Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].CC1(C)C(C)(C)OB([C:50]2[CH:51]=[C:52]([OH:56])[CH:53]=[CH:54][CH:55]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:50]6[CH:55]=[CH:54][CH:53]=[C:52]([OH:56])[CH:51]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6cccc(O)c6)c5)nn34)c(Cl)c21
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 73.4 %

Procedure:
A mixture of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (120 mg, 0.188 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61.9 mg, 0.281 mmol) and 2M Na2CO3 (0.188 mL, 0.375 mmol) in DMF (2 mL) was degassed for 15 min by bubbling N2 through the reaction mixture. Then, tetrakis(triphenylphosphine)pallafium(0) (15.17 mg, 0.013 mmol) was added and the degassing was continue for another 5 min. The mixture was then heated at 90° C. for 16 h. After cooling to room temperature, water was added and the mixture was extracted with ether (2×50 mL), washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. The residue was then purified by biotage (10-40% EtOAc/hexane) to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.138 mmol, 73.5% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 8.02 (t, J=1.6 Hz, 1H), 7.82 (dt, J=7.6, 1.4 Hz, 1H), 7.54-7.51 (m, 1H), 7.47-7.43 (m, 1H), 7.33-7.29 (m, 1H), 7.19-7.13 (m, 1H), 7.10 (t, J=8.1 Hz, 1H), 7.02-7.00 (m, 1H), 6.98 (s, 2H), 6.93 (s, 1H), 6.81 (ddd, J=8.0, 2.5, 0.9 Hz, 1H), 6.42 (dd, J=8.1, 2.3 Hz, 2H), 6.39-6.35 (m, 1H), 6.10-5.98 (m, 1H), 5.40-5.30 (m, 2H), 5.07 (s, 1H), 4.29-4.18 (m, 2H), 3.67 (s, 3H), 3.18 (t, J=4.4 Hz, 2H), 2.87 (s, 3H), 1.18 (s, 9H). LCMS (M+H)=653.4.
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]=[CH:11]2)=[C:5]([F:21])[CH:4]=1)#[N:2].[CH2:22]([S:24]([NH2:27])(=[O:26])=[O:25])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([C:3]1[C:8]([NH:27][S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])=[CH:7][C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]=[CH:11]2)=[C:5]([F:21])[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(F)c(-n2cnc(C(F)(F)F)cc2=O)cc1F
Reactant: CCS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCS(=O)(=O)Nc1cc(-n2cnc(C(F)(F)F)cc2=O)c(F)cc1C#N
Temperature: 60 °C
Reaction time: 6 h
Yield: 1.8 %

Procedure:
A mixture of 4.3 g (14.3 mmol) of 3-(4-cyano-2,5-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-4-one (cf. Example 1), 1.6 g (14.3 mmol) of ethanesulphonamide, 2.0 g (14.3 mmol) of potassium carbonate and 50 ml of dimethyl sulphoxide is stirred at 60° C. for 6 hours and then concentrated under reduced pressure. The residue is taken up in water and, after acidification, shaken with methylene chloride. The organic phase is dried with sodium sulphate and filtered. The filtrate is concentrated, and the crude product obtained as residue is purified by column chromatography (silica gel, ethyl acetate/chloroform, 1:1 by volume). 100 mg (2% of theory) of 3-(4-cyano-5-ethylsulphonylamino-2-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-4-one of melting point 170° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[O:41][CH3:42])=[C:5]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)[N:9](S(C3C=CC=CC=3)(=O)=O)[C:6]2=[N:7][CH:8]=1)#[N:2].[OH-].[Na+]>CO.O1CCCC1.O>[C:1]([C:3]1[C:4]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[O:41][CH3:42])=[C:5]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: COc1ccc(F)cc1-c1c(C#N)cnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(F)cc1-c1c(C#N)cnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of Example 236D (400 mg, 0.680 mmol) in 5 mL methanol and 5 mL tetrahydrofuran was added 1N aqueous sodium hydroxide (3398 μL, 3.40 mmol) and the mixture was stirred at room temperature overnight and at 70° C. for 1 hour. The mixture was diluted with water, neutralized to pH 5-6 and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (AnaLogix IntelliFlash 280) eluting with 0-3% methanol in dichloromethane to afford the title compound. MS (ESI+) m/z 449 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([NH:18][C@H:19]([C@H:27]1[O:31][C:30](=[O:32])[CH2:29][CH2:28]1)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]I)=[CH:37][CH:36]=1.C(O)(=O)CC.C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C.O.CN1C(=O)N(C)CCC1>[C:11]([NH:18][C@H:19]([C@H:27]1[O:31][C:30](=[O:32])[C@H:29]([CH2:39][C:38]2[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=2)[CH2:28]1)[CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12]
Reactant: COc1ccc(CI)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C[C@@H]2C[C@@H]([C@H](CC3CCCCC3)NC(=O)OC(C)(C)C)OC2=O)cc1
Temperature: -75 °C
Reaction time: 0.33 h

Procedure:
880 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF are added dropwise, at -70° C., under an argon atmosphere and within the space of 20 min, to 130 g (400 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]dihydrofuran-2-(3H)-one which is dissolved in 1000 ml of abs. THF and 108 ml of DMPU. After 20 min, a solution of 110 g (443 mmol) of p-methoxybenzyl iodide [preparation, see Example 7e)] in 60 ml of abs. THF is added dropwise, and this mixture is thoroughly stirred at -75° C. for 2 h. The mixture is subsequently protonate at -70° C. with 152 ml of propionic acid followed by 250 ml of water (temperature rises to -20° C.); 1 l of ethyl acetate is then added and the reaction mixture is poured onto 2 l of 15% NaHCO3 solution. The aqueous phase is separated off and extracted with 1 l of ethyl acetate. The organic phases are washed 2× with sat. NaHCO3 solution, water and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 9:1) and crystallization from hexane yields the pure title compound: TLC Rf (E)=0.45; tRet (II)=18.6 min; FAB-MS (M+H)+ =432.
Reaction SMILES: Cl[CH:2]([NH:7][C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16](=[O:18])[CH3:17])[C:3]([Cl:6])([Cl:5])[Cl:4].[CH:20]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([CH3:27])[CH:21]=1.C(N(CC)CC)C.O>CC(C)=O>[CH3:27][C:22]1[CH:21]=[CH:20][C:25]([O:26][CH:2]([NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16](=[O:18])[CH3:17])[C:3]([Cl:6])([Cl:5])[Cl:4])=[CH:24][CH:23]=1
Reactant: CC(=O)Oc1ccccc1C(=O)NC(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccc(O)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)NC(Oc1ccc(C)cc1)C(Cl)(Cl)Cl
Yield: 83.9 %

Procedure:
15.0 g of N-(1',2',2',2'-tetrachloroethyl)-2-acetoxybenzamide and 5.65 g of p-cresol were dissolved in 250 ml of acetone. 5.3 g of triethylamine were added dropwise thereto at a temperature below 12° C. After effecting the reaction at room temperature for 30 minutes, the reaction mixture was poured into water. 15.2 g of white N-(1'-p-methylphenoxy-2',2',2'-trichloroethyl)-2-acetoxybenzamide were obtained. The compound was suspended in 300 ml of ethanol, then 3.6 ml of concentrated hydrochloric acid were added thereto and the reaction was carried out at --60°-70° C. for three hours. After cooling, the reaction mixture was poured into water to obtain 14.3 g of N-(1'-p-methylphenoxy-2',2',2'-trichloroethyl)-2-hydroxbenzamide as white crystals. M.p. 126°-127° C.
Reaction SMILES: [CH3:1][CH:2]([C:5](=O)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:3]#[N:4].O.[NH2:14][NH2:15]>CCO>[CH3:1][C:2]1[C:5]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:14][NH:15][C:3]=1[NH2:4]
Reactant: NN
Reactant: CC(C#N)C(=O)c1cccnc1
Solvent: O
Solvent: CCO
Product: Cc1c(-c2cccnc2)n[nH]c1N
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-3-oxo-3-(pyridin-3-yl) propanenitrile (1.5 g, 9.4 mmol) in EtOH (20 mL) was added 85% hydrazine hydrate (2 mL). The resulting mixture was heated to reflux for 2 hours. After cooling to rt, the solvent was removed in vacuo and the crude product purified by column chromatography (DCM:MeOH=10:1) to give the desired product: MS (m/z): 175.0 [M+H]+, 1HNMR (400 MHz, CD3OD) δ 8.71 (d, 1H, J=2.0 Hz), 8.50-8.51 (m, 1H), 7.99 (d, 1H, J=8.0 Hz), 7.50-7.55 (m, 1H), 2.06 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:33]3[CH2:37][CH:36]([OH:38])[CH:35]=[CH:34]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[H][H]>[Pd].C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:33]3[CH2:34][CH2:35][CH:36]([OH:38])[CH2:37]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: [H][H]
Reactant: COc1cc(-c2nn(C3C=CC(O)C3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: [Pd]
Solvent: CCO
Product: COc1cc(-c2nn(C3CCC(O)C3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Yield: 68.4 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-hydroxy-2-cyclopentenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.10 g, 0.19 mmol) and 10% palladium on carbon (0.03 g) in ethanol (10 mL) was stirred at ambient temperature under one atmosphere of hydrogen overnight. The mixture was filtered and the filtrate was purified by preparative HPLC to yield N1-{4-[4-amino-1-(3-hydroxycyclopentyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.07 g, 0.13 mmol) as a white sold: 1H NMR (DMSO-d6, 400 MHz) δ 9.91 (dd, 1H), 8.31(d, 1H), 8.24 (s, 1H), 8.00 (t, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.34 (s, 1H), 7.30 (d, 1H), 6.90 (br, 2H), 5.17 (m, 1H), 4.97 (m, 1H), 4.22 (m, 1H), 3.94 (s, 3H), 1.79-2.41 (m, 6H); MS: MH+ 531.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4](S(C)=O)[N:3]=1.[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(Cl)c1C#N
Reactant: OCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(Cl)nc(N)nc1OCc1ccccn1

Procedure:
From 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 261 (M+, 75), 184 (46), 108 (95), 92 (100), 65 (70), 39 (45).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][C:12]=1[CH2:13]O)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:23]>COCCOC>[Br:23][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][C:7]=1[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1CO
Reactant: BrP(Br)Br
Solvent: COCCOC
Product: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1CBr
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To N-(3-tert-butylsulfanylmethyl-4-hydroxymethyl-phenyl)-2,2-dimethyl-propionamide (1.6 g, 5.17 mmol) in DME (60 mL) at 0° C. was added phosphorus tribromide (0.54 mL, 5.69 mmol) slowly via syringe. The reaction was stirred at 0° C. for 20 minutes, until no starting material was seen by analytical tlc. The mixture was quenched with H2O and diluted with EtOAc (300 mL) and H2O (100 mL). The organic layer was separated and washed with H2O, and then dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:18][C@H:19]3[O:23]C(C)(C)[N:21]([C:26]([O:28][C@@H:29]4[C@H:36]5[C@H:32]([O:33][CH2:34][CH2:35]5)[O:31][CH2:30]4)=[O:27])[C@H:20]3[CH2:37][C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[OH-].[Na+]>O1CCOCC1.C(Cl)Cl.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:18][C@@H:19]([OH:23])[C@@H:20]([NH:21][C:26](=[O:27])[O:28][C@@H:29]3[C@H:36]4[C@H:32]([O:33][CH2:34][CH2:35]4)[O:31][CH2:30]3)[CH2:37][C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of 0.60 g (0.95 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]methyl}-4-(4-hydroxybenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate in 5 mL of 1,4-dioxane was treated with 0.25 mL of water followed by 5 mL of 4N HCl in 1,4-dioxane and the resulting solution was stirred at RT. After 1.5 hours the solution was diluted with 25 mL of CH2Cl2 and the pH adjusted to approximately 12 by addition of 1N aqueous NaOH. The mixture was diluted with water and extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were washed with aqueous brine (3×), dried over MgSO4, and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, 8:2 EtOAc/hexane) to afford the desired compound as a white solid in 81% yield. 1H NMR (CDCl3): 7.29 (dd, 1H), 7.13 (s, 1H), 7.01 (d, 2H), 6.85 (d, 2H), 6.70 (d, 2H), 6.05 (s, 2H), 5.61 (d, 1H), 5.01 (m, 2H), 3.92 (dd, 1H), 3.80 (m, 4H), 3.68 (m, 2H), 3.08 (dd, 1H), 2.91 (m, 5H), 2.81-2.62 (m, 2H), 1.80 (m, 1H), 1.64 (m, 1H), 1.47 (m, 1H), 0.90 (d, 3H), 0.82 (d, 3H). MS(ESI): 593(M+H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]>N1C=CC=NC=1>[N:1]1[CH:6]=[C:5]([NH:7][C:9](=[O:10])[O:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cncnc1
Solvent: c1cncnc1
Product: O=C(Nc1cncnc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of pyrimidin-5-amine (190 mg, 2.0 mmol) in pyrimidine (3 mL) was added 4-nitrophenyl chloroformate (403 mg, 2.0 mmol). The resulting mixture was stirred at RT overnight, and then heated to 60° C. overnight. After cooling to RT, the solvent was removed under vacuum to give the title compound as a brown solid, which was used in the next step without further purification. MS (ESI, positive ion) m/z: 261 (M+H).
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17](=O)[C:18]([OH:20])=[O:19]>>[CH2:12]([O:11][C:9]([C:7]1[CH:6]=[N:5][N:4]([CH2:3][C:2]2[S:14][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[N:1]=2)[CH:8]=1)=[O:10])[CH3:13]
Reactant: O=C(O)C(=O)CBr
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Product: CCOC(=O)c1cnn(Cc2nc(C(=O)O)cs2)c1
Yield: 57.9 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (1.07 g, 5.0 mmol) obtained in Example 1b and bromopyruvic acid (920 mg, 5.5 mmol), the title compound (814 mg, 57%) was obtained as bister crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([S:13]([CH3:15])=O)[O:7]2.[OH:17][C:18]1[CH:23]=[CH:22]C(S)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([S:13][C:15]1[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=1)[O:7]2
Reactant: Oc1ccc(S)cc1
Reactant: CS(=O)c1cc(=O)c2c(O)cc(O)cc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1cc(Sc2ccc(O)cc2)oc2cc(O)cc(O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
A mixture consisting of 32 mg (0.134 mmol) 5,7-dihydroxy-2-methylsulfinylchromone, 20 mg (0.161 mmol) 4-hydroxybenzenethiol, 41 mg (0.295 mmol) potassium carbonate, and 2 ml acetone was stirred overnight at room temperature. The solution thus reacted was neutralized by addition of dilute hydrochloric acid. Subsequently, the product was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled out under reduced pressure. The resulting crude product was subjected to recrystallization from acetone-hexane, whereby 14.6 mg of 5,7-dihydroxy-2-(4-hydroxyphenylthio)chromone was obtained (yield: 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:18](=[O:19])[CH2:17][Cl:16])[CH:7]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccnc(NC(=O)CCl)c1
Reaction time: 1 h

Procedure:
A solution of 2-amino-4-methylpyridine (10.8 grams) in ether (150 ml), and triethylamine (10 grams) are placed in a reaction flask equipped with stirrer, thermometer and addition funnel. The reaction mixture is cooled to a temperature of about 0° C and chloroacetyl chloride (11.3 grams) dissolved in ether (30 ml) is slowly added thereto resulting in the formation of a precipitate. Stirring is continued for a period of about 1 hour. After this time the reaction mixture is filtered to recover the precipitate that has formed. The precipitate is washed with aqueous potassium carbonate and with water. The washed precipitate is then dried to yield the desired product N-(4-methyl-2-pyridyl)-α-chloroacetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[C:25]=1[CH3:35])(=[O:12])=[O:11].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:57]1([CH2:62][C@H:63]2[CH2:67][CH2:66][CH2:65][NH:64]2)[CH2:61][CH2:60][CH2:59][CH2:58]1>CN(C=O)C.O.C([O-])(O)=O.[Na+]>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32](=[O:33])[N:64]2[CH2:65][CH2:66][CH2:67][C@@H:63]2[CH2:62][N:57]2[CH2:61][CH2:60][CH2:59][CH2:58]2)[C:25]=1[CH3:35])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Reactant: C1CN[C@@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCC[C@@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid (178 mg, 0.33 mmol), EDAC (97 mg, 0.51 mmol) and HOBt (67 mg, 0.5 mmol) in DMF (4 mL) was added (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (106 mg, 0.68 mmol) and TEA (0.1 mL). The mixture was stirred at rt for 20 hours. The reaction was diluted with water and NaHCO3, extracted with DCM. The combined DCM was concentrated and the residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>>[NH2:10][CH:9]1[NH:1][CH:2]=[N:3][C:4]2[N:5]([CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[N:7][C:8]1=2
Reactant: Nc1ncnc2nc[nH]c12
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCn1cnc2c1N=CNC2N
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
Adenine (10.00 g., 74.00 mmol) was placed into a clean, dry 500 ml round bottom flask equipped with a magnetic stirring bar, reflux condenser, and a CaCl2 drying tube. Absolute ethanol (360 ml) was added and the solution was stirred. To the suspension was added a small piece of Sodium (approximately 75 mg). When the Sodium had completely reacted, 22.2 g (0.222 mol) ethyl acrylate was added to the suspension and the mixture was brought to reflux. Reflux was continued overnight for approximately 18 hours and the resulting lime colored homogeneous solution was allowed to cool slowly to room temperature. Crystals were allowed to form at 4° C. The solution was filtered by Buchner vacuum filtration and the solid was washed with anhydrous ether. Upon drying, 15.2 g (64.6 mmol) of 3-(1,6-dihydro-6-amino-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0026) was obtained. Yield: 87%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1.N[C:17](N)=[O:18]>ClC(Cl)Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][C:17]2=[O:18])[CH:2]=1
Reactant: NC(N)=O
Reactant: Nc1ccccc1NCc1cccnc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1[nH]c2ccccc2n1Cc1cccnc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A mixture of 25 parts of N-(3-pyridinylmethyl)-1,2-benzenediamine and 11 parts of urea is melted together to 180°-190° C. and the melt is stirred for 30 minutes at this temperature. The reaction mixture is cooled and dissolved in a mixture of trichloromethane and methanol. The solvent is evaporated and the residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 24 parts (86%) of 1,3-dihydro-1-(3-pyridinylmethyl)-2H-benzimidazol-2-one; mp. 160.5° C.