Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:27]([O:29]C)=O)=[N:11][NH:12][C:13]=1[C:14]([N:16]([CH2:18][CH:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[C:35]([C:41]([NH:43][CH3:44])=[O:42])[CH:34]=1>>[CH2:1]([O:8][C:9]1[C:10]([C:27]([NH:38][CH2:37][C:36]2[CH:39]=[CH:40][C:33]([F:32])=[CH:34][C:35]=2[C:41]([NH:43][CH3:44])=[O:42])=[O:29])=[N:11][N:12]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:18][N:16]([CH3:17])[C:14](=[O:15])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)c1cc(F)ccc1CN
Reactant: COC(=O)c1n[nH]c(C(=O)N(C)CC(O)c2ccccn2)c1OCc1ccccc1
Agent: Cl
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2c1ccccn1

Procedure:
The title compound was prepared from methyl 4-(benzyloxy)-5-{[(2-hydroxy-2-pyridin-2-ylethyl)(methyl)amino]carbonyl}-1H-pyrazole-3-carboxylate using a procedure similar to that described in Example 43, Steps 2-4, except that 4-fluoro-2-[(methylamino)carbonyl]benzylamine hydrochloride was used in place of 4-fluorobenzylamine. Purification was achieved by removing the solvent in vacuo, and purifying the resulting residue by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions afforded the product. ES MS (M+1)=543.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:23]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NC(=O)c1c(N)ncn1CCCc1ccccc1
Product: NC(=O)c1c(NC(=O)c2ccccc2F)ncn1CCCc1ccccc1
Yield: 88 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 22 using 1.50 g (6.14 mmol) of 4-amino-1-(3-phenylpropyl)-5-imidazolecarboxamide which was prepared in the same manner as in Example 114 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain 1.97 g of 4-(2-fluorobenzoylamino)-1-(3-phenylpropyl)-5-imidazolecarboxamide (yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.[C@H:10]12[CH2:16][C@H:13]([NH:14][CH2:15]1)[CH2:12][O:11]2.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([N:14]2[CH2:15][C@@H:10]3[CH2:16][C@H:13]2[CH2:12][O:11]3)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Clc1cc(I)cc(Cl)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Clc1cc(N2C[C@@H]3C[C@H]2CO3)cc(Cl)n1
Temperature: 140 °C
Yield: 44.1 %

Procedure:
To a microwave vial charged with 2,6-dichloro-4-iodopyridine (100 mg, 0.37 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (49.19 mg, 0.44 mmol) and cesium carbonate (66.29 mg, 0.48 mmol) in dioxane (5 mL) was added Pd2(dba)3 (3.5 mg, 0.048 mmol) and xantphos (3.5 mg, 0.048 mmol) under nitrogen. The vial was sealed and heated by microwave irradiation at 140° C. for 1 h. The reaction mixture was concentrated in vacuo, and resulting residue was purified by TLC (PE:EA=2:1) to afford (1S,4S)-5-(2,6-dichloropyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (40 mg, 35% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl.O>[OH:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: COc1cnc2[nH]ccc2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Oc1cnc2[nH]ccc2c1
Yield: 56.7 %

Procedure:
A suspension of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (210 mg, 1.42 mmol), (Heterocycles 50, (2), 1065-1080, (1999)), in dichloromethane (10 ml) was stirred in an inert atmosphere, a 1.0M solution of boron tribromide in dichloromethane (4.3 ml, 4.3 mmol) added dropwise and the mixture stirred at ambient temperature overnight. The reaction mixture was taken to pH6 by the dropwise addition of 5N aqueous sodium hydroxide and further diluted with water. The aqueous solution was extracted several times with ethyl acetate, the extracts combined, washed with water followed by brine and dried over magnesium sulphate. The ethyl acetate solvent was removed ‘in vacuo’ and the residue purified by column chromatography, eluting with dichloromethane/methanol (95/5), to give a white solid. The solid was triturated with ether, filtered and dried to give 5-hydroxy-1H-pyrrolo[2,3-b]pyridine (108 mg, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([OH:22])=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[CH:29]1(Br)[CH2:33][CH2:32][CH2:31][CH2:30]1.O>C(Cl)(Cl)Cl>[CH:29]1([O:22][C:17]2[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COc1cc2nccc(Oc3cccnc3O)c2cc1OC
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cccnc3OC3CCCC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
6,7-Dimethoxy-4-(2-hydroxy-pyridin-3-yloxy)-quinoline (21 mg) was dissolved in chloroform (7 ml) to prepare a solution. Potassium carbonate (300 mg) and cyclopentyl bromide (0.2 ml) were added to the solution. The mixture was stirred at room temperature overnight, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (14 mg, yield 55%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Br[CH:7]([C:15]([CH3:17])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O>CN(C=O)C>[C:1]([O:4][CH:7]([C:15]([CH3:17])=[O:16])[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(=O)C(Br)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of sodium acetate (30.76 g, 375 mmol) in DMF (250 mL) was added dropwise tert-Butyl 2-bromo-acetoacetate (59.27 g, 250 mmol). After stirring at ambient temperature for 90 minutes, water (415 mL) was added, followed by extraction with ethyl acetate (3×325 mL). The combined organic layers were washed with water (3×325 mL) and brine (325 mL), dried over Na2SO4 and after filtration, the solvent was removed in vacuo. The resulting oil was purified by distillation (12 mbar, 128°)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][C:15](=[O:22])[C:14]=3[C:13]=2[C:23]([OH:25])=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][Mg]Br>C(OCC)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][C:15]([OH:22])([CH3:26])[C:14]=3[C:13]=2[C:23]([OH:25])=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=C1CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(C(=O)O)c21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(C(=O)O)c21
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A mixture of Example 103B (40 mg, 0.11 mmol) in diethyl ether (3 mL) and THF (2 mL) was treated with methylmagnesium bromide (3M solution in diethyl ether, 0.11 mL), stirred at 45° C. for 2 hours, quenched with saturated NH4Cl, and partitioned between diethyl ether and brine. The organic phase was dried (Na2SO4), filtered, concentrated, and purified by reverse-phase HPLC to provide the desired product. MS (ESI) m/e 378 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 12.18 (br s, 1H), 8.5 (s, 1H), 7.75 (m, 2H), 7.52 (m, 2H), 7.32 (d, 1H), 6.85 (d, 1H), 2.56 (m, 2H), 1.82-1.73 (m, 1H), 1.72-1.61 (m, 1H), 1.53-1.37 (m, 2H), 1.33 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2ccnc3[nH]c(=O)c4ccccc4c23)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
Compound 83 (50 mg, 0.22 mmol), 3-methoxyphenylboronic acid (49 mg, 0.33 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), S-Phos (9 mg, 0.02 mmol), and K2CO3 (90 mg, 0.65 mmol) were dissolved in dioxane/H2O (2.2 mL, 10/1, v/v), and stirred overnight at 100° C. The reaction mixture was concentrated. The crude product was purified directly via Biotage eluting with a gradient of 25 to 85% EtOAc in hexanes to provide 152 (11 mg, 17% yield) as a white solid. LC-MS (M+H=303, obsd.=303).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:33])[C:8]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]([OH:32])[C@H:28]([OH:31])[CH2:29][OH:30])=[CH:21][C:9]=4[C:10]([CH3:20])([CH3:19])[C:11]=3[N:12]2[CH2:15][C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1.[CH3:34][Si](C=[N+]=[N-])(C)C>CO>[CH3:34][O:17][C:16](=[O:18])[CH2:15][N:12]1[C:11]2[C:10]([CH3:20])([CH3:19])[C:9]3[CH:21]=[C:22]([O:25][CH2:26][C@@H:27]([OH:32])[C@H:28]([OH:31])[CH2:29][OH:30])[CH:23]=[CH:24][C:8]=3[C:7](=[O:33])[C:6]=2[C:5]2[C:13]1=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C)c2cc(OC[C@@H](O)[C@H](O)CO)ccc2C(=O)c2c1n(CC(=O)O)c1cc(Br)ccc21
Solvent: CO
Product: COC(=O)Cn1c2c(c3ccc(Br)cc31)C(=O)c1ccc(OC[C@@H](O)[C@H](O)CO)cc1C2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
[3-Bromo-6,6-dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihydro-benzo[b]carbazol-5-yl]-acetic acid (Compound T22-6, 15.0 mg, 29.0 μmol) was dissolved in methanol (0.30 mL), added with trimethylsilyldiazomethane (0.10 mL), and then stirred at room temperature for 1 hr. The residues obtained from the reaction solution after concentration under reduced pressure were purified by silica gel column chromatography (methylene chloride/methanol) to obtain the target compound (15.2 mg, 96%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4].O1CCCCC1[O:30][C@@H:31]1[CH2:39][N:34]2[CH2:35][CH2:36][NH:37][CH2:38][C@@H:33]2[CH2:32]1>C1COCC1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:37]2[CH2:36][CH2:35][N:34]3[CH2:39][C@@H:31]([OH:30])[CH2:32][C@H:33]3[CH2:38]2)[S:7][C:8]=1[C:16]([CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17]
Reactant: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: C1CCC(O[C@H]2C[C@H]3CNCCN3C2)OC1
Solvent: C1CCOC1
Product: O=C(CN1CCN2C[C@@H](O)C[C@H]2C1)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 33.7 %

Procedure:
Compound 531 (120 mg, 0.300 mmol) was dissolved in THF (2 mL), and (7S,8aS)-7-(tetrahydropyran-2-yl)oxyoctahydropyrrolo[1,2-a]pyrazine (204 mg, 0.900 mmol) was added thereto, followed by stirring at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethanol (3 mL), and 2 mol/L hydrochloric acid (3 mL) was added thereto, followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was poured into water. A 2 mol/L sodium hydroxide solution added thereto to adjust the pH to 8, followed by extraction with chloroform. The organic layer was washed with a solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=23:2), followed by recrystallizing from a mixed solvent of ethanol and diethyl ether to afford the entitled Compound 569 (46.5 mg, 34%).
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:29]1[N:30]=[C:31]([NH:34]C=O)[S:32][CH:33]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]3[S:20][CH:21]=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8].Cl.CO>O1CCCC1>[CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]3[S:20][CH:21]=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
A mixture of 7-[2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.58 g.), conc. hydrochloric acid (0.405 g.), methanol (8.7 ml.) and tetrahydrofuran (5 ml.) was stirred for 2 hours and 10 minutes at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous solution of sodium hydroxide (pH 7~8.5). An insoluble material was filtered off and the filtrate was adjusted to pH 3.4 with 10% hydrochloric acid under ice-cooling and stirred for 30 minutes. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.4 g.).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[C:9]1[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].C(N(CC)CC)C>O>[C:23]([C:25](=[CH:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]=1[Cl:19])[C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24]
Reactant: O=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Reactant: CCOC(=O)CC#N
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Reaction time: 96 h

Procedure:
To 5.83 g of 1-benzyl-2-chloroindole-3-carbaldehyde, dissolved in 200 ml of abs. EtOH, was added 6.1 g of ethyl 2-cyanoacetate and 6.6 g of triethylamine. After 4 days with stirring, the solution was added to water, and the precipitate collected by filtration and dried to give (1a). Yield 6.72 g of (1a), m.p. 130°-131° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([CH:17]=[CH:18][C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:25])[C:7]=2[N:6]=[CH:5]1>CO.[Pd]>[CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=4)[CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:25])[C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(C=Cc4ccncc4)cc3c21
Agent: [Pd]
Solvent: CO
Product: CC(C)Cn1cnc2c(N)nc3ccc(CCc4ccncc4)cc3c21
Reaction time: 168 h
Yield: 18 %

Procedure:
1-(2-Methylpropyl)-8-(2-pyridin-4-ylvinyl)-1H-imidazo[4,5-c]-quinolin-4-amine (2.1 g, 6.1 mmol) was treated according to the method described in Example 123; the reaction was allowed to run for seven days. An analysis by proton nuclear magnetic resonance spectroscopy indicated the presence of starting material in the purified product. The product mixture was dissolved in methanol (100 mL), and 10% palladium on carbon (200 mg) was added. The reaction was placed under hydrogen pressure (40 psi, 2.8×105 Pa) for four days, and the product was isolated as described in Example 123. The crude product was purified by flash column chromatography on silica gel (eluting with 90:10 chloroform:CMA) followed by recrystallization from acetonitrile to provide 380 mg of 1-(2-methylpropyl)-8-(2-pyridin-4-ylethyl)-1H-imidazo[4,5-c]-quinolin-4-amine as pale, yellow crystals, mp 221–224° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].O.Cl>O1CCOCC1.CO.C(OCC)(=O)C>[OH:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:16][CH2:17][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][CH2:20]2)[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OC2CCN(S(C)(=O)=O)CC2)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)N1CCC(Oc2ccc(C(=O)O)c(O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.87 mL) was added to a solution mixture of the obtained methyl 2-hydroxy-4-((1-(methylsulfonyl)piperidin-4-yl)oxy)benzoate (0.19 g) in dioxane (0.95 mL) and methanol (0.95 mL), followed by stirring at room temperature for 3 hours. A 2 mol/L aqueous solution of sodium hydroxide (0.58 mL) was added to the reaction mixture, followed by heating to reflux for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then water was added thereto. After adjusting the pH to 3 with 6 mol/L hydrochloric acid, ethyl acetate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 0.18 g of 2-hydroxy-4-((1-(methylsulfonyl)piperidin-4-yl)oxy)benzoic acid as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][CH:14]([CH3:16])[NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:26][CH:27]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]([NH:15][CH2:27][CH:26]=[C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:16])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)Cc1ccc(OCc2ccccc2)cc1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCC=C(c1ccccc1)c1ccccc1

Procedure:
The starting material is prepared as follows: The solution of 12 g of dl-p-benzyloxyamphetamine, and 10.4 g of β-phenyl-cinnamaldehyde in 300 ml of absolute ethanol is treated dropwse with the solution of 3 g of sodium borohydride in 6.7 ml of water while stirring. It is refluxed for 18 hours, concentrated to remove most of the ethanol and diluted with water. The mixture is extracted with ethyl acetate and the organic layer washed with brine, dried and evaporated, to yield the dl-1-(p-benzyloxyphenyl)-2-(3,3-diphenylallylamino)-propane; its maleate melts at 177°-178°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.Br[C:17]1[C:26]2[C:21](=[CH:22][C:23]([S:27]([N:30](CC3C=CC(OC)=CC=3)[C:31]3[S:32][CH:33]=[CH:34][N:35]=3)(=[O:29])=[O:28])=[CH:24][CH:25]=2)[CH:20]=[N:19][C:18]=1[OH:45].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[OH:45][C:18]1[N:19]=[CH:20][C:21]2[C:26]([C:17]=1[C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=1[O:2][CH3:1])=[CH:25][CH:24]=[C:23]([S:27]([NH:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1)(=[O:29])=[O:28])[CH:22]=2
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)c(O)ncc3c2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)ccc1-c1c(O)ncc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane adduct (28.2 mg, 0.035 mmol), 2-methoxy-4-(trifluoromethyl)phenylboronic acid (76 mg, 0.346 mmol), 4-bromo-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide (175 mg, 0.346 mmol) and sodium carbonate (2M, 346 μl, 0.691 mmol) in Dioxane was heated to 100° C. in a microwave for 1 h. LC/MS showed mostly product, after cooling to rt, the crude material was purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over 20 min. The pure fractions were combined and concentrated in vacuo. The residue was dissolved in DCM (2 ml) and TFA (0.2 ml). The mixture was shaken at room temperature at 2 hr. LC-MS indicated product as the major species. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with a gradient of 0% to 100% EtOAc in hexane and then washed with pure methanol, to provide 3-hydroxy-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide as yellow solid. m/z (ESI) 482.0 [M+1].
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:4]=[N:3]1>C(O)C.[C].[Pd]>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:5]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:4]=[N:3]1
Reactant: CCOC(=O)/C=C/c1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 104.6 %

Procedure:
A solution of ethyl (E)-3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)acrylate (60 g, 137 mmol) in ethanol (700 ml) was treated with 10% palladium carbon (6.0 g) under a hydrogen atmosphere at room temperature for 3 hours. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was triturated with hexane and dried in vacuo to give ethyl 3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)propionate (63 g) as a colorless solid.