Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15]([C:17]([F:20])([F:19])[F:18])=[C:14]([C:21]3[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[CH:13]=2)=[CH:8][CH:7]=1.O>C(OC(=O)C)(=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:16][C:15]([C:17]([F:19])([F:18])[F:20])=[C:14]([C:21]3[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[C:13]=2[N+:1]([O-:4])=[O:3])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccc(Cl)cc3)[nH]c2C(F)(F)F)s1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(-c2c(C(F)(F)F)[nH]c(-c3ccc(Cl)cc3)c2[N+](=O)[O-])s1
Temperature: 25 °C

Procedure:
A 90% nitric acid solution (0.02 g, 0.28 mmol) is added to a solution of 5-(p-chlorophenyl)-3-(5-nitro-2-thienyl)-2-(trifluoromethyl)pyrrole (0.13 g, 0.34 mmol) in acetic anhydride. The reaction mixture is stirred at room temperature for ten minutes, treated with additional 90% nitric acid solution (0.02 g, 0.28 mmol), stirred at room temperature for 15 minutes, poured into water, stirred at room temperature overnight and extracted with ether. The combined organic extracts are dried over MgSO4 and concentrated in vacuo to obtain the title product as a tan solid which is identified by 1HNMR spectral analysis.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:11]([O:18][C:19]1[CH:31]=[CH:30][C:22]([CH:23]=[CH:24][C:25](OCC)=[O:26])=[CH:21][C:20]=1[O:32][CH3:33])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)O>C(OCC)C.O>[CH2:11]([O:18][C:19]1[CH:31]=[CH:30][C:22]([CH:23]=[CH:24][CH2:25][OH:26])=[CH:21][C:20]=1[O:32][CH3:33])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C=Cc1ccc(OCc2ccccc2)c(OC)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: COc1cc(C=CCO)ccc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 79 %

Procedure:
A solution of aluminum chloride (7.07 g) in diethyl ether (90 ml) was added dropwise, at 0° C., to a suspension of lithium aluminum hydride (7.59 g) in diethyl ether (300 ml). The mixture was stirred for 15 minutes, to which was added dropwise, at 0° C., a solution of ethyl 4-benzyloxy-3-methoxycinnamate (50,0 g) in diethyl ether (250 ml). The mixture was stirred for one hour at room temperature, to which was added water (200 ml), then, was carefully added 5N sulfuric acid (280 ml) at 0° C. The diethyl ether layer was taken. The aqueous layer was extracted with ethyl acetate. Organic layers were combined, washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (3:2, v/v), 3-(4-benzyloxy-3-methoxyphenyl)-2-propen-1-ol (34.2 g, 79%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 81-82° C.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24](C)(C)[CH3:25])[CH2:17][CH2:16]2)[CH:10]=1.FC(F)(F)[C:32](O)=[O:33].C([O-])(O)=O.[Na+].C(N(CC)CC)C.ClC(OCCOC)=O>O.C(Cl)Cl>[F:1][CH:2]([F:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][CH2:24][CH2:25][O:33][CH3:32])[CH2:17][CH2:16]2)[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(-c3ccccc3C(F)F)ncn2)CC1
Agent: COCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COCCOC(=O)NC1CCN(c2cc(-c3ccccc3C(F)F)ncn2)CC1
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl 1-(6-(2-(difluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-ylcarbamate (0.05 g, 0.1 mmol), CH2Cl2 (0.5 mL), and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 30 minutes. The reaction was made basic with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined extracts were dried over Na2SO4 and evaporated. The residue was dissolved in CH2Cl2 (0.4 mL) and triethylamine (16 μL, 0.12 mmol), and the reaction was cooled in a dry ice/acetone bath. 2-Methoxyethyl chloroformate (16 μL, 0.1 mmol) was added, and the reaction was stirred for 15 minutes. The reaction was diluted with H2O and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4 and evaporated. The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give 2-methoxyethyl 1-(6-(2-(difluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-ylcarbamate. LC/MS: m/z 407.4 (M+H)+ at 2.18 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][N:41]=2)[CH:36]=[CH:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[N:34]1([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=2)[C:42]2=[N:41][CH:40]=[CH:39][CH:38]=[C:37]2[CH:36]=[CH:35]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cn2ccc3cccnc32)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
To a 50-mL round-bottomed flask was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (50 mg, 0.095 mmol, Intermediate B), 7-azaindole (16.76 mg, 0.142 mmol, Alfa Aesar, Ward Hill, Mass.) and cesium carbonate (62 mg, 0.19 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 80° C. for 18 h. The mixture was allowed to cool to room temperature. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. Purification by silica gel chromatography, eluting with 50% EtOAc in hexanes gave 2-(4-((S)-2-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (28 mg) as a mixture of two isomers.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([CH2:41]O)[CH:38]=[CH:37][C:36]=1[N:43]1[S:47](=[O:49])(=[O:48])[N:46]([CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:45](=[O:56])[CH2:44]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([CH2:41][I:25])[CH:38]=[CH:37][C:36]=1[N:43]1[S:47](=[O:49])(=[O:48])[N:46]([CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:45](=[O:56])[CH2:44]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CO)cc2OCc2ccccc2)S1(=O)=O
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CI)cc2OCc2ccccc2)S1(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To slurry of resin-bound PPh3 (850 mg, 2.5 mmol) in DCM (10 mL) at 0° C., in a pressure vessel, is added imidazole (200 mg, 2.8 mmol) and iodine (650 mg, 2.5 mmol). The mixture is vigorously stirred at 0° C. for 30 min. To the mixture is added a solution of 5-(2-benzyloxy-4-hydroxymethylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (550 mg, 1.2 mmol) in DCM (10 mL) dropwise. The vessel is sealed and heated to 45° C., with stirring, for 2 h. The reaction is allowed to cool to ambient temperature and the mixture is filtered through a plug of cotton to remove the resin. The organic solution is washed with saturated Na2SO3 and saturated NaCl, then dried over MgSO4. The solvent is removed under reduced pressure to afford 5-(2-benzyloxy-4-iodomethylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one as a white solid, which is used in the next step without further purification: MS (M+H)+=576.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][NH:9][NH2:10])=[CH:6][CH:5]=1.[CH3:13][C:14]([CH2:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=O)=O>C(O)(=O)C>[CH3:13][C:14]1[N:9]([CH2:8][C:7]2[CH:11]=[CH:12][C:4]([CH3:3])=[CH:5][CH:6]=2)[N:10]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=1
Reactant: COC(=O)C(=O)CC(C)=O
Reactant: Cc1ccc(CNN)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)n(Cc2ccc(C)cc2)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
A mechanically stirred suspension of 4-(methylbenzyl)hydrazine dihydrochloride (Step 3, 81.8 g, 391 mmol) and methyl acetopyruvate (51.2 g, 356 mmol) in acetic acid (825 mL) was warmed to 90° C. and stirred for 4 h. The solid gradually dissolved, leaving an orange solution. After being cooled to rt, the reaction mixture was concentrated to an orange oil. The organic residue was diluted with EtOAc, washed with water (1×250 mL), NaHCO3 (1×250 mL), and brine (1×250 mL), was dried (Na2SO4), filtered and concentrated to an orange oil. Purification with an ISCO CombiFlash Companion, using a gradient from 0% to 30% EtOAc in hexanes afforded the title compound as a yellow-orange oil (39 g, 45%): 1H NMR (300 MHz, d6-DMSO) δ 2.20 (s, 3H), 2.24 (s, 3H), 3.75 (s, 3H), 5.31 (s, 2H), 6.56 (s, 1H), 7.01 (d, 2H), 7.12 (d, 2H). ES-MS m/z 245.0 (MH)+, HPLC RT (Method A) 3.13 min.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].O>ClCCl>[OH:13][C@H:11]1[CH2:12][NH:8][C@H:9]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:10]1.[C:28]([OH:30])([C:27]([F:32])([F:31])[F:26])=[O:29]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCC(=O)O
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC[C@@H]1C[C@@H](O)CN1
Reaction time: 8 h

Procedure:
To a solution of 3-((2R,4R)-1-(tert-butoxycarbonyl)-4-{[tert-butyl(dimethyl)silyl]oxy}-pyrrolidin-2-yl)propanoic acid (5.1 g, 13.65 mmol) in dichloromethane (100 ml) at 0° C. were added trifluoroacetic acid (14 ml) and water (3 ml). The reaction mixture was allowed to warm up and stirred overnight. The reaction mixture was concentrated in vacuo to afford 3-[(2R,4R)-4-hydroxypyrrolidin-2-yl]propanoic acid as TFA salt (3.74 g). Yield: 100%
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:8]2[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:6]3[C:10]([C:2]([F:1])=[CH:3][CH:4]=[CH:5]3)=[N:9]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(F)c3nn2C2CCCC2)cc1
Yield: 5.7 %

Procedure:
Prepared according to Example 116 from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.75 g, 3.1 mmol), sodium hydride (60% in oil, 0.124 g, 3.1 mmol) and cyclopentylbromide (0.36 mL, 3.3 mmol) to give the title compound (0.055 g) as a white solid.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:30]([OH:32])[CH3:31])[CH:27]=[CH:28][CH:29]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([OH:32])[CH3:31])[CH:25]=3)=[O:20])=[CH:21][CH:22]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: CC(O)c1cccc(N)c1
Product: CC(O)c1cccc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)c1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 1-(3-aminophenyl)ethanol (33 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-(1-hydroxyethyl)phenyl)benzamide as a white solid. Yield: 38 mg (36%). 1H-NMR: 10.42 (br s, 1H), 8.06 (d, J=8.5 Hz, 2H), 7.77-7.71 (m, 3H), 7.63 (d, J=8.0 Hz, 2H), 7.28 (t, J=8.0 Hz, 1H), 7.24-7.18 (m, 1H), 7.12-7.06 (m, 2H), 5.19 (d, J=4.0 Hz, 1H), 4.74-4.66 (m, 1H), 3.84-3.80 (m, 2H), 2.46 (t, J=7.5 Hz, 2H), 1.67-1.59 (m, 2H), 1.31 (d, J=6.5 Hz, 3H).
Reaction SMILES: C[Si](C)(C)[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:12](=[O:16])[NH:11][C:10]([NH2:17])=[N:9][C:8]1=2.O.O.[O-2].[O-2].[O-2].[O:25]=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C(O)(=O)C>[OH:25][CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:12](=[O:16])[NH:11][C:10]([NH2:17])=[N:9][C:8]1=2
Reactant: C[Si](C)(C)CCOCn1cnc2c(=O)[nH]c(N)nc21
Reactant: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Temperature: 5 °C
Yield: 69 %

Procedure:
A mixture of 9-(2-trimethylsilylethoxymethyl)guanine (15.8 g), water (250 ml), and acetic acid (20 ml) was heated to reflux, giving a solution. The hot solution was treated with a small amount of Montmorillonite K10 (an acidic clay) to remove any color, filtered, and the filtrate slowly cooled to 5° C. The white crystalline solid thus produced was filtered off, to yield 9-(2-hydroxyethoxymethyl)guanine (8.8 g, 69%). 1H NMR 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet).
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])=[CH2:2].C([OH:11])=C.[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C)C=O>[CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])=[CH2:2].[Br:12][CH2:13][C:14]([O-:15])=[O:11]
Reactant: O=C(Br)CBr
Reactant: C=CO
Agent: C=CN1CCCC1=O
Solvent: CN(C)C=O
Product: O=C([O-])CBr
Reaction time: 1 h

Procedure:
A solution containing 330 mg of 1-vinyl pyrrolidone/vinyl alcohol copolymer (VI) in 8 mL of dry dimethyl formamide was taken in a two-neck round-bottomed flask and connected to nitrogen. The other neck was capped with a septum stopper. The flask was cooled in an ice bath. To the flask 0.25 mL of bromoacetyl bromide dissolved in 2 mL of DMF was added dropwise with a syringe through the septum stopper. The reaction was allowed to proceed at room temperature for 1 hour in the dark. The precipitation of the reaction mixture in 15-fold diethyl ether for 5 times yielded 270 mg of 1-vinyl pyrrolidone/bromoacetate copolymer (VII). A test of alkylating agents using 4-(p-nitrobenzyl)pyridine was positive indicating the presence of alkyl bromide in the copolymer (5). C-13 NMR (CD3OD) : 19.2, 27.4, 32.5, 33.7-37.1, 43.6-45.5, 48.2-48.9, 70.0-71.5, 168.6, 177.7. Elemental Analysis: found (Calcd): C, 40.05 (43.5); H, 4.87 (5.11); Br, 30.97 (28.94); N, 5.43 (5.07).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](O)([CH3:12])[NH:10][C:9]([CH3:14])=[N:8][CH:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)=[O:5])[CH3:2]>P(Cl)(Cl)(Cl)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)=[N:8][CH:9]([CH3:14])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(c2cccc([N+](=O)[O-])c2)N=C(C)NC1(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C1=C(C)NC(C)N=C1c1cccc([N+](=O)[O-])c1
Yield: 50.9 %

Procedure:
150 mg of 5-ethoxycarbonyl-6-hydroxy-2,6-dimethyl-4-(3-nitrophenyl)-1,4,5,6-tetrahydropyrimidine was dissolved in 14 ml of phosphorus oxychloride and the solution was heated to reflux for 30 minutes. After phsophorus oxychloride was evaporated under reduced pressure, a saturated aqueous potassium carbonate solution was added to the residue and the mixture was extracted with chloroform. After the chloroform layer was dried with anhydrous potassium carbonate, the solvent was evaporated to produce 72 mg of the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:40]1[CH:45]=[N:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:45]=[N:44][CH:43]=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Clc1cnccn1
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: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cnccn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), chloropyrazin (231 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (217 mg, 43%) as a light yellow solid.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([C:27]([NH2:29])=[O:28])[CH:8]=1)[CH2:2]2.C1C[O:33]CC1>O>[OH:6][CH:1]1[CH:5]([OH:33])[CH2:4][N:3]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([C:27]([NH2:29])=[O:28])[CH:8]=2)[CH2:2]1
Reactant: C1CCOC1
Reactant: NC(=O)c1cc(N2CC3OC3C2)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Solvent: O
Product: NC(=O)c1cc(N2CC(O)C(O)C2)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
To a suspension of the 6-(6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide (0.050 g, 0.13 mmol) in THF (5 mL) and water (1 mL) was added a 60% HClO4 solution (0.1 mL). After stirring overnight, the reaction was heated at 50° C. for 2 days. After the reaction cooled it was quenched with solid NaHCO3 and evaporated in vacuo. The residue was chromatographed over silica gel with 50-100% acetone in hexanes. The product fractions were evaporated and the resulting residue dissolved in 1 mL acetonitrile with warming. Upon cooling a solid formed. The solid was filtered and rinsed once with 1 mL acetonitrile. The remaining solid was suspended in 1 mL warm acetonitrile, filtered and air-dried to give 6-(3,4-dihydroxypyrrolidin-1-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as a fine crystalline powder (0.009 g, 0.02 mmol, 17%). 1H NMR (400 MHz, DMSO-d6): 8.55 (2H, d, J=8.8 Hz), 8.34 (1H, d, J=2.4 Hz), 7.88 (1H, d, J=2.4 Hz), 7.31-7.24 (2H, m), 7.19-7.13 (2H, m), 7.05 (2H, d, J=9.0 Hz), 6.90 (1H, s), 5.29 (1H, d, J=3.7 Hz), 5.22 (1H, d, J=3.3 Hz), 4.14-4.10 (1H, m), 4.09-4.05 (1H, m), 3.76-3.63 (3H, m), 3.35-3.30 (1H, m). LC/MS: m/z=411.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCBr
Reactant: COc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(OC)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A mixture of 2-bromo-4-methoxyphenol (available from Betapharma Inc.) (1.50 g, 7.39 mmol), 1-bromobutane (available from Aldrich) (0.95 mL, 8.87 mmol), and cesium carbonate (3.13 g, 9.60 mmol) in DMF (40 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 4.1 (1.49 g, 78% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.15 (d, J=2.7 Hz, 1H), 6.84 (d, J=9.0 Hz, 1H), 6.80 (dd, J=3.1, 9.0 Hz, 1H), 3.97 (t, J=6.5 Hz, 2H), 3.76 (s, 3H), 1.79 (m, 2H), 1.53 (m, 2H), 0.98 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=1.[CH3:19][NH2:20]>CN(C=O)C>[CH3:19][N:20]1[CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:8][C:9](=[O:18])[CH2:10][CH:11]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(/C=C/c1cccnc1)/C=C/c1cccnc1
Reactant: CN
Solvent: CN(C)C=O
Product: CN1C(c2cccnc2)CC(=O)CC1c1cccnc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 95.2 %

Procedure:
A suspension of (1E,4E)-1,5-di(pyridin-3-yl)penta-1,4-dien-3-one (1 g, 3.2 mmol) in DMF (10 mL) was treated with N-methylamine (40% in H2O, 2.8 mL, 32 mmol) at 0° C. The solution was stirred for 6 h at 0° C. The reaction mixture was poured into ice-water (150 mL) and was extracted with DCM. The combined organic layers were dried with MgSO4, filtered and evaporated in vacuo. The crude product was purified by flash-chromatography (CH2Cl2/MeOH 9:1) to obtain NW-B593 as a bright yellow solid (814 mg, 94%). mp: 103-106° C. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.67 (d, 4J=1.8 Hz, 2H, HAr), 8.59 (dd, 3J=4.8 Hz, 4J=1.6 Hz, 2H, HAr), 7.85 (d, 3J=7.9 Hz, 2H, HAr), 7.37 (dd, 3J=7.9 Hz, 3J=4.8 Hz, 2H, HAr), 3.58 (dd, 3J=12.0 Hz, J=2.8 Hz, 2H, CH2), 2.84 (t, 3J=13.0 Hz, 2H, CH), 2.55 (dd, 3, J=13.9 Hz, J=1.8 Hz, 2H, CH2), 1.64 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 204.9 (C), 149.4 (CH), 148.8 (CH), 138.1 (C), 134.8 (CH), 124.1 (CH), 67.5 (CH), 50.2 (CH2), 41.0 (CH3). MS (FAB) m/z: 268.2 (M+). Anal. calcd for C16H17N3O.0.3H2O: C, 70.46; H, 6.50; N, 15.41. Found: C, 70.45; H, 6.38; N, 15.32%.