Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CCCCC1.[NH2:45][CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:45][CH2:46][C:47]4[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CC3CCCCC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CCCCC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 52 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclohexylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 52% yield: mp 134-136° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.57-8.47 (m, 2H), 7.68 (d, J=7.2 Hz, 1H), 7.27 (s, 1H), 6.31 (br s, 1H), 4.55 (d, J=5.7 Hz, 2H), 4.11-4.03 (m, 2H), 3.57 (m, 2H), 3.09 (d, J=7.2 Hz, 2H), 2.57 (s, 3H), 1.84-1.56 (m, 5H), 1.24-0.84 (m 6H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.6, 153.6, 148.9, 148.5, 135.9, 134.2, 123.7, 116.5, 50.3, 43.0, 42.0, 41.3, 36.0, 30.7, 26.2, 25.6, 17.2; MS (ES+) m/z 414.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[Br:19][C:20]1[S:24][C:23]([C:25]([OH:27])=O)=[CH:22]C=1.C([N:31](C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Br:19][C:20]1[S:24][C:23]([C:25]([NH:1][C:2]2[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]3[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:16])[CH:5]=[CH:4][N:3]=2)=[O:27])=[CH:22][N:31]=1
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1)c1cnc(Br)s1
Temperature: 60 °C
Yield: 29.9 %

Procedure:
To a solution of N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (282 mg, 1.00 mmol), 5-bromothiophene-2-carboxylic acid (624 mg, 3.0 mmol) in N,N-dimethylformamide (5 mL) was added diisopropylethylamine (700 μL, 4.00 mmol), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.14 g, 3.0 mmol). The mixture was heated at 60° C. for 24 hours. The mixture was then concentrated under reduced pressure and the residue was partitioned between EtOAc (30 mL) and 1 N NaOH (20 mL). The aqueous layer was extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure. The redidue was purified by silica gel column chromatography (0-40% EtOAc/hexane) to afford the desired product as an-off-white solid (141 mg, 30% yield). 1H NMR (400 MHz, DMSO) δ 11.24 (s, 1H), 8.65 (s, 1H), 8.44 (d, J=1.6 Hz, 1H), 8.33 (d, J=5.7 Hz, 1H), 7.66-7.47 (m, 5H). LCMS (ESI) m/z: 472.7 [M+H+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[O:7].C(Cl)(=O)C(C)(C)C.[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH:28]([S:30][C:31]3[NH:35][N:34]=[N:33][N:32]=3)[CH3:29])[CH2:26][S:27][C@H:22]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>CN(CC1C=CC=CC=1)C.C(Cl)Cl.C(N(CC)CC)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH:8]([CH3:12])[C:9]([NH:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH:28]([S:30][C:31]3[NH:32][N:33]=[N:34][N:35]=3)[CH3:29])[CH2:26][S:27][C@H:22]12)=[O:11])=[O:7]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C(=O)O)S(=O)c1cccs1
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)Cc1ccccc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(C)S(=O)c3cccs3)[C@H]2SC1
Temperature: -10 °C

Procedure:
408 mg. of 2-(2-thienylsulfinyl)propionic acid of the R form were dissolved in 12 ml. of dry methylene chloride and 0.3 ml. of triethylamine and 2 drops of N,N-dimethylbenzylamine were added to the solution. The mixture was agitated and cooled to -10° C., and 0.2 g. of pivaloyl chloride was added thereto. Then the mixture was agitated at -10° C. for 2 hours, and a liquid mixture of 656 mg. of 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, 20 ml. of dry methylene chloride and 400 mg. of bis-trimethylsilylacetamide blended and stirred at room temperature for 1 hour, was added to the above mixture, and agitated for 30 minutes at -10° C., for 30 minutes at 0° C. and for another 1 hour at room temperature. After completion of the reaction the solvent was distilled off under reduced pressure and the residue was dissolved in 3% aqueous sodium bicarbonate solution. Then the solution was extracted with ethyl acetate 3 times, and the pH of the aqueous layer was adjusted to 3.0 by 2 N hydrochloric acid. The aqueous layer was allowed to stand in a cooling place until precipitate was formed. The precipitate was collected, dried and recrystallized from water-methanol to obtain 7-[2-(2-thienylsulfinyl)propionamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. The filtrate separated from the precipitate was extracted with ethyl acetate. The organic layer was dried by magnesium sulfate and concentrated, and the resulting residue was dissolved in methanol. The solution was subjected to column chromatography using Sephadex LH-20(manufactured and sold by Pharmacia Fine Chemicals AB, Sweden) and the product was fractionally recovered and concentrated. The resulting powder was the same as the above crystal obtained by recrystallization from water-methanol. The total amount of the obtained product was 440 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH3:25])[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CNc1ccc(C(=O)OC)cc1N
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Yield: 75 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester (842 mg) was prepared by following General Procedure D starting from 3-amino-4-methylamino-benzoic acid methyl ester (650 mg), 2-amino-6-chloro-benzothiazole (556 mg), 1,1′-thiocarbonyldiimidazole (715 mg), and EDC (865 mg). LC/MS: m/z 373.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.84 (s, 1H), 7.64 (s, 1H), 7.50 (d, 1H), 7.38 (d, 1H), 3.86 (s, 3H), 3.62 (bs, 3H).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][N:11]2[CH:15]=[C:14](/[CH:16]=[CH:17]/[C:18]([O:20]C)=[O:19])[CH:13]=[N:12]2)[CH2:6][CH2:5]1>CO.C1COCC1>[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][N:11]2[CH:15]=[C:14](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[CH:13]=[N:12]2)[CH2:6][CH2:5]1
Reactant: COC(=O)/C=C/c1cnn(CC2CCN(C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(Cn2cc(/C=C/C(=O)O)cn2)CC1

Procedure:
An aqueous 3N sodium hydroxide solution (2 mL) was added to a solution of (E)-methyl 3-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)acrylate (220 mg) in MeOH (5 mL) and THF (3 mL) was added aq NaOH (3N, 2 mL) to saponify the methyl ester. Workup was performed as described in Example 12 to generate 209 mg of pure product (0.84 mmol, 100%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O-:16].[Na+].C[OH:19].O>CCO>[CH3:15][O:16][C:5]1[CH:4]=[CH:3][C:2]2[C:1](=[O:8])[C:9]3[C:14]([O:19][C:7]=2[CH:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CO
Reactant: C[O-]
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(=O)c3ccccc3oc2c1
Yield: 80.7 %

Procedure:
A solution of the benzophenone intermediate (12.51 g) in EtOH (200 ml) was treated with a solution of NaOMe in MeOH (25 wt. %, 22.86 ml, 0.1 mole) at room temperature, the color of the mixture changed from yellow to orange immediately. The reaction mixture was brought to reflux for 100 min. Cooled to 0°, the reaction mixture was treated with water (100 ml), to produce a fine white precipitate. The solid was filtered on a Buchner funnel, washed with water and EtOH, and finally dried in vacuo, yielding 3-methoxy-9H-xanthen-9-one 8 (9.12 g, 80.7%) as a white powder: m.p. 127-129° C.; 1H NMR (CDCl3): delta 8.31 (1H, dd, J=7.9, 1.2 Hz), 8.23 (1H, J=8.6 Hz), 7.68 (1H, m), 7.44 (1H, d, J=8.6 Hz), 7.35 (1H, m), 6.93 (1H, m), 6.87 (1H, d, J=2.4 Hz) and 3.92 (3H, s); 1R (CHCl3): 2999, 1644, 1605, 1460, 1434, 1321, 1273, 1254, 1159, 1101, 1029, 968 and 848 cm-1.
Reaction SMILES: C1C=C2N=NN(O)C2=CC=1.O.C(N(CC)CC)C.C(OC(Cl)=O)C.[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:29]([OH:31])=O.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C=O)C.O>[NH2:25][C:26]1[CH:27]=[C:28]([C:29]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[O:31])[CH:32]=[CH:33][C:34]=1[NH2:35]
Reactant: CN1CCNCC1
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: CCOC(=O)Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(N)c(N)c2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 17.8 %

Procedure:
HOBT monohydrate (2.00 g, 13.1 mmol) was dissolved in DMF (20 mL), and the solution was added with triethylamine (2.54 mL, 18.2 mmol) and ethylchloroformate (1.24 mL, 13.0 mmol), followed by stirring at 0° C. for 3 hours. Then, the mixture was added with triethylamine (4.22 mL, 30.3 mmol) and 3,4-diaminobenzoic acid (1.86 g, 12.2 mmol), followed by stirring at the same temperature for 2 hours. The mixture was added with a solution of N-methylpiperazine (1.21 mL, 10.9 mmol) in DMF (20 mL), followed by further stirring for 30 minutes. The reaction mixture was added with water (2 mL) and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol/7 mol/L ammonia-methanol solution=50/0.5/0.5-7/0.5/0.5) and preparative thin-layer chromatography (chloroform/methanol/7 mol/L ammonia-methanol solution=4/0.5/0.5) to obtain (3,4-diaminophenyl)(4-methylpiperazin-1-yl)methanone (455 mg, yield 18%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[F:35][CH:36]([F:46])[O:37][CH2:38][C@@:39]([CH3:45])([CH:43]=[CH2:44])[C:40]([OH:42])=[O:41].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>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]>[F:35][CH:36]([F:46])[O:37][CH2:38][C@@:39]([CH3:45])(/[CH:43]=[CH:44]/[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:30])[CH3:31])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1)[C:40]([OH:42])=[O:41]
Reactant: C=C[C@](C)(COC(F)F)C(=O)O
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/[C@](C)(COC(F)F)C(=O)O)cc3n2)N1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (160 mg, 0.3 mmol), (R)-2-difluoromethoxymethyl-2-methyl-but-3-enoic acid (54 mg, 0.3 mmol), tri(o-tolyl)phosphine (18 mg, 0.06 mmol) and triethylamine (91 mg, 0.125 mL, 0.9 mmol) in 1,4-dioxane (6 mL) was stirred at 50° C. under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added and the reaction mixture was heated at reflux for 40 minutes. The reaction mixture was cooled to room temperature and the mixture was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude (E)-(R)-2-difluoromethoxymethyl-4-{2-[(R)-1-({(S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carbonyl}-amino)-ethyl]-quinolin-7-yl}-2-methyl-but-3-enoic acid (0.3 mmol) which was used in the next step. LCMS (m/z) 634.2 [M+H], Tr=2.04 min.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:31]=[C:30]([CH3:32])[C:29]([O:33]C(OC)=O)=[CH:28][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.Cl>CO.O>[F:3][C:4]1[CH:31]=[C:30]([CH3:32])[C:29]([OH:33])=[CH:28][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(NC(=O)CCN4CCOCC4)ccc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(F)c(Nc2ncnc3cc(NC(=O)CCN4CCOCC4)ccc23)cc1O
Reaction time: 1 h
Yield: 80 %

Procedure:
2M Aqueous sodium hydroxide solution (453 μl, 0.9 mmol) was added to a suspension of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(3-morpholinopropionamido)quinazoline (219 mg, 0.45 mmol) in methanol (6 ml) and the mixture stirred for 1 hour. The reaction mixture was diluted with water and then adjusted to pH6 with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and ethanol, and dried. The solid was dissolved in methylene chloride/methanol and a 5M solution of hydrogen chloride in isopropanol (0.3 ml) added. The volatiles were removed by evaporation, the resulting solid was washed with ether, and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(3-morpholinopropionamido)quinazoline (1-86 mg, 80%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Temperature: 78 °C
Yield: 68.8 %

Procedure:
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.2 g, 3.205 mmol) and ethyl formate (0.800 mL, 9.903 mmol) were dissolved in anhydrous ethanol (10 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (3.6 mL, 9.643 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.887 g, 2.204 mmol, 69%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([C:13]([C:15]2[N:16]=[CH:17][N:18]3[CH:22]=[CH:21][S:20][C:19]=23)=[O:14])[CH:10]=[N:11][CH:12]=1)=[N+:2]=[N-:3].[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>>[N:1]([CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([C:13]([C:15]2[N:16]=[CH:17][N:18]3[CH:22]=[C:21]([Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])[S:20][C:19]=23)=[O:14])[CH:10]=[N:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCSc1cncc(C(=O)c2ncn3ccsc23)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(SCCN=[N+]=[N-])c3)c2s1

Procedure:
The title compound (857 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 667 mg of 7-[5-(2-azidoethylthio)pyridin-3-yl]carbonylimidazo[5,1-b]-thiazole, 0.603 ml of tri-n-butylstannyl chloride, and 3.7 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])=[CH:4][CH:3]=1.[P:16]([O-:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19].CCN(CC)CC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:9][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:3][CH:4]=1
Reactant: CCOP([O-])OCC
Reactant: NC(c1ccccc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(N)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To 2-b′ (9 g, 25 mmol), diethyl phosphite (10.5 g, 75 mmol) and Et3N (8.5 g, 75 mmol) in toluene was added PdCl2(dppf) (7.5 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into ethyl acetate and washed with saturated NH3Cl. The organic layer was concentrated under vacuum and the residue was purified over silica gel to provide the crude product 2-c (15 g). (M+Na)+=442.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C(Cl)(Cl)Cl.Br.[Br:12][CH2:13][CH2:14][NH2:15].[OH-].[Na+]>O>[Br:12][CH2:13][CH2:14][NH:15][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: NCCBr
Reactant: C=C1CC(=O)O1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(=O)NCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.4 g. (0.1 mole) of diketene in 150 ml. of chloroform is added 21 g. (0.11 mole) of 2-bromoethylamine hydrobromide in 30 ml. of water, and the resulting mixture stirred vigorously at 0° C. while 4.1 g. (0.11 mole) of sodium hydroxide in 20 ml. of water is added dropwise over a period of 20 minutes. The reaction mixture is allowed to stir at room temperature for 1 hour, after which the chloroform layer is separated, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to yield the intermediate, N-(2-bromoethyl)acetoacetamide, as a white crystalline residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.Cl.Cl.[CH3:28][NH:29][CH2:30][CH:31]1[O:36][CH2:35][CH2:34][NH:33][CH2:32]1.N12CCCN=C1CCCCC2>C(#N)C>[F:19][C:17]1[CH:16]=[C:15]([F:21])[CH:14]=[CH:13][C:18]=1[N:9]1[C:3]2[C:4](=[CH:5][C:6]([F:8])=[C:7]([N:33]3[CH2:34][CH2:35][O:36][CH:31]([CH2:30][NH:29][CH3:28])[CH2:32]3)[C:2]=2[F:1])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1
Reactant: CNCC1CNCCO1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)CCO1

Procedure:
A solution of 710 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 487 mg of 2-(methylaminomethyl)morpholine dihydrochloride and 1035 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene in 10 ml of acetonitrile is refluxed for 21 hours. The reaction mixture is concentrated under reduced pressure and to the residue is added 10 ml of methanol. The obtained crystals are collected by filtration and washed with methanol, water and then acetone to give 1-(2,4-difluorophenyl)-7-[2-(methylaminomethyl)morpholino]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 224°-227° C. with decomposition.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:13][S:14][CH3:15].ClN1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([CH2:13][S:14][CH3:15])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: CSC
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1c(N)c([N+](=O)[O-])cc(F)c1F
Yield: 34.9 %

Procedure:
To a solution of 2-nitro-4,5-difluoroaniline (1.0 g) and dimethylsulfide (1.79 g) in dichloromethane (40 ml) is added gradually N-chlorosuccinimide (3.82 g) with stirring at below 15° C. The mixture is stirred for 30 minutes, and thereto is added triethylamine (2.89 g), and the mixture is refluxed for 21 hours. After allowing to cool, the reaction mixture is washed with 10% aqueous sodium hydroxide, water and aqueous sodium chloride in this order and dried. The solvent is removed by concentration, and the resulting residue is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=30:1) and then recrystallized from n-hexane to give 2-nitro-4,5-difluoro-6-methylthiomethylaniline (0.47 g) as yellow needles, m.p. 110°-111.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][CH2:28][NH:29][C:30](=[O:38])[C:31]2[CH:36]=[CH:35][C:34](F)=[CH:33][CH:32]=2)=[CH:25][CH:24]=1>CS(C)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][NH:29][C:30]([C:31]2[CH:32]=[CH:33][C:34]([O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=3)=[CH:35][CH:36]=2)=[O:38])=[CH:39][CH:40]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
Tert-butyl 2-(4-hydroxyphenyl)acetate (200 mg, 0.960 mmol) was diluted with DMSO (4 mL) followed by the addition of K2CO3 (133 mg, 0.960 mmol) and N-(4-chlorophenethyl)-4-fluorobenzamide (267 mg, 0.960 mmol). The reaction was stirred at 85° C. overnight, and then stirred at 138° C. for 12 hours. The reaction was cooled to ambient temperature, diluted with DCM and 10% aq. sodium carbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel chromatography, eluting with hexanes:ethyl acetate (4:1) to yield tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)phenyl)acetate (20 mg, 4.47% yield) as an off white solid.