Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH2:17][CH:5]([C:6]3([CH3:16])[C:10]1([CH3:11])[C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[Br:18]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>O1CCCC1.CN(C)C=O>[Br:18][C:13]1[CH:14]=[CH:15][C:8]2[O:7][C:6]3([CH3:16])[CH:5]4[CH2:17][C:2]([CH3:1])([C:10]3([CH3:11])[C:9]=2[CH:12]=1)[CH2:3][CH2:4]4
Reactant: CC12CCC(C1)C1(C)Oc3ccccc3C21C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC12CCC(C1)C1(C)Oc3ccc(Br)cc3C21C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
11.42 g (50 mmol) of (-)-1,2,3,4-tetrahydro1,4a,9b-trimethyl-1,4-methanodibenzofuran obtained in Example 1 were dissolved in 110 ml of tetrahydrofuran and were treated dropwise with a solution containing 8.9 g of N-bromosuccinimide (NBS) in 50 ml of dimethylformamide (DMF). The reaction medium was maintained under stirring at room temperature for 2 h, 30 min, then poured into ice-cold water and extracted with 500 ml of ethyl ether. After rinsing with water, drying over magnesium sulfate, filtration and evaporation, 13.8 g (90w) of the expected compound, melting at 119.8° C., were isolated after chromatography on silica in hexane; αD =+4.60 (c=1, chloroform).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Br:15][Si](C)(C)C.O>ClCCl.C(N(CC)CC)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[N:8][CH:9]=1)=[O:3]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)c1ccc(-n2ccnn2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CBr)c1ccc(-n2ccnn2)nc1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
Next, the obtained 5-acetyl-2-(1H-1,2,3-triazole-1-yl)pyridine is dissolved in dichloromethane and triethylamine. The resulting solution is cooled down to about 0° C., and then bromotrimethylsilane is added thereto. This reaction solution is stirred at room temperature for 10-24 hours. Then, the reaction solution is poured into water and extracted with dichloromethane, and the dichloromethane layer is concentrated. The oily substance resulting from concentration is dried sufficiently and dissolved in tetrahydrofuran. This mixture is cooled down to about 0° C., N-bromosuccinimide is added thereto and stirred at room temperature for about 10-60 minutes. After the completion of the reaction, the solvent is distilled off and purified by chromatography, to obtain 5-(2-bromoacetyl)-2-(1H-1,2,3-triazole-1-yl)pyridine (FIG. 1, step 2). The amount of bromotrimethylsilane may be an amount equivalent or more relative to the reaction substrate, and is typically about 2.0 times greater in molar ratio than 5-acetyl-2-(1H-1,2,3-triazole-1-yl)pyridine. In addition, the amount of triethylamine may be an amount that can neutralize hydrobromic acid generated during reaction, and is typically an amount excessive relative to trimethylsilane bromide. The amount of N-bromosuccinimide may be an amount equivalent or more to the reaction substrate, and is preferably about 1.0 time in molar ratio as much as 5-acetyl-2-(1H-1,2,3-triazole-1-yl)pyridine.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[CH3:12][C:11]([Si:8]([CH3:10])([CH3:9])[O:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])([CH3:14])[CH3:13]
Reactant: O=C1NCC[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A mixture of 14 g of (S)-3-hydroxy-2-pyrrolidinone, 45 g of tert-butyldimethylsilyl chloride, 50 ml of triethylamine and 500 ml of dichloromethane was stirred overnight. The solution was washed four times with water, once with brine, dried and concentrated in vacuo. The residue was dissolved in 500 ml of methanol, refluxed overnight and concentrated in vacuo. The residue was purified by chromatography (silica gel), giving 21.5 g of (S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone; [α]D260 =-52° (dichloromethane); mp 48°-49° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:10]=1[O:11][C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[NH:14][N:13]=1.[C:27](Cl)(=[O:30])[O:28][CH3:29]>O1CCCC1>[CH3:29][O:28][C:27]([N:14]1[C:15]([CH3:21])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:12]([O:11][C:10]2[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:9]=2[CH3:8])=[N:13]1)=[O:30]
Reactant: COC(=O)c1c(Oc2cccc(C)c2C)n[nH]c1C
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(Oc2cccc(C)c2C)nn(C(=O)OC)c1C

Procedure:
A mixture of 5.6 g of triethylamine, 13 g of 3-(2',3'-dimethylphenoxy)-5-methyl-4-methoxycarbonyl pyrazole and 100 ml of tetrahydrofuran is prepared, and, while stirring and cooling, 4.9 g of methyl chlorocarbonate is dripped in. After stirring for 16 hours, the precipitated hydrochloride is filtered off. The filtrate is concentrated and the residue is recrystallized from ethyl acetate. Melting point: 115° C.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C-:16]#[N:17].[Na+]>O>[C:16]([CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1)#[N:17]
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CBr)C2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(C)(CC#N)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 102.4 %

Procedure:
2-Bromomethyl-2,4,6,7-tetramethyl-2,3dihydrobenzofuran (6.5 g, 18.6 mmol) was dissolved in dimethylsufoxide (30 ml). Sodium cyanide (1.43 g, 88 mmol) was added and the resulting mixture was stirred at 80° C. for 18 hours. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 2:1). The crude crystals obtained were recrystallized from methanol to obtain the desired compound (4.1 g, yield: 79.7%), m.p. 58°-59° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([NH:22][C@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26](=[O:28])[NH2:27])(=[O:21])[CH3:20].CO>CC(C)=O>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C@@H:13]([NH2:18])[CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([NH:22][C@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26](=[O:28])[NH2:27])(=[O:21])[CH3:20]
Reactant: CC(C)CC(N)c1ccccc1N1CCCCC1
Agent: CC(=O)N[C@@H](CCC(N)=O)C(=O)O
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)C[C@H](N)c1ccccc1N1CCCCC1
Reaction time: 8 h

Procedure:
A stirred solution of 122 g (0.495 mol) of racemic 1-(2-piperidino-phenyl)-3-methyl-1-butylamine in 1000 ml of acetone is mixed with 93.7 g (0.495 mol) of N-acetyl-L-glutaminic acid. The mixture is refluxed over a vapour bath and methanol is added in batches (a total of about 80 ml) until a clear solution is obtained. After this has been left to cool and stand overnight at ambient temperature, the crystals obtained are removed by suction filtering, washed twice with 200 ml of cold acetone at -15° C. and then dried. The product obtained [98.9 g; melting point: 163-166° C.; [α]D20 =+0.286° (c=1 in methanol)] is recrystallised from 1000 ml of acetone with the addition of 200 ml of methanol, thereby obtaining the (S)-1-(2-piperidino-phenyl)-3-methyl-1-butylamine as the addition salt of N-acetyl-L-glutaminic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C(N(C(C)C)CC)(C)C>ClCCl>[O:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(=O)C1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
Part A: To a solution of oxalyl chloride (1.3 mL, 15 mmol) in 20 mL of dichloromethane at −60° C. was added methyl sulfoxide dropwise over period of 10 min. After stirring at −60° C., a solution of 1,1-dimethylethyl 3-hydroxypyrrolidine-1-carboxylate (1.87 g, 10 mmol) in 20 mL of dichloromethane was added over 20 min. Then, diisopropylethylamine (8.8 mL, 50 mmol) was added over 5 min. The resulting mixture was stirred at −60° C. for 25 min, and at room temperature for 30 min. The reaction was diluted with dichloromethane (100 mL). The organic layer was washed sequentially with saturated sodium bisulfate solution (2×), saturated sodium bicarbonate solution, water, and brine; dried over sodium sulfate; and concentrated to afford 1.8 g (97%) of 1,1-dimethylethyl 3-oxo-pyrrolidine-1-carboxylate: 1H-NMR (CDCl3) δ3.75 (4H, m), 2.58 (2H, t, J=7.8 Hz), 1.49 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13]Br.[OH-].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH:12]([O:15][CH3:16])[O:11][CH3:10])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1O
Reactant: COC(CBr)OC
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC(COc1ccc(Br)cc1C)OC

Procedure:
A mixture of 4-bromo-2-methylphenol (5 g), bromoacetaldehyde dimethyl acetal (3.8 ml) and potassium hydroxide (3.0 g) in dimethylsulphoxide (15 ml) was heated to reflux for 21/2 h. Water (50 ml) was added to the cooled mixture which was then extracted with ether (4×50 ml). The extracts were washed with 5N sodium hydroxide (50 ml) and brine (50 ml), dried (MgSO4), then evaporated in vacuo to give the title compound as a brown oil (6 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Mg]Br.C(#N)C1C=CC=CC=1.[Br-]>O1CCCC1>[C:4]1([C:8]([OH:9])([CH3:10])[CH3:11])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(Cl)c1
Agent: [Br-]
Solvent: N#Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1

Procedure:
When n is the bridging group --C(CH3)2 --, an appropriately substituted or unsubstituted phenyl methyl ketone, for example, methyl (3-chlorophenyl) ketone, is prepared by the reaction of methylmagnesium bromide and an appropriate benzonitrile in tetrahydrofuran. The ketone is in turn treated with methylmagnesiun bromide in tetrahydrofuran, yielding the corresponding 2-phenylpropan-2-ol, which is then converted to the 2-bromo-2-phenylpropane by the treatment of the alcohol with lithium bromide and trimethylsilyl chloride in acetonitrile. The Grignard reagent of the 2-bromo-2-phenylpropane is then prepared and reacted with 1,4-cyclohexanedione mono-ethylene ketal in tetrahydrofuran, yielding the corresponding 1-(2-phenylpropan-2-yl)-1-cyclohexen-4-one. The so-prepared cyclohexenone is reduced with hydrogen gas in the presence of 10% palladium on charcoal, yielding the 4-(2-phenylpropan-2-yl)cyclohexanone, which is in turn reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-(2-phenylpropan-2-yl)-5,6,7,8-tetrahydroquinazoline. Example 7 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH3:23]COC(C)=O>C1COCC1>[C:1]([N:8]([C@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:23])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCOC(C)=O
Reactant: C#C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#C[C@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(R)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne was synthesized according to Method Y above by the treatment of (R)-N-Boc-2-amino-1-(-tert-butyldimethylsilyloxy)-but-3-yne (200 mg, 0.67 mmol) (Example 104B) with NaH (21 mg, 0.87 mmol) and Mel (189 mg, 1.34 mmol) in THF (12 mL). The product was obtained after silica gel column chromatography with a 0-10% EtOAc in hexanes gradient. (Yield 200 mg, 95%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[C:23]1[N:27]2[CH:28]=[C:29](F)[CH:30]=[CH:31][C:26]2=[N:25][N:24]=1>CN(C=O)C.O>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[C:23]1[N:27]2[CH:28]=[C:29]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:30]=[CH:31][C:26]2=[N:25][N:24]=1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.2 %

Procedure:
To a solution of Intermediate 1 (6.59 g, 40.4 mmol) in dry DMF (80 mL) under N2 was added sodium hydride (60% dispersion in oil, 3.20 g, 80.0 mmol) and the resulting opaque brown solution was stirred at RT for 45 min (CARE: gas evolution). A solution of Intermediate 3c (9.93 g, 40.0 mmol) in dry DMF (20 mL) was added and the solution stirred at RT for 24 h. The reaction was carefully quenched with saturated NH4Cl (CARE: gas evolution) solution and H2O. The brown mixture was stirred for 30 min. The mixture was concentrated in vacuo and dissolved in MeOH (125 mL), charcoal was added to the solution and the mixture was stirred at RT for 1 h, and then filtered through Celite. The solution was evaporated under reduced pressure to afford a residue, which was suspended in H2O (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (75 mL), dried over Na2SO4, filtered and concentrated in vacuo to leave a brown foam (14.6 g, 93%). The foam was triturated with pentane (2×75 mL) using sonication and stirring, the solution was decanted and the solid was left to dry under vacuum and at RT affording a solid (14.2 g, 90%). LCMS (Method 3): Rt 2.32 min, m/z 392 [Mf1+].
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:14]([CH2:22][CH3:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[CH3:21][C:17]1[CH:16]=[C:15]([N:14]([CH2:12][CH3:13])[CH2:22][CH3:23])[CH:20]=[CH:19][C:18]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: CCN(CC)c1cccc(C)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1

Procedure:
In a manner similar to that of part A of Example 1 condensation of phthalic anhydride (60 g.) and N,N-diethyl-m-toluidine (162.8 g.) in contact with aluminum chloride (120 g.) and with chlorobenzene (360 ml.) as diluent afforded 2-(2-methyl-4-(diethylamino)benzoyl)benzoic acid (IV: Y2 = CH3, Y'4 = (CH3CH2)2N, Z4 = Z"5 = Z"6 = Z7 = H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl>C(OCC)C.O>[CH2:21]([O:20][C:18]([NH:11][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(O)cc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1ccc(O)cc1C(=O)O)OCc1ccccc1
Yield: 96.6 %

Procedure:
To a mixture of 5-hydroxyanthranilic acid (50 g, 0.33 mol), sodium hydrogen carbonate (109 g, 1.3 mol) and water (200 ml) was added dropwise a solution of benzyl chloroformate (52 ml, 0.36 mol) in diethyl ether (200 ml) with stirring, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was acidified by adding conc. hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained crystals were washed with diisopropyl ether and hexane to give 2-{[(benzyloxy)carbonyl]amino}-5-hydroxybenzoic acid (91.6 g, yield 98%) as brown crystals.
Reaction SMILES: I[C:2]1[S:6][CH:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.[CH3:9][N:10](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[OH:8][CH2:7][C:4]1[CH:3]=[C:2]([C:9]#[N:10])[S:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: OCc1csc(I)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(CO)cs1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of (5-iodo-thiophene-3-yl)methanol (42 g, 176 mmol) in 150 mL of DMF is added zinc cyanide (12.4 g, 106 mmol) and tetrakis(triphenylphospine)palladium (0) (8.13 g, 7.04 mmol). The solution is heated to 80° C. After 6 h, the solution is diluted with 3 L of EtOAc. The resulting solution is washed with 1N NH4OH, H2O and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (10 g, 72 mmol) as a clear oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:15][S:16]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.03 g, 0.0250 mol, Aldrich Cat. No. 495484) in methylene chloride (50 mL) were added methanesulfonyl chloride (2.03 mL, 0.0262 mol, Aldrich, Cat. No. 471259) and triethylamine (3.66 mL, 0.0262 mol) at 0° C. The solution was stirred at r.t. overnight, then diluted with ethyl acetate, and washed with NaHCO3 aqueous solution and brine successively. The organic layers were dried over MgSO4 and then concentrated under reduced pressure to afford the desired product which was directly used in next step. LCMS (M+Na)+: m/z=302.3.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:15][S:16]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (550 mg, 2.5 mmol) and DMAP (296 mg, 2.5 mmol) in dichloromethane (15 mL) cooled to 0° C. by ice/water bath was added methanesulfonylchloride (189 μL, 2.5 mmol) and the resulting mixture stirred for 10 min at 0° C. and then for an additional hour at RT. The mixture was quenched with ice water and extracted with ethyl acetate (2×30 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue oil was purified via silica gel preparative plates (3×1000 mM) eluting with 50% ethyl acetate in hexane to afford the title compound (555 mg, 89%). ESI-MS calculated for C11H21NO5S: Exact Mass: 279.11. Found 302.13 (MNa)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[C:21]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
To a suspension of O-tert-butyl N-(piperidin-4-yl)carbamate (4.0 g) in dichloromethane (40 ml) were added pyridine (1.94 ml), dichloromethane (40 ml), acetic anhydride (20.8 ml) and then N,N-dimethylaminopyridine (0.1 g) at ambient temperature. After stirring for 3 hours, the mixture was washed with 0.1N hydrochloric acid, water, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. After rinse with diisopropyl ether, O-tert-butyl N-(1-acetylpiperidin-4-yl)carbamate (4.01 g) was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)(S)=[S:8])C=CC=CC=1.[CH2:16]([O:18][C:19](=[O:24])[CH:20]([C:22]#[N:23])[CH3:21])[CH3:17].CCOC(C)=O>C(O)(C)C>[NH2:23][C:22](=[S:8])[CH:20]([CH3:21])[C:19]([O:18][CH2:16][CH3:17])=[O:24]
Reactant: S=P(S)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(C)C#N
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)C(N)=S
Yield: 54.8 %

Procedure:
A mixture of diphenylphosphinodithioic acid (ALFAAESAR, 37.4 g, 149 mmol) and 2-cyanopropionic acid ethyl ester (ABCR, 9.90 mL, 74.7 mmol) in isopropanol (350 mL) was heated under reflux for 5 h. TLC (Hex:EtOAc 7:3) showed reaction had gone to completion. Reaction mixture was allowed to cool and was placed in the fridge overnight. Reaction mixture was filtered off and washed with isopropanol. Residue was partitioned between ethyl acetate (250 mL) and 1N NaOH (250 mL). Phases were separated and organic phase was washed with water (300 mL), brine (300 mL), dried over sodium sulfate and concentrated to dryness. Crude was purified by chromatography on silica gel using a hexane/EtOAc gradient. Appropriate fractions were combined and evaporated to yield title compound as a white solid (6.6 g, 40.9 mmol, 54.8% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.60 (s, 1H), 9.40 (s, 1H), 4.05 (q, 2H), 3.74 (q, 1H), 1.29 (d, 3H), 1.15 (t, 3H). [ES+MS] m/z 162 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]([OH:27])([CH3:26])[CH3:25])[N:18]=[C:17]2[CH2:28][CH2:29][CH3:30])=[CH:11][CH:10]=1)#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:27][C:24]([C:19]1[N:18]=[C:17]([CH2:28][CH2:29][CH3:30])[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:33][N:32]=[N:31][N:2]=3)=[CH:14][CH:13]=2)[C:20]=1[C:21]([OH:23])=[O:22])([CH3:25])[CH3:26]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 45 %

Procedure:
Into the same device as used in Example 34 were placed 43.5 g (0.10 mole) of ethyl ester of 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid, 8.5 g (0.13 mole) of sodium azide, 20.8 g (0.15 mole) of triethylamine hydrochloride and 206 ml of toluene. The mixture was reacted and treated in the same manner as in Example 34, giving 20.3 g(0.045 mole) of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid (yield 45.0% based on ethyl ester of 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid).