Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:24](Cl)(=[O:26])=[O:25])[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH3:28][NH2:29]>CC(C)=O.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([S:24]([NH:29][CH3:28])(=[O:26])=[O:25])[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCc1c(Cl)nc(S(=O)(=O)Cl)n1COCC[Si](C)(C)C
Reactant: CN
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CNS(=O)(=O)c1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of 4-chloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonyl chloride (0.341 g, 0.72 mmol) in acetone (4.5 mL) and THF (2.5 mL) was added to a 0° C. solution of methylamine (3.6 mL of a 2M solution in THF, 7.2 mmol) in THF (2 mL). The reaction mixture was stirred at RT for 1 h and evaporated. The residue was taken up in EtOAc and washed with brine. The organic phase was dried (Na2SO4), filtered evaporated, and purified by silica gel chromatography (0-25% EtOA/hexanes) to give the title compound (0.23 g, 68%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.85 (br. s., 1H), 5.73 (s, 2H), 4.75 (s, 2H), 3.59-3.68 (m, 2H), 2.86 (d, J=5.1 Hz, 3H), 0.93 (d, J=8.4 Hz, 2H), 0.89 (s, 9H), 0.10 (s, 6H), −0.01 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)=[C:15](Cl)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.C1COCC1.[CH3:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CO>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)=[C:15]([C:39]4[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)cc4)nc3c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)cc4)nc3c2-c2ccc(C)cc2)cc1
Temperature: 70 °C
Yield: 61.2 %

Procedure:
To a stirring solution of 2-(4-(trifluoromethyl)benzyl)-8-chloro-7-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (41.7 mg, 0.10 mmol) in a 1:1 mixture of THF and methanol (4 mL) at room temperature under argon was added 4-methylphenylboronic acid (40.8 g, 0.30 mmol), PXPd (16.2 g, 0.03 mmol), and K2CO3 (41 mg, 0.3 mmol). The resulting suspension was heated at 70° C. under argon for 10 min. Analysis by HPLC/MS indicated that starting material had been consumed. After cooling the reaction mixture to room temperature, water (25 mL) and EtOAc (25 mL) were added. The layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to obtain 29 mg of the title compound as a white lyophilate. HPLC/MS: retention time=4.36 min, [M+H]+=474. 1H NMR (CDCl3): δ 7.78 (d, J=7.5 Hz, 1H), 7.59 (d, J=7.1 Hz, 2H), 7.50 (d, J=7.1 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 7.09-7.00 (m, 6H), 6.65 (d, J=7.5 Hz, 1H), 5.22 (s, 2H), 2.32 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]([CH2:11][OH:12])[CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:12][CH2:11][CH:3]1[CH2:4][N:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1][CH2:2]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCC2CCCCN2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCC2CCCCN2C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 90.7 %

Procedure:
Octahydro-2H-quinolizin-3-ylmethanol (600 mg, 3.55 mmol) was dissolved in dichloromethane (8 mL) and triethylamine (1.5 mL, 10.8 mmol) was added at 0° C. followed by dropwise addition of methanesulfonyl chloride (0.56 mL, 7.16 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford octahydro-2H-quinolizin-3-ylmethyl methanesulfonate as an orange oil (796 mg, 3.22 mmol, 91% yield). MS (EI) for C11H21NO3S: 248 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:28]=[CH:29][C:30]=2[CH3:31])[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:28]=[CH:29][C:30]=4[CH3:31])[CH2:21][CH2:20]3)=[O:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(Cl)cc3)CCC2)CC1

Procedure:
Example 86 was prepared from 1-(4-chlorophenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.46 (d, 1H, J=1.6 Hz), 7.34 (s, 4H), 7.28–7.23 (m, 2H), 7.10 (d, 1 H, J=8.4 Hz), 6.45 (br s, 1H), 3.31 (dd, 2H, J=5.6, 11.6 Hz), 2.95 (d, 2H, J=11.6 Hz), 2.88–2.81 (m, 2H), 2.68 (m, 1H), 2.54–2.44 (m, 3H), 2.33 (t, 2H, J=6.4 Hz), 2.29 (s, 3H), 2.11–1.90 (m, 4H), 1.76–1.63 (m, 6H), 1.26 (d, 6H, J=7.2 Hz); ESMS m/e: 510.3 (M+H)+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[ClH:15].C(N(CC)CC)C.[CH:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])[CH3:24].[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43](=O)[NH:42][N:41]=2)=[CH:35][CH:34]=1>O>[ClH:15].[ClH:15].[CH:23]([C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]2[C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:40]([CH2:39][C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)=[N:41][N:42]=2)=[CH:28][CH:27]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 210 °C
Reaction time: 4 h

Procedure:
In the manner described in Example 45, a mixture of 1.80 g (12.68 mmol) phosphorus pentoxide, 1.73 g (12.6 mmol) triethylamine hydrochloride, 1.8 ml (12.74 mmol) 4-isopropylaniline, and 1 g (4.2 mmol) 4-(4-pyridylmethyl)-1 (2H)-phthalazinone is stirred for 4 h at 210° C. The frozen melt is then suspended in water using an ultrasonic bath, filtered, and the filtrate evaporated in the RE. The oil-like residue is distributed between dichloromethane and a mixture of 20 ml water and 5 ml conc. ammonia, and the organic phase dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The residue is then stirred with acetonitrile, filtered off from some non-transformed 4-(4-pyridylmethyl)-1(2H)-phthalazinone, and the filtrate evaporated under vacuum. Flash chromatography of the residue on silica gel with a particle size of 0.04-0.06 mm using acetate/methanol mixtures (20:1 and 10:1) yields a resin (free base of the title compound), which is dissolved in a mixture of 4 ml methanol and 1.5 ml of 3 N methanolic HCl. After evaporation under vacuum, recrystallization of the residue from methanol/ether, drying under HV (8 h, 120° C.), and equilibration for 16 h at 20° C. and in room atmosphere, title compound is obtained with a water content of 9.4%; m.p. >250° C.; ESI-MS: (M+H)+=355.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:11]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:10]=1.Br[CH2:35][C:36]([NH2:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Cl:8][C:9]1[N:10]=[C:11]([N:28]2[CH2:29][CH2:30][N:31]([CH2:35][C:36]([NH2:38])=[O:37])[CH2:32][CH2:33]2)[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:25])[CH3:26])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:13]([CH3:15])[N:14]=1
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCNCC1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(CC(N)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-4-methyl-6-piperazin-1-yl-pyrimidine trifluoroacetic acid salt (722 mg), 2-bromoacetamide (290 mg, 2.11 mmol) and potassium carbonate (871 mg, 6.30 mmol) in DMA (10 mL) is stirred at room temperature for 3 h. The reaction mixture is partitioned between EtOAc (30 mL) and water (10 mL), the organic layer is separated, washed with water (10 mL×2), brine (10 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to yield a yellow oil. Purification by chromatography on silica gel affords the title compound as a colorless oil that solidifies on standing. 1H NMR (CDCl3) δ=7.10 (d, 1H), 6.92 (br, s, 1H), 6.82 (d, 1H), 6.74 (s, 1H), 5.54 (br, s, 1H), 4.83 (s, 2H), 3.61, (m, 4H), 3.04 (s, 2H) 2.90 (m, 1H), 2.63 (m, 4H), 2.47 (s, 3H), 2.14 (s, 3H), 1.27 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[C:3]=1[O:11][C:12]1[CH:13]=[C:14]([C:20]#[N:21])[CH:15]=[C:16]([CH:19]=1)[C:17]#[N:18].ClC1C=C(C=C(OC2C3N=NNC=3C=CC=2Cl)C=1)C#N.Br[CH2:43][C:44]1[C:52]2[C:47](=[N:48][CH:49]=[CH:50][CH:51]=2)[N:46](C(OC(C)(C)C)=O)[N:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH2:43][C:44]3[C:52]4[C:47](=[N:48][CH:49]=[CH:50][CH:51]=4)[NH:46][N:45]=3)[N:7]=[N:8][C:4]=2[C:3]=1[O:11][C:12]1[CH:13]=[C:14]([C:20]#[N:21])[CH:15]=[C:16]([CH:19]=1)[C:17]#[N:18]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: N#Cc1cc(C#N)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Agent: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C#N)cc(Oc2c(Cl)ccc3c2nnn3Cc2n[nH]c3ncccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A partially purified product prepared in the manner described in Example 4A, step 5, except on a larger scale, was found to contain approximately 10 mol % 5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]isophthalonitrile in addition to 3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile. A solution of tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (Intermediate 1; 23 g, 74 mmol) in DMF (100 mL) was added to a suspension of the partially purified product (25 g, 82 mmol) and cesium carbonate (28 g, 86 mmol) in DMF (80 mL) at room temperature, and the resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was then quenched with aqueous saturated ammonium chloride (200 mL), diluted with water (100 mL) and extracted with ethyl acetate (2×700 mL). The combined organic fractions were washed with dilute brine (3×500 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was adsorbed onto silica gel and subjected to automated silica gel chromatography eluting with a gradient of 25-50% ethyl acetate in hexanes to afford the crude title product. This mixture was then purified by reverse phase column chromatography eluting with 5-95% CH3CN/H2O (0.1% TFA) to yield the title compound. 1H NMR (DMSO-d6) δ 8.53 (dd, J=4.6 Hz, J=1.5 Hz, 1H), 8.22 (m, 1H), 8.15 (dd, J=8.2 Hz, J=1.5 Hz, 1H), 8.00 (m, 2H), 7.92 (d, J=8.9 Hz, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.21 (dd, J=8.0 Hz, J=4.5 Hz, 1H), 6.39 (s, 2H). LRMS (M+1)=426.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:34])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(N)c2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
Into a solution of 4.00 g (16.0 mmol) of tert-butyl 4-(3-aminophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate and 5.60 mL (32.0 mmol) of diisopropylethylamine in 100 mL dichloromethane was slowly added 1.90 mL (19.0 mmol) of isobutyryl chloride. The reaction mixture was stirred at room temperature for 2 hours, washed with water, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography (silica, 50:46:3:1, hexanes:dichloromethane:methanol:isopropyl amine) to afford 2.90 g (52.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.34 (d, 1H, J=7.8 Hz), 7.27 (t, 1H, J=7.8 Hz), 7.11 (d, 1H, J=7.8 Hz), 6.04 (s, 1H), 4.05 (s, 2H), 3.62 (apparent t, 2H, J=4.9 Hz), 2.51 (m, 3H), 1.49 (s, 9H), 1.25 (d, 6H, J=7.4 Hz); ESMS m/e: 345.5 (M+H)+. Anal. Calc. for C20H28N2O3+0.175CHCl3: C, 66.33; H, 7.77; N, 7.67. Found: C, 66.20; H, 7.41; N, 7.88.
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH3:7])[NH2:6].[NH2:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>B([O-])([O-])[O-]>[NH2:6][C@H:5]([C:4]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:3])[CH3:7]
Reactant: COC(=O)[C@H](C)N
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [O-]B([O-])[O-]
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
3 μl of the same enzyme fraction as used in Example 5 was added to 100 μl of 100 mM borate buffer (pH 9.0) containing 100 mM L-alanine methyl ester hydrochloride, 200 mM L-glutamine and 10 mM EDTA, and allowed to react at 18° C. As a result, as shown in FIG. 3, 83 mM L-alanyl-L-glutamine (L-Ala-L-Gln) was formed in the case of an enzyme-added lot, and the concentration of by-product L-Ala-L-Ala-L-Gln was 1.3 mM. On the other hand, there was scarcely any production of L-Ala-L-Gln observed in an enzyme-non-added lot, and the enzyme concentration was only about 0.07 mM after reacting for 120 minutes.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[F:17][C:18]1[CH:19]=[C:20]([N:32]2[CH2:36][C@H:35]([CH2:37][NH2:38])[O:34][C:33]2=[O:39])[CH:21]=[CH:22][C:23]=1[CH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([N:32]2[CH2:36][C@@H:35]([CH2:37][N:38]=[C:1]=[S:2])[O:34][C:33]2=[O:39])[CH:21]=[CH:22][C:23]=1[CH:24]1[CH2:25][CH2:26][S:27](=[O:30])(=[O:31])[CH2:28][CH2:29]1
Reactant: NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: O=C1O[C@H](CN=C=S)CN1c1ccc(C2CCS(=O)(=O)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,1′-thiocarbonyldi-2(1H)-pyridone (304 mg, 1.31 mmol) in anhydrous methylene chloride (13 mL) at 0° C. under a nitrogen atmosphere was treated with a solution of (S)-(−)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone, as prepared in Example 11, Step 1, (375 mg, 1.09 mmol) in anhydrous methylene chloride (88 mL) over 30 minutes. The resulting mixture was stirred at 0° C. for 30 minutes and at ambient temperature for 30 minutes and was then diluted with methylene chloride (40 mL), washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (230-400 mesh, 45 g), eluting with acetonitrile/methylene chloride (7.5/92.5), and those fractions with an Rf=0.64 by TLC (acetonitrile/methylene chloride, 20/80) were pooled and concentrated to give (S)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone, mp 158-162° C. (dec.).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:25][CH3:26])=[C:9]([CH:24]=1)[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[O:11])(=[O:3])N.C([OH:29])C.[OH-].[Na+].O>C(OCC)C>[CH3:26][O:25][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:1]([OH:29])=[O:3])=[CH:24][C:9]=1[C:10](=[O:11])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: CCO
Reactant: COc1ccc(CC(N)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(CC(=O)O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1

Procedure:
To 700 mg of 5-carbamoylmethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added 21 ml of ethanol, 7 ml of 1 mol/l aqueous solution of sodium hydroxide, and the mixture was refluxed for 18 hours. The reaction mixture was poured into water, washed with ethyl acetate, and further the aqueous layer was adjusted to pH value of 1 to 2 with 2 mol/l hydrochloric acid, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine in sequence and dried again over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was suspended with diethyl ether to collect the crystals by filtration. The crystals obtained were recrystallized from methylene chloride to obtain 435 mg of aimed product as colorless crystals.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].B(Br)(Br)Br.C([O-])(O)=O.[Na+].C(OCC)C>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16]
Reactant: COc1ccc(NC(=O)C(F)(F)F)c(OC)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1ccc(O)cc1O)C(F)(F)F
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of N-(2,4-dimethoxy phenyl)-2,2,2-trifluoro-acetamide (2.50 g; 10 mmol) in CH2Cl2 (20 mL) cooled to −10° C. was added 1 M BBr3 (CH2Cl2; 24 mL; 24 mmol) under N2 atmosphere. The mixture was allowed to warm to room temperature over 2 hours and poured onto H2O (150 mL). Saturated aqueous NaHCO3 (100 mL) and diethylether (100 mL) was added to dissolve any precipitated material. The organic layer was Isolated, washed with H2O (50 mL), dried (MgSO4), filtered and the eluate evaporated to dryness to yield 1.85 g (83%) of the desired compound as a greyish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1OC
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)c(OC)c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.4 %

Procedure:
3,4-Dimethoxyaniline (0.246 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.110 g, 0.216 mmol, 40%).
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH2:24][CH2:23]2)[N:9]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: C=CCCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 0.33 h
Yield: 41.7 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.78 g of 4-pentenoyl chloride, after which the mixture was stirred at room temperature for 15 hours. The resulting crystals were collected by filtration, washed with water and recrystallized from ethanol, to give 1.02 g of the desired Compound No. 6 in the form of pale brown needles melting at 219°-220° C.
Reaction SMILES: [C:1]([C@H:5]1[C:39](=[O:40])[N:38]2[CH2:41][C@@H:35]([CH2:36][C@H:37]2[C:42]([O:44][CH3:45])=[O:43])[O:34][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25](OS(C(F)(F)F)(=O)=O)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:46][C@H:9]2[O:8][C:7](=[O:47])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[N:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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:1]([C@H:5]1[C:39](=[O:40])[N:38]2[CH2:41][C@@H:35]([CH2:36][C@H:37]2[C:42]([O:44][CH3:45])=[O:43])[O:34][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([C:51]3[CH:52]=[CH:53][N:48]=[CH:49][CH:50]=3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:46][C@H:9]2[O:8][C:7](=[O:47])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OS(=O)(=O)C(F)(F)F)O2
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1-c1ccncc1)O2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of the product from step 1 (50 mg, 0.073 mmol) in dioxane (5 ml) was added pyridine-4-boronic acid, (35.9 mg, 0.292 mmol), potassium phosphate tribasic (38.7 mg, 0.182 mmol) and tetrakis (16.85 mg, 0.015 mmol). After purging with N2 for 5 min, the reaction was stirred at 80° C. for 16 hours. After cooling to room temperature, water was added and the reaction was extracted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. Purification by PTLC (40% EtOAc/hexane) provided the desired compound.