Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(N)CN.C(O)(=[O:14])C(C)C.[C:16]([O-:20])(=[O:19])[CH2:17][OH:18].CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-]>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:17]([OH:14])(=[O:18])[C:16]([OH:20])=[O:19]
Reactant: CC(C)C(=O)O
Reactant: O=C([O-])CO
Reactant: O=C(O)CO
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: NCCN
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Temperature: 5 °C
Reaction time: 2.25 h

Procedure:
A 300-mL EZE-Seal stirred autoclave reactor equipped with Dispersimax Impeller (Autoclave Engineers) was charged with 100 mL of a solution containing glycolic acid (0.750M), ethylenediamine (0.863M), isobutyric acid (0.100M, HPLC internal standard), and flavin mononucleotide (0.01 mM), at pH 9.3, and the solution cooled to 5° C. To the reactor was then added 11.9 g of Hansenula polymorpha transformant strain GO1 (100 IU glycolate oxidase and 998,000 IU catalase) which had been permeabilized by treatment with 0.1% Triton X-100/1 freeze-thaw, and the reactor purged with oxygen. The mixture was then stirred at 500 rpm, and oxygen was bubbled through the mixture at 100 mL/min using a sparge tube located below the surface of the reaction mixture. The reaction was monitored by taking a 0.40 mL aliquot of the reaction mixture at regular intervals, filtering the aliquot using a Millipore Ultrafree-MC 10,000 NMWL Filter Unit, and analyzing the filtrate by HPLC. After 2.25 h, the yields of glyoxylic acid, oxalic acid, and formic acid were 100%, 0%, and 0%, respectively, with no glycolic acid remaining. The recovered activities of permeabilized-cell glycolate oxidase and catalase were 158% and 82% of their initial values, respectively.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[S:17](Cl)Cl.C(N(CC)CC)C.[CH2:27]([O:29][C:30](=[O:37])[CH2:31][NH:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH3:28]>C(Cl)Cl>[CH2:33]([N:32]([CH2:31][C:30]([O:29][CH2:27][CH3:28])=[O:37])[S:17][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCNCC(=O)OCC
Reactant: ClSCl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(CC(=O)OCC)SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 11 g quantity (0.05 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate was dissolved in 70 ml of methylene chloride, 5.2 g (0.05 mole) of sulfur dichloride was added to the solution with cooling, and 5 g (0.05 mole) of triethylamine was further added dropwise to the solution at -10° to -5° C. The mixture was stirred at 0° C. for one hour and further at room temperature for 2 hours. After cooling to -10° to -5° C., 8.0 g (0.05 mole) of N-butylglycine ethyl ester was added dropwise to the mixture, and 5 g (0.05 mole) of triethylamine was further added dropwise to the mixture. The resulting mixture was stirred at 0° C. for 2 hours and thereafter allowed to stand overnight at room temperature. With addition of 100 ml of methylene chloride, the reaction mixture was washed with 100 ml of water three times. The methylene chloride layer was dried and then concentrated in a vacuum to give an oily product, which was almost entirely composed of the desired product although containing small amounts of impurities. Yield: 15.7 g (76.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[Br:10]Br.S([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[Br:10][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:9])=[C:4]([Cl:8])[CH:5]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Oc1c(Cl)cc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
A stirred solution of 2,6-dichlorophenol (20 g, 123.4 mmol) in acetonitrile (200 mL) was cooled to 0° C. and bromine (23.7 g) in acetonitrile (50 mL) was added dropwise. The red solution was stirred at 0° C. for 2 h and a saturated aqueous solution of sodium sulphite was added until the red color disappeared. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. Concentration of the combined organic phases gave a yellow oil, which was purified on a silica gel column (heptane/ethyl acetate, 10:1) to give 17.8 g of 4-bromo-2,6-dichlorophenol as a white solid. Yield: 60%; 1H NMR (400 MHz, CDCl3): δ 7.42 (s, 2H), 5.9 (br s, 1H) ppm.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[S:11][CH:12]=[CH:13][C:14]=3[C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[C:4]2[CH:3]=[CH:2]1.[CH3:22][NH:23][CH3:24].[O:25]1[CH2:29]CCC1>>[CH3:22][N:23]([CH3:24])[C:29]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)=[CH:16][CH:17]=1)=[O:25]
Reactant: CNC
Reactant: C1CCOC1
Reactant: Nc1ccc(-c2ccsc2-c2ccnc3[nH]ccc23)cc1
Product: CN(C)C(=O)Nc1ccc(-c2ccsc2-c2ccnc3[nH]ccc23)cc1

Procedure:
Following the procedure described in Example 5a with 4-[2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-thienyl]aniline and 2M dimethylamine in tetrahydrofuran provided title compound. ESMS [M+H]+: 363.2
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:19]=4[CH3:34])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl.C1COCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C:20]2[C:19]([CH3:34])=[C:18]([C:7]3[C:6]4[C:5]5[C:13](=[CH:14][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:3][CH:4]=5)[NH:12][C:11]=4[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=3)[CH:23]=[CH:22][CH:21]=2)=[O:33])=[CH:31][CH:30]=1
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(N)ccc3c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(NS(C)(=O)=O)ccc3c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 7-amino-4-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-1-carboxamide (Example 54-5, 30 mg, 0.066 mmol) and TEA (0.018 mL, 0.133 mmol) in DCM-THF (2:1, 3 mL) was treated with methanesulfonyl chloride (10 μL, 0.133 mmol). The mixture was stirred at rt for 1.5 h, and was concentrated and purified by preparative HPLC to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(methylsulfonamido)-9H-carbazole-1-carboxamide as a white solid (Example 59-1, 3.5 mg, 9%). 1H NMR (500 MHz, methanol-d4) δ 7.91-8.01 (2H, m), 7.83 (1H, d, J=7.8 Hz), 7.45 (1H, d, J=1.7 Hz), 7.42 (1H, d, J=7.8 Hz), 7.34 (1H, t, J=7.8 Hz), 7.12-7.20 (3H, m), 6.95 (1H, d, J=7.8 Hz), 6.88 (1H, d, J=8.6 Hz), 6.73 (1H, dd, J=8.5, 2.1 Hz), 2.85 (3H, s), 1.90 (3H, s). Mass spectrum m/z 531.0 (M+H)+. Also obtained was 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(N-(methylsulfonyl)methylsulfonamido)-9H-carbazole-1-carboxamide as a white solid (Example 59-2, 14 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 11.67 (1H, s), 10.08 (1H, s), 8.21 (1H, br. s.), 7.97-8.08 (3H, m), 7.79 (1H, d, J=1.8 Hz), 7.53 (1H, br. s.), 7.48 (1H, d, J=7.3 Hz), 7.26-7.39 (3H, m), 7.15 (1H, d, J=6.5 Hz), 6.93-7.03 (2H, m), 6.86 (1H, d, J=8.3 Hz), 3.46 (6H, d, J=9.0 Hz), 1.86 (3H, s). Mass spectrum m/z 607.2 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:24]=4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.NC1C=C(C2N=C3N(C=2C2C=CN=C(NC4C=CC=C(OCCCN5CCOCC5)C=4)N=2)C=CS3)C=CC=1.[CH3:75][C:76]1[CH:84]=[CH:83][CH:82]=[CH:81][C:77]=1[C:78](Cl)=[O:79].FC1C=CC=C(F)C=1C(Cl)=O>>[CH3:75][C:76]1[CH:84]=[CH:83][CH:82]=[CH:81][C:77]=1[C:78]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:24]=4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:3]=1)=[O:79]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1
Agent: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Agent: O=C(Cl)c1c(F)cccc1F
Product: Cc1ccccc1C(=O)Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1

Procedure:
The title compound was prepared as described in EXAMPLE 297, with the following substitutions: 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(2-morpholinoethyl)phenyl)pyrimidin-2-amine for 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(3-morpholinopropoxy)phenyl)pyrimidin-2-amine and 2-methylbenzoyl chloride for 2,6-difluorobenzoyl chloride. (ESI(+)) m/e 616 (M+H)+; (ESI(−)) m/e 614 (M−H)−; 1H-NMR (300 MHz, DMSO-d6) □ 10.40 (s, 1H), 9.61 (s, 1H), 8.81 (d, 1H), 8.29 (d, 1H), 8.06 (s, 1H), 7.84 (d, 1H), 7.25-7.64 (m, 9H), 7.21 (t, 1H), 6.86 (d, 1H), 6.65 (d, 1H), 3.53-3.62 (m, 4H), 3.17 (d, 2H), 2.67-2.77 (m, 2H), 2.36-2.44 (m, 7H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[O:4].FC(F)(F)[C:7]1[CH:8]=[C:9]([C:17](C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)(O)[C@@H:18]2CCCN2)[CH:10]=[C:11](C(F)(F)F)[CH:12]=1.C1(CCC=O)C=CC=CC=1.[CH:50](OC)([O:53][CH3:54])[O:51][CH3:52].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:17]([C@H:18]([CH:50]([O:53][CH3:54])[O:51][CH3:52])[C@@H:3]([OH:4])[CH2:2][Cl:1])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:7][CH:8]=1
Reactant: COC(OC)OC
Reactant: O=CCCl
Reactant: OC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=CCCc1ccccc1
Solvent: O
Product: COC(OC)[C@@H](Cc1ccccc1)[C@@H](O)CCl
Temperature: 23 °C

Procedure:
To a 40% aqueous chloroacetaldehyde solution (0.75 mmol, 123 μL) were added (S)-2-[bis(3,5-bis-trifluoromethylphenyl)hydroxymethyl]pyrrolidine (0.05 mmol, 10 mol % relative to 3-phenylpropanal), the solvent shown in Table 1 (0.5 mL) and 3-phenylpropanal (aldehyde compound (1), 0.5 mmol). The reaction mixture was stirred at 23° C. for the time shown in Table 1, trimethyl orthoformate (6.0 mmol) and p-toluenesulfonic acid monohydrate (0.1 mmol) were added thereto, and the mixture was stirred at 23° C. for 1 hr. The acetalization reaction was quenched by the addition of saturated aqueous sodium hydrogen carbonate solution. The organic materials were extracted with chloroform (threetimes), and the extract was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:hexane=1:6) to give (2R,3S)-3-benzyl-1-chloro-4,4-dimethoxybutan-2-ol. The yield, syn/anti ratio and enantiomeric excess are shown in Table 1. The yield was calculated as a yield over two steps. The syn/anti ratio was determined by 1H-NMR spectrum. The enantiomeric excess was determined by HPLC equipped with CHIRALPAK AD-H column (iPrOH:hexane=1:100) (0.25 mL/min, the retention time of the minor enantiomer=32.1 min, the retention time of the major enantiomer=41.8 min) after conversion to the corresponding 3,5-dinitrobenzoate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([S:14]([N:17]([C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])[C:18]3[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:30]([O:29][C:27]([N:17]([C:18]1[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=1)[S:14]([C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH:35]([C:36]([O:38][CH3:39])=[O:37])[CH3:40])=[CH:3][CH:4]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:16])=[O:15])=[O:28])[CH:31]([CH3:33])[CH3:32]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(O)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Yield: 57.3 %

Procedure:
A mixture of 2-(4-hydroxyphenyl)-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.472 g), methyl 2-bromopropionate (217mg) and potassium carbonate (166 mg) in acetone (20 ml) was heated under reflux for 15 hours. Volatile material was removed by evaporation and water (25 ml) was added to the residue. The mixture was extracted with ethyl acetate (25 ml) and the extracts were washed with 2M sodium hydroxide solution (10 ml) and water (20 ml). The solution was dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give N-(isobutoxycarbonyl)-2-(4-[1-(methoxycarbonyl)ethoxy]phenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.32 g); 1H NMR (DMSO-d6): 0.6 (d, 6 H), 1.5-1.7 (m, 4 H), 2.5 (s, 3 H), 3.7 (s, 3 H), 3.8 (d, 2 H), 4.0 (s, 3 H), 5.1 (q, 1 H), 6.95 (d, 2 H), 7.5 (d, 2 H), 7.7-7.8 (m, 1 H), 8.2 (s, 1 H), 8.85 (d, 1 H), 8.9 (d, 1 H).
Reaction SMILES: [C:1]([C:4]1([CH2:11][CH:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6]C1=O)(=[O:3])C.[OH:26]O>C(O)(C)(C)C.S(=O)(=O)(O)O>[C:22]([O:21][C:19]([CH:12]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:11][C:4]1([C:1]([OH:26])=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COCCOCC(CC1(C(C)=O)CCCCC1=O)C(=O)OC(C)(C)C
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: COCCOCC(CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-acetyl-2-[2-(tert-butoxycarbonyl)-3-(2-methoxyethoxy)propyl]cyclohexanone (see Preparations 5 and 11) (50 mg, 0.14 mmol) in tert-butanol (0.5 ml) was added a 30% aqueous hydrogen peroxide solution (0.02 ml, 0.168 mmol and concentrated sulphuric acid (one drop) at room temperature. The mixture was stirred at room temperature for 4 hours, partitioned between dichloromethane (10 ml) and water (10 ml), and the layers separated. The aqueous layer was extracted with dichloromethane (2×10 ml), the combined organic extracts dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound, (49 mg). Rf. 0.36 (silica, ethyl acetate). 1H-NMR (300 MHz, CDCl3):=1.43 (s, 9H), 1.43-1.60 (m, 2H), 1.61-1.65 (m, 4H), 1.78 (dd, 1H), 2.0 (dd, 1H), 2.08-2.20 (m, 2H), 2.59-2.70 (m, 1H), 3.38 (s, 3H), 3.48-3.65 (m, 6H) ppm.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[NH2:19][CH2:20][CH2:21][N:22]1[C@@H:27]([CH3:28])[CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][C@H:23]1[CH3:36]>>[NH3:3].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:19][CH2:20][CH2:21][N:22]1[C@@H:27]([CH3:28])[CH2:26][N:25]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:24][C@H:23]1[CH3:36])=[O:18]
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCN
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Product: N

Procedure:
The title compound was prepared by a similar method to Preparation 4 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and tert-butyl (cis)-4-(2-aminoethyl)-3,5-dimethyl-1-piperazinecarboxylate [see Preparation 7]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 4:1:0 changing to 93:7:1, by volume, dichloromethane:methanol:0.88 aqueous ammonia solution in 1% increments to afford tert-butyl (cis)-4-[2-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)ethyl]-3,5-dimethyl-1-piperazinecarboxylate as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C@@H](/N=C/CC(C)(C)C)C)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)\[C:26]#[N:27])[CH:21]=[CH:22][CH:23]=1.C([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])C>ClCCCl>[C:1]([O:5][C:6]([C:40]1([CH3:41])[CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)[C:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)([C:26]#[N:27])[CH:38]([CH2:39][C:1]([CH3:4])([CH3:3])[CH3:2])[NH:37]1)=[O:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](/N=C/CC(C)(C)C)C(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)CC1NC(C)(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 87 %

Procedure:
In a manner similar to the method described in Example 1c, (S)-2-[3,3-dimethyl-but-(E)-ylideneamino]-propionic acid tert-butyl ester prepared in Example 33a (2.4 g, 11 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (2.4 g, 8.8 mmol) prepared in Example 1b, AgF (1.6 g, 13 mmol), and triethylamine (2.4 g, 24 mmol) in 1,2-dichloroethane (150 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2.4 g, 54%).
Reaction SMILES: [C:1]1([C:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](B(O)O)=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[C:1]1([C:7]2[C:20]3[C:15]([C:14]([C:28]4[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][CH:27]=4)=[C:13]4[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]4)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: Brc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Yield: 43.8 %

Procedure:
An amount of 2.46 g (8.26 mmol) of 10-phenylanthracene-9-boronic acid synthesized in the same manner as in Exemplary Synthesis 2, 9.75 g (41.3 mmol) of p-dibromobenzene, and 250 mg of tetrakis triphenylphosphine palladium as catalysis were dissolved in a mixed solvent of 60 ml of toluene and 15 ml of ethanol. Then, 30 ml of 2M sodium carbonate solution was added and allowed to react at 90° C. for 12 hours. After the reaction was completed, the organic layer was separated and purified by column chromatography to obtain 1.48 g (3.62 mmol) of 9-phenyl-10-(4-bromophenyl)anthracene. The yield was 43.8%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[CH2:29][NH2:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]3[C:15]=2[CH2:29][NH:30][C:39](=[O:41])[N:21]3[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(NCc3ccccc3)c2CN)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc3c2CNC(=O)N3Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The crude 4-(2-aminomethyl-3-benzylamino-6-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester of step 3 was dissolved in 10 mL dichloromethane and cooled to 0° C. Triethylamine (293 μL, 3 eq., 2.1 mmol) and 69 mg (1 eq., 0.233 mmol) triphosgene were added. The reaction mixture was stirred for 10 minutes. The mixture partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated. Column chromatography, eluting with acetone/dichloromethane provided 141 mg of 4-(1-benzyl-6-fluoro-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:7]=[N:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:4]1.C(O[C@@H:18]1[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:29]([O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:19]1[O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C.ClCCCl>C1C=CC=CC=1>[C:21]([O:20][C@@H:19]1[C@H:29]([O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:40][C@H:18]1[N:3]1[CH:7]=[N:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:4]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: C[Si](C)(C)n1cnc(CC(=O)O)n1
Solvent: ClCCCl
Solvent: c1ccccc1
Product: O=C(O)Cc1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Yield: 85.5 %

Procedure:
55 mmoles of 1-trimethylsilyl-3-carboxymethyl-1,2,4-triazole and 55 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose were combined, in 100 ml. of 1,2-dichloroethane, with 5 mmoles of (CH3)3Si--O--SO2CF3 in 20 ml. of C6H6 and refluxed for 4 hours at a bath temperature of 100° C. After working up the mixture as usual, 24 g. (85.5%) of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-3-carboxymethyl-1,2,4-triazole was produced.
Reaction SMILES: O.ON1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2N=N1.[NH2:12]OC1CCCCO1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)C[C:21]2=[O:22]>CN(C=O)C>[C:21]([NH2:12])(=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: NOC1CCCCO1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 388.9 %

Procedure:
To a solution of 2-[4-benzo[b]thiophene-2-sulfonylamino]benzoic acid (300 mg, 0.90 mmol) in DMF (20 mL) at room temperature were added 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 207 mg, 1.08 mmol), and 1-Hydroxybenzotriazole hydrate (HOBT, 182 mg, 1.35 mmol). The mixture was stirred 20 min. at room temperature then NH2OTHP (158 mg, 1.35 mmol) was added. The resulting mixture was heated at 50° C. for 24 h then stirred at room temperature for 24 h. The DMF solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2 and washed with brine or a saturated aqueous solution of NaHCO3. The combined organic extracts were dried over (MgSO4) then condensed. The crude compound was purified by flash chromatography using CH2Cl2/MeOH (9:1) as solvent mixture. The residue was then dissolved in methanol (20 mL) then 10-camphorsulfonic acid (CSA, 100 mg, 0.45 mmol) was added. The mixture was stirred 2 h at room temperature then the solvents were evaporated under reduced pressure at room temperature to avoid thermal decomposition. The crude was purified by flash chromatography using CH2Cl2/MeOH (9:1) as solvent mixture. A second purification was performed using a preparative high pressure liquid chromatography using a gradient of water/CH3CN (10-85%) as solvent giving the title compound 13 as a red solid (212 mg, 68%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.Cl.[C-:10]#[N:11].[K+]>O>[OH:8][C:5]1([C:10]#[N:11])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(=O)CC1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Product: CN1CCC(O)(C#N)CC1
Temperature: 10 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To freshly distilled 1-methylpiperidin-4-one (81.72 g, 0.72 mole) in water (200 cc), were added about 100 cc HCl 37% to pH 3. The reaction mixture was cooled in an ice bath and potassium cyanide (49 g, 0.75 mole) in water (200 cc) was added at an adequate rate in order to maintain an internal temperature of about 10° C. The reaction was stirred two hours more after the addition and then filtered. After washing with water and drying, the product, 4-hydroxy-4-cyano-1-methylpiperidine, was obtained in 67% yield as a white powder (67 g, 0.48 mole, mp. 135° C.),