Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2NC=N[C:7]=2[CH:6]=1)[NH2:4].C(C1C=C2C([CH2:20][CH2:21][N:22]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]2)=CC=1)#N>>[NH2:4][C:3](=[N:2][OH:1])[C:5]1[CH:6]=[C:7]2[C:8]([CH2:20][CH2:21][N:22]([CH2:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:23]2)=[CH:12][CH:13]=1
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Reactant: CC(C)(C)OC(=O)CN1CCc2ccc(C#N)cc2C1
Product: CC(C)(C)OC(=O)CN1CCc2ccc(C(N)=NO)cc2C1

Procedure:
The title compound was prepared following procedure described for Intermediate 1, step 2, but starting from tert-butyl (7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)acetate obtained in step 1 (3.32 g; 12.19 mmol) as a pale yellow powder (3.69 g; 99%). 1H NMR (DMSO-d6) δ 9.50 (s, 1H), 7.43-7.40 (m, 1H), 7.33 (m, 1H), 7.08 (d, J=8 Hz, 1H), 5.71 (bs, 2H), 3.68 (s, 2H), 3.30 (s, 2H), 2.78 (s, 4H), 1.43 (s, 9H). HPLC (Method A), Rt 1.82 min (Purity: 91.1%). LC/MS (Method B): 306.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(F)c(Cl)c2)C1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a 50 ml of toluene solution containing 5.0 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (27 mmol) and 5.7 g of 4-bromo-2-chloro-1-fluorobenzene (27 mmol) were added 1.7 g of BINAP (2.7 mmol), 0.30 g of palladium acetate (1.3 mmol) and 3.5 g of sodium tert-butoxide (36 mmol). The mixture was heated under reflux under a nitrogen atmosphere for 8 hours, and then cooled to room temperature. Water was added to the reaction solution, and extraction with ethyl acetate was performed. After drying over sodium sulfate and concentration under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate 4:1). The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to thereby obtain 4.76 g of white powdery 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.[Cl:9][CH2:10][C:11](Cl)=[O:12].O.Cl>C(Cl)Cl>[Cl:9][CH2:10][C:11]([C:5]1[S:1][C:2]2[CH:8]=[CH:7][S:6][C:3]=2[CH:4]=1)=[O:12]
Reactant: c1cc2sccc2s1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)c1cc2sccc2s1
Temperature: 0 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
Thieno[3,2-b]-thiophene (38.5 mmol) was solubilized in anhydrous DCM (77 mL) and the chloroacetylchloride (39.66 mmol) was added. The reaction mixture was cooled down to 0° C. and A1Cl3 (43.12 mmol) solubilized in DCM (385 mL) was added slowly. The mixture was stirred at room temperature during 5 hrs. The reaction mixture was cooled again to 0° C. and water and 2N HCl were added until pH=1. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give intermediate E71 as a yellow solid in 43% yield. MS (ESI, EI+) m/z=216.8 (MH+).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][N+:12]=1[O-:19].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[K+].[N-]=C=O.C1(S)C=CC=CC=1.C(=O)([O-])[O-]>O1CCCC1.C(O)C>[Cl:10][C:11]1[N+:12]([O-:19])=[CH:13][C:14]([CH2:17][N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[CH:15][CH:16]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: [O-][n+]1cc(CN2CCN(c3ccccc3)CC2)ccc1Cl
Temperature: 25 °C
Yield: 82.9 %

Procedure:
PS-Diisopropylethylamine (3.54 mmol/g, 0.4 g, 1.40 mmol) was washed with tetrahydrofuran and 2-chloro-5-(chloromethyl)pyridine 1-oxide (100 mg, 0.56 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16, 333) was added followed by tetrahydrofuran (1 mL). A solution of 1-phenylpiperazine (182 mg, 1.12 mmol) in tetrahydrofuran (1 mL) and a catalytic amount of potassium iodide were added, and the mixture was gently stirred (100 r/min) at room temperature for one week. PS-Isocyanate (1.76 mmol/g, 0.80 g, 1.40 mmol) was washed with tetrahydrofuran and added to the mixture followed by additional tetrahydrofuran (1 mL). The suspension was gently stirred (100 r/min) at room temperature for 19 h. The suspension was filtered (20 μm polyethylene filter), and the resins were washed with methylene chloride, tetrahydrofuran, and ethanol. Volatiles were removed in vacuo, and the residue was suspended in a 1:1-mixture of tetrahydrofuran and ethanol (8 mL) followed by the addition of N-ethyl-N,N-diisopropylamine (50 μL, 0.28 mmol). The mixture was added to PS-Thiophenol (1.35 mmol/g, 0.21 g, 0.28 mmol), and MP-Carbonate (3.20 mmol/g, 90 mg, 0.28 mmol), both pre-swelled in tetrahydrofuran. The mixture was stirred (100 r/min) at room temperature overnight followed by filtration. The resins were washed with methylene chloride, tetrahydrofuran, and ethanol, and the filtrate was concentrated in vacuo to give 141 mg (83% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 8.42 (s, 1 H), 7.45 (d, J=8 Hz, 1 H), 7.30-7.26 (m, 2 H), 7.25-7.21 (m, 1 H), 6.95-6.90 (m, 2 H), 6.89-6.85 (m, 1 H), 3.51 (s, 2 H), 3.22-3.18 (m, 4 H), 2.65-2.60 (m, 4 H); MS (ES) m/z 304 (M++1).
Reaction SMILES: C[O:2][C:3]1[CH:25]=[C:24]([O:26]C)[CH:23]=[CH:22][C:4]=1[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH3:18])[C:9](=[O:19])[C@H:8]1[CH2:20][CH3:21])=[O:6].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[OH:2][C:3]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:4]=1[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH3:18])[C:9](=[O:19])[C@H:8]1[CH2:20][CH3:21])=[O:6]
Reactant: CC[C@@H]1C(=O)N(C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1OC
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CC[C@@H]1C(=O)N(C)c2ccc(F)cc2N1C(=O)c1ccc(O)cc1O
Yield: 49 %

Procedure:
(3R)-4-(2,4-Dimethoxybenzoyl)-3-ethyl-6-fluoro-1-methyl-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-4-(2,4-dihydroxybenzoyl)-3-ethyl-6-fluoro-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (49%). MS (ESI) m/z 345 ([M+H]+); MS (ESI) m/z 343 ([M−H]−); HRMS: calcd for C18R17FN2O4, 344.1172; found (ESI_FT), 345.12407.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:13])[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:13]=[C:9]2[CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCCC(=N)Nc1ccc(Cl)cc1
Product: CCCc1nc(C(=O)OCC)cn1-c1ccc(Cl)cc1

Procedure:
The imidazole derivative (6) is prepared by a conventional method [Bayer Pharmaceuticals, WO 03/040107, 2003], for example, by subjecting a nitrile (2) to a reaction with an aniline derivative (1) using aluminum chloride to produce N-(4-chloro phenyl)-butyrimidamide (3). Subsequent reaction of the resulting compound (3) with ethyl 3-bromo-2-oxopropanoate (4) provides an intermediate ethyl 1-(4-chlorophenyl)-2-propyl-1H-imidazole-4-carboxylate (5). An acid form (6) is prepared from the ester (5) using lithium hydroxide, followed by acidification, as shown in Reaction Scheme 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:36].[H][H]>CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:36]
Reactant: O=C(NCC/C=C\c1ccccc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Na+]
Solvent: CO
Product: O=C(NCCCCc1ccccc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a solution of sodium (Z)-6-chloro-7-(4-(4-(2-chlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylate (0.16 g, 0.31 mmol) in methanol (2 mL) was added platinum(IV) oxide (0.018 g, 0.079 mmol), and to the resulting stirred mixture at ambient temperature was fitted a balloon of hydrogen. The flask was purged and refilled five times with hydrogen, and the resulting mixture was stirred at ambient temperature under a balloon of hydrogen for 30 minutes, by which time the catalyst had clumped up. The methanol supernatant was decanted away from the catalyst with a pipet and concentrated, and the residue concentrated from diethyl ether to afford sodium 6-chloro-7-(4-(4-(2-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylate as a white glass (142 mg, 87% yield). MS (apci) m/z=514.1 (M+2H-Na).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:4](=[O:19])[NH:3]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O.Br[C:70]1[CH2:71][C:72](=[O:75])[O:73][CH:74]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:4](=[O:19])[N:3]1[C:70]1[CH2:74][O:73][C:72](=[O:75])[CH:71]=1
Reactant: O=C1CC(Br)=CO1
Reactant: CC1CC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1C1=CC(=O)OC1
Temperature: 60 °C

Procedure:
A mixture of tert-butyl 3-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (I-13) (505 mg, 1.88 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (109 mg, 0.188 mmol), palladium(II) acetate (21 mg, 0.094 mmol), potassium carbonate (520 mg, 3.76 mmol), water (102 μl, 5.65 mmol) and commercially available 4-bromofuran-2-one (368 mg, 2.26 mmol) in toluene (13 mL) was degassed and then heated at 60° C. for 16 hours. The mixture was filtered through a pad of CELITE®, and the filter cake was washed with ethyl acetate. The filtrates were concentrated and the residue was purified by column chromatography eluting with 10-100% ethyl acetate/hexane gradient to give the title compound. LC-MS (IE, m/z): 373.3 (M+23)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][C:10]1([CH3:18])[O:17][C:15](=[O:16])[CH2:14][C:12](=[O:13])[O:11]1.N1CCC[C@H]1C(O)=O>C(#N)C>[CH3:9][C:10]1([CH3:18])[O:17][C:15](=[O:16])[C:14](=[CH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:12](=[O:13])[O:11]1
Reactant: O=Cc1ccncc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC#N
Product: CC1(C)OC(=O)C(=Cc2ccncc2)C(=O)O1
Yield: 84.7 %

Procedure:
Pyridine-4-carboxaldehyde (2.04 g) was mixed with Meldrum's acid (2,2-Dimethyl-[1,3]dioxane-4,6-dione, 2.7 g) and proline (0.20 g) in acetonitrile (40 ml) with stirring under a nitrogen atmosphere. Almost immediately product began to precipitate. The mixture was stirred overnight, filtered and washed with ether, affording 3.7 g of 2,2-dimethyl-5-pyridin-4-ylmethylene-[1,3]dioxane-4,6-dione which was used with no further purification in the next step.
Reaction SMILES: [Cl:1]C1C=CC(O)=CC=1.CC1C=CC(S)=CC=1.[CH3:17][N:18]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][S:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[CH2:26][CH2:25]2)=[CH:22][C:21](=[O:41])[N:20]([CH3:42])[C:19]1=[O:43]>>[ClH:1].[CH3:17][N:18]1[C:23]([N:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][CH2:32][S:33][C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)[CH2:28][CH2:29]2)=[CH:22][C:21](=[O:41])[N:20]([CH3:42])[C:19]1=[O:43]
Reactant: Oc1ccc(Cl)cc1
Agent: Cc1ccc(S)cc1
Agent: Cc1ccc(SCCCN2CCN(c3cc(=O)n(C)c(=O)n3C)CC2)cc1
Product: Cl

Procedure:
The same treatment as in Example 3 was effected except that 4-chlorophenol was replaced with 4-methylthiophenol, thereby obtaining 12.5 g of the crystals of 1,3-dimethyl-6-[4-(3-[4-methylthiophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]([NH:16][C:17](=[O:32])[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:25])=[C:20]([CH3:31])[CH:19]=1)[C:6]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:8]=2[N:7]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].C(N(CC)CC)C.ClCl>O1CCCC1.ClCCl.CO>[C:33]([NH:1][CH2:2][CH2:3][CH2:4][C@H:5]([NH:16][C:17](=[O:32])[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:25])=[C:20]([CH3:31])[CH:19]=1)[C:6]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:8]=2[N:7]=1)(=[O:35])[CH3:34]
Reactant: Cc1cc(C(=O)N[C@@H](CCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: CC(=O)OC(C)=O
Agent: ClCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 73 %

Procedure:
Prepared analogously to Example 124 from (1S)—N-[4-amino-1-(5-chloro-1H-benzimidazol-2-yl)butyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, acetic anhydride, and triethylamine in tetrahydrofuran. Yield: 73%; Rf value: 0.73 (silica gel; dichloromethane/methanol=95:5); C26H30ClN5O3 (496.01); mass spectrum: (M+H)+=496/498 (chlorine isotope) and (M−H)-=494/496 (chlorine isotope).
Reaction SMILES: C(S(NS(F)(=O)=O)(=O)=O)(F)(F)F.[Cl:13][C:14]([Cl:20])([Cl:19])[S:15]([NH2:18])(=[O:17])=[O:16].S(Cl)(Cl)=O.[Cl:25][S:26](O)(=[O:28])=[O:27]>>[C:14]([S:15]([NH:18][S:26]([Cl:25])(=[O:28])=[O:27])(=[O:17])=[O:16])([Cl:20])([Cl:19])[Cl:13]
Reactant: O=S(=O)(O)Cl
Reactant: NS(=O)(=O)C(Cl)(Cl)Cl
Agent: O=S(=O)(F)NS(=O)(=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: O=S(=O)(Cl)NS(=O)(=O)C(Cl)(Cl)Cl

Procedure:
This example illustrates synthesis of CF3SO2NHSO2F by the reaction of trichloromethane sulfonamide (CCl3SO2NH2), thionyl chloride (SOCl2), chlorosulfonic acid (ClSO3H) to produce CCl3SO2NHSO2Cl intermediate, and fluorinating the intermediate with anhydrous hydrogen fluoride (HF) to produce CF3SO2NHSO2F.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.CN(CCN(C)C)C.[Li]CCCC.[I:31]I.C1C2C3C=CC=CC=3OC=2C=CC=1>C(OCC)C.C(Cl)Cl.OS([O-])=O.[Na+]>[I:31][C:15]1[C:10]2[O:9][C:8]3[C:3]([Si:2]([CH3:17])([CH3:16])[CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: II
Reactant: C[Si](C)(C)c1cccc2c1oc1ccccc12
Agent: CN(C)CCN(C)C
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccc2c(c1)oc1ccccc12
Product: C[Si](C)(C)c1cccc2c1oc1c(I)cccc12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 103.4 %

Procedure:
To a solution of 4-trimethylsilyldibenzofuran (4) (7.93 g, 33.0 mmol) in dry diethyl ether (70 mL ) and TMEDA (7.97 mL, 52.8 mmol) cooled in an ice-water bath was slowly added n-BuLi (33.0 mL of 1.6 M solution in hexanes, 52.8 mmol) via a syringe. The resulting dark brown solution was stirred at room temperature for 5.5 hours. In a separate oven dried, 500 mL round bottom flask, I2 (19.2 g, 75.9 mmol) was dissolved in dry Et2O (70 mL) and cooled to -78° C. in an acetone-dry ice bath. The dibenzofuran anion was then slowly canulated into the stirring I2 solution. The resulting brown mixture was allowed to warm to room temperature while stirring overnight. The mixture was transferred to a cold (0° C.) solution of 20% NaHSO3 (~500 mL) and stirred vigorously. It was diluted with CH2Cl2 (~200 mL) and additional solid NaHSO3 was added until the mixture became pale yellow. Vigorous stirring was continued for 2.5 hours. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were extracted with 20% NaHSO3 (2×150 mL), dried over magnesium sulfate and concentrated under reduced pressure to give a pale yellow solid. Dissolving the yellow solid in hexanes allowed separation of the compound from a brown, gummy, insoluble impurity. The hexane solution was decanted and concentrated under reduced pressure to give 12.5 g of compound (5). The crude material in hexanes (35 mL) was filtered through a silica gel column using hexanes (~300 mL ) as eluant. In this filtration only two 125 mL fractions were collected (t.l.c. rf=0.45 in hexanes). Since the second fraction appeared slightly yellowish, the two fractions were analyzed separately and combined later to give 8.57 g of a cream colored solid (75% based on 95% monosilylated dibenzofuran in the starting material). The melting points for the first and second fractions were 62-69° C. and 71-78° C., respectively. However, the two fractions were identical by 1H-NMR and HPLC. An analytical sample was obtained after purification by preparative C4 HPLC as a white solid: mp 74-77° C.; 1H NMR (CD3Cl) d 7.92 (dd, Jo=7.6, Jm=1.4, 1H, Ar H3), 7.90 (dd, Jo=7.6, Jm=1.5, 1H, Ar H7), 7.79 (dd, Jo=7.8, Jm=1.1, 1H, Ar H1), 7.56 (dd, Jo=7.2, Jm=1.4, 1H, Ar H9), 7.35 (t, Jo=7.6, 1H, Ar H8), 7.09 (t, Jo=7.7, 1H, Ar H2), 0.50 (s, 7H, --Si(CH3)3); 13C NMR (CD3Cl) d 156.33, 150.04, 135.47, 132.91, 124.39, 124.12, 123.50, 122.94, 122.88, 122.03, 120.47, -1.06; EIMS m/z 365.9877, M+ calcd for C15H15OISi 365.9939 and 350.9676, [M-CH3]+ calc 350.9704.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[NH:19]1[CH2:22][CH:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:28][C:26]1[O:25][N:24]=[C:23]([CH:21]2[CH2:22][N:19]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]3[CH:7]=[C:6]4[C:11](=[N:10][CH:9]=3)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]4)[CH2:20]2)[N:27]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: Cc1nc(C2CNC2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C2CN(C(=O)/C=C/c3cnc4c(c3)CCC(=O)N4)C2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-azetidin-3-yl-5-methyl-1,2,4-oxadiazole hydrochloride (25 mg, 0.14 mmol; which may be prepared as described in Step 5), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a white solid. This solid was triturated in acetone and diethyl ether, filtered, washed with acetone and diethyl ether then dried to give the title compound (23 mg, 56%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([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)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(2-naphthyl)propionate hydrochloride (Bachem), the title compound was prepared as a solid (mp=166° C.). The reaction was monitored by tlc (Rf=0.55 in 5% MeOH/methylene chloride) and the product was purified by preparative tlc using 5% MeOH/methylene chloride as the eluent.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:12][CH2:13][CH2:14]O)[C:10]#[N:11])=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:12][CH2:13][CH2:14][Cl:18])[C:10]#[N:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: N#CC(Cc1ccc(Cl)nc1)NCCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: N#CC(Cc1ccc(Cl)nc1)NCCCl

Procedure:
This compound was prepared in a manner analogous to that set forth in Step C of Example 1, using 5.7 grams (0.0255 mole) of 2-{[(6-chloro(3-pyridyl)methyl](2-hydroxyethylamino}ethanenitrile 3.2 grams (0.0268 mole) of thionyl chloride and one drop (catalyst) of pyridine in 50 mL of chloroform. The yield of the subject compound was 6.0 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([CH3:13])=[C:5]([C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])[CH:6]=[O:7].Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22]>CO.C1(C)C=CC=CC=1>[CH3:13][C:4]1[C:3]([O:2][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])=[C:10]([CH3:11])[CH:9]=[C:8]([CH3:12])[C:5]=1[CH:6]=[O:7]
Reactant: O=C1NCCN1CCCl
Reactant: Cc1cc(C)c(C=O)c(C)c1O
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(OCCN2CCNC2=O)c(C)c1C=O

Procedure:
To a solution of sodium (1.63 g, 0.071 mol) in methanol (60 mL) is added dropwise 3-hydroxy-2,4,6-trimethylbenzaldehyde (11.90 g, 0.073 mol) in anhydrous toluene (300 mL). The mixture is heated under reflux and then the methanol is distilled off (volume of azeotropic mixture collected 80-90 mL). After returning to 80-90° C., (2-chloroethyl)imidazolidin-2-one (10.45 g, 0.070 mol) is added all at once to the reaction medium. After heating for 7 hours under reflux, the solvents are evaporated under reduced pressure (Tbath 50° C., 25 mbar). Dichloromethane (150 mL) and water (30 mL) are added to the mixture obtained. The organic phase is then washed twice with water (20 mL). After drying over Na2SO4, the dichloromethane is evaporated under reduced pressure (Tbath 35° C., 33 mbar). Petroleum ether (3 times 50 mL) and water (50 mL) are added to the mixture obtained (24 g) and the precipitate obtained is filtered and washed on the filter with water (15 mL) and petroleum ether (twice 15 mL).