Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:11][O:12][N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][O:12][N:13]([CH3:18])[C:14]([CH:15]=[CH:16][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])=[O:17]
Reactant: NC(=O)c1cccc(I)c1
Reactant: C=CC(=O)N(C)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1cccc(C(N)=O)c1
Yield: 58 %

Procedure:
3-Iodo-benzamide compound 32 (3.0 g, 12.1 mmol), N-methoxy-N-methylacrylamide (Molander, G. G.; Stengel, P. J. Tetrahedron 1997, 53, 26, 8887-8912.) (1.8 g, 15 mmol), palladium (II) acetate (40 mg, 0.18 mmol), and triethylamine (2.1 mL, 15 mmol) were stirred in acetonitrile (12 mL) under argon in a sealed tube at 100° C. for 2.5 h. The reaction was allowed to cool, and solvent was removed. The residue was dissolved in CH2Cl2, washed with 0.1 N HCl and then with brine, dried (MgSO4), and concentrated. Recrystallization twice from methanol gave 1.64 g (58%) of 3-[2-(methoxy-methylcarbamoyl)-vinyl]benzamide 43 as a white solid. 1H NMR (CDCl3) δ 8.06 (1 H, s), 7.78 (1 H, d, J=7.8 Hz), 7.73 (1 H, d, J=16.2 Hz), 7.69 (1 H, d, J=7.8 Hz), 7.46 (1 H, t, J 7.8 Hz), 7.10 (1 H, d, J=16.2 Hz), 6.33 (1 H, br s), 5.97 (1 H, br s), 3.77 (3 H, s), 3.31 (3 H, s); IR (KBr) 3385, 3173, 1680, 1649, 1613, 1582, 1476, 1433, 1397, 1182, 1105 cm−1. Anal. (C12H14N2O3.0.33 H2O) C, H, N.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:32]=5)[N:27]=4)[CH2:22][CH2:21]3)=[O:19])[CH2:12][CH2:11]2)=[CH:5][C:4]=1[C:40]([F:43])([F:42])[F:41])#[N:2].[H-].[Na+].I[CH3:47]>C1COCC1.O>[CH3:47][N:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:40]([F:42])([F:43])[F:41])[CH:5]=1)[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]([F:37])([F:38])[F:39])[CH:32]=4)[N:27]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:12][CH2:11]1
Reactant: CI
Reactant: N#Cc1ccc(NC2CCC(OCC(=O)N3CCN(c4ccc5cc(C(F)(F)F)ccc5n4)CC3)CC2)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ccc(C#N)c(C(F)(F)F)c1)C1CCC(OCC(=O)N2CCN(c3ccc4cc(C(F)(F)F)ccc4n3)CC2)CC1
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of 2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]-cyclohexyl)oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]ethan-1-one (100 mg, 0.16 mmol) in THF (3 ml) was added sodium hydride (25 mg, 0.63 mmol, 3.9 eq.) and the mixture was stirred for 30 minutes. The mixture was then treated with iodomethane (100 mg, 0.7 mmol, 4 eq.) and stirred for 5 days. The resulting mixture was diluted with water (30 ml), and extracted with ethyl acetate (30 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue from which the product was purified by silica gel column flash chromatography eluting with ethyl acetate/heptanes to afford 2-[(4-[methyl[4-cyano-3-(trifluoromethyl)phenyl]-amino]-cyclohexyl)oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl)piperazin-1-yl]ethan-1-one as a yellow solid (100 mg, 98%). (CI, m/z): [M+H]+ 620; 1H NMR (400 MHz, DMSO-d6): δ 8.24 (d, J=9.3 Hz, 1H), 8.17 (s, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.13-7.07 (m, 2H), 4.23 (s, 2H), 3.94-3.76 (m, 5H), 3.63-3.57 (m, 4H), 3.41-3.32 (m, 1H), 2.85 (s, 3H), 2.14-2.05 (m, 2H), 1.69-1.57 (m, 4H), 1.50-1.38 (m, 2H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[N:12][O:13][CH3:14])[CH2:10][CH3:11])[C:4](OCC)=[O:5].[CH3:15][NH2:16]>>[CH3:15][NH:16][C:4](=[O:5])[C:3](=[N:2][OH:1])[C:9](=[N:12][O:13][CH3:14])[CH2:10][CH3:11]
Reactant: CN
Reactant: CCOC(=O)C(=NO)C(CC)=NOC
Product: CCC(=NOC)C(=NO)C(=O)NC
Reaction time: 0.08 h

Procedure:
a mixture of 7.6 parts ethyl 2-hydroxyimino-3-methoxyiminovalerate was mixed with 7 parts 40% aqueous methylamine solution at 25° C. and stirred till homogeneous (5 minutes). The mixture was allowed to stand 18 hours and then evaporated under reduced pressure (15 mm) at 50° C. water-bath temperature to dryness. Recrystallization of the residue from acetonitrile gave 4.3 parts of N-methyl-2-hydroxyimino-3-methoxyiminovaleramide, m.p. 168°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20](O)=[O:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:27][O:26][N:25]([CH3:24])[C:20]([C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[CH:8][C:7]=2[CH:19]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:21]
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(=O)O)c3o2)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(OC)cc(C(=O)N(C)OC)c3o2)cc1
Yield: 72 %

Procedure:
A solution of 23 (1.7 g, 5.7 mmol), N,O Dimethylhydroxyamine HCl (1.7 g, 17.1 mmol), DMAP (2.1 g, 17.1 mmol), and EDCl (1.9 g, 10 mmol) in DMF (30 ml) was stirred at rt for 1 hr. The reaction was then poured into 2 NHCl and extracted with EtOAc which was dried over MgSO4, concentrated, and the product was purified by column chromatography on silica gel (30% EtOAc/Hex) to give 121 as a solid (1.4 g, 74%); Mp=109-111° C.; 1H NMR (CDCl3) δ 7.77 (d, 2 H, J=8.7 Hz), 7.09 (d, 1 H, J=2.4 Hz), 6.99-6.95 (m, 3 H), 6.84 (s, 1 H), 3.86 (s, 6 H), 3.69 (s,3 H), 3.40 (s,3 H); MS 342 (M+H)+
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[NH2:6][C:7]([C:9]1[C:10]([Cl:23])=[C:11]([CH:16]=[CH:17][C:18]=1[S:19]([CH3:22])(=[O:21])=[O:20])[C:12]([O:14][CH3:15])=[O:13])=[O:8]>C1(C)C=CC=CC=1>[Cl:23][C:10]1[C:9]([C:7]2[O:8][C:2](=[O:3])[S:4][N:6]=2)=[C:18]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(N)=O)c1Cl
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(S(C)(=O)=O)c(-c2nsc(=O)o2)c1Cl
Yield: 70.5 %

Procedure:
9.80 g (75 mmol) of chlorocarbonylsulfenyl chloride were added dropwise to a solution of 4.37 g (15 mmol) of methyl 3-aminocarbonyl-2-chloro-4-methylsulfonylbenzoate in 150 ml of dry toluene. The mixture was stirred under reflux for 48 hours, and the solvent was then removed under reduced pressure and the residue was chromatographed over silica gel (eluent: ethyl acetate/cyclohexane=1/1). 3.70 g (70% of theory) of methyl 2-chloro-3-(1,3,4-oxathiazolin-2-on-5-yl)-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[NH3:25]>C(#N)C>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=[C:5]([NH2:25])[N:10]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: N
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(N)n2)cc1
Reaction time: 18 h

Procedure:
A solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (2 g, 5.258 mmol) in acetonitrile (30 ml) was treated with 0.880 ammonia (6 ml) dropwise. The resulting mixture was then stirred at 20 C. for 18 h. This gave the title compound as a colourless precipitate which was collected by filtration and dried (1.53 g)
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12](O)[CH2:13][NH:14][CH3:15])=[CH:8][CH:7]=1.O>ClC1C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:6]2[CH:11]=[CH:10][C:9]([Cl:1])=[CH:8][CH:7]=2)[CH2:13][NH:14][CH3:15])=[CH:8][CH:7]=1
Reactant: CNCC(O)c1ccc(Br)cc1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: O
Solvent: Clc1ccccc1
Product: CNCC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Aluminium chloride (278 mg, 2.087 mmol) was added portionwise to a stirred solution of 1-(4-Bromo-phenyl)-2-methylamino-ethanol (160 mg, 0.696 mmol) in chlorobenzene (3 ml) and the reaction mixture stirred at room temperature for 17 hours. Water (2 ml) was added dropwise and the reaction mixture was then partitioned between dichloromethane (100 ml) and saturated NaHCO3 (30 ml). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was then purified by Phenomenex_Strata_SCX column chromatography eluting with methanol followed by 2N ammonia in methanol to afford the desired product. LC/MS: (PS-B3) Rt 3.58 [M+H]+ 324.
Reaction SMILES: O[C:2]1C=C2C(=CC=1)NC(=O)CC2.N1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31][CH2:30]2)(=[O:21])=[O:20]>>[C:14]1([S:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32](=[O:37])[CH2:31][CH2:30]3)(=[O:21])=[O:20])[CH:2]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCc2cc(OCCCCS(=O)(=O)c3ccccn3)ccc2N1
Reactant: O=C1CCc2cc(O)ccc2N1
Product: O=C1CCc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 4 from 6-hydroxy-3,4-dihydro-carbostyril and 4-phenylsulfonyl-butyl bromide (prepared from 4-(phenylmercapto)-butyl bromide by oxidation analogous to Example 3).
Reaction SMILES: S1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[C:15]4[C:20](=[N:21][CH:22]=3)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]4)[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.O[O:27][S:28]([O-:30])=O.[K+]>O1CCOCC1.O>[O:27]=[S:28]1(=[O:30])[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[C:15]4[C:20](=[N:21][CH:22]=3)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]4)[CH:10]=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(C4=CCSCC4)c3)cnc21
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)N1CCCc2cc(-c3cncc(C4=CCS(=O)(=O)CC4)c3)cnc21
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To 6-[5-(3,6-dihydro-2H-thiopyran-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (57 mg, 0.16 mmol) in 2 mL of 1:1 dioxane/H2O is added oxone (266 mg, 0.32 mmol). The mixture is stirred for 2 h. The mixture is quenched by addition of sodium sulfite and concentrated. The residue is suspended into MeOH and filtered. The filtrate is concentrated and purified via the Preparative HPLC (5%-70% CH3CN/H2O) to give 62.6 mg of the titled product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+]>C1COCC1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Brc1ccccc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)cc1
Yield: 94.4 %

Procedure:
Bromobenzene (79 mg, 0.50 mmol) reacted with 4-methoxyphenylboronic acid (99 mg, 0.65 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in THF solvent at room temperature to give the title compound (87 mg, 95%) as a white solid. The reaction of 4-chloroanisole (71 mg, 0.50 mmol) with phenylboronic acid (92 mg, 0.75 mmol) gave the title compound (74 mg, 80%) using 1/2 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF in THF solvent at 40° C. 1H-NMR (400 MHz, CDCl3): δ 7.61 (m, 4H), 7.48 (t, 2H, J=7.6 Hz), 7.37 (app.t, 1H, J=7.2 Hz), 7.04 (d, 2H, J=8.8 Hz), 3.90 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 159.09, 140.76, 133.69, 128.66, 128.08, 126.67, 126.60, 114.14, 55.26. GC/MS(EI): m/z 184 (M+). Anal. Calcd for C13H12O: C, 84.75; H, 6.56. Found: C, 84.86; H, 6.76.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([C:17](=[O:19])[CH3:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][N:11]([C:17](=[O:19])[CH3:18])[CH2:12][CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 100.5 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (6.7 g, 47.5 mmol), 1-piperazin-1-yl-ethanone (6.7 g, 52.3 mmol) and K2CO3 (6.6 g, 47.5 mmol) in DMSO (60 mL) was heated at 100° C. for 18 h. After cooling, the mixture was poured into H2O (0.5 L). The resulting yellow precipitate was filtered and washed with H2O to afford of 1-[4-(4-nitro-phenyl)-piperazin-1-yl]-ethanone (11.9 g). This was partially dissolved in EtOH (100 mL) and AcOH (50 mL). The mixture was warmed to ca. 65° C. and iron powder (−325 mesh, 12.0 g, 215 mmol) was added in 1-g portions. The mixture was heated at reflux for 2 hr and filtered through a pad of Celite. The filtrate was evaporated to leave a black oil, which was basified by addition of 2 M aq NaOH and was extracted with EtOAc. The combined organics were washed with brine, dried on MgSO4, filtered, and evaporated in vacuo to afford 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (6.7 g) as a yellow solid. An aliquot of this material (2.0 g, 9.12 mmol) was dissolved in EtOH (5 mL) and HNO3 was added (69% aq soln., 1.26 mL, 19.61 mmol), followed by cyanamide (50% w/v aq soln., 2.48 mL, 31.92 mmol). The resulting mixture was heated at reflux for 18 h. It was cooled to room temperature and poured into Et2O (100 mL). The ethereal layer was separated and concentrated. The resulting precipitate was filtered and washed with iPrOH/Et2O, then neat Et2O. The light brown solid was dried to afford N-[4-(4-acetyl-piperazin-1-yl)-phenyl]-guanidine nitrate (1.2 g). This material (1.1 g, 2.84 mmol) was dissolved in 2-methoxyethanol (14 mL) and K2CO3 (0.79 g, 5.68 mmol) was added, followed by 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (0.60 g, 2.84 mmol). The resulting mixture was heated at 115° C. for 18 h. It was cooled and concentrated. The residue was purified by SiO2 chromatography (9:1 EtOAc/2 M NH3 in MeOH) and recrystallisation from iPr2O/MeOH to afford the title compound (930 mg) as a light brown solid. 1H-NMR (CDCl3) δ: 2.15 (s, 3H, CH3), 2.69 (s, 3H, CH3), 2.71 (s, 3H, CH3), 3.12 (t, 2H, J=5.4 Hz, CH2), 3.15 (t, 2H, J=5.4 Hz, CH2), 3.63 (t, 2H, J=5.4 Hz, CH2), 3.79 (t, 2H, J=5.4 Hz, CH2), 6.90 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 6.96 (m, 2H, Ph-H), 6.98 (br. s, 1H, NH), 7.54 (m, 2H, Ph-H), 8.39 (d, 1H, J=5.4 Hz, pyrimidinyl-H). MS (ESI+) m/z 409.6 (C21H24N6OS requires 408.5).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].Cl[CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:21][C:22]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([O:15][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)c1cc(O)cc(OCC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OCC)cc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of ethyl 3-ethoxy-5-hydroxybenzoate (3.00 g), 4-chloromethyl-5-methyl-2-phenyloxazole (3.26 g), potassium carbonate (2.17 g) and N,N-dimethylformamide (60 ml) was stirred at 80° C. for 2 hrs. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and ethyl 3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzoate (5.40 g, 99%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25](O)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>O1CCCC1>[N:44]1[CH:45]=[CH:46][CH:47]=[C:42]([NH:41][C:25](=[O:26])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:43]=1
Reactant: Nc1cccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Nc1cccnc1
Reaction time: 0.25 h
Yield: 22.6 %

Procedure:
N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine (I) (3.71 g) was dissolved in dry tetrahydrofuran (100 ml) and, under ice cooling, triethylamine (1.5 ml) was added thereto. After stirring for 15 minutes, ethyl chlorocarbonate (1.10 g) was added, followed by stirring for 30 minutes. To this solution was added 3-aminopyridine (0.94 g) and the reaction was carried out at room temperature for 7 hours. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate. After a conventional post-treatment, N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine 3-pyridylamide (II) (1.01 g) was obtained.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:14])[NH:4][N:5]=[C:6](OCC)[CH2:7][CH2:8][CH2:9][CH3:10].[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1)#[N:16]>CCO>[CH3:1][S:2][C:3](=[NH:14])[NH:4][N:5]=[C:6]([NH:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]#[N:16])=[CH:28][CH:27]=1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Reactant: CCCCC(=NNC(=N)SC)OCC
Solvent: CCO
Product: CCCCC(=NNC(=N)SC)NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 71.4 %

Procedure:
A mixture of 5.50 g (25.3 mmol) of ethyl valerate S-methylisothiosemicarbazone (from Step B), 6.55 g (31.5 mmol) of [(2'-cyanobiphenyl-4-yl)methyl]amine (EP 0412594 published Feb. 13, 1991, Merck Case No. 17959IA), and 57 ml of dry EtOH was stirred under N2 at room temperature for 6 days and then concentrated in vacuo at ≤30° C. The residue was chromatographed on a column of silica gel (38×8.8 cm) packed in CH2Cl2. Gradient elution with 0.5-2% MeOH in CH2Cl2 and concentration of combined product fractions gave 6.86 g (71%) of the title compound as a yellow gum; satisfactory purity by TLC in 19:1 CH2Cl2 -MeOH. NMR indicated a mixture of syn and anti isomers.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:44])[CH2:15][C@@H:16]([C:22]1[CH:43]=[CH:42][C:25]([O:26][CH2:27][C:28]2[CH:29]=[C:30]([NH:34]C(=O)OC(C)(C)C)[CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][O:26][C:25]1[CH:42]=[CH:43][C:22]([C@@H:16]([C:17]2[CH:21]=[CH:20][O:19][N:18]=2)[CH2:15][C:14]([N:9]2[C@@H:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:44])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a cooled solution (0° C.) of carbamate 27.2 (430 mg, 0.719 mmol) in DCM (4 mL), was slowly added TFA (4 mL). The reaction mixture was allowed to slowly warm to room temperature over three hours. The mixture was then concentrated to dryness under reduced pressure and dissolved in DCM (100 mL). The resulting mixture was extracted with saturated sodium bicarbonate solution (1×30 mL). The aqueous layer was then extracted with DCM (1×50 mL). The organic layers were then combined and washed with brine (1×50 mL) and dried over magnesium sulfate. The filtrate was concentrated, and the residue was purified by medium pressure chromatography (silica gel, 20 to 60% EtOAc:DCM) to give 27.3 (204 mg). MS ESI (pos.) m/e 498.1 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (1H, d, J=1.6 Hz), 7.09-7.29 (8H, m), 6.75-6.88 (4H, m), 6.68 (1H, dd, J=7.6, 2.2 Hz), 6.06 (1H, d, J=1.6 Hz), 4.89 (2H, s), 4.67 (1H, dd, J=8.2, 6.7 Hz), 4.50-4.58 (1H, m), 4.01-4.06 (2H, m), 3.94 (1H, dd, J=17.6, 8.6 Hz), 3.42-3.49 (1H, m), 3.13 (1H, dd, J=13.5, 3.3 Hz), 2.68 (1H, dd, J=13.5, 9.6 Hz).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[C:9](Br)=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH2:14]([O:17][C:18]1[C:23]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][C:21]([CH2:28][CH3:29])=[CH:20][C:19]=1B(O)O)[CH2:15][CH3:16].C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=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:1]([C:4]1[O:8][C:7]2[C:9]([C:19]3[CH:20]=[C:21]([CH2:28][CH3:29])[CH:22]=[C:23]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:18]=3[O:17][CH2:14][CH2:15][CH3:16])=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2cccc(Br)c2o1
Reactant: CCCOc1c(B(O)O)cc(CC)cc1C(C)(C)C
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: Cc1ccccc1
Product: CCCOc1c(-c2cccc3cc(C(C)=O)oc23)cc(CC)cc1C(C)(C)C
Temperature: 25 °C

Procedure:
To a mixture of 57 mg (0.049 mmol, 5%) of Pd(PPh3)4, 362 mg (1.26 mmol) of 2-acetyl-7-bromobenzo[b]furan and 2.52 mmol of 2-propoxy-3-tert-butyl-5-ethyl phenylboronic acid in 10 mL of toluene, and 5 mL of ethanol was added 1.3 mL of a 2N Na2CO3 aqueous solution. The mixture was heated to reflux for 3 hours and after cooling (room temperature) extracted with ethyl acetate. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was filtrated over a short silica plug (eluent: ethyl acetate/hexane: 10/90) and recrystallized from hexane to afford 2-acetyl-7-(2-propoxy-3-tert-butyl-5-ethylphenyl)benzo[b]furan as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]([OH:18])=O)=[CH:8]1.[ClH:19].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:41][C:42]([NH2:44])=[NH:43]>O1CCCC1>[ClH:19].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]([NH:43][C:42]([NH2:44])=[NH:41])=[O:18])=[CH:8]1
Reactant: O=C(O)c1cn(-c2ccccn2)c2ncccc12
Reactant: N=C(N)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: N=C(N)NC(=O)c1cn(-c2ccccn2)c2ncccc12
Temperature: 20 °C
Reaction time: 384 h

Procedure:
1-(Pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 0.46 g (2.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.027 g (0,2 mmol) of 1-hydroxybenzotriazole were added to 0.59 g (10 mmol) of guanidine in 15 cm3 of tetrahydrofuran under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 days, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) and the residue was triturated in 20 cm3 of methanol and then filtered. The filtrate was concentrated to dryness under reduced pressure (2.7 kPa) and the residue was purified by flash chromatography on silica gel, elution being carried out with a 100% of dichloromethane to dichloromethane/methanol/triethylamine (50/48/2 by volume) gradient over 90 min. After concentrating the fractions comprising the expected product to dryness under reduced pressure (2.7 kPa), the solid obtained was triturated in 20 cm3 of ethanol and filtered off, affording 0.028 g of N-[1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine hydrochloride in the form of a beige powder melting at 205–207° C. 1H N.M.R. spectrum (300 MHz, (CD3)2SO, 8 in ppm): from 7.30 to 7.45 (m, 2H), 8.08 (ddd, J=9, 8 and 2 Hz, 1H), 8.43 (dd, J=5 and 2 Hz, 1H), 8.59 (dd, J=5 and 2 Hz, 1H), 8.84 (dd, J=8 and 2 Hz, 1H), 8.89 (s, 1H), 8.95 (d, J=9 Hz, 1H).