Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:17])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:4]([CH3:18])=[N:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CC(OC)(C)C>[CH3:1][N:2]1[C:6]([N:7]([CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:36][CH:37]=2)[C:8](=[O:17])[C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][C:4]([CH3:18])=[N:3]1
Reactant: Cc1cc(NC(=O)C(=O)c2ccccc2)n(C)n1
Reactant: FC(F)(F)c1ccc(CCBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: Cc1cc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)C(=O)c2ccccc2)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of N-(2,5-dimethyl-2H-pyrazol-3-yl)-2-oxo-2-phenyl-acetamide (200 mg, 0.82 mmol) in DMF (2 mL) was added at 0° C. potassium bis(trimethylsilyl)amide (0.91 M in THF, 1.1 mL, 0.99 mmol) over a period of 5 min. The ice bath was removed and the solution was stirred for 1 h at ambient temperature. After the addition of 1-(2-bromo-ethyl)-4-trifluoromethyl-benzene (which might be prepared according to WO2005123748, 250 mg, 0.99 mmol) the reaction mixture was stirred for 18 h at ambient temperature. After the addition of cesium carbonate (1.40 g, 4.11 mmol) and further 1-(2-bromo-ethyl)-4-trifluoromethyl-benzene (996 mg, 3.95 mmol) it was stirred for 20 h at ambient temperature. The resulting mixture was diluted with TBME (15 mL) and washed twice with water (10 mL) and brine (10 mL). The combined aqueous layers were extracted with TBME (15 mL) and the combined organic layers were dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (113 mg, 33%) as a light brown oil. MS m/e: 416.3 [M+H]+.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3[O:14][C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.[CH:49]1[CH:50]=[CH:51][C:52]([NH2:63])=[C:53]([C:55]([CH2:57][C@H:58]([NH2:62])[C:59]([OH:61])=[O:60])=[O:56])[CH:54]=1>>[CH:49]1[CH:50]=[C:51]([OH:14])[C:52]([NH2:63])=[C:53]([C:55]([CH2:57][C@H:58]([NH2:62])[C:59]([OH:61])=[O:60])=[O:56])[CH:54]=1
Reactant: Nc1ccccc1C(=O)C[C@H](N)C(=O)O
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: Nc1c(O)cccc1C(=O)C[C@H](N)C(=O)O

Procedure:
The reaction mixture contained: 75 μl of suspended homogenate; 100 μl of substrate solution containing 50 mM K-phosphate buffer pH 7.5, 2 mM MgCl2, 0.4 mM NADPH, 50 μM L-kynurenine (final concentration), and 25 μl of different concentrations of inhibitor solutions. The reaction was stopped by addition of 200 μl of 1 M HClO4 after 60 min incubation. L-3-hydroxykynurenine formed was quantified by HPLC with coulometric detection at a working voltage of +0.2 V. The column was a 10 cm C18 reversed phase (3 μm. The mobile phase consisted of 950 ml distilled water, 20 ml acetonitrile, 9 ml triethylamine, 5.9 ml phosphoric acid, 100 mg sodium EDTA and 1.5 g heptanesulfonic acid. The flow rate was 1 ml/min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[O:28]1[CH2:30][C@H:29]1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl.CO>[CH2:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:30][C@H:29]([OH:28])[CH2:31][O:32][C:33]3[CH:34]=[CH:35][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:37][CH:38]=3)=[CH:27][CH:26]=2)[CH2:10][CH2:11]1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CS(=O)(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(NS(C)(=O)=O)cc3)cc2)CC1
Yield: 12.1 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide (0.245 g, 0.58 mmol) was reacted with N-{4-[(2S)oxiranylmethoxy]phenyl}methanesulfonamide (0.13 g, 0.53 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.04 g, 0.064 mmol).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][N:15]3[CH2:20][C@@H:19]4[CH2:21][C@H:16]3[CH2:17][N:18]4C(OC(C)(C)C)=O)=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1.Cl.O1CCOCC1>CO>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH2:14][N:15]3[CH2:20][C@@H:19]4[CH2:21][C@H:16]3[CH2:17][NH:18]4)=[N:12][N:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: FC(F)(F)c1ccc(-n2nnnc2CN2C[C@@H]3C[C@H]2CN3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a solution of 1,1-dimethylethyl (1S,4S)-5-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (470 mg, 1.107 mmol, Intermediate 17) in methanol was added 4M hydrogen chloride in 1,4-dioxane (5 mL, 20 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and poured onto a 5 g SCX cartridge. The cartridge was washed with methanol (2 column volumes) and eluted with ammonia in methanol (2 column volumes). The ammonia in methanol fractions were concentrated and the residue dried in vacuo to yield the title compound as white crystals (363 mg)
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].Cl.[OH:13][CH2:14][CH2:15][N:16]1[C:20]([CH2:21][CH3:22])=[CH:19][N:18]=[C:17]1[NH2:23].[O-]CC.[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([CH:7]=[N:23][C:17]2[N:16]([CH2:15][CH2:14][OH:13])[C:20]([CH2:21][CH3:22])=[CH:19][N:18]=2)=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Reactant: CCc1cnc(N)n1CCO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1cnc(N=Cc2cnc([N+](=O)[O-])n2C)n1CCO
Reaction time: 8 h

Procedure:
To a solution of 0.4 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde dissolved in 25 ml. of ethanol, 0.494 g. of 1-(2-hydroxyethyl)-2-amino-5-ethylimidazole hydrochloride and 0.175 ml. of sodium ethoxide in 2.89 ml. of ethanol are added. After standing overnight, the solid which precipitates is collected on the filter and washed with water. Yield: 0.269 g., m.p. 185°-187° C.
Reaction SMILES: I[Si](C)(C)C.C[O:7][C:8]1[CH:9]=[C:10]([CH3:20])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1>ClC(Cl)Cl>[CH3:20][C:10]1[CH:9]=[C:8]([OH:7])[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1
Reactant: COc1cc(C)cc(-c2ccccc2)c1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)cc(-c2ccccc2)c1
Yield: 93 %

Procedure:
Iodotrimethyl silane (26.4 ml; 0.185 mol) was added to a solution of 3-methoxy-5-phenyltoluene (26.6 g; 0.168 mol) in trichloromethane (110 ml). The mixture was reflux for 12 hours and extracted with ether. The organic phase was evaporated and purified by flash chromatography, eluting with petroleum ethyl acetate (90/10) to give 3-methyl-5-phenylphenol as a foam. Yield=93%.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[C:34]([C:42](O)=[O:43])[C:33]2=[O:45])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(OCC)(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:42]([C:34]5[C:33](=[O:45])[N:32]([C:29]6[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=6)[C:37]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:35]=5)=[O:43])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: O=C(O)c1ccc(C(F)(F)F)n(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1)c1ccc(C(F)(F)F)n(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.4 %

Procedure:
To a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (90 mg, 0.276 mmol) and 1-(4-fluorophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid (100 mg, 0.331 mmol) in N,N-dimethylformamide (2 mL) were added N,N-diisopropylethylamine (95 μL, 0.552 mmol) and HATU (126 mg, 0.331 mmol), and the mixture was stirred at room temperature for 6 hr. Ethyl acetate, tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration. The obtained slightly yellow solid was suspended in ethanol (3 mL), and the mixture was stirred at 70° C. for 17 hr. The suspension was collected by filtration and washed with ethanol to give the title compound (32.7 mg, 19%) as a slightly yellow solid.
Reaction SMILES: OC1C2C(=CC=CC=2)C(NS(C2SC=CC=2)(=O)=O)=CC=1SCC(O)=O.[C:26]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:31]=[CH:30][C:29]([S:32]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]([OH:46])=[C:38]([S:47][CH2:48][C:49]([O:51]CC)=[O:50])[CH:37]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[C:26]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:27]=[CH:28][C:29]([S:32]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]([OH:46])=[C:38]([S:47][CH2:48][C:49]([OH:51])=[O:50])[CH:37]=2)(=[O:33])=[O:34])=[CH:30][CH:31]=1
Reactant: CCOC(=O)CSc1cc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2c1O
Agent: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: O=C(O)CSc1cc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2c1O

Procedure:
5.2.61 2-(4-(biphenyl-4-ylsulfonamido)-1-hydroxynaphthalen-2-ylthio)acetic acid (14s) was prepared according to the procedure of procedure B for 10a except using ethyl 2-(4-(biphenyl-4-ylsulfonamido)-1-hydroxynaphthalen-2-ylthio)acetate (14r) and applying r.t. overnight to the reaction, which afforded the title compound 19.2 mg (40.7%) as a grey solid, m.p.: 170° C. (dec.).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dioxane (1.0 mL) at room temperature was added 2-chloro-5-trifluoromethyl-pyridine (0.11 g, 0.6 mmol) and diisopropylethyl amine (0.21 mL, 1.2 mmol). The reaction mixture was stirred at 150° C. in a microwave for 180 minutes, concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate in hexane to provide (4-methyl-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 394 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.38 (d, 1H), 7.61 (d, d 1H), 7.40-7.30 (m, 5H), 6.66 (d, 1H), 5.07 (s, 2H), 4.71-4.67 (m, 1H), 3.93 (m, 2H), 3.36 (m, 2H), 2.10 (m, 2H), 1.68 (m, 2H), 1.42 (s, 3H).
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:34])[C:18]([CH3:33])([CH3:32])[CH2:19][NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].O.CO>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:21]([NH:20][CH2:19][C:18]([CH3:33])([CH3:32])[C:17]([N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][C:9]([OH:35])=[O:8])[CH2:16][CH2:15]2)=[O:34])=[O:31])=[CH:27][CH:26]=1)(=[NH:29])[NH2:30]
Reactant: CC(C)(CNC(=O)c1ccc(C(=N)N)cc1)C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(CNC(=O)c1ccc(C(=N)N)cc1)C(=O)N1CCC(CC(=O)O)CC1

Procedure:
N-(N-4-Amidinobenzoyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid benzyl ester (0.10 g) was stirred under a hydrogen atmosphere in a 50% water/methanol mixed solution under the presence of palladium hydroxide catalyst at a room temperature for 6 hours. The catalyst was removed by filtration and the solvents were distilled off. The residue was dissolved in a 1N aqueous solution of acetic acid and the resulting solution was purified with a high performance liquid chromatography (HPLC) [column: ODS 5C18 (μ bondasphere, φ 19×150 mm), mobile phase: (A) 0.1% TFA, (B) 100% CH3CN/0.1% TFA, gradient: (A):(B)=80:20-70:30, 20 minutes, flow rate: 17 ml/min]. The desired fractions were collected and lyophilized to yield N-(N-4-amidinobenzoyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid (15 ml).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:14][CH:13]=2)=[C:8]([O:30][CH2:31][CH3:32])[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH2:31]([O:30][C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:11]=[CH:10][C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH:23][S:24]([CH:27]([CH3:28])[CH3:29])(=[O:26])=[O:25])=[CH:14][CH:13]=1)[CH3:32]
Reactant: CCOC(=O)c1ccc(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)c(OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cc(C(=O)O)ccc1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
The resultant ester may be hydrolyzed in the following manner: Mix 2-ethoxy-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid ethyl ester (38 g, 80 mmol), in ethanol (100 mL) and NaOH 2 M in water (400 mL) and stir the reaction mixture for one hour at RT. Evaporate the ethanol and wash the aqueous mixture with 200 mL of EtOAc. Acidify the aqueous mixture to pH 2 using HCl 1N. Extract the desired product with EtOAc. Dissolve the crude in warmed acetone (500 ml) and add water (600 ml), maintaining the temperature at 55° C. Stir the mixture at 60° C. for 1 hour and then to RT. overnight. Filtrate the precipitate and dry under vacuum at 45° C. overnight. Yield 28 g, 78%. 1H NMR (300 MHz, DMSO): δ 1.14 (d, J=7.0 Hz, 6H), 1.31 (t, J=7.0 Hz, 3H), 3.06 (sept, J=7.0 Hz, 1H), 4.13 (q, J=7.0 Hz, 2H), 7.10 (d, J=5.3 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.54 (d, J=5.3 Hz, 1H), 7.58-7.68 (m,4H), 7.72 (d, J=8.4 Hz, 2H), 9.22 (bs, 1H), 13.04 (bs, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:10]=[C:9]1[CH2:23]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:25][CH2:26][CH3:27].[Na+]>C(O)C>[CH2:1]([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:10]=[C:9]1[CH2:23][O:25][CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(CBr)n(Cc2ccccc2)c1C(=O)OCC
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccccc1
Reaction time: 13 h

Procedure:
A solution of 1.80 g of diethyl 1-benzyl-2-bromomethylimidazole-4,5-dicarboxylate [prepared as described in Preparation42(ii)] in 50 ml of ethanol was added dropwise to a solution of sodium ethoxide in ethanol (prepared from 0.18 g of sodium and 50 ml of ethanol), and the resulting mixture was left at room temperature for 13 hours. At the end of this time, a procedure similar to that described in preparation42(iii) was repeated, and the residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.14 g of the title compound as a syrup.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[N:19]O)[NH2:18])=[N:15][CH:16]=1>>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]1[O:9][N:19]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][N:15]=2)[N:18]=1
Reactant: O=C(O)c1occc1Br
Reactant: NC(=NO)c1ccc(Cl)cn1
Product: Clc1ccc(-c2noc(-c3occc3Br)n2)nc1

Procedure:
The title compound was prepared from 3-bromo-furan-2-carboxylic acid (381.7 mg, 2.00 mmol) and 5-chloro-pyridine-2-amidoxime (343 mg, 2.00 mmol), similar to Example 70, and yielded 353 mg (54%) of white solid. 1H NMR (CDCl3): 8.81 (d, J=2.47 Hz, 1H), 8.22 (d, J=8.24 Hz, 1H), 7.90 (dd, J=8.25, 2.48 Hz, 1H), 7.71 (d, J=1.93 Hz, 1H), 6.79 (d, J=1.64 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N=C(C1C=CC=CC=1)C#N)=O)([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22].C(N(CC)CC)C.O1CCOCC1>CO.O>[C:1]([O:5][C:6]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
2-tert-Butoxycarbonyloxyimino-2-phenylacetonitrile (1.25 g.) was added to a solution of L-proline (575 mg.) and triethylamine (0.7 ml.) in a mixture of methanol (7.5 ml.), dioxane (2.5 ml.) and water (5.0 ml.) at room temperature. The mixture was stirred for 1.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure and benzene and water were added to the residue. After shaking the resultant mixture, the aqueous layer was separated from the mixture, washed with benzene, acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. A mixture of ether and n-hexane was added to the residue and the precipitated crystals were collected by filtration and dried to give N-tert-butoxycarbonyl-L-proline (845 mg.), mp 133° to 134° C.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]([CH3:18])[CH2:14][C:15](O)=[O:16].[CH3:19][N:20]1[C:28]2[CH:27]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][NH:38][CH3:39])=[C:31]([C:40]([F:43])([F:42])[F:41])[CH:30]=3)[N:25]=[C:24]([C:44]#[N:45])[C:23]=2[N:22]=[N:21]1.Cl>C1COCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:44]([C:24]1[C:23]2[N:22]=[N:21][N:20]([CH3:19])[C:28]=2[CH:27]=[C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][N:38]([CH3:39])[C:15](=[O:16])[CH2:14][N:13]([CH3:18])[CH3:12])=[C:31]([C:40]([F:41])([F:43])[F:42])[CH:30]=2)[N:25]=1)#[N:45]
Reactant: CNCCCc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CC(=O)N(C)CCCc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
EDCI (290 mg) was added to the mixture of 2-(dimethylamino)acetic acid (155 mg), methyl-6-(4-(3-(methylamino)propyl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]-triazolo[4,5-c]pyridine-4-carbonitrile, triethylamine (0.5 ml) in THF (5 ml). The mixture was stirred at rt for 5 hours, then diluted with ethyl acetate (100 ml), washed with sodium bicarbonate (50 ml), brine (50 ml), dried over sodium sulphate, solvent removed, residue dissolved in MeOH/NMP (3:1, 6 ml), and purified by basic hplc to give free base which was then converted to HCl salt as usual (70 mg). 1H NMR (CD3OD) δ: 8.68 (s, 1H), 8.5 (s, 1H), 8.46 (d, 1H), 7.65 (d, 1H), 4.47 (s, 3H), 4.27 (s, 2H), 3.60 (t, 2H), 3.04 (s, 3H), 2.96 (s, 6H), 2.90 (t, 2H), 1.95 (m, 2H). MS m/z 460 (M+H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([CH3:26])[C@@H:6]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])=[N+:2]=[N-:3].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:27][S:28]([O:9][CH2:8][C@@H:7]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:17])[C@H:6]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[C@@H:5]([CH3:26])[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of tert-butyl [(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(hydroxymethyl)-3-methylbutyl]carbamate (0.56 g, 1.4 mmol) in pyridine (7.3 mL) at 0° C., methanesulfonyl chloride (0.14 mL, 1.9 mmol) was added followed by DMAP (0.04 g, 0.3 mmol). After stirring at 0° C. for 1 h, the mixture was diluted with EtOAc, washed with saturated aq. NaHCO3 and brine, then dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-25% EtOAc in hexanes) to afford the sub-title compound (0.59 g, 88%). LCMS calc. for C13H31N4O4SSi (M+H-Boc)+: m/z=367.2. found 367.2.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2)=[O:11])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:33]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:17]2)=[O:11])=[O:8])=[CH:25][CH:26]=1)(=[S:33])[NH2:2]
Reactant: CCOC(=O)COC1CCN(C(=O)NC(=O)c2ccc(C#N)cc2)CC1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)COC1CCN(C(=O)NC(=O)c2ccc(C(N)=S)cc2)CC1

Procedure:
In a similar manner to Example 1, starting material step (b), the product from step (c) (1.2 g), pyridine (84 ml), triethylamine (7 ml) and H2S gas were reacted to give ethyl N-[N-(4-thiocarbamoylbenzoyl)carbamoyl]piperidin-4-yloxyacetate (0.74 g) as a yellow gum: NMR Spectrum (DMSO-d6) 1.20 (3H, t), 1.50 (2H, m), 1.87 (2H, m), 3.20 (2H, m), 3.66 (3H, m), 4.12 (2H, q), 4.15 (2H, s), 7.90 (4H, m), 9.63 (1H, br s), 10.00 (1H, br s); Mass Spectrum m/Z 394 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:40])/[CH:3]=[CH:4]\[C:5]([C:7]1[CH:34]=[CH:33][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:29]=[CH:28][C:19]3[CH2:20][CH2:21][CH:22]([C:24]([O:26]C)=[O:25])[O:23][C:18]=3[C:17]=2[CH2:30][CH2:31][CH3:32])=[C:9]([CH2:35][CH2:36][CH3:37])[C:8]=1[O:38][CH3:39])=[O:6].[Li+].[OH-].Cl>C(OCC)(=O)C>[CH3:40][N:2]([CH3:1])/[CH:3]=[CH:4]\[C:5]([C:7]1[CH:34]=[CH:33][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:29]=[CH:28][C:19]3[CH2:20][CH2:21][CH:22]([C:24]([OH:26])=[O:25])[O:23][C:18]=3[C:17]=2[CH2:30][CH2:31][CH3:32])=[C:9]([CH2:35][CH2:36][CH3:37])[C:8]=1[O:38][CH3:39])=[O:6]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)/C=C\N(C)C)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc(C(=O)/C=C\N(C)C)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2
Reaction time: 2.5 h

Procedure:
The compound of Example 2 (0.11 g, 0.199 mmol) was mixed with 3.0 ml of 4:1methanol/THF and 0.3 ml of 1M LiOH and allowed to react at 0° C. for15 minutes then at room temperature for 2.5 hours. The reaction mixture waspoured into ethyl acetate and 0.5N hydrochloric acid, and the ethyl acetatelayer was washed with brine, dried over sodium sulfate, and concentrated togive the product.