Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[Cl:13][C:14]([Cl:25])([Cl:24])[CH:15]1[N:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[C:17](=[O:23])[O:16]1.C(Br)C=C.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([C:18]12[CH2:22][CH2:21][CH2:20][N:19]1[CH:15]([C:14]([Cl:13])([Cl:24])[Cl:25])[O:16][C:17]2=[O:23])[CH:1]=[CH2:2]
Reactant: O=C1OC(C(Cl)(Cl)Cl)N2CCCC12
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC12CCCN1C(C(Cl)(Cl)Cl)OC2=O
Temperature: -68 °C
Reaction time: 0.67 h

Procedure:
To a solution of diisopropylamine (60 ml) in tetrahydrofuran (160 ml) was added dropwise n-butyllithium (2.64M hexane solution, 161 ml) over 20 minutes under ice-cooling, and the mixture was directly stirred for 40 minutes. To the mixture cooled to −68° C. was added dropwise a solution of 3-trichloromethyltetrahydropyrrolo[1,2-c]oxazol-1-one (80.0 g) in tetrahydrofuran (640 ml) over 30 minutes, and the mixture was directly stirred for 20 minutes. To the mixture was added allyl bromide (57 ml), and the mixture was directly stirred for 1 hour. To the reaction mixture was added saturated aqueous ammonium chloride solution (1000 ml), and the mixture was extracted with ethyl acetate (800 ml). The separated organic layer was washed with water (800 ml) and saturated aqueous sodium chloride solution (500 ml). The separated aqueous layer was extracted with ethyl acetate (400 ml, 500 ml) twice. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the titled compound (86.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[S:24][C:18]2[CH:19]([CH3:23])[NH:20][CH2:21][CH2:22][C:17]=2[CH:16]=1>>[Cl:14][C:15]1[S:24][C:18]2[CH:19]([CH3:23])[N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH2:21][CH2:22][C:17]=2[CH:16]=1
Reactant: CC1NCCc2cc(Cl)sc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2sc(Cl)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2-chloro-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine to provide the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH:15](F)F)[N:8]=[C:7]([C:18]([F:21])([F:20])[F:19])[C:6]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl.[Zn]>[CH:1]1([NH:4][C:5]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:15])[N:8]=[C:7]([C:18]([F:20])([F:21])[F:19])[C:6]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC1CC1
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)(F)F)nc(C)c(C(=O)OC)c1NC1CC1
Yield: 58.7 %

Procedure:
This compound was prepared as described in Example 85: 17 g (0.264 mol) of zinc dust, 4.76 g (0.012 mol) of product of Example 56 and 17 ml of trifluoroacetic acid in 100 ml of CH2Cl2 were reacted affording 2.44 g (59%) of product after kugelrohr distillation at 100°-140° C./53 Pa as a light yellow oil, nD25 1.5032.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][C:4]1([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]([CH3:26])[CH2:3][C:4]1([CH2:18][C:19]([OH:21])=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17]
Reactant: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC1(CC(=O)O)CCN(CCc2ccccc2)C1=O
Yield: 92 %

Procedure:
A solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (659 mg, 1.83 mmol), trifluoroacetic acid (6.5 mL) and CH2Cl2 (6.5 mL) is stirred at room temperature for 1 hour. The solution is concentrated from CH2Cl2 (3×50 mL), dissolved in 1N NaOH (10 ml), and the basic layer is extracted with Et2O (2×25 mL). The pH of the basic layer is adjusted to pH 1 with 6N HCl. The acidic layer is extracted with CH2Cl2 (2×25 mL), the combined CH2 Cl2 layers dried (MgSO4), filtered and concentrated to give 511 mg (92%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[P:25](Cl)(Cl)=[O:26]>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[P:25]1(=[O:26])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][N:8]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(P(=O)(Cl)Cl)c(OC)c1
Reactant: c1ccc(CNc2ccccc2)cc1
Product: COc1ccc(P2(=O)c3ccccc3CN2c2ccccc2)c(OC)c1
Yield: 66 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and 2,4-dimethoxyphenyl phosphonic dichloride. The reaction of the dilithio compound and the 2,4-dimethoxyphenyl phosphonic dichloride was conducted at -76° C. to yield 1-(2,4-dimethoxyphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (7.2 g, 66% yield) as a white solid having a melting point of 173°-175° C. and the following analysis:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[C:19]([CH3:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[CH3:21])=[O:8].[C:24]([Si:28]([CH3:38])([CH3:37])[O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:28]([O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[CH:4][C:5]([F:23])=[C:6]([CH:22]=2)[C:7]([NH:9][C:10]2[C:19]([CH3:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[CH3:21])=[O:8])[CH2:32]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCNC1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(Br)ccc2F)c(C)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2F)c(C)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a solution of methyl 4-[(5-bromo-2-fluoro-benzoyl)amino]-3,5-dimethyl-benzoate (0.40 g, 1.05 mmol), tert-butyl-dimethyl-(3-piperidylmethoxy)silane (0.362 g, 1.57 mmol) and Cs2CO3 (1.04 g, 3.15 mmol) in 1,4-dioxane (6 ml) is added Pd2(dba)3 (0.10 g, 0.105 mmol) followed by S-Phos (0.043 g, 0.105 mmol). The reaction mixture is purged with nitrogen for 5 minutes and then heated at 90° C. After 16 hours, the reaction is cooled to ambient temperature, filtered through Celite™, and washed with EtOAc. The combined filtrates are dried over sodium sulfate, filtered, and concentrated under reduced pressure and purified by flash chromatography (silica gel) using 10% EtOAc in hexane to afford the title compound as a pale yellow oil (0.22 g, 40%). Mass spectrum (m/z): 529.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([N+:16]([O-:18])=[O:17])=[C:10]([O-:15])[CH:11]=2)[C:6]1=[O:19].[K+].S(OC)(O[CH3:26])(=O)=O>CN(C=O)C>[CH3:26][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[N+:16]([O-:18])=[O:17])[C:6](=[O:19])[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:20])[C:13]2=[O:14]
Reactant: COC(=O)CN1C(=O)c2cc([O-])c([N+](=O)[O-])cc2C1=O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)c2cc(OC)c([N+](=O)[O-])cc2C1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of potassium 2-(2-methoxy-2-oxoethyl)-6-nitro-1,3-dioxoisoindolin-5-olate (0.380 g, 1.194 mmol) in DMF (10 ml), dimethyl sulfate (0.324 ml, 3.34 mmol) was added, and the mixture was heated at 60° C. for 6 hours and then stirred at 40° C. overnight. Additional dimethyl sulfate (0.116 ml, 1.194 mmol) was added, and the reaction mixture was heated at 60° C. for 4 hours. The mixture was partitioned between 1N NaHCO3 (150 ml) and diethyl ether (100 ml). The organic phase was washed with 1N NaHCO3 (100 ml), and the combined aqueous layers were extracted with diethyl ether (2×100 ml). The organic layers were mixed, washed twice with brine (2×100 ml) and dried over sodium sulfate; the solvent was removed under vacuum affording methyl 2-(5-methoxy-6-nitro-1,3-dioxoisoindolin-2-yl)acetate (0.225 g, 0.765 mmol, 64% yield). MS/ESI+ 294.9 [MH]+). This product was used without any further purification.
Reaction SMILES: C(OC([N:8]([C:16]1[C:17]2[N:25]=[C:24](Cl)[CH:23]=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34].C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.CC(N(C)C)=O>[C:28]1([CH3:27])[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][C:24]1[CH:23]=[CH:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH2:8])[C:17]=2[N:25]=1
Reactant: Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2ccc(Cl)nc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1Oc1ccc2ncnc(N)c2n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To an 8 mL screw-cap vial was added tert-butyl N-tert-butoxycarbonyl-N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)carbamate 50-A (0.20 mmol, 76 mg) followed by 2-methylphenol (2 equiv., 0.40 mmol, 43 mg), potassium carbonate (2 equiv., 0.40 mmol, 55 mg) and dimethylacetamide (0.4 mL), and 4-dimethylaminopyridine, 0.05 equiv., 0.01 mmol, 1 mg). The reactions were capped and shaken at 80° C. for 2 h. The reaction was filtered, and concentrated via GeneVac. Crude was then taken up in dichloromethane (0.25 mL), followed by trifluoroacetic acid (0.5 mL). The reaction was capped and shaken for 1 h, then concentrated. Crude was purified by reverse phase HPLC to yield 27 mg of product. 1H NMR (400 MHz, DMSO) δ 8.40-8.33 (s, 1H), 8.17-8.11 (d, J=9.0 Hz, 1H), 7.44-7.35 (dd, J=13.1, 8.3 Hz, 2H), 7.32-7.26 (m, 1H), 7.26-7.17 (m, 2H), 2.17-2.13 (s, 3H). LCMS M/Z (M+H)=253.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25](O)=[O:26])[CH:23]=3)[NH:18][CH:17]=2)=[N:6][C:5]=1[CH3:28])(=[O:3])[CH3:2].FC1C(O)=C(F)C(F)=C(F)C=1F.C[CH2:42][N:43](C(C)C)[CH:44](C)C.C(Cl)CCl.CNC>CN(C=O)C>[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([N:43]([CH3:44])[CH3:42])=[O:26])[CH:23]=3)[NH:18][CH:17]=2)=[N:6][C:5]=1[CH3:28])(=[O:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)c1sc(N2CCOC[C@@H]2Cc2c[nH]c3ccc(C(=O)O)cc23)nc1C
Agent: CNC
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)c1sc(N2CCOC[C@@H]2Cc2c[nH]c3ccc(C(=O)N(C)C)cc23)nc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.3 %

Procedure:
To a stirred solution of Example 11 (0.115 g, 0.29 mmol) in DMF (2 mL) was added pentafluorophenol (0.064 g, 0.35 mmol), DIPEA (0.100 mL, 0.57 mmol) and EDC (0.072 g, 0.37 mmol). The reaction mixture was stirred at r.t. for 48 h. Dimethylamine (40% w/v in water, 5 mL) was added and the reaction mixture stirred for 16 h at r.t. The reaction mixture was concentrated in vacuo. DCM (5 mL) and water (5 mL) were added. The aqueous layer was extracted with DCM (2×3 mL). The combined organic fractions were washed with water (3×15 mL), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (Method 6) to give the title compound (0.040 g, 45%) as a white solid. δH (CD3OD) 8.07 (1H, s), 7.42 (1H, m), 7.25-7.19 (2H, m), 4.39-4.29 (1H, m), 4.14-3.99 (1H, m), 3.88 (1H, d, J 11.9 Hz), 3.72-3.51 (4H, m), 3.42 (1H, dd, J 13.8 Hz and J 10.2 Hz), 3.19-3.03 (7H, m), 2.57 (3H, s), 2.43 (3H, s). Exchangeable proton not observed. LCMS (ES+) 427.0 (M+H)+, RT 2.59 minutes (Method 2).
Reaction SMILES: C(OC([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:11]([C:21](=[O:23])[CH3:22])[O:10]C1(C)C)=O)(C)(C)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(O)C>[C:26]1([CH3:36])[CH:27]=[CH:28][C:29]([S:32]([OH:35])(=[O:33])=[O:34])=[CH:30][CH:31]=1.[NH2:8][CH:12]([CH:11]([OH:10])[C:21](=[O:23])[CH3:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1
Reactant: CC(=O)C1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(=O)C(O)C(N)Cc1cccc(F)c1

Procedure:
3-t-Butyloxycarbonyl-2,2-dimethyl-5-(1-oxoethyl)-4-(3-fluorophenyl)methyloxazolidine (17.94 g, 51.1 mmol) was dissolved in ethanol (180 ml), and p-toluenesulfonic acid.1H2O (10.7 g, 56.2 mmol) was added to it and the mixture was heated under reflux for 2 hours with stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was dried with a vacuum pump (2 mmHg) at 50° C., whereby crude 2-amino-1-(3-fluorophenyl)-3-hydroxy-4-oxopentane p-toluenesulfonate (21.5 g) was obtained as solid. This solid was subjected without further purification to the subsequent condensation reaction.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:91]=[CH:90][CH:89]=[CH:88][C:64]=1[CH2:65][O:66][C:67]([NH:69][CH2:70][CH2:71][CH2:72][C@H:73]([NH:80][C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C:74](OCC#N)=[O:75])=[O:68])=[N+:61]=[N-:62]>C(#N)C>[N:60]([C:63]1[CH:91]=[CH:90][CH:89]=[CH:88][C:64]=1[CH2:65][O:66][C:67]([NH:69][CH2:70][CH2:71][CH2:72][C@@H:73]([NH:80][C:81]([O:83][C:84]([CH3:86])([CH3:87])[CH3:85])=[O:82])[C:74]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:75])=[O:68])=[N+:61]=[N-:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (160 mg, 0.252 mmol) and (S)-cyanomethyl 5-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk62) (450 mg, 1.008 mmol) in acetonitrile (1.5 mL) was added to buffer A (33 mL), and the mixture was stirred at room temperature for 2 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk63) (51.3 mg, 20%).
Reaction SMILES: [C:1]1([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)[CH:2]=1>Cl>[C:1]1([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCCNCCCNCc1cccc(CNCCCNCCCNC(=O)OC(C)(C)C)c1
Agent: Cl
Product: NCCCNCCCNCc1cccc(CNCCCNCCCN)c1
Reaction time: 2 h
Yield: 56 %

Procedure:
To the crude di-tert-butyl (((((1,3-phenylenebis(methylene))bis(azanediyl))-bis(propane-3,1-diyl))bis(azanediyl))bis(propane-3,1-diyl))dicarbamate from Step 1 was added methanolic HCl (150 mL, 1.0 M). The reaction mixture was stirred for 2 h and concentrated under reduced pressure. The solid was collected by vacuum filtration, and it was washed with Et2O (30 mL) and hot MeOH (30 mL) to afford the desired product (1.1 g, 56%) as a white solid. 1H NMR (500 MHz, D2O) δ ppm 7.62 (s, 4H), 4.36 (s, 4H), 3.28-3.21 (m, 12H), 3.15 (t, J=8.0 Hz, 4H), 2.23-2.11 (m, 8H). 13C NMR (125 MHz, D2O) 131.4, 131.3, 131.1, 130.2, 50.8, 44.7, 44.6, 44.1, 36.5, 23.6, 22.6. LRMS [M+H]+365.3.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:3])[CH3:2]>C(#N)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]=[C:1]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1Nc1ccccc1N
Solvent: CC#N
Product: CC(C)c1ccccc1-n1c(-c2ccccc2)nc2ccccc21
Temperature: 25 °C
Yield: 58.2 %

Procedure:
N1-(2-isopropylphenyl)benzene-1,2-diamine (20 g, 88 mmol) and benzldehyde (8.5 g, 80 mmol) were reacted in acetonitrile (100 mL) under reflux for 3 hours. The reaction mixture was cooled to room temperature. Ferric chloride (0.13 g, 0.8 mmol) was added. The reaction mixture was heated up again to reflux overnight. Air was bubbled through the reaction while reflux. The solvent was evaporated. The residue was dissolved in dichloromethane (200 mL) and ran through a short silica gel plug. The crude product was purified by column chromatography using dichloromethane to 3% of ethyl acetate in dichloromethane. The product was further purified by recrystallizing form ethanol. 8 g of desired product was obtained.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[CH2:39][CH2:40][C:41](OCC)=[O:42]>C1COCC1.CCCC(C)C.CCOCC>[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[CH2:39][CH2:40][C:41](=[O:42])[CH2:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CCOC(=O)CCc1ncccn1
Reactant: CS(=O)(=O)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCC(C)C
Product: O=C(CCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 1-(methylsulfonyl)-4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazine (13.3 g, 39.2 mmol) in THF (200 mL) at −70° C. was added LHMDS (75 mL, 75 mmol) drop wise and the reaction stirred for 20 minutes. A solution of ethyl 3-pyrimidin-2-ylpropanoate (9.2 g, 51 mmol) in THF (55 mL) was then added at −70° C., warmed to −20° C. and stirred for 2 hours. The reaction was then quenched by addition of a saturated solution of NH4Cl (250 mL), extracted twice with EtOAc (3×250 mL), combined organics were washed with brine (250 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid. The solid was stirred for 20 minutes in 20% isoHexane/ether (100 mL), filtered and washed with isoHexane and dried to give 4-pyrimidin-2-yl-1-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)butan-2-one as an off white solid (15.2 g, 32.2 mmol, 82%).
Reaction SMILES: [K].[C:2]1([C:8]2[CH:16]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:11]3[O:10][C:9]=2[CH2:17][C:18]([OH:20])=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][O:23][CH3:24]>CN(C)C=O>[C:2]1([C:8]2[CH:16]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:11]3[O:10][C:9]=2[CH2:17][C:18]([O:20][CH2:22][O:23][CH3:24])=[O:19])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1
Reactant: COCCl
Agent: [K]
Solvent: CN(C)C=O
Product: COCOC(=O)Cc1oc2cccc-2cc1-c1ccccc1

Procedure:
The potassium salt of 3-phenyl-7-benzofuranacetic acid is reacted with chloromethoxymethane in dimethylformamide to provide methoxymethyl 3-phenyl-7-benzofuranacetate.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([O:7][CH2:8][CH2:9][CH3:10])[NH:4][C:3]=1[CH:11]=[O:12].[C:13]([O:17][C:18]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Br)=[C:28]([F:34])[CH:27]=2)=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:13]([O:17][C:18]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:4]3[C:3]([CH:11]=[O:12])=[C:2]([Br:1])[N:6]=[C:5]3[O:7][CH2:8][CH2:9][CH3:10])=[C:28]([F:34])[CH:27]=2)=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCOc1nc(Br)c(C=O)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Yield: 98.8 %

Procedure:
5-Bromo-2-propoxy-3H-imidazole-4-carbaldehyde (2.1 g, 8.8 mmol), 4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (3.2 g, 8.8 mmol) and potassium carbonate (3.6 g, 26.4 mmol) were dissolved in DMF (100 mL). The solution was stirred until the reaction was complete, as determined by HPLC. The mixture was extracted with EtOAc (200 mL), washed with saturated aqueous NaCl (4×100 mL), dried over MgSO4, evacuated to dryness, and purified by flash chromatography (EtOAc/hexanes) to yield compound A (4.5 g).