Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:30]=[CH:29][O:28][N:27]=3)=[O:24])=[CH:18][CH:17]=2)[N:4]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:15][C@H:10]1[CH2:11][O:12][CH2:13][CH2:14][N:9]1[C:7]1[CH:8]=[C:3]([CH2:2][O:1][S:39]([CH3:38])(=[O:41])=[O:40])[N:4]=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:30]=[CH:29][O:28][N:27]=3)=[O:24])=[CH:20][CH:21]=2)[N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)Nc3ccon3)cc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccon3)cc2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(1,2-oxazol-3-yl)urea (300 mg) was partially dissolved in DCM (10 mL) and triethylamine (0.153 mL) and the solution was cooled to 0° C. Methane sulfonyl chloride was added (0.086 mL) and the reaction was stirred for 45 mins at RT. The reaction was then washed with water (2 mL) and dried over magnesium sulphate. The solution was vacuumed to dryness to give the desired material as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH2:14][C:15](=[O:29])[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18].Cl>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][CH2:14][C:15](=[O:29])[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:18])[CH2:4][CH2:3]1
Reactant: CN1CCN(CCO)CC1
Reactant: O=C(CCl)CC(=O)OCCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(CCOCC(=O)CC(=O)OCCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.1 %

Procedure:
2-(4-Methyl-1-piperazinyl)ethanol (8.14 g, 56.5 mmol) in THF (50 mL) was added dropwise to a suspension of sodium hydride (3.5 g, 87.5 mmol) in THF (200 mL) at 0° C. The mixture was then stirred for 3 h at room temperature, cooled to 0° C., 3-phenylpropyl 4-chloroacetoacetate (11.10 mL, 51.5 mmol) in THF (50 mL) was added dropwise, and the reaction mixture was then stirred for 18 h whilst warming to room temperature. 1N Hydrochloric acid was added until the mixture was acidic and the aqueous layer was then separated. The organic layer was extracted twice more with 1N hydrochloric acid. The combined acid layers were washed two times with ethyl acetate and then made basic to pH 8 with sodium hydrogen carbonate and extracted with chloroform three times. The combined extracts were washed with brine, dried and evaporated to give the title compound (8.8 g) as an oil. Electrospray MS m/z 363 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][C:4]1=[O:10])[CH3:2].[H-].[Na+].[I-].CS[C:16]1[S:20][CH:19]=[CH:18][S+:17]=1>CN(C)C=O>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[C:5](=[C:16]2[S:20][CH:19]=[CH:18][S:17]2)[C:4]1=[O:10])[CH3:2]
Reactant: CSc1scc[s+]1
Reactant: CCN1CCC(=O)CC1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC(=O)C(=C2SC=CS2)C1=O
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
1-Ethyl-2,4-dioxopiperidine (1.06 g) is dissolved in N,N-dimethylformamide (50 ml), and the solution is added dropwise to a suspension of sodium hydride (60% dispersion in oil, 332 mg) in N,N-dimethylformamide (50 ml) under ice-cooling. The mixture is stirred for 20 minutes, and thereto is added 2-methylthio-1,3-dithiolium iodide (1.89 g). After stirring at room temperature overnight, the reaction mixture is poured onto water and extracted with ethyl acetate. The extract is washed with water, dried and distilled to remove the solvent. The residue is purified by silica gel column chromatography (developer: ethyl acetate) and then recrystallized from ethyl acetate-isopropyl ether to give 1-ethyl-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (1.10 g) as pale yellow needles. m.p. 114.5°-117° C.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:21]1([CH2:3][C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(CCBr)c1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccccc2)c(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 50 ml of DMF was dissolved 13.6 g of ethyl 2-(bromoethyl)biphenyl-4-carboxylate, and then a suspension of 50 ml of DMF, 6.2 ml of piperidine, and 9.2 g of potassium carbonate were added thereto under ice cooling, followed by 3 hours of stirring at room temperature. Water was added to the reaction solution, the whole was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous magnesium sulfate, followed by removal of the solvent by evaporation. The obtained residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia) to obtain 12.6 g of ethyl 2-(piperidin-1 -ylmethyl)biphenyl-4-carboxylate as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:20](=[O:32])[C@@H:19]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][Li]>C(OCC)C>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C@:20]([CH3:42])([OH:32])[C@@H:19]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CO[C@H]2C(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](OCC[Si](C)(C)C)[C@@H]2OCc2ccccc2)cc1
Reactant: [Li]C
Solvent: CCOCC
Product: COc1ccc(CO[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCC[Si](C)(C)C)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@]2(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
A stirred solution of 5.07 (9.2 g, 15 mmol) in ethyl ether (250 mL) was chilled to −78° C. then methyl lithium (48 mL of 1.6 M solution in diethyl ether, 76 mmol) was added dropwise over 20 minutes. The reaction was kept at −78° C. for an additional 4 h then warmed to room temperature and carefully quenched with saturated NH4Cl and transferred to a separatory funnel containing diethyl ether. The organic phase collected then washed with H2O and brine, dried over over Na2SO4, decanted, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (8-12% EtOAc/petroleum ether) to give the desired glucopyranoside product 5.08 (7.2 g, 11.6 mmol, 76%) and its galactopyranoside diastereomer (2.1 g, 3.4 mmol, 22%). Desired glucopyranoside product 5.08: 1H NMR (500 MHz, CDCl3): δ ppm 7.38-7.27 (m, 7H, ArH), 6.86 (d, J=8.8 Hz, 2H, PMPH), 4.89, 4,71 (ABq, J=10.7 Hz, 1H each, OCH2Ar), 4.84, 4.79 (ABq, J=11.0 Hz, 1H each, OCH2Ar), 4.44 (d, J=7.8 Hz, 1H, H-1), 4.04-3.97 (m, 1H, OCHHCH2SiMe3), 3.92-3.81 (m, 2H, H-6), 3.80 (s, 3H, OMe), 3.57-3.65 (m, 1H, OCHHCH2SiMe3), 3.49 (d, J=9.8 Hz, 1H, H-3), 3.42 (t, J=6.8 Hz, 1H, H-5), 3.27 (dd, J=9.8, 7.8 Hz, 1H, H-2), 1.30 (s, 3H, Me2), 1.05 (t, J=8.3 Hz, 2H, OCH2CH2SiMe3), 0.93 (s, 9H, SiCMe3), 0.13, 0.12 (s, 3H each, SiMe), 0.04 (s, 9H, SiMe3); 13C NMR (125 MHz, CDCl3): δ ppm 159.21, 138.96, 131.46, 129.60, 128.41, 128.14, 127.66, 113.85, 103.85, 86.30, 81.41, 75.78, 75.32, 75.16, 75.10, 67.85, 62.73, 55.36, 25.99, 18.71, 18.31, 16.37, −1.29, −5.32, −5.48; HRMS calcd for C33H58NO7Si2 [M+NH4]+: 636.3752. found 636.3726.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.Br[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:22]([CH3:35])[CH:21]=1>C1(C)C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[C:22]([CH3:35])[CH:21]=1)[CH2:13][CH2:12]2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Reactant: Fc1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(F)ccc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0 mmol) were added to dry toluene (150 mL purged with argon for 30 minutes) and stirred for 30 minutes under argon. Potassium tert-butoxide (4.75 mg, 42.3 mmol), 6-fluoro-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (3.2 g, 17.0 mmol), and N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g, 16.8 mmol) were then added, and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature and recrystallized from toluene to afford the title compound as a solid. (5.11 g, 83%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[NH2:31][CH2:32][CH2:33][CH2:34][OH:35]>>[Cl:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:31][CH2:32][CH2:33][CH2:34][OH:35])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: NCCCO
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCNCCCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 3-aminopropan-1-ol following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 2H), 7.85 (d, 1H), 7.00 (d, 1H), 4.68 (s, 1H), 3.95 (t, 2H), 3.88 (s, 3H), 3.43 (t, 2H), 2.59 (t, 2H), 2.52 (m, 2H), 1.74 (m, 2H), 1.54 (m, 2H), 1.48-1.28 (m, 6H) [NH's & OH not seen]; MS (ESI): 509.3.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH2:27][CH3:28])[CH:24]([CH3:26])[CH3:25])[CH2:19][C@H:18]2[CH2:29][O:30][CH3:31])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:32])[CH:8]=2)[N:3]=1.[CH3:33][NH:34][CH3:35]>O1CCCC1>[Cl:32][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:34]([CH3:35])[CH3:33])[N:11]=[C:10]2[NH:12][CH2:13][C:14]([NH:16][C@H:17]1[CH2:22][CH2:21][C@@H:20]([N:23]([CH2:27][CH3:28])[CH:24]([CH3:25])[CH3:26])[CH2:19][C@H:18]1[CH2:29][O:30][CH3:31])=[O:15]
Reactant: CCN(C(C)C)[C@@H]1CC[C@H](NC(=O)CNc2nc(Cl)nc3ccc(Cl)cc23)[C@H](COC)C1
Reactant: CNC
Solvent: C1CCOC1
Product: CCN(C(C)C)[C@@H]1CC[C@H](NC(=O)CNc2nc(N(C)C)nc3ccc(Cl)cc23)[C@H](COC)C1

Procedure:
A solution of 2-(2,6-dichloroquinazolin-4-ylamino)-N-((1S,2R,4R)-4-(ethyl(isopropyl)amino)-2-(methoxymethyl)cyclohexyl)acetamide (61 mg) in tetrahydrofuran (2 mL) was treaded with dimethylamine (2 M in tetrahydrofuran, 80 μL) and the mixture was heated at reflux overnight. Additional dimethylamine solution (0.825 mL) was added and heating was continued for 3 more days. Concentration under vacuum and purification by reverse phase HPLC and lyophilization provided the bis-trifluoroacetic acid salt of the title product, 2-(6-chloro-2-(dimethylamino)quinazolin-4-ylamino)-N-((1S,2R,4R)-4-(ethyl(isopropyl)amino)-2-(methoxymethyl)cyclohexyl)acetamide, as a white powder (54 mg). MS found: (M+H)+=491.7.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=[C:5]2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.C(O)(=O)C.[CH3:33][N:34]([CH3:39])[C:35](=[O:38])[CH2:36][NH2:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:33][N:34]([CH3:39])[C:35]([CH2:36][NH:37][C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=1)=[O:13])=[O:38]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Reactant: CN(C)C(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CN(C)C(=O)CNC(=O)c1cnc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 43.2 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid dimethylcarbamoylmethyl-amide (25 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (48 mg), glycine dimethylamide acetate (21 mg), HBTU (53 mg), and DIEA (31 uL). LC/MS: m/z 493.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (t, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 4.13 (d, 2H), 3.65 (bs, 3H), 3.03 (s, 3H), 2.87 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cc2ncc[nH]2)cc1
Yield: 68.7 %

Procedure:
A mixture of 13.6 g of imidazole, 43.2 g of p-bromomethylnitrobenzene and 55.2 g of anhydrous potassium carbonate in 300 ml of dry toluene was refluxed for 18 hours. After concentration under reduced pressure, 200 ml of dichloromethane was added to the residue and insoluble salts were filtered off. The filtrate was evaporated and the residue was chromatographed on silica gel using dichloromethane-ethanol (20:1 by volume) to give 27.9 g of p-(1-imidazolylmethyl)nitrobenzene as pale yellow platelets. Then, a solution of 2.0 g of this product in 50 ml of ethanol was hydrogenated over 0.2 g of palladium on carbon at room temperature under a hydrogen pressure of 4 atms. After filtration and evaporation, the residual solid was recrystallized from ethanol-diethyl ether-petroleum ether to give 1.4 g of p-(1-imidazolylmethyl)aniline as colorless needles. M.P.: 134°-137° C.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Li]CCCC.[O:15]1[C:19]2([CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[S:4]1[C:5]([C:22]2([OH:25])[CH2:23][CH2:24][C:19]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:20][CH2:21]2)=[CH:6][N:7]=[CH:3]1
Reactant: C[Si](C)(C)c1nccs1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cncs2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-trimethylsilanyl-thiazole (Fluka, 5.0 g, 31.8 mmol) in THF (20 mL) at −78° C. was treated with n-BuLi (2.5 M in hexanes, 15.3 mL, 38.2 mmol) dropped slowly over 10 min. The reaction was stirred for an additional 20 min. at −78° C. A solution of 1,4-dioxa-spiro[4.5]decan-8-one (Aldrich, 6.0 g, 38 mmol) in THF (15 mL) was slowly dropped into the reaction. After addition, the reaction was stirred for an additional 2 hours at −78° C. The reaction was then quenched with water and warmed to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid. To this solid in THF (20 mL) was added TBAF (1.0 N in THF, 30 mL) at room temperature. The reaction was stirred for 1 hour. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:43][O:44][CH2:45][C:46]1[NH:47][CH:48]=[C:49]([OH:53])[C:50](=[O:52])[N:51]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][CH2:45][C:46]2[NH:47][CH:48]=[C:49]([OH:53])[C:50](=[O:52])[N:51]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(-c5ccc(O)c(O)c5)nc5ccnn45)CS[C@H]23)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(/C(=N/OCc2nc(=O)c(O)c[nH]2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(-c5ccc(O)c(O)c5)nc5ccnn45)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 14 h
Yield: 104.6 %

Procedure:
(6R, 7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (125 mg) (0.2 mmol), 41 mg (0.26 mmol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 50 mg (0.26 mmol) of p-toluenesulphonic acid hydrate are dissolved in 3 ml of absolute dimethylacetamide. After stirring at room temperature for 14 hours the mixture is concentrated in a high vacuum at room temperature and the residue is treated with water. The product is filtered off and washed in succession with water, ethanol and diethyl ether. There are obtained 160 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrimidinyl)methoxy]imino]acetamido]-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid as a yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[S:22][C:21]([C:23]([OH:25])=O)=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:19]=3[CH:32]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[N:36]1([CH2:35][CH2:34][NH:33][C:23]([C:21]2[S:22][C:18]3[CH:17]=[CH:16][C:15]([NH:14][S:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=4)(=[O:12])=[O:13])=[CH:32][C:19]=3[C:20]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)O)c(-c4ccccc4)c3c2)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)NCCN4CCOCC4)c(-c4ccccc4)c3c2)cc1
Yield: 14 %

Procedure:
According to Step 1, after reaction of 5-(4-tert-Butylbenzenesulfonylamino)-3-phenyl-1-benzothiophene-2-carboxylic acid (155 mg, 0.33 mmol) with N—(2-aminoethyl)-morpholine (0.046 mL, 0.35 mmol) followed by chromatographic purification (silica gel, dichloromethane/methanol (0-10% methanol)) and recrystallization from ethyl acetate/hexane, the desired compound is obtained at 14% yield (27 mg).
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].[ClH:19].OC(C1C=CN=CC=1)(C)CC1C=CC=CC=1.Cl>[Pd].O.C(O)(=O)C>[ClH:19].[OH:1][C:2]([CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(O)(Cc1ccccc1)c1ccncc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(O)(Cc1ccccc1)C1CCNCC1

Procedure:
The mixture of 4.0 g of 4-(α-hydroxy-α-methylphenethyl)-pyridine, 100 ml of glacial acetic acid, 20 ml of water and 2.0 g of 10% palladium on charcoal is treated with hydrogen at 4.1 atm and room temperature. Following the theoretical uptake of hydrogen the reaction mixture is filtered to remove the catalyst. The filtrate is evaporated to dryness under reduced pressureand the residue treated with 50% aqueous sodium hydroxide. The resulting mixture is extracted with methylene chloride; the extract is dried and evaporated under reduced pressure to give an oil which is converted into the hydrochloride with ethanolic hydrogen chloride to give 4-(α-hydroxy-α-methylphenethyl)-piperidine hydrochloride of melting point 162°-164°.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:22])=[CH:3]\[C:4]([O:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:12][CH:11]=1)=[O:5].[N+:23]([C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][CH:40]=1)[CH:29]=[C:30]([C:35]([CH3:37])=O)[C:31]([O:33][CH3:34])=[O:32])([O-:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:22][C:2]1[NH:1][C:35]([CH3:37])=[C:30]([C:31]([O:33][CH3:34])=[O:32])[CH:29]([C:28]2[CH:38]=[CH:39][CH:40]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)[C:3]=1[C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)=[O:5]
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: C/C(N)=C/C(=O)OCC=Cc1ccc(Cc2ncc[nH]2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
2.97 g (10 mM) of 3-[4-(1-imidazolylmethyl)phenyl]-2-propen-1-yl 3-aminocrotonate and 2.49 g (10 mM) of methyl 2-(3-nitrobenzylidene)acetoacetate were dissolved in 50 ml of toluene and then the solution was refluxed for eight hours. After cooling, the crystals were filtered off and then recrystallized from methanol whereby the captioned compound was obtained. The yield was 4.01 g (76%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]2[C:13]3[C:18]([O:19][CH2:20][C:3]=12)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=3.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[OH:21][C:16]1[CH:17]=[C:18]2[O:19][CH2:20][C:3]3[C:4](=[N:5][C:6]4[C:11]([C:2]=3[C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=3)=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=4)[C:13]2=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1Br
Product: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1-c1ccc(C(F)(F)F)cc1
Yield: 95 %

Procedure:
This compound was prepared from 7-bromo-3,9-dihydroxy-6H-chromeno[4,3-b]quinoline (7) using 4-trifluoromethylphenylboronic acid according to method M. Yellow powder; Yield: 95%; mp 175-177° C. (dec.); 1H-NMR (400 MHz, DMSOd-6) δ 5.00 (s, 2H), 6.36 (d, J=2.3 Hz, 1H), 6.56 (d, J=2.6 Hz, 1H), 6.61 (dd, J=8.6, 2.2 Hz, 1H), 7.26 (dd, J=9.1, 2.6 Hz, 1H), 7.64 (d, J=7.9 Hz, 2H), 7.92 (d, J=9.0 Hz, 1H), 7.98 (d, J=8.1 Hz, 2H), 8.16 (d, J=8.6 Hz, 1H), 9.84 (s, 1H), 10.00 (s, 1H); 19F-NMR (400 MHz, DMSOd-6) δ −61.43 (s); MS (ESI) m/z 408 ([M−H]−), 410 ([M+H]+); HRMS (ESI+) calcd for C23H14F3NO3 410.0999 ([M+H]+). Found: 410.0992.