Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13](C(OC(C)(C)C)=O)[C:14]2[N:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl.CCOC(C)=O.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cnc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccccc3)C2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)cn1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To an ice-cooled solution of ethyl (2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinyl)acrylate (4.63 g) in dichloromethane (7.8 ml) were added anisole (4.7 ml) and trifluoroacetic acid (15.6 ml), the mixture was stirred at 25° C. for 3.5 hours. The mixed solution was poured into a mixture of water and AcOEt. The pH of the aqueous layer was adjusted to ca.8 with NaHCO3. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give crude powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.F[B-](F)(F)F.[N:37]1(OC(N(C)C)=[N+](C)C)[C:41]2[CH:42]=CC=C[C:40]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)(C)C>C(#N)C.C(OCC)(=O)C.O>[CH:41]([NH:37][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]=1)=[O:22])([CH3:42])[CH3:40]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.175 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (84 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.076 ml, 0.44 mmol) were dissolved in acetonitrile (1.75 ml). Isopropylamine (0.018 ml, 0.21 mmol) was added and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added, the layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 45 mg (52%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide. (M+H)+=500.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([OH:12])=O)[CH:5]=1)([CH3:3])[CH3:2].[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1>>[NH:15]1[C:14]([NH:13][C:10]([C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][N:7]=2)=[O:12])=[N:18][N:17]=[N:16]1
Reactant: CC(C)c1ccnc(C(=O)O)c1
Reactant: Nc1nnn[nH]1
Product: CC(C)c1ccnc(C(=O)Nc2nnn[nH]2)c1
Yield: 28.8 %

Procedure:
0.42 g of 4-isopropyl-2-pyridinecarboxylic acid, 0.42 g of N,N'-carbonyldiimidazole and 0.24 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and water, whereby 0.17 g of N-(5-tetrazolyl)-4-isopropyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:49][NH:50]C(OC(C)(C)C)=O)[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:42]=[CH:43][C:44]=1[CH2:45][N:46]([CH3:48])[CH3:47])[C:9]([NH:11][C@H:12]([B:29]1[O:37]C2C(C)(C3CC(C2)C3(C)C)[O:30]1)[CH2:13][C:14]1[C:15](OC)=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19]C(C)(C)C)=[O:18])=[O:10])=[O:4].B(Cl)(Cl)Cl>>[NH2:1][C@@H:2]([CH2:49][NH2:50])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:42]=[CH:43][C:44]=1[CH2:45][N:46]([CH3:48])[CH3:47])[C:9]([NH:11][C@H:12]1[CH2:13][C:14]2[CH:26]=[CH:25][CH:24]=[C:16]([C:17]([OH:19])=[O:18])[C:15]=2[O:37][B:29]1[OH:30])=[O:10])=[O:4]
Reactant: COc1c(C[C@H](NC(=O)c2ccc(CN(C)C)c(NC(=O)[C@@H](N)CNC(=O)OC(C)(C)C)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: CN(C)Cc1ccc(C(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)cc1NC(=O)[C@@H](N)CN

Procedure:
Prepared from tert-butyl 3-((2R)-2-(3-((S)-2-amino-3-(tert-butoxycarbonylamino)propanamido)-4-((dimethylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 470 (MH)+.
Reaction SMILES: [Si]([O:8][CH:9]([CH3:21])[CH:10]([OH:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)(C(C)(C)C)(C)C.[H-].[Na+].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[CH2:34]Br.C(OCC)C>O1CCCC1.CN(C)C=O.O>[Cl:19][C:14]1[CH:13]=[C:12]([CH2:11][CH:10]([O:20][CH2:34][C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)[CH:9]([OH:8])[CH3:21])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)C(Cc1ccc(Cl)c(Cl)c1)OCc1ccc2ccccc2c1
Yield: 18.5 %

Procedure:
2.32 g of the alcohol compound thus obtained was dissolved in a liquid mixture of 100 ml of tetrahydrofuran and 20 ml of dimethylformamide, and 0.34 g of 60% oily sodium hydride was added thereto with stirring under cooling with ice. The mixture was stirred at the same temperature for 30 minutes. Then, 1.47 g of 2-naphthylmethyl bromide was added thereto, and the mixture was stirred at room temperature for 20 hours. Then, ethyl ether and water were added to the reaction solution for liquid separation. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane+hexane/ethyl acetate=50/1) for rough purification and then added to a liquid mixture of 100 ml of tetrahydrofuran and 8 ml of a 1M tetrahydrofuran solution of tetrabutylammonium fluoride. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was extracted by an addition of ethyl acetate and water. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=20/1→5/1) to obtain 0.46 g (yield: 18%) of 4-(3,4-dichlorophenyl)-3-(2-naphthylmethoxy)-2-butanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][CH2:20][CH3:21].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][O:19][CH2:20][CH3:21])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1ccc(Br)cc1Cl
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a mixture of 4-bromo-2-chlorophenol (15.92 g) and potassium carbonate (15.9 g) in DMF (100 ml) was added at room temperature 2-bromoethylethyl ether (9.51 ml), and the mixture was stirred at 60° C. for 18 hours. To the mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give pale yellow oil of 4-bromo-2-chloro-1-(2-ethoxyethoxy)benzene (21.76 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].I[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>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]=[CH:6][C:5]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Oc1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
4-Chloro-3-(trifluoromethyl)phenylboronic acid (448 mg, 2 mmol) and 4-iodophenol (440 mg, 2 mmol) were dissolved in dioxane (10 mL). Caesium carbonate (1.95 g, 6 mmol), water (2 mL) and tetrakis(triphenylphosphine)palladium (0) (231 mg, 0.2 mmol) were added and the reaction stirred at 80° C. for 1 hour. The reaction was quenched with 2M HCl (5 mL) and partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate was separated, dried over MgSO4 and evaporated. The crude product was chromatographed on silica eluting with a gradient of heptane:ethyl acetate 100:0 to 80:20 to give the title compound (150 mg, 0.55 mmol, 27%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](C(OCC)=O)[CH2:4][CH:3]1[CH2:13][CH3:14]>[OH-].[Na+]>[NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH2:13][CH3:14]
Reactant: CCOC(=O)N1CCC(N)C(CC)C1
Agent: [Na+]
Agent: [OH-]
Product: CCC1CNCCC1N
Temperature: 120 °C
Reaction time: 120 h

Procedure:
Ammonium acetate (33 g) was added to the stirred solution of 1-carbethoxy-3-ethyl-4-piperidinone (8.2 g, 41 mmol) in methanol (125 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (2.5 g, 39 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish crude 4-amino-1-carbethoxy-3-ethylpiperidine, which was used as such in the next step. 4-Amino-1-carbethoxy-3-ethylpiperidine was suspended in 5 M NaOH solution (36 ml), stirred at 120° C. for 120 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to dryness to afford 4-amino-3-ethylpiperidine. Yield 3.1 g (59.6%), C7H16N2, m/z 129 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]>C(O)C>[N+:12]([C:11]1[CH:10]=[CH:9][S:8][C:7]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([O-:14])=[O:13]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccsc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccsc1-n1ccnc1
Yield: 45.4 %

Procedure:
Imidazole (860 mg, 12.63 mmol) was added to a solution of 2-chloro-3-nitro-thiophene (1 g, 6.10 mmol) in abs. ethanol (20 mL). The reaction mixture was heated to reflux in a sealed tube for 3 days and then concentrated under reduced pressure. Purification by flash chromatography (silica, 25:75 ethyl/hexane) gave 1-(3-nitrothiophen-2-yl)-1H-imidazole (540 mg, 45%). See Erker, T. J. et al., J. Heterocylic. Chem. 39 (2002) 857-861. Method [3] m/z 195.9 (M+H); retention time=0.615.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Br>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:2]([CH3:4])([CH3:3])[C:1]#[N:5]
Reactant: CC(C)C#N
Reactant: BrCc1ccccc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)Cc1ccccc1Br
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
To a solution of isobutyronitrile (3.58 g, 52 mmol) in dry THF (30 mL) was added LiHMDS (1.0 M in THF) (80 mL, 80 mmol) at 0° C., stirred for 20 min, and to this solution was added 1-bromo-2-(bromomethyl)benzene (10 g, 40 mmol) in THF (70 mL). After 3 h at room temperature, the reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc (2×), the combined organics were washed with H2O, brine, dried over Na2SO4, filtered and concentrated to give 9.5 g (99%) of Intermediate 6A as red liquid. 1H NMR (400 MHz, CDCl3) δ 7.57-7.60 (2H, m), 7.30-7.34 (1H, m), 7.12-7.17 (1H, m), 3.08 (2H, s), 1.4 (6H, s) ppm.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][C:5]=2[CH2:4][CH2:3]1.C1(C)C=CC=CC=1>O.[Zn]>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][C:5]=2[CH2:4][CH2:3]1
Reactant: O=C(O)CCC(=O)c1ccc2c(c1)CCO2
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCCc1ccc2c(c1)CCO2
Reaction time: 8 h

Procedure:
300 g of zinc and 30 g of mercuric chloride are added with stirring to a mixture containing 510 ml of concentrated hydrochloric acid in 240 ml of water, 141 g of 4-(2,3-dihydro-5-benzofuranyl)-4-oxobutanoic acid obtained above and 300 ml of toluene. The reaction medium is brought to reflux for 6 hours. 150 ml of concentrated hydrochloric acid are added and refluxing is continued overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:17].C(=O)(O)[O-].[Na+].Cl[CH2:24][C:25](Cl)=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.CCOC(C)=O>[C:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:25](=[O:26])[CH2:24][O:17][C:3]=3[CH:4]=2)(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1COc2cc(S(=O)(=O)c3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A solution of 2-amino-5-benzenesulfonyl-phenol (0.392 g., 1.57 mmol) in 10 mL of acetonitrile was cooled to O° C. To this solution was added sodium bicarbonate (0.263 g., 3.14 mmol) in 4 mL water. With stirring, 2-chloroacetyl chloride (0.162 mL, 2.097 mmol) was added dropwise over 2 minutes. Stirring was continued for one hour as the reaction mix was warmed to room temperature. Potassium carbonate (0.261 g., 1.89 mmol) was then added and the system was warmed to reflux (85° C.) for two hours. The reaction mixture was added to 50 mL EtOAc, the aqueous fraction was separated and the organic layer was washed twice with 50 mL water, dried over Na2SO4 and concentrated in vacuo. The crude solid was recrystallized from a mixture of 30 mL each of ethanol and water to give 0.382 g (1.32 mmol, 84%) of 7-benzenesulfonyl-4H-benzo[1,4]oxazin-3-one as a yellow solid. MS: 288 (M−H)−. Step 6:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1)[CH3:2].CC(OC(C)=O)=[O:13]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([OH:13])[CH:5]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1cc[n+]([O-])cc1
Product: CCOc1ccnc(O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
A mixture of 4-ethoxypyridine 1-oxide (20 g, 144 mmol) in Ac2O (200 mL, 7.836 mol) was heated to refluxed for 4 h. Then, the solvent was removed in vacuo, and the residue was dissolved in MeOH (50 mL) and water (50 mL) and stirred at 25° C. for 16 h. The mixture was then concentrated and the crude material was purified by silica column chromatography (DCM/MeOH=10:1). All fractions found to contain product by TLC (DCM/MeOH=10:1, Rf=0.6) were combined and concentrated to yield a dark yellow solid of 4-ethoxypyridin-2-ol (17 g, 104 mmol, 72% yield). 1H NMR (400 MHz, MeOH-d4) δ 8.20 (d, J=7.6 Hz, 2H), 7.12 (d, J=7.6 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 1.42 (t, J=6.8 Hz, 3H); ES-LCMS m/z: 140.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:17][C:18]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O.C(OCC)(=O)C>[NH2:17][C:18]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=[O:21]
Reactant: Nc1nc(Cl)ccc1C(=O)O
Reactant: NCc1ccc(NCc2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)ccc1C(=O)NCc1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of (4-aminomethylphenyl)-benzylamine described in Preparation Example 19 (369 mg, 1.74 mmol) and 2-amino-6-chloro-nicotinic acid (300 mg, 1.74 mmol) in N,N-dimethylformamide (10 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (924 mg, 2.09 mmol) and triethylamine (0.49 mL, 3.48 mmol), and the solution was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water, and then, dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and the title compound (310 mg, 49%) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[O:8][CH:7]=[CH:6][C:5]=1O)=[O:3].P(Cl)(Cl)(Cl)(Cl)[Cl:11].O>C(Cl)Cl>[C:2]([C:4]1[O:8][CH:7]=[CH:6][C:5]=1[Cl:11])(=[O:3])[CH3:1]
Reactant: CC(=O)c1occc1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1occc1Cl
Reaction time: 1 h

Procedure:
Isomaltol (6.3 g, 0.05 moles) in 60 ml of CH2Cl2 was added dropwise over 10 minutes to a solution of PCl5 (10.4 g, 0.05 moles) in 125 ml of CH2Cl2 at 4° C. After stirring at 4°-5° C. for 1 hour, the reaction was allowed to come to room temperature, poured into 350 ml of water and the CH2Cl2 layer separated. The aqueous layer was then extracted with CH2Cl2, the CH2Cl2 layers combined and then concentrated to yield a dark oil, 7.0 g. Pure 2-acetyl-3-chloro-furan was obtained by chromatography from silica gel, NMR (CDCl3, δ) 7.5 (1H, d, J=2Hz), 6.56 (1H, d, J=2Hz), 2.53 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[N:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Brc1cncnc1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3cncnc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 5-bromopyrimidine.
Reaction SMILES: O=[C:2]1NCCN(S(C2C=CC(C)=CC=2)(=O)=O)C(CC(N[C@H]2C3C(=CC(CN4CCCCC4)=CC=3)CCC2)=O)[CH2:3]1.[O:40]=[C:41]1[NH:47][CH2:46][CH2:45][N:44]([S:48]([C:51]2[CH:57]=[CH:56][C:54]([CH3:55])=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH:43]([CH2:58][C:59]([OH:61])=[O:60])[CH2:42]1.N1(CC2C=C3C(=CC=2)[C@H](N)CCC3)CCCCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[O:40]=[C:41]1[NH:47][CH2:46][CH2:45][N:44]([S:48]([C:51]2[CH:57]=[CH:56][C:54]([CH3:55])=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH:43]([CH2:58][C:59]([O:61][CH2:2][CH3:3])=[O:60])[CH2:42]1
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)CC2CC(=O)N[C@@H]2CCCc3cc(CN4CCCCC4)ccc32)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)CC2CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CC(=O)NCCN1S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
A solution of the product of step A (1.34 g, 5.44 mmol) was stirred in THF (30 ml) at 0*C. Bu3SnOTf (90%, 2.73 g, 5.60 mmol) in THF 8.0 ml was added dropwise over 6 min, and the mixture was heated to reflux for 22 h. The reaction was cooled to 0° C., and triethylamine (1.52 ml, 10.9 mmol) and dimethylaminopyridine (0.135 g, 1.11 mmol) were added followed by p-toluenesulfonyl chloride (2.09 g, 11.0 mmol) in THF 4.0 ml. The reaction was allowed to r.t. and after 4 h concentrated under reduced pressure. AcOEt (100 ml) was added to the residue and washed with 0.1 N HCl aq. (100 ml×2), sat'd NaHCO3 aq. (100 ml×2) and sat'd NaCl aq. (100 ml×2), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica (AcOEt→AcOEt/-MeOH=80/1) to yield the title compound. MS:355.2 C. 2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)acetic acid (3) To a solution of the product of step B (0.416 g, 1.17 mmol) in 1,4-dioxane (24 ml) and MeOH (24 ml), 0.13 N LiOH (28 ml, 3.6 mmol) was added, and the mixture was heated to reflux for overnight. The reaction was cooled to r.t. and AcOEt (400 ml) was added and washed with sat'd NaCl (400 ml×5), dried over Na2SO4 and concentrated under reduced pressure to yield the title compound. MS: 327.1 D. (R)-2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide. To a mixture of 2-(7-oxo-4-tosyl-1,4-diazepan-5-yl)acetic acid (0.115 g, 0.352 mmol), (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (0.0945 g, 0.387 mmol) and HOBt (<5% H2O, ˜0.398 mmol) in DMF (3.0 ml) was added EDCI*HCl (0.0805 g, 0.420 mmol), and stirred overnight under N2. AcOEt (60 ml) was added and washed with sat'd NaHCO3 aq. (60 ml×3) and sat'd NaCl aq. (60 ml×3), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica (CH2Cl2/MeOH with 2N NH3=10/1) to yield the title compound. MS: 553.1
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(S)C.[N:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:28]([C:29]4[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=4)=[CH:27][CH:26]=[C:25]([CH3:37])[N:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>ClCCCl>[N:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:28]([C:29]4[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=4)=[CH:27][CH:26]=[C:25]([CH3:37])[N:24]=3)=[CH:21][CH:22]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COc1ccc(-c2ccc(C)nc2-c2ccc(OCCN3CCOCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc(O)cc2)c(-c2ccc(OCCN3CCOCC3)cc2)n1
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
The AlCl3 (5 g, 38 mmol) was stirred in 100 mL of DCE at 0° C., ethanethiol (4 mL, 54 mmol) was added, and the mixture stirred for 15 min. The 2-[4-[2-(4-morpholinyl)ethoxy]phenyl]-3-(4-methoxyphenyl)-6-methylpyridine (2.2 g, 5.4 mmol) in 50 mL DCE was added dropwise to the reaction mixture and stirred for 2 h as it was allowed to come to rt, then quenched with 50 mL THF at 0° C., followed by 50 mL 1N HCl and worked up. The crude product was triturated with Et2O/ pet. ether, filtered, and dried in vacuo to give 1.9 g (90 % yield) of white solid: mp 75-80 ° C.; 1H NMR (CDCl3) d 2.59-2.62 (comp, 7H, morpholine and pyr-CH3), 2.79-2.83 (t, 2H, J=5 Hz, CH2N), 3.74-3.77 (m, 4H, morpholine), 4.07-4.11 (t, 2H, J=5 Hz, OCH2), 6.63-6.71 (m, 4H, ArH), 6.94-6.97 (d, 2H, J=8 Hz, ArH), 7.11-7.13 (d, 1H, J=8 Hz, ArH), 7.24-7.27 (d, 2H, J=8 Hz, ArH), 7.53-7.56 (d, 1H, J=8 Hz, ArH); MS(FD) 390 (M+). Anal. Calcd for C24H26N3O3 : C, 73.82; H, 6.71; N, 7.17. Found: C, 73.75; H, 6.71; N, 7.05.