Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:9][N:10]=1)(=[O:4])=[O:3].P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].[CH3:26][N:27]1[C:31]([S:32][CH2:33][C:34]2[CH2:35][S:36][C@@H:37]3[CH:44]([NH2:45])[C:43](=[O:46])[N:38]3[C:39]=2[C:40]([OH:42])=[O:41])=[N:30][N:29]=[N:28]1>CC(C)=O.O.CCCCCC.C(OCC)C.C(Cl)Cl>[CH3:26][N:27]1[C:31]([S:32][CH2:33][C:34]2[CH2:35][S:36][C@@H:37]3[CH:44]([NH:45][C:12](=[O:14])[CH2:11][C:8]4[S:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[N:10][CH:9]=4)[C:43](=[O:46])[N:38]3[C:39]=2[C:40]([OH:42])=[O:41])=[N:30][N:29]=[N:28]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CS(=O)(=O)Nc1ncc(CC(=O)O)s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cnc(NS(C)(=O)=O)s3)[C@H]2SC1
Yield: 45.8 %

Procedure:
To a mixture of 2-methanesulfonamidothiazol-5-ylacetic acid (1.65 g.), dried methylene chloride (40 ml.) and diethyl ether (4 ml.) was added phosphorus pentachloride (3.5 g.) under ice-cooling and stirring and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added n-hexane, and the precipitated crystals were washed by decantation three times. Thus obtained crystals were gradually added to a solution, which is prepared by adding sodium bicarbonate (2.15 g.) to a suspension of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (2.1 g.) in a mixture of acetone (25 ml.) and water (25 ml.) and then by cooling it at 0° to 5° C., under ice-cooling and stirring while the mixture was kept to pH 7.5 to 8 with a saturated sodium bicarbonate aqueous solution. The mixture was further stirred for 40 minutes at about the same pH and temperature. After the reaction, acetone was removed by washing the reaction mixture with benzene. The aqueous layer was adjusted to pH 5 with 5% hydrochloric acid and filtered. To the aqueous filtrate was overlayed ethyl acetate, and the mixture was gradually adjusted to pH 2 with 5% hydrochloric acid under ice-cooling. The ethyl acetate layer was separated from the mixture, and the remaining aqueous layer was extracted twice with ethyl acetate (70 ml.). The ethyl acetate layers were combined together, washed with water and a saturated sodium chloride aqueous solution in turn and then dried over magnesium sulfate. The solvent was distilled off from the ethyl acetate layer, and the resulting yellow powder was dried to give a mixture (1.6 g.) of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-(2-methanesulfonamidothiazol-5-yl)acetamido-3-cephem-4-carboxylic acid (hereinafter referred to Amino compound) and 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-(2-methanesulfonimido-2,3-dihydrothiazol-5-yl)acetamido-3-cephem-4-carboxylic acid (hereinafter referred to Imino compound).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:46]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
A 250 mL three necked round bottom flask equipped with a stir bar, thermocouple and nitrogen in/outlet was charged with 5.0 g (12.7 mmol) of bendamustine hydrochloride, 4.2 g (12.9 mmol, 1.01 eq) of docosyl alcohol, 2.7 g (12.9 mmol, 1.01 eq) of dicyclohexyl carbodiimide (DCC), 50 mL of dichloromethane (MDC) and 0.16 g (1.27 mmol, 0.1 eq) of N,N-dimethylamino pyridine (DMAP). The reaction mixture was stirred at room temperature overnight at which time an HPLC analysis indicated the reaction was complete. Solids were removed by vacuum filtration and the wetcake was washed with 50 mL. Two alternate purification procedures were developed. The filtrate was washed with DI water (2×150 mL), dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The resultant waxy residue was chromatographed on 80 g of silica gel 60, 230-400 mesh eluting with a gradient beginning with 100% MDC, then 0.5% methanol/MDC and finally 1% methanol/MDC collecting 100-150 mL fractions. Fractions containing the desired product were combined and concentrated to dryness in vacuo. The residue was again triturated with 20 mL of MDC and the undesired solids removed by filtration. The filtrate was concentrated in vacuo to yield 3.65 g (5.5 mmol, 43.1%) of the desired product as a waxy white solid with a purity of 95.7 A %. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.72 Hz, 1H), 7.08 (d, J=2.28 Hz, 1H), 6.78 (dd, J=2.36, 8.72 Hz, 1H), 4.05 (t, J=6.76 Hz, 2 H), 3.72 (m, 4H), 3.70 (s, 3H), 3.63 (m, 4H), 2.91 (t, J=7.44 Hz, 2H), 2.49 (t, J=7.08 Hz, 2H), 2.18 (m, 2H), 1.60 (m, 2H), 1.32 (m, 38H), 0.88 (t, J=6.64 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH2:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH:17][C:25](=[O:27])[CH3:26])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: Cn1cc2c3c(c(Cl)cc2n1)CCC3=CCN
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCC=C1CCc2c(Cl)cc3nn(C)cc3c21
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
2-(5-Chloro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethanamine (105 mg, 0.424 mmol) was dissolved in tetrahydrofuran (4 mL), triethylamine (88.6 μL, 0.636 mmol) and acetic anhydride (48.1 μL, 0.509 mmol) were added under ice-cooling, and the mixture was stirred for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (96.7 mg, yield 79%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[C:12]([I:13])[C:5]=12.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[CH:11]=[C:12]([I:13])[C:5]=12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ccnc2[nH]cc(I)c12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ccnc32)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
Under an atmosphere of protective gas (argon), 63.5 g (1.59 mol) of sodium hydride are suspended in 1000 ml of abs. THF. With cooling, at a temperature of 0-5° C., a solution of 402 g (1.44 mol) of 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine in 3000 ml of abs. THF is added dropwise, and the reaction mixture is, after the end of the addition, allowed to stir for 15 minutes. 358 g (1.88 mol) of p-toluenesulfonyl chloride are added a little at a time to the reaction mixture, so that the temperature is kept between 5 and 10° C. After the end of the addition, the mixture is allowed to warm to 20° C. and stirred at this temperature for another hour. After complete conversion (the conversion is monitored by TLC), 20 l of saturated sodium bicarbonate solution and 10 l of ethyl acetate are added to the reaction mixture, the mixture is extracted and the organic phase is separated off. The aqueous phase is reextracted two more times with in each case 10 l of ethyl acetate and the organic phases are combined, dried and, under water pump vacuum, freed from volatile components. For purification of the crystalline crude product, the product is taken up in dichloromethane and chromatographed on silica gel (dichloromethane:petroleum ether=3:7). The solvents are removed under reduced pressure and the crystal slurry is triturated with diethyl ether, filtered off with suction and dried at 20° C. under high vacuum. 372 g (60% of theory) of the title compound are isolated as a solid.
Reaction SMILES: [CH:1]1[C:2]([CH2:19][C:20]([OH:22])=[O:21])=[CH:3][C:4]([I:18])=[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)[C:6]=1[I:7].O=S(Cl)Cl.O.[CH3:28]O>>[CH3:28][O:21][C:20](=[O:22])[CH2:19][C:2]1[CH:1]=[C:6]([I:7])[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)=[C:4]([I:18])[CH:3]=1
Reactant: O=C(O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Yield: 61 %

Procedure:
In anhydrous conditions, Tetrac (5.0 g, 6.7 mmol, 1.0 eq.) was dissolved in anhydrous methanol (200 mL). To the solution was then added dropwise SOCl2 (485 μL, 6.7 mmol, 1.0 eq.). The reaction was set to reflux for 2 days. Water was then added to the reaction medium (200 mL) and then the solution was concentrated to yield a precipitate. The precipitate was then collected by vacuum filtration and then recrystallized to give orange crystals (3.10 g, 4.0 mmol) of methyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetate in 61% yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[CH2:8][N:9]1[C:13](=[O:14])[C:12]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10]1)=[O:4].O.[OH-].[Li+]>CO.O>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C:12]2([N:11]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][N:9]([CH2:8][C:7]3[CH:6]=[C:5]([CH:35]=[CH:34][CH:33]=3)[C:3]([OH:4])=[O:2])[C:13]2=[O:14])[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)O)c1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a solution of tert-Butyl 3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2 g, 4.17 mmol) in methanol (28 mL) was added lithium hydroxide monohydrate (0.35 g, 8.34 mmol) in water (14 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo, acidified with dilute citric acid, extracted with dichloromethane. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to obtain 3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid (1.88 g, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[C:10]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([N:11]([C:16](=[S:26])[NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Zn].C(O)(=O)C>[C:18]([NH:17][C:16]([NH:11][C@:10]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:14]([CH2:13][OH:12])[CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[S:26])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC2CON(C(=S)NC(=O)c3ccccc3)C2(c2ccccc2)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@](NC(=S)NC(=O)c2ccccc2)(c2ccccc2)C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A mixture of tert-butyl-1-(benzoylcarbamothioyl)-6a-phenyl-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (2.3 g, 5.1 mmol), acetic acid (20 mL), and powdered zinc (3.3 g, 50 mmol) is vigorously stirred at 40° C. for 1 hour, followed by an additional hour at 45-50° C. The reaction is concentrated under reduced pressure. To the residue is added diatomaceous earth and water, followed by a saturated solution of sodium bicarbonate. The mixture is filtered and washed with ethyl acetate. The filtrate is extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (0:1) to give the title compound (1.6 g, 70%). ES/MS (m/e): 456 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[C:13]([NH:15][C:16]([CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8]Cl)#[N:2].[CH3:22][C:23]([NH2:27])([C:25]#[CH:26])[CH3:24]>C(O)C>[C:1]([C:3]1[CH:14]=[C:13]([NH:15][C:16]([CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH:27][C:23]([CH3:24])([C:25]#[CH:26])[CH3:22])#[N:2]
Reactant: N#Cc1cc(NC(=O)C2CCC2)ccc1OCC(O)CCl
Reactant: C#CC(C)(C)N
Solvent: CCO
Product: C#CC(C)(C)NCC(O)COc1ccc(NC(=O)C2CCC2)cc1C#N

Procedure:
7.5 gm (0.024 mol) of 1-(2-cyano-4-cyclobutylcarbonylamino-phenoxy)-2-hydroxy-3-chloro-propane were dissolved in 20 ml of ethanol, 8.3 gm (0.1 mol) of 2-methyl-but-3-in-2-yl-amine were added to the solution, and the mixture was refluxed for 3.5 hours. The ethanol was then distilled off, and the residue was digested with H2O. After being acidified with HCl, the mixture was washed with ether, the acidic aqueous phase was made alkaline with NH4OH, and the base precipitated thereby was extracted by shaking twice with ethyl acetate. The organic phase was washed with H2O, dried over MgSO4 and the ethyl acetate was distilled off in vacuo. The crystalline residue (base) was recrystallized twice from acetonitrile, and 3.7 gm of pure substance were obtained. Melting point: 139°-141° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:25][CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:33][CH:34](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:35]>CN(C=O)C>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:35][CH2:34][Cl:33])=[C:3]([O:25][CH3:26])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: COc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OC(C)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the DMF solution (10 mL) of tert-butyl 4-(7-hydroxy-6-methoxyquinazolin-4-yl)piperazinecarboxylate (1.8 g, 5 mmol), Cs2CO3 (3.3 g, 10 mmol) added 1-chloroethyl-tosylate (1.8 mL, 10 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated and the crude residue was purified by RP-HPLC (reverse-phase high performance liquid chromatography) to afford the intermediate tert-butyl-4-[6-methoxy-7-(2-chloroethoxy)quinazolin-4-yl]piperazinecarboxylate as the desired product (850 mg, 40%). MS (ES) 423 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:35][C:36](=[O:42])[C:37](OCC)=[O:38])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:20]([O:33][CH3:34])[CH:19]=3)[S:17][C:10]=12.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][CH2:52][NH2:53]>>[F:1][C:2]1[CH:3]=[C:4]([NH:35][C:36](=[O:42])[C:37]([NH:53][CH2:52][CH2:51][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[O:44][CH3:43])=[O:38])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:20]([O:33][CH3:34])[CH:19]=3)[S:17][C:10]=12
Reactant: COc1ccccc1CCN
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Product: COc1ccccc1CCNC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Amino ester 140 (80 mg, 0.13 mmol) and 2-(2-methoxyphenyl)ethanamine (0.2 mL, 1.34 mmol) were mixed together and stirred at room temperature until completion of the reaction. The mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (eluent: 3% MeOH/97% DCM to 5% MeOH/95% DCM). This solid product was then triturated with ethyl acetate to afford pure title compound 136 as a white solid (52 mg, 57% yield). 1H NMR (DMSO-d6) 6 (Ppm): 11.03 (s, 1H), 9.04 (t, J=5.9 Hz, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.05-8.01 (m, 2H), 7.82 (d, J=9.0 Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.38 (dd, J=2.2 and 8.2 Hz, 1H), 7.21 (td, J=1.8 and 7.8 Hz, 1H), 7.14 (dd, J=1.8 and 7.4 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H), 6.88 (td, J=1.0 and 7.3 Hz, 1H), 6.60 (d, J=5.5 Hz, 1H), 4.14 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 3.59-3.57 (m, 4H), 3.46-3.41 (m, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.73-2.70 (m, 2H), one peak (4H) did not show, it was probably under H2O or DMSO. MS (m/z): 701.1 (M+H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:24][CH:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[Si](OCCCc1ccc(OCC(=O)O)cc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
A solution of methyl [4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]acetate (4.36 g, 9.4 mmol) in 80% aqueous ethanol (100 ml) was treated with potassium hydroxide (2 g) and the resulting mixture was heated at 50° C. for 2 hours. The solvent was then evaporated in vacuo. Ice water and ethyl acetate were added and the aqueous phase was carefully adjusted to pH with 1N hydrochloric acid. The organic phase was then washed with brine, dried (magnesium sulfate) and evaporated under reduced pressure to give a white solid. Recrystallization from hexane gave 3.41 g (81%) of the title acid as white crystals: mp 87-88° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8](Cl)[N:7]=1)=[O:5])[CH3:2].ClC(Cl)C(O)=[O:17].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](=[O:17])[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: O=C(O)C(Cl)Cl
Reactant: CCOC(=O)c1nc(Cl)ccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1[nH]c(=O)ccc1C
Temperature: 25 °C

Procedure:
A mixture of 6-chloro-3-methyl-pyridine-2-carboxylic acid ethyl ester (650 mg, 3.26 mmol), dichloroacetic acid (5 mL) and water (0.5 mL) was refluxed for 1 h. After cooling to r.t., the mixture was neutralized with saturated NaHCO3 and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 230 mg of the title compound as a white solid. MS: (+) m/z 182.25 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7](O)([CH3:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17](#[N:19])[CH3:18]>C1C=CC=CC=1>[CH3:18][C:17]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]([CH3:15])([CH3:6])[N:19]=1
Reactant: CC#N
Reactant: CC(C)(O)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC1=NC(C)(C)Cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To conc. sulfuric acid (10 ml) was added a solution of 2-methyl-1-phenylpropan-2-ol (7.0 g) and acetonitrile (1.62 ml) in benzene (7.0 ml) dropwise and the mixture was stirred for 24 hours at room temperature. The mixture was neutralized by adding to a mixture of ice and a saturated aqueous solution of sodium bicarbonate dropwise, and it was extracted with ethyl acetate twice. The extract was dried over anhydrous magnesium sulfate and was concentrated under reduced pressure. The residue was dissolved in ether and was extracted with 1N hydrochloric acid and 2N hydrochloric acid. The extract was washed with ether and to the mixture was added 5N aqueous solution of sodium hydroxide and was extracted with ether twice. The extract was washed with water and a saturated aqueous solution of sodium chloride successively, and dried over anhydrous magnesium sulfate and was concentrated under reduced pressure to give the title compound (2.53 g) having the following physical data.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([C:19]4[CH:23]=[C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:21][C:20]=4[S:28]([NH:31]C(C)(C)C)(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:47]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:48]>C(Cl)Cl.O>[CH2:50]([O:49][C:47]([NH:31][S:28]([C:20]1[S:21][C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:23][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1)(=[O:29])=[O:30])=[O:48])[CH2:51][CH2:52][CH3:53]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccccc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 3-[3-(2-phenylimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (31.2 mg, 0.0615 mmol; see step (a)) in CH2Cl2 (1 mL) was added BCl3 (0.2 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (29.3 mg, 0.277 mmol), water (2 mL) and butyl chloroformate (15.6 μL, 0.123 mmol), and the reaction mixture was stirred for 11 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the title compound as a white solid in 87% yield, over two steps, (29.4 mg, 0.0533 mmol).