Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]([Br:14])=[C:12]([Br:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2)([O-:3])=[O:2].[OH-].[K+].[NH2:20]OS(O)(=O)=O>O>[NH2:20][N:9]1[C:10]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[C:13]([Br:14])=[C:12]([Br:15])[CH:11]=2)[NH:6][C:7](=[O:17])[C:8]1=[O:16]
Reactant: O=c1[nH]c2cc(Br)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c([N+](=O)[O-])c(Br)c(Br)cc21
Reaction time: 0.08 h
Yield: 63.8 %

Procedure:
The procedure of Shin, S. C. and Lee. Y. Y., Taehan Hwahakhoe Chi 27(5):382-4 (1983) was adapted. To a stirred red solution of 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (120 mg, 0.33 mMol) and 3N KOH (2 mL) in distilled water (5 mL) at 65° C. was dropwise added a colorless solution of NH2OSO3H (56 mg, 0.50 mMol) in distilled water (0.5 mL) with stirring, whereupon a yellow precipitate came out after 5 mins. The mixture was stirred at 65° C. for 1 h and allowed to stand at room temperature overnight, then the precipitate was collected by filtration at 50° C., washed with distilled water (2 mL), then air dried at 50° C. overnight, affording 80 mg (64%) of crude 1-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (free base Na+ by NMR, D2O), as a yellow amorphous solid (80% desired 1-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione with 20% starting material by NMR). (It is not known if the reaction actually gave the 1-amino or 4-amino isomer.) A 80 mg sample of crude 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (0.211 mMol) was dissolved into distilled water (10 mL) at 50° C., then acidified with AcOH to pH=5. After the insoluble material was removed by filtration, it was heated at 60°-70° C. until a clear solution was obtained, then slowly cooled, and a yellow precipitate came out. The precipitate was crystallized from hot EtOH, collected by filtration, and washed with cold ethanol (2 mL), then dried in the air at 60° C. for 4 h, affording 57 mg (45.6%) of pure 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (free base H). NH2OSO3H (40 mg, 0.35 mMol) was added to the mother liquid, and allowed to react at 65°-70° C. for 30 min to give a second crop of pure 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (26 mg, 21%), using the same procedure as above. The total yield is 66%. Mp was measured: the color of 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione changed to dark yellow at 301° C.; the decomposition of 1(4)-amino-5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione is obvious at 310° C. and it melted to a black liquid at 320°-1° C. IR (KBr, cm-1): 3414; 3211; 1745; 1728; 1682; 1631; 1546. NMR (1H, DMSO-d6): δ5.832 (s, 2H); 8.047 (s, 1H); 12.565 (s, 1H). HRMS: calcd for C8H4N4O4Br2 (M+) m/z: 377.8613; found: 377.8583.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[C:19]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18]3)[C:12]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O-]S(C(F)(F)[F:32])(=O)=O.F[N+]1C=CC=CC=1>ClCCCl>[F:32][C:20]1[C:19]2[C:13]([CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1ccccc1
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccc(-c2c(F)c3cccccc-3c2-c2ccccc2)cc1
Temperature: 0 °C
Yield: 47.6 %

Procedure:
To a solution of 2-(4-methylsulfonylphenyl)-1-phenylazulene (0.20 g) in 1, 2-dichloroethane (20.0 ml) was added 1-fluoropyridinium triflate (0.28 g), and the reaction mixture was heated under reflux for 30 min. The mixture was poured into ice-water, and extracted with CHCl3. The combined CHCl3 extracts were washed with water and brine, dried over Na2 SO4, and concentrated. The crude product was purified by SiO2 column chromatography (benzenee/EtOAc, 20:1) to give the title compound (0.10 g) as green crystals; mp 120°-122° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]#[N:15])=[CH:5][CH:4]=1.[O:16]=[C:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(C(C)C)CC)(C)C.[Li+].[Br-]>C1COCC1>[C:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH:18]([C:17](=[O:16])[CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:5]=1)#[N:15]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#Cc1ccsc1-c1ccc(CBr)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2sccc2C#N)cc1)C(=O)OCC
Yield: 97.7 %

Procedure:
A mixture of 50 g of 2-(4-bromomethylphenyl)-3-cyanothiophene, prepared above, 40 g of ethyl 3-oxohexanoate, prepared in Example 1, 300 ml of THF, 62 ml of diisopropylethylamine and 15.6 g of LiBr is refluxed for 15 h. It is concentrated under vacuum, a dilute solution of hydrochloric acid is added and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with water, dried and evaporated to give 62.4 g of ethyl 2-[4-(3-cyano-2-thienyl)benzyl]-3-oxohexanoate in the form of an oil, which is used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.I[C:9]1[C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:11][CH:10]=1.[CH2:41]([O:44][CH3:45])[C:42]#[CH:43]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[N:22]=[CH:21][N:20]=[C:19]2[NH:18][C:12]1[C:13]2[O:17][CH2:16][O:15][C:14]=2[C:9]([C:43]#[C:42][CH2:41][O:44][CH3:45])=[CH:10][CH:11]=1
Reactant: C#CCOC
Reactant: COc1cc2c(Nc3ccc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COCC#Cc1ccc(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
Bis(Triphenyl-phosphine)palladium(II) chloride (94 mg), copper iodide (19 mg) and diisopropylamine (68 mg) were added to a stirred solution of N-(7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (200 mg) and methyl propargyl ether (47 mg) in ethyl acetate (5 mls) at −20° C. The reaction was allowed to warm to ambient temperature and stirred over 16 hours. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The product was purified by column chromatography on silica using a gradient of 0-10% methanol/methylene chloride as eluent. The resultant yellow gum was dissolved in minimal methylene chloride, diluted with diethyl ether and precipitated as an HCl salt by the addition of 1.0 M ethereal hydrogen chloride. The resultant solid was centrifuged and washed with diethyl ether (3 times) and dried to give the title compound as a yellow solid (55 mg); NMR Spectrum: DMSOd6) 2.29-2.36 (m, 2H); 3.03-3.14 (m, 2H); 3.24 -3.31 (m, 2H), 3.32 (s, 3H), 3.43-3.54 (m, 2H), 3.76-3.86 (m, 2H), 3.94 -4.00 (m, 5H), 4.31 (t, 2H), 4.35 (s, 2H), 6.13 (s, 2H), 6.98 (d, 1H), 7.02 (d, 1H), 7.40 (s, 1H), 8.27 (s, 1H), 8.80 (s, 1H); Mass Spectrum: M+H+ 507.11
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[CH:9]=2)=[O:4]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1c(O)c2ccc(-c3ccc(OC)cc3)cc2sc1=O
Yield: 71.2 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) (180 mg, 0.57 mmol) in dimethoxyethane (DME) (2.5 mL) was added 4-methoxyphenylboronic acid (104 mg, 0.69 mmol), Pd(PPh3)4 solid (66 mg, 0.06 mmol) and then 2M aqueous Na2CO3 solution (0.7 mL). The resulting mixture was purged with nitrogen gas for 1 min and heated to reflux for 2 h. After cooling the reaction mixture was diluted with water (50 mL) and acidified using 1 N HCl to pH 3-4. The precipitate was collected by filtration, rinsed with water and dissolved in CH2Cl2. The organic solution was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated with MeOH (5 mL) and the solid collected, rinsed with MeOH (2 mL) and dried in vacuo to provide 4-hydroxy-7-(4-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (139 mg). MS ESI(+) m/e: 343.11 (M+1).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[Cl:30].C([O-])([O-])=O.[K+].[K+].[C:37]([O:42][CH2:43][CH3:44])(=[O:41])[C:38]#[C:39][CH3:40]>CN(C=O)C.C(Cl)Cl>[Cl:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[C:16]1[N:15]2[N:14]=[C:39]([CH3:40])[C:38]([C:37]([O:42][CH2:43][CH3:44])=[O:41])=[C:20]2[CH:19]=[CH:18][C:17]=1[CH3:21]
Reactant: CC#CC(=O)OCC
Reactant: COc1ccc(-c2c(C)ccc[n+]2N)c(Cl)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2c(-c3ccc(OC)cc3Cl)c(C)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
A solution of crude 1-amino-2-(2-chloro-4-methoxyphenyl)-3-methylpyridinium 2,4,6-trimethylbenzenesulfonate (2.63 g, 5.9 mmol) in DMF (15 mL) was treated with K2CO3 (4.05 g, 29.3 mmol). A solution of ethyl but-2-ynoate (0.77 g, 6.9 mmol) in DMF (2 mL) was added and the reaction was stirred at ambient temperature for 16 hours then quenched with water and filtered to give a waxy yellow solid which was dissolved in CH2Cl2. The solution was washed with H2O, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to give a yellow oil (1.02 g). The original aqueous filtrate from the reaction was concentrated in vacuo to remove DMF and partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 and the combined organic layers was dried over MgSO4, concentrated in vacuo, combined with the yellow oil and subjected to column chromatography (30% ethyl acetate/heptane) to give 0.89 g (42%) of a yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=9.0 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.04 (dd, J=8.5, 2.5 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 3.92 (s, 3H), 2.63 (s, 3H), 2.17 (s, 3H), 1.46 (t, J=7.1 Hz, 3H); MS m/z 359.39 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[NH:27][C:28](=[O:30])[NH:29][C:22]=23)=[CH:18][CH:17]=1>C1COCC1>[O:30]=[C:28]1[NH:27][C:23]2=[N:24][CH:25]=[CH:26][C:21]([O:20][C:19]3[CH:31]=[CH:32][C:16]([NH:15][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]([F:14])([F:12])[F:13])[CH:4]=4)=[S:10])=[CH:17][CH:18]=3)=[C:22]2[NH:29]1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2nccc(Oc3ccc(NC(=S)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)c2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.6 %

Procedure:
A mixture of 4-chloro-3-trifluoromethylphenyl-isothiocyanate (20 μL, 0.12 mmol) and 7-(4-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one (29 mg, 0.12 mmol) in anhydrous THF (2 mL) was stirred at room temperature for 3 days. The solvent was evaporated and the solid residue was washed with DCM to afford the title compound (47 mg, 82%). 1H-NMR (δ, ppm, DMSO-d6): 6.40 (d, 1H, HPy,6, J=5.8 Hz), 7.15 (d, 2H, Harom,Ph,3+5, J=8.70 Hz), 7.54 (d, 2H, Harom,Ph,2+6, J=8.75 Hz), 7.67 (d, 1H, HPy,6, J=8.55 Hz), 7.80 (broad s, 2H, Harom′), 8.08 (s, 1H, Harom′), 10.03 (s, 1H, NHthiourea,1), 10.10 (s, 1H, NHthiourea,3), 11.18 (s, 1H, NHPy3), 11.36 (s, 1H, NHPy2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:25]N(C)C)[C:9]([C:11]1[S:24][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=O.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:36][C:37]([NH2:39])=[NH:38]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:11]2[S:24][C:14]3[C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=4[O:17][CH2:18][CH2:19][C:13]=3[CH:12]=2)=[N:38][C:37]([NH2:39])=[N:36][CH:25]=1
Reactant: CN(C)C=C(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ncc(-c2ccccc2Cl)c(-c2cc3c(s2)-c2ccccc2OCC3)n1
Temperature: 90 °C

Procedure:
To a solution of crude 2-(2-chlorophenyl)-1-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-3-(dimethylamino)prop-2-en-1-one (ca. 0.22 mmol) in ethanol (2 mL) was added potassium carbonate (87 mg, 0.63 mmol) and then guanidine hydrochloride (40 mg, 0.42 mmol). The whole was sealed and heated at 90° C. for 8 h, cooled to room temperature and concentrated. The residue was diluted with water and extracted with ethyl acetate. The combined organics were purified by reverse phase HPLC to give 282. MS (ESI) 406.2
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C(OCC)(=O)C.CO>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([NH:10][S:11]([CH2:14][CH3:15])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCS(=O)(=O)Nc1cccc(C(C)=O)c1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CCS(=O)(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Temperature: 150 °C
Yield: 56 %

Procedure:
2 g (8.8 mmol) of N-(3-acetyl-phenyl)-ethanesulfonamide were dissolved in 15 ml of N,N-dimethylformamide dimethyl acetal and heated at 150° C. for 12 h. The solvent was removed by reduced pressure distillation to yield a crude which was chromatographied (silica gel) using ethyl acetate/methanol as eluent. 1.4 g (yield=56%) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-ethanesulfonamide were obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])[N:8]=1)#[N:2].Cl.[NH2:20][OH:21].C(N(CC)CC)C>O1CCOCC1>[NH2:2]/[C:1](=[N:20]/[OH:21])/[CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])[N:8]=1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(CC#N)n2)s1
Reactant: NO
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C/C(N)=N\O)n2)s1
Temperature: 80 °C
Yield: 95 %

Procedure:
N-[2-(cyanomethyl)-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl]acetamide, Compound (3) (50 mg; 0.18 mmol; 1 eq.), is dissolved in dioxane (10 ml). Hydroxylamine hydrochloride (15 mg; 0.22 mmol; 1.20 eq.) and N,N-diethylethanamine (0.03 ml; 0.22 mmol; 1.20 eq.) are added and reaction mixture is heated at 80° C. overnight. Reaction mixture is cooled down and dioxane evaporated. The residue is taken up in EtOAc and washed several times with water (3×10 mL). The organic phases are dried over MgSO4, filtrated and evaporated. Crude material is purified by flash chromatography on silica gel (cyclohexane/ethylacetate, 50/50), affording the title compound as an oil (50 mg; 95%).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[N:21]=[N:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[N:18]2)=[CH:13][CH:12]=1)([CH3:10])[CH3:9].[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.ClCCl>[C:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:19]2[N:20]=[N:21][N:17]([C:14]3[CH:13]=[CH:12][C:11]([CH:8]([CH3:10])[CH3:9])=[CH:16][CH:15]=3)[N:18]=2)=[CH:27][CH:26]=1)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)c1ccc(-n2nnc(-c3ccc(O)cc3)n2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(-n2nnc(-c3ccc(OC(=O)C(C)(C)C)cc3)n2)cc1
Reaction time: 1 h
Yield: 54.9 %

Procedure:
Triethylamine (0.167 g) and 4-dimethylaminopyridine (0.02 g) were added to a solution of 4-[2-(4-isopropylphenyl)tetrazol-5-yl]phenol (0.42 g), obtained in the reference example 2, in dichloromethane (5 ml), and pivaloyl chloride (0.199 g) was added to the solution under ice cooling. Stirring was continued for 1 h at the same temperature. The mixture was washed with water, dried and evaporated to dryness. The residue was recrystallized from ethyl acetate-hexane to give 0.3 g (55%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]([OH:18])=O)N=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:19][O:20][C:21]([C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1)=[O:22].[CH2:29](N(C(C)C)C(C)C)C>CC(N(C)C)=O.C(Cl)Cl>[CH3:19][O:20][C:21]([C:23]1[N:24]=[C:25]([NH:28][C:16]([C:11]2[CH:29]=[C:9]([C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)[CH:14]=[C:13]([CH3:15])[N:12]=2)=[O:18])[S:26][CH:27]=1)=[O:22]
Reactant: Cc1cc(-c2cc(F)cc(F)c2)nc(C(=O)O)n1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1csc(N)n1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COC(=O)c1csc(NC(=O)c2cc(-c3cc(F)cc(F)c3)cc(C)n2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 100 mg (0.40 mmol) of 4-(3,5-Difluorophenyl)-6-methyl-pyrimidine-2-carboxylic acid, and 2-Amino-thiazole-4-carboxylic acid methyl ester in 5 ml of dry Dimethylacetamide were added 0.34 ml N-Ethyldiisopropylamine and 141.7 mg (0.44 mmol) of o-(Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU). After stirring overnight at room temperature, the mixture was diluted with 15 ml of methylene chloride, and worked up according to standard procedures. The crude material was purified by flash chromatography on silicagel using an Ethyl acetate/Heptane 1:4 mixture as eluant to yield the title compound as a light yellow crystalline solid, MS (ISP): m/e=390.2 (M+H)+.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:22][C:23]1[C:24]([C:28]2[N:32]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Br:40])[CH:34]=3)C(=O)O[N:29]=2)=[N:25][O:26][N:27]=1.[C:42]([O:46][C:47](=[O:52])[NH:48][CH2:49][CH:50]=O)([CH3:45])([CH3:44])[CH3:43]>C1COCC1>[Br:40][C:35]1[CH:34]=[C:33]([N:32]2[C:28]([C:24]3[C:23]([NH:22][CH2:50][CH2:49][NH:48][C:47](=[O:52])[O:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[N:27][O:26][N:25]=3)=[N:29][C:3](=[O:4])[O:5]2)[CH:38]=[CH:37][C:36]=1[F:39]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNc1nonc1-c1nc(=O)on1-c1ccc(F)c(Br)c1
Temperature: -5 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of trifluoroacetic acid (20.0 mL) and tetrahydrofuran (10.0 mL) was added sodium triacetoxyborohydride (10.59 g, 49.97 mmol, 10.0 equiv.) in portions with stirring under nitrogen. This mixture was stirred for 10 min at room temperature and then cooled to −5° C. A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (1.71 g, 5.0 mmol) and tert-butyl(2-oxoethyl)carbamate (Sigma-Aldrich) (1.99 g, 12.5 mmol, 2.5 equiv.) in THF (15.0 mL) was added drop-wise over 30 min with stirring while maintaining the temperature below 0° C. The reaction was stirred at −5 to 0° C. and additional portions of tert-butyl(2-oxoethyl)carbamate (0.20 g, 1.2 mmol, 0.24 equiv.) in THF (1.0 mL) were added drop-wise at 20 min, 40 min at 4 h intervals. HPLC indicated reaction completed after 5.25 h. The reaction mixture was poured into the ice-cold sodium bicarbonate (500 mL) and this solution was stirred at room temperature overnight. The precipitate was collected by filtration and washed with brine. The resulting residue was mixed with heptane (40 mL) and diethyl ether (40 mL) and stirred at room temperature for 5 h. The precipitate was collected by filtration, washed with diethyl ether and dried in a vacuum oven to give the desired product (1953 mg, 80.5%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.08 (m, 1H), 7.71 (m, 1H), 7.59 (t, 1H, J=8.7 Hz), 6.94 (m, 1H), 6.52 (m, 1H), 3.32 (m, 2H), 3.15 (m, 2H), 1.36 (s, 9H); C17H18BrFN6O5 (MW 485.26); LCMS (EI) m/e 507/509 (M++Na).
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9](O)[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].C(N(S(F)(F)[F:43])CC)C>ClCCl>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9]([F:43])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC(C)(CC)C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=[PH](O)O
Solvent: ClCCl
Product: CCC(C)(CC)C(F)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -70 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
A solution of diethyl 3-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 24) in dichloromethane (3 ml) was added dropwise with stirring at -70° C., to a solution of diethylaminosulphur trifluoride (0.37 g) in dichloromethane (7 ml). The mixture was stirred at -70° C. for two hours, allowed to warm to room temperature and, after a further one hour, diluted with dichloromethane, washed with water and sodium bicarbonate solution, dried over magnesium sulphate, and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (19:1) as eluant, to give diethyl 3-fluoro-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.50 g, m.p. 97-98° C.). NMR (CDCl3): δ 1.3(6H,t), 1.7-2.0(2H,m), 2.1-2.5(2H,m), 4.1(4H,m), 5.5-5.7(1H,m), 7.1-7.3(15H,m), 7.95(1H,s). M/S: M+ 507.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[N:9][S:10][C:11]=1[O:12][CH3:13])(=O)=O.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:25]([CH3:36])[C:24]=1[CH3:37]>>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([C:8]2[C:7]([CH2:6][O:5][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([CH3:36])[C:24]=3[CH3:37])=[C:11]([O:12][CH3:13])[S:10][N:9]=2)=[CH:15][CH:16]=1)[CH3:21]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CCc1ccc(-c2nsc(OC)c2COS(C)(=O)=O)cc1
Product: CCc1ccc(-c2nsc(OC)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Steps 2-6 by coupling of (3-(4-ethylphenyl)-5-methoxyisothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid.