Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[C:10]1[N:14]([CH2:15][CH2:16][CH2:17][OH:18])[C:13]2[C:19]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:21]([F:23])=[CH:22][C:12]=2[N:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:19]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:20]=[C:21]([F:23])[CH:22]=3)[N:14]2[CH2:15][CH2:16][CH2:17][O:18]1
Reactant: CCN(CC)c1cc(F)cc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)c1cc(F)cc2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Reaction time: 90 h
Yield: 23.8 %

Procedure:
To a stirred solution of 3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-5-fluoro-1H-benzimidazol-1-yl}propan-1-ol (Reference example 212, 44.0 mg, 0.100 mmol) and triphenylphosphine (26.2 mg, 0.100 mmol) in tetrahydrofuran (2 mL) was added a solution of diethyl azodicarboxylate in toluene (40%, 68.3 μL, 0.150 mmol) at room temperature. After 90 h, the reaction mixture was concentrated in vacuo, and purified by column chromatography on NH silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give colorless oil (10.1 mg, 0.0238 mmol, 24%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:5]([CH3:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[N+:32]([O-:34])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(O)(C)C.CCOC(C)=O.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.[Pd]>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]2[C:5]([CH3:21])=[CH:4][N:3]=[C:2]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=3[N+:32]([O-:34])=[O:33])[N:7]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Cc1cnc(Cl)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Cc1cnc(Nc2ccc(C(=O)O)cc2[N+](=O)[O-])nc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 34.1 %

Procedure:
A mixture of tert-butyl 4-(2-chloro-5-methylpyrimidin-4-yl)piperazine-1-carboxylate (0.15 g, 0.48 mmol), 4-amino-3-nitrobenzoic acid (97 mg, 0.53 mmol), BrettPhos-Pd Admixture (20 mg, 0.015 mmol), and cesium carbonate (470 mg, 1.44 mmol) in tBuOH (2.4 mL) was heated in a sealed tube at 100° C. overnight. The mixture was diluted with EtOAc, filtered through a celite plug, loaded onto silica gel and purified using 0-10% MeOH/DCM gradient to give the title compound (75 mg, 34%). MS (ES+) C21H26N6O6 requires: 458. Found: 459 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29].C(N(CC)CC)C>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[C:7]5[CH:8]=[N:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:21][CH:22]=1
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(Cl)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NC1=c2cnc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccc(Cl)cc1
Temperature: 90 °C
Yield: 70.3 %

Procedure:
A mixture of Example 69e (0.04 g, 0.106 mmol), ethanesulfonyl chloride (0.054 g, 0.2423 mmol), and triethylamine (0.064 g, 0.635 mmol) in dichloromethane (3 mL) was stirred at ambient temperature for 2 hours. The solvent was removed, and the residue was treated with dioxane (3 mL) and 2.0 N NaOH (2 mL). The reaction mixture was heated at 90° C. for 2 hours. The solvents were partially removed, and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC(C18, CH3CN/water (0.1% TFA), 0-100%) to afford 0.035 g (56.6%) of the title compound as the TFA salt. 1H NMR (500 MHz, DMSO-d6) δ 10.87 (d, J=5.8, 1H), 10.15 (s, 1H), 8.17 (d, J=2.75 Hz, 1H), 8.00 (d, J=2.75 Hz, 1H), 7.82 (s, 1H), 7.09 (d, J=5.8 Hz, 1H), 7.03-7.07 (m, 2H), 6.58-6.62 (m, 2H), 4.62 (s, 2H), 4.07 (s, 3H), 3.26 (q, J=7.32 Hz, 2H), 1.29 (t, J=7.32 Hz, 3H). MS (DCI+) m/z 470.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]([C:6]1[CH:7]=[N:8][C:9]([NH:15][CH2:16][CH:17]=[CH2:18])=[C:10]([N+:12]([O-])=O)[CH:11]=1)=[O:5])[CH3:2].O.O.[Sn](Cl)Cl>CN(C=O)C>[NH2:12][C:10]1[CH:11]=[C:6]([C:4]([N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])=[O:5])[CH:7]=[N:8][C:9]=1[NH:15][CH2:16][CH:17]=[CH2:18]
Reactant: C=CCNc1ncc(C(=O)N(CC)CC)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: C=CCNc1ncc(C(=O)N(CC)CC)cc1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of N,N-diethyl-5-nitro-6-(2-propenylamino)-3-pyridinecarboxamide (4.83 g, 17.25 mmol) in DMF (50 mL) at room temperature was added tin dichloride dihydrate (8.56 g, 37.95 mmol). The mixture was stirred overnight at 80° C. The reaction was brought to room temperature and concentrated in vacuo. The residue was taken up into NaHCO3 saturated aqueous solution (100 mL) and EtOAc (100 mL). The suspension was filtered and the phases separated. The aqueous phase was back-extracted with additional EtOAc (100 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([5% MeOH+1% NH4OH aq] in CH2Cl2) to provide 2.10 g of the title compound 5-amino-N,N-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide (49.0% yield from N,N-diethyl-5-nitro-6-(2-propenylamino)-3-pyridinecarboxamide). 1H-NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.2 Hz, 6H), 3.23 (br s, 1H), 3.45 (m,4H), 4.12 (m, 2H), 4.44 (br s, 2H), 5.17 (d, J=12.5 Hz, 1H), 5.26 (d, J=17.2 Hz, 1H), 6.04 (m, 1H), 7.00 (d, J=2.0 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H). MS (ESI) (M+H)+: 2.49.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.Br[CH:16]([CH3:24])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH:16]([CH3:24])[C:17](=[O:18])[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(Br)C(=O)N1CCCC1
Reactant: COC(=O)c1c(C)[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)n(C(C)C(=O)N2CCCC2)c2ccccc12
Temperature: 100 °C
Yield: 61.2 %

Procedure:
To a solution of methyl 2-methyl-1H-indole-3-carboxylate (0.52 mmol, 0.1 g) in N,N-dimethylformamide (5 mL), 2-bromo-1-(pyrrolidin-1-yl)propan-1-one (0.52 mmol, 0.137 mg) and cesium carbonate (1.05 mmol, 384 mg) was added. The reaction mixture was heated at 100° C. for 12 hours. LC-MS showed the start material was consumed. The solvent was evaporated and the residue was washed with water (10 ml), extracted with dichloromethane (20 ml). The organic layer was separated, concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=45:1) to give methyl 2-methyl-1-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)-1H-indole-3-carboxylate (100 mg, 93%). 1H NMR (300 MHz, CD3OD): δ 8.07-8.03 (m, 1H), 7.44-7.40 (m, 1H), 7.19-7.14 (m, 2H), 5.53-5.49 (m, 1H), 3.90 (s, 3H), 2.80 (s, 3H), 2.00-1.80 (m, 2H), 1.74 (d, J=5.1 Hz, 3H), 1.67-1.64 (m, 4H), 1.32-1.28 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][C:9]1[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=1[C:11]([O:13][CH2:14][CH2:15][O:16][C:17](ON1C(=O)CCC1=O)=[O:18])=[O:12]>>[OH:4][CH2:3][C@@H:2]([NH:1][C:17]([O:16][CH2:15][CH2:14][O:13][C:11]([C:10]1[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=1[CH3:8])=[O:12])=[O:18])[C:5]([OH:7])=[O:6]
Reactant: N[C@H](CO)C(=O)O
Reactant: Cc1ccccc1C(=O)OCCOC(=O)ON1C(=O)CCC1=O
Product: Cc1ccccc1C(=O)OCCOC(=O)N[C@H](CO)C(=O)O
Yield: 32.6 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (252 mg, 2.4 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylbenzoate (642 mg, 2.0 mmol) were reacted to provide 203 mg (33% yield) of the title compound (25) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=7.85 (br d, 1H), 7.39 (m, 1H), 7.20 (m, 2H), 7.01 (m, 1H), 6.61 (br s, 1H), 6.08 (t, 1H), 4.40 (m, 1H), 4.02 (m, 1H), 3.94 (m, 1H), 2.58 (s, 3H), 1.58 (2d, 3H). MS (ESI) m/z 312.01 (M+H)+; 329.08 (M+NH4)+; 334.06 (M+Na)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH:22]([CH3:24])[CH3:23])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([C:19]#[N:20])=[CH:8][CH:7]=2.[OH-:25].[Na+]>CS(C)=O>[NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH:22]([CH3:24])[CH3:23])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([C:19]([NH2:20])=[O:25])=[CH:8][CH:7]=2
Reactant: [OH-]
Reactant: CC(C)Cc1nc2ccc(C#N)cc2c(-c2ccccc2)c1CN
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)Cc1nc2ccc(C(N)=O)cc2c(-c2ccccc2)c1CN
Temperature: 80 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a solution of 3-(aminomethyl)-2-isobutyl-4-phenylquinoline-6-carbonitrile (0.11 g, 0.35 mmol) in dimethyl sulfoxide (4 ml) was added 1N aqueous sodium hydroxide solution (2 ml) and the mixture was stirred at 80° C. for 3 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and 1N aqueous sodium hydroxide solution (50 ml) and the aqueous layer was extracted 4 times with ethyl acetate (50 ml). The organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by preparative HPLC. The objective fractions were combined and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (25 ml)-tetrahydrofuran (25 ml) and 1N aqueous sodium hydroxide solution (25 ml). The organic layer was washed with saturated brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from diisopropyl ether-ethyl acetate to give the title compound (0.043 g, yield 37%) as pale-yellow crystals.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20](=[O:55])[C@@H:21]([NH:37][C:38](=[O:54])[C@@H:39]([NH:43][C:44](=[O:53])[CH2:45][C@H:46]([O:51][CH3:52])[CH2:47][CH2:48][CH:49]=[CH2:50])[CH:40]([CH3:42])[CH3:41])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:24]=3)[NH:15]2)=[O:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=C>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl>[C:33]([Si:30]([CH3:31])([CH3:32])[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][C@@H:21]1[NH:37][C:38](=[O:54])[C@H:39]([CH:40]([CH3:42])[CH3:41])[NH:43][C:44](=[O:53])[CH2:45][C@H:46]([O:51][CH3:52])[CH2:47][CH2:48][CH:49]=[CH:50][C:7]2=[CH:6][C:5](=[CH:4][CH:3]=[CH:8]2)[C@@H:9]([CH3:10])[O:11][C:12](=[O:13])[C@H:14]2[NH:15][N:16]([CH2:17][CH2:18][CH2:19]2)[C:20]1=[O:55])([CH3:35])([CH3:36])[CH3:34]
Reactant: C=CCC[C@H](CC(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)O[C@H](C)c2cccc(C=C)c2)N1)C(C)C)OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CO[C@@H]1CC/C=C/c2cccc(c2)[C@@H](C)OC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)C1
Solvent: ClCCCl
Product: CO[C@@H]1CCC=Cc2cccc(c2)[C@@H](C)OC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)C1

Procedure:
A stirred solution of (S)-1-{(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-[(S)-2-((R)-3-methoxy-hept-6-enoylamino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (R)-1-(3-vinyl-phenyl)-ethyl ester (123 mg, 0.158 mmol) and Hoveyda-Grubbs 2nd generation catalyst (10 mg, 0.0158 mmol) in 1,2-dichloroethane (60 mL) was heated at 80° C. for 1.5 hours. The reaction mixture was cooled before adding silica gel. The mixture was evaporated then purified by silica gel chromatography using ethyl acetate to give the title compound (54 mg, 46%) as a pale brown solid. 1H NMR (300 MHz, CDCl3) δ 0.16 (s, 6H), 0.80-1.00 (m, 17H), 1.34-1.94 (m, 12H), 2.00-2.20 (m, 5H), 2.34-2.53 (m, 3H), 2.63-3.03 (m, 3H), 3.38 (s, 3H), 3.52-3.70 (m, 2H), 4.27-4.38 (m, 2H), 4.92-5.10 (m, 2H), 5.29 (d, J=10.9 Hz, 1H), 5.64-5.98 (m, 2H), 6.52-6.99 (m, 4H), 7.22-7.42 (m, 2H). LCMS (m/z) 749.3 [M+H] Tr=5.91 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7](Br)[CH2:8][CH2:9][CH2:10][CH3:11]>C(O)(C)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCBr
Reactant: COCCCN
Solvent: CC(C)O
Product: CCCCCNCCCOC
Temperature: 90 °C
Yield: 49 %

Procedure:
891 g (10 moles) of 3-methoxypropylamine are mixed with one liter of isopropanol at ambient temperature in a reactor. 755 g (5 moles) of n-pentyl bromide are added to the solution and then heated under reflux (about 90° C.) for 12 hours. The solvent is evaporated at a reduced pressure, the residue diluted with two liters of 2N sodium carbonate, a supernatent oil is separated and distilled at reduced pressure, the 104°-8° C./20 mmHg fraction being collected. Thus 390 g of product are obtained. Yield 73%.
Reaction SMILES: Br[C:2]1[C:3]([NH:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:15]1([CH2:21][C:22]#[CH:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:21]([C:22]1[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]2[N:4]=[C:5]([C:8]#[N:9])[N:6]=[CH:7][C:2]=2[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#CCc1ccccc1
Reactant: CC(C)CNc1nc(C#N)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(Cc2ccccc2)cc2cnc(C#N)nc21
Yield: 40.6 %

Procedure:
5-Bromo-4-isobutylamino-pyrimidine-2-carbonitrile (0.39 mmol), 3-phenyl-1-propyne (0.78 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.02 mmol), copper (I) iodide (0.04 mmol) and triethylamine (1.2 mmol) in DMF (3 ml) is stirred at 75° C. for 2.5 h. After the reaction mixture is treated with saturated ammonium chloride, the mixture is extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and evaporated down. The crude product is applied to a column chromatography on silica gel, which is eluted with following solvents: n-hexane:AcOEt=10:1 (v/v) and n-hexane:AcOEt=8:1 (v/v). The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 40.6%, Rf=0.53 (n-hexane:AcOEt=1:1).
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:21](Cl)(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:21]([C@@:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3])(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)[C@@]1(n2cnc3c(=O)[nH]c(N)nc32)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL flask was added guanosine (2.0 g, 7.06 mmol) and N,N-dimethyl-4-aminopyridine (0.017 g, 0.14 mmol). N,N-dimethylformamide (25 mL) was added via cannula with stirring, the flask was purged with argon gas and pyridine (14 mL) was added via cannula. The slurry was allowed to cool 10 min. in an ice/NaCl bath and octanoyl chloride (1.6 mL, 9.2 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25° C. After 18 h, the mixture was poured into 300 mL of ice-cold 0.1 M sodium bicarbonate solution giving a white solid which was isolated by suction filtration, washed with 3×100 mL hot water, air dried, and recrystallized from hot methanol.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]3[C:75]([C:76]([F:79])([F:78])[F:77])=[CH:74][N:73]=[C:72]([NH:80][C:81]4[CH:95]=[CH:94][C:84]([CH2:85][P:86](=[O:93])([O:90]CC)[O:87][CH2:88][CH3:89])=[CH:83][C:82]=4[O:96][CH3:97])[N:71]=3)=[CH:61][CH:60]=2)[C:56]([O:98][CH3:99])=[N:55]1>>[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]3[C:75]([C:76]([F:77])([F:78])[F:79])=[CH:74][N:73]=[C:72]([NH:80][C:81]4[CH:95]=[CH:94][C:84]([CH2:85][P:86](=[O:90])([OH:93])[O:87][CH2:88][CH3:89])=[CH:83][C:82]=4[O:96][CH3:97])[N:71]=3)=[CH:61][CH:60]=2)[C:56]([O:98][CH3:99])=[N:55]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cn(CCCO)nc4OC)nc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cn(CCCO)nc4OC)nc3C(=O)NC)n2)c(OC)c1
Yield: 48.1 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({6-[1-(3-hydroxypropyl)-3-methoxy-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 48B, 286 mg, 0.395 mmol) affording 132 mg of the title compound (48%). 1H NMR (400 MHz, CD3OD) δ 8.86 (br. s., 1H), 8.29 (br. s., 2H), 7.63-7.77 (m, 2H), 7.12 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 4.14 (t, J=6.7 Hz, 2H), 4.07 (s, 3H), 3.80-3.90 (m, 5H), 3.59 (t, J=6.1 Hz, 2H), 2.99-3.08 (m, 2H), 2.96 (s, 3H), 2.07 (quin, J=6.4 Hz, 2H), 1.17 (t, J=7.1 Hz, 3H). MS (ESI): m/z=695.56 [M+H]+. UPLC: tR=1.15 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])=[C:7]2[OH:26].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(Cl)c2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cccc(Cl)c21
Yield: 99.8 %

Procedure:
A solution of 1,1-dimethylethyl N-((8-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.162 g, 0.427 mmol) in TFA (5.00 mL, 67.3 mmol) was stirred at 25° C. for 10 minutes. The solution was concentrated, azeotroped using DCM (2×100 mL), and dried in vacuo to give the title compound (0.138 g). MS m/e=324 (M+H)+. Calculated for C15H14ClNO5 323.06.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH3:23])[CH2:8][CH2:7][N:6]([CH2:9][C@@H:10]([C:12]2[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=2[CH3:22])[OH:11])[CH2:5]1.[CH3:24][C:25]1[C:33]2[CH2:32][O:31][C:30](=[O:34])[C:29]=2[CH:28]=[CH:27][C:26]=1[C@@H:35]1[CH2:37][O:36]1>>[OH:11][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[C:13]=1[CH3:22])[CH2:9][N:6]1[CH2:7][CH2:8][C:4]([CH2:3][NH:2][CH2:37][C@H:35]([OH:36])[C:26]2[CH:27]=[CH:28][C:29]3[C:30](=[O:34])[O:31][CH2:32][C:33]=3[C:25]=2[CH3:24])([CH3:23])[CH2:5]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c([C@@H](O)CN2CCC(C)(CN)C2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CNCC2(C)CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)C2)ccc2c1COC2=O

Procedure:
5-{(1R)-1-Hydroxy-2-[3-({[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}methyl)-3-methylpyrrolidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-[(R)-2-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 7] and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one [INTERMEDIATE 2B].
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][NH:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([S:16]([F:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:21])=[O:5])=[O:20])=[CH:15][CH:14]=1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(S(=O)(=O)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)c1ccc(S(=O)(=O)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.9 %

Procedure:
A solution of the crude (4-fluorosulfonyl-benzoylamino)-acetic acid tert-butyl ester (541 mg, 1.70 mmol) (from step A above) in 2 mL of methylene chloride was treated with 2 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated in vacuo to provide crude (4-fluorosulfonyl-benzoylamino)-acetic acid (407.9 mg, 92%) as a solid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([Cl:17])[Cl:16])[CH:11]=1)[C:5](OC)=[O:6].[C:33](=[N:37]O)([NH2:36])[CH2:34][CH3:35].[Na]>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([Cl:17])[Cl:16])[CH:9]=[C:4]([C:5]2[O:6][N:37]=[C:33]([CH2:34][CH3:35])[N:36]=2)[C:3]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][N:24]=1
Reactant: COC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Reactant: CCC(N)=NO
Agent: [Na]
Solvent: CCO
Product: CCc1noc(-c2cc(OCC=C(Cl)Cl)cc(Cl)c2OCCCOc2ccc(C(F)(F)F)cn2)n1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
0.05 g of methyl 3-chloro-5-(3,3-dichloroprop-2-enyloxy)-2-[3-(5-trifluoromethylpyrid-2-yloxy)propyloxy]benzoate and 0.028 g of propionamidoxime were dissolved in 1 ml of anhydrous ethanol. A solution of 0.008 g of sodium in 0.5 ml of ethanol was added to this solution. The mixture was stirred at 40° C. for 2 hours and at room temperature for 20 hours. The mixture was then concentrated, and diethyl ether and water were added. After shaking, the ether phase was isolated, dried and concentrated under reduced pressure, and the crude product was purified chromatographically. Yield: 0.017 g (32%)