Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18](Cl)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:1][CH:2]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:20])[CH3:19]
Reactant: CCOC(=O)C(O)c1cccc2cnccc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(OC(C)=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
The product of Example 70B (1.0202 g, 4.41 mmol) in pyridine (15 mL) was treated with acetyl chloride (0.35 mL, 4.92 mmol) dropwise. The solution was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was purified by column chromatography (2% methanol/CH2Cl2) to provide the title compound as yellow oil (0.8100 g, 67%). MS (ESI+) m/z 274 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 1.07 (t, J 7.1, 3H), 2.17 (s, 3H), 4.13 (m, 2H), 6.62 (s, 1H), 7.74 (m, 1H), 7.94 (d, J 7.1, 1H), 8.03 (d, J 6.1, 1H), 8.22 (d, J 7.6, 1H), 8.60 (d, J 5.7, 1H), 9.39 (s, 1H).
Reaction SMILES: [Cl-].[Li+].[CH2:3]([C:10]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23][C:24]([N:26]2[C@@H:30]([CH:31]([CH3:33])[CH3:32])[C:29]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:28][C:27]2=[S:46])=[O:25])[O:14][CH2:13][CH2:12][O:11]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:57][O:58][CH2:59][CH2:60][C:61](=[O:69])[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63].C(O)(=O)C>C1COCC1>[CH2:3]([C:10]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@H:23]([C:24]([N:26]2[C@@H:30]([CH:31]([CH3:33])[CH3:32])[C:29]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[O:28][C:27]2=[S:46])=[O:25])[C@@:61]([OH:69])([CH2:60][CH2:59][O:58][CH3:57])[C:62]([O:64][C:65]([CH3:66])([CH3:67])[CH3:68])=[O:63])[O:11][CH2:12][CH2:13][O:14]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COCCC(=O)C(=O)OC(C)(C)C
Reactant: CCCCCCCC1(CCCCCC/C=C/CC(=O)N2C(=S)OC(c3ccccc3)(c3ccccc3)[C@@H]2C(C)C)OCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N2C(=S)OC(c3ccccc3)(c3ccccc3)[C@@H]2C(C)C)[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Temperature: -78 °C
Yield: 79.5 %

Procedure:
Lithium chloride (5.12 g, 121 mmol) was heat dried with a heat gun under reduced pressure. Under a nitrogen atmosphere, a mixture of No. 5499685 (E)-10-(2-heptyl-[1,3]dioxolan-2-yl)-1-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidin-3-yl)-dec-3-en-1-one (25.0 g, 40.3 mmol) and THF (80 mL) was added at room temperature. Further THF (145 mL) was then added to the reaction vessel. The mixture was stirred until it became homogeneous and then cooled to −78° C. Lithium hexamethyldisilazide (1 M solution in THF, 7.74 mL, 7.74 mmol) was added, and the mixture was stirred for 2 h. To the reaction mixture was added dropwise a mixture of tert-butyl 4-methoxy-2-oxo-butyrate (10.6 g, 56.5 mmol) and THF (25 mL) and the mixture was stirred for further 1 hour. To the reaction mixture was added acetic acid (4.61 mL, 80.6 mmol) and the cooling bus was removed. Water was added and the mixture was extracted with ethyl acetate. The organic layer was then washed with water, an aqueous solution of 1% NaHCO3, water, and a saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified with SP1 (SiO2 cartridge, 20% ethyl acetate/n-hexane, Rf=0.3) to obtain No. 6801291, tert-butyl (E)-(2S,3S)-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-3-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidine-3-carbonyl)-2-(2-methoxy-ethyl)-undec-4-enoate (25.9 g, 80% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=1[NH2:6].Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[NH:31][C:30]4[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=4[CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[N:14]=1>CN(C=O)C>[F:3][C:4]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=1[NH:6][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[NH:31][C:30]4[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=4[CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5ccc(F)cc5F)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
To NaH (60 wt % in mineral oil; 0.071 g, 1.763 mmol) in 1 mL DMF was added 2,4-difluoroaniline (0.178 ml, 1.763 mmol). After 10 min, 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added as a solid and the reaction became dark red. The reaction was heated at 70° C. for 4 h, and then cooled to RT and partitioned between saturated aq. NH4Cl and EtOAc. The organic layer was separated and sequentially washed with saturated aq. NH4Cl and saturated aq. NaCl, and the organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-50% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 2-(2-((2,4-difluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.021 g, 0.054 mmol, 21% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (1H, br. s), 9.27 (1H, s), 8.13 (1H, d, J=9.0 Hz), 7.83-8.00 (2H, m), 7.59 (1H, dt, J=7.6, 0.9 Hz), 7.46 (1H, ddd, J=11.2, 8.8, 2.9 Hz), 7.28 (1H, t, J=7.6 Hz), 7.17-7.24 (1H, m), 7.14 (1H, d, J=9.0 Hz), 6.89-6.96 (2H, m), 3.35-3.41 (2H, m), 2.57 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 391.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:25]([O-:27])=[O:26])=[C:6]([CH:24]=1)[O:7][C@@H:8]1[CH2:12][O:11][C@@H:10]2[C@H:13](OS(C(F)(F)F)(=O)=O)[CH2:14][O:15][C@H:9]12.[F-:28].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C(Cl)Cl>[F:28][C@@H:13]1[C@H:10]2[O:11][CH2:12][C@@H:8]([O:7][C:6]3[CH:24]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N+:25]([O-:27])=[O:26])[C@H:9]2[O:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OS(=O)(=O)C(F)(F)F
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2F

Procedure:
3.7 g (8.9 mmol) [(3R,3aR,6R,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]trifluoromethanesulfonate (prepared as described for III.3 from III.1) in 53.2 ml of a 1M solution of tetrabutylammonium flouride in THF (53.2 mmol) is stirred at RT for 3 h. Water and DCM are added and the organic layer is separated, washed with water, dried and evaporated. The residue was purified by FC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25](Br)([CH3:27])[CH3:26])=[O:24])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:25]([C:23]([C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=2)=[O:24])([CH3:27])[CH3:26])=[CH:4][CH:3]=1
Reactant: CC(C)(Br)C(=O)c1ccc(Cl)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
A solution of 59.2 g (0.47 mol) of dimethyl sulphate and 32 g (0.517 mol) of dimethyl sulphide in 270 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 87 g of 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone in 80 ml of acetonitrile is then added dropwise at 20° to 25° C., in the course of approx. 2 hours. 28.7 g (0.53 mol) of sodium methylate are introduced at the same temperature, and the mixture is stirred for a further 12 hours and then concentrated. The residue is stirred overnight with a mixture of 200 ml of ethyl acetate and 150 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 49 g (76% of theory) of crude 2-(4 chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane are obtained, and this compound is directly reacted further. ##STR158## 52 g (0.3982 mol) of p-chlorophenol and 55 g (0.3982 mol) of potassium carbonate in 400 ml of toluene are heated under reflux for 2 hours in a water separator. The mixture is cooled to 40° C., and a solution of 2-bromo-prop-2-yl 4-chlorophenyl ketone in 170 ml of toluene is added dropwise. This reaction mixture is stirred for a further 5 hours at 100° C. and then cooled, water is added and the organic phase is separated off. This is washed with dilute sodium hydroxide solution and water, dried over sodium sulphate and concentrated. 87 g (85% of theory) of crude 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone are obtained, and this compound is directly reacted further. ##STR159## 1 ml of hydrogen bromide/glacial acetic acid is added to 65.5 g (0.36 mol) of 4-chlorophenyl isopropyl ketone in 200 ml of chloroform, and 57.5 g (0.36 mol) of bromine are then added dropwise at 30° C. The mixture is stirred for a further 30 minutes at room temperature, and thereafter concentrated in vacuo. 86.6 g (92% of theory) of crude 2-bromo-prop-2-yl 4-chlorophenyl ketone are obtained, and this compound is directly reacted further.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2C(O)=O)=[CH:10][CH:9]=[CH:8][N:7]=1.C1(P([N:42]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH2:42])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Nc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
2-(3-Chlorophenoxy)-3-[3-(3-carboxypyridin-4-yl)propoxy]-pyridine (0.50 g, 1.3 mmol) obtained in Example 24 is dissolved in tert-butanol (20 ml), and thereto are added diphenylphosphoryl azide (0.42 ml, 2.0 mmol) and triethylamine (0.27 ml, 2.0 mmol), and the mixture is heated under reflux for 8 hours. The reaction is quenched with a saturated brine (50 ml), and the reaction solution is extracted with ethyl acetate (50 ml×2). The organic layer is washed with a saturated brine (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in methylene chloride (10 ml), and thereto is added trifluoroacetic acid (5 ml), and the mixture is stirred at 25° C. for 30 minutes. The reaction solution is concentrated under reduced pressure, and to the residue is added a saturated aqueous sodium hydrogen carbonate solution (50 ml), and the mixture is extracted with ethyl acetate (50 ml×2). The organic layer is washed with a saturated brine (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform/methanol), and further recrystallized from diethyl ether to give the title compound (0.23 g) as colorless crystals, m.p. 140-142° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([O:15]C(=O)C)[N:8](C(=O)C)[C:9]=1[CH2:10]Br)=[O:4].[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:15])[NH:8][C:9]=1[CH2:10][S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:4]
Reactant: COC(=O)c1nc(OC(C)=O)n(C(C)=O)c1CBr
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1[nH]c(=O)[nH]c1CSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.5 %

Procedure:
To a solution of 4c (640 mg, 2 mmol) in 20 mL of MeOH was added 4-mercaptophenol (380 mg, 3.0 mmol) and K2CO3 (550 mg, 4.0 mmol). The solution was stirred at rt for 6 h. 20 mL of water was then added and 2 mL of 1N HCl was carefully added. This aqueous solution was extracted with Et2O. The aqueous solution was then concentrated and the residue was first dissolved in 5 mL of MeOH and the diluted with 50 mL of CH2Cl2. Filtration and concentration provided 5-(4-hydroxy-phenylsulfanyl methyl)-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid methyl ester 4d (440 mg, 80%). MS (ESI+) (M+AcN+1)=322.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH:5]([NH2:14])/[CH:6]=[C:7](\[CH3:13])/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])C>O>[NH2:14][CH:5](/[CH:6]=[C:7](\[CH3:13])/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)C(N)/C=C(\C)CP(=O)(O)O
Solvent: O
Product: C/C(=C\C(N)C(=O)O)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester are stirred under reflux in 70 ml of water for 19 hours. The reaction mixture is slowly cooled to room temperature, stirred in an ice bath for one hour, filtered and washed with cold water. In this manner there is obtained E-2-amino-4-methyl-5-phosphono-3-pentenoic acid in the form of the monohydrate, m.p. 163° (decomp.).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]1[S:16][CH2:15][CH:14]([OH:17])[CH:13]=[C:12]1[N+:18]([O-:20])=[O:19].Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C@H:11]1[S:16][CH2:15][CH:14]([OH:17])[CH2:13][C@@H:12]1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])C1=CC(O)CSC1c1cc(F)ccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=[N+]([O-])[C@H]1CC(O)CS[C@@H]1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium borohydride (190 mg, 5.03 mmol) 37.8 was added over 10 min to an ice cold solution of 6-(2,5-difluorophenyl)-5-nitro-3,6-dihydro-2H-thiopyran-3-ol 4 (570 mg, 2.08 mmol) in MeOH (25 mL). The mixture was slowly warmed to room temperature and stirred for an additional 18 h. The orange solution was cooled in an ice bath and 2N HCl (2.6 mL, 5.2 mmol) was added dropwise. After 5 min, the solution was added to a mixture of EtOAc (100 mL) and saturated aqueous NaHCO3 (50 mL), the aqueous layer was re-extracted with additional EtOAc (2×50 mL), the combined EtOAc layers were washed with brine (1×50 mL), dried with MgSO4, filtered and evaporated to give the title compound as a foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]1.[F-].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.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>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[N:21]=[CH:20]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1cnc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of Example A1 (1.5 g, 5.96 mmol), N-methyl-4-(tributylstannyl)imidazole (3.32 g, 8.94 mmol) and Pd(PPh3)4 (0.344 g, 0.298 mmol) in toluene (30 mL) sparged with Ar and heated at 110° C. overnight. The mixture was cooled to RT, treated with 10% KF and EtOAc, stirred at RT for 2 h, the solids removed via filtration through diatomaceous earth and washed with 5% MeOH/DCM. The layers of the filtrate were separated and the organic layer was washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was washed with a small amount of Et2O and dried to afford 2-(1-methyl-1H-imidazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.61 g, 91%). 1H NMR (400 MHz, Acetone-d6): δ 8.54 (d, J=2.8 Hz, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.44-8.43 (m, 1H), 7.98 (dd, J=8.9, 2.8 Hz, 1H), 7.69 (d, J=1.4 Hz, 1H), 7.62 (d, J=2.6 Hz, 1H), 7.55 (s, 1H), 6.97 (dd, J=5.6, 2.6 Hz, 1H), 3.81 (s, 3H); MS (ESI) m/z: 298.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.Cl[CH2:11][SiH:12]([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15].BrC1C=CC(Br)=CC=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Si:12]([CH3:11])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)O[SiH](CCl)OC(C)C
Reactant: Br[Mg]c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: Brc1ccc(Br)cc1
Product: CC(C)O[Si](C)(OC(C)C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
A solution of 4-bromophenyl magnesium bromide (7.82 g, 50 mmol) in THF (100 ml) was added at 0° C. to a solution of chloromethyldiisopropyloxysilane (10 g, 48 mmol). The mixture was stirred at room temperature for 24 hours. After evaporation of the solvent, the yellow solid was extracted by 200 ml of dry pentane and filtered. The solvent was then pumped off to afford a yellow oil. Residual 1,4-dibromobenzene was sublimated under vacuum at 80° C. to give 4-bromo-1-(methyldiisopropyloxysilyl)benzene as a colourless oil in 33% yield (5.1 g, 16 mmol). 1H NMR (CDCl3, δ, ppm) 7.52 (4H, m); 4.22 (2H, heptuplet); 1.24 (12H, d); 0.39 (3H, s). 13C NMR (CDCl3, δ, ppm) 136.1, 134.5, 131.3, 125.1, 65.8, 26.1, −2.8. 29Si NMR (CDCl3, δ, ppm) −21.8.
Reaction SMILES: OC1C(NC([C@H]2N3C(=O)[C@@H](NC(=O)C4C=CC=CC=4)CC=CC[C@@H]3CC2)=O)CC(=O)O1.C(OC(=O)NC1CC(=O)OC1OCC)C=C.N1C(=O)CC(=O)NC1=O.[C:57]([NH:65][CH:66]1[C:73](=[O:74])[N:72]2[CH:75]([C:78]([OH:80])=[O:79])[CH2:76][CH2:77][CH:71]2[CH2:70][CH:69]=[CH:68][CH2:67]1)(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.ON1C2C=CC=CC=2N=N1>ClCCl.O>[C:57]([NH:65][C@@H:66]1[C:73](=[O:74])[N:72]2[C@H:75]([C:78]([OH:80])=[O:79])[CH2:76][CH2:77][C@H:71]2[CH2:70][CH:69]=[CH:68][CH2:67]1)(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: O=C(NC1CC=CCC2CCC(C(=O)O)N2C1=O)c1ccccc1
Agent: C=CCOC(=O)NC1CC(=O)OC1OCC
Agent: O=C1CC(=O)NC(=O)N1
Agent: O=C1CC(NC(=O)[C@@H]2CC[C@H]3CC=CC[C@H](NC(=O)c4ccccc4)C(=O)N32)C(O)O1
Solvent: O
Solvent: ClCCl
Product: O=C(N[C@H]1CC=CC[C@@H]2CC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
Preparation of (3S,6S,10aS)-6-benzoylamino-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide (11) To a solution of (2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester (183 mg, 0.8 mmol) (prepared according to Chapman, K. T. Bioorganic Med. Chem. Lett., 2(6), 1992, pp. 613–618) in dichloromethane (6 mL) is added barbituric acid (300 mg, 1.9 mmol) and tetrakistriphenyl phosphine palladium (92 mg, 0.08 mmol). The solution is stirred for 10 minutes and 6-benzoylamino-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid, 10, (105 mg, 0.32 mmol) is added followed by 1-hydroxybenzotriazole (99 mg, ) 0.74 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (141 mg, 0.74 mmol). The solution is stirred for 6 hours. Water is added and the organics are washed with NaHSO4, brine, NaHCO3, and water. The organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is purified over silica to afford the desired product. 1H NMR (CDCl3): δ 7.83 (d, J=7.3, 2H), 7.54–7.41 (m, 4H), 5.89–5.71 (m, 2H), 5.49 (dt, J=13.9, 7.0 Hz, 1H), 4.61 (m, 2H), 4.33 (m, 1H), 2.99 (m, 3H), 2.41 (m, 3H), 2.18 (m, 2H), 2.06–1.91 (m, 2H). 13C NMR (CDCl3): δ 176.2, 172.9, 171.6, 167.5, 133.4, 132.3, 131.0, 128.8, 127.6, 125.9, 61.7, 59.0, 50.7, 33.9, 33.4, 32.2, 27.0, 20.9. ESI MS 428.01 (M+H).
Reaction SMILES: Cl.[CH2:2]([C@@H:4]1[CH2:8][NH:7][CH2:6][C@H:5]1[C:9]1[NH:10][C:11](=[O:24])[C:12]2[CH:17]=[N:16][N:15]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:13]=2[N:14]=1)[CH3:3].C(N(CC)CC)C.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=[CH:34][C:33]=1[C:42](Cl)=[O:43]>ClCCl>[CH2:2]([C@@H:4]1[CH2:8][N:7]([C:42]([C:33]2[CH:34]=[N:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:32]=2)=[O:43])[CH2:6][C@H:5]1[C:9]1[NH:10][C:11](=[O:24])[C:12]2[CH:17]=[N:16][N:15]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:13]=2[N:14]=1)[CH3:3]
Reactant: CC[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H]1CN(C(=O)c2cnc3ccccc3n2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-[(3S,4S)-4-ethylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrogen chloride (73 mg) in dicloromethane (2 mL) was added triethylamine (62 mg) and 2-quinoxaloylchloride (40 mg) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 18 h. The reaction mixture was quenched with saturated sodium bicarbonate, extracted with methylene chloride, dried with magnesium sulfate, filtered and concentrated. Purification via CombiFlash flash chromatography eluting with 24% MeOH/methylene chloride provided the title compound. 400 MHz 1H NMR (CDCl3) δ 12.78-12.62 (m, 1H), 9.41 (d, J=7.5, Hz, 1H), 8.18-8.00 (m, 3H), 7.87-7.73 (m, 2H), 4.84-4.81 (m, 1H), 4.55-3.86 (m, 6H), 3.61-3.53 (m, 2H), 3.38-3.31 (m, 1H), 2.75 (m, 1H), 2.39-2.34 (m, 2H), 1.93-1.89 (m, 2H), 1.58-1.56 (m, 1H), 1.63-1.50 (m, 1H), 1.01-0.88 (m, 3H). MS: (M+H m/z 474.2).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[NH2:13][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[CH:17]=[CH:16][CH:15]=1>CO.C(O)(=O)C>[C:14]1([N:13]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:13][C:14]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[CH:17]=[CH:16][CH:15]=3)[CH3:11])[N:5]=2)[CH3:2])[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=Nc1cccc2c1CCCC2)c1cccc(C(C)=Nc2cccc3c2CCCC3)n1
Reaction time: 48 h
Yield: 29.6 %

Procedure:
Chemicals 2,6-Diacetylpyridine (1.0 g, 6.1 mmol) and 1-amino-5,6,7,8-tetrahydronaphthalene (3.6 g, 24.5 mmol) were dissolved in a round-bottom flask, to which 50 ml of anhydrous methanol were added. Three drops of glacial acetic acid were added, and the flask was sealed. After stirring the solution for two days, a yellow solid was collected and re-crystallized from methanol to give 760 mg (30%) of the desired ligand for catalyst 3. H NMR (C6D6) δ 8.48 (d, 2), 7.30 (t, 1), 7.10 (m, 2), 6.85 (d, 2), 6.56 (d, 2).
Reaction SMILES: C([O:8][CH2:9][CH:10]=[CH:11][C@H:12]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH3:13])C1C=CC=CC=1.[H][H].ClCCl>C(OCC)(=O)C.[C].[Pd]>[F:17][C:16]([F:18])([F:19])[C:15]([NH:14][C@H:12]([CH3:13])[CH2:11][CH2:10][CH2:9][OH:8])=[O:20]
Reactant: [H][H]
Reactant: C[C@H](C=CCOCc1ccccc1)NC(=O)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](CCCO)NC(=O)C(F)(F)F
Temperature: 70 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
The product (1.0 g) obtained in Step 1 was dissolved in ethyl acetate (10 mL). To the solution, 10% palladium-carbon (300 mg) was added, and the mixture was stirred at 70° C. for 3 hours in a hydrogen atmosphere. After the completion of reaction, the mixture was returned to room temperature, and dichloromethane (5 mL) was added, followed by filtration through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in methanol. 10% palladium-carbon (200 mg) was added again thereto, and the mixture was stirred at 70° C. for 16 hours in a hydrogen atmosphere. The mixture was returned to room temperature, and dichloromethane (5 mL) was added, followed by filtration through celite. The filtrate was concentrated under reduced pressure to obtain the compound of interest as a colorless oil (676 mg, 98.3%).