Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([F:14])[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6]1)=[O:4].O[Li].O>CCO.CO.O.CCOC(C)=O>[F:14][C:5]1([C:3]([OH:4])=[O:2])[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6]1
Reactant: COC(=O)C1(F)COc2ncccc21
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)C1(F)COc2ncccc21
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 3-fluoro-2,3-dihydrofuro[2,3-b]pyridine-3-carboxylic acid methyl ester (0.30 mmol) in 3 mL EtOH and 2 mL MeOH was added a solution of LiOH.H2O (0.33 mmol) in 1 mL H2O. The reaction was stirred at RT for 50 min. The reaction mixture was diluted with 10 mL EtOAc and extracted twice with water. The water phase was acidified to pH 3 and extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to obtain the desired product as white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:21][CH:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH:22]([CH3:26])[C:23]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:24]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a mixture of tert-butyl piperazine-1-carboxylate (2.0 g, 11 mmol) in methylene chloride (20 mL) was added triethylamine (3.0 mL, 21 mmol) followed by 2-chloropropanoyl chloride (1.5 g, 12 mmol) drop-wise at 0° C. The reaction was stirred for 1 h, quenched with water, and extracted with dichloromethane. The combined organic layers were washed with water, brine, dried over magnesium sulfate and then evaporated to dryness to provide the crude product (3 g, 101%). LCMS calculated for C8H14ClN2O3 (M-Bu+H)+: m/z=221.1; Found: 221.1.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[C:18](=[O:21])[O:19][CH2:20][C:16]=2[CH:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=C.[O:24]=[O+][O-].CSC>CO.CCOC(C)=O>[O:21]=[C:18]1[C:17]2[CH:22]=[CH:23][C:14]([CH2:13][CH2:12][N:4]([CH2:1][CH:2]=[O:24])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[CH:15][C:16]=2[CH2:20][O:19]1
Reactant: C=CCN(CCc1ccc2c(c1)COC2=O)C(=O)OC(C)(C)C
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CSC
Product: CC(C)(C)OC(=O)N(CC=O)CCc1ccc2c(c1)COC2=O

Procedure:
To a solution of tert-butyl allyl[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]carbamate (0.58 g, 1.8 mmol) in MeOH (50 mL) was bubbled ozone until it turned blue. Nitrogen was bubbled through the solution to remove excess ozone, which was followed by addition of dimethyl sulfide (1.4 mL, 18 mmol). The solution was allowed to warm up slowly. The mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated to afford the product. The crude material was used directly in the next step without further purification.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:21]=[C:22](CCN)[CH:23]=[CH:24][CH:25]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:23]=[CH:22][CH:21]=1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Reactant: COc1cccc(CCN)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(CCNC(=S)Nc2nc3ccccc3[nH]2)c1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(3-methoxyphenyl)ethylamine (0.78 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 1.2 g (73%) of the titled product as a white solid:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1)=[O:6]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[N:4]([CH2:3][CH2:2][OH:1])[CH3:16])=[CH:9][CH:10]=1)=[O:15]
Reactant: CN(CCO)C(=O)Nc1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CN(CCO)C(=O)Nc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
To a solution of 1-(2-hydroxyethyl)-3-(4-(hydroxymethyl)phenyl)-1-methylurea (0.50 g, 2.23 mmol) in DCM (30 mL) was added manganese (IV) oxide (0.78 g, 8.92 mmol). The reaction mixture was stirred at RT for 3 hours. The suspension was filtered through celite and the filter pad washed with further DCM. The filtrate was evaporated at reduced pressure to afford the title compound (0.23 g, 49%).
Reaction SMILES: [C@@H]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=O)[C:12]=3[N:11]=[CH:10]2)O[C@H](CO)[C@@H](O)C1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N)C[NH2:35]>N1C=CC=CC=1>[NH2:17][C:16]1[N:18]=[C:19]2[C:12]([NH:11][CH:10]=[N:9]2)=[C:13]([NH2:35])[N:15]=1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: NCCN
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Nc1nc(N)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To 2′-deoxyguanosine (2 mmol), dried by coevaporation with pyridine, suspended in 40 mL of pyridine and cooled in an ice bath under an argon atmosphere, trifluoroacetic anhydride (16 mmol) is added following the procedure of Kung and Jones (Tetraheron Lett., 32, 3919, 1991). After 40 minutes, ethylenediamine (30 mmol) is added and stirred for 24 h at room temperature. The reaction mixture is concentrated and purified by silica column chromatography. The product is guanylated with reagent 5 as in Example 8 and protected at N2-position with an isobutyryl group by treating with isobutyric anhydride, 5′-dimethoxytritylated at the 5′-position and purified. The resulting compound is treated with benzoic anhydride (N6 protection) and then phosphitylated following the procedures described above to afford the 2,6-diaminopurine derivative functionalized at the 6-position (35).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([S:7][C:8]2[CH:9]([CH3:22])[C@@H:10]3[CH:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])[CH2:4][NH:3]1.[Na+].[CH3:24][C:25]1[O:29][C:28](=[O:30])[O:27][C:26]=1[CH2:31]Br>>[O:1]=[C:2]1[CH2:6][CH:5]([S:7][C:8]2[C@H:9]([CH3:22])[C@@H:10]3[C@@H:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O:15][CH2:31][C:26]2[O:27][C:28](=[O:30])[O:29][C:25]=2[CH3:24])=[O:14])[CH2:4][NH:3]1
Reactant: CC1C(SC2CNC(=O)C2)=C(C(=O)[O-])N2C(=O)C([C@@H](C)O)[C@@H]12
Reactant: Cc1oc(=O)oc1CBr
Agent: [Na+]
Product: Cc1oc(=O)oc1COC(=O)C1=C(SC2CNC(=O)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 79.5 %

Procedure:
Following a procedure similar to that described in Example 39, but using 50 mg of sodium 2-(2-oxo-4-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate and 55 mg of 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl bromide, 50 mg of the title compound were obtained as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH:41][C:42](N1C=CN=C1)=[O:43]>CN(C=O)C.[Cl-].[Na+].O>[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH:41][C:42]([N:24]1[CH2:23][CH2:22][CH:21]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)[CH2:26][CH2:25]1)=[O:43]
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Reactant: Cc1cnc(CN(C2CCNCC2)C2CCCc3cccnc32)c(C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(CN(C2CCN(C(=O)Nc3ncc[nH]3)CC2)C2CCCc3cccnc32)c(C)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a warm (70° C.), stirred, solution of (3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.43 g, 0.41 mmol) and DIPEA (0.43 mL, 2.47 mmol) in DMF (4 mL) was added imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equivs). After 1 hour, the mixture was cooled to room temperature, diluted with brine (5 mL) and extracted with CH2Cl2 (4×10 mL). The combined organic extracts were washed with water (5×10 mL), dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 70 mg (31%) of COMPOUND 368 as a white solid. 1H NMR (CDCl3) δ 1.52-2.06 (m, 8H), 2.21 (s, 3H), 2.38 (s, 3H), 2.56-2.79 (m, 5H), 3.91-4.21 (m, 5H), 6.68 (s, 2H), 6.96 (dd, 1H, J=7.5, 4.5 Hz), 7.12 (s, 1H), 7.23-7.27 (m, 1H), 8.09 (s, 1H), 8.41 (d, 1H, J=3.6 Hz); 13C NMR (CDCl3) δ 18.27, 19.02, 22.26, 29.28, 29.81, 30.93, 31.98, 44.84, 44.98, 53.77, 58.48, 60.37, 112.13, 121.44, 123.44, 131.64, 133.40, 132.32, 136.38, 139.06, 145.49, 146.39, 147.30, 155.71, 155.77, 159.01; ES-MS m/z 460 (M+H). Anal. Calcd. For C26H33N7O.1.1CH2Cl2: C, 58.86; H, 6.42; N, 17.73. Found: C, 59.01; H, 6.32; N, 17.68.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][O:6][C:5]=1[CH2:9][OH:10].I[CH3:12]>O1CCCC1>[CH3:12][O:10][CH2:9][C:5]1[O:6][CH:7]=[CH:8][C:4]=1[CH3:3]
Reactant: CI
Reactant: Cc1ccoc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1occc1C
Reaction time: 1 h
Yield: 113.2 %

Procedure:
Under an inert atmosphere sodium hydride (0.25 g ˜60%, 6.2 mmol, 1.1 equiv.) was suspended in dry tetrahydrofuran. At 5° C. a solution of (3-methyl-furan-2-yl)-methanol (0.63 g, 5.6 mmol) in dry tetrahydrofuran was added dropwise. The mixture was stirred at room temp. for one hour, then iodomethane (0.9 g, 6.2 mmol, 1.1 equiv.) was added dropwise. The mixture was stirred overnight at room temp., quenched with diluted acid and extracted with diethyl ether. The combined, organic extracts were washed with brine, dried over magnesium sulfate dihydrate, filtered and concentrated under reduced pressure to give 0.8 g of the title compound as a light yellow oil. GC-MS (EI): M=126.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COc1cccc(C(=O)O)c1
Product: COc1cccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c1
Yield: 67 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 3-methoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=80:20 to 20:80, 205 mg, 67%) which was obtained as a white solid. MS: m/e=334.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:64]=[C:63]([F:65])[CH:62]=[CH:61][C:57]=1[C:58](Cl)=[O:59]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:58](=[O:59])[C:57]2[CH:61]=[CH:62][C:63]([F:65])=[CH:64][C:56]=2[F:55])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCN(C(=O)c2ccc(F)cc2F)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2,4-difluorobenzoyl chloride as the starting materials in 30% yield. LCMS for C30H27ClF2N7O3 (M+H)+: m/z=606.0.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[CH2:27][S:28][CH2:29][C:30]([OH:32])=O)=[C:21]([C:34]([O:36]C)=[O:35])[CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[CH2:27][S:28][CH2:29][C:30]([N:3]([CH2:1][CH3:2])[C:4]2[CH:5]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][C:9]=2[CH3:10])=[O:32])=[C:21]([CH:20]=1)[C:34]([OH:36])=[O:35]
Reactant: CCNc1cc(-c2ccc(F)cc2)ccc1C
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Product: CCN(C(=O)CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)c1cc(-c2ccc(F)cc2)ccc1C

Procedure:
Using the same method as in Example 15-(i), N-ethyl-4′-fluoro-4-methylbiphenyl-3-amine was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-([((2-[ethyl(4′-fluoro-4-methylbiphenyl-3-yl)amino]-2-oxoethyl)sulfanyl)acetyl]amino)benzoic acid.methyl ester (yield: 28%).
Reaction SMILES: C(=O)=[O:2].CO.[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23][OH:24].C(O)(=O)C(C(C(O)=O)O)O>C(Cl)Cl.C(OO)(C)(C)C.C1(C)C=CC=CC=1.O.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]1[O:2][C@H:22]1[CH2:23][OH:24]
Reactant: O=C=O
Reactant: COCCOCOCCCCCCCC/C=C/CO
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COCCOCOCCCCCCCC[C@@H]1O[C@H]1CO
Reaction time: 0.12 h

Procedure:
200 ml of absolute CH2Cl2 are cooled to between -25° C. and -30° C. (dry ice/methanol) in a three-neck flask which has been dried by heating and flushed with nitrogen. 20 mmol of tetraisopropyl titanate [Ti(O--i--C3H7)4 ] and 20 mmol of L-(+)-diethyl tartrate (L-(+)-DET), dissolved in 2 ml of absolute CH2Cl2, are added with stirring through a septum. After 5 to 10 minutes, 20 mmol of the allyl alcohol 4 are added, dissolved in a little absolute CH2Cl2, and finally 40 mmol of a 3.0 molar solution of tert.butyl hydroperoxide (TBHP) in toluene are added. The resultant solution is left to stand overnight at -25° C. 50 ml of a 10% strength solution of tartaric acid in water are then added with stirring at -25° C. After 30 minutes, the cooling bath is removed, and stirring is continued at room temperature until the aqueous solution separates out and is clear. The phases are separated, the organic phase is washed once with water, and the solvent is removed on a rotary evaporator. The residue is taken up in 150 ml of Et2O, and 60 ml of a precooled 1N NaOH solution are added to the resultant solution at 0° C. The two-phase system is stirred at 0° C. for 30 minutes. The phases are then separated, the etherial phase is washed once with saturated NaCl solution and dried over MgSO4, and the solvent is stripped off. The crude substance obtained is purified by flash chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:37]=[CH:38][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Br:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: COc1ccc(OCC(=O)O)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(Br)cc3)sc2n1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(CCc5ccc(Br)cc5)nc34)CC2)cc1
Yield: 40 %

Procedure:
This compound was prepared from 2-(4-bromophenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 40%, according to the procedure for the synthesis of example 50. 1H NMR (300 MHz, CDCl3, 25° C.): δ=7.40 (d, 2H, PhH), 7.07 (d, 2H, PhH), 6.82-6.93 (m, 4H, PhH), 4.71 (s, 2H, NH2), 4.70 (s, 2H, OCH2), 4.23 (br s, 2H, NCH2), 4.19 (br s, 2H, NCH2), 3.77 (s, 3H, CH3), 3.67-3.75 (m, 4H, N(CH2)2), 3.23 (t, 2H, CH2), 3.05 (t, 2H, CH2) ppm
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Li+].[CH3:24]I>>[CH3:24][N:14]1[C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[N:19][C:11]=2[S:10][C:9]1=[N:8][C:7]1[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=c1nc(Nc2ccc([N+](=O)[O-])cc2)sc2ncccc12
Reactant: CI
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccc([N+](=O)[O-])cc2)sc2ncccc2c1=O
Yield: 80.2 %

Procedure:
The reaction procedure of Example 11 was followed except that 901 mg (3.0 mmol) of 2-(4-nitroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 30 mg of lithium hydride and 511 mg of methyl iodide were used. The resulting residue was then purified through silica gel chromatography (eluant: chloroform) to obtain 756 mg of 2,3-dihydro-3-methyl-2-[(4-nitrophenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (80%, recrystallized from a mixture of ether and ethanol).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]2[N:10]=[C:11]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:8]2[N:7]=[C:6]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[N:5]=1.IC.[CH3:28]C(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CN(C)C=O.O>[F:25][C:20]1[CH:19]=[C:18]([C:6]2[N:5]=[C:4]([NH:3][CH3:28])[N:9]3[N:10]=[C:11]([C:13]4[O:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[C:8]3[N:7]=2)[CH:23]=[C:22]([F:24])[CH:21]=1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: Nc1nc(-c2cc(F)cc(F)c2)nc2nc(-c3ccco3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1nc(-c2cc(F)cc(F)c2)nc2nc(-c3ccco3)nn12

Procedure:
Sodium hydride (86 mg of a 50% dispersion in oil) was added to a stirred solution of 7-amino-5-[3,5-difluorophenyl]-2-(2-furyl)-1,2,4-triazolo[1,5-a][1,3,5]triazine (0.421 g) in dimethylformamide (5 ml). The mixture was stirred until the effervesence had ceased and a clear solution was obtained. Iodomethane (0.256 g, 0.11 ml) was then added and the reaction mixture was stirred at ambient temperature for 2 hours. Water (25 ml) and glacial acetic (0.5 ml) were then added and the resulting aqueous suspension was extracted with ethyl acetate (3×50 ml). The organic extracts were combined and washed with water (2×25 ml) and brine (25 ml), dried (MgSO4) and evaporated to give a yellow solid. This was purified by chromatography on silica. Elution with toluene containing ethyl acetate (10% v/v) gave 5-[3,5-difluorophenyl]-2-(2-furyl)-7-methylamino-[1,2,4]triazolo[1,5-a][1,3,5]triazine as a white solid m.p. 231°-4° C. microanalysis, found: C, 55.0; H, 3.1; N, 25.5% C15H10F2N6O requires C15H10F2N6O C, 54.9; H, 3.1; N, 25.6%; NMR 3.16 (s, 3H, CH3N), 6.73 (d of d, 1H, furyl-4H), 7.21 (d of d, 1H, furyl-3H), 7.47 (t of t, 1H, phenyl-4H), 7.93 (d, 1H, furyl-5H), 7.97-8.05 (complex, 2H, phenyl-2H and phenyl-6H) and 9.31 (s, 1H, NH); m/e 329 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:25])=[C:19]([NH2:24])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:25])=[C:19]([NH:24][S:34]([C:28]3[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])(=[O:36])=[O:35])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}amine (500 mg, 1.313 mmol) and 2,6-difluorobenzenesulfonyl chloride (0.214 mL, 1.575 mmol) the title compound of Step C was obtained as a light yellow solid (653 mg, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 8.63 (d, J=5.3 Hz, 1H), 7.63-7.74 (m, 1H), 7.52 (td, J=8.7, 6.0 Hz, 1H), 7.17-7.35 (m, 3H), 6.99 (d, J=5.3 Hz, 1H), 1.42 (s, 9H). MS (ESI): 556 [M+H]+.
Reaction SMILES: C[C:2]([CH3:16])([CH2:12][N+:13]([O-:15])=[O:14])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[BH4-].[Na+].[CH3:19]O>>[CH3:16][CH:2]([CH2:12][N+:13]([O-:15])=[O:14])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)([OH:5])[CH3:19]
Reactant: CO
Reactant: CC(C)(CC(=O)c1cccnc1)C[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Product: CC(C[N+](=O)[O-])CC(C)(O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 3,3-dimethyl-4-nitro-1-pyridin-3-yl-butan-1-one (1 g, 4.5 mmol) in methanol (6 mL) under nitrogen add sodium borohydride (684 mg, 18 mmol). Stir at room temperature for 2 h, evaporate the methanol, dissolve in ethyl acetate and wash with water. Dry the organic layer over anhydrous sodium sulfate and concentrate to obtain 860 mg (85%) of the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([CH2:11][CH2:12][C@H:13]([NH2:17])[C:14]([OH:16])=[O:15])=[O:10])=[CH:3][CH:2]=1.[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>C1(C)C=CC=CC=1>[CH2:7]([O:8][C:9]([CH2:11][CH2:12][C@H:13]([N:17]1[C:21](=[O:22])[C:20]2[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]1=[O:23])[C:14]([OH:16])=[O:15])=[O:10])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Solvent: Cc1ccccc1
Product: O=C(CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Yield: 60.5 %

Procedure:
16 g of L-glutamic acid γ-benzyl ester and 11 g of phthalic anhydride, both finely powdered, were stirred in 20 ml of toluene at reflux temperature for 2 hours. 50 ml of toluene were added and the mixture was evaporated. A further 80 ml of toluene were then added and the mixture was left to crystallize. Recrystallization from toluene yielded 15 g of α(S)-(2-benzyloxycarbonylethyl)-1,3-dihydro-1,3-dioxo-2-isoindoleacetic acid of melting point 96°-98° C.; [α]D20 =-50.4° (c=1 in methanol).