Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C@H:20]2[O:37][C@H:36]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])[C@@H:12]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:11][C@H:6]1[O:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].[SH:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.C(CC(C)(C)C)(C)C>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.C1C=CC=CC=1.O>[C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C@H:20]2[O:37][C@H:36]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])[C@@H:12]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:11][C@H:6]1[O:7][CH2:8][CH2:9][S:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])(=[O:3])[CH3:2]
Reactant: COC(=O)CCS
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)CC(C)(C)C
Product: COC(=O)CCSCCO[C@@H]1O[C@H](COC(C)=O)[C@H](O[C@H]2O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
2-Bromoethyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-β-D-galactopyranoside (15) (251 mg; 0.338 mmol), methyl 3-mercaptopropionate (38 μl; 0.35 mmol) methyltrioctylammonium chloride (ca 10 mg) and cesium carbonate (114 mg; 0.35 mmol) were dissolved in benzene (0.5 ml) and water (0.5 ml). The reaction mixture was stirred (magnet) over night and analyzed by TLC (SiO2, ethyl acetate:isooctane 4:1; reaction 2/3 completed). Methyl 3-mercaptopropionate (ca 20 μl) was added and the reaction mixture was stirred for 24 h (TLC showed complete reaction). The phases were separated, the water phase was extracted twice with methylene chloride and the combined organic phases were dried (sodium sulfate) which gave a yellow to green solution. Evaporation gave a syrup which was chromatographed (SiO2, ethyl acetate:isooctane 2:1) to give the title compound (22) as a syrup. Yield: 211 mg (80%). [α]D23 +70.0° (c 0.6; CHCl3); 1H-NMR (CDCl3, TMS) δ 5.57 (d, 1H, J3',4' =3.0 Hz, H4'), 5.39 (dd, 1H, J2',3' =11.0 Hz. H2'), 5.19 (dd, 1H, H3'), 5.17 (dd, 1H, J2,3 =11 Hz, H2), 5.00 (d, 1H, J1',2' =4.0 Hz, H1'), 4.80 (dd, 1H, J3,4 =3.0 Hz, H3), 4.51 (d, 1H, J1,2 =8.0 Hz, H1), 3.70 (s, 3H, CH3 --O), 2.82, 2.75, 2.63 (t, 2H each, J=7 Hz, CH2 --S, CH2 --CO), 2.13, 2.11, 2.08, 2.08, 2.06, 2.04, 1.98 (s, 3H each, CH3CO) ppm. 13C-NMR (CDCl3, TMS) δ 172.3 (COOCH3), 170.7, 170.6, 170.5, 170.4, 170.1, 169.8, 169.2 (CH3CO), 101.1 (Cl), 99.4 (Cl'), 77.1, 72.7, 72.0, 68.6, 68.5, 67.9, 67.4, 67.1 (C2-C5, C2'-C5'), 69.5 (OCH2), 62.0, 60.5 (C6, C6'), 51.8 (COOCH3), 34.7, 31.4, 27.4 (CH2S, CH2 --CO), 21.0, 20.7 (CH3CO) ppm.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6]N=O.[CH2:9]=[C:10]=[O:11].[C]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O.ClC1C=CC=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:10]([CH3:9])=[O:11]
Reactant: CCCCCON=O
Reactant: C=C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C]=O
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: CN1CCCC1=O
Product: CCCCCOC(C)=O
Reaction time: 5 h
Yield: 14.7 %

Procedure:
To the same reaction vessel as in Example 9 were charged bistriphenylphosphinedibromopalladium (0.198 g, 0.25 mmole), stannous chloride (0.095 g, 0.5 mmole), tetra-n-butylammonium chloride (0.139 g, 0.5 mmole) and n-amyl nitrite (60 ml, 406.6 mmoles), together with monochlorobenzene (200 ml). Then, ketene, carbon monooxide and nitrogen were introduced to the mixture at the rate of 10.4 ml/min (0.46 mmole/min), 300 ml/min and 100 ml/min, respectively, and the reaction was effected for 5 hours. During the reaction, 10 ml of a solution of triphenylphosphine and stannous chloride (0.25 mmole each) in N-methylpyrrolidone was added to the reaction system in 2.5 ml portions every 1 hour. The reaction proceeded smoothly for 5 hours without termination of the reaction to give di-n-amyl malonate (116.2 mmoles, 83.8%) and n-amyl acetate (20.5 mmoles, 14.7%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCCO3)c2n1
Yield: 92.5 %

Procedure:
A solution of 2-butyloxy-8-methoxy-9-[2-(tetrahydro-2H-pyran-2-yl)ethyl]-9H-purin-6-amine (88 mg) in methanol (2 mL) was treated with 4N HCl in 1,4-dioxane (1 mL) for 1 h. The reaction was evaporated and the residue treated with water then basified with saturated sodium bicarbonate solution. The resulting white solid was filtered, washed with water and dried to give the title compound (78.1 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[N:14][CH:15]=1)#[CH:9].Br[C:18]1[C:26]2[NH:25][C:24]3[CH:27]4[CH2:33][CH2:32][N:30]([CH2:31][C:23]=3[C:22]=2[CH:21]=[CH:20][CH:19]=1)[CH2:29][CH2:28]4>O1CCCC1.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.[Cu]I>[CH3:16][C:13]1[N:14]=[CH:15][C:10]([C:8]#[C:9][C:18]2[C:26]3[NH:25][C:24]4[CH:27]5[CH2:33][CH2:32][N:30]([CH2:31][C:23]=4[C:22]=3[CH:21]=[CH:20][CH:19]=2)[CH2:29][CH2:28]5)=[CH:11][CH:12]=1
Reactant: C#Cc1ccc(C)nc1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C#Cc2cccc3c4c([nH]c23)C2CCN(CC2)C4)cn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Triethylamine (2 mL) was added to a mixture of bis(tri-t-butylphosphino)palladium (8.8 mg, 0.017 mmol; Aldrich), 5-ethynyl-2-methylpyridine (60 mg, 0.52 mmol; International Publication No. WO2005090333), CuI (3.3 mg, 0.017 mmol; Aldrich) and the product of Example 1B (100 mg, 0.34 mmol) in anhydrous tetrahydrofuran (2 mL). The mixture was purged with a nitrogen stream for 2 minutes, then stirred under nitrogen at 100° C. for 5 hours in a sealed tube. The mixture was cooled to ambient temperature and concentrated under vacuum. The residue was taken up in dimethyl sulfoxide (5 mL), filtered through a glass microfiber frit and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (500 MHz, methanol-d4 ) δ ppm 2.05-2.16 (m, 4 H), 2.56 (s, 3 H), 3.02-3.12 (m, 2 H), 3.17-3.21 (m, 1 H), 3.21-3.29 (m, 2 H), 4.24 (s, 2 H), 7.00 (t, J=7.6 Hz, 1 H), 7.24 (dd, J=7.3, 0.9 Hz, 1 H), 7.34 (d, J=7.9 Hz, 1 H), 7.36 (dd, J=7.9, 0.9 Hz, 1 H), 7.94 (dd, J=8.1, 2.3 Hz, 1 H), 8.68 (d, J=1.8 Hz, 1H); MS (APCI) m/z 328 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:34])[N:14]([N:23]=[C:24]3[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([F:33])([F:32])[F:31])[CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:35]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:34])[N:14]([NH:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([F:33])([F:31])[F:32])[CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=C1CCCC(C(F)(F)F)C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NC1CCCC(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 248A (0.103 g, 0.20 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.15 mL, 0.30 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (m, 4 H) 1.76 (m, 2 H) 2.31 (m, 1 H) 3.11 (m, 2 H) 3.97 (m, 1 H) 5.81 (d, J=19.85 Hz, 1 H) 7.05 (m, 1 H) 7.28 (m, 2 H) 7.53 (m, 2 H) 7.66 (d, J=8.09 Hz, 1 H) 7.75 (d, J=7.72 Hz, 1 H) 8.06 (dd, J=8.09, 1.47 Hz, 1 H). MS (ESI−) m/z 505 (M−H)−.
Reaction SMILES: C(O[C:6](=[O:28])[NH:7][CH2:8][CH:9]([C:13]([N:15]1[CH2:19][CH:18]([Cl:20])[CH:17]2[O:21][CH2:22][C:23]([O:26][CH3:27])([O:24][CH3:25])[CH:16]12)=[O:14])[CH:10]([CH3:12])[CH3:11])(C)(C)C.C(Cl)(=O)C.Cl.N1C=CC=C1.Cl.[F:40][C:41]1[S:45][C:44]([N:46]2[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]2)=[N:43][C:42]=1[C:53]1[CH:61]=[CH:60][C:56](C(O)=O)=[CH:55][CH:54]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[Cl:20][CH:18]1[CH2:19][N:15]([C:13]([CH:9]([CH:10]([CH3:11])[CH3:12])[CH2:8][NH:7][C:6](=[O:28])[C:56]2[CH:60]=[CH:61][C:53]([C:42]3[N:43]=[C:44]([N:46]4[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH2:51]4)[S:45][C:41]=3[F:40])=[CH:54][CH:55]=2)=[O:14])[CH:16]2[C:23]([O:24][CH3:25])([O:26][CH3:27])[CH2:22][O:21][CH:17]12
Reactant: COC1(OC)COC2C(Cl)CN(C(=O)C(CNC(=O)OC(C)(C)C)C(C)C)C21
Reactant: CN1CCN(c2nc(-c3ccc(C(=O)O)cc3)c(F)s2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CC(=O)Cl
Solvent: c1cc[nH]c1
Product: COC1(OC)COC2C(Cl)CN(C(=O)C(CNC(=O)c3ccc(-c4nc(N5CCN(C)CC5)sc4F)cc3)C(C)C)C21
Yield: 85 %

Procedure:
[2-(6-Chloro-3,3-dimethoxy-hexahydrofuro[3,2-b]pyrrole-4-carbonyl)-3-methylbutyl]-carbamic acid tertbutyl ester (78 mg, 0.185 mmol) was deprotected under acidic conditions (acetyl chloride in methanol) as described in Example 4, and the crude pyrrole hydrochloride intermediate was then coupled with the HCl salt of 4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzoic acid using the HATU conditions as described in Example 2, which gave the title compound (98 mg, 85%). MS m/z 624.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][SH:7])[NH2:5].[CH:9]([CH2:11][CH2:12][CH2:13][C@H:14]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])[C:15]([OH:17])=[O:16])=O>O1CCCC1.C(Cl)(Cl)Cl>[C:15]([CH:14]([N:18]1[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]2[C:22]1=[O:23])[CH2:13][CH2:12][CH2:11][CH:9]1[NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:8])[CH2:6][S:7]1)([OH:17])=[O:16]
Reactant: COC(=O)[C@@H](N)CS
Reactant: O=CCCC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CSC(CCCC(C(=O)O)N2C(=O)c3ccccc3C2=O)N1

Procedure:
A solution of L-cysteine methyl ester (1.71 g) and 5-formyl-2(S)-phthalimidopentanoic acid (3.49 g) in 120 ml of tetrahydrofuran was stirred under nitrogen for 2.5 hours and then taken to dryness to yield a white foam. This residue was dissolved in 250 ml of chloroform and washed with water (2×30 ml). The combined aqueous layers were back extracted with chloroform (2×30 ml). The organic layers were dried (Na2SO4) and then concentrated in vacuo to give a white foam, 4.83 g. Tlc on silica [4:1 Ethyl acetate:acetic acid] indicated a major spot at Rf =0.72. Exact mass measurement showed a molecular ion at 392.1024 (calcd. 392.1041). 'H NMR spectrum (CDCl3) showed a multiplet at δ7.72 (4H) and a singlet at δ3.78(3H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:7][N:6]1[C:2]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:25])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cn1cncc1Br
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (3.22 g, 19.98 mmol) in DCM (15 mL) was added ethyl magnesium bromide (6.66 mL, 19.98 mmol, 3.0 M in diethyl ether) dropwise over a 10 minute period. The resulting orange-red solution was stirred at room temperature for 15 minutes, cooled in an ice bath to 0° C. and N-methoxy-N-methyl-4-nitrobenzamide (3.5 g, 16.65 mmol, Intermediate 7: step a) dissolved in DCM (10 mL) was added dropwise. The ice bath was removed and the solid suspension stirred at room temperature for 48 hours. Water was added followed by 6 M aqueous HCl to a neutral pH (pH=6-7). The aqueous mixture was extracted with DCM, dried over Na2SO4, filtered and concentrated. Et2O was added and the mixture sonicated. The precipitate was collected by filtration and dried to provide the title compound as a tan solid.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[NH2:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20]>CO>[N+:8]([C:7]1[C:2]([NH:18][CH:19]([CH3:20])[C:21]([OH:23])=[O:22])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C[C@H](N)C(=O)O
Reactant: O=[N+]([O-])c1cccnc1F
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(Nc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Yield: 43.7 %

Procedure:
A mixture of 2-fluoro-3-nitro-pyridine (12 g), Et3N (30 mL), and racemic alanine (11.87 g) was refluxed in methanol (200 mL) overnight. The mixture was cooled to ambient temperature and the filtrate was concentrated in vacuo. The residue was partitioned between DCM and water. The organic layer was dried over Na2CO3, filtered, and concentrated in vacuo to afford 2-(3-nitro-pyridin-2-ylamino)-propionic acid (7.8 g). This material was dissolved in AcOH (50 mL) and iron (8.2 g) was added. The mixture was refluxed for 1.5 h. After cooling to ambient temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was washed with water and dried to afford 3-methyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.4 g). This material was mixed with 5% aq NaOH (92 mL) and water (18 mL) before 30% aq hydrogen peroxide (9.2 mL) was added. The mixture was stirred at 60° C. for 10 h. After cooling to ambient temperature the pH was adjusted to neutral to precipitate 3-methyl-1H-pyrido[2,3-b]pyrazin-2-one (1.2 g). This material was dissolved in DMF (10 mL) and treated with PyBroP (4.6 g) and DIPEA (1.6 mL) at ambient temperature of 16 h. The precipitated white solid was filtered off, washed with ethanol and dried to afford 2-(benzotriazol-1-yloxy)-3-methyl-pyrido[2,3-b]pyrazine (0.4 g). This material (0.4 g) and hydrazine hydrate (0.5 mL) were refluxed in ethanol (5 mL) for 10 min. After cooling to ambient temperature, the precipitated white solid was filtered off, washed with ethanol and dried to afford give IIa (0.2 g) sufficiently pure for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([C:20](O)=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:24].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[OH:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([C:20]([N:53]2[CH2:54][CH2:55][N:50]([CH2:49][CH2:48][OH:47])[CH2:51][CH2:52]2)=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:24]
Reactant: OCCN1CCNCC1
Reactant: Cn1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C(=O)N3CCN(CCO)CC3)ccc21
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
In a similar manner to Step 1 of Example 20, Compound 157 (20.0 mg, 0.0587 mmol) was dissolved in DMF (1 mL), and the solution was treated with EDCI (23 mg, 0.12 mmol), HOBT monohydrate (7.9 mg, 0.059 mmol) and 1-(2-hydroxyethyl)piperazine (31 mg, 0.24 mmol). The mixture was added with water and ethyl acetate and extracted with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium carbonate to adjust the pH to 9 and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, and the solution was added with hexane and stirred for 30 minutes. The solid was collected by filtration and washed with hexane, followed by drying under reduced pressure to obtain Compound 159 (18.5 mg, yield 70%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([OH:14])=O)[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].C1C(=O)[N:34](Br)C(=O)C1.C(OC(Cl)=O)C(C)C.CN1CCOCC1.N>ClCCl.O1CCOCC1.C(O)(C)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH2:34])=[O:14])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1ccc(C(N)=O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a suspension of 3-[5-Bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (0.15 g, 0.00039 mol, obtained from step 1) in dichloromethane (5.0 mL) and dioxane (1.0 mL) is added NBS (0.075 g, 0.00042 mol). The resulting reaction mixture is stirred at room temperature for 1 hour and then concentrated to dryness. The residue is dried in a desiccator for 1 hour, dissolved in dimethylacetamide (2.5 mL), isobutylchloroformate (0.075 mL, 0.00058 mol) is added, N-methylmorpholine (0.14 mL, 0.0013 mol) is then added, and the reaction mixture is stirred at 0° C. for 5 min under argon. After stirring the reaction mixture at room temperature for 30 min, it is cooled to 0° C., a solution of ammonia in isopropanol (1.2 mL of 2M ammonia in isopropanol) is added and the resulting reaction mixture is stirred at 0° C. for 30 min. The resulting mixture is concentrated to dryness under reduced pressure and the residue is purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=464) are combined and concentrated to a small volume (˜25 mL), cooled, 5% NaHCO3 solution (5.0 mL) is added and then the mixture is extracted with dichloromethane (2×20 mL). The combined organic extracts are dried (Na2SO4), filtered, and concentrated to dryness to afford the desired product (0.115 g, 77%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 7.95 (m 1H), 7.12 (d, 1H J=1.6 Hz), 7.62 (m 1H), 7.61 (m, 1H), 7.01 (m, 2H), 5.58 (m, 2H), 2.16 (s, 3H), and 2.12 (s, 3H); ES-HRMS m/z 464.0436 (M+H calcd for C20H17N3O3F2Br requires 464.0416). 19F NMR(CD3OD/400 MHz) −111.85(m) and −115.92 (m).
Reaction SMILES: C(=O)([O-])[O-].[Na+:5].[Na+].Br.Br[C:9]1[N:10]=[C:11]([OH:17])[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1.[CH3:18][C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[CH:21][C:20]=1[NH:34][C:35]([C:37]1[S:41][C:40]2[CH2:42][CH2:43][CH2:44][CH2:45][C:39]=2[CH:38]=1)=[O:36]>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.O1CCOCC1>[CH3:15][N:13]1[CH:14]=[C:9]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:34][C:35]([C:37]3[S:41][C:40]4[CH2:42][CH2:43][CH2:44][CH2:45][C:39]=4[CH:38]=3)=[O:36])[C:19]=2[CH3:18])[N:10]=[C:11]([O-:17])[C:12]1=[O:16].[Na+:5]
Reactant: Cn1cc(Br)nc(O)c1=O
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c([O-])n1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A 250-mL three-neck round-bottomed flask equipped with a mechanical stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (100 mL) and aqueous 2.0 M sodium carbonate (15 mL, 29.5 mmol). After bubbling nitrogen through the resulting solution for 15 minutes, 5 (8.44 g, 29.5 mmol), 9 (12.9 g, 32.5 mmol) and tetrakis(triphenylphosphine)palladium (2.38 g, 2.06 mmol) were added and the reaction mixture then heated at reflux for 20 h. After this time the reaction was cooled to room temperature and filtered through a pad of Celite 521. The filter cake was washed with a 1:1 solution of methanol/methylene chloride (350 mL) and the filter cake discarded. On standing a precipitate formed in the filtrate and this solid was filtered. The filter cake was triturated with ethyl acetate (50 mL), filtered and dried under vacuum. The resulting solid was suspended in water (75 mL), filtered and the filter cake washed with water (25 mL). The filter cake was dried to a constant weight to give a 53% yield (6.57 g) of 10 as a light yellow solid: mp 225-230° C. dec, 1H NMR (500 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.66 (s, 1H), 7.21 (m, 1H), 7.16 (m, 2H), 6.37 (s, 1H), 2.75 (m, 2H), 2.61 (m, 2H), 2.20 (s, 3H), 1.77 (m, 4H); MS (ESI+) m/z 418(M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:33][C@H:32]1[CH2:44][CH2:45]Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(OCC)(=O)C>CN(C)C(=O)C>[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:33][C@H:32]1[CH2:44][CH2:45][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCl
Reactant: Oc1ccc(F)cc1CCc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
248 mg of 4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenol (prepared as described in Preparation 6) were dissolved in 10 ml of N,N-dimethylacetamide, and then 125 mg of potassium t-butoxide and 405 mg of (2S,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-(2-chloroethyl)pyrrolidine were added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred at room temperature for 3 hours, after which 150 ml of ethyl acetate were added to the reaction mixture. The reaction mixture was then washed with water and with a saturated aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then concentrated by evaporation under reduced pressure. The resulting oily substance was purified by silica gel column chromatography, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 433 mg (yield 73%) of the title compound as a colorless oily substance.