Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].[NH4+].[Cl-]>C1COCC1>[OH:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: OCCc1coc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a cooled (0° C.) solution of (6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester (0.42 g, 2.0 mmol) in THF (18 mL) was added LAH (2 M in THF, 3.1 mL, 6.1 mmol) and the reaction mixture was stirred (0° C., 1 h). The reaction mixture was warmed (rt, 1 h). The reaction mixture was treated with Rochelle's salt (20 mL) and neutralized with saturated NH4Cl (20 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH:DCM (0-15%) to provide the title compound as a tan semisolid (0.34 g, 94%). 1H NMR (500 MHz, CDCl3): 7.41 (s, 1H), 7.37 (d, J=8.3, 1H), 6.95 (d, J=2.5, 1H), 6.78 (dd, J=8.3, 2.5, 1H), 3.93-3.91 (br s, 2H), 2.92-2.89 (m, 2H), the two hydroxyl protons were not detected.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].O.[NH2:23][NH2:24]>>[CH2:1]([C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:20])[NH:23][N:24]=3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: NN
Reactant: CCc1nc(C)cn1-c1ccc(C(=O)CCC(=O)O)cc1
Solvent: O
Product: CCc1nc(C)cn1-c1ccc(C2=NNC(=O)CC2)cc1

Procedure:
Similarly, reaction of 4-(2-ethyl-4-methyl-1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(2-ethyl-4-methyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone (3d).
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=[C:33]([C:38]6[NH:42][C:41]([C@@H:43]7[CH2:47][CH2:46][CH2:45][N:44]7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=[N:40][CH:39]=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:121])[C:82]2[CH:81]=[C:80]([C:83]3[N:84]=[C:85]([C@@H:88]([NH:92][C:93](=[O:106])[C@@H:94]([NH:101][C:102](=[O:105])[O:103][CH3:104])[CH:95]4[CH2:100][CH2:99][O:98][CH2:97][CH2:96]4)[CH:89]([CH3:91])[CH3:90])[NH:86][CH:87]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:107]1C=CC3N=C([C@@H]4CCCN4)N[C:111]=3[CH:120]=1)=[CH:74][CH:75]=2>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:44]1[CH2:45][CH2:46][CH2:47][C@H:43]1[C:41]1[NH:42][C:38]2[CH:33]=[C:107]([C:73]3[CH:74]=[CH:75][C:76]4[C:77]5[C:82](=[CH:81][C:80]([C:83]6[N:84]=[C:85]([C@@H:88]([NH:92][C:93](=[O:106])[C@@H:94]([NH:101][C:102]([O:103][CH3:104])=[O:105])[CH:95]7[CH2:100][CH2:99][O:98][CH2:97][CH2:96]7)[CH:89]([CH3:91])[CH3:90])[NH:86][CH:87]=6)=[CH:79][CH:78]=5)[C:70]([F:121])([F:69])[C:71]=4[CH:72]=3)[CH:120]=[CH:111][C:39]=2[N:40]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](c1nc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6)[nH]c5c4)ccc2-3)c[nH]1)C(C)C)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N[C@H](c1nc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c5c4)ccc2-3)c[nH]1)C(C)C)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-((S)-1-(4-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)-2-methylpropylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 915.94 [M+H]+. (52 mg, 32%).
Reaction SMILES: C([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[NH:19][C:18](=[O:20])[N:17]([C@H:21]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][C:36]([I:38])=[CH:37][C:31]=4[N:30]=3)[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]2=[O:39])=[CH:11][CH:10]=1)(C)(C)C.ClCCl.C(#N)C.[I-].[Na+].Cl[Si](C)(C)C>C(OCC)(=O)C>[OH:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[NH:19][C:18](=[O:20])[N:17]([C@H:21]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][C:36]([I:38])=[CH:37][C:31]=4[N:30]=3)[CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:16]2=[O:39])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OCCOc1ccc([C@H]2NC(=O)N([C@@H](Cc3ccccc3)c3nc4cc(I)ccc4[nH]3)C2=O)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC#N
Product: O=C1N[C@H](c2ccc(OCCO)cc2)C(=O)N1[C@@H](Cc1ccccc1)c1nc2cc(I)ccc2[nH]1
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of (R)-5-[4-(2-tert-butoxy-ethoxy)-phenyl]-3-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-imidazolidine-2,4-dione (140 mg, 0.22 mmol) in 1:1 v/v dichloromethane/acetonitrile (2 mL) at 0° C. under an atmosphere of nitrogen was added sodium iodide (62 mg, 0.42 mmol) followed by chlorotrimethylsilane (78 μL, 0.61 mmol), the resulting solution was allowed to stir for 30 minutes. Additional sodium iodide (62 mg, 0.42 mmol) followed by chlorotrimethylsilane (78 μL, 0.61 mmol) was added and stirring continued for a further 45 minutes. The reaction was poured into ethyl acetate (30 mL) and washed with 10% aqueous sodium thiosulfate solution. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 60 to 80% v/v ethyl acetate/hexanes to give (R)-5-[4-(2-hydroxy-ethoxy)-phenyl]-3-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-imidazolidine-2,4-dione (83 mg, 65%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]
Reactant: Nc1ccccc1I
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccccc1N
Yield: 85 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol) was converted (using 2-iodo-aniline instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=100:0 to 50:50, 139 mg, 85%) which was obtained as a light brown oil. MS: m/e=375.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[OH:4].O=[C:16]([CH3:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:29][O:28][C:26]([CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH:16]([NH:1][CH2:2][CH:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[OH:4])[CH3:30])=[CH:24][CH:23]=1)=[O:27]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1ccc2ccccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2ccc3ccccc3c2)cc1
Yield: 51.2 %

Procedure:
Following a procedure similar to that described in Example 6, but using 3 g of 2-amino-1-(2-naphthyl)ethanol (prepared as described in Preparation 9), 3.87 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 2.49 g of sodium cyanoborohydride, 3.23 g of the title compound were obtained having an Rf=0.15 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:49])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([S:21]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]3[S:33]([CH2:35][C:36]3[C:41]([CH3:42])=[C:40]([O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH:39]=[CH:38][N:37]=3)=[O:34])(=[O:23])=[O:22])[CH:15]=2)(=O)=O)=CC=1.C([O-])(O)=O.[Na+:55]>CC#N.O>[Na+:55].[CH3:48][O:47][CH2:46][CH2:45][CH2:44][O:43][C:40]1[CH:39]=[CH:38][N:37]=[C:36]([CH2:35][S:33]([C:25]2[N:24]([S:21]([C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=3[CH3:20])[C:13]([O-:49])=[O:12])(=[O:23])=[O:22])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=2)=[O:34])[C:41]=1[CH3:42]
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cc(C(=O)OCCS(=O)(=O)c3ccc(C)cc3)ccc2C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cc(C(=O)[O-])ccc2C)c1C
Temperature: 65 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To the solution of 3-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}-4-methylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 53, 1.5 g, 1.97 mmol) in 15 mL of CH3CN was added a solution of NaHCO3 (200 mg, 2.36 mmol, 1.2 eq) in 7 mL of H2O at room temperature, and then the mixture was heated to 65° C. for 2 h. Thereafter most of the CH3CN was removed, the mixture was extracted with EtOAc, and the aqueous layer was lyophilized overnight. The solid was dissolved in CH2Cl2, and then the mixture was filtered to remove insoluble solids. The filtrate was concentrated to near dryness. The residual oil was dissolved in about 2 mL of CH2Cl2 and EtOAc-hexane (7:1) was added to precipitate a white solid. The precipitate was collected by filtration, washed with EtOAc-hexane (7:1), and dried under vacuum to give 950 mg (80%) of 3-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}-4-methylbenzoic acid sodium salt (Compound 28) as a white solid.
Reaction SMILES: C([NH:4][C@H:5]([C:23]([OH:25])=[O:24])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])(=O)C.[ClH:26]>C(O)(=O)C>[ClH:26].[C:17]1([S:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([CH2:6][C@@H:5]([C:23]([OH:25])=[O:24])[NH2:4])(=[O:9])=[O:8])=[CH:11][CH:12]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: N[C@@H](CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)O
Reaction time: 19 h
Yield: 78 %

Procedure:
A solution of the title compound of Example 11c (30.0 g) in glacial acetic acid (100 mL) and concentrated HCl (100 mL) was heated to 11 degrees C. for 19 hours. The solution was concentrated and trituration with diethyl ether yielded the title compound as a white solid (17.1 g, 78% for 3 steps): Anal. Calcd. for C15H15NO4S2.1.1 HCl.0.25 H2O: C, 47.16; H, 4.38; N, 3.67; Cl, 10.21. Found: C, 47.16; H, 4.27; N, 3.91; Cl, 9.95.
Reaction SMILES: [K].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].[CH3:14][C:15]1([O:18][CH2:17]1)[CH3:16].C1(O)C=CC=CC=1>O.CC#N>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][C:15]([CH3:17])([OH:18])[CH3:16]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: CC1(C)CO1
Agent: [K]
Solvent: CC#N
Solvent: O
Solvent: Oc1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1OCC(C)(C)O
Temperature: 170 °C
Yield: 98.6 %

Procedure:
A steel bomb, fitted with an internal thermocouple, pressure gauge and safety release valve rated at 3000 psi, with ˜55 mL capacity was charged with the potassium salt of 2-methoxy-4-nitrophenol (6 g, 29 mmol), NaH2PO4 (3.3 g, 27.7 mmol), isobutylene oxide (2.8 g, 35 mmol) and 30 mL of 15% H2O/MeCN. The sealed bomb was heated at 170° C. for three hr. Following cooling, HPLC revealed all starting phenol had been converted to product. The biphasic solution was concentrated using a rotary evaporator before being partitioned between CH2Cl2 and H2O. The aqueous phase was extracted 3× with CH2Cl2; the combined CH2Cl2 fractions were washed 3× with aq KHCO3/K2CO3 and once with H2O. After drying over Na2SO4, concentration under vacuum yielded 6.9 g of desired product as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:8]=[C:9]([N:11]=[N+:12]=[N-:13])[CH:10]=1)=[O:4].[C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(=O)[CH:22]([CH3:24])[CH3:23].CC[O-].[Na+]>CCO>[CH2:30]([O:29][C:27]([C:26]1[N:13]=[N:12][N:11]([C:9]2[CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=2)[C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:28])[CH3:31]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: COC(=O)c1cc(N=[N+]=[N-])cc(-c2ccc(C)cc2)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nnn(-c2cc(C(=O)OC)cc(-c3ccc(C)cc3)c2)c1C(C)C
Temperature: 80 °C

Procedure:
To a mixture of 5-azido-4′-methyl-biphenyl-3-carboxylic acid methyl ester (200 mg, 0.75 mmol) and ethyl isobutyrylacetate (119 mg, 0.75 mmol) in EtOH (5 mL) was added EtONa (51 mg, 0.75 mmol) and the mixture was heated to 80° C. for two hours, then cooled to room temperature. EtOH was removed from the reaction mixture to afford 5-isopropyl-1-(5-methoxycarbonyl-4′-methyl-biphenyl-3-yl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester as a gel which was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].[F-].[Cs+]>C(#N)C>[F:21][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1
Reaction time: 0.17 h

Procedure:
Procedure EE: In a microwave reactor vessel, add (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone (1.0 mmol), 4-methanesulfonylphenyl boronic acid (2.5 mmol), dichloropalladium di-triphenylphosphine (0.2 mmol), cesium fluoride (9.0 mmol) and acetonitrile (0.20M) and run in a CEM microwave reactor for 10 minutes at 120° C. with 75 W power and cooling on. After this time, wash the reaction with water while extracting with 10% isopropanol/dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Purify the title compound via radial chromatography eluting with 2M ammonia in methanol and dichloromethane. MS (m/e): 431.2 (M+1)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][NH:20][CH2:19][CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:38]1(=O)[CH2:41][CH2:40][CH2:39]1.S([O-])([O-])(=O)=O.[Mg+2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][N:20]([CH:38]3[CH2:41][CH2:40][CH2:39]3)[CH2:19][CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl (2R)-2-[(4-benzylpiperazin-1-yl)carbonyl]piperazine-1-carboxylate (4.5 g) was dissolved in tetrahydrofuran (300 ml) and stirred at room temperature. N,N-Diisopropyl-ethylamine (5.95 ml) was added followed by cyclobutanone (3.25 g) and magnesium sulphate (300 mg). After 45 minutes, sodium triacetoxyborohydride (9.78 g) was added and stirring continued overnight. Inorganic residues were removed by filtration and the filtrate concentrated in vacuo. The residue was purified by chromatography eluting with 0-10% methanol/dichloromethane. This gave tert-butyl (2R)-2-[(4-benzylpiperazin-1-yl)carbonyl]-4-cyclobutylpiperazine-1-carboxylate as a colourless gum (5.12 g).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][NH:7]2.[F:13][C@@H:14]1[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:16](N2C=CC(=O)NC2=O)[CH2:15]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[F:13][C@@H:14]1[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:16]([N:7]2[CH:6]=[N:5][C:4]3[C:8]2=[N:9][CH:10]=[N:11][C:3]=3[N:2]([CH3:12])[CH3:1])[CH2:15]1
Reactant: CN(C)c1ncnc2[nH]cnc12
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(C)c1ncnc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 144 h
Yield: 46.6 %

Procedure:
6-Dimethylamino-9H-purine (0.42 g, 2.6 mmoles), (Aldrich Chemical Company) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 moles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 6 days, 172 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (92:8). Solvent was removed and lyophilization yielded 0.341 g of 9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-dimethylamino-9H-purine (55%): mp 105°-107° C.; [α]D20 -23.3 (c=0.52, DMF); UV λmax (ε×10-3) at pH 7, 275 (25.1); at pH 13, 274 (18.4); 1H NMR (300 MHz, DMSO-d6) δ8.35 and 8.20 (2s, 2H, H2 and H8), 6.40 (dd, 1H, H1', J=9.3 Hz, J=5.6 Hz), 5.46 (t, 1H, OH5', J=5.7 Hz), 5.43 (dd, 1H, H3', J=53.8 Hz, J=4.5 Hz), 4.22 (dt, 1H, H4', J=27.1 Hz, J=4.4 Hz), 3.58-3.61 (m, 2H, H5' and H"), 3.43 (b, 6H, CH3NCH3), and 2.82-3.10 and 2.55-2.70 (m, 2H, 2' and H2"); MS (ci) 282 (M+1), 262 (M-F), 164 (MH2 --C5H8FO2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To acetone 40 mL solution of 4-bromo-2-nitrobenzoic acid 4.0 g were added potassium carbonate 3.4 g and dimethylsulfate 2.3 mL at room temperature, and it was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. Water and ethyl acetate were added to the obtained residue. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution,1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure to give methyl 4-bromo-2-nitrobenzoate 4.1 g of white solid.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]([CH:10]([CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:12][C:13](O)=[O:14])[CH3:9])=[O:7].C(N(CC)CC)C.[CH2:45]([NH2:49])[CH2:46][CH2:47][CH3:48].C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH2:45]([NH:49][C:13](=[O:14])[CH:12]=[CH:11][CH:10]([N:8]([C:6](=[O:7])[C:5]1[CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=[C:3]([C:2]([F:1])([F:37])[F:36])[CH:4]=1)[CH3:9])[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:46][CH2:47][CH3:48]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C=CC(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CCCCN
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNC(=O)C=CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 100 mg (0.19 mmol) of 4-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methyl-amino]-5,5-diphenyl-pent-2-enoic acid and 37 μl (0.27 mmol) of triethylamine in 3 ml of N,N-dimethylformamide at 0° C. is treated with 23 μl (0.23 mmol) of butylamine, followed by 38 μl (0.23 mmol) of diethyl cyanophosphonate. After stirring for 4 h at room temperature, the reaction mixture is concentrated, diluted with ethyl acetate, and then washed with saturated sodium bicarbonate solution. The aqueous layer is further extracted with ethyl acetate (3×). The organic layers are combined, dried with sodium sulfate and concentrated. The residue is then purified by flash chromatography (95:5 methylene chloride/methanol) to give the title compound as a white solid. TLC: methylene chloride/methanol (95:5) Rf =0.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:19][CH2:18]/[CH:17]=[C:16](\[CH3:20])/[CH2:15][CH2:14][C:4]1[C:5]([CH3:13])=[C:6]([O:11][CH3:12])[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1])(=[O:23])[CH3:22]
Reactant: COc1c(C)c(C)c(OC)c(CC/C(C)=C/CO)c1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1c(C)c(C)c(OC)c(CC/C(C)=C/COC(C)=O)c1C
Temperature: 0 °C

Procedure:
A solution of 4.17 g (15 mmol) of (E)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-penten-1-ol in pyridine (10 ml) and acetic anhydride (2 ml) was stirred at room temperature for 5 hours and thereafter poured into ice-cold 2N hydrochloric acid solution. The mixture was extracted with ether. The combined extracts were washed with water, dried and freed from solvent; the residue obtained was purified on silica gel with hexane/ethyl acetate (95:5), yielding 3.8 g of (E)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate as a colourless oil.