Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:19])[NH:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1)[CH3:2].[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[C:30]([O:38][C@@H:39]3[O:56][C@H:55]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[C@@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:40]3[O:41][C:42](=[O:44])[CH3:43])=[N:31][NH:32][C:33]=2[C:34]([F:37])([F:36])[F:35])=[CH:24][CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[C:30]([O:38][C@@H:39]3[O:56][C@H:55]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[C@@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:40]3[O:41][C:42](=[O:44])[CH3:43])=[N:31][NH:32][C:33]=2[C:34]([F:37])([F:36])[F:35])=[CH:24][CH:23]=1)[CH3:21].[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:19][C@@H:39]3[O:56][C@H:55]([CH2:57][OH:58])[C@@H:50]([OH:51])[C@H:45]([OH:46])[C@H:40]3[OH:41])=[N:12][NH:13][C:14]=2[C:15]([F:17])([F:18])[F:16])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Agent: CCc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C(F)(F)F)cc1
Product: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(F)(F)F)cc1

Procedure:
4-[(4-Ethylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole was prepared in a similar manner to that described in Example 26 using 4-[(4-ethylphenyl)methyl]-1,2-dihydro-5-trifluoromethyl-3H-pyrazol-3-one instead of 1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one. Then, the title compound was prepared in a similar manner to that described in Example 35 using 4-[(4-ethylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole instead of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([F:27])[CH:18]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:28].C([Li])CCC.CCCCCC.Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>O1CCCC1>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[C:19]([F:27])[CH:18]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH:7]([CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:6]1=[O:28]
Reactant: COc1cc2c(cc1-c1ccc(C(F)(F)F)c(F)c1)CCC(=O)N2Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc2c(cc1-c1ccc(C(F)(F)F)c(F)c1)CC(CC(=O)OC(C)(C)C)C(=O)N2Cc1ccc(F)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (14 mg, 0.03 mmol) in anhydrous tetrahydrofuran (1 mL) at −78° C. in a dry flask equipped with an inlet of dry nitrogen was added fresh 1.6 M n-butyl lithium in n-hexane (40 μL, 0.06 mmol) with stirring. The reaction mixture was stirred at −78° C. for 30 minutes, then at 0° C. for 1 hour. The reaction mixture was re-cooled to −78° C., a solution of tert-butyl bromoacetate (98 mg, 0.50 mmol) in anhydrous tetrahydrofuran added (0.5 mL), and the reaction mixture stirred overnight, allowing it to warm up to room temperature. The reaction was followed by LCMS, and stirring was continued as needed until the starting material was consumed. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (5 mL) with stirring, concentrated under reduced pressure, diluted with ethyl acetate (10 mL) and diluted with aqueous ammonium chloride (5 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL), and the combined organic phase was successively washed with 2N sodium carbonate (10 mL), 30% ammonium chloride (10 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a crude mixture which was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford tert-butyl 2-(1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (12 mg, 0.02 mmol, 67%). LCMS mz 524.0 (M-tBu), 602.0 (M+Na), anal HPLC>98% in purity. 1H NMR (400 MHz; acetone-d6) δ7.77 (t, J=8.0 Hz, 1H); 7.60 (m, 2H); 7.38 (m, 2H); 7.11 (m, 1H); 7.00 (m, 1H); 6.81 (s, 1H); 5.35 (s, 2H); 3.80 (s, 3H); 2.70-3.30 (m, 3H); 2.40-2.60 (m, 2H); 1.48 (s, 9H).
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH2:18]([C:25]1[N:30]=[C:29]([CH3:31])[C:28]([C:32](O)=[O:33])=[CH:27][N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>O>[CH2:18]([C:25]1[N:30]=[C:29]([CH3:31])[C:28]([C:32]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])=[O:33])=[CH:27][N:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: Cc1nc(Cc2ccccc2)ncc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1cnc(Cc2ccccc2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To 10 ml of N,N-dimethylformamide were dissolved 1.00 g (5.0 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 1.30 g (5.5 mmol) of 2-benzyl-4-methylpyrimidine-5-carboxylic acid, followed by the addition of 0.50 g (6.0 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over an hydrous magnesium sulfate, the addition of “Florisil” and filtering. The solution was concentrated under reduced pressure to obtain 1.30 g (yield: 78%) of 4,4-difluoro-3-methyl-3-butenyl 2-benzyl-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:2]=1.[CH3:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:17][C:18]1[N:19]=[C:20]([NH:23][C:13](=[O:15])[C:12]2[CH:16]=[C:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:9]=[N:10][CH:11]=2)[S:21][CH:22]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(O)c1cncc(Oc2cccnc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)c2cncc(Oc3cccnc3)c2)n1
Yield: 38.9 %

Procedure:
Compound 6 (30 mg, 0.14 mmol, 1.0 eq), 4-methylthiazol-2-amine (19 mg, 0.17 mmol, 1.2 eq), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.289 mmol, 2.10 eq), and N,N-Diisopropylethylamine (38 mg, 0.29 mmol, 2.1 eq) were dissolved in CH2Cl2 (1.5 mL) and DMF (0.30 mL) and stirred at rt for 72 h. The reaction was quenched with water, and the layers were separated via phase separation. The organic layer was dried on air concentrator and purified by reverse-phase preparatory HPLC to afford 17 mg (38%) of the title compound as a mono-TFA salt: 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J=1.7 Hz, 1H), 8.69 (d, J=2.8 Hz, 1H), 8.56 (d, J=2.8 Hz, 1H), 8.49 (dd, J=4.7, 1.2 Hz, 1H), 8.04 (t, J=2.2 Hz, 1H), 7.68 (ddd, J=8.4, 2.8, 1.2 Hz, 1H), 7.54 (dd, J=8.4, 4.7 Hz, 1H), 7.23 (d, J=1.2 Hz, 1H), 2.36 (d, J=1.0, 3H); ES-MS [M+1]+:313.1.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2(O)[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4](OC(C)=O)[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2OC([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=O)[C@:11]2(OC(C)=O)[CH2:51]O[C@@H:10]2[CH2:9][C@@H:8]1O)=O.CC1[C@@H]([O:82][C:83]([C@H:85]([OH:101])[C@@H:86]([NH:93]C(OC(C)(C)C)=O)C2C=CC=CC=2)=[O:84])C[C@]2(O)C(C)(C)C=1[C@@H](O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O.CC1[C@@H](OC([C@H](O)[C@@H](NC(C(C)C)=O)C2C=CC=CC=2)=O)C[C@]2(O)C(C)(C)C=1[C@@H](OC(C)=O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O>>[CH3:51][C@H:11]1[C@H:12]2[CH2:13][C@H:14]3[C:15]([CH3:16])([CH3:17])[C@@H:3]([CH2:4][CH2:5][C@:7]2([CH3:58])[CH2:8][CH2:9][CH2:10]1)[C@H:2]([CH3:1])[CH2:19][CH2:18]3.[C:45]1([NH:93][CH2:86][CH:85]([C:83]([OH:84])=[O:82])[OH:101])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)C(C)C)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Product: C[C@@H]1CCC[C@@]2(C)CC[C@H]3[C@H](C)CC[C@@H](C[C@H]12)C3(C)C
Product: O=C(O)C(O)CNc1ccccc1

Procedure:
In brief, the present invention relates to an improved semi-synthetic process to produce a taxane intermediate, which can ultimately be used to produce taxane derivatives, such as paclitaxel, docetaxel and canadensol and its derivatives. In the process of the present invention, the protected taxane intermediate from which the taxane derivative can be derived is produced in a yield of over 65% of a single isomer by direct esterification of a protected taxane of formula (I) with a single isomeric open chain phenyl isoserine side chain. By using a single isomeric phenyl isoserine side chain, a single isomeric taxane intermediate is obtained at a yield of over 65%. This is substantially greater than the 40% yield of the process advanced by Denis et al in U.S. Pat. No. 4,924,011. In addition, by using the same hydroxyl protecting group to protect both the C-7 position and the 2′-position on the phenylisoserine side chain, simplifies and reduces the reaction route. These are all features which would be recognised as being advantageous in industrial scale up of the present process.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9](O)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.Cl.[CH2:33]([N:35]1[CH2:40][C:39]2([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[O:38][CH2:37][C:36]1=[O:46])[CH3:34]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([N:43]2[CH2:44][CH2:45][C:39]3([O:38][CH2:37][C:36](=[O:46])[N:35]([CH2:33][CH3:34])[CH2:40]3)[CH2:41][CH2:42]2)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1
Reactant: CCN1CC2(CCNCC2)OCC1=O
Reactant: NC(=O)C(O)c1c(F)cc(Br)cc1F
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN1CC2(CCN(C(C(N)=O)c3c(F)cc(Br)cc3F)CC2)OCC1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 121.8 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)-2-hydroxyacetamide (0.86 g, 3.2 mmol) and triethylamine (1.4 mL, 9.7 mmol) in anhydrous acetonitrile (5 mL) was added neat methanesulfonyl chloride (0.33 mL, 4.2 mmol). The reaction mixture was stirred vigorously at 40° C. for 3 h, at which point the reaction had progressed to completion. To this mesylate intermediate mixture was added more triethylamine (1.4 mL, 9.7 mmol) followed by 4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.11 g, 0.48 mmol). The reaction mixture was heated at 90° C. for 3 h until the starting material was consumed. The reaction was diluted with water and was extracted with ether (3×35 mL). The combined ether phases were dried over sodium sulfate, filtered, and evaporated under reduced pressure. Purification of the residue by flash chromatography (65-100% of 10% methanol in dichloromethane:dichloromethane) afforded the title product (261 mg, 18% yield). MS(ES)+ m/e 446 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.12 (t, J=7.20 Hz, 3 H) 1.64-1.71 (m, 1 H) 1.73 (dd, J=4.17, 2.65 Hz, 1 H) 1.90-1.99 (m, 2 H) 2.19-2.27 (m, 1 H) 2.54-2.66 (m, 1 H) 2.67-2.73 (m, 1 H) 2.75-2.81 (m, 1 H) 3.15 (s, 2 H) 3.41 (q, J=6.91 Hz, 2 H) 3.98 (s, 2 H) 4.69 (s, 1 H) 5.68 (br. s., 1 H) 7.15-7.25 (m, 2 H) 7.36 (br. s., 1 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[F:7][C:8]1[C:17]2[NH:16][CH:15]=[C:14]3[C:18](=[O:30])[N:19]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](Cl)=[O:25])[N:20]=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl>O1CCCC1>[F:7][C:8]1[C:17]2[NH:16][CH:15]=[C:14]3[C:18](=[O:30])[N:19]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:25])[N:20]=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Reactant: COCCCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCCNC(=O)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
3-Methoxypropylamine (0.026 g, 0.29 mmol) was added to a stirred solution of 3-(6-fluoro-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoyl chloride (intermediate 4) (26 mg 0.29 mmol) in tetrahydrofuran (2 ml) and the mixture stirred at room temperature for 15 min. Triethylamine (0.2 ml, 1.4 mmol) was then added and the resulting mixture stirred overnight. 1M Hydrochloric acid (3-4 ml) was added dropwise to precipitate a yellow solid which was filtered and dried under suction to give the amide (79 mg, 0.20 mmol) as a yellow solid, LCMS m/z 395.25 [M+H]+ @ RT 1.04 min; δH(400 MHz, (CD3)2SO) 8.59 (1H, m), 8.57 (1H, s), 8.39 (1H, app d J 9.3 Hz), 8.08 (1H, app d J 7.3 Hz), 7.66-7.53 (5H, m), 3.37-3.33 (4H, m), 3.27 (3H, s), 1.83-1.77 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8](=[CH:11][CH:12]=1)[C:9]#[N:10].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20].C(N(CC)CC)C>CC(C)=O.CC(C)=O.CCCCC>[C:13]([C:7]1[CH:6]=[C:5]([CH:12]=[CH:11][C:8]=1[C:9]#[N:10])[O:4][C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[NH:1][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=1)#[N:14]
Reactant: N#Cc1ccc(Oc2ccccc2N)cc1C#N
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CC(C)=O
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Oc2ccccc2NC(=O)c2cccc([N+](=O)[O-])c2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of 4-(2-aminophenoxy)phthalonitrile (0.5 g, 2.1 mmol), 3-nitrobenzoylchloride (0.43 g, 2.3 mmol) and triethylamine (0.54 g, 0.74 ml, 5.3 mmol) in acetone (20 ml) was stirred for 2 hours at room temperature. The mixture was evaporated in vacuo. The crude product was dissolved in methylene chloride (25 ml) and water (25 ml) and 1N hydrochloric acid (1 ml) was added. The water phase was extracted with methylene chloride (2×15 ml). The combined organic phase was dried over magnesium sulphate, filtered and evaporated in vacuo giving 700 mg of the crude product. The product was recystallised in acetone/pentane to give white crystals of N-[2-(3,4-dicyanophenoxy)phenyl]-3-nitrobenzamide (yield: 650 mg (81%)). Mp: 176.5-178.1° C.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C1C=CC=CC=1>[Br-:20].[C:22]([CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 95.5 %

Procedure:
A solution of triphenylphosphine (33.8 g, 129 mmol) and t-butyl bromoacetate (25 g, 128.2 mmol) in dry benzene (150 ml) was stirred for 16 hours at room temperature. The precipitated product was collected by filtration, washed with dry ether and dried in vacuo to give 56 g (96% of theory) of carbo-t-butoxymethyl triphenylphosphonium bromide.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]=[CH:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2].C(N(CC)CC)C.ClCCl.[C:29](Cl)(=[O:33])[O:30][CH2:31][CH3:32]>O>[CH2:31]([O:30][C:29]([N:16]1[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12][C:11]1=[N:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:33])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: CC(C)c1ccccc1N=C1N=CC(C)(C)CS1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC(C)(C)CSC1=Nc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g), triethylamine (0.15 g) and dichloromethane (5 ml) was added dropwise for 5 minutes ethyl chlorocarbonate (0.13 g). The mixture was stirred at room temperature for 2 hours. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 3-(ethoxycarbonyl)-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.23 g, yield: 68%) as a white crystal. M.p. 84-86° C.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]([C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:13])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:2].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:12]([C:5]1[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:3]([NH:1][NH:2][S:27]([CH3:26])(=[O:29])=[O:28])[N:4]=1)=[O:13]
Reactant: NNc1nc(C(=O)c2cccs2)c2sccc2n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)NNc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
A mixture of 2-hydrazinothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (110 mg, 0.4 mmol) and Et3N (61 μL, 0.44 mmol) in THF (5 mL) was treated with methanesulphonyl chloride (31 μl, 0.4 mmol), stirred at room temperature for 20 min, poured into water (25 mL), extracted with EtOAc (2×5 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography [SiO2: (EtOAc) to give the title compound (92 mg, 65%) as an orange solid.
Reaction SMILES: C(O[C:4](=[O:16])[CH:5](Br)[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)C.[NH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][NH:19][C:18]1=[S:27]>C(O)C>[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([CH:5]2[S:27][C:18]3=[N:17][C:26]4[C:21]([CH2:20][N:19]3[C:4]2=[O:16])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: S=C1NCc2ccccc2N1
Reactant: CCOC(=O)C(Br)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: O=C1C(c2ccc([N+](=O)[O-])cc2)SC2=Nc3ccccc3CN12
Yield: 88.1 %

Procedure:
A solution of bromo-(4-nitrophenyl)acetic acid ethyl ester (0.92 g, 3.2 mmol) in ethanol (15 ml) was added to a suspension of 3,4-dihydro-1H-quinazoline-2-thione (0.5 g, 3.0 mmol) in ethanol (10 ml) and the resulting mixture was heated at reflux for 3 h. A brown solid was filtered, washed with ethanol, and dried under reduced pressure to yield 0.86 g (88%) of a yellowish solid. 1H NMR (500 MHz, DMSO-D6) δ ppm 4.89 (m, 2H) 5.95 (s, 1H) 7.12 (d, J=7.63 Hz, 1H) 7.17 (t, J=7.48 Hz, 1H) 7.26 (m, 2H) 7.82 (d, J=8.85 Hz, 2H) 8.25 (d, J=8.85 Hz, 2H). MS (ESI) m/z 326 (MH+); HPLC (Column YMC Xterra OSD 4.6×33 mm S 7) rt 1.53 min; Purity (93%).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[CH2:3].ClC(OCC)=O.C(N(CC)CC)C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>O.C(#N)C>[NH2:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])=[CH:26][CH:25]=1)(=[O:28])=[O:29]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: C=C(C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 70 °C
Yield: 65.1 %

Procedure:
A 500-mL three-necked flask equipped with a stirrer, a condenser and a dropping funnel was charged with 31.0g(0.36 moles) of methacrylic acid, 39.1 g (0.36 moles) of ethyl chloroformate and 200 mL of acetonitrile, and the mixture was stirred under cooling on an ice water bath. 36.4 g (0.36 moles) of triethylamine was dropped to this mixture over about one hour from the dropping funnel. After completion of dropping, the ice water bath was removed, and the mixture was stirred at room temperature for 30minutes. 51.7g(0.30 moles) of p-aminobenzenesulfonamide was added to the reaction mixture, and the mixture was stirred for one hour while warming on an oil bath at 70 ° C. After completion of the reaction, the reaction mixture was thrown into one liter of water while stirring this water; and the resulting mixture was stirred for 30 minutes. This mixture was filtered to take out a deposit, which was then formed into a slurry upon addition of water. This slurry was filtered, and the thus obtained solid was dried to obtain a white solid of N-(p-aminosulfonylphenyl)methacrylamide (yield: 46.9 g). Next, a 20 -mL three-necked flask equipped with a stirrer, a condenser and a dropping funnel was charged with 4.61 g(0.0192 moles) of N-(p-aminosulfonylphenyl)methaciylamide, 2,94 g (0.0258moles) of ethyl methacrylate, 0.80 g (0.0 15 moles) of acrylonitrile, and 20 g of N,N-dimethylacetarnide, and the mixture was stirred while heating on a warm water bath at 65 °C. 0.15 g of “V-65” (manufactured by Wako Pure Chemical Industries, Ltd.) was added to this mixture, and the mixture was stirred under a nitrogen gas stream for 2 hours while keeping at 65° C. To the reaction mixture, a mixture of 4.61 g of N-(p-amino -sulfonylphenyl)methacrylamide, 2,94 g of ethyl methacrylate, 0.80 g of acrylonitrile, N,N-dimethylacetamide, and 0.15 g of “V-65” was further dropped over 2 hours from the dropping funnel. After completion of dropping, the resulting mixture was further stirred at 65° C. for 2 hours. After completion of the reaction, 40 g of methanol was added to the mixture and cooled. The resulting mixture was thrown into two liters of water while stirring this water, and the mixture was stirred for 30 minutes. A deposit was taken out and dried to obtain 15 g of a white solid. The weight average molecular weight (as reduced into polystyrene) of this specified copolymer was measured by gel penneation chromatography and found to be 53,000.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([NH2:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:2].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([Br:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([NH:21][C:26]1[C:27]([Br:31])=[CH:28][N:29]=[C:24]([Cl:23])[N:25]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](N)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Nc1nc(Cl)ncc1Br)c1ccc(O[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of (R)-3-amino-3-(4-(tert-butyldimethylsiloxy)pheny)-propanoic acid ethyl ester (1.0 eq), 2,4-dichloro-5-bromopyrimidine (1.2 eq) and DIEA (1.2 eq) in DMF was stirred at 50° C. for 2 hr, and then the DMF was evaporated. The residue was dissolved in EtOAc, and the resulting solution was washed successively with 0.1 M H3PO4, sat. NaHCO3 and sat. NaCl. The EtOAc extracts were treated with MgSO4, filtered, and evaporated to give (R)-3-(5-bromo-2-chloropyrimidin-4-ylamino)-3-(4-(tert-butyldimethylsiloxy)phenyl)propanoic acid ethyl ester.