Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C:15]([F:18])([F:17])[F:16])[C:11](O)=[O:12])[C:7](=[O:19])[CH:6]=1.[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]2)[CH2:27][O:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C:15]([F:17])([F:18])[F:16])[C:11]([NH:36][C:33]2[CH:34]=[CH:35][N:31]([CH2:30][C@@H:28]3[CH2:27][O:26][C:25]([CH3:37])([CH3:24])[O:29]3)[N:32]=2)=[O:12])[C:7](=[O:19])[CH:6]=1
Reactant: O=C(O)C(CC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
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(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC(F)(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4,4-trifluoro-butyric acid (144 mg, 0.41 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 97 mg, 0.49 mmol) in N,N-dimethylformamide (4 mL). To this mixture was added N,N-diisopropyethylamine (200 μL, 1.23 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (271 mg, 0.62 mmol) and stirred for 16 h at 25° C. After this time, the mixture was diluted with ethyl acetate (25 mL) and washed with a saturated aqueous solution of ammonium chloride (25 mL), saturated aqueous solution of sodium bicarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL), dried over sodium sulfate, and then concentrated with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 80% ethyl acetate) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-4,4,4-trifluoro-butyramide (168 mg, 77%) as a white foam: HR-ES-MS m/z calculated for C23H24N4O5ClF3 [M+H]+ 529.1460, observed 529.1457.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:16]#[C:17][C:18]2([CH3:32])[CH2:23][CH2:22][C:21]3[C:24]([CH3:31])=[C:25]([OH:30])[C:26]([CH3:29])=[C:27]([CH3:28])[C:20]=3[O:19]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1.C(O)C>[Pd].C(O)(=O)C>[OH:30][C:25]1[C:26]([CH3:29])=[C:27]([CH3:28])[C:20]2[O:19][C:18]([CH2:17][CH2:16][C:4]3[CH:3]=[C:2]([OH:1])[C:7]([OH:8])=[CH:6][CH:5]=3)([CH3:32])[CH2:23][CH2:22][C:21]=2[C:24]=1[CH3:31]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(OCc3ccccc3)c(O)c1)O2
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCc1ccc(O)c(O)c1)O2
Yield: 62.6 %

Procedure:
A mixture of 1 g of rac-3,4-dihydro-2-{[3-hydroxy-4-(phenylmethoxy)phenyl]ethynyl}-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 0.5 g of 5% palladium on carbon. 100 ml of ethanol and 10 ml of glacial acetic acid was hydrogenated at atmospheric pressure for 4.5 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic layer was dried and evaporated and the residue was crystallized from ether/hexane to give 0.5 g of colorless crystals with m.p. 167°-170°.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)[CH3:2].S1C=CC=[C:12]1C(O)=O.ICCC>>[CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)[CH2:2][CH3:12]
Reactant: CCc1ccc(C(=O)O)s1
Reactant: O=C(O)c1cccs1
Solvent: CCCI
Product: CCCc1ccc(C(=O)O)s1

Procedure:
The title compound is prepared in analogy to 5-ethyl-thiophene-2-carboxylic acid starting from 2-thiophenecarboxylic acid and 1-iodopropane; LC-MS: tR=0.87 min, 1H NMR (CDCl3): δ 0.99 (t, J=7.0 Hz, 3H), 1.74 (hex, J=7.3 Hz, 2H), 2.83 (t, J=7.6 Hz, 2H), 6.82 (d, J=3.5 Hz, 1H), 7.73 (d, J=3.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[S:24](Cl)(=[O:26])=[O:25])([O:17][CH3:18])=[O:16]>C1COCC1>[CH3:18][O:17][C:15]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[S:24](=[O:26])(=[O:25])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: Nc1ccccc1
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of an aniline (1.02 g, 10.9 mmol, 11.1 equivalents) dissolved in dry THF (35 mL) and triethylamine (1.53 mL, 1.1 equivalents) at room temperature, sealed with a septum and a nitrogen inlet, was added 2-carbomethoxythiophene-3-sulfonyl chloride (2.5 g, 9.9 mmol, 95% purity). The reaction mixture was stirred at room temperature over night. Upon completion, the reaction will be extracted by diluting with ethyl acetate and washing with aqueous HCl (2N), water and saturated, aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The solution will be decanted and evaporated under reduced pressure to give the desired 3-phenylsulfamoylthiophene-2-carboxylic acid methyl ester (2.6 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:16])=[O:5])[CH3:2].[CH3:17][C:18]1([CH3:29])[O:23][C:22](=[O:24])[C:21](=COC)[C:20](=[O:28])[O:19]1>C(O)C>[CH3:17][C:18]1([CH3:29])[O:23][C:22](=[O:24])[C:21](=[N:16][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15]3)[C:20](=[O:28])[O:19]1
Reactant: CCOC(=O)c1cnc2c(N)cccc2c1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: CCOC(=O)c1cnc2c(N=C3C(=O)OC(C)(C)OC3=O)cccc2c1
Yield: 80 %

Procedure:
A mixture of 3-ethoxycarbonyl-8-amino-quinoline (9.9 g), 2,2-dimethyl-5-methoxymethylene-1,3-dioxan-4,6-dione (Monatsh. Chem., 98:564-78 (1967))(10.3 g) and ethanol (80 ml) was stirred at reflux for 2 hours. The mixture was cooled and filtered. The solid so obtained was washed with ethanol to give 8-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylideneamino)-3-ethoxycarbonylquinoline in 80% yield, mp 228-231° C.
Reaction SMILES: BrBr.[OH-:3].[Na+].[CH3:5][C:6]1([CH3:22])[C@@H:8]([C:9](=[O:11])C)[C@@H:7]1[CH:12]=[C:13]([Cl:21])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>O.O1CCOCC1>[CH3:22][C:6]1([CH3:5])[C@@H:8]([C:9]([OH:11])=[O:3])[C@@H:7]1[CH:12]=[C:13]([Cl:21])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: CC(=O)[C@H]1[C@H](C=C(Cl)c2ccc(Cl)cc2)C1(C)C
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)[C@@H](C=C(Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)O
Reaction time: 3 h
Yield: 75 %

Procedure:
13.8 g of bromine were added dropwise to a solution of 11.5 g of sodium hydroxide in 60 ml of water at 5°-10° C., and a solution of 8.1 g (0.029 mol) of trans-3,3-dimethyl-2-(2-chloro-2-(4-chloro-phenyl)-vinyl)-1-acetylcyclopropane in 30 ml of dioxane was then added dropwise at 0°-5° C. The mixture was subsequently stirred for 3 hours, without cooling, pouredonto 250 ml of water and extracted twice with 50 ml of ether each time. The aqueous phase was freed from adhering ether in vacuo and then brought to pH 2 by adding aqueous hydrochloric acid. After crystallization, the product was filtered off and rinsed with water. 6.2 g (77% of theory) of trans-3,3-dimethyl-2-(2-chloro-2-(4-chlorophenyl)-vinyl)-cyclopropanecarboxylic acid were thus obtained in the form of pale yellow-colored crystals with a melting point of 103°-106° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[N:5]=[CH:6][C:7]=1[O:8][CH3:9].C(O)C.C(N(CC)CC)C>O.[Pd]>[CH3:9][O:8][C:7]1[CH:6]=[N:5][N:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:3](=[O:16])[CH:2]=1
Reactant: COc1cnn(C2CCCCO2)c(=O)c1Cl
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cnn(C2CCCCO2)c(=O)c1
Temperature: 43 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
4-Chloro-5-methoxy-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone (2486 g, 10.16 moles), ethanol (8 L), triethylamine (2L, 14.23 moles), and 5% Pd-C (100 g of 50% water-wet Pd-C) were added to a 22 L autoclave. The mixture was hydrogenated at 50-60 psi (345-414 kilopascals) of H2 and heated to a maximum temperature of 43° C. After 24 h, the reaction was complete. The reaction mixture was diluted with a small amount of water and vacuum filtered through celite. The filtrate was concentrated and partitioned with 10 L of ethyl acetate and 8 L of H2O. The aqueous phase was extracted with ethyl acetate (2×2 L). The combined organics were washed with 5 L brine, dried (MgSO4), and vacuum filtered. The solution was concentrated in vacuo to give 2133 g (100% yield) of 5-methoxy-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone as a dark oil which later crystallized to give a tan product suitable for further transformations. The product was purified by recrystallization from ethyl acetate/cyclohexane to give a white solid, mp=76°-78° C.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:17](C)C(O)=O>>[C:1]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH3:17])[C:10]1=[O:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)C(=O)O
Reactant: O=C1COCCN1C(=O)c1ccccc1
Product: CC1OCCN(C(=O)c2ccccc2)C1=O

Procedure:
Synthesized as for N-benzoyl-3-oxomorpholine (Example I) using 2-chloropropionic acid (Aldrich) in place of chloroacetic acid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[CH2:13][NH:12]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([N:12]1[CH2:13][C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CNN1C1C2CC3CC(C2)CC1C3
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CN(Cc2ccccc2)N1C1C2CC3CC(C2)CC1C3
Reaction time: 24 h
Yield: 51.3 %

Procedure:
Under an argon atmosphere, a solution of 2-(adamantan-2-yl)-1,2-diazetidin-3-one (10.2 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL), potassium carbonate (28.0 mg, 0.100 mmol) and benzyl bromide (35.0 mg, 0.100 mmol) were added at room temperature, and the resultant was stirred at the same temperature for 24 hours. The reaction solution was added with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (7.60 mg, 48.6%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][Sn:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][C:5]([NH:7][NH2:8])=[O:6].[CH3:11][C:12]([CH3:14])=O>>[CH3:11][C:12](=[N:8][NH:7][C:5](=[O:6])[CH2:4][CH2:3][Sn:2]([CH3:10])([CH3:9])[CH3:1])[CH3:14]
Reactant: C[Sn](C)(C)CCC(=O)NN
Reactant: CC(C)=O
Product: CC(C)=NNC(=O)CC[Sn](C)(C)C

Procedure:
4.0 g (0.016 mole) of 3-trimethylstannylpropionic acid hydrazide of Example 1 and 5.0 ml (0.068 mole) of reagent grade acetone were placed in a 50 ml single-neck flask equipped with a stirrer. The flask was stoppered and the solution was then stirred for about fifteen minutes, at which time the reaction mixture turned solid. Recrystallization of the air-dried solid from acetone-water mixture containing 50% by weight of acetone gave 3.8 g of 3-trimethylstannylpropionic acid 1-methylethylidenehydrazide, Compound 1 of Table I. The infrared spectrum (KBr disc) showed the characteristic bands at 3200 and 3050 cm-1 for N--H and at 1655 and 1550 cm-1 for carbonyl absorption of ##STR9## The carbon-tin bond was characterized by infrared absorption bands at 760, 522, 515 and 503 cm-1. Nuclear magnetic resonance spectroscopy suggested that the compound exists as a tautomeric mixture in CDCl3 solution with one form predominating over the other. The NMR spectra of the dominant isomer showed the following: a broad singlet at 8.38 delta (1H, N--H); a triplet centered at 2.82 delta (2H, --CH2CO); two 3-proton signlets at 1.82 delta and 1.92 delta (--N=C(CH3)2); a triplet centered at 1.02 delta (2H, --CH2Sn); a singlet at 0.06 delta (9H, Sn(CH3)3) flanked by the J(117/119Sn--CH3) doublets.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:5][CH:4]([NH:6][C:7]([C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH2:12][N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[O:8])[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[F:29][C:2]1([F:1])[CH2:5][CH:4]([NH:6][C:7](=[O:8])[C:9]2[CH:28]=[CH:27][CH:26]=[C:11]([CH2:12][N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH:10]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NC3CC(F)(F)C3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CC(F)(F)C1)c1cccc(CN2CCNCC2)c1
Yield: 81.5 %

Procedure:
tert-Butyl 4-(3-(3,3-difluorocyclobutylcarbamoyl)benzyl)piperazine-1-carboxylate (12.65 mmol, 5.179 g) was stirred at room temperature in dichloromethane (10 mL)/trifluoroacetic acid (10 mL) for 1 hour with sonication. The solvent was removed under vacuum and the resulting residue was purified by strong cation exchange column chromatography to afford the title compound (3.19 g). MS (ESI) m/z 310.4 [M+H]+
Reaction SMILES: [CH2:1]([C:8]([NH:38]C(=O)OC(C)(C)C)([CH2:36][OH:37])[CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[C:16]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[C:14]([C:24]([NH:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH3:28])=[O:25])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)(Cl)Cl>[NH2:38][C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:36][OH:37])[CH2:9][NH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:20])=[O:21])[CH:17]=1)[C:24]([NH:26][C@@H:27]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[CH3:28])=[O:25].[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]
Reactant: C[C@@H](NC(=O)c1cc(CNCC(CO)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C[C@@H](NC(=O)c1cc(CNCC(N)(CO)Cc2ccccc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1

Procedure:
Treatment of Boc derivative from step B with 50% TFA in CHCl3 for 30 min, followed by concentration under a stream of nitrogen, and purification by preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) afforded 3-{[(2-amino-2-benzyl-3-hydroxypropyl)amino]methyl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide as a bis TFA salt. 1H NMR (400 MHz, d4-MeOH) δ 8.85 (d, J=7.9 Hz, 1H), 7.84 (s, 2H), 7.67 (s, 1H), 7.46-7.38 (m, 2H), 7.36-7.25 (m, 3H), 7.25-7.18 (m, 2H), 7.10-7.00 (m, 2H), 5.40-5.18 (m, 1H), 4.12-4.00 (m, 2H), 3.66 (A of AB, d, J=11.0 Hz, 1H), 3.61 (B of AB, d, J=11.0 Hz, 1H), 3.35 (s, 3H), 3.06-2.88 (m, 2H), 2.95 (s, 3H), 1.58 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH2:14][CH:15]([CH2:17][N:18]=[N+]=[N-])[O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH2:14][CH:15]([CH2:17][NH2:18])[O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cccc3c2CC(CN=[N+]=[N-])O3)cc1
Agent: [Pd]
Product: Cc1ccc(-c2cccc3c2CC(CN)O3)cc1
Yield: 93 %

Procedure:
Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.0 mmol), o-tolylboronic acid (2.66 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.651 mmol), and potassium carbonate (4.51 g, 32.63 mmol) generally according to the procedure described for Intermediate 37 provided 4.0 g (77%) of (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a yellow oil. Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (3.8 g, 9.63 mmol) with sodium azide (2.5 g, 38.53 mmol) generally according to the procedure described for Intermediate 98 gave 2.39 g (94%) of [4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.239 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.3 g (93%) of (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 239-241° C.; Anal. calcd. for C16H17NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 69:36; H, 6.64; N, 4.93.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(Cl)Cl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: OCc1ccc2c(c1)Sc1ccc(F)cc1C=C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)Sc1ccc(F)cc1C=C2
Yield: 106.4 %

Procedure:
Dissolve 568 mg (2.2 mmole) of 2-fluoro-7-hydroxymethyldibenzo[b,f]thiepin in 30 ml of methylene chloride and add 647 mg of 98% pyridinium chlorochromate. Stir the mixture and follow the reaction by thin layer chromatography (Merck silica gel F254 with 5% ethyl acetate in toluene). When complete, filter the mixture through a bed of Florisil, and wash through with methylene chloride. Evaporate the filtrate to obtain a brown solid (600 mg). Purify the crude product by chromatography on silica gel using totluene as solvent to obtain the title compound as a yellow solid, m.p. 137°-139° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.O.[CH2:11]([O:18][C:19]1[CH:36]=[CH:35][C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=2[N+:32]([O-:34])=[O:33])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.OOS([O-])=O.[K+]>CN(C)C=O>[CH2:11]([O:18][C:19]1[CH:36]=[CH:35][C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]3[NH:9][C:4]4[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=4[N:8]=3)=[CH:26][C:25]=2[N+:32]([O-:34])=[O:33])=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Br)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2nc3ccc(Br)cc3[nH]2)ccc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
A solution of 4-bromo-1,2-benzenediamine (214 mg, 1.145 mmol) in N,N-dimethylformamide (12 mL) containing water (0.4 mL) was treated with the product of Example 147A (400 mg, 1.145 mmol) and OXONE (458 mg, 0.7443 mmol), and the reaction stirred at room temperature for 30 minutes. Water (40 mL) was then added and the reaction stirred for 10 minutes. The mixture was vacuum filtered and the solid washed with water, then dried under vacuum. Purification by silica gel chromatography using a gradient of 3% to 4% ethyl acetate/methylene chloride as eluent provided the title compound as a yellow solid (305 mg, 51%).
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.Cl.[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH2:26][S:27][CH3:28])[NH2:24].C(N(CC)CC)C>[OH-].[Li+].CCOCC.ClCCl.CO>[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH2:26][S:27][CH3:28])[NH:24][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:5]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(I)cc1-c1ccccc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(I)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of the 4-iodo-2-phenylbenzoic acid methyl ester prepared in Example 21° C. (2.77 g, 8.20 mmol) in aqueous saturated lithium hydroxide (3 mL) and methanol (10 mL) was heated at 60° C. for 12 hours. The mixture was then acidified with concentrated HCl to pH about 2, and extracted twice with ethyl acetate (50 mL each). The combine extracts was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was suspended in dichloromethane (10 mL), and oxalyl chloride (2.0 M in dichloromethane, 6.2 mL)was added, followed by a small drop of DMF. The mixture was stirred at room temperature for 1 hour, and then was concentrated in vacuo, followed by further drying under high vacuum for 10 minutes. To the residue was added dichloromethane (20 mL), L-methionine methyl ester hydrochloride (1.64 g, 8.05 mmol) and triethylamine (3.4 mL, 24.6 mmol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was diluted with ether (50 mL), filtered through silica gel (30 g), and concentrated in vacuo. The crude product was purified by column chromatography (40:40:20 hexane-chloroform-ether) to give (4-iodo-2-phenylbenzoyl)methionine methyl ester (3.46 g, 90%). 1H NMR (300 MHz, CDCl3) δ 7.76 (m, 2H), 7.42 (m, 6H), 5.88 (br d, 1H), 4.65 (m, 1H), 3.68 (s, 3H), 2.05 (m, 2H), 2.00 (s, 3H), 1.90 (m, 1H), 1.73 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:6][NH:7]2.C(O)C.C1COCC1.[OH-].[Li+]>O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)=[CH:6][NH:7]2
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(C(=O)OC)cc3)c[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(C(=O)O)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
Methyl 4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzoate (330 mg, 0.93 mmol) was suspended in a mixed solvent of ethanol (3 ml) and THF (3 ml). A 1.24N lithium hydroxide aqueous solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and then the resulting mixture was extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure to thereby obtain 300 mg of powdery white 4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzoic acid (yield: 95%).
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[CH:8]=2)[N:3]=1.CO[CH:16]([O:19]C)[CH2:17][NH2:18]>>[F:13][C:7]1[CH:8]=[C:9]2[C:4]([NH:3][C:16](=[O:19])[C:17]3[N:10]2[CH:11]=[CH:2][N:18]=3)=[CH:5][CH:6]=1
Reactant: COC(CN)OC
Reactant: Fc1ccc2nc(Cl)c(Cl)nc2c1
Product: O=c1[nH]c2ccc(F)cc2n2ccnc12

Procedure:
By reacting 2,3-dichloro-6-fluoroquinoxaline with aminoacetaldehyde dimethyl acetal, following a procedure that is similar to that described in example 1, there is obtained 8-fluoroimidazo[1,2-a]quinoxalin-4(5H)-one (m.p. >300° C.) and, subsequently, 4-chloro-8-fluoroimidazo[1,2-]quinoxaline. By reacting this product with cyclopentyl amine according to the method described in example 3, there is obtained 4-cyclopentylamino-8-dichloroimidazo[1,2-a]quinoxaline. m.p. (DSC)=85.7° C.(onset); IR (KBr): 3255, 2964, 1551 cm-1 ; 1H-NMR (CDCl3): δ7.8 (1H,m), 7.7÷7.35 (1H,dd, JHF =16 Hz), 7.5 (1H,d, J=2 Hz), 7.6÷7.25 (1H,dd, JHF =16 Hz), 7.05 (1H,dd), 6.0 (1H,d), 4.55 (1H,m), 2.35÷1.3 (8H,m); UV (EtOH): λmax =226, 268, 285, 296, 323, 336 nm. Elementary analysis for C15H15FN4 (m.w. 270.31): calcd. C 66.65, H 5.59, N 20.73%; found C 66.36, H 5.66, N 20.86%.