Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]2[O:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]2[CH2:17][CH2:16]2)=[CH:11][N:10]=1.FC(F)(F)C(O)=O.CCOC(C)=O.C1COCC1>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]2[O:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][C:12]([CH:15]2[CH2:17][CH2:16]2)=[CH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C4CC4)cn3)c(Cl)c2)C1
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(C2CNCCO2)ccc1Nc1ncc(C2CC2)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 104.2 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(3-chloro-4-(5-cyclopropylpyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (35 mg) in acetonitrile (1.5 ml) and water (4.5 ml) was added trifluoroacetic acid (77.3 μl). The reaction mixture was then capped and the mixture was shaken at 80° C. for 3 h. The reaction mixture was then cooled to room temperature and poured into EtOAc/THF (1:1) and washed with 1 M aq. NaOH. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (RS)—N-(2-chloro-4-(morpholin-2-yl)phenyl)-5-cyclopropylpyrimidin-2-amine (28 mg, 76%) as a white solid. MS (ISP): 333.1 ([{37Cl}M+H]+), 331.1 ([{35Cl}M+H]+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]([C:14]1[C:19]([Br:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.Cl.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40]Cl)[CH2:34][CH2:33]1>CS(C)=O>[NH:7]([C:14]1[C:19]([Br:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:40][CH2:39][CH2:38][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:26][CH:27]=2)[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reactant: CN1CCN(CCCCl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(CCCOc2ccc(Nc3ncc(Br)c(Nc4ccccc4)n3)cc2)CC1
Temperature: 100 °C
Yield: 16.8 %

Procedure:
A mixture of potassium carbonate (180 mg, 1.3 mmol), 4-anilino-5-bromo-2-(4-hydroxyanilino)pyrimidine (Method 4, 150 mg, 0.42 mmol) and 3-(4-methyl-1-piperazinyl)propyl chloride dihydrochloride (120 mg, 0.48 mmol) in DMSO (2 ml) was heated at 100° C. for 12 hours. Silica (1 g) was added and volatile material was removed by evaporation. The residue was loaded onto a Varian Mega Bond Elut column and the column was eluted with 50:50 iso-hexane: DCM (2×20 ml), DCM (2×20 ml), 2% 2M NH3/MeOH/DCM (2×20 ml), 4% 2M NH3/MeOH/DCM (2×20 ml), 6% 2M NH3/MeOH/DCM (2×20 ml) and 10% 2M NH3/MeOH/DCM (8×20 ml). Concentration of the appropriate fractions gave the product as a yellow solid (35 mg, 17%). MS (MH+): 497, 499; HPLC (RT): 2.74.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][C:15]=1[OH:16].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([O:16][C:15]2[CH:14]=[CH:13][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][C:10]=2[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(=O)Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c(F)c1
Yield: 78.1 %

Procedure:
A mixture of 2,4-dichloropyrimidine (Aldrich, 1.5 g, 10.0 mmol), N-(3-fluoro-4-hydroxyphenyl)acetamide (0.85 g, 5.0 mmol), K2CO3 (0.76 g, 5.5 mmol), and CH3CN (100 mL) was heated at reflux for 2 h. The mixture was concentrated and the residue partitioned between EtOAc and saturated NaHCO3 solution. The EtOAc phase was washed with sat NaHCO3 solution, brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient form 30% EtOAc in hexanes to 100% EtOAc to give the title compound (1.1 g, 78%) as a white solid. 1H NMR (DMSO-d6) δ 10.22 (s, 1H), 8.63 (d, 1H, J=5.6 Hz), 7.74 (dd, 1H, J=12.6, 2.4 Hz), 7.34-7.26 (m, 3H), 2.01 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]([OH:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]([O:28][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:10][C:9]1([CH3:29])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(O)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CC(CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-benzyl-5-(3-ethoxycarbonyl-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (50.68 g) in pyridine (380 ml) was stirred at 15° C. under an atmosphere of nitrogen during the dropwise addition of methanesulfonyl chloride (18.4 ml). The reaction mixture was then allowed to warm to ambient temperature and stirred for a further 2 hours and evaporated. The residue was dissolved in diethyl ether, washed sequentially with 2M aqueous hydrochloric acid (500 ml and 250 ml), water, 5% aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate) and evaporated to afford 4-benzyl-5-(3-ethoxycarbonyl-2-methanesulfonyloxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (64 g) as a pale yellow gum Mass spectrum 500 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C:3]1([NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.O1CCOCC1.[ClH:38]>C1COCC1>[ClH:38].[F:1][CH2:2][C:3]1([NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(CF)(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1(CF)CCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 578 mg (1.29 mmol) of tert-butyl 3-(fluoromethyl)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-1-carboxylate in 5 mL of THF was added 2 mL of 4 N HCl dioxane solution. The reaction mixture was stirred at room temperature for 1 h and evaporated to give the yellow solid, N-(2-{[3-(fluoromethyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide HCl salt: MS (m/e): 347 (M+1)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C[O:7][C:8]1C=CC=[C:10]([CH:11]=O)[C:9]=1O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:3]([C:2]1[CH:1]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:7])=[CH2:4]
Reactant: COc1cccc(C=O)c1O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (19.65 g, 55.00 mmol) in tetrahydrofuran (200 mL) cooled to 0° C. is added n-butyllithium (1.6 M in hexanes, 37.5 mL, 60.00 mmol) and the reaction mixture is allowed to stir at 0° C. for 30 min. The ylide is added via cannula to a solution of 3-methoxysalicylaldehyde (3.80 g, 25.00 mmol) in tetrahydrofuran (100 mL) and the reaction mixture is allowed to stir at room temperature for 3 hours. The reaction mixture is quenched by the addition of aqueous ammonium chloride (100 mL) and diluted with water (300 mL). The aqueous layer is separated and extracted with diethyl ether (3×200 mL). The combined organic extracts are washed with water (300 mL) and aqueous sodium chloride (300 mL), dried (magnesium sulfate), and filtered through a plug of silica (10 cm×5 cm). The solvent is removed in vacuo to give the 2-vinylphenol as a crude oil which is dissolved in tetrahydrofuran (200 mL). To the resulting solution is added (S)-2-hydroxy-3-buten-1-yl p-tosylate (7.27 g, 30.00 mmol), triphenylphosphine (7.87 g, 30.00 mmol), and diethyl azodicarboxylate (5.22 g, 30.00 mmol). The reaction mixture is allowed to stir at room temperature for 12 hours. The reaction mixture is quenched by the addition of water (200 mL). The aqueous layer is separated and extracted with ethyl acetate (2×250 mL). The combined organic extracts are washed with water (200 mL) and aqueous sodium chloride (300 mL), dried using magnesium sulfate, and the solvent is removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) provides 5.33 g (57% y, >97% ee) of (2R)-2-(2-methoxy-6-vinylphenoxy)-3-butenyl 4-methylbenzenesulfonate as a colorless oil. [α]D25=−8.06 (c 9.93 in chloroform, >97% ee); Rf=0.57 (silica, ethyl acetate:hexanes 3:7); Anal. Calcd. for C20H22O5S.0.2H2O: C, 63.57; H, 5.97. Found: C, 63.37; H, 5.66.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:17]2[S:16][N:15]=[C:14]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([NH:5][S:6]([C:9]1[C:17]2[S:16][N:15]=[C:14]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[CH:26][CH:25]=3)=[O:31])[C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c(NCCCNC(=O)c3ccc(I)cc3)nsc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)NCCCNc3nsc4c(S(=O)(=O)NC(C)(C)C)cccc34)cc2)cc1
Yield: 28.1 %

Procedure:
A mixture of N-(3-(7-(N-tert-butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4-iodobenzamide (50 mg, 0.09 mmol), 4-methoxyphenylboronic acid (14 mg, 0.09 mmol), tetrabutylammonium bromide (29 mg, 0.09 mmol), sodium carbonate (29 mg, 0.27 mmol) and palladium (II) acetate (1 mg) in water (3 mL) was microwaved at 160° C. for 5 min. The reaction was diluted with methylene chloride and the mixture was washed successively with aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 98:2 methylene chloride:methanol yielded N-(3-(7-(N-tert-Butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4′-methoxybiphenyl-4-carboxamide (14 mg), as a white solid. 1H NMR (300 MHz, DMSO-d6): 8.50 (t, 1H), 8.32 (d, 1H), 7.83-7.99 (m, 3H), 7.50-7.71 (m, 5H), 7.03 (d, 2H), 4.80 (s, 3H), 3.38-3.51 (m, 4H), 1.93 (t, 2H), 1.10 ppm (s, 9H). MW=533 confirmed by LC-MS, tr=4.30 min (Method B) MH+=554.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:12]3[C:11](=[O:17])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2[N:37](C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C1CCCCC1.C(OCC)(=O)C>[NH2:37][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:12]3[C:11](=[O:17])[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Br)cc2)n2cccc12
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2n[nH]c(=O)c3cccn23)cc1
Reaction time: 0.5 h

Procedure:
To 1.181 g 4-(4-bromophenyl)pyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (4.07 mmol) in toluene (10 ml) was added 0.080 g 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.2004 mmol), 0.063 g tris(dibenzylideneacetone)dipalladium(O) chloroform adduct (0.061 mmol) and 10.58 ml lithium bis(trimethylsilyl)amide 1M in toluene (10.58 mmol) under nitrogen at room temperature and the reaction was subsequently heated at 150° C. for 5 minutes by microwave (Biotage Initiator 2.5). Thin layer chromotography in cyclohexane/ethyl acetate=1/1 showed no starting material. After cooling the reaction mixture, 7 ml of 2N aqueous HCl was added, the mixture stirred for 30 minutes, and the mixture was basified until pH=10 by addition of aqueous NaOH (2N). A precipitate was formed. The solid was filtered and washed with ether and dried overnight to obtain the title compound. LCMS: m/z 227.0 (M+H). The filtrate was extracted with ethyl acetate. The organic phase was combined with the ether from the washing, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The raw material was adsorbed on silica (dissolved in ethyl acetate), then purified by silica gel chromatography (cyclohexane:ethyl acetate gradient, the product was eluted at 80% of ethyl acetate) to afford additional title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.85 (br. s., 1H), 7.32-7.44 (m, 3H), 7.09 (dd, J=3.8, 1.3 Hz, 1H), 6.66-6.77 (m, 3H), 5.67 (s, 2H). 13C NMR (400 MHz, DMSO-d6) δ 154.15, 150.86, 137.98, 129.55, 123.98, 118.70, 116.65, 113.95, 113.32, 110.58.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:5]=2[N:6]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:12][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:3][C:4]=2[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: Nc1nc2c(F)cc(F)cc2s1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1nc2c(F)cc(F)cc2s1)c1ccccc1

Procedure:
Using 2-amino-4,6-difluoro-benzothiazole and benzoyl chloride the title compound was prepared as a beige solid (82% yield), MS: m/e=290 (M+).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:14]([C:11]1[CH:12]=[N:13][C:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[N:9][CH:10]=1)=[O:16])(=[O:30])=[O:31]
Reactant: O=C(O)c1cnc(-c2cccnc2)nc1
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cccnc3)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of 2-(3-pyridyl)-pyrimidine-5-carboxylic acid hydrochloride (237 mg 1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) in dry DMF (15 mL) is treated with diisopropylethylamine (0.36 mL) and stirred at room temperature for 30 min. 3-Methylsulfamoylbenzylamine hydrochloride (355 mg, 1.5 mmol) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue is partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase is separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated with EtOAc. The resulting solid is filtered, washed with ether to afford 2-(3-pyridyl)-pyrimidine-5-carboxylic-acid-3-methylsulfamoyl-benzylamide (185 mg, 48%). MS: 384 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.43 (d, 3H), 4.65 (d, 2H), 7.45-7.55 (q, 1H), 7.60-7.75 (m, 3H), 7.80 (s, 1H), 8.72-8.80 (m, 2H), 9.35 (s, 2H), 9.55 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[N:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O:26][C:27]([C:29]1[C:30]([S:41][CH3:42])=[N:31][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:33]=1[NH2:34])=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:27](=[O:26])[C:29]3[C:30]([S:41][CH3:42])=[N:31][N:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:33]=3[N:34]=[C:9]2[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[N:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(-c2ccnc(Cl)n2)cc1
Reactant: CCOC(=O)c1c(SC)nn(-c2ccccc2)c1N
Product: CSc1nn(-c2ccccc2)c2nc(-c3ccc(-c4ccnc(Cl)n4)cc3)n(-c3ccc(Cl)cc3)c(=O)c12

Procedure:
5-(4-Chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one is prepared from N-(4-chloro-phenyl)-4-(2-chloro-pyrimidin-4-yl)-benzamide and 5-amino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester by following a similar procedure as described in example 2. 1H NMR (CDCl3) δ (ppm) 8.68(d, 1H), 8.15(d, 2H), 8.01(d, 2H), 7.63(d, 1H), 7.49(m, 4H), 7.32(m, 3H). 7.11(d, 2H), 2.73(s, 3H). HPLC-MS calculated C28H18Cl2N6OS (M+1+): 557.1. Found: 557.1.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][N:6]=1.CC[N:13](CC)CC>>[Cl:1][C:2]1[S:3][C:4]([S:7]([NH2:13])(=[O:9])=[O:8])=[CH:5][N:6]=1
Reactant: O=S(=O)(Cl)c1cnc(Cl)s1
Reactant: CCN(CC)CC
Product: NS(=O)(=O)c1cnc(Cl)s1
Yield: 61 %

Procedure:
Prepared by general procedure III from 2-Chloro-thiazole-5-sulfonyl chloride (1.1 g, 5 mmol) and NH40H (0.42 mL, 6 mmol) with Et3N (0.77 mL, 6 mmol to give the title compound as a light-brown solid (610 mg, 61%). MS (ISN) 197[(M−H)−].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9](O)=[CH:8][C:7]1=[O:13].[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>>[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20][NH:21][C:9]1[CH:10]=[CH:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)[C:7](=[O:13])[CH:8]=1
Reactant: NCc1ccc(F)cc1F
Reactant: O=c1cc(O)ccn1Cc1cccc(F)c1
Product: O=c1cc(NCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1

Procedure:
The product from Step 2 (0.5 g, 2.28 mmol) and 2,4-difluoro benzylamine (4 mL, 33.6 mmol) were combined in a nitrogen flushed culture tube. The tube was capped and heated at 180 C for 24 h. The excess amine was distilled in vacuo and the residue was chromatographed on silica (95:5 ethyl acetate: methanol). The final compound was isolated as a light yellow solid (0.16 g, 36%). 1H NMR (400 MHz, CD3OD) δ 7.33 (m, 3H), 7.03 (d, J=8 Hz, 1H), 6.96 (m, 3H), 6.95 (m, 1H), 5.97 (dd, J=3.2 and 8.0 Hz, 1H), 5.48 (d, J=2.56 Hz, 1H), 5.02 (s, 2H), 4.33 (s, 2H) ppm. 19F NMR (400 MHz, CD3OD) δ−113.88 (1 F), −115.33 (1 F), −116.78 (1 F) ppm. ES-HRMS m/z 345.1221 (M+H calcd for C19H17F3N2O requires 345.1209). Step 4 Preparation of 3-bromo-4-[(2,4-difluorobenzyl)amino]-1-(3-fluorobenzyl)pyridin-2(1H)-one
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[NH:7][C:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14]3)[N:10]=1)([CH3:5])[CH3:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH3:53][O:54][CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][CH:60]([C:63](O)=[O:64])[CH2:59][CH2:58]1>CN(C=O)C.ClCCl>[CH3:4][C:3]([C:6]1[NH:10][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14]3)=[C:8]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[N:7]=1)([CH3:5])[CH2:2][NH:1][C:63]([CH:60]1[CH2:59][CH2:58][N:57]([CH2:56][CH2:55][O:54][CH3:53])[CH2:62][CH2:61]1)=[O:64]
Reactant: CC(C)(CN)c1nc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)[nH]1
Reactant: COCCN1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCN1CCC(C(=O)NCC(C)(C)c2nc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
A mixture of the product of Example 1, Step 6 (0.1 g, 0.29 mmol), 1-hydroxybenzotriazole (0.06 g, 0.44 mmol) and polymer bound 1,3-dicyclohexylcarbodiimide (0.4 g, 0.6 mmol, 1.52 mmol/g) in a 1:1 mixture of dichloromethane and DMF (4 ml) was stirred at room temperature for 30 min. A solution of 1-(2-methoxy-ethyl)-piperidine-4-carboxylic acid hydrochloride [WO 97/25309] (0.098 g, 0.44 mmol) in DMF (2 ml) was then added and the mixture stirred at room temperature overnight. The reaction mixture was then filtered, the solvent removed in vacuo and the crude residue purified by silica gel chromatography eluting with a 1:9:90 mixture of 0.88 ammonia solution:methanol:dichloromethane to give the title compound (0.12 g, 80%) as a yellow oil; MS(AP+) m/e 516 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[S:11](=[O:24])(=[O:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([Cl:21])[C:14]=1[CH3:22])=O.C1CCC(N=C=NC2CCCCC2)CC1.[N+](C1C=CC=CC=1O)([O-])=O>C(#N)C>[OH:10][C@@H:9]1[CH2:8][CH2:7][N:6]2[C@@H:5]1[C:3](=[O:2])[N:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([Cl:21])[C:14]=1[CH3:22])[S:11]2(=[O:24])=[O:23]
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1S(=O)(=O)Nc1ccc(C#N)c(Cl)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccccc1O
Solvent: CC#N
Product: Cc1c(N2C(=O)[C@@H]3[C@H](O)CCN3S2(=O)=O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To a suspension of 1B (82 mg, 0.228 mmol) in 5 mL of acetonitrile at rt was added DCC (47 mg, 0.228 mmol) followed byp-nitrophenol (63 mg, 0.456 mmol). The suspension was refluxed for 1 h, cooled to rt and filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes, 50:50 and 75:25) to afford the title compound (61 mg) as an off-white solid. 1H NMR (CD3OD) δ 2.21-2.23 (m, 2H), 2.37, 2.39 (s, 3H), 3.61-3.64 (m, 1H), 3.97-4.04 (m, 1H), 4.66, 4.68 (s, 1H), 4.79 (d, J=3.9, 1H), 7.45, 7.55 (d, J=8.3, 1H), 7.83 (d, J=8.3, 1H); 13C NMR (DMSO-d5) δ 15.47, 15.94, 35.32, 35.44, 48.21, 48.36, 69.77, 69.82, 73.74, 114.68, 115.59, 129.50, 132.70, 132.90, 134.25, 136.92, 138.96, 163.11, 163.59; HPLC a) column: Phenominex C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 2.65 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.52 min retention time (100%); HPLC c) column: Daicel Chiralcel OD 4.6×250 mm, Isocratic 25% Isopropanol/Hexanes, 30 min, 1 mL/min, UV detection at 220 nm, 11.86 min retention time (99%); MS (ES) m/z 340 [M−H]−.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11]>C(O)(=O)C>[C:4]([CH2:3][CH2:2][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([OH:6])=[O:5]
Reactant: O=C1CCC(=O)O1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CC(=O)O
Product: O=C(O)CCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Succinic anhydride (67 mmoles, 6.7 g.) is dissolved in 100 ml. of hot glacial acetic acid and cooled to room temperature. To this, while stirring (67 mmoles, 7.7 g.) L-proline is added. After 20 hours at room temperature, the reaction mixture is concentrated to dryness in vacuo. The residue is extracted three times with hot ethyl acetate and cooled to room temperature. To the pooled extracts containing the 1-(3-carboxypropanoyl)-L-proline, dicyclohexylamine is added and crystals form which are recrystallized from hot isopropanol, yield 11.3 g. The dicyclohexylamine salt has m.p. (170) 175°-177°.