Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[S:16](O)(=O)=O>>[O:8]=[C:1]1[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:16][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=2
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=S(=O)(O)O
Product: CCOC(=O)C1Sc2ccccc2C1=O
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 114.3 %

Procedure:
Ethyl benzoylacetate (100.0 g, 0.52 mol) was added dropwise over a period of 1.5 h under vigorous mechanical stirring to fuming H2SO4 37% (500.0 g) cooled at 5° C. in an ice bath. After the addition was complete the reaction mixture was stirred for 1.5 h and then added to 1000 g of ice. The solid product was collected by filtration and washed with cold water (30 ml) to give 132.1 g (85%) of Compound X as a pale yellow solid:melting point 138°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][C@@H:17]3[CH2:19][C@H:14]2[CH2:15][O:16]3)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.Cl.[CH3:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][N:39]=1)[C:34](Cl)=[O:35]>C1COCC1.ClCCl>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][N:39]=[C:31]([CH3:30])[CH:32]=3)[S:11][C:7]=2[C:6]([N:13]2[CH2:18][C@@H:17]3[CH2:19][C@H:14]2[CH2:15][O:16]3)=[CH:5][CH:4]=1
Reactant: Cc1cc(C(=O)Cl)ccn1
Reactant: COc1ccc(N2C[C@@H]3C[C@H]2CO3)c2sc(N)nc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2C[C@@H]3C[C@H]2CO3)c2sc(NC(=O)c3ccnc(C)c3)nc12
Reaction time: 24 h
Yield: 89.5 %

Procedure:
To a stirred solution of 111 mg (0.40 mmol) 4-methoxy-7-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-benzothiazol-2-ylamine and 0.26 ml (1.50 mmol) N-ethyldiisopropylamine in 20 ml THF at room temperature was added dropwise a solution of 127 mg (0.66 mmol) 2-methyl-isonicotinoyl chloride hydrochloride in 20 ml dichloromethane and stirring continued at room temperature for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (3/97 methanol/ethyl acetate) followed by trituration in ether afforded 142 mg (90%) N-[4-methoxy-7-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-benzothiazol-2-yl]-2-methyl-isonicotinamide as a yellow crystalline solid. ES-MS m/e (%): 419 (M+Na+, 17), 397 (M+H+, 100).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1.[CH3:17][NH:18][CH3:19].C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([N:18]([CH3:19])[CH3:17])=[O:16])=[N:12][CH:13]=1
Reactant: CNC
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cnc(Cl)cn1
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (1.7 mL, 19 mmol) was added to a suspension of 5-chloropyrazine-2-carboxylic acid (CAS no. 36070-80-1) (2.53 g, 16.0 mmol) in dichloromethane (25 mL) and DMF (4 drops) at RT and under argon. The mixture was allowed to stir for 1.5 h, concentrated in vacuo to and the residue was re-dissolved in dichloromethane (25 mL). Dimethylamine (2M in THF, 8.77 mL, 17.6 mmol) was then added dropwise followed by triethylamine (4.9 mL, 35 mmol) and allowed to stir for a further 5.5 hours. The reaction mixture was concentrated in vacuo and the residue was re-dissolved in dichloromethane and filtered. The filtrate was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexanes to give the desired compound (1.88 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][CH3:26])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CO.[Pd].CCO>[CH2:25]([N:8]([C@@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:26]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CCCNC1
Reaction time: 4 h

Procedure:
A solution of (R)-benzyl 3-(tert-butoxycarbonyl(ethyl)amino)piperidine-1-carboxylate (5.00 g, 13.8 mmol) in a mixture of EtOH:MeOH (1:1, 50 mL) was added to a suspension of 10% palladium on activated carbon (1.47 g, 1.38 mmol) in EtOH (20 mL) under N2 atmosphere. The mixture was degassed under N2 (3 cycles) and back filled with H2 (3 cycles) using a H2 balloon. The mixture was then stirred under H2 atmosphere for 4 hours. The reaction mixture was then filtered through a pad of celite washing with 5% MeOH/EtOAc (3×30 mL). The filtrate collected was concentrated in vacuo to provide the crude (R)-tert-butyl ethyl(piperidin-3-yl)carbamate. LCMS (APCI+) m/z 229 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]2[C:10]([NH2:15])=[N:11][NH:12][C:13]=2[NH2:14])[CH:4]=1.C(O[CH:19]=[C:20]([CH3:23])[CH:21]=O)C.C(O)(=[O:26])C.ClC1C=CC=C(C(OO)=O)C=1>C(O)(C)C.C(OCC)(=O)C.[OH-].[Na+]>[CH3:23][C:20]1[CH:19]=[N:14][C:13]2[N:12]([N:11]=[C:10]([NH2:15])[C:9]=2[C:5]2[CH:4]=[C:3]([S:2]([CH3:1])=[O:26])[N:8]=[CH:7][N:6]=2)[CH:21]=1
Reactant: CSc1cc(-c2c(N)n[nH]c2N)ncn1
Reactant: CC(=O)O
Reactant: CCOC=C(C)C=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cnc2c(-c3cc(S(C)=O)ncn3)c(N)nn2c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
4-(6-(methylthio)pyrimidin-4-yl)-1H-pyrazole-3,5-diamine (1.0 g, 4.5 mmol) was combined with 3-ethoxy-2-methylacrylaldehyde (0.63 g, 5.3 mmol) in isopropanol (12 mL). Acetic acid (0.1 mL) was added to the reaction mixture which was then sealed in a microwave vessel and heated to 160° C. for 15 min. The reaction mixture was diluted with ethyl acetate (200 mL) and 1N NaOH (60 mL), the layers separated and the organic layer concentrated to 60 mL. This solution was cooled to 0° C. and 77% m-chloroperbenzoic acid (1.9 g, 8.5 mmol) was added. After 1 hr. a yellow precipitate formed which was filter off, washed with ethyl acetate and dried to give the product, 0.39 g, 30% yield. LCMS MH+289.29. H NMR (500 MHz, DMSO-d6) 9.02 (s, 1H) 8.91 (s, 1H), 8.88 (s, 1H), 8.54 (s, 1H), 7.14 (s, 2H), 2.91 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.NC1C=CC=CC=1.[NH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][C:24]=1[OH:33].C[CH2:35][O:36]C(C)=O>C(Cl)Cl>[Cl:29][C:27]1[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][C:24]([OH:33])=[C:23]([NH:22][C:35]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:14][CH:13]=2)=[O:36])[CH:28]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: CCOC(C)=O
Reactant: Nc1ccc(Cc2ccncc2)cc1
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: O=C(Nc1ccc(Cc2ccncc2)cc1)Nc1cc(Cl)c([N+](=O)[O-])cc1O
Temperature: 42.5 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
A solution of 4-(4-pyridinylmethyl)aniline (0.300 g, 1.63 mmol) and N,N′-carbonyldiimidazole (0.268 g, 1.65 mmol) in CH2Cl2 (10 mL) was stirred at room temp. for 1 h at which time TLC analysis indicated no starting aniline. The reaction mixture was then treated with 2-amino-4-chloro-5-nitrophenol (0.318 g, 1.65 mmol) and stirred a 40-45° C. for 48 h. The resulting mixture was cooled to room temp. and diluted with EtOAc (25 mL). The resulting precipitate was separated to give the desired product (0.416 g, 64%): TLC (50% acetone/50% CH2Cl2) Rf 0.40; 1H-NMR (DMSO-d6) δ 3.90 (s, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.21 (d, J=6 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.54 (s, 1H), 8.43-8.45 (m, 3H), 8.78 (s, 1H), 9.56 (s, 1H), 11.8 (br s, 1H); FAB-MS m/z (rel abundance) 399 ((M+H)+, 10%). B6. General Method for the Synthesis of Symmetrical Diphenyl Ureas as Side-Products of Urea Forming Reactions
Reaction SMILES: NC1N=[C:6]([CH3:8])[C:5](C)=[C:4](C)N=1.[S:11]([N:17]=C=O)(N=C=O)(=[O:13])=[O:12].C1N2[CH2:26][CH2:27]N(CC2)C1>C(#N)C>[C:4]1([S:11]([NH2:17])(=[O:13])=[O:12])[C:5]([S:11]([NH2:17])(=[O:13])=[O:12])=[CH:6][CH:8]=[CH:26][CH:27]=1
Reactant: C1CN2CCN1CC2
Reactant: Cc1nc(N)nc(C)c1C
Reactant: O=C=NS(=O)(=O)N=C=O
Solvent: CC#N
Product: NS(=O)(=O)c1ccccc1S(N)(=O)=O

Procedure:
A mixture of 0.8 g of 2-amino-4,5,6-trimethylpyrimidine, 2.8 g of the crude sulfonyl isocyanate from Example 9 and a few crystals of DABCO in 25 ml of acetonitrile is stirred at room temperature for 16 hours. A small amount of unreacted aminopyrimidine is filtered off and the filtrate concentrated in-vacuo to give a hard glass. Crystallization from methanol gives N,N-diethyl-N'[4,5,6-trimethylpyrimidin-2-yl)aminocarbonyl]-1,2-benzenedisulfonamide as a white solid.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:13]=[C:12]([O:14][Si](C)(C)C)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27].CN(C=O)C.O1CCOCC1>CO>[CH3:29][O:28][C:26]([C:25]1[CH:24]=[C:23]([CH:32]=[CH:31][CH:30]=1)[CH2:22][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:14])[NH:13][C:4]1=[O:3])=[O:27]
Reactant: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccccc2n1
Reactant: COC(=O)c1cccc(CBr)c1
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Temperature: 122.5 °C
Yield: 83.7 %

Procedure:
The intermediate product 2,4-di(trimethylsilyloxy)quinazoline, methyl 3-(bromomethyl)benzoate (2.1 g, 9.2 mmol) and DMF (1 mL) were added in turn into a 50 mL single-mouth flask, and then the temperature were raised to 115-130° C. and reacted for 3 hours. 1,4-dioxane (6 mL) and methanol (10 mL) were added after the reaction mixture was cooled to 100° C. Then the mixture was refluxed for 30 minutes. The mixture was filtered after it was cooled to room temperature. The precipitate was washed with water (20 mL) and methonal (10 mL), respectively, and dried to give the title compound (1.6 g, 83.7% yield) as white powder. 1H NMR (DMSO-d6): 11.76 (s, 1H), 8.00 (dd, J=7.8 and 1.2 Hz, 1H), 7.89 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.65-7.43 (m, 3H), 7.25-7.20 (m, 2H), 5.36 (s, 2H), 3.80 (s, 3H). MS: m/z 311.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CO>[CH2:20]([NH:22][C:23](=[O:24])[O:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1)[CH3:21]
Reactant: CCN=C=O
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3O)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)OC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
A cooled (0° C.) solution of (rac)-4-(8-hydroxy-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 11) (50 mg, 200 μmol) in CH2Cl2 (1.4 mL) was treated with ethyl isocyanate (24.8 μL, 300 μmol) and Et3N (24.8 μL, 300 μmol). After stirring 1 night at room temperature and 1 h at reflux again ethyl isocyanate (24.8 μL, 300 μmol) and Et3N (24.8 μL, 300 μmol) were added. The solution was refluxed for 9 h, treated again with ethyl isocyanate (24.8 μL, 300 μmol), Et3N (24.8 μL, 300 μmol) and DMAP (2.4 mg, 20 μmol). After 1 night at room temperature MeOH (2 mL) was added. The reaction mixture was poured on aq. sat. NaHCO3 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. sat. NaCl solution. The combined organic phases were dried (Na2SO4), filtered and purified by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH 1%). Precipitation from CH2Cl2 with n-pentane gave the title compound (33 mg, 51%) as off-white foam. MS: 322.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Br:5].[Zn:10].BrCCBr>C1COCC1>[Br-:5].[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Zn+:10]
Reactant: [Zn]
Reactant: Fc1ccccc1CBr
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Fc1ccccc1C[Zn+]
Product: [Br-]

Procedure:
2-Fluoro-benzyl bromide (1 g, 5.29 mmol), zinc (0.380 g, 5.82 mmol) and 1,2-dibromoethane (0.050 mL, 0.58 mmol) were mixed in THF (10 ML) and heated to reflux overnight. After cooling a solution of the title compound was obtained that was used directly and immediately in the next step.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26](Cl)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:30][N:31]([CH3:40])[C:32]1[CH:33]=[C:34]([CH2:38][OH:39])[CH:35]=[CH:36][CH:37]=1.C(C(CCC)[O-])(C)(C)C.[K+].C(O)(C)(C)C>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]([O:39][CH2:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([N:31]([CH3:40])[CH3:30])[CH:33]=4)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C)c1cccc(CO)c1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2Cl)CC1
Agent: CCCC([O-])C(C)(C)C
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN(C)c1cccc(COc2nsnc2N2CCN(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (0.1 g, 0.21 mmol, 1.0 eq.), (3-Dimethylamino-phenyl)-methanol (0.065 g, 0.062 mL, 0.43 mmol, 2.0 eq) and 1M potassium tert-butyl butoxide in t-butanol (0.65 ml, 0.65 mmol, 3.0 eq). The mixture was stirred at room temperature overnight. After removal of solvent in vacuo, the crude mixture was purified on preparative HPLC, affording the title compound N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[3-(dimethylamino)phenyl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide as a white solid (0.06 g, 55% yield). 1H NMR (DMSO-d6) 9.23 (s, 1H), 8.18 (s, 2H), 7.59 (s, 1H), 7.22 (m, 1H), 6.89 (s, 1H), 6.78 (m, 2H), 5.39 (m, 4H), 3.61 (m, 4H), 3.53 (m, 4H), 2.92 (s, 6H) ppm.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(#N)C>[O:26]1[CH2:27][CH2:28][N:23]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:24][CH2:25]1
Reactant: C1COCCN1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 112.5 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4.0 ml) and DIPEA (0.26 ml, 1.48 mmol) and morpholine (0.13 ml, 1.481 mmol) were sequentially added. The solution was stirred at room temperature for 1.5 hours. Acetonitrile was evaporated and the residue was purified by flash chromatography (petroleum ether/EtOAc=85/15) to obtain ethyl 2-morpholino-2-phenylacetate (345 mg, quantitative yield) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=O)[C:12]([OH:14])=[O:13])=[CH:2]1.CC1C(O)=C(CN)C(COP(O)(O)=O)=C[N:18]=1.P([O-])([O-])([O-])=O>O>[NH2:18][C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: Cc1ncc(COP(=O)(O)O)c(CN)c1O
Reactant: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 37 °C
Reaction time: 2 h

Procedure:
To a solution containing 20.3 g (100 mmol) of indole-3-pyruvic acid and 26.5 g (100 mmol) of pyridoxamine-5-phosphate in 1000 ml of distilled water buffered at pH 6.5 with 0.5M phosphate buffer and maintained at 37° C. is added 50 mg of the monoclonal antibodies prepared according to Example 15. The reaction mixture is gently agitated for 2 hours. The monoclonal antibodies are then recovered by ultrafiltration. Dialysis of the reaction mixture followed by lyophilization yields the product L-tryptophan.
Reaction SMILES: [Cl:1][C:2]1[C:27]([OH:28])=[CH:26][C:5]2[C:6]([C:9]3[C:10]([CH2:23][CH2:24][CH3:25])=[N:11][CH:12]=[CH:13][C:14]=3OC3C=CC(Cl)=CC=3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:30][C:31]([O:33]C)=[O:32].[C:35](=[O:38])([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:27]([O:28][CH2:30][C:31]([OH:33])=[O:32])=[CH:26][C:5]2[C:6]([C:9]3[C:10]([CH2:23][CH2:24][CH3:25])=[N:11][C:12]([O:38][C:35]4[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCCc1nccc(Oc2ccc(Cl)cc2)c1-c1noc2cc(Cl)c(O)cc12
Reactant: COC(=O)CBr
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(OCC(=O)O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the phenol from Step 10 (0.42 g, 1.0 mmol), methyl bromoacetate (0.23 g, 1.5 mmol) and cesium carbonate (0.49 g, 1.5 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and concentrated. The residue was taken up in methanol (10 mL) and treated with 2 NNaOH (1.5 mL) for 1 h. The mixture was acidified with acetic acid (1 mL) and concentrated. The residue was purified by preparative HPLC on a RP-C18 column using 10-100% acetonitrile in water gradient solvent system modified with 0.1% acetic acid to give the title compound as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:28]([CH3:39])=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[C:28]([CH3:39])=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1c(NC(=O)C(C)C)cccc1C1CCN(CCCN)CC1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: Cc1c(NC(=O)C(C)C)cccc1C1CCN(CCCNC(=O)C(c2ccccc2)c2ccccc2)CC1

Procedure:
Example 33 was prepared from diphenyl acetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-2-methyl phenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.49 (d, 1H, J=8.0 Hz), 7.35–7.19 (m, 11H), 7.09–7.02 (m, 3H), 4.90 (s, 1H), 3.41 (dd, 2H, J=5.6, 11.6 Hz), 2.99 (d, 2H, J=12.8 Hz), 2.72 (m, 1H), 2.59 (m, 1H), 2.43 (t, 2H, J=6.4 Hz), 2.19 (s, 3H), 2.06–2.00 (m, 2H), 1.75–1.60 (m, 6H), 1.30 (d, 6H, J=6.8 Hz); ESMS m/e: 512.5 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H][H].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CCOC(C)=O.C(Cl)Cl.[Pd]>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CC=C(c2cccc(C(F)(F)F)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CCC(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a solution of Intermediate 3C (650 mg, 2.71 mmol) in EtOAc (10 mL) was added Pd/C (0.15 g, 0.27 mmol) in a pressure bottle. The mixture was stirred under 45 psi of hydrogen for 16 h. The catalyst was carefully filtered under nitrogen and the solvent was removed under vacuum. The residue was dissolved in DCM (10 mL) and Dess-Martin periodinane (1.26 g, 2.98 mmol) was added as one single portion. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with DCM, washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography on a 24 g cartridge with 0 to 100% EtOAc in hexanes over 15 min to give Intermediate 3D (276 mg, 1.14 mmol, 42.1% yield). LCMS, RT=2.01 min (Method B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:37])[CH2:9][CH2:10][C@@H:11]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=3)[N:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:12]2=[O:36])=[CH:4][CH:3]=1.[C:38]([O:41][C@@H:42]1[C@@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:46]([O:52][C:53](=[O:55])[CH3:54])[C@@H:45]([CH2:56][O:57][C:58](=[O:60])[CH3:59])[O:44][C@H:43]1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63](Br)[CH:62]=1)(=[O:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[C:38]([O:41][C@@H:42]1[C@@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:46]([O:52][C:53](=[O:55])[CH3:54])[C@@H:45]([CH2:56][O:57][C:58](=[O:60])[CH3:59])[O:44][C@H:43]1[C:61]1[CH:62]=[C:63]([C:18]2[CH:17]=[CH:16][C:15]([C@@H:14]3[C@@H:11]([CH2:10][CH2:9][C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[OH:37])[C:12](=[O:36])[N:13]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:20][CH:19]=2)[CH:64]=[CH:65][CH:66]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(Br)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC1(C)OB(c2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccccc3)cc2)OC1(C)C
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](O)c5ccc(F)cc5)C(=O)N4c4ccccc4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 18.4 %

Procedure:
(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one (51.3 mg, 0.102 mmol) and (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol (35.5 mg, 0.073 mmol) were dissolved in 2.0 mL of toluene and 0.25 mL of ethanol. 0.075 mL of 4 N potassium carbonate was added to the mixture followed by 5.0 mg of tetrakis(triphenylphosphine)palladium(0). The entire reaction was degassed three times with argon then heated to reflux for 4 h. The reaction was cooled to room temperature, diluted with 5 mL of water, and extracted with ethyl acetate (3×25 mL). The organic layers were combine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford 10.5 mg (13%) of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol as a clear oil.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:5]2[N:6]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cu][C:28]#[N:29].C(=O)(O)[O-].[Na+]>CN(C)C=O>[O:9]=[C:7]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:5]2[C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:2]([C:28]#[N:29])=[CH:3][C:4]=2[NH:8]1
Reactant: O=c1[nH]c2cc(Br)cc(C(F)(F)F)c2n1Cc1cccc(C(F)(F)F)c1
Reactant: N#C[Cu]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2Cc1cccc(C(F)(F)F)c1
Yield: 92.5 %

Procedure:
To a solution of 5-bromo-7-(trifluoromethyl)-1-[3-(trifluoromethyl)benzyl]-1,3-dihydro-2H-benzimidazol-2-one (171.9 mg) and copper(I) cyanide (76.3 mg) in N,N-dimethylformamide (10 ml) was heated at reflux for 11 hours. Copper(I) cyanide (51.0 mg) was further added, and the mixture was heated at reflux for 13 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted 5 times with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (139.5 mg, 93%).