Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[CH2:9]([N:4]1[CH2:5][CH2:6][CH2:7][CH:8]=[CH:2][C:3]1=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCN1CCCCC(Br)C1=O
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCN1CCCC=CC1=O
Temperature: 25 °C

Procedure:
A solution of 10.0 g (28 mmol) of 3-bromo-1-dodecylazacycloheptan-2-one and 5.1 g (47 mmol) of 2,6-lutidine was refluxed for 3 hours, then cooled to room temperature. 100 ml of toluene was added, the mixture was filtered, and the filtrate was concentrated in vacuo to yield a crude oil. Purification by flash chromatography (silica gel; 7:3 petroleum ether/ether V/V) gave the product as a colorless oil, Rf =0.38; Kuglerohr distilled at 165°-170° C./0.2 mm Hg.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:21]=[N+:22]=[N-:23])(C)C.C([Sn](=O)CCCC)CCC.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2[NH:23][N:22]=[N:21][N:16]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Oc2ccccc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccc(Cc3nnn[nH]3)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-phenoxyphenylacetonitrile (1.16 g) in anhydrous toluene (30 ml) was added trimethylsilylazide (1.1 ml) and dibutyltin oxide (0.19 g). The mixture was heated to reflux for 19 hours then allowed to cool to room temperature. The reaction mixture was then added to 1M sodium hydroxide (100 ml) and washed with diethyl ether (3×50 ml). The aqueous layer was acidified with concentrated hydrochloric acid (30 ml) then washed with 5:1 ethyl acetate/tetrahydrofuran (60 ml) and ethyl acetate (2×50 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give 5-(4-phenoxyphenylmethyl)-1H-tetrazole as a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.ClCCl>O1CCCC1.[Cl-].[Na+].O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:27]([C:26]3[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=3)=[NH:28])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(F)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: N=C(Nc1ccc2c(c1)OCCO2)c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 2.39 g (15.8 mmol) of 1,4-benzodioxan-6-amine in 30 mL of tetrahydrofuran at ambient temperature was added 8.7 mL (17.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide and the resulting solution was stirred for 20 min. To this reaction mixture was added 1.91 g (15.8 mmol) of 4-fluorobenzonitrile all at once. The resulting mixture was stirred at ambient temperature overnight and then poured into brine (50 mL) and dichloromethane (150 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate; filtered and concentrated in vacuo to yield the title compound as yellow solid which was used without further purification. LC/MS 273.2 (M+1). Step B: Ethyl 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylate. To a mixture of the compound from Step A and 4.0 g (48 mmol) of sodium bicarbonate in 50 mL of 1,4-dioxane was added 3.0 mL (24 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave the title compound as yellow solid. LC/MS 369.1 (M+1). Step C: 1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylic acid. To a solution of 2.1 g (5.7 mmol) of ethyl 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylate in 20 mL of tetrahydrofuran, 1 0 mL of water and 1 0 mL of methanol was added 2.0 mL (10 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a pale yellow foam. LC/MS 341.0 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1[O:5][C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.[O-2].[Ca+2:37].O>CO.O>[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[Ca+2:37]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Solvent: O
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)[O-])C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Pseudomonic acid (10.01 g, 20 mmole) was dissolved in a mixture of methanol/water (50 ml and 36 ml). Calcium oxide (0.78 g, 14 mmole) was added portionwise to the mixture and was stirred for 1 h. The solution was filtered, and the methanol was evaporated from the filtrate at reduced pressure to give a final volume of 30 ml. Water (20 ml) was added to the solution. Then the solution was freeze dried to obtain 9.11 grams of product.
Reaction SMILES: COC[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10]CC)=O.CO[CH2:19][N:20](CC1C=CC=CC=1)[CH2:21][Si](C)(C)C>>[CH2:19]1[NH:20][CH2:21][C@@H:7]2[CH2:8][O:10][C:13]3[CH:14]=[CH:15][CH:16]=[CH:4][C:5]=3[C@@H:6]12
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C=Cc1ccccc1COC
Product: c1ccc2c(c1)OC[C@H]1CNC[C@H]21

Procedure:
Ethyl 2-methoxymethyl-cinnamate and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine were treated, in an analogous manner as described in Examples 3A-C.
Reaction SMILES: COCOC1C=CC2OC(C3C=CC(OCOC)=CC=3)C3CC(O)CC3C=2C=1.[F:29][C@@H:30]1[CH2:50][C@H:33]2[C@@H:34]([C:43]3[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=3)[O:35][C:36]3[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][C:41]=3[C@H:32]2[CH2:31]1>>[F:29][C@H:30]1[CH2:50][C@H:33]2[C@@H:34]([C:43]3[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=3)[O:35][C:36]3[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][C:41]=3[C@H:32]2[CH2:31]1
Reactant: Oc1ccc([C@H]2Oc3ccc(O)cc3[C@H]3C[C@H](F)C[C@H]32)cc1
Agent: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(O)CC32)cc1
Product: Oc1ccc([C@H]2Oc3ccc(O)cc3[C@H]3C[C@@H](F)C[C@H]32)cc1

Procedure:
Fluorocyclopentane 47 was prepared from alcohol 27 in a manner substantially similar to fluorocyclopentane 45. HRMS(ES+) calcd for C18H18FO3: 301.1240; found: 301.1241 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][C:8]([O:21]C)=[CH:9][CH:10]=3)[C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1>O>[CH:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([OH:21])[CH:7]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][C:3]=1[OH:2]
Reactant: COc1ccc2c3ccccc3c3ccc(OC)cc3c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc2c3ccccc3c3ccc(O)cc3c2c1
Temperature: 220 °C
Yield: 93.8 %

Procedure:
A mixture of 2,11-dimethoxytriphenylene (8.8 g, 30.5 mmol) and pyridine hydrochloride (31.73 g, 274.6 mmol) was heated to 220° C. for 2 hours. The mixture was cooled and water was added. The resulting solid was filtered off, washed with water, and dried under high vacuum. 7.45 g (94%) desired product was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:32])=[C:16]([N:19]4[CH2:23][CH2:22][CH:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)[CH:17]=3)[C:12](=[O:33])[N:11]([O:34]CC3C=CC=CC=3)[C:10]2=[O:42])[CH:6]=[CH:7][CH:8]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:32])=[C:16]([N:19]4[CH2:23][CH2:22][CH:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:20]4)[CH:17]=3)[C:12](=[O:33])[N:11]([OH:34])[C:10]2=[O:42])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCC(NC(=O)OC(C)(C)C)C4)cc32)c1
Agent: [Pd]
Product: COc1cccc(-n2c(=O)n(O)c(=O)c3cc(F)c(N4CCC(NC(=O)OC(C)(C)C)C4)cc32)c1
Yield: 94.9 %

Procedure:
Using the General Method 6A, the reaction of 10% Pd/C (0.05 g) with 1-(3-methoxyphenyl)-6-fluoro-3-benzyloxy-7-(3-t-butoxycarbonylamino-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione (Example V-1, 0.15 g, 0.26 mmol) afforded 0.12 g of 1-(3-methoxyphenyl)-6-fluoro-3-hydroxy-7-(3-t-butoxycarbonylamino-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione as a solid.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C@@H:8]([OH:25])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[OH:24])[CH2:6]1)(=[O:3])[CH3:2]>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[C:1]([S:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C:8](=[O:25])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@@H]1CC[C@@]2(C)C(C1)[C@@H](O)C[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 1.5 h
Yield: 77.3 %

Procedure:
To a stirred suspension of 3α-acetylthioandrostane-6α,17β-diol (1.40 g) in CH2Cl2 (50 mL), NMNO (1.37 g), TPAP (68 mg) and powdered molecular sieves 4 Å (2.1 g) were added at room temperature. After 2 hrs NMNO (0.7 g), TPAP (34 mg) and molecular sieves 4 Å (1 g) were added again and the reaction was stirred for further 1.5 hrs. The crude product was purified by flash chromatography (SiO2, cyclohexane:EtOAc 7:3) to give 3α-acetylthioandrostane-6,17-dione (1.07 g, 76%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.99 (1H, bb), 2.55-1.20 (23H, m), 0.86 (3H, s), 0.79 (3H, s).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19](C(O)=O)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N-:25]=[C:26]=[O:27].[CH2:28]([CH:30]([NH:33][OH:34])[CH2:31][CH3:32])[CH3:29]>>[OH:34][N:33]([CH:30]([CH2:31][CH3:32])[CH2:28][CH3:29])[C:26]([NH:25][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)=[CH:21][CH:20]=1)=[O:27]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCC(CC)NO
Reactant: [N-]=C=O
Product: CCCCCCCCOc1ccc(-c2ccc(NC(=O)N(O)C(CC)CC)cc2)cc1

Procedure:
Using the general method of Compound 76, 4'-octyloxy-4-biphenylcarboxylic acid (3.26 g, 10 mmole) was converted to the isocyanate then reacted with N-(1-ethylpropyl)hydroxylamine (1.4 g, 13.5 mmole) to provide 2.0 g of the desired product as a light tan crystalline solid, m.p. 151°-152.5° C. Analysis: Calculated for C26H38N2O3 : %C, 73.20; %H, 8.98; %N, 6.57; Found: %C, 73.19; %H, 9.01; %N, 6.50.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[C:8]2[CH2:16][OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[C:23]([F:26])[C:24]=1O.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[C:23]([F:26])[C:24]=1[O:17][CH2:16][C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:10][C:9]=1[C:12]([F:13])([F:14])[F:15]
Reactant: OCc1c(C(F)(F)F)ccn1-c1ccccc1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccccc2)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [1-phenyl-3-(trifluoromethyl)-1H-pyrrol-2-yl]methanol (260 mg, 1.05 mmol, 1.00 equiv, 97%), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (281 mg, 1.22 mmol, 1.20 equiv), ADDP (642 mg, 2.56 mmol, 2.50 equiv), Bu3P (309 mg, 1.53 mmol, 1.50 equiv) and toluene (5 mL). The resulting solution was stirred overnight at 60° C. in an oil bath. The resulting mixture was then concentrated under vacuum. The resulting mixture was washed with diethyl ether (50 mL). The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to yield ethyl 3-(3,5-difluoro-4-[[1-phenyl-3-(trifluoromethyl)-1H-pyrrol-2-yl]methoxy]phenyl)propanoate as yellow oil (220 mg, 45%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=O)[O:4][N:3]=1.[CH3:9][NH2:10].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]2[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[N:10]2[CH3:9])[O:4][N:3]=1
Reactant: CN
Reactant: Cc1cc(C=O)on1
Reactant: O=C1CCC(=O)O1
Product: Cc1cc(C2C(C(=O)O)CC(=O)N2C)on1

Procedure:
3-Methyl-5-formyl-isoxazole (prepared following the procedure of Tetrahedron Lett., (32), 2961-4, 1979) is reacted with methylamine and succinic anhydride to provide 3-methyl-5-(1-methyl-3-carboxy-5-oxo-2-pyrrolidinyl)-isoxazole. This acid is converted to the ester and then selectively reduced with sodium borohydride to give the corresponding alcohol, which is reacted with methanesulfonyl chloride. The resulting mesylate is converted to the fluoromethyl isoxazole by treatment with tetrabutylammonium fluoride. Following the procedure of Example 24b, the 3-methyl-5-(1-methyl-3-fluoromethyl-5-oxo-2-pyrrolidinyl)-isoxazole is reacted with borane, and the resulting product is converted to the oxalate salt to afford the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N+:13]([O-])=O)=[CH:4][CH:3]=1>CO.[C].[Pd]>[NH2:13][C:5]1[C:6]([CH3:12])=[C:7]([C:2]([F:1])=[CH:3][CH:4]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(F)ccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1c(F)ccc(N)c1C
Reaction time: 12 h
Yield: 63 %

Procedure:
To a solution of a crudely purified product (27.7 g, 130 mmol) of methyl 6-fluoro-2-methyl-3-nitrobenzoate in methanol (260 mL) was added palladium carbon (6.00 g, 10 wt %) and the mixture was stirred under hydrogen atmosphere for 12 hr. The catalyst was filtered off through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (15.0 g, yield 63%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1>>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=3)[N:7]=2)=[CH:9][CH:10]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)Cc1ccc(-c2ccnc(Cl)n2)cc1
Reactant: COc1cc(CCN)ccc1O
Product: COc1cc(CCNc2nccc(-c3ccc(CC(C)C)cc3)n2)ccc1O

Procedure:
Intermediate 49 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 378. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1H) 7.99 (d, 2H) 7.25 (d, 2H) 6.95 (d, 1H) 6.85 (m, 1H) 6.74 (m, 2H) 5.5 (br s, 1H) 3.8 (s, 3H) 3.75 (m, 2H) 2.87 (t, 2H) 2.52 (t, 2H) 1.88 (m, 1H) 0.9 (d, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN(C)C)c4cc(Cl)ccc34)nc12
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3nn(CCN(C)C)c4cc(Cl)ccc34)nc12
Reaction time: 2 h
Yield: 77.4 %

Procedure:
2-[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)amide (50 mg, 0.085 mmol) was combined with dichloromethane (1 mL) and trifluoroacetic acid (0.19 ml, 2.56 mmol) was added. After stirring for 2 h, the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (1 mL). Ethylenediamine (0.17 ml, 2.56 mmol) was added. After stirring for 20 min, the reaction was concentrated in vacuo. The residue was triturated with water (2 mL). The precipitate was filtered, washed with water and dried to obtain 30 mg (73%) of 2-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a yellow solid. MS: (M+H)+=456; 1H NMR (DMSO-d6) δ: 9.11 (s, 1H), 8.51 (d, J=8.5 Hz, 1H), 8.44 (s, 1H), 8.45 (s., 1H), 8.20 (d, J=8.0 Hz, 1H), 8.06 (s, 1H), 7.26 (d, J=8.3 Hz, 1H), 4.62 (br. s., 2H), 4.38 (br. s., 1H), 3.50 (dd, J=16.1, 4.0 Hz, 2H), 3.28 (s, 3H), 2.81 (br. s., 2H), 2.21 (s, 6H), 1.31 (d, J=6.5 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][CH:22]([F:33])[CH2:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[F:21][CH:22]([F:33])[CH2:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:1]1[CH:2]([C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(OCC(F)F)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OCC(F)F)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-(2,2-difluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 406.06 g/mol.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][CH2:8][CH3:9].[CH:15]1([CH2:21][C@H:22]2[C@H:26]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[O:25][C:24]([CH3:34])([CH3:33])[N:23]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(CC2COC(C)(C)N2C(OC(C)(C)C)=O)CCCCC1>O1CCCC1.CO>[CH2:6]([NH:10][S:11]([CH2:14][C:27]([C@@H:26]1[O:25][C:24]([CH3:34])([CH3:33])[N:23]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C@H:22]1[CH2:21][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH2:28][CH2:29][CH2:30][CH3:31])[OH:32])(=[O:13])=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNS(C)(=O)=O
Reactant: CCCCC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Agent: CC(C)(C)OC(=O)N1C(CC2CCCCC2)COC1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: CCCCNS(=O)(=O)CC(O)(CCCC)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (4.48 ml., 11.2 mmole, 2.8 eq., 2.5M in hexane) was added to a solution of N-butylmethanesulfonamide [846 mg., 5.6 mmole, 1.4 eq., prepared as described in Example 1(a)] in tetrahydrofuran (16 ml., 0.35M) at -40° and stirred for 10 minutes. The reaction was then warmed to 0°, stirred for 30 minutes and cooled to -40°. (4S-trans)-4-(Cyclohexylmethyl)-2,2-dimethyl-5-(1-oxopentyl)-3-oxazolidinecarboxylic acid, 1,1-dimethylethyl ester (1.5 g., 3.93 mmole, 1 eq.) in tetrahydrofuran (4 ml., 1.0M) was then added. After 90 minutes at -40°, the reaction was quenched with aqueous saturated NH4Cl, warmed to room temperature and extracted three times with ether. The organic extracts were dried (Na2SO4), filtered through MgSO4, and concentrated. The residue was chromatographed on silica gel (Merck, 80 g.) eluting with hexane:acetone (10:1) to provide 237 mg. of (4S-trans)-5-[2-[butylamino)sulfonyl]-1-butyl-1-hydroxyethyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylic acid, 1,1-dimethylethyl ester, isomer A; [α]D =+4.2° (c=1.0, methanol) and 101 mg. of isomer B; m.p. 138°-140°; [α]D =+5.5° (c=1.0, methanol) and 1.518 g. of a mixture of isomer A and isomer B.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]([C:9]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:10])([CH3:8])[CH3:7].[CH3:21]SC.CI>>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][C:9]1([C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)([CH3:8])[CH3:7])[CH2:21][O:10]1
Reactant: CSC
Reactant: CC(C)(C(=O)CCc1ccc(Cl)cc1Cl)C1OCCO1
Solvent: CI
Product: CC(C)(C1OCCO1)C1(CCc2ccc(Cl)cc2Cl)CO1

Procedure:
In accordance with Example 3, reaction of 83 g (0.262 mol) of b 2,4-dichlorophenylethyl 2-(1,3-dioxolan-2-yl)-prop-2-yl ketone with 28.2 g (0.455 mol) of dimethyl sulphide/60 g of methyl iodide gives 90 g of 2-(2,4-dichlorophenylethyl)-2-[2-(1,3-dioxolan-2-yl)-prop-2-yl]-oxirane as an oil, which is directly reacted further. ##STR103##
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)=[O:9].CS(O[CH2:22][CH2:23][C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)(=O)=O.O>CN(C)C=O>[CH3:16][N:13]1[CH2:14][CH2:15][CH:10]([C:8]([C:4]2[N:3]([CH2:22][CH2:23][C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: CN1CCC(C(=O)c2ncc[nH]2)CC1
Reactant: CS(=O)(=O)OCCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)c2nccn2CCc2ccsc2)CC1
Yield: 61.8 %

Procedure:
A dispersion of sodium hydride in mineral oil (50%) (0.088 mol) was added portionwise in N,N-dimethylformamide (150 ml) under nitrogen with stirring. (1H-imidazol-2-yl)-(1-methyl-4-piperidinyl)methanone (0.08 mol) was added portionwise and the mixture was stirred for 1 hour. 3-Thiopheneethanol methanesulfonate (ester) (0.086 mol) dissolved in a little N,N-dimethylformamide was added dropwise and the mixture was stirred on an oil bath at 60° C. overnight. The mixture was cooled, decomposed with water and extracted with dichloromethane. The organic layer was dried, filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3)95/5). The pure fractions were collected and evaporated, yielding 15 g (61.8%) of (1-methyl-4-piperidinyl)[1-[2-(3-thienyl)ethyl]-1H-imidazol-2-yl]methanone (interm. 8).