Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[CH2:2][CH:3]=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][C:26]1([CH3:33])[NH:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH2:3]([N:28]1[C:27](=[O:32])[C:26]([CH3:33])([CH3:25])[NH:30][C:29]1=[O:31])[CH:2]=[CH2:1]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: C=CCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=CCN1C(=O)NC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
A solution of 3-buten-1-ol (1 g,13.9 mmol), triphenylphosphine (4.73 g, 18 mmol) and 5,5-dimethylhydantoin (2.1 g, 16.7 mmol) in THF (50 mL) was treated dropwise with diethylazodicarboxylate (3.13 g, 18.0 mmol), stirred at ambient temperature for 1 hour, treated with water, and partitioned between ethyl acetate and brine. The organic layer was dried (Na2SO4), filtered, and concentrated to provide crude product which was purified on silica gel with 50% ethyl acetate/hexanes to provide 2.5 g (100%) of the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.[CH:34](OC(=O)C)=[O:35]>>[CH:34]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:5][CH2:6]1)=[O:35]
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OC=O
Product: O=CN1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and acetic formic anhydride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=O)[CH2:12]Br)[NH:8][N:7]=1)=[O:5])[CH3:2].[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:15]=[C:16]([NH2:18])[S:17][CH:12]=2)[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)CBr)[nH]n1
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1cc(-c2csc(N)n2)[nH]n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A mixture of 5-(2-bromoacetyl)pyrazole-3-carboxylic acid ethyl ester (6.2 g), thiourea (1.8 g), and ethanol (100 ml) was stirred at 60° C. for 30 minutes and concentrated. The residue was dissolved in 100 ml of 1N HCl solution, and washed with ethyl ether (2×100 ml). The aqueous solution was neutralized with NaHCO3. The resulting precipitates were collected through a filtration to afford 4.05 g of 5-(2-aminothiazol-4-yl)pyrazole-3-carboxylic acid ethyl ester as brown solids, mp 205°-207° C. NMR: 1.40 (t, 3H), 4.39 (q, 2H), 5.8 (bs, 2H), 6.85 (s, 1H), 7.03 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:34]([NH2:38])[CH:35]([CH3:37])[CH3:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:38][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC(C)CN
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Product: CC(C)CNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0265 cm3 of isobutylamine. 46 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-isobutylbenzamide are thus obtained in the form of a white powder [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 0.89 (d, J=7 Hz, 6H), 1.85 (mt, 1H), 2.98 (s, 3H), 3.09 (t, J=6.5 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.88 (broad d, J=8 Hz, 1H), 8.51 (t, J=6 Hz, 1H)].
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH2:15]=[C:16]([CH3:18])[CH3:17].C(=O)([O-])O.[Na+]>ClCCl>[O:1]=[C:2]1[O:6][CH:5]([C:7]([O:9][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:8])[CH2:4][CH2:3]1
Reactant: C=C(C)C
Reactant: O=C1CCC(C(=O)O)O1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(=O)O1
Reaction time: 8 h

Procedure:
In 100 ml of dichloromethane was dissolved 5.0 g of 5-oxo-2-tetrahydrofurancarboxylic acid. To the solution was added 0.3 ml of concentrated sulfuric acid at -60° C., to which was added an excess volume of isobutene (about 50 ml). The reaction mixture was allowed to stand at room temperature overnight in a sealed vessel, which was then poured into a cooled aqueous solution of sodium hydrogen carbonate. The dichloromethane layer was taken, washed with water and dried (Na2SO4), followed by concentration to give t-butyl 5-oxo-2-tetrahydrofurancarboxylate as colorless oil.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CO[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][CH2:25][C:26]([CH3:29])([CH3:28])[N:27]=1>O1CCCC1>[CH2:1]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][CH2:25][C:26]([CH3:29])([CH3:28])[N:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Reactant: CCCCCCCCCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccccc1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To freshly prepared dodecylmagnesium bromide (from 30.13 mmoles of dodecyl bromide and 26.20 mmoles of magnesium) in distilled tetrahydrofuran (50 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline [A. I. Meyers et al., J. Org. Chem., 43, 1372 (1978)] (17.88 mmoles) in tetrahydrofuran (30 ml). The resultant yellow solution was stirred under argon at ambient temperature for 20 hours. The solution was cooled in an ice water bath and quenched with aqueous ammonium chloride (100 ml). The reaction product was extracted into diethyl ether (100 ml) and the organic phase was washed with saturated sodium chloride solution (50 ml) and then dried over anhydrous magnesium sulfate. Evaporation of the organic phase afforded a colorless oil which was purified by flash chromatography over silica gel with 5 percent ethyl acetate in hexane as eluant to afford the desired product as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>S(=O)(=O)(O)O>[C:19]([N:3]1[C:4]([CH3:17])([CH3:16])[CH2:5][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:7][C:2]1([CH3:18])[CH3:1])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1
Agent: O=S(=O)(O)O
Product: CC(=O)N1C(C)(C)CC(N2CCCCCC2=O)CC1(C)C
Temperature: 120 °C
Yield: 65.2 %

Procedure:
A solution of 50.5 g (0.2 mole) of N-(2,2,6,6-tetramethylpiperidin-4-yl)-epsilon-caprolactam, prepared in Example 1, in 102 g of acetic anhydride with 0.2 g of sulfuric acid catalyst is heated for four hours at 120° C. At the end of this period the excess acetic anhydride is removed in vacuo. The residue is then dissolved in 200 ml of methylene chloride, washed thrice with 100 ml portions of water, then with 10% aqueous sodium bicarbonate and finally dried over anhydrous magnesium sulfate. The solvent is allowed to evaporate to give a crude product which when recrystallized from toluene:hexane (1:3) yields 38.4 g of white solid melting at 104°-108° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH2:24][CH:23]([CH2:25][C:26]([OH:28])=O)[O:22][N:21]=3)=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.F[P-](F)(F)(F)(F)F.[N:36]1([O:45][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.NO>CN(C=O)C>[OH:45][NH:36][C:26](=[O:28])[CH2:25][CH:23]1[O:22][N:21]=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:19][CH:18]=2)[CH2:24]1
Reactant: Cc1cc(COc2ccc(C3=NOC(CC(=O)O)C3)cc2)c2ccccc2n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(COc2ccc(C3=NOC(CC(=O)NO)C3)cc2)c2ccccc2n1
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
The {3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-acetic acid (0.15 g, 0.4 mmol) was combined with BOP (0.265 g, 0.6 mmol) and diisopropylethylamine (0.5 mL) in DMF (5 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 15 minutes, and then hydroxylamine hydrochloride (0.042 g, 0.6 mmol) was added. The reaction was stirred overnight, concentrated in vacuo, and triturated with water saturated KH2PO4 solution to give a precipitate. The crude product was purified by HPLC on a C-18 column eluting with an acetonitrile/water/TFA gradient to give the title compound (0.05 g, 25%) as an amorphous solid. MS found: (M+H)+=392.
Reaction SMILES: [CH3:1][CH:2]([CH:4](O)[CH:5]([CH3:7])[CH3:6])[CH3:3].S(=O)(=O)(O)O.[CH:14]([OH:16])=[O:15]>>[CH3:1][C:2]([CH3:3])([CH2:4][CH:5]([CH3:7])[CH3:6])[C:14]([OH:16])=[O:15]
Reactant: CC(C)C(O)C(C)C
Reactant: O=CO
Agent: O=S(=O)(O)O
Product: CC(C)CC(C)(C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,4-Dimethyl-3-pentanol (29 g, 0.25 mole), dissolved in formic acid (98%, 46 g, 1 mole), was added dropwise over one hour to a rapidly-stirred, ice-cooled mixture of formic acid (98%, 3 ml) and concentrated sulfuric acid (270 ml). During the addition the reaction mixture foamed vigorously and was stirred for a further one hour at 10°-20° C. The mixture was poured on to ice (1 kg) and the resulting solution extracted with hexanes (3×200 ml). The combined organic phases were extracted with 2N potassium hydroxide (2×200 ml) plus ice (50 g) and the aqueous extracts washed with hexanes (100 ml). The aqueous phase was then acidified (pH 2) and the product extracted into hexanes (3×200 ml). After washing with saturated sodium chloride and drying (MgSO4), the solution was evaporated under reduced pressure and the residue distilled to give 2,2,4-trimethylpentanoic acid (36 g).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[C:11]([NH2:25])=[N:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[H-].[Na+].[N:28]1[CH:33]=[CH:32][C:31]([C:34](=O)[CH2:35][C:36](OCC)=[O:37])=[N:30][CH:29]=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[C:11]2=[N:25][C:34]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][N:30]=3)=[CH:35][C:36](=[O:37])[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: CCOC(=O)N1CCN=C(N)C(N2C(=O)c3ccccc3C2=O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a suspension of 33.00 g (89.97 mmol) of (+/−)-5-amino-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,3,6,7-tetrahydro-[1,4]diazepine-1-carboxylic acid ethyl ester hydrochloride (1:1) in 300 mL of tetrahydrofuran was added 6.47 g (161.94 mmol) of sodium hydride (60% in oil), the reaction mixture was stirred at room temperature for 1 h and 17.47 g (89.97 mmol) of ethyl 3-(pyrimidin-4-yl)-3-oxopropionate dissolved in 300 mL of toluene was added. The resulting solution was evaporated to remove tetrahydrofuran, heated under reflux and 5.00 mL of glacial acetic acid was added. The reaction mixture was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The mixture was dissolved in dichloromethane, washed with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was triturated with diethyl ether and filtered to afford 18.60 g (45%) of the product as a brown powder. The compound was used as such in the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+].[C:23](#N)[CH3:24]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:24]2[CH:23]=[CH:6][CH:7]=[CH:2][CH:3]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1
Reactant: CC#N
Reactant: N#CC1CCN(c2c(Cl)cncc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CC1CCN(c2c(Cl)cncc2-c2ccccc2)CC1
Yield: 22 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonitrile E48 (100 mg, 0.39 mmol), phenyllboronic acid (57 mg, 0.47 mmol), tetrakis(triphenylphosphine)palladium(0) (22 mg, 5 mol %), 0.5 M sodium carbonate (1.1 mL, 0.55 mmol) and acetonitrile (3.5 mL) for 45 min. The crude product was purified by preparative hplc (H2O, MeCN, 90:10-10:90, 30 min) to furnish the title compound (25 mg, 22%), LC-MS (ESI, 3.5 min) Rt 2.24 min, m/z 298 (100%, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[CH3:16]O>>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:16])=[O:8])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)s1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 5-chloro-2-thiophenecarboxylic acid (10 g, 61.5 mmol) in methanol (200 ml) was added sulfuric acid (0.983 ml, 18.45 mmol). The resulting solution stirred at 50° C. overnight. H2O (50 mL) was added and the reaction was cooled to 0° C. in an ice-bath. The pH was adjusted to ˜12 and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification providing methyl 5-chloro-2-thiophenecarboxylate (7.2 g, 40.8 mmol, 66.3% yield): LCMS (ES) m/z 178 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([OH:24])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: O=C=NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 24 h

Procedure:
A solution of 3.2 g (12.3 mmol) of (1-benzyloxycarbonyl-piperidin-4-yl)isocyanate from Step A in 25 mL of DMF was slowly added to a suspension of CuCl3 in 25 mL of DMF and 12 mL of t-butanol. The reaction was stirred for 24 h and then diluted with water and extracted twice with 1:1 ether:ethyl acetate. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FCC eluting with 20% ethyl acetate/hexanes to afford 685 mg of title compound. 1H NMR (400 MHz, CDCl3): δ 1.26 (m, 2H), 1.42 (s, 9H), 1.90 (br d, J=12, 2H), 2.90 (br t, 2H), 3.58 (m, 1H), 4.08 (m, 2H), 4.42 (br s, 1H), 5.09 (s, 2H), 7.33 (m, 5H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[CH3:24])[C:10]([CH2:12][C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][C:10]1[N:9]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[CH3:24])[C:8]2[CH:25]=[CH:26][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Cc1ccco1)n2C1CCCCC1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCCCC1n1c(Cc2ccco2)nc2cc(C(=O)O)ccc21
Reaction time: 16 h
Yield: 54.5 %

Procedure:
To 1.30 g of 2-Furan-2-ylmethyl-1-(2-methyl-cyclohexyl)-1H-benzoimidazole-5-carboxylic acid methyl ester in 15 ml of methanol were added 6 ml of 2 M aqueous sodium hydroxide solution. The reaction stirred at it for 16 h. The reaction mixture was adjusted to pH 5 by the addition of 2M aqueous hydrochloric acid and was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. The residue was precipitated using heptane to yield 0.68 g (54%) of 2-Furan-2-ylmethyl-1-(2-methyl-cyclohexyl)-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1([C:18]([O:20]CC)=[O:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)#[N:4]>C1COCC1.C(OCC)C>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([C:3]#[N:4])([C:18]([OH:20])=[O:19])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
An aqueous solution of lithium hydroxide (2M, 39.0 mL, 77.92 mmol) was added to a stirred solution of 1-tert-butyl 4-ethyl 4-cyanopiperidine-1,4-dicarboxylate (Intermediate 7) (5.5 g, 19.48 mmol), in THF (78 mL) at 25° C. The resulting mixture was stirred at 25° C. for 3 hours and monitored by TLC. The reaction mixture was diluted with diethyl ether (150 mL), and washed with water (100 mL). The aqueous layers were combined and then acidified with citric acid (1N, 200 mL). The product was extracted into DCM. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford 1-(tert-butoxycarbonyl)-4-cyanopiperidine-4-carboxylic acid (4.50 g, 91%). This material was used in the next steps without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].C1([O:10][C:11](=O)[NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:32]#[N:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[CH:15][CH:14]=2)C=CC=CC=1>O1CCOCC1>[C:32]([C:26]1([C:22]2[CH:21]=[C:20]([S:19][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:11]([NH:2][NH2:3])=[O:10])=[CH:18][CH:17]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)#[N:33]
Reactant: NN
Reactant: N#CC1(c2cccc(Sc3ccc(NC(=O)Oc4ccccc4)cc3)c2)CCOCC1
Solvent: C1COCCO1
Solvent: O
Product: N#CC1(c2cccc(Sc3ccc(NC(=O)NN)cc3)c2)CCOCC1
Temperature: 110 °C

Procedure:
Hydrazine hydrate (99%, 0.44 g, 8.72 mmol) was added to a solution of phenyl(4-{[3-(4-cyanotetrahydro-2H-pyran-4-yl)phenyl]thio}phenyl)carbamate (1.50 g, 3.49 mmol) (example 5) in 1,4-dioxane (10 mL). The reaction mixture was refluxed at 110° C. for about 4 hours. The solvent was evaporated under vacuum and water was added. The white solid so obtained was filtered under vacuum and dried to obtain the title compound. Yield: 1.0 g
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:13]([NH:17][OH:18])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([N+:17]([O-:18])=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)NO
Product: CC(C)(C)[N+]([O-])=Cc1ccc(S(N)(=O)=O)cc1

Procedure:
Using 4-aminosulfonylbenzaldehyde and N-tert-butylhydroxylamine and following the procedures described herein, the title compound was prepared as a white powder, m.p. 219.1-219.4° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[NH:7][C:6]=2[N:14]=1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:23])C=1Cl>C1COCC1.O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[C:12](=[O:23])[CH2:11][CH2:10][CH2:9][C:8]=3[NH:7][C:6]=2[N:14]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Brc1ccc2c3c([nH]c2n1)CCCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCCc2[nH]c3nc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.2 %

Procedure:
A solution of 2-bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole (3.84 g, 15.2 mmol) in THF (135 mL) and H2O (15.2 mL) was cooled to 0° C. and treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.92 g, 30.5 mmol) in THF (60.3 mL) at such a rate that the reaction mixture did not exceed 0° C. The resulting solution was warmed to ambient temperature and stirred for 5 h. The solution was diluted with saturated NaHCO3 solution (100 mL), and the aqueous solution was extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (80 g ISCO dry load 80:18:2 CH2Cl2/MeOH/NH4OH, 1000 mL) followed by trituration with MeOH provided the title compound (1.58 g, 39%) as an off-white solid: 1H NMR (500 MHz, THF-d8) δ 8.23 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0, 1H), 4.73 (s, 1H), 3.02 (t, J=8.0 Hz, 2H), 2.51-2.47 (m, 2H), 2.27-2.22 (m, 2H); ESI MS m/z 265 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]([N:14]3[CH2:18][C@H:17]([SH:19])[CH2:16][C@H:15]3[CH2:20][O:21][CH2:22][C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[F:31])=[O:13])[C:5]=2[O:4][CH2:3][CH2:2]1.[C:32](Cl)(=[O:34])[CH3:33]>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]([N:14]3[CH2:18][C@H:17]([S:19][C:32](=[O:34])[CH3:33])[CH2:16][C@H:15]3[CH2:20][O:21][CH2:22][C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[F:31])=[O:13])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(Oc1cccc2c1OCCO2)N1C[C@H](S)C[C@H]1COCc1cc(F)c(F)cc1F
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)S[C@@H]1C[C@@H](COCc2cc(F)c(F)cc2F)N(C(=O)Oc2cccc3c2OCCO3)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
A solution of 10 g (21.96 mmol) (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2,3-dihydro-benzo [1,4]dioxin-5-yl ester in 130 ml pyridine were treated at 0° C. with 3.12 ml (43.92 mmol) acetyl chloride and stirred for 6 h at RT. The reaction was poured on ice water and extracted wit Et2O (3×). The organic phases were washed with aqueous 1 N HCl and 10% NaCl, dried (Na2SO4) and evaporated. Flash chromatography on silica gel (CH2Cl2/Et2O 99.5:0.5 to 98:2) gave 9.94 g (91%) (2S,4R)-4-Acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidin-1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester, MS: 498 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11](=[O:12])[O:13][CH2:14][CH3:15]
Reactant: CCOC(=O)Cl
Reactant: NCc1ccccc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NCc1ccccc1Cl
Reaction time: 0.67 h

Procedure:
2-Chlorobenzylamine (1.7734 g) was dissolved in pyridine (10 ml), and to the solution was added dropwise ethyl chloroformate (1.437 ml) during 20 minutes under ice-cooling. After the mixture was stirred for 40 minutes, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (2.715 g, quantitative yield).