Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=2[OH:27])[CH2:16][C:15]2[C:17]3[C:11]([CH:12]=[CH:13][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:6]1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:36]([CH3:38])[CH3:37]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=2[O:27][CH:36]([CH3:38])[CH3:37])[CH2:6][C:7]2[C:17]3[C:11]([CH:10]=[CH:9][CH:8]=2)=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16]1)=[O:4]
Reactant: CC(C)Br
Reactant: COC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2cccc3cccc(c23)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2cccc3cccc(c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a suspension of 2-(2-hydroxy-3-methyl-benzoylamino)-2,3-dihydro-1H-phenalene-2-carboxylic acid methyl ester (22) (175 mg, 0.47 mmol), anhydrous Cs2CO3 (306 mg, 0.94 mmol), and KI (16 mg, 0.09 mmol) in DMF (8 mL) is added 2-bromo-propane (220 μL, 2.35 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (20 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-40% EtOAc in heptane) to give the pure product (25) as white solid (143 mg, 73%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2)(=[O:4])=[O:3].[ClH:16]>C(O)C.[Pt](=O)=O>[ClH:16].[CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][CH2:11]2)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1cccc2cnccc12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)Nc1cccc2c1CCNC2
Reaction time: 16 h

Procedure:
A solution of 5-methanesulfonamidoisoquinoline (3.50 g, 0.0156 mol) in ethanol (250 ml) was treated with platinum dioxide (1.5 g) and 1N aqueous hydrochloric acid (15.7 ml). The mixture was hydrogenated at a pressure of 414 kPa (60 psi) for 16 hours, after which time the reaction mixture was filtered. The filtrate was evaporated under reduced pressure and triturated with dichloromethane to afford the subtitle compound as a colourless solid. The solid residue from the filtration was taken up into methanol:water (1:2, v/v), and the suspension filtered, washing with dichloromethane (3×). This filtrate was evaporated to afford a second crop of the subtitle compound (total yield 3.45 g, 84%). Rf 0.21 (0.880 aqueous ammonia:methanol:dichloromethane, 1:10:90, v/v). 1H NMR (D6-DMSO) Γ: 2.96-3.10 (2H, m), 3.31 (3H, m), 4.21 (2H, s), 7.12 (1H, m), 7.26 (2H, m), 9.24 (1H, s), 9.61 (2H, bs).
Reaction SMILES: CN1C(C(F)(F)F)=C([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)C=N1.Br[C:21]1[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=1[F:26]>>[F:26][C:25]1[N:24]([CH3:27])[N:23]=[C:22]([CH3:28])[C:21]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1
Reactant: Cn1ncc(B2OC(C)(C)C(C)(C)O2)c1C(F)(F)F
Reactant: Cc1nn(C)c(F)c1Br
Product: Cc1nn(C)c(F)c1B1OC(C)(C)C(C)(C)O1

Procedure:
Following the procedure of Intermediate 149, replacing 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole with 4-bromo-5-fluoro-1,3-dimethyl-1H-pyrazole (commercial) provided the title compound.
Reaction SMILES: C(=O)([O-])OCC[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([F:14])=[CH:7][C:6]=1[Cl:15].[C:18](=O)([O-])[O-:19].[Cs+].[Cs+].IC.CO>CN(C)C=O.O>[Cl:15][C:6]1[CH:7]=[C:8]([F:14])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[O:19][CH3:18]
Reactant: O=C([O-])OCCc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A solution of 15.0 g of (2-chloro-4-fluoro-5-nitrophenyl)- ethyl carbonate in 100 ml of dimethyl formamide was treated with 18.6 g of cesium carbonate, 7.1 ml of iodomethane and 7 ml of methanol and stirred overnight at room temperature. The reaction mixture was poured into water and extracted twice with ether. The extracts were washed twice with water and then with brine, dried over magnesium sulfate and concentrated to afford 11.4 g of the subtitle compound. mp. 69-70° C. Ex. 57, C.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[Cl:16].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC([O-])=O.CC([O-])=O.[Cu+2].ClCCl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[Cl:16]
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
Triethylamine (0.52 mL, 3.75 mmol) was added to a mixture of 4-bromo-3-chlorophenol (156 mg, 0.75 mmol), phenyl boronic acid (187 mg, 1.53 mmol), Cu(OAc)2 (208 mg, 1.15 mmol), molecular sieves (4 Å), and dichloromethane (7.5 mL). The mixture was stirred at room temperature overnight, and then additional phenyl boronic acid (186, 1.53 mmol) was added. The reaction was stirred at rt for an additional 7 h and filtered through Celite with dichloromethane. The filtrate was concentrated and purified by silica gel chromatography (100% hexanes) to give 1-bromo-2-chloro-4-phenoxybenzene (90 mg) as a clear liquid. 1H NMR (400 MHz, DMSO-d6): δ 7.75 (d, 1H), 7.42-7.47 (m, 2H), 7.27 (d, 1H), 7.23 (t, 1H), 7.11 (d, 2H), 6.92 (dd, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[CH:12]2[CH2:13][C:14](=[O:16])[CH2:15][CH:11]2[CH2:10][NH:9]1.[OH:17][CH2:18][C:19](O)=[O:20].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(#N)C>[OH:20][CH2:19][C:18]([N:9]1[CH2:10][CH:11]2[CH2:15][C:14](=[O:16])[CH2:13][CH:12]2[CH2:8]1)=[O:17]
Reactant: O=C1CC2CNCC2C1
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CC2CN(C(=O)CO)CC2C1
Yield: 64 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f (764.8 mg, 3.2 mmol) and 2-hydroxyl ethanoic acid (267.5 mg, 3.52 mmol) were dissolved in 10 mL of acetonitrile. Upon cooling by an ice-water bath, hydroxyacetic acid (1.3 g, 9.6 mmol), 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride (1.23 g, 6.4 mmol) and triethylamine (1.3 mL, 9.6 mmol) were added. The ice-water bath was removed and the reaction mixture was reacted overnight at 25° C. The mixture was concentrated and diluted with 20 mL of ethyl acetate. The mixture was filtered under reduced pressure and the filtrate was washed with 20 mL of water. The organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-(2-hydroxy-acetyl)-hexahydro-cyclopenta[c]pyrrol-5-one 3a (0.375 g, yield 64%) as a colorless oil.
Reaction SMILES: O=C1CCC(=O)C1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[OH:25]>CO>[OH:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[NH:18][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)C1C(=O)OCc1ccccc1
Reactant: NC1CCCCC1O
Solvent: CO
Product: O=C(NC1CCCCC1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of benzyl 2,5-dioxocyclopentanecarboxylate (2.58 g, 10.35 mmol) in MeOH (20 mL) at 0° C. was added 2-aminocyclohexanol (1.25 g, 10.87 mmol). The reaction mixture was stirred at room temperature for 18 hr and quenched by addition of 0.25 N HCl (8 mL). MeOH was removed in vacuo and the aqueous layer was extracted with CH2Cl2 (4×10 mL). The combined organic portions were washed with saturated NaCl (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulted brown oil was purified by ISCO chromatography (40 g column) using hexanes/EtOAc (0-5% over 15 min, 5-10% over 7 min) to give benzyl 2-hydroxycyclohexylcarbamate as a light yellow solid at a retention time of 11-13 min (2.15 g, 83% yield) HPLC: RT=2.83 min, Purity 95% (HPLC Method 1) NMR: 400 MHz 1H (CDCl3) 7.33 ppm, 5 H, m; 5.16 ppm, 1 H, m; 5.09 ppm, 2 H, s; 3.95 ppm, 1 H s; 3.68 ppm, 1 H m; 1.54 ppm, 8 H, m.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:23]=1)[C:11](ON1C(=O)CCC1=O)=[O:12].Cl.[NH2:32][CH2:33][C@@H:34]([C:57]([O:59][CH3:60])=[O:58])[NH:35][C:36](=[O:56])[C:37]1[C:42]([Cl:43])=[CH:41][C:40]([C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([OH:54])[CH:49]=2)=[O:45])=[CH:39][C:38]=1[Cl:55].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:23]=1)[C:11]([NH:32][CH2:33][C@@H:34]([C:57]([O:59][CH3:60])=[O:58])[NH:35][C:36](=[O:56])[C:37]1[C:42]([Cl:43])=[CH:41][C:40]([C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([OH:54])[CH:49]=2)=[O:45])=[CH:39][C:38]=1[Cl:55])=[O:12]
Reactant: COC(=O)[C@H](CN)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Reactant: O=C(ON1C(=O)CCC1=O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Yield: 51.5 %

Procedure:
A solution of 1-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]oxy]-2,5-pyrrolidinedione (2.10 g, 5.0 mmol), 3-amino-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester hydrochloride (Example 75; 2.00 g, 4.2 mmol), and triethylamine (500 mg, 4.9 mmol) in N,N-dimethylformamide (20 Ml) was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate (125 mmol) was added. The solution was washed with 0.2 M HCl (125 Ml) and the aqueous wash was back-extracted with ethyl acetate (100 Ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and brine (30 Ml each), evaporated, and chromatographed (50–100% ethyl acetate/hexanes) to give 3-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]amino]-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]-carbonyl]benzoyl]-L-alanine, methyl ester (1.61 g, 52%) as a white foam.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:16]([O:15][C:13](=[O:14])[CH2:12][NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNOCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of O-benzylhydroxylamine hydrochloride (5 g, 31.3 mmol) in dry DMF (20 ml) was added tert-butyl 2-bromoacetate (4.7 ml, 1 eq.) and potassium carbonate (4.5 g, 1 eq.). The solution was stirred for 16 h at room temperature. The precipitate was filtered off. The solvent was removed, the residue was dissolved in ethyl acetate and extracted with small portions of 1 N HCl, sodium carbonate solution and brine. After drying over sodium sulfate, the solvent was removed to dryness to give 5.86 g (79%) of the title compound as an oil of sufficient purity. MS 182.1 (M+1-tert-butyl)+
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26]([OH:36])[CH2:27][CH2:28]2)=[CH:23][CH2:22]3)[CH2:19][CH2:18]1)=[CH2:16]>CC(C)=O>[CH3:16][C:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH2:27][CH2:28]2)[C:23](=[O:3])[CH2:22]3)[CH2:19][CH2:18]1)=[CH2:14]
Reactant: CC(C)=O
Reactant: C=C(C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C=C(C)[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.33 h
Yield: 57.4 %

Procedure:
Jones reagent (2.67 M, 1.83 ml, 4.89 mmol) was added to a solution of 20-methylpregna-5,20-dien-3β-ol (400.0 mg, 1.272 mmol) in 45 ml of acetone and the reaction was stirred 20 min. After quenching with 2-propanol (0.91 ml) the mixture was poured into 85 ml of water and extracted three times with 40 ml portions of ethyl acetate. The combined organic extracts were washed with 40 ml of saturated sodium bicarbonate+40 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization of the solid residue from aqueous ethanol gave yellow crystals (235.0 mg, 0.7298 mmol, 57%), m.p. 148-150° C. TLC (20% ethyl acetate/hexanes on silica gel) showed a major product at Rf 0.24 with a minor impurity at the origin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=[O:21])=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH:11]=[CH:12][CH:13]=[O:21]
Reactant: CCCc1ccc(OC)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1ccc(C=CC=O)cc1OC
Temperature: 95 °C
Yield: 79 %

Procedure:
A solution of 3,4-dimethoxyphenylpropane (1 g) in 40 mL of dry dioxane was placed in 100 ml round bottom flask. To this was added a catalytic amount of para-toluenesulphonic acid (0.04 to 0.1 g and 4.5 g of DDQ and finally started refluxing the mixture at 50 to 140° C. for 7 to 16 hrs. The mixture was cooled and the precipitated DDQH2 was filtered and further washed with chloroform. The filtrate and washings were combined and evaporated under reduced pressure. The product was taken in ether (50 ml) and the ether layer was washed with aqueous NaOH (15%, 2×10 ml). The combined aqueous layers are further extracted with ether (3×10 ml). The ether layers were combined and washed with saturated sodium chloride (3×10 ml), dried over anhydrous sodium sulphate and filtered. The solvent was removed to afford a crude yellow liquid which was loaded on silica gel column and the column was eluted with hexane (40-50 ml) and then with an increasing amount of hexane/ethyl acetate (9:1 to 1:9). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 3,4-dimethoxycinnamaldehyde in 79% yield as a yellow solid; mp 74-77° C. ; 1H NMR δ 9.67 (1H, d, H-3′), 7.43 (1H, d, H-1′), 7.15 (1H, d, H-5), 7.08 (1H, s, H-3), 6.91 (1H, d, H-3), 6.61 (1H, dd, H-2′), 3.94 (s, 3H, 3-OCH3), 3.93 (s, 3H, 4-OCH3). The remaining physical and spectral data was found similar as reported.
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[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:50][O:51][C:52]1[C:53]([NH2:58])=[CH:54][CH:55]=[CH:56][CH:57]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:50][O:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[NH:58][C:22](=[O:24])[CH2:21][O:20][C:19]1[CH:25]=[CH:26][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Reactant: COc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 79.7 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenoxy}acetic acid (150 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl) (122 mg), and 1-hydroxybenzotriazole hydrate (HOBT.H2O) (86 mg) were dissolved in chloroform (5 ml) to prepare a solution. o-Anisidine (63 mg) was then added to the solution, and the mixture was heated under reflux for 3 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with 1 N hydrochloric acid, water, and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (155 mg, yield 80%).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10](OCC)=[O:11])=O.[BH4-].[Na+].II.CO>O1CCCC1>[CH3:1][NH:2][CH2:3][CH2:5][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][OH:11]
Reactant: CCOC(=O)COc1ccccc1CC(=O)NC
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCCc1ccccc1OCCO
Temperature: 25 °C
Yield: 28.9 %

Procedure:
At 0° C., a solution of ethyl 2-(2-((N-methylcarbamoyl)methyl)phenoxy)acetate (5.00 g, 19.9 mmol) in tetrahydrofuran (75 ml) was added dropwise to a suspension of sodium borohydri- de (2.26 g, 59.7 mmol) in tetrahydrofuran (75 ml). A solution of iodine (5.05 g, 19.9 mmol) in tetrahydrofuran (150 ml) was added dropwise. The solution was warmed to room temperature and heated to reflux for 16 h. It was cooled to 0° C. Methanol (150 ml) was added dropwise. The solvent was removed in vacuo. The solid residue was dissolved in 20% aqueous so- dium hydroxide solution/tert-butyl methyl ether (150 m/i50 ml). The phases were separated.The aqueous phase was extracted with tert-butyl methyl ether (3×150 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using dichloromethane/methanol/10% aqueous ammonia (first: 100:10:1, then 70:30:3) as eluent, to give 1.124 g of 2-(2-(2-(Methylamino)ethyl)phenoxy)ethanol.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[NH:10])=[N:6][CH:7]=1.[C:21]1(OB(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC.O.C(O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][NH:11][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][N:6]=1)=[NH:10]
Reactant: OB(O)Oc1ccccc1
Reactant: COc1ccccc1CNC(=N)Nc1ccc(I)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COc1ccccc1CNC(=N)Nc1ccc(-c2ccccc2)cn1
Temperature: 120 °C
Yield: 27.6 %

Procedure:
0.102 g (0.251 mmol) N-(5-iodopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine, 0.041 g (0.337 mmol) phenylboric acid, 0.075 g (0.708 mmol) sodium carbonate, and 0.015 g (0.013 mmol) tetrakis-(triphenylphosphine) palladium(0) were combined and added to 7.0 mL of a solvent mixture of 1,2-dimethoxyethane/water/ethanol (7:3:2). The mixture was degassed under a strong nitrogen stream and heated for 110 min at 120° C. in a CEM microwave (150 watts) and reacted. After filtration through a Millipore filter (Ø=25 mm, 0.45 μm) the solvent was removed under vacuum and the crude mixture was purified via preparative HPLC (Merck Chromolith RP-18 100×25 mm, eluent: water/acetonitrile/0.1 M acetic acid), with a flow rate of 20 mL/min and with gradients of 10% to 30% of the acetonitrile fraction in 10 min. Following freeze drying with a lyophilizing agent, 23 mg of the desired product N-(2-methoxybenzyl)-N′-(5-phenylpyridin-2-yl)guanidine was isolated.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(N)cccc1Br
Reactant: OB(O)c1ccsc1
Product: N#Cc1c(N)cccc1-c1ccsc1
Yield: 94 %

Procedure:
Prepared as in Example 129c from thiophen-3-ylboronic acid and 2-amino-6-bromobenzonitrile in 94% yield as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 6.08 (br s, 2H), 6.70 (dd, J=1.2, 7.6 Hz, 1H), 6.77 (dd, J=1.2, 8.4 Hz, 1H), 7.31 (dd, J=7.6, 8.4 Hz, 1H), 7.38 (dd, J=1.2, 4.8 Hz, 1H), 7.66 (dd, J=2.8, 4.8 Hz, 1H), 7.78 (dd, J=1.2, 2.8 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.Cl>>[O:19]=[C:13]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1ccc(C(=O)CCC(=O)O)cc1
Reaction time: 3 h

Procedure:
5 cm3 of ethylbenzene and 2.6 g of aluminum chloride are mixed with magnetic stirring in a 50-cm3 flask. The solution is cooled in an ice bath and 1 g of succinic anhydride is then added. The reaction mixture is stirred for 1 h 30 min at a temperature of 0° C. and then for 3 h at room temperature. It is poured into ice. The resulting mixture is acidified by adding 1N hydrochloric acid (pH 3-4). It is extracted with 3 volumes of ether. The organic phases are washed 3 times with 10% potassium carbonate solution. The aqueous phases are combined and acidified by adding concentrated hydrochloric acid. The precipitate obtained is drained and then recrystallized.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].C(=O)([O-])O.[Na+].[CH3:14][C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]=1[C:26](Cl)=[O:27]>O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:26]([C:16]1[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][O:19][C:15]=1[CH3:14])=[O:27]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: NCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1onc(-c2ccccc2)c1C(=O)NCc1ccccn1
Yield: 92.5 %

Procedure:
A mixture of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (4.06 g, 20 mmol, commercially available) and thionyl chloride (5 mL) was heated under reflux for 3 h. Evaporation of all volatiles afforded 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride (4.4 g, 93%) as yellow oil, which was used without further purification in the next reaction. To a mixture of an aqueous solution of 2-picolylamine (0.182 g, 1.68 mmol) in water (2 mL) and ethyl acetate (4 mL) were added sodium hydrogen carbonate (362 mg, 4.2 mmol) in one portion. Then, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride (0.31 g, 1.4 mmol) in ethyl acetate (2 mL) was added dropwise with vigorous stirring under ice-bath cooling keeping the temperature at 0° C. After addition, the reaction mixture was stirred at room temperature for 18 h. The resulting solution was then diluted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were then washed with brine, dried over sodium sulphate) and concentrated to afford the title compound (0.38 g, 93%) as a white solid. MS: m/e: 294.1 [M+H]+.