Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H:2]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:3].[C-:9]1([C@H:14](O)[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:17].C(OC(=O)C)(=O)C.CCCCCC.[N:31]1[CH:36]=CC=C[CH:32]=1>>[CH3:32][N:31]([CH3:36])[C@@H:2]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:3].[C-:9]1([C@H:14]([N:31]([CH3:36])[CH3:32])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:17]
Reactant: c1ccncc1
Reactant: C[C@@H](O)[c-]1cccc1
Agent: [Fe+2]
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: C[C@H]([c-]1cccc1)N(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
32.7 g (about 111 mmol) of crude (R,R)-1,1'-bis(1-hydroxyethyl)ferrocene were dissolved in 30 ml of pyridine and admixed with 30 ml of acetic anhydride. After stirring for 16 hours at 25° C., the excess anhydride was hydrolysed with 200 ml of ice water and the mixture was extracted three times with 100 ml each Time of diethyl ether. The combined organic phases were washed once more with about 150 ml of water, dried over magnesium sulphate and evaporated. The residue was admixed with 200 ml of hexane and the solvent was removed on a rotary evaporator (<40° C). This procedure was repeated two more times. The resulting dark brown oil was dissolved in 200 ml of isopropyl alcohol and admixed with 120 ml of dimethylamine (50% in water). After stirring at 25° C. (16 hours), 200 ml of water were added and the pH of the reaction mixture was adjusted to 1 using 100 ml of 32% strength HCl and the aqueous phase was washed twice with 100 ml each time of diethyl ether. The aqueous phase was basified with sodium hydroxide solution (40% strength) to a pH of 12-14 and extracted three times with 100 ml each time of diethyl ether. The combined organic phases were dried over magnesium sulphate and evaporated. In order to remove isopropyl alcohol still present, the oil obtained was admixed with about 100 ml of hexane and again evaporated on a rotary evaporator. This procedure was repeated two more times. Drying in a high vacuum gave 24.1 g (66%, based on 1,1'-diacetylferrocene) of the title compound in the form of a dark brown oil. (Without hydrochloric acid treatment, the yield rises to 86%).
Reaction SMILES: [C:1]([C:3]1[C:12](=O)[C:11]2[C:6](=[CH:7][C:8]([NH:16][C:17](=[O:19])[CH3:18])=[C:9]([O:14][CH3:15])[CH:10]=2)[NH:5][CH:4]=1)#[N:2].P(Cl)(Cl)([Cl:22])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:22][C:12]1[C:11]2[C:6](=[CH:7][C:8]([NH:16][C:17](=[O:19])[CH3:18])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(=O)c(C#N)c[nH]c2cc1NC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2c(Cl)c(C#N)cnc2cc1NC(C)=O
Temperature: 100 °C
Yield: 91.1 %

Procedure:
An amount of 10 g (0.039 mol) of N-(3-cyano-6-methoxy-4-oxo-1,4-dihydro-7-quinolinyl)acetamide was subsequently stirred in 29 mL (0.31 mol) of phosphorus oxychloride, heated at 100° C. for 0.5 hours, and cooled to 0° C. To this was slowly added a saturated solution of sodium bicarbonate and ethyl acetate. After separation of the layers, the organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated to give a brown solid (9.8 g, 73% yield), mp 230-235° C.; 1H NMR (DMSO-d6) δ 9.77 (s, 11-1), 8.98 (s, 1H), 8.94 (s, 1H), 7.50 (s, 1H), 4.11 (s, 3H), 2.25 (s, 3H); HRMS (EI) m/z 275.0466 (M+1). Analysis for C13H10ClN3O2.0.75H2O: Found: C, 53.99; H, 3.83; N, 14.53. Calcd: C, 53.62; H, 3.68; N, 14.98.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)(O)[O-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C(O)C.C1(C)C=CC=CC=1>[CH3:31][O:30][C:28]([C:27]1[CH:32]=[CH:33][C:24]([C:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:13][CH:12]=2)=[CH:25][CH:26]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 96.6 %

Procedure:
Toluene (20 mL), ethanol (6 mL), and water (2 mL) were added to commercially available 1-N—BOC-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (1.00 g, 3.23 mmol), methyl 4-bromobenzoate (695 mg, 3.23 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy biphenyl (266 mg, 0.65 mmol), palladium(II) acetate (73 mg, 0.32 mmol), and tripotassium phosphate (2.06 g, 9.70 mmol) under nitrogen atmosphere, and the mixture was stirred at 90° C. for 5 hours. The reaction mixture was cooled to room temperature and a saturated aqueous sodium bicarbonate solution and ethyl acetate were added for partition. The aqueous layer was extracted with ethyl acetate three times and then the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=19:1-13:7) to obtain the title compound (0.99 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>C1COCC1>[CH:23]([NH:26][C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1)=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)N=C=O
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59.9 %

Procedure:
To a solution of 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) in 1.6 mL THF was added isopropyl isocyanate (0.0074 mL, 0.076 mmol) and the reaction stirred at rt. After 45 min, the reaction was briefly warmed to approximately 50° C. and then allowed to cool to rt. After 2.5 hours, an additional 0.0074 mL (0.076 mmol) isopropyl isocyanate was added, the THF evaporated to 1 mL using a stream of nitrogen, the reaction briefly warmed to approximately 50° C. several times, and then stirred at rt overnight. At 21 hours, the reaction was quenched with MeOH, evaporated, then triturated with hot EtOAc to give the title compound as an off-white solid (15.6 mg, 60%). 1H NMR (DMSO-d6) δ: 10.67 (br. s, 1H), 8.25 (s, 1H), 7.97 (dd, J=8.1, 1.3 Hz, 1H), 7.40-7.46 (m, 1H), 7.34 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.5 Hz, 2H), 6.98-7.09 (m, 2H), 5.96 (d, J=7.3 Hz, 1H), 4.15-4.24 (m, 1H), 3.65-3.80 (m, 2H), 3.44-3.59 (m, 2H), 2.86-2.98 (m, 1H), 1.10 (s, 3H), 1.08 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12]C)=[O:11])=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[CH:6]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][N:5]([CH:7]([CH3:8])[CH3:9])[CH:6]=1
Reactant: COC(=O)c1nn(C(C)C)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)n1cc(Cl)c(C(=O)O)n1
Temperature: 105 °C
Yield: 100.3 %

Procedure:
To a solution of methyl 4-chloro-1-(1-methylethyl)-1H-pyrazole-3-carboxylate (105 mg) in 1,4-dioxane (3 ml) was added 2M hydrochloric acid (3 ml) and the mixture heated at 105° C. for 18 h. The solvent was removed in vacuo to give the title compound as a yellow oil (98 mg).
Reaction SMILES: [ClH:1].C([NH:12][C@H:13]([C:21]([NH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([CH3:35])=[CH:29][C:30](=[O:34])[O:31]2)=[CH:26][CH:25]=1)=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])(OCC1C=CC=CC=1)=[O:3].[H][H]>CO.C(O)(=O)C.O.[C].[Pd]>[OH2:3].[ClH:1].[NH2:12][C@H:13]([C:21]([NH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([CH3:35])=[CH:29][C:30](=[O:34])[O:31]2)=[CH:26][CH:25]=1)=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20].[NH2:12][C@H:13]([C:21]([NH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([CH3:35])=[CH:29][C:30](=[O:34])[O:31]2)=[CH:26][CH:25]=1)=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20].[ClH:1]
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1cc(=O)oc2cc(NC(=O)[C@@H](N)CCCNC(=N)N)ccc12
Yield: 99.8 %

Procedure:
7-(Nα -carbobenzoxy-L-arginyl)amino-4-methyl-coumarin hydrochloric acid salt (251 mg, 0.5 mM) was dissolved in a mixture of methyl alcohol (50 ml), acetic acid (5 ml) and water (10 ml), and 5% palladium-carbon catalyst (25 mg) was added thereto. This mixture was stirred while being treated with hydrogen gas at room temperature. The catalyst was removed by filtration, and from the filtrate the solvent was distilled off under reduced pressure. To the residue ether (50 ml) was added and the precipitated powder was separated by filtration to give 7-L-arginylamino-4-methylcoumarin hydrochloric acid salt hemihydrate (188 mg, yield: 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:10][CH:9]2[CH:4]([CH:5]([CH2:11]O)[O:6][C:7]2=[O:8])[O:3]1.N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[N-:43]=[N+:44]=[N-:45].[Na+]>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1([CH3:13])[O:10][CH:9]2[CH:4]([CH:5]([CH2:11][N:43]=[N+:44]=[N-:45])[O:6][C:7]2=[O:8])[O:3]1
Reactant: CC1(C)OC2C(=O)OC(CO)C2O1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC2C(=O)OC(CN=[N+]=[N-])C2O1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
To a cooled (-25° C.) solution of 2,3-O-isopropylidene-D-lyxono-1,4-lactone 3 (10.0 g, 53.2 mmol) and pyridine (8.38 g, 8.56 mL, 106.4 mmol) in CH2Cl2 (125 mL) was added dropwise via syringe triflic anhydride (16.5 g, 9.82 mL, 58.5 mmol) at a rate such that the reaction temperature did not exceed -18° C. After the addition was complete the reaction was gradually warmed to 0° C. over 1.5 h. TLC (silica, ethyl acetate/hexane:1/1) indicated no 3 remaining and the presence of a single new product (Rf= 0.45). The reaction mixture was poured into ice/water (250 mL), partitioned and the aqueous layer extracted with CH2Cl2 (2 x 50 mL). The organic layers were combined, washed with cold saturated aqueous CuSO4 (3×50 mL), water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated to provide a bright red-orange glassy solid (Rf, silica=0.12, tetrahydrofuran (THF)/hexane: 30/70) which still contained solvent. Crude triflate 5 was dissolved in N,N-dimethyformamide (DMF) (100 mL), cooled with an ice/water bath and sodium azide (6.92 g, 106.4 mmol) was slowly added. After the addition was complete, the cooling bath was removed and the mixture stirred at room temperature for 2.5 h. The DMF was removed by bulb-to-bulb distillation under vacuum (31° C. @0.7 mm Hg). The receiver bulb was cooled with a dry ice/acetone bath to increase the efficiency of the distillation. The resultant thick pasty residue was dissolved in CH2Cl2 (150 mL) and filtered to remove the inorganic salts. The filter cake was washed with CH2Cl2 (150 mL) and the combined filtrates were concentrated under vacuum. If desired, the resulting partially purified product can be used directly in the synthesis of compound 7. In this example, the residue was further purified by subjecting it to the above bulb-to-bulb distillation technique (for removal of the last traces of DMF) to provide 15.5 g of a crude red solid which was purified by flash chromatography [silica gel (100 g), ethyl acetate/hexane:1/1]to provide 10.09 g of 6 (89% yield) of a pale yellow solid: (Rf,silica=0.21, THF/hexane: 30/70), DISC mp 59.7° C.; Analysis Calculated for C8H11N3O4 : C, 45.07; H, 5.20; N, 19.71. Found: C, 44.98; H, 5.28; N, 19.28.
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][CH2:20][NH:21][CH2:22][C@@H:23]3[C@H:26]([NH:27][C:28](=[O:55])/[C:29](=[N:43]\[O:44][C:45]([CH3:54])([CH3:53])[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])/[C:30]4[N:31]=[C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[S:33][CH:34]=4)[C:25](=[O:56])[NH:24]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C.C1(C)C=CC=CC=1>[NH2:18][CH2:19][CH2:20][NH:21][CH2:22][C@@H:23]1[C@H:26]([NH:27][C:28](=[O:55])/[C:29](=[N:43]\[O:44][C:45]([CH3:54])([CH3:53])[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])/[C:30]2[N:31]=[C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[S:33][CH:34]=2)[C:25](=[O:56])[NH:24]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCNC(=O)OCC2c3ccccc3-c3ccccc32)cs1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCN)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A solution of tert-butyl 2-(((Z)-(2-(((2R,3S)-2-(((2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (435 mg, 0.549 mmol) in DMF (2.75 mL) was treated with piperidine (1.1 mL, 11 mmol). After stirring at rt for 1 h it was diluted with toluene and concentrated (3×). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (238 mg, 64%) as a white powder. LCMS: Rt=0.68 min, m/z=570.3 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J=8.9 Hz, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 7.21 (s, 1H), 5.17 (dd, J=8.3, 4.9 Hz, 1H), 3.76 (dt, J=8.7, 4.7 Hz, 1H), 2.81-2.51 (m, 6H), 1.44 (s, 9H), 1.41 (s, 3H), 1.39 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:6]([CH3:18])=[C:5]2[CH:19]=O.Cl.[NH2:22][OH:23].CO>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:6]([CH3:18])=[C:5]2[CH:19]=[N:22][OH:23]
Reactant: NO
Reactant: Cc1c(C=O)c2cc(Cl)ccc2n1-c1ccc(O)cc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(C=NO)c2cc(Cl)ccc2n1-c1ccc(O)cc1
Yield: 68 %

Procedure:
A mixture of 5-chloro-1-(4-hydroxyphenyl)-2-methyl-1H-indole-3-carbaldehyde (0.63 g, 2.2 mmol), hydroxylamine hydrochloride (0.30 g, 4.3 mmol), methanol (25 mL) and pyridine (1 mL) was reacted according to the procedure used in Example 4 to afford a white solid (68%): mp 212-213° C.; 1H NMR (DMSO-d6): δ 2.29 (3H, s), 6.96 (3H, d, J=8.7 Hz), 7.12 (1H, dd, J=2.2 Hz, J=8.7 Hz), 7.24 (2H, d, J=8.7 Hz), 8.03 (1H, d, J=2.1 Hz), 8.40 (1H, s), 9.93 (1H, s), 10.75 (1H, s); MS m/Z (M+H)+ 301/303 (1 Cl). Anal. for C16H13ClN2O2: Calc'd: C, 63.90; H, 4.36 N, 9.31. Found: C, 63.63; H, 4.12; N, 9.17.
Reaction SMILES: CC1(C)OB([C:7]2[CH:8]=[N:9][N:10](C(OC(C)(C)C)=O)[CH:11]=2)OC1(C)C.Br[C:23]1[C:24]([O:38][CH:39]2[CH2:42][CH2:41][CH2:40]2)=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([O:35][CH3:36])=[O:34])[C@@H:28]([CH3:37])[CH2:27][CH2:26]2.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[CH:39]1([O:38][C:24]2[C:23]([C:7]3[CH:11]=[N:10][NH:9][CH:8]=3)=[CH:32][CH:31]=[C:30]3[C:25]=2[CH2:26][CH2:27][C@H:28]([CH3:37])[N:29]3[C:33]([O:35][CH3:36])=[O:34])[CH2:40][CH2:41][CH2:42]1
Reactant: COC(=O)N1c2ccc(Br)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)N1c2ccc(-c3cn[nH]c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A 100-mL round-bottom flask was charged with tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.250 g, 0.85 mmol), (S)-methyl 6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.317 g, 0.89 mmol), sodium carbonate (0.150 g, 1.42 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.070 g, 0.085 mmol), 1,4-dioxane (10 mL), and water (2 mL). The resulting mixture stirred overnight at 100° C., was cooled to room temperature, and water (10 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 5:1, ethyl acetate/petroleum ether) to afford (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.200 g, 52%) as yellow oil. MS (ESI, pos. ion) m/z 342 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16]2)=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc2ccc(OCc3ccccc3)cc2c1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccc2ccc(O)cc2c1
Temperature: 60 °C
Yield: 61.6 %

Procedure:
A suspension of 7-benzyloxy-2-naphthoic acid (208 mg, 0.75 mmol) and 10% palladium on carbon (208 mg) in 1,4-cyclohaxadiene (1 mL) and ethanol (2 mL) is heated at 60° C. for 24 hours. The reaction is allowed to cool and filtered through a plug of AG50W×2 resin (H+ form). The plug is washed with methanol and the washes are evaporated to dryness to give 7-hydroxy-2-naphthoic acid as a tan solid (87 mg, 62%). 1H NMR (400 MHz, CD3OD) δ 8.4, 7.8, 7.2.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]2[NH:12][C:11](=[O:13])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([O:20][C:21](=O)[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)C=CC=CC=1>>[N:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:21]([N:12]2[C@@H:9]([CH2:8][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10][C:11]2=[O:13])=[O:20])=[CH:25][CH:26]=1
Reactant: O=C1CC(CSc2ccccc2)N1
Reactant: O=C(NCc1ccncc1)Oc1ccccc1
Product: O=C1C[C@H](CSc2ccccc2)N1C(=O)NCc1ccncc1

Procedure:
Following the same procedure as in example 4, step D, but using 4-(phenylsulfanylmethyl)azetidin-2-one and (pyridin-4-ylmethyl)carbamic acid phenyl ester as reactants gave 2-oxo-4(R)-(phenylsulfanylmethyl)azetidine-1-carboxylic acid (pyridin-4-ylmethyl)amide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[C:8]([C:10]2[N:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:9]=1)=[O:4].[CH:20]([B-](F)(F)F)=[CH2:21].[K+].C(N(CC)CC)C>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:20]([C:7]1[S:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:9][C:8]=1[C:10]1[N:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1)=[CH2:21]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)c1cc(-c2cnc3cccnn23)c(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCCO
Solvent: ClCCl
Product: C=Cc1sc(C(=O)OC)cc1-c1cnc2cccnn12
Temperature: 100 °C

Procedure:
Methyl-5-bromo-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylate (200 mg, 0.591 mmol), potassium vinyltrifluoroborate (119 mg, 0.887 mmol), PdCl2(dppf)-CH2Cl2 adduct (48 mg, 0.059 mmol), and triethylamine (0.165 mL, 1.18 mmol) was dissolved in n-propanol (5.91 mL) and purged with nitrogen for 5 minutes in a sealed tube. The solution was heated at 100° C. for 18 h. the reaction was cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (×3) and the organic layers combined, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound as an orange solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.61 (d, 1H); 8.23 (d, 1H); 8.16 (s, 1H); 7.95 (s, 1H); 7.32 (dd, 1H); 6.94 (dd, 1H); 5.87 (d, 1H); 5.44 (d, 1H); 3.85 (s, 3H). LRMS (APCI) calc'd for (C14H11N3O2S) [M+11]+, 286.1. found 286.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)[CH3:2].Cl.C[OH:23]>[C].[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[OH:23])[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(O)c2cccc(C(=O)OC)c2)cc1
Reactant: CO
Agent: [Pd]
Agent: Cl
Product: CCc1ccc(Cc2cc(C(=O)OC)ccc2O)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88 %

Procedure:
The thus obtained methyl 3-[(4-ethylphenyl)hydroxy-methyl]benzoate (2.88 g, 10.0 mmol), 10% palladium carbon (200 mg), concentrated hydrochloric acid (0.5 mL) and methanol (15 mL) were mixed and stirred under a hydrogen atmosphere at room temperature for 14 hours. After filtration to remove the insoluble materials, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to give methyl 3-(4-ethylbenzyl)-4-hydroxybenzoate (2.38 g, 88%) as a colorless powder.
Reaction SMILES: [Mg].O(CC)CC.Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=[O:25])[CH:22]=2)[CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:8]1([CH:24]([C:21]2[CH:22]=[C:23]3[C:18]([CH:17]=[CH:16][CH:15]=[N:14]3)=[CH:19][CH:20]=2)[OH:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Brc1ccccc1
Reactant: O=Cc1ccc2cccnc2c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccccc1)c1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26.6 %

Procedure:
To a stirred mixture of 1.25 parts of magnesium, 14 parts of 1,1'-oxybisethane and 8 parts of bromobenzene was added a solution of 8 parts of intermediate 1, namely 7-quinolinecarboxaldehyde, in 72 parts of tetrahydrofuran, keeping the temperature between 0° C. and 5° C. After stirring for 12 hours at room temperature, the reaction mixture was poured into 300 parts of ice-water. The product was extracted with 1,1'-oxybisethane (3×70 parts). The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 3.2 parts (26.6%) of α-phenyl-7-quinolinemethanol; mp. 118° C. (interm. 2). In a similar manner there were also prepared the intermediates listed in Table 1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12][C:13]1[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[K+]>ClC(Cl)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:13]1[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)=[O:38]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(COc2ccc(SCc3ccc4ccccc4n3)cc2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(Cl)Cl
Product: O=C(O)c1ccc(COc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1

Procedure:
4-(4-(2-quinolinylmethylthio)phenoxymethyl)benzoic acid (4 mmol) in dichloroethane (50 ml) is stirred with m-chloroperbenzoic acid (4 mmol) and solid potassium hydrogen carbonate (1.0 g). The reaction is assayed by TLC and upon consumption of the starting thio compound, the mixture is filtered, washed with dilute aqueous sodium bisulfate, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfinyl)phenoxymethyl)benzoic acid.