Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11](COCC[Si](C)(C)C)C=1.C[O:36][C:37]([C:39]1[S:43][C:42](Br)=[N:41][CH:40]=1)=[O:38].C(#[N:47])C.C([O-])([O-])=O.[Na+].[Na+]>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:42]3[S:43][C:39]([C:37]([OH:36])=[O:38])=[CH:40][N:41]=3)[CH:16]=2)[NH:11][N:47]=1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CC#N
Reactant: COC(=O)c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ncc(C(=O)O)s3)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
Into a 20 mL Personal Chemistry microwave reaction vial were added 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (0.4992 g, 1.038 mmol), 2-Bromo-thiazole-5-carboxylic acid methyl ester (0.2592 g, 1.167 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (95.4 mg, 0.117 mmol), acetonitrile (5 mL) and 2M aqueous Na2CO3 (5 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 130° C. for 30 min. The reaction mixture was diluted with EtOAc and acidified with acetic acid to pH 5. The layers were separated, and the aqueous phase was extracted 5× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in 10 mL of a solution consisting of 1 part HClO4 (70%, ACS) and 20 parts glacial acetic acid, and the solution was stirred at rt for 4 h. The reaction mixture was concentrated under vacuum, and neutralized to pH 7 with saturated NaHCO3 followed by solid NaHCO3. The quenched reaction mixture was partitioned between EtOAc and water, the layers were separated, and the aqueous phase was extracted 2× with EtOAc. The aqueous phase was then acidified to pH 4 with acetic acid and extracted 5× with EtOAc. The combined organic extracts was treated with brine, dried (Na2SO4), filtered and concentrated. Trituration with Et2O afforded the title compound as a greenish-brown powder (0.296 g, 81% yield). 1H-NMR (500 MHz, d6-DMSO) δ 13.73 (br. s, 1H), 9.16 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 1H), 7.10 (t, J=7.5 Hz 1H), 3.87 (s, 3H); MS: m/z 353.1 [MH+].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.CCN(CC)CC.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1>[C:39]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:23]=3)[N:9]=2)[CH2:3]1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a solution of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (27.5 mg, 0.065 mmol) and Et3N (0.014 mL, 0.097 mmol) in THF (2 mL) was added benzoyl chloride (10.93 mg, 0.078 mmol). The reaction mixture was stirred at rt for 10 min, quenched with satd. NaHCO3, extracted twice with CH2Cl2, separated, and concentrated. The residue was purified by ISCO (100% ethyl acetate, 12 g column) to obtain 24 mg of (R)-6-(3-benzamidopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a white solid. LCMS: (M+H)+=529.38. 1H NMR (400 MHz, CDCl3) δ ppm 11.22 (1H, s), 7.66 (2H, d, J=8.56 Hz), 7.59-7.64 (2H, m), 7.53 (1H, d, J=9.06 Hz), 7.42-7.49 (1H, m), 7.37 (1H, d, J=7.81 Hz), 7.31 (1H, d, J=8.56 Hz), 6.55 (1H, d, J=6.80 Hz), 6.11-6.18 (1H, m), 5.60 (2H, s), 4.17-4.28 (1H, m), 3.86-3.94 (1H, m), 3.53-3.83 (11H, m), 1.96-2.06 (1H, m), 1.88-1.95 (1H, m), 1.74-1.85 (1H, m), 1.67-1.73 (1H, m).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[N:12]=1.C1COCC1.[OH-].[Na+]>CCO>[F:21][C:19]([F:20])([F:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:23])=[O:2])[O:9][CH:10]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2C(F)(F)F)co1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCCCc1nc(-c2ccccc2C(F)(F)F)co1

Procedure:
Combine 5-[4-(2-trifluoromethyl-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.35 g, 9.9 mmol) with THF (3 mL), EtOH (3 mL) and 2N NaOH (15 mL) and stir until hydrolysis is complete. Concentrate the mixture, dilute the residue with water and adjust the pH to 3.0-4.0 using aq HCl. Extract the mixture with EtOAc and dry the extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for recovery of 5-[4-(2-trifluoromethyl-phenyl)-oxazol-2-yl]-pentanoic acid (2.36 g, 76%). MS (ES): (M+1)+ 314.2 m/z.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].N1C=CC=CC=1.[F:13][CH:14]([CH2:16][C:17](Cl)=[S:18])[F:15]>ClCCl>[F:13][CH:14]([CH2:16][C:17]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[S:18])[F:15]
Reactant: FC(F)CC(=S)Cl
Reactant: CCOCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOCCOC(=S)CC(F)F
Yield: 60 %

Procedure:
To a stirred and ice cooled solution of 2-ethoxyethanol (1.2 equivalents) and pyridine (1.3 equivalents) in dichloromethane (5 parts by weight) is dropwise added difluoromethylthioacetyl chloride. After stirring for 4 hours, the mixture is washed with saline, dried and concentrated. The residual liquid is distilled to give oily 2-ethoxyethyl difluoromethylthioacetate. Yield: 60%.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].FC(F)(F)C(O)=O.[Cl:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:42]=[C:28]4[CH:29]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)[CH2:30][C:31](=[O:34])[CH2:32][CH2:33][N:27]4[N:26]=3)=[CH:20][C:19]=2[O:43][CH3:44])[CH:17]=1.C(O)(C(F)(F)F)=O>C1COCC1.[Cu]I>[Cl:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:42]=[C:28]4[CH:29]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)[CH2:30][C:31]([CH2:1][CH3:2])([OH:34])[CH2:32][CH2:33][N:27]4[N:26]=3)=[CH:20][C:19]=2[O:43][CH3:44])[CH:17]=1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reactant: CC[Mg]Br
Agent: [Cu]I
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCC1(O)CCn2nc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2C(c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 13.4 %

Procedure:
A 25 mL round bottom flask was charged with copper (I) iodide (8.16 mg, 0.043 mmol) in THF (1 mL), and cooled to 0° C. A solution of ethylmagnesium bromide (0.714 mL, 2.142 mmol, 3 M in Et2O) was added dropwise to the stirred solution and stirred for 20 min. To this was added 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (100 mg, 0.214 mmol, from example 137) in THF (1 mL) and the reaction was stirred at 0° C. for an additional 2 h and then slowly warmed to rt and stirred for 16 h. The reaction mixture was quenched slowly with saturated ammonium chloride, and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were then washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (14.2 mg, 10% yield) as a TFA salt. LC-MS (M+H)+ 497.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.14 (1 H, br. s.), 7.45-7.97 (2 H, m), 7.05-7.20 (6 H, m), 4.63-4.77 (2 H, m), 4.36-4.49 (1 H, m), 3.88 (3 H, s), 1.88-2.35 (4 H, m), 1.71 (2 H, q, J=7.4 Hz), 1.24-1.51 (1 H, m), 1.03 (3 H, t, J=7.5 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:38][O:39][C:40]1[C:41]2[N:54]=[C:53]([NH2:55])[S:52][C:42]=2[C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[N:44][CH:45]=1>C1COCC1>[CH3:1][O:2][CH2:3][C:4]([NH:55][C:53]1[S:52][C:42]2[C:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:44][CH:45]=[C:40]([O:39][CH3:38])[C:41]=2[N:54]=1)=[O:6]
Reactant: COCC(=O)O
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCC(=O)Nc1nc2c(OC)cnc(N3CCOCC3)c2s1

Procedure:
From methoxyacetic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 339 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@H:15]3[C@H:17]([NH2:20])[CH2:18][CH2:19][C@H:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C(=O)[C:24]([CH3:27])([CH3:26])[CH3:25].[CH3:29][C:30](C)=[O:31]>>[CH:17]([NH:20][C@H:29]([C:30]([NH:20][C@@H:17]1[C@@H:15]2[C@@H:14]([CH2:13][N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=3)(=[O:10])=[O:11])[CH2:16]2)[CH2:19][CH2:18]1)=[O:31])[CH2:27][CH:24]([CH3:25])[CH3:26])([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)(C)C=O
Product: CC(C)C[C@H](NC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N1-((3aR,4S,6aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydrocyclopenta[c]pyrrol-4-yl)-L-leucinamide from Step B for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine and acetone for pivalaldehyde in the procedure described in Example 281: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.38 (s, 1H), 8.30-8.33 (m, 1H), 8.20 (d, J=7.9 Hz, 1H), 7.90-7.93 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 4.20-4.26 (m, 1H), 3.86 (dd, J=9.9, 2.3 Hz, 1H), 3.35 (dd, J=8.9, 5.1 Hz, 1H), 3.14-3.20 (m, 2H), 2.97 (dd, J=9.6, 6.8 Hz, 1H), 2.83 (hept, J=6.2 Hz, 1H), 2.52-2.56 (m, 2H), 2.07-2.81 (m, 1H), 1.78-2.01 (m, 3H), 1.64 (ddd, J=13.6, 8.4, 5.2 Hz, 1H), 1.47-1.59 (m, 2H), 1.25-1.36 (m, 1H), 1.04 (d, J=6.3 Hz, 3H), 1.02 (d, J=6.1 Hz, 3H), 0.91 (d, J=6.7 Hz, 3H), 0.85 (d, J=6.6 Hz, 3H); MS (ESI−) m/z 488 (M−H)−.
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([S:18]([N:9]2[CH2:8][CH2:7][NH:6][C:5]3[N:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]2=3)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Ic1cnc2c(c1)NCCN2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)N1CCNc2ncc(I)cc21
Temperature: 100 °C
Yield: 23 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was dissolved in anhydrous pyridine. Phenylsulfonyl chloride (1.0 eq) was added and the reaction mixture was heated to 100° C. in a microwave oven for 10 minutes. Silica gel chromatography gave the title compound as a pale orange solid (23% yield). M.p. 145-146° C., LCMS: m/z=407.71 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.94-2.99 (m, 2H), 3.74 (t, J=5.0 Hz, 2H), 4.83 (bs, 1H), 7.45-7.49 (m, 2H), 7.58-7.65 (m, 3H), 8.06 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([O:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=2[CH2:38][CH3:39])=[O:25])[CH:14]=[CH:15][C:16]=1[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][C:49]=1[F:50])[C:44]([NH2:46])=[O:45].O.[C:52]([OH:56])(=[O:55])[CH:53]=O>>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([O:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH:53]([NH:40][C:41]3[CH:42]=[C:43]([C:44](=[O:45])[NH2:46])[CH:47]=[CH:48][C:49]=3[F:50])[C:52]([OH:56])=[O:55])=[CH:31][C:30]=2[CH2:38][CH3:39])=[O:25])[CH:14]=[CH:15][C:16]=1[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(B(O)O)ccc1CCOC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(CN(C)C(=O)OC(C)(C)C)c1
Reactant: O=CC(=O)O
Reactant: NC(=O)c1ccc(F)c(N)c1
Solvent: O
Product: CCc1cc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)ccc1CCOC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(CN(C)C(=O)OC(C)(C)C)c1
Yield: 62 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 43B (362 mg, 0.65 mmol) was reacted with 3-amino-4-fluorobenzamide and glyoxylic acid monohydrate to afford 43C (296 mg, 62%) as a yellow oil. MS (ESI) m/z 729.3 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[C:11]([C:17]([F:20])([F:19])[F:18])=[N:12][C:13](Cl)=[N:14][CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25]>O1CCOCC1>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[C:11]([C:17]([F:20])([F:19])[F:18])=[N:12][C:13]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([F:29])=[C:22]([Cl:21])[CH:23]=3)=[N:14][CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCC1)c1cnc(Cl)nc1C(F)(F)F
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: C1COCCO1
Product: O=C(NCC1CCCC1)c1cnc(Nc2ccc(F)c(Cl)c2)nc1C(F)(F)F
Yield: 66.2 %

Procedure:
2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclopentylmethyl-amide (116 mg Example 183a), 3-chloro-4-fluoroaniline (ex-Aldrich, 275 mg), and 1,4-dioxan (1.2 ml) were stirred at 100° C. under nitrogen for 6 h. The cooled reaction mixture was evaporated in vacuo, treated with ethyl acetate (5 ml), washed with aqueous 2M hydrochloric acid (2×3 ml), followed by brine, and dried (Na2SO4). The solution was evaporated in vacuo to give the title compound (104 mg).
Reaction SMILES: C([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[C:13]=2[O:15][CH3:16])[C:8](=[O:19])[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:6]1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[F:18][C:11]1[CH:10]=[C:9]2[C:14](=[C:13]([O:15][CH3:16])[C:12]=1[F:17])[NH:5][CH:6]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]2=[O:19]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2c(OC)c(F)c(F)cc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c2c(OC)c(F)c(F)cc2c1=O
Yield: 99.9 %

Procedure:
A solution of ethyl 1-tert-butyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (4.00 g, 11.8 mmol) in CH2Cl2 (20 mL) and trifluoroacetic acid (4.0 mL) was stirred at 0° C. for 30 min. The mixture was concentrated in vacuo and poured into 500 mL of ice-water. The resulting precipitate was removed by filtration, washed with water and then dried to yield ethyl 6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (3.34 g, quant) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[S:38][C:8]2[C:9](=[O:37])[N:10]([C:12]3[C:13]([CH3:36])=[C:14]([C:18]4[CH:19]=[C:20]([NH:25][C:26]5[CH:35]=[C:29]6[CH2:30][N:31]([CH3:34])[CH2:32][CH2:33][N:28]6[N:27]=5)[C:21](=[O:24])[NH:22][N:23]=4)[CH:15]=[CH:16][CH:17]=3)[CH2:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:39]=[O:40]>CO>[C:1]([C:5]1[S:38][C:8]2[C:9](=[O:37])[N:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:19]=[C:20]([NH:25][C:26]5[CH:35]=[C:29]6[CH2:30][N:31]([CH3:34])[CH2:32][CH2:33][N:28]6[N:27]=5)[C:21](=[O:24])[N:22]([CH2:39][OH:40])[N:23]=4)[C:13]=3[CH3:36])[CH2:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: Cc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)[nH]n2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Solvent: CO
Product: Cc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(CO)n2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 101 (2.50 g, 4.72 mmol), methanol (30 mL) and a 37% solution of formaldehyde in methanol (30 mL, 100 mmol). A reflux condenser was attached to the flask, and the reaction mixture was heated at 60° C. for 3 h under nitrogen atmosphere. After this time, the mixture was stirred at room temperature for 1 h and filtered through a Buchner funnel. The filter cake was washed with methanol (3×5 mL) and dried under vacuum at 40° C. for 12 h to afford 108a in a 93% yield (2.45 g) as a white solid: mp 185-187° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.79 (s, 1H), 7.47 (m, 1H), 7.39 (s, 1H), 7.38 (s, 1H), 7.14 (s, 1H), 6.77 (t, J=7.8 Hz, 1H), 5.99 (s, 1H), 5.43 (d, J=7.5 Hz, 2H), 4.78 (s, 2H), 3.97 (t, J=5.0 Hz, 2H), 3.51 (s, 2H), 2.79 (t, J=5.0 Hz, 2H), 2.35 (s, 3H), 2.13 (s, 3H), 1.41 (s, 9H); MS (ESI+) m/z 530.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H+].[B-](F)(F)(F)F.[Si](C=[N+]=[N-])(C)(C)[CH3:26].O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH2:16][O:17][CH3:26])[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(NC1(CO)CCCC1)OCc1ccccc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: ClCCl
Product: COCC1(NC(=O)OCc2ccccc2)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold solution (0° C.) of (1-hydroxymethyl-cyclopentyl)-carbamic acid benzyl ester (250 mg, 1 mmol) and 48% aqueous HBF4 (0.13 mL, 1 mmol) in CH2Cl2 (4 mL) was added TMSCHN2 (2N in hexane, 2 mL, 4 mmol) via syringe. The resulting mixture was stirred, at 0° C., for ½ hour followed by the addition of water (10 mL). The aqueous mixture was extracted with CH2Cl2 (2×50 mL), and the combined organic layers were dried (sodium sulfate), filtered, concentrated and chromatographed with 30% ethyl acetate/hexane to provide the titled compound. MS (DCI) m/e 264 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH2:13][CH3:14])=[C:9]([CH3:12])[C:10]=1[CH3:11])(OCC)=O.[CH3:15]C1OC(C)OC(C)O1>>[CH2:13]([C:8]1[NH:7][C:6]([CH2:1][CH3:15])=[C:10]([CH3:11])[C:9]=1[CH3:12])[CH3:14]
Reactant: CC1OC(C)OC(C)O1
Reactant: CCOC(=O)c1[nH]c(CC)c(C)c1C
Product: CCc1[nH]c(CC)c(C)c1C

Procedure:
2-Carbethoxy-3,4-dimethyl-5-ethyl-pyrrole was reductively alkylated with paraldehyde to yield 2,5-diethyl-3,4 dimethyl-pyrrole. ##STR84##
Reaction SMILES: [CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C@H:2]1[NH2:13].[CH2:14]1[O:20][C@@H:19]2[O:21][C@H:15]1[C@@H:16]([OH:24])[C@H:17]([OH:23])[C@H:18]2[OH:22].N.[Na]>C1COCC1>[CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C@H:2]1[NH2:13].[O:20]=[CH:14][C@@H:15]([C@H:16]([C@@H:17]([C@@H:18]([CH2:19][OH:8])[OH:22])[OH:23])[OH:24])[OH:21]
Reactant: O[C@@H]1[C@@H](O)[C@@H]2OC[C@@H](O2)[C@H]1O
Agent: N
Agent: N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na]
Solvent: C1CCOC1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.5 h

Procedure:
1.09 g (1.41 mmol) of 1,6-anhydro-4-O-benzyl-2-deoxy-2-[1D-(1N,2,4/3)-2,3,4-tri-O-benzyl-5-C-benzyloxymethyl-2,3,4-trihydroxy-5-cyclohexen-1-yl)amino]-β-D-glucopyranose (compound 3) was dissolved in THF (20 ml) and liquid ammonia (~100 ml) was added at ~78° C. Sodium (0.42 g) was added and the reaction mixture was stirred for 30 minutes at this temperature. NH4 Cl(2 g) was then added and ammonia and THF were evaporated at room temperature. The residue was acetylated in pyridine (5 ml) and acetic anhydride (5 ml). Excess of acetic anhydride was quenched by the addition of methanol. The reaction mixture was evaporated and dissolved in dichloromethane (100 ml) and washed sequentially with 5% HCl solution (2×100 ml), saturated NaHCO3 solution (2×100 ml) and water (2×100 ml) before evaporation to a syrup. The syrup was purified by chromatography on silica gel using toluene:ethylacetate (3:1) as eluent to provide 1,6-anhydro-3-4-di-O-acetyl-2-deoxy-2-[1D-(1N,2,4/3)-(2,3,4-tri-O-acetyl-5-C-acetoxymethyl-2,3,4-trihydroxy-5-cyclohexen-1-yl)amino]-β-D-glucopyranose (compound 4) (613 mg, 75.8%).
Reaction SMILES: [P:1]([O:13][CH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH2:17][O:18][Si](C(C)(C)C)(C)C)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[P:1]([O:13][CH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH2:17][OH:18])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:2]
Reactant: CC(C)(CCO[Si](C)(C)C(C)(C)C)COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(CCO)COP(=O)(OC(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of the product from Example 10B (0.435 g, 1.03 mmol) in THF (3.8 mL) was added a solution of tetrabutylammonium fluoride in THF (1 M, 1.2 mL), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 33% ethyl acetate in hexane, to give the title compound (0.239 g, 75%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(C1C=CC=CC=1)(=O)CCCCCCCCCC.S(Cl)([Cl:42])(=O)=O>C(Cl)(Cl)Cl>[Cl:42][C:5]1[C:4]([OH:8])=[C:3]([C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCCCCCCC(=O)c1c(O)cccc1O
Agent: CCCCCCCCCCC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC(=O)c1c(O)ccc(Cl)c1O

Procedure:
In a 100 ml three-neck flask was placed 50 ml of 2',6'-dihydroxyundecanophenone and after dissolving the undecanophenone in 50 ml of chloroform, the solution thus formed was stirred under ice-cooling. To the solution was added dropwise 10 ml of a chloroform solution of 1.4 ml of sulfuryl chloride over a period of 15 minutes. Thereafter, the mixture was stirred for 2 hours at room temperature and then after adding thereto n-hexane, the mixture was washed twice with water. After drying the reaction mixture with magnesium sulfate, the product was concentrated and the residue thus obtained was recrystallized from methanol to provide the light yellow crystals of 3'-chloro-2',6'-dihydroxyundecanophenone having a melting point of 76°-77° C. The structure was confirmed by carrying out analysis such as mass spectrography and nuclear magnetic resonance spectra.
Reaction SMILES: [C:1]([O:4]C=C)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([CH:16]=[CH:17][CH:18]=[CH2:19])[CH2:12][CH2:13]CC>C1(C)C=CC=CC=1>[C:1]([O:4][CH:11]1[CH2:16][CH2:17][C:18]([CH3:19])=[CH:13][CH2:12]1)(=[O:3])[CH3:2]
Reactant: C=CC=CCCCCC
Reactant: C=COC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=O)OC1CC=C(C)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of vinyl acetate 4A (20 mL) in anhydrous toluene (220 mL) is added aluminum chloride (2.89 g). The flask is cooled to 0° C., and the isoprene 1C (R=methyl) (21.7 mL) is added dropwise. The reaction mixture is stirred 5 hours at 0° C., then allowed to stand at 4° C. for a further 16 hours. The reaction mixtire is then sequentially extracted with two portions (150 mL each) of 1% hydrochloric acid solution, water (75 mL), and brine (75 mL). It is dried over sodium sulfate, filtered through Celite, and concentrated in vacuo. The product is distilled to give 30 g of clear, colorless liquid.