuum. The residual oil (Mes-D-Leu-OH, 7.5 g, 0.0375 mol) was dissolved at 0° C. in 75 ml of chloroform containing 5.0 g (0.0375 mol) of Gly-OC2H5.HCl while maintaining the solution at pH 8 with triethylamine. To this solution at 0° C. was added 8.2 g (0.04 mol) of DCC in 15 ml of dry chloroform. This reaction mixture was held at 0° C. for 4 hours and then at 20° C. for 20 hours. The precipitated dicyclohexylurea was filtered and washed with CHCl3. The filtrate was washed with 30 ml 5% NaHCO3, 30 ml 10% KHSO4 and 2×30 ml of H2O, dried over anhydrous MgSO4 and evaporated under vacuum. The residual oil (Mes-D-Leu-Gly-OC2H5, 8.4 g, 0.03 mol) was dissolved in 45 ml of methanol, and to the solution was added 20 ml of 2N NaOH. The solution was held at 20° C. for 24 hours and then diluted with water to a volume of 100 ml. This solution was concentrated under vacuum to a volume of 35 ml; this mixture was washed with 15 ml of chloroform and neutralized with concentrated HCl to pH 3. The mixture was washed with 15 ml of chloroform and the water was evaporated under vacuum. The residue was dissolved in 50 ml of acetone, the precipitated NaCl was removed by filtration, and the acetone was evaporated under vacuum. Yield 47.4%; mp 122°-126° C.; [α]D20 =+4.0 (C 1; CH3OH); Anal. Calcd. for C9H18N2SO5 :C 40.59, H 6.81, N 10.52, S 12.04; Found:C 40.47, H 6.93, N 10.28, S 12.32.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].N12CCCN=C1CCCCC2.[CH:28]([C:30]([CH2:32][CH3:33])=[O:31])=[CH2:29]>O1CCCC1>[CH2:1]([C:5]1([CH2:29][CH2:28][C:30](=[O:31])[CH2:32][CH3:33])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Cc2cc(OC)ccc2C1=O
Reactant: C=CC(=O)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCC1(CCC(=O)CC)Cc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.8 %

Procedure:
A solution of crude 2-butyl-5-methoxy-1-indanone (218 mg, 1 mmol) in tetrahydrofuran (THF, 2 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.030 mL, 0.2 mmol) and ethyl vinyl ketone (EVK, 0.200 mL, 2 mmol). The resulting solution was stirred under a nitrogen atmosphere at room temperature for 16 hours, followed by heating in an oil bath at 60° C. for 24 hours. Evaporation of the solvent under vacuum left a residue that was shown by NMR to be approximately a 1:1 mixture of starting material and product. The residue was purified by preparative layer chromatography on three 0.1×20×20 cm silica gel GF plates using 5% EtOAc in CH2Cl2 as developing solvent. The product band was eluted with EtOAc to provide 2-butyl-5-methoxy-2-(3-oxo-pentyl)-1-indanone (84 mg) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([C:21]([O:23]CC)=[O:22])=[C:12]2[Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([C:21]([OH:23])=[O:22])=[C:12]2[Cl:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2cc(OC)c(OCc3ccccc3)cc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2ncc(C(=O)O)c(Cl)c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Ethyl 6-(Benzyloxy)-4-chloro-7-methoxy-3-quinolinecarboxylate (11.9 g, 32 mmol) was dissolved in a mixture of tetrahydrofurane (THF) and methanol (300 ml) in a ratio of 1:1. Aqueous sodium hydroxide (2.0 M, 65 ml, 130 mmol) was added and the mixture stirred at room temperature for 2 hours. The organic solvents were removed by rotatory evaporation and the resulting solution diluted with more water (200 ml) cooled on ice and acidified to pH 2–3 with hydrochloric acid under vigorous stirring. The precipitate was filtered off washed twice with water, twice with ethanol and ether and finally dried in vacuum at 50° C. over night to give a white solid, 11.0 g (100% yield).