Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)O[C:2]2=[O:3].[C:13](OC(=O)C)(=O)C.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[OH:3][C:2]1[C:1]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[N+:21]=1[O-:22]
Reactant: NO
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nc2ccccc2c(O)[n+]1[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
The isatoic anhydride, acetic anhydride and pyridine were combined in a round bottomed flask equipped with a thermometer, reflux condenser and protected from atmospheric moisture by a drying tube. The reaction mixture was heated to 90°-100° C for 1 hour. The reaction mixture was cooled to room temperature and the hydroxylamine-hydrochloride was added all at once. The reaction mixture was stirred at room temperature for 24 hours. Most of the pyridine was removed from the reaction product by distillation under reduced pressure. The solid residue was slurried with 150 ml of cold water. The solid was isolated and crystallized from 200 ml of methanol to give 7.4 parts (70% yield) of 4-hydroxy-2-methylquinazoline-3-oxide. It is obvious from the above that part of the reaction product may exist in the tautomeric form.
Reaction SMILES: [Br:1]C1C(Cl)=C(CC2C=CC(OCC)=CC=2)C=C([C@H]2[C@H](OCC3C=CC=CC=3)[C@@H](OCC3C=CC=CC=3)[C@H](OCC3C=CC=CC=3)[C@@H](COCC3C=CC=CC=3)O2)C=1O.[CH2:59]([C:66]1[C:67]([Cl:112])=[C:68]([OH:111])[CH:69]=[C:70]([C@H:72]2[C@H:77]([O:78][CH2:79][C:80]3[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=3)[C@@H:76]([O:86][CH2:87][C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)[C@H:75]([O:94][CH2:95][C:96]3[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=3)[C@@H:74]([CH2:102][O:103][CH2:104][C:105]3[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=3)[O:73]2)[CH:71]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH2:59]([C:66]1[C:67]([Cl:112])=[C:68]([OH:111])[C:69]([Br:1])=[C:70]([C@H:72]2[C@H:77]([O:78][CH2:79][C:80]3[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=3)[C@@H:76]([O:86][CH2:87][C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)[C@H:75]([O:94][CH2:95][C:96]3[CH:97]=[CH:98][CH:99]=[CH:100][CH:101]=3)[C@@H:74]([CH2:102][O:103][CH2:104][C:105]3[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=3)[O:73]2)[CH:71]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: Oc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(Cc2ccccc2)c1Cl
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)c(Br)c2Cl)cc1
Product: Oc1c(Cl)c(Cc2ccccc2)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1Br

Procedure:
Similar procedure with preparation of 28 proceeded except for using compound 170 to obtain the compound 171.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:27])[C:23]=1[CH:24]1[CH2:26][CH2:25]1)=O)(=O)OC.O.[NH2:29][NH2:30]>>[CH:24]1([C:23]2[N:22]([CH3:27])[N:21]=[CH:20][C:19]=2[C:17]2[N:30]=[N:29][C:4]3[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][C:5]=3[CH:16]=2)[CH2:26][CH2:25]1
Reactant: CC1(C)CC(=O)C(=O)C1
Reactant: NN
Reactant: COP(=O)(CC(=O)c1cnn(C)c1C1CC1)OC
Solvent: O
Product: Cn1ncc(-c2cc3c(nn2)CC(C)(C)C3)c1C1CC1

Procedure:
yellow gum. MS (ESI): 269.2 (MH+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, [2-(5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].O[C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH2:17].O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:6]2[O:7][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=3[N:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2oc(-c3cccc(C(F)(F)F)c3)nc2c1

Procedure:
3-Trifluoromethylbenzoyl chloride (9.03 g, 0.043 mol) and 2-hydroxy-5-nitroaniline (6.58 g, 0.041 mol) in toluene (200 ml) are refluxed for 48 hours. POCl3 (20 ml) is added, the mixture is refluxed for a further 2 hours and concentrated, and the solid is recrystallized from NaOH (pH=10). The product is filtered off and recrystallized from water and finally from isopropyl ether. Yield: 10.3 g (78%); Rf (8/2 petroleum ether/ethyl acetate): 0.58; IR (KBr): 3085, 1620, 1531, 1425, 1340 cm−1.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[CH:44]=[CH:43][CH:42]=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:36])[C:34]3[CH:41]=[CH:42][CH:43]=[CH:44][C:33]=3[Cl:32])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccccc1Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a magnetically stirred solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-(trifluoromethyl)-benzenesulfonamide (1.5 g, 3.03 mmol) in anhydrous THF (15 mL) was added 2 M isopropylmagnesium chloride in THF (3.3mL, 6.6 mmol) at −20° C. The temperature was allowed to slowly rise to 10° and then 2-chloro-N-methoxy-N-methylbenzamide (1.2 g, 6.0 mmol) was added and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred for 16 h. It was then quenched with saturated aqueous NH4Cl (50 mL), and extracted with ethyl acetate (3×100 mL). The combined extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using ethyl acetate-hexane mixtures (2:98, 5:95) to provide 4-chloro-N-[5-chloro-2-(2-chloro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide mass spectrum m/z 574.8 (M+Na); 521.0 (M−31).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>CN(C)C=O>[CH:24]([NH:27][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CC(C)NCc1nc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)no1
Yield: 67.3 %

Procedure:
3.30 g (10 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 2.5 hours with 3 g (50 mmol) of isopropylamine and 20 ml of N,N-dimethylformamide. After evaporating the solvent the residue was dissolved in methylene chloride and the solution was washed twice with water. The organic solution was dried over magnesium sulfate and concentrated. By recrystallizing the residue from ethyl acetate there were obtained 2.37 g (67%) of 3-(5-isopropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 142°-144°, which was converted into the hydrochloride of m.p. 252°-254°.
Reaction SMILES: C(OC(=O)CC(N1C=CC(C2C=CC=CC=2)=C1)C(NC1CC2=CN(C3C2=CC=CC=3)CCOCCNC1=O)=O)C1C=CC=CC=1.[CH2:46]([O:53][C:54](=[O:72])[CH2:55][C@@H:56]([NH2:71])[C:57]([NH:59][C@H:60]([C:65](=[O:70])[N:66]([O:68][CH3:69])[CH3:67])[CH2:61][CH:62]([CH3:64])[CH3:63])=[O:58])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[C:73]1([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH:78]=[CH:77][C:76]([CH:79]2[CH2:83][CH:82](OC)O[CH:80]2OC)=[CH:75][CH:74]=1.FC(F)(F)C(O)=O.C(OC(=O)[C@H](N1C=CC(C2C=CC(C3C=CC=CC=3)=CC=2)=C1)CC(N[C@H](C(=O)N(OC)C)CC(C)C)=O)C1C=CC=CC=1>ClCCCl>[CH2:46]([O:53][C:54](=[O:72])[CH2:55][C@@H:56]([N:71]1[CH:82]=[CH:83][C:79]([C:76]2[CH:77]=[CH:78][C:73]([C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)=[CH:74][CH:75]=2)=[CH:80]1)[C:57]([NH:59][C@H:60]([C:65](=[O:70])[N:66]([O:68][CH3:69])[CH3:67])[CH2:61][CH:62]([CH3:63])[CH3:64])=[O:58])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CC(=O)OCc1ccccc1
Agent: CON(C)C(=O)[C@H](CC(C)C)NC(=O)C[C@H](C(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Agent: O=C(CC(C(=O)NC1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccccc2)c1)OCc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 48 %

Procedure:
As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17]-octadeca-11(18), 12,14,16-tetraen-9-yl)-3-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-amino-N-(1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl)succinamic acid benzyl ester was deprotected. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to provide in 48% yield 3 (R)-(3-biphenyl-4-yl-1H-pyrrol-1-yl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl]succinamic acid benzyl ester as an amorphous solid. 1H NMR (CDCl3) δ 7.62 (d, 2H, J=7.4 Hz), 7.58 (s, 3H), 7.44 (t, 2H, J=7.7 Hz), 7.35-7.21 (m, 7H), 7.10 (s, 1H), 6.80 (t, 1H, J=2.2 Hz), 6.60 (bs, 1H), 5.17-1.13 (m, 1H), 5.10 (s, 2H), 4.97-4.92 (m, 1H), 3.77 (s, 3H), 3.44 (dd, 1H, J=5.7, 17.1 Hz), 3.17 (s, 3H), 3.03 (dd, 1H, J=8.8, 16.5 Hz), 1.67-1.36 (m, 3H), 0.92 (d, 3H, J=6.25 Hz), 0.87 (d, 3H, J=6.3 Hz). Anal. Calculated for C35H39N3O5: C, 72.27; H, 6.76; N, 7.22. Found: C, 72.19; H, 6.78; N, 7.16.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:20]([NH2:22])[CH3:21]>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14]([NH:22][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCN
Reactant: Clc1ncccc1-c1nnsc1-c1cccnc1Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCNc1ncccc1-c1snnc1-c1cccnc1Cl
Temperature: 105 °C
Yield: 66.3 %

Procedure:
A mixture of 4, 5-di-(2-chloropyridin-3-yl)-1, 2, 3-thiadiazole (1.823 g), and ethylamine (0.61 g) in dioxane (9 mL) was heated at 105° C. in a sealed tube 3 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel gave 4-(2-chloropyridin-3-yl)-5-(2-ethylaminopyridin-3-yl)-1, 2, 3-thiadiazole (1.243 g) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:2].C([O-])(=O)C.[K+].[I:19]I.O>CO.C(OCC)(=O)C>[CH2:1]([C:3]1[NH:7][C:6]([I:19])=[N:5][C:4]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: II
Reactant: CCc1[nH]cnc1-c1cccnc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCc1[nH]c(I)nc1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a solution of 5-ethyl-4-(3-pyridyl)imidazole (1.50 g) and potassium acetate (2.55 g) in methanol (40 ml) was added iodine (2.86 g), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and ethyl acetate, and the organic layer was collected, washed with a saturated aqueous sodium thiosulfate solution and brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by NH silica gel flush column chromatography (solvent: ethyl acetate) to obtain 5-ethyl-2-iodo-4-(3-pyridyl)imidazole (1.75 g).
Reaction SMILES: BrBr.[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([NH2:15])=[S:14])[CH:7]=1.CCOCC>C(O)(=O)C>[CH3:3][O:4][C:5]([C:6]1[C:7]2[S:14][C:13]([NH2:15])=[N:12][C:8]=2[CH:9]=[CH:10][CH:11]=1)=[O:16]
Reactant: COC(=O)c1cccc(NC(N)=S)c1
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1cccc2nc(N)sc12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
At 0° C. a solution of bromine (13.4 mmol) in acetic acid (9.4 mL) is added dropwise to a vigorously stirred solution of 3-thioureido-benzoic acid methyl ester (12.5 ml) in acetic acid (37 mL). The mixture is allowed to reach RT, stirred at 70° C. for 4 h and cooled to RT. Ether is added and the precipitate is filtered off. The residue is stirred vigorously in a sat aqueous NaHCO3 solution, filtered off and washed with water. The obtained solid is dried in vacuo to give the desired product which is used without further purification. LC-MS: tR=0.62 min; [M+H]+=209.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[C:3]=1[OH:15].[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17]>O1CCCC1>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][C:4]1[C:3]2[O:15][C:16](=[O:17])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(OC2CCCCO2)c1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc(OC3CCCCO3)c2o1
Yield: 87.2 %

Procedure:
To a solution of 2-amino-6-(tetrahydropyran-2-yloxy)phenol (2.0 g) in anhydrous tetrahydrofuran (30 ml) was added 1,1'-carbonyldiimidazole (2.03 g), and the mixture was refluxed for 2 hours under nitrogen atmosphere. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (chloroform:methanol=40:1, v/v) and crystallized with diisopropyl ether to give 7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone (1.96 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=O)[CH2:6][C:7](=[O:9])[CH3:8])[CH3:2].Cl.[CH3:13][O:14][NH2:15].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:11])[C:5](=[N:15][O:14][CH3:13])[CH2:6][C:7](=[O:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: CON
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC(C)=O)=NOC
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.1 %

Procedure:
A mixture of 2,4-dioxo-pentanoic acid ethyl ester (5.4 mL, 50 mmol), methoxyamine hydrochloride (4.4 g, 52.5 mmol), molecular sieves (3 Å, 35 g) and sodium sulfate (15 g) in ethanol (50 mL) is stirred at ambient temperature for 5 hours. The reaction mixture is filtered and washed with ethanol. The combined filtrate is concentrated under reduced pressure and is partitioned between ethyl ether and saturated sodium bicarbonate. The organic layer is dried (MgSO4), filtered, and concentrated. The residue is purified by column chromatography (0 to 15% EtOAc in hexanes) to give the title compound as a colorless oil (3 g, 32%). 1H NMR (400 MHz, CDCl3) δ 4.33 (q, 2H), 4.06 (s, 3H), 3.70 (s, 3H), 2.20 (s, 3H), 1.34 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][N:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](=[O:24])[NH:16][C:15]1=[O:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:16]2[C:17](=[O:24])[CH:18]=[C:19]([C:20]([F:22])([F:23])[F:21])[N:14]([CH3:13])[C:15]2=[O:25])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: Cn1c(C(F)(F)F)cc(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Into 10 ml of dimethylsulfoxide was dissolved 1.77 g of 2,4,5-trifluoronitrobenzene and 1.94 g of 3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydro pyrimidine. After adding 1.52 g of anhydrous potassium carbonate at room temperature, the mixture was stirred at 80° C. for 1 hour. The reaction solution was cooled to room temperature, and then the solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica-gel column chromatography to give 1.51 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:33])[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nncs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(F)cc1Br
Yield: 70.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.06 g, 2.5 mmol) was reacted with NBS (0.5 g, 2.8 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.89 g, 71%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].C(OCC)C.C(N(CC)CC)C>O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCCN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ccc(C(=O)N2CCCC2=O)cc1

Procedure:
40.0 g. of p-methoxybenzoyl chloride, 25.0 g. of 2-pyrrolidinone and 110 ml. of absolute diethyl ether are treated at between 0° C. and 10° C. while stirring with 52.5 ml. of triethylamine. The mixture is stirred at room temperature for a further 30 minutes and at reflux for 3 hours, then cooled down and treated at 2° C. with cold water. The insoluble constituents are filtered off under suction and washed with water and diethyl ether. The thus-obtained solid substance is recrystallized from alcohol after drying over phosphorus pentoxide. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone which melts at 121°-122° C.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([OH:14])[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:14][C@H:12]1[CH2:11][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[CH2:9][NH:8][CH2:13]1
Reactant: OC1C=C(c2ccc(C(F)(F)F)cc2)CN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O[C@@H]1CNC[C@H](c2ccc(C(F)(F)F)cc2)C1

Procedure:
A solution of 1-benzyl-5-hydroxy-1,2,5,6-tetrahydro-3-(p-trifluoromethylphenyl)pyridine (5.9 g) in methanol (200 ml) was hydrogenated over 10% palladium on carbon (500 mg) in a Parr apparatus at 30 psi (about 2.11×104 kg/sq.m.) and room temperature. After the theoretical uptake of hydrogen had occurred (about 3 hours), the catalyst was removed by filtration and the solvent evaporated under reduced pressure. Recrystallisation of the residue from toluene gave the title compound as the free base (4 g). The free base was dissolved in a small volume of IPA and treated with an excess of etherial hydrogen chloride. On cooling crystals of the title compound hydrochloride separated, m.p. 189°-92°.
Reaction SMILES: CS[CH:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[C:8]([C:17]([F:20])([F:19])[F:18])[NH:7][C:6]=2[C:5](=[O:21])[NH:4]1.[NH2:22][NH2:23]>O>[CH2:12]([N:11]1[C:10]2[N:9]=[C:8]([C:17]([F:20])([F:19])[F:18])[NH:7][C:6]=2[C:5](=[O:21])[NH:4]/[C:3]/1=[N:22]\[NH2:23])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NN
Reactant: CCCCCN1c2nc(C(F)(F)F)[nH]c2C(=O)NC1SC
Solvent: O
Product: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A mixture of 2-(methylthio)-3-pentyl-8-(trifluoromethyl)-1,2,3,7-tetrahydro-6H-purin-6-one (0.61 g, 0.95 mmol), hydrazine (3 mL, 100 mmol) and water (3 mL) was stirred at 100° C. for 1 h. The reaction solution was concentrated under reduced pressure. The residue was dissolved in DMSO and purified by preparative LCMS. The product fractions were collected and lyophilized to give the desired product (0.25 g, 65%). LCMS calculated for C11H15F3N6O: (M+H) 305.1. Found 305.1.
Reaction SMILES: [CH2:1]([Li])CCC.[Si:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Si:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:1])=[CH:16][CH:15]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
p-OSi-St chain transfer agent was synthesized in two steps. In a 500 ml flask equipped with a magnetic stirring bar, 70.4 g of imidazole was mixed with 52.4 g (0.42 mol) of 4-hydroxybenzaldehyde and 77.4 g of t-butyldimethylsilyl chloride in THF solution. The mixture was stirred at ambient temperature for 4 hours before being poured into cold water. The organic layer was separated and extracted with ether, then dried with magnesium sulfate. After evaporating the solvent, 94 g of 4-(t-butyldimethylsilyloxy)benzaldehyde (90% yield), a deep yellow color liquid, was obtained. The second reaction step was performed under a nitrogen atmosphere. In a 500 ml flask equipped with a magnetic stirring bar, 123.6 g of methyltriphenylphosphonium bromide suspended in THF was treated with 149.6 ml of n-butyllithium (2.5M in hexane). After 1 hour, 80.0 g of 4-(t-butyldimethylsilyloxy)benzaldehyde was introduced dropwise into the red solution. The mixture was stirred overnight at room temperature and then poured into cold water. The organic layer was separated by ether extraction and dried with magnesium sulfate. Further purification was performed by distillation under vacuum (10 Torr) at elevated temperature (80° C.). 65 g of p-OSi-St was obtained with a yield of more than 90%. Its structure was confirmed by 1H NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>O.CC(C)=O.[OH-].[Na+]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5]
Reactant: NCCCC(=O)O
Reactant: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)NCCCC(=O)O)c2)C1
Temperature: 25 °C

Procedure:
2-Chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoyl chloride (1.75 g.) is added to a solution of 4-aminobutyric acid (0.54 g.) in water (30 ml.), acetone (30 ml.) and 1N sodium hydroxide (10 ml.). After stirring at room temperature for a half hour, the acetone is removed by evaporation, and the aqueous solution is acidified with concentrated hydrochloric acid. The precipitate is dissolved in 50 ml. of hot acetone-methanol (1:1) and concentrated to half volume. Hexane is added to crystallize the product, m.p. 193°-195° C.