Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[OH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([N:11]([CH3:12])[C:20](=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:1]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C(O)c1ccccc1)N(C)C(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Into a dry 1 L round-bottomed flask equipped with a magnetic stirrer was added (+)-pseudoephedrine (22.34 g, 135.22 mmol, 1.0 equiv), triethylamine (21.5 mL, 154 mmol, 1.14 equiv), and tetrahydrofuran (300 mL). The solution was cooled to 0° C. and hydrocinnamoyl chloride (25.08 g, 148.74 mmol, 1.1 equiv) in tetrahydrofuran (100 mL) was added via cannula over a 20 minute interval. After 30 minutes, the reaction was quenched with water. The amide was extracted from water (1 L) with ethyl acetate (400 mL, 120 mL, 120 mL), and the combined organic extracts were dried over sodium sulfate. After removal of the solvent under reduced pressure, a white solid was obtained, which was recrystallized from 2:1:1 ether/dichloromethane/hexanes (500 mL) affording the hydrocinnamide as white crystals (30.24 g, 75% yield): mp 102°-104° C.; 1H NMR (300 MHz, C6D6) δ7.0-7.4 (m, 5H), 4.59 (br, 1H), 4.48 (t, 1H, J=7.1 Hz), 4.20 (m, 1H), 4.01 (dd, 1H, J=8.4 Hz, 2.4 Hz), 3.66 (m, 1H), 3.15 (m, 2H), 2.93 (t, 2H, J=7.7 Hz), 2.79 (s, 3H), 2.49 (m, 2H), 2.13 (m, 2H), 2.02 (s, 3H), 0.92 (d, 3H, J=7.0 Hz), 0.49 (d, 3H, J=6.8 Hz); 13C NMR (75.5 MHz, CDCl3) δ174.3, 173.2, 142.2, 141.5, 141.3, 141.1, 128.6, 128.39, 128.36, 128.31, 128.29, 128.2, 127.6, 126.8, 126.4, 126.1, 125.9, 76.3, 75.3, 58.0, 36.1, 35.4, 32.3, 31.5, 31.1, 26.9, 15.2, 14.3; FTIR (neat film) cm-1 3374 (br, m), 3027 (m), 1621 (s), 1495 (m), 1454 (m), 1406 (m), 1118(m), 1048 (m), 753 (m), 701 (m); HRMS (FAB) Calcd for C19H24NO2 (MH+): 298.1808; Found: 298.1806.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16](C1C=C(C=CC=1)C(Cl)Cl)C1C=CC=CC=1.C1N2CN3CN(C2)CN1C3.Cl>C(O)C.C(O)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)c1cccc(Oc2ccccc2)c1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=Cc1cccc(Oc2ccccc2)c1

Procedure:
A process according to claim 1, wherein the mixture of m-phenoxybenzyl chloride (II) and m-phenoxybenzal chloride (III) (X = chlorine) is reacted with 1 to 2 molar equivalent of hexamethylenetetramine in hot aqueous ethanol or hot aqueous acetic acid and hydrolyzing the mixture with dilute hydrochloric acid to yield m-phenoxybenzaldehyde (I).
Reaction SMILES: [ClH:1].[C:2]([O:5][CH:6]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24]CC3C=CC=CC=3)[CH:20]=2)[CH:15]=1)[CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])(=[O:4])[CH3:3]>[C].[Pd].C(O)C>[ClH:1].[C:2]([O:5][CH:6]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=2)[CH:15]=1)[CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])(=[O:4])[CH3:3]
Reactant: CC(=O)OC(COCCN(C)C)c1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)OC(COCCN(C)C)c1ccc2cc(O)ccc2c1
Yield: 47.7 %

Procedure:
A mixture of 2.0 g of 1-acetoxy-1-(6-benzyloxy-2-naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethane hydrochloride, 0.5 g of 5% palladium-carbon and 40 ml of ethanol was subjected to hydrogenation at room temperature under atmospheric pressure. After the completion of the reaction, the palladium-carbon was removed by filtration. The solvent was removed by distillation under reduced pressure. Acetone was added to the residue thus obtained. The resulting crystals were collected by filtration and dried to obtain 0.76 g of 1-acetoxy-1-(6-hydroxy-2-naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethane hydrochloride (compound No. 287).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=[N:6][C:7]=1S(C)(=O)=O.Cl.[OH-:29].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:7](=[O:29])[NH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: [OH-]
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2[nH]c(=O)c(N)nc2-c2ccccc2)ccc1=O

Procedure:
A solution of 6-[5-amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (200 mg) in a mixture of 1N aq. NaOH (1 ml) and dioxane (2 ml) was refluxed for 6 hours. After cooling, the mixture was adjusted to pH 4 with 1N HCl to give a precipitate. The precipitate was collected by filtration and crystallized from DMSO and water to give 6-(5-amino-6-oxo-3-phenyl-1,6-dihydro-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (123 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:14])[CH:3]=1.S(Cl)([Cl:17])=O>ClCCl>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[C:4]([Cl:14])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: Nc1cc(Cl)c(C(=O)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 4-amino-2-chloro-5-nitro-benzoic acid (2.60 g, 12.0 mmol) in 200 mL dichloromethane with 20 mL thionyl chloride was refluxed for 4 h, cooled to ambient temperature, filtrated and concentrated to dryness i.vac. The residue was further reacted without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](Br)[CH:18]=1>CCOC(C)=O>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH:18]=1
Reactant: Brc1cncc(Br)c1
Reactant: CSc1ccc(B(O)O)cc1
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2cncc(Br)c2)cc1

Procedure:
Prepared according to the procedure Coupling-2 using [4-(methylthio)phenyl]boronic acid and 3,5-dibromopyridine as starting material. Flash chromatography (Hex:EtOAc; 95:5-85:15) afforded the title compound
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:31]([CH:32]=1)[CH2:30][C:8]1([CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[O:7]2)([O-:3])=[O:2].FC(F)(F)C(O)=O.C(N(CC)CC)C.Cl[C:48]1[O:49][C:50]2[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=2[N:52]=1>C(Cl)Cl.O>[O:49]1[C:50]2[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=2[N:52]=[C:48]1[N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:14]([N:11]2[CH2:12][CH2:13][C:8]3([O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:32][N:31]4[CH2:30]3)[CH2:9][CH2:10]2)=[O:29])[CH2:17][CH2:18]1
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC3(CC2)Cn2cc([N+](=O)[O-])nc2O3)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCN(c2nc3ccccc3o2)CC1)N1CCC2(CC1)Cn1cc([N+](=O)[O-])nc1O2
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.4 %

Procedure:
Tert-butyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidine]-1′-yl)-2-oxoethyl]piperazine-1-carboxylate prepared in Example 653 (227 mg, 0.50 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. To the residue, methylene chloride (1 ml) and triethylamine (1 ml) were added followed by stirring at room temperature for 5 minutes, and then the solution was concentrated under reduced pressure. The residue was dissolved in DMF (5 ml). To the solution, triethylamine (0.21 ml, 1.52 mmol) and 2-chlorobenzoxazole (86 μl, 0.76 mmol) were added followed by stirring at 80° C. for 2 hours. To the reaction mixture, water was added, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was crystallized from methylene chloride-ethyl acetate to afford 2-[4-(benzoxazol-2-yl)piperazin-1-yl]-1-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidin]-1′-yl)ethanone (99 mg, 42%) as a light yellow powder.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32]C(=O)OC(C)(C)C)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:23][CH3:24])=[N:8][CH:9]=1)(=[O:3])[CH3:2].CO>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][N:8]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:23][CH3:24])[N:6]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1ncc(C(C)=O)c(Nc2ccccc2NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cc(N2CCOCC2)ccc1Nc1ncc(C(C)=O)c(Nc2ccccc2N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
To a solution of tert-butyl 2-(5-acetyl-2-(2-methoxy-4-morpholinophenyl amino)pyrimidin-4-ylamino)phenylcarbamate (100 mg) in DCM (5 ml), TFA (1 ml) was added at 0° C., and the mixture was stirred for 1 h at rt. TLC showed completion of starting material (TLC system: 5% methanol in DCM (Rf): 0.5). After removal of TFA under reduced pressure, the residue was triturated with diethyl ether to give the desired compound as a yellow solid 85 mg (Yield: 98%). MS: m/z 435.2 (ES+).
Reaction SMILES: C([O:3][CH2:4][C:5]1[N:6]([CH2:17][C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:19]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:15])[C:8]=2[N:16]=1)C.B(Br)(Br)Br>ClCCl.CO>[NH2:15][C:9]1[C:8]2[N:16]=[C:5]([CH2:4][OH:3])[N:6]([CH2:17][C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH:19]=3)[C:7]=2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1Cc1cc(-c2ccc(F)cc2)no1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(N)c2nc(CO)n(Cc3cc(-c4ccc(F)cc4)no3)c2c1C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (0.8545 g, 2.161 mmol) in dichloromethane (50 mL) was cooled to about 6° C., and boron tribromide (5.4 mL of a 1 M solution in dichloromethane) was added dropwise. The reaction was heated at reflux under nitrogen for two hours and diluted with dichloromethane and methanol. The resulting solution was washed sequentially with aqueous potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure. The resulting solid was stirred in water overnight, isolated by filtration, purified by column chromatography on silica gel (eluting with 3% to 5% CMA in chloroform), and dried to provide 0.283 g of (4-amino-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-2-yl)methanol as a tan powder, mp 164.0-165.0° C.
Reaction SMILES: [CH2:1]([N:4]1[C:9]2[CH:10]=[CH:11][C:12]([S:14][CH3:15])=[CH:13][C:8]=2[C:7](=[O:16])[C:6]([CH3:18])([CH3:17])[S:5]1(=[O:20])=[O:19])[CH:2]=[CH2:3].[BH4-].[Na+]>CO>[CH3:17][C:6]1([CH3:18])[CH:7]([OH:16])[C:8]2[CH:13]=[C:12]([S:14][CH3:15])[CH:11]=[CH:10][C:9]=2[N:4]([CH2:1][CH:2]=[CH2:3])[S:5]1(=[O:20])=[O:19]
Reactant: C=CCN1c2ccc(SC)cc2C(=O)C(C)(C)S1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCN1c2ccc(SC)cc2C(O)C(C)(C)S1(=O)=O
Reaction time: 8 h
Yield: 95.7 %

Procedure:
1-(prop-2-en-1-yl)-3,3-dimethyl-6-methylthio-1H-2,1-benzothiazine-4-(3H)-one 2,2-dioxide (2 g; 0.006 mol) was dissolved in methanol (40 mL) and sodium borohydride (0.45 g; 0.012 mol) was added in one portion. After the initial effervescence, the reaction was left stirring overnight. The solvent was removed under vaccuo, water added and the product extracted with chloroform. After washing the organic extracts with water, drying over magnesium sulphate and filtering, the product was isolated as a white solid (1.8 g; 90%) of 3,4-dihydro-3,3-dimethyl-6-methylthio-1-(prop-2-en-1-yl)-1H-2,1-benzothiazin-4-ol 2,2-dioxide, used immediately in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].CC1C=CC(S(O[C@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][N:10]1[CH:11]=[CH:12][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([O:1][C@@H:36]3[CH2:40][CH2:39][O:38][CH2:37]3)[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=2)=[N:9]1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OCc3ccccc3)c2)n1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H]3CCOC3)c2)n1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
A suspension of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (450 mg, 1.39 mmol), (3S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (507 mg, 2.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give N-(1-methyl-1H-pyrazol-3-yl)-3-[(phenylmethyl)oxy]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide as a white foam. This was dissolved in ethanol (5 mL) and ammonium formate (182 mg, 2.88 mmol) added in one portion. The reaction was blanketed with argon and 10% palladium on activated carbon (30 mg) was added. This mixture was heated in a microwave reactor at 140° C. for 10 minutes, the catalyst filtered off and the volatiles removed in vacuo to give the title product as a white solid (305 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]=1.[CH2:17]([Zn]CC)C.ICI>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]12[CH2:17][CH:12]1[CH:13]([OH:16])[CH2:14][CH2:15]2
Reactant: CC[Zn]CC
Reactant: OC1C=C(c2ccc3ccccc3c2)CC1
Solvent: ICI
Solvent: ClCCl
Product: OC1CCC2(c3ccc4ccccc4c3)CC12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-(naphthalen-2-yl)cyclopent-2-enol (2.32 g, 11.0 mmol) in dichloromethane (80 mL) was treated with diethylzinc (1.0 M in hexane; 54.6 mL, 54.6 mmol, 5.0 eq.). After 10 min, the reaction mixture was cooled to 0° C., treated with a solution of diiodomethane (4.51 mL, 55.5 mmol, 5.0 eq) in dichloromethane (20 mL) dropwise over 10 min and allowed to warm to ambient temperature. After 2 h, the reaction mixture was quenched with saturated aqueous ammonium chloride (40 mL). The reaction mixture was extracted with dichloromethane (3×40 mL). The combined organic phases were dried over magnesium sulphate, concentrated in vacuo to afford the desired compound in a quantitative yield as a white solid which was not further purified. 1H NMR (400 MHz, CDCl3) δ ppm 0.94-1.01 (1H, m, CH), 1.27-1.41 (2H, m, CH2), 1.98-2.02 (1H, m, CH), 2.10-2.20 (2H, m, CH2), 2.24-2.33 (1H, m, CH), 4.71-4.80 (1H, m, CH), 7.23-7.26 (1H, m, ArH), 7.40-7.48 (2H, m, ArH), 7.64 (1H, s, ArH), 7.72-7.84 (3H, m, ArH).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19])C1C=CC=CC=1>[Pd].CO>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Reaction time: 3 h

Procedure:
Palladium on carbon (30.5 mg; 10% Pd/C) was added to a solution of tert-butyl 4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperidine-1-carboxylate (151 mg, 0.33 mmol) in methanol (3 mL), and the resulting mixture was stirred under hydrogen (balloon) for 3 hours. TLC analysis showed the reaction was complete. The reaction mixture was filtered through a microfilter and the filtrate was concentrated under vacuum to afford the title compound as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][O:1][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:10][CH:9]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13]1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCOCc3ccccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 24 (t)] with 2-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[3-(pyridin-2-ylmethoxy)-propyl]-phenyl]-piperidine-1-carboxylate as a colourless, amorphous solid, which was used in the following step without further purification and characterization.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7](=[N:10][NH:11][C:12](N)=O)[CH2:8][CH3:9].[OH-].[Na+].CN([CH:20]=[O:21])C>>[CH2:8]([C:7]1[C:6]([CH:20]=[O:21])=[CH:12][NH:11][N:10]=1)[CH3:9]
Reactant: CCC(C)=NNC(N)=O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1n[nH]cc1C=O
Temperature: 0 °C
Yield: 16 %

Procedure:
To cool DMF (50 mL) at 0° C., POCl3 (30 mL) was added dropwise over 30 minutes, and maintained at 0° C. for 1 hour. To the mixture was added butan-2-one semicarbazone (10 g, 78 mmol) in portions at 70° C. and maintained at 70° C. for 4 hours. The mixture was poured into crushed ice (700 g), neutralized using 10% NaOH solution and extracted using ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×80 mL), saturated aqueous NaCl (100 mL), dried over anhydrous Na2SO4 and concentrated to obtain a crude product, which was purified by column chromatography (60-120 mesh silica gel) using 3-5% methanol in chloroform as eluents to afford 3-ethyl-1H-pyrazole-4-carbaldehyde (1.5 g, 16%) as solid. 1H NMR (CDCl3) δ 9.95 (s, 1H), 8.0 (s, 1H), 3.0 (q, 2H), 1.35 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OB(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.Br[C:22]1[CH:32]=[CH:31][C:25]2[CH2:26][C:27]([CH3:30])([CH3:29])[O:28][C:24]=2[CH:23]=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.C(OCC)(=O)C.O.C(COC)OC>[CH3:29][C:27]1([CH3:30])[CH2:26][C:25]2[CH:31]=[CH:32][C:22]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:23][C:24]=2[O:28]1
Reactant: CC1(C)Cc2ccc(Br)cc2O1
Reactant: Cc1ccc(OB(O)O)cc1
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: CCO
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)OC(C)(C)C3)cc1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 55.9 %

Procedure:
4-methylphenylboric acid (1.35 g, 9.91 mmol), tetrakis(triphenylphosphine)palladium (382 mg, 0.331 mmol), an aqueous solution of 2N sodium carbonate (4.5 mL) and ethanol (83 mL) were sequentially added to a solution of dimethoxyethane (9 mL) containing 6-bromo-2,2-dimethyl-2,3-dihydro-1-benzofuran (1.50 g, 6.61 mmol) synthesized in Reference Example 7, and the mixture was stirred under microwave irradiation at 150° C. for 10 minutes. After cooled to room temperature, water was added to the reaction solution, and extraction was performed using ethyl acetate. The extract was washed with saturated sodium hydrogencarbonate and saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 99:1 to 93/7) to give 880 mg of the title compound (yield: 56%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15]O>[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([O:1][CH3:15])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: CO
Agent: [Pd]
Product: COC(=O)c1cc(N)ccc1OC

Procedure:
The hydrogenation of methyl 2-hydroxy-5-nitrobenzoate (700 mg, 3.3 mmol) using 10% Pd—C (100 mg) and Na7SO4 (100 mg) in MeOH at 50 psi gave methyl 5-amino-2-methoxybenzoate (600 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1.I[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=1.CCOC(C)=O.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: C#Cc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(C#Cc2cccc(Br)c2)cc1
Reaction time: 4 h

Procedure:
To a solution of 3-bromophenylacetylene (9.1 g, 50.26 mmol), TEA (22.4 g, 221 mmol, 30.8 mL), bis(triphenylphosphine)dichloropalladium(II) (1.41 g, 2.01 mmol), and CuI (230 mg, 1.2 mmol) in DMF (60 mL) was added 4-iodo(difluoromethoxy)benzene (10.85 g, 40.21 mmol) at room temperature. The reaction mixture had gotten warm after the addition was completed. The mixture was stirred for 4 h then the mixture was portioned between EtOAc and water. The aqueous layer was separated and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated over 40 g Celite. Flash chromatography (SiO2, Hexanes) gave 12 g, 92%, of the title compound as a yellow oil that had crystallized into a solid after being undisturbed for 3d. 1H NMR 500 MHz (DMSO-d6) δ 7.34 (dt, 2H, J=8.92 Hz, 4.70 Hz); 7.42 (t, 1H, 72.99 Hz); 7.54 (t, 1H, J=7.88 Hz); 7.85-7.88 (m, 1H); 7.94-7.97 (m, 1H); 8.00 (dt, 1H, J=8.93 Hz, 4.87 Hz); 8.04 (t, 1H, J=1.80 Hz).