Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])(=[O:20])=[O:19])=[CH:14][CH:15]=2)[C:10]([CH3:31])=[N:9]1)=O)(C)(C)C.I[Si](C)(C)C>C(Cl)(Cl)Cl>[CH3:30][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2[CH3:31])(=[O:20])=[O:19])(=[O:28])=[O:29]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12
Yield: 30.8 %

Procedure:
2-Methylsulfonyl-N-(3-methyl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 6 from 1.45 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide, 12.6 ml of chloroform and 0.44 ml of iodotrimethylsilane. 0.35 g of 2-methylsulfonyl-N-(3-methyl-1H-indazol-5-yl)benzenesulfonamide is thus obtained in the form of a white solid melting above 260° C. (analysis: C15H15N3O4S2 % calculated C, 49.30; H, 4.14; N, 11.50; O, 17.51; S, 17.55. % found C, 48.99; H, 4.45; N, 11.67; S, 17.23).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=1.I[CH3:21].O>CN(C)C=O>[CH3:21][O:3][C:4]1[CH:5]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=1
Reactant: CI
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OC)cc(C(=O)OCC)n1
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To a suspension of 60% sodium hydride (0.351 g, 8.77 mmol) in dimethylformamide (7.5 mL), a solution of diethyl 4-hydroxy-2,6-pyridinedicarboxylate (1.4 g, 5.85 mmol) in dimethylformamide (9 mL) was added dropwise under argon at room temperature and the reaction mixture was stirred for 5 minutes. Iodomethane (1.245 g, 8.77 mmol) was added and the reaction was stirred at room temperature for 20 hours. The mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was dried, concentrated to give 1.45 g (97.8%) diethyl 4-methoxy-2,6-pyridinedicarboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[Br:22]Br>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([Br:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1COC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ncc2[nH]c3ccc(Br)cc3c2c1COC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 284 mg of 4-methoxymethyl-beta-carboline-3-carboxylic-acid-ethylester in 13 ml of chloroform is cooled to -30° C. and is dropwise mixed with 0.05 ml bromine in 1 ml of chloroform. This mixture is stirred for 2 h at -20° C. to -10° C., is poured into ice-cold 10% sodium hydrogen sulfite solution and extracted with methylene chloride. The crystallization in ethyl acetate yields 240 mg of 6-bromo-4-methoxymethyl-beta-carboline-3-carboxylic-acid-ethylester with a m.p. 207°-209° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:10]([NH:25]S(C(C)(C)C)=O)[CH2:11][CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl>C(Cl)Cl>[NH2:25][C@@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:32][O:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:11][CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(/C=C/CC[C@@H](NS(=O)C(C)(C)C)[C@@H](COc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(/C=C/CC[C@@H](N)[C@@H](COc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108.2 %

Procedure:
To the solution of methyl 4-{(1E,5R,6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(tert-butylsulfinyl)amino]-7-phenoxyhept-1-en-1-yl}benzoate from step A (1.05 g, 1.74 mM) in 10 ml of methylene chloride was added 1 ml of HCl (4M, in dioxane) and the resulting mixture stirred at RT for 15 min. Removal of the volatiles under reduced pressure afforded 0.93 g of the title compound (as HCl salt) which was directly used for the next step. LC-MS: m/z (ES) 470.41 (M+1).
Reaction SMILES: [I:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[F:11][C@@H:12]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@H:13]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>[F:11][C@@H:12]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@H:13]1[N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[I:1]
Reactant: Ic1ncnc2nc[nH]c12
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: OC[C@H]1O[C@@H](n2cnc3c(I)ncnc32)[C@H](F)[C@@H]1O
Temperature: 37 °C
Reaction time: 8 h

Procedure:
6-Iodopurine (Sigma Chemical Company; 0.7 g, 2.7 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.4 g, 1.7 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 20 ml of 10 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (2,640 I.U.) and purine nucleoside phosphorylase (4,360 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 37° C. On day 21, the reaction was diluted to 50 ml with 5 mm potassium phosphate buffer, pH 7, which contained 0.04% (w/v) potassium azide and 4000 I.U. of thymidine phosphorylase and 6,500 I.U. of purine nucleoside phosphorylase were added. On day 43, the reaction was diluted to 250 ml with water and 2,000 I.U. thymidine phosphorylase and 3,250 I.U. purine nucleoside phosphorylase were added. On day 57, the reaction was filtered. The filtrate was evaporated. The residue was suspended in warm methanol and filtered. The filtrate was evaporated. The residue was dissolved in water/n-propanol (7/3) and applied to a 7.5×90 cm column of Biogel P-2 (Bio-Rad) with water/n-propanol (7/3) as the solvent. Product containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in hot methanol and water added until a precipitate formed. The methanol was removed under vacuum. After standing overnight the suspension was filtered. The filter cake contained the bulk of the product. The filtrate was evaporated and the above procedure repeated to precipitate the remaining product. The filter cakes were combined and suspended in water. Lyophilization yielded the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([Li])[CH2:11][CH2:12][CH3:13].[Si]([N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27])(C(C)(C)C)(C)C.BrCCC=C>C1COCC1>[CH2:10]([CH:24]1[CH2:25][CH2:26][NH:22][C:23]1=[O:27])[CH2:11][CH:12]=[CH2:13]
Reactant: CC(C)(C)[Si](C)(C)N1CCCC1=O
Reactant: [Li]CCCC
Agent: C=CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCCC1CCNC1=O
Temperature: 0 °C
Yield: 62.4 %

Procedure:
DIPEA (0.393 mL, 2.76 mmol) was dissolved in THF (25 mL) and chilled to −78° C. n-Butyllithium (1.10 mL, 2.76 mmol) was then added, and the reaction was warmed to 0° C. and re-chilled to −78° C. 1-(tert-Butyldimethylsilyl)pyrrolidin-2-one (0.500 g, 2.51 mmol) was then added as a solution in THF (1 mL), and the reaction mixture was warmed to room temperature for 1 hour. The reaction was then re-cooled to −78° C., and 4-bromobut-1-ene (0.305 mL, 3.01 mmol) was added dropwise in THF (1 mL). The reaction mixture was slowly warmed to room temperature overnight. The reaction was concentrated to an oil and loaded onto CELITE®. Purification by flash column chromatography using 0-30% acetone/hexanes provided the title compound (0.218 g, 62%): 1H NMR (400 MHz, CDCl3) δ 6.15 (s, 1H), 5.82 (ddt, J=17.0, 10.2, 6.6 Hz, 1H), 5.09-4.87 (m, 2H), 3.42-3.24 (m, 2H), 2.44-2.25 (m, 2H), 2.24-2.05 (m, 2H), 1.99 (dddd, J=13.6, 9.4, 6.9, 4.1 Hz, 1H), 1.78 (dq, J=12.1, 8.4 Hz, 1H), 1.45 (dtd, J=13.7, 9.1, 5.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 180.44, 137.92, 115.13, 40.29, 40.16, 31.45, 30.05, 27.60; ESIMS m/z 138 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10](=O)[CH2:9][S:8][C:7]=2[CH:12]=1.[BH4-].[Na+]>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:12]=1
Reactant: COc1ccc2c(c1)SCC2=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2ccsc2c1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
6-Methoxybenzo[b]thiophen-3(2H)-one (1.4 g, 7.76 mmol) was dissolved in a mixture of methanol (18 mL) and 2.5 M sodium hydroxide (3 mL). The mixture was treated with sodium borohydride (0.589 g, 15 mmol) in 10 mL of methanol and 3 mL of 2.5 M sodium hydroxide. The reflux was heated to reflux for 1 h and then at 60° C. overnight. The reaction was cooled down to room temperature and the methanol removed in vacuo. The remaining aqueous layer was acidified to pH 4 with 1 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate and washed with 1 N HCl. The organic layer was further washed with water, saturated sodium bicarbonate, water and brine. The organic layer was dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 20 to 50% ethyl acetate in hexanes to afford a clear oil (0.843 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=[O:20])=[O:12])=[CH:3][CH:2]=1.[NH:29]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]1>>[OH:34][CH:31]1[CH2:32][CH2:33][N:29]([C:19]([C:18]2[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=2)[CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[NH:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[O:20])[CH2:30]1
Reactant: O=C(O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Reactant: OC1CCNC1
Product: O=C(NOCc1cccc(C(=O)N2CCC(O)C2)c1)c1ccccc1NCc1ccncc1

Procedure:
Prepared by a similar procedure as described for preparation of example 405. Starting materials: 3-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 403) and 3-pyrrolidinol (Aldrich).
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)C.[BrH:20].O>C(OCC)C>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][Br:20])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccccc1Oc1ccc(Br)cc1
Reactant: Br
Solvent: CCOCC
Solvent: O
Product: BrCc1ccccc1Oc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
A mixture of 413.0 g of the 2-(4-bromophenoxy)benzyl alcohol and 1290 ml of 48% hydrobromic acid is boiled under reflux for 4 hours, then cooled and poured onto 2000 ml of ice and water. The greenish oil that separates out is dissolved in 2000 ml of diethyl ether. The organic phase is washed twice with 400 ml of water and with 400 ml of a 1N aqueous sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation at 40° under 11 mm Hg. The 2-(4-bromophenoxy)benzyl bromide, obtained in the form of an oily residue, is used without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22]([CH2:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+]>>[NH:36]1[C:19]([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:21]=[C:22]([CH2:24][CH2:25][C:26]5[CH:35]=[CH:34][C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=5)[N:23]=[C:8]4[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)=[N:20][N:38]=[N:37]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cn1
Agent: [Na+]
Product: c1ccc2nc(CCc3cn4c(-c5ccc(-c6nnn[nH]6)nc5)cnc(N5CCOCC5)c4n3)ccc2c1
Yield: 10 %

Procedure:
Compound 3b (300 mg, 0.650 mmol) was treated with NaN3 as described in Example 1, Step H to obtain the title compound 77 as a light yellow solid (37.2 mg, 10% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.79 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.04-8.02 (m, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 7.70 (t, J=7.2 Hz, 1H), 7.56-7.46 (m, 3H), 4.21-4.09 (m, 4H), 3.75-3.65 (m, 4H), 3.35-3.25 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H24N10O: 505.2 (M+H). Found 505.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:4]=1[CH:5]=[CH:6][CH2:7]Cl.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:7][CH:6]=[CH:5][C:4]3[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:3]=3[O:2][CH3:1])[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: COc1cccc(C=CCCl)c1OC
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1cccc(C=CCN2CCc3nc(N)sc3CC2)c1OC
Yield: 39 %

Procedure:
Prepared from 2,3-dimethoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 39% of theory, Melting point: 87°-9 1° C. (ether).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])[CH3:7]>CO>[O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH3:7]
Reactant: COC(=O)C=Cc1ccccc1[C@@H](C)OC[C@H]1CO1
Solvent: CO
Product: COC(=O)CCc1ccccc1[C@@H](C)OC[C@H]1CO1
Yield: 87.5 %

Procedure:
Methyl 3-[2-[(1R)-1-(((2R)-oxiranyl)methoxy)ethyl]phenyl]acrylate (330 mg) obtained in Step 2 was dissolved in methanol (10 ml), 5% rhodium-alumina (43 mg) was added, and the mixture was hydrogenated at atmospheric pressure overnight. The reaction mixture was filtered through Celite, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (291 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].O1CCCC1.[C:17]([O:20][C@H:21]1[CH2:45][CH2:44][C@@:43]2([CH3:46])[C:23](=[CH:24][CH2:25][C@@H:26]3[C@@H:42]2[CH2:41][CH2:40][C@@:39]2([CH3:47])[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@H:31]([CH3:38])[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:22]1)(Cl)=[O:18]>O.C(Cl)(Cl)Cl>[CH3:37][CH:35]([CH2:34][CH2:33][CH2:32][C@H:31]([C@@H:30]1[C@:39]2([CH3:47])[C@H:27]([C@H:26]3[C@H:42]([CH2:41][CH2:40]2)[C@:43]2([CH3:46])[C:23]([CH2:22][C@@H:21]([O:20][C:17]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:18])[CH2:45][CH2:44]2)=[CH:24][CH2:25]3)[CH2:28][CH2:29]1)[CH3:38])[CH3:36]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of β-alanine (56 mg) and sodium bicarbonate (84 mg) in water (10 ml) were added tetrahydrofuran (20 ml) and cholesterol chlorocarbonate (449 mg) at 0° C. The mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo and to the residue were added 0.1N hydrochloric acid (10 ml) and chloroform (40 ml). Organic layer was separated, washed with water and dried over magnesium sulfate. Evaporation of the solvent gave a crude product, which was dissolved in chloroform and applied to a silica gel column (40 g). Elution with a mixture of chloroform and methanol gave N-(cholest-5-en-3β-oxycarbonyl)-β-alanine (187 mg) as a white powder.
Reaction SMILES: [CH2:1]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:22]([O-])(=[O:24])[CH3:23].[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[OH:21][C:17]1[CH:16]=[C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:20]=[CH:19][C:18]=1[C:22](=[O:24])[CH3:23]
Reactant: CCCCCCCCCCCCCCc1cccc(O)c1
Reactant: CC(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1ccc(C(C)=O)c(O)c1

Procedure:
A 20 g portion of 3-tetradecylphenol, acetate was heated at 110° C. and 8.4 g of aluminum chloride was added in portions over a 3 hour period. The mixture was allowed to cool, then diluted with ether, poured onto ice containing 10 ml of concentrated hydrochloic acid and extracted several times with ether. The ether extracts were combined, washed with water, brine and dried. The crude material was chromatographed on silica gel, eluting with hexane:ethyl acetate (50:1), giving 15.8 g of the desired compound, mp 45°-46° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([CH:10]([C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:11][CH2:12][CH3:13])=[CH:2]1
Reactant: CCCC=O
Reactant: c1cnc2[nH]ccc2c1
Product: CCCC(c1c[nH]c2ncccc12)c1c[nH]c2ncccc12
Yield: 15 %

Procedure:
ST 1436 was prepared as described in example 2/2 from 7-azaindole and butyraldehyde. The reaction, however, was heated under reflux for 48 hours. The end product was isolated and purified chromatographically on a silica column eluting with a CH2Cl2:CH3COCH3 gradient ranging from 9:1 to 4:6. Yield 15%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C=O)C.C(Cl)(=O)C([Cl:41])=O.Cl>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([Cl:41])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reaction time: 4 h

Procedure:
To a solution of 439 mg. (0.93 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 4.4 ml. of DMF cooled in an ice bath was added dropwise 118 mg. (0.07 ml., 0.93 mmole) of oxalyl chloride. The reaction mixture was allowed to stand for 4 hours at room temperature and was then poured into a mixture of aqueous 5% hydrochloric acid and ethyl acetate. The organic layer was separated and was washed sequentially with 5% hydrochloric acid, water and a saturated solution of sodium chloride. The washed layer was dried and evaporated to dryness to yield the reaction product, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate as an amorphous solid. The product was obtained crystalline by triturating the amorphous residue with ether. Yield: 360 mg. The infrared spectrum and NMR spectrum of the crystalline product were consistent with the spectra of authentic material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccccc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A solution of [tert-Butoxycarbonylmethyl-(2-hydroxy-phenyl)-amino]-acetic acid tert-butyl ester (11) (7.4 g, 21.9 mmol) in dry THF (50 mL) was treated with sodium hydride (0.81 g, 33.8 mmol) at 0° C. under an Ar atmosphere. After stirring at 0° C. for 30 min, benzyl bromide (3.9 mL, 32.7 mmol) was added. The mixture was stirred at 0° C. for another 30 min and then warmed to room temperature overnight. The reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with CH2Cl2/hexane/EtOAc=1:4:0.2 to yield 6.3 g (67%) of the desired product 12 as a colorless oil. Rf=0.33 (in CH2Cl2/hexane/EtOAc=1:4:0.2); 1H NMR (300 MHz, CDCl3) δ 7.45-7.28 (m, 5H), 6.84 (m, 4H), 5.12 (s, 2H), 4.08 (s, 4H), 1.40 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 170.5, 150.5, 139.6, 137.5, 128.4, 127.6, 127.2, 121.9, 121.4, 119.4, 114.7, 81.0, 70.9, 54.6, 28.0; mass spectrum, calculated for C25H33NO5 (MH+) 428.2, Found 427.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[C:7]=2[CH:24]=1.[CH3:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31]CBr>>[CH3:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[C:7]=2[CH:24]=1
Reactant: COC(=O)CCCCCBr
Reactant: COc1ccc2nc(-c3ccccc3)n(-c3ccccc3C)c2c1
Product: COC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3C)c2c1

Procedure:
6-Methoxy-1-(2-methylphenyl)-2-phenyl-1H-benzimidazole was reacted according to general operating instructions 6. The crude product was reacted with 6-bromohexanoic acid methyl ester according to general operating instructions 8.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].N1C=CN=C1.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[Si:11]([O:1][CH2:2][CH2:3][C:4]#[N:5])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: N#CCCO
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxyproprionitrile (7.11 g, 100 mmol) and imidazole (68.08 g, 100 mmol) in dry THF (100 ml) was stirred at room temperature for 45 mins and tert-butyldiphenylsilylchloride (28.86 g, 105 mmol) was added slowly by syringe over 10 mins. The clear solution was stirred at room temperature overnight during which time a white precipitate formed. The reaction was filtered and the filtrate evaporated in vacuo to leave an oil which was chromatographed on silica (eluting with 10% petrol in ether) to give the product as a clear slightly yellow oil (31.41 g, quant.) δH (CDCl3) 7.76-7.65 (4H, m, PhH4), 7.48-7.35 (6H, m, PhH6), 3.86 (2H, t, J 6.5, OCH2CH2CN), 2.54 (2H, t, J 6.5, OCH2 CH2CN), 1.09 (9H, s, tert-Bu).