Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCCP(O)(O)=O.[CH3:26][N:27]1[C:32]2=[CH:33][N:34]([CH2:43][CH2:44][CH2:45][C:46]([OH:48])=O)[C:35]([C:36]3[CH:37]=[C:38]([CH3:42])[CH:39]=[CH:40][CH:41]=3)=[C:31]2[C:30](=[O:49])[N:29]([CH3:50])[C:28]1=[O:51]>CN(C=O)C.C(OCC)(=O)C>[CH3:26][N:27]1[C:32]2=[C:33]3[N:34]([C:35]([C:36]4[CH:37]=[C:38]([CH3:42])[CH:39]=[CH:40][CH:41]=4)=[C:31]2[C:30](=[O:49])[N:29]([CH3:50])[C:28]1=[O:51])[CH2:43][CH2:44][CH2:45][C:46]3=[O:48]
Reactant: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCCC(=O)O)c1
Agent: CCCP(=O)(O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCCC3=O)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of T3P® (1-propylphosphonic acid cyclic anhydride 50% solution in DMF) (1.0M, 329 μL, 0.56 mmol) was added to solid 4-(1,3-dimethyl-2,4-dioxo-5-m-tolyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)butanoic acid (step 2) (200 mg, 0.56 mmol), giving a paste. DMF (1 mL) was added and a solution formed. The solution was stirred at room temperature for 1 hour and at 100° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with sat. sodium bicarbonate (1×5 mL) and brine (3×5 mL). The organic phase was dried with magnesium sulfate and the solvent was removed under vacuum to give the title compound.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=O)[OH:5])[OH:3].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13]>C1(C)C=CC=CC=1.CCOCC.CCCCCC>[O:10]=[C:1]1[C@@H:2]([O:3][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[C@H:4]([O:5][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[C:6](=[O:8])[O:9]1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: CC(C)C(=O)Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)C(=O)O[C@@H]1C(=O)OC(=O)[C@H]1OC(=O)C(C)C
Reaction time: 22 h
Yield: 70.6 %

Procedure:
To a suspension of D-tartaric acid (5.0 g, 33.3 mmol) in toluene (60 mL) was added isobutyryl chloride (11.3 mL, 107 mmol). The resulting suspension was heated to reflux and stirred for 22 h at reflux temperature. The reaction mixture was then concentrated in vacuo to afford a crystalline solid, which was suspended in a mixture of ether and hexane (1:3), filtered, washed with hexane and dried to afford the desired compound (30) as a white crystalline solid (6.4 g, 71%). 1H-NMR (400 MHz, CDCl3): δ 1.25 (d, J=6.8 Hz, 12H), 2.72 (hept, J=6.8 Hz, 2H), 5.63 (s, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([O:25][CH3:26])[CH:17]=[C:18]3[C:23]=2[N:22]=[C:21]([CH3:24])[CH:20]=[CH:19]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].CCOC(C)=O.CCCCCC>CO.[Pd]>[CH3:26][O:25][C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:15]=1)[N:22]=[C:21]([CH3:24])[CH:20]=[CH:19]2
Reactant: COc1cc(N2CCN(Cc3ccccc3)CC2)c2nc(C)ccc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(N2CCNCC2)c2nc(C)ccc2c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A mixture of 1-benzyl-4-(6-methoxy-2-methylquinolin-8-yl)piperazine (0.527 g, 1.52 mmol), 10% Pd/C (0.20 g), and ammonium formate (0.96 g, 15.2 mmol) in methanol (10 mL) were heated at reflux under N2 for 3 hours. TLC analysis (35% EtOAc/hexane) indicated only a trace of starting material remained. After cooling to room temperature, the reaction was filtered through celite, washing with excess methanol. The filtrate was concentrated, diluted with CH2Cl2 (50 mL), and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 0.37 g (95%) of the title compound as a yellow oil, which was used in the subsequent reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:9][CH3:10])[C:12]2[S:11][CH2:17][C:15](=[O:16])[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=S)N1
Reactant: CCNc1cccc(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C1=NC(=O)CS1)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 76.6 %

Procedure:
To a solution of (3-fluorophenyl)-ethylamine (3.06 g, 22 mmol) and rhodanine (2.66 g, 20 mmol) in acetonitrile (70 mL) was added DIEA (7.66 mL, 44 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (5.97 g, 22 mmol) was added in two portions. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (500 mL) and methanol (250 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in ethyl acetate (25 mL) at hot condition and stored in the refrigerator overnight. Then, the solids were collected by filtration and washed with ethyl acetate. After drying in air, 3.65 g (76.6% yield) of 2-[(3-fluorophenyl)-ethylamino]-thiazol-4-one was isolated as a white amorphous solid: HRES(+) m/e calcd for C11H11FN2OS (M+H)+239.0649, found 239.0647.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC(OCC(C)C)=O.[NH2:30][C:31]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34]>C(Cl)Cl.CN1CCOCC1>[O:34]=[C:33]1[C:32]2[CH:36]=[CH:37][CH:38]=[C:39]([C:40]([F:41])([F:42])[F:43])[C:31]=2[N:30]=[C:19]([CH:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:21]1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC(COCc1ccccc1)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Yield: 39.9 %

Procedure:
Using the procedure of Step A of Example 7, a solution of 29.5 g of BOC-O-benzyl L-serine in 200 ml of methylene chloride, 27.5 ml of N-methyl-morpholine, 26.2 g of isobutyl chloroformate in methylene chloride and 20.5 g of 2-amino-3-trifluoromethyl benzoic acid in 200 ml of methylene chloride and 11 ml of N-methyl-morpholine were reacted for 16 hours. The mixture was extracted with methylene chloride and chromatography on silica gel (eluent: methylene chloride) yielded 18.5 g of 1,1-dimethylethyl N-[1-[4-oxo-8-trifluoromethyl-4H-3,1-benzoxazin-2-yl]-2-(phenylmethoxy)-ethyl]-carbamate melting at 98° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:15][OH:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH:15]=[O:16]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(CO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To propane-1-sulfonic acid (4-fluoro-3-hydroxymethyl-phenyl)-amide (671, 0.483 g, 0.00195 mol) in tetrahydrofuran (10.0 mL), cooled with ice/water, was added Dess-Martin periodinane (1.00 g, 0.00236 mol). The reaction was stirred at room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid (672, 360 mg, 75%). MS (ESI) [M−H+]−=244.1.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1.C>C1CCCCC1.C(O)(=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[CH3:6])=[N:11][CH:12]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: Cc1ccc(C)n1-c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Hexane-2,5-dione (97 mL, 831 mmol) was added to a solution of 2-amino-5-bromo-pyridine (125 g, 722 mmol) in cyclohexane (625 mL) and acetic acid (20 mL). The solution was heated to reflux under argon atmosphere with a Dean-Stark trap. A total of 30 mL of water was collected from the Dean-Stark trap. The mixture was allowed to cool to room temperature, diluted with water, and extracted with diethyl ether. The organic phase was washed with 1N hydrochloric acid (4×), saturated aqueous sodium bicarbonate solution (2×) and saturated aqueous sodium chloride solution (2×). The organic phase was dried (MgSO4) and concentrated in vacuo to yield a yellow solid. The product was dissolved in hot hexanes (200 mL). Charcoal was added and the mixture filtered. Crystallization proceeded over three hours at 0° C. The solid was collected by filtration to yield yellow crystals (145 g, 80%). Mp=69° C.; 1H NMR (CDCl3, 300 MHz) δ 8.66 (d, 9 Hz, 1 H), 7.96 (dd, 9 Hz, 8 Hz, 1 H), 7.15 (d, 8 Hz, 1 H), 5.91 (s, 2 H), 2.14 (s, 6 H); MS (CI) m/z 251 (MH+); Anal. Calcd. for C11H11BrN2 : C, 52.61; H, 4.42; N, 11.16; Br, 31.82. Found: C, 52.62; H, 4.56; N, 11.18; Rf =0.4 (60:40 dichloromethane/hexanes).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.CCN(CC)CC>C(#N)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNC1
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCCl)c2n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCN3CCCC3)c2n1
Temperature: 70 °C
Yield: 72.2 %

Procedure:
A solution of 5-butyl-3-(6-chlorohex-1-yn-1-yl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (30 g, 65.8 mmol), pyrrolidine (16.32 mL, 197 mmol) and Et3N (27.5 mL, 197 mmol) in Acetonitrile (400 mL) was heated at 70° C. for 16 hours. Further pyrrolidine (7 g) was added and the solution was heated at 70° C. for 8 hours. The cooled solution was evaporated and the residue was purified on a silica cartridge (750 g) eluted with EtOAc (2 column volumes) followed by 20-30% MeOH (+1% Et3N)/EtOAc (16 column volumes) to give the title compound as a yellow gum (23.3 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:22][CH3:23])=[C:7]([CH:21]=1)[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[O:13][C:14]=1[CH3:15].[CH2:24]([N:31]1[CH:35]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:33]([OH:41])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:24]([N:31]1[CH:35]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:33]([O:41][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:8][CH2:9][C:10]3[N:11]=[C:12]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[O:13][C:14]=3[CH3:15])[CH:21]=2)=[N:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: COc1ccc(CCl)cc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OC)c(OCc2nc(-c3ccco3)oc2C)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 75.8 %

Procedure:
A mixture of 4-(5-chloromethyl-2-methoxyphenoxy)methyl-2-(2-furyl)-5-methyl-1,3-oxazole (2.24 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give ethyl 1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate (2.51 g, yield 76%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 147-148° C.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[O:8]=[C:9]1[NH:13][CH2:12][C@H:11]([C@H:14]([O:16][C:17]2[C:18]3[N:19]([N:35]=[CH:36][C:37]=3[C:38]#[N:39])[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:22]=2)[CH3:15])[CH2:10]1.CCN(CC)CC.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:1]([N:32]1[CH2:31][CH2:30][N:29]([C:26]2[CH:25]=[CH:24][C:23]([C:21]3[N:22]=[C:17]([O:16][C@@H:14]([C@@H:11]4[CH2:10][C:9](=[O:8])[NH:13][CH2:12]4)[CH3:15])[C:18]4[N:19]([N:35]=[CH:36][C:37]=4[C:38]#[N:39])[CH:20]=3)=[CH:28][CH:27]=2)[CH2:34][CH2:33]1)(=[O:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cn2ncc(C#N)c12)[C@H]1CNC(=O)C1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(-c3cn4ncc(C#N)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1
Reaction time: 1.5 h

Procedure:
The crude TFA salt of 5.67 (0.107 mmol) was dissolved in DCM (2 mL) and was treated with Et3N (0.15 mL, 1.1 mmol) followed by acetic anhydride (13 μL, 0.13 mmol). After stirring for 1.5 h, the reaction mixture was partitioned between DCM and water, and the aqueous phase was extracted with DCM. The combined organic phase was dried over Na2SO4, filtered, and concentrated, and the concentrate was purified by silica gel (0-15% MeOH in DCM) to afford 6-(4-(4-acetylpiperazin-1-yl)phenyl)-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile (5.68). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H28N7O3: 474.2; found: 474.3. 1H NMR (400 MHz, Chloroform-d) δ 8.41 (s, 1H), 8.18 (s, 1H), 7.86-7.78 (m, 2H), 7.04-6.96 (m, 2H), 6.10 (s, 1H), 5.65-5.52 (m, 1H), 3.85-3.73 (m, 2H), 3.66 (dd, J=6.4, 4.0 Hz, 2H), 3.63-3.55 (m, 1H), 3.44 (dd, J=9.9, 6.7 Hz, 1H), 3.34-3.23 (m, 4H), 3.12-2.96 (m, 1H), 2.60 (dd, J=17.1, 9.2 Hz, 1H), 2.43 (dd, J=17.1, 8.0 Hz, 1H), 2.15 (s, 3H), 1.54 (d, J=6.2 Hz, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:23])[CH2:13][CH2:12]4)[C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[CH2:39](O)[CH2:40][OH:41].C(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3([O:41][CH2:40][CH2:39][O:23]3)[CH2:13][CH2:12]4)[C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: ClCCl
Product: CC(=O)OCCCCCCCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@@]3(C)[C@@H](CCC34OCCO4)[C@H]12

Procedure:
7.85 g of 3-acetoxy-7α-(11-acetoxyundecyl)-1,3,5(10)-estratrien-17-one is stirred under reflux in 51 ml of dichloromethane and 51 ml of ethylene glycol with 24 ml of trimethyl orthoformate and 159 mg of p-toluenesulfonic acid for 0.5 hour. For working up purposes, the mixture is diluted with dichloromethane, washed with sodium bicarbonate and sodium chloride solutions, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, yielding 6.5 g of pure 3-acetoxy-7α-(11-acetoxyundecyl)-17,17-ethylenedioxy-1,3,5(10)-estratriene, [α]D =13.4°, as an oil.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[N:11]=[C:10]([C:37]([OH:39])=[O:38])[N:9]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([S:24]([NH:23][C:12]2[N:11]=[C:10]([C:37]([OH:39])=[O:38])[N:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:13]=2[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)(=[O:25])=[O:26])=[CH:32][CH:31]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C(=O)O)nc2OCCOC(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C(=O)O)nc2OCCO)c1
Yield: 40.8 %

Procedure:
0.09 g of 4-(2-acetoxy-ethoxy)-6-(4-tert.butyl-phenyl-sulphonylamino)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid in 4 ml of methanol and 1.5 ml of water was stirred with 0.05 g of sodium carbonate at 20° C. for 2 hours. The methanol was evaporated and the residue was partitioned between chloroform and aqueous 1N hydrochloric acid. The organic phase was dried and evaporated. The residue was purified over silica gel with chloroform-methanol-water, 60:35:5. There was obtained 0.034 g of 6-(4-tert.butyl-phenylsulphonylamino)-4-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid, MS: (M-H)- 515.9.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][CH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[C@H:21]1([NH:20][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: NC1CCc2ccccc21
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 20 h
Yield: 59.7 %

Procedure:
For 20 hours, 1.83 g 6-chloropurine riboside, 0.95 g (R) (-)-1-aminoindane and 0.862 g triethylamine are refluxed in 50 ml absolute ethanol under nitrogen atmosphere. The solvent is evaporated to dryness and residue is treated with 50 ml cold water. The solid material is filtered, dissolved in excess ethanol, and volatiles are evaporated under reduced pressure to remove water. Residue upon treatment with ethanol affords solid material. It is filtered and dried. One more crop of the same material is obtained from the mother liquor yielding 1.46 g (60% of theory) of N(6) [1-(R)-indanyl]adenosine having a melting point of 185°-187° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:31])[C:9]1[C:10](OS(C(F)(F)F)(=O)=O)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[N:45]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[N:44]=[CH:43]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH2:1]([N:8]([CH3:31])[C:9]1[C:10]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[N:45]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[N:44]=[CH:43]3)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)Cc3ccccc3)nc2c1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c(N(C)Cc3ccccc3)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of methyl 3-(benzyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (300 mg, crude) in ethylene glycol dimethyl ether (7 mL) was added tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate (181 mg, 0.53 mmol), sodium carbonate (93 mg, 0.88 mmol), and Pd(PPh3)4 (25 mg, 0.02 mmol). The resulting solution was stirred for 1 h at 90° C. under an inert atmosphere of nitrogen, quenched with water (100 mL) and extracted with dichloromethane (3×50 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (3% ethyl acetate in petroleum ether) to afford methyl 3-(benzyl(methyl)amino)-2-(1-(tert-butoxycarbonyl)-1H-indazol-5-yl)quinoxaline-6-carboxylate as a yellow solid (120 mg).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:8]2[C@@H:5]([C:6](=[O:20])[N:7]2CC2C=CC(OC)=C(OC)C=2)[N:4]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:3]1.[Na].O=C1[C@@H]2[C@@H](CCN2C(OCC2C=CC=CC=2)=O)N1S(O)(=O)=O>>[OH:1][C@@H:2]1[C@@H:8]2[C@@H:5]([C:6](=[O:20])[NH:7]2)[N:4]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:3]1
Reactant: COc1ccc(CN2C(=O)[C@@H]3[C@H]2[C@@H](O)CN3C(=O)OCc2ccccc2)cc1OC
Agent: O=C(OCc1ccccc1)N1CC[C@@H]2[C@H]1C(=O)N2S(=O)(=O)O
Agent: [Na]
Product: O=C1N[C@H]2[C@@H]1N(C(=O)OCc1ccccc1)C[C@@H]2O

Procedure:
Benzyl (1S,4S,5S)-4-hydroxy-7-oxo-2,6-diazabicyclo-[3.2.0]heptane-2-carboxylate was prepared from benzyl (1S,4S,5S)-4-hydroxy -6-(3,4-dimethoxybenzyl)-7-oxo-2,6-diazabicyclo-[3.2.0]heptane-2-carboxylate (Example 1) in the same manner as described for benzyl (1S,5R)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (Example 1).
Reaction SMILES: CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:35][S:36]([C:39]1[CH:44]=[CH:43][C:42]([CH:45]([CH2:57][CH:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[C:46]([NH:48][C:49]2[S:50][C:51]([C:54](O)=[O:55])=[CH:52][N:53]=2)=[O:47])=[CH:41][CH:40]=1)(=[O:38])=[O:37].Cl.[CH3:65][NH:66][O:67][CH3:68]>CN(C=O)C>[CH3:68][O:67][N:66]([CH3:65])[C:54]([C:51]1[S:50][C:49]([NH:48][C:46](=[O:47])[CH:45]([C:42]2[CH:41]=[CH:40][C:39]([S:36]([CH3:35])(=[O:38])=[O:37])=[CH:44][CH:43]=2)[CH2:57][CH:58]2[CH2:59][CH2:60][O:61][CH2:62][CH2:63]2)=[N:53][CH:52]=1)=[O:55]
Reactant: CNOC
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2ncc(C(=O)O)s2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
NEt3 (647 μL, 4.64 mmol) and BOP (976 mg, 2.21 mmol) were added to a stirred solution of 2-[2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionylamino]thiazole-5-carboxylic acid (EXAMPLE 127, 968 mg, 2.21 mmol) in anhydrous DMF (30 mL). After 5 min, N,O-dimethylhydroxylamine hydrochloride (237 mg, 2.43 mmol) was added, then the mixture was stirred at 20° C. for 18 h. The solvents were removed in vacuo, then the residue was dissolved in EtOAc (75 mL). The EtOAc solution was washed with saturated aqueous Na2CO3 (40 mL), 2M HCl (40 mL), and brine (40 mL), before being dried (MgSO4). Filtration and solvent evaporation provided the title compound: RTB=1.27 min; m/z (ES+)=482.0 [M+H]+.