Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([CH3:15])([S:7]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:9])=[O:8])[CH3:6])C.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:15][C:5]([S:7]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:9])=[O:8])([CH3:6])[C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)CCC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CCS(=O)(=O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
To a solution of 3.78 g (15.09 mol) of 2-methyl-2-(3-methyl-butane-1-sulfonyl)-propionic acid ethyl ester in THF/water (4/1, 50 mL) are added 1.58 g (37.74 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 18 h. The reaction mixture is concentrated under reduced pressure and the residue dissolved in DCM (20 mL) and extracted with water (50 mL). The aqueous layer is cooled in an ice bath and then acidified with 6M aqueous HCl solution to pH 1. The resulting precipitate is isolated by filtration, and dried under reduced pressure at 50° C. to afford 3.35 g of 2-methyl-2-(3-methyl-butane-1-sulfonyl)-propionic acid as white crystalline solids. Yield: 100%; ES-MS: m/z 221 [M−H].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:23][Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([CH3:23])[N:11]=1)=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2onc(-c3ccccc3)c2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2onc(-c3ccccc3)c2c1O
Temperature: 130 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A mixture of 7-bromo-4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (231 mg, 0.64 mmol), tetramethyltin (177 μl, 1.28 mmol), bis(triphenylphosphine)palladium(II) dichloride (45 mg, 0.06 mmol), and dimethylformamide (2.5 ml) was stirred at 130° C. for 1 h before it was cooled to room temperature, quenched with water, and filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (95 mg): MS: (+) m/z 299.49 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=3[CH:15]=[C:7]2[C:6]2[N:17]=[C:18]([C:21]3[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:23][C:24]4[O:28][C:27]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=4[CH:40]=3)[CH:19]=[CH:20][C:5]=2[O:4]1.[CH3:47][O:48][C:49]([N:51]1[CH2:55][CH2:54][CH2:53][C@H:52]1[C:56](O)=[O:57])=[O:50].CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:13]1[C:14]2[CH:15]=[C:7]3[C:6]4[N:17]=[C:18]([C:21]5[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:43])=[O:44])=[CH:23][C:24]6[O:28][C:27]([C:29]7[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=7)=[C:26]([C:36](=[O:37])[NH:38][CH3:39])[C:25]=6[CH:40]=5)[CH:19]=[CH:20][C:5]=4[O:4][CH:3]([CH2:2][NH:1][C:56]([C@@H:52]4[CH2:53][CH2:54][CH2:55][N:51]4[C:49]([O:48][CH3:47])=[O:50])=[O:57])[N:8]3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)N1CCC[C@H]1C(=O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN)O4)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CNC(=O)[C@@H]3CCCN3C(=O)OC)O4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A mixture of 5-(6-(aminomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (70 mg, 0.11 mmol), (S)-1-(methoxycarbonyl)pyrrolidine-2-carboxylic acid (38 mg, 0.22 mmol), EDCI (12 mg, 0.27 mmol), DMAP (40 mg, 0.33 mmol) and triethylamine (33 mg, 0.33 mmol) in CH2Cl2 (2 mL) was stirred at room temperature overnight. The mixture was then purified using Prep-TLC(CH2Cl2:EtOAc=1:1) to provide (2S)-methyl 2-(((11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (60 mg, yield: 69.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.86˜8.05 (m, 3H), 7.28˜7.69 (m, 4H), 7.16˜7.27 (m, 5H), 6.85 (d, J=9.2 Hz, 1H), 6.60 (dd, J=5.2, 7.2 Hz, 1H), 5.98˜6.25 (m, 1H), 4.31 (br. s, 1H), 3.65 (br. s, 5H), 3.39 (s, 5H), 2.97 (d, J=3.2 Hz, 3H), 2.72 (br. s, 3H), 1.90˜2.49 (m, 2H), 1.63˜1.79 (m, 2H). MS (M+H)+: 799.
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(C)C.[BH4-].[Na+]>C1COCC1.CO>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@H]1CC[C@@H](C(=O)O)CC1)OCc1ccccc1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@H]1CC[C@@H](CO)CC1)OCc1ccccc1
Temperature: 0 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of cis-4-benzyloxycarbonylaminocyclohexanecarboxylic acid (417 mg, 1.50 mmol) in THF (15 mL) was added BH3.Me2S complex (2.0 M in THF, 1.5 mL, 3.00 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h30. More BH3.Me2S complex (2.0 M in THF, 1.0 mL, 2.00 mmol) was added at 0° C. followed by NaBH4 (12 mg, 0.30 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. MeOH was carefully added to quench the reaction, the volatiles were removed under reduced pressure and the residue co-evaporated with MeOH (2×). Purification by FC (hept-EA, 1:0->3:2) gave pure cis-4-benzyloxycarbonylaminocyclohexane-methanol as a colorless oil. TLC:rf (1:2 hept-EA)=0.45. LC-MS-conditions 01: tR=0.82 min; [M+H]+=264.07.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][S:34]([CH:31]3[CH2:33][CH2:32]3)(=[O:36])=[O:35])=[CH:27][CH:28]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Solvent: ClCCl
Product: O=C(Nc1nc(-c2ccc(NS(=O)(=O)C3CC3)cc2)cs1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of (S)-2-[4-(4-Amino-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5050, Example 50, 0.06 g, 0.14 mmol) in DCM (2.0 mL) at 0° C. was added TEA (0.0.025 mL) followed by addition of cyclopropanesulfonyl chloride (0.016 mL). The reaction mixture was stirred at room temperature for 1 h then was concentrated in vacuo to give the crude product. Purification of the crude product by reverse phase HPLC furnished the desired product. 1HNMR (DMSO-d6) δ(ppm) 7.87-7.83 (m, 2H), 7.37-7.07 (m, 7H), 5.17-5.13 (m, 2H), 4.89-4.87 (m, 3H), 4.52-4.47 (m, 1H), 3.69-3.54 (m, 2H), 2.60-2.56 (m, 1H), 2.38-2.35 (m, 1H), 2.08-1.96 (m, 3 H), 1.07-0.95 (m, 4H); MS: 527.1 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12](O)([CH2:15][CH3:16])([CH3:14])[CH3:13].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:12]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11])([CH2:15][CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CCC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)c1cc(C(C)(C)C)ccc1O
Yield: 40 %

Procedure:
4-t-butylphenol (73 g, 0.49 mole) is dissolved in 200 ml anhydrous trifluoroacetic acid (TFA). T-amyl alcohol (47 g, 0.53 mole) is added with stirring. The mixture is stoppered and stirred for 19 hours at ambient (~22° C.) temperature. The solution is then diluted into 400 ml of 1M NaOH, and the resulting upper organic layer is isolated in a separatory funnel. The crude product is dried over anhydrous magnesium sulfate. The product, 2-t-amyl-4-t-butylphenol, is purified by eluting 35 g of the mixture with 60:40 hexanes:dichloromethane (v/v) in a 5×20 cm silica column and eluted with 300 to 700 ml of solvent and collected in aliquots of 50 ml. Aliquots showing a single spot by Thin Layer Chromatography (TLC) (on silica eluted with 60:40 hexanes:dichloromethane v/v)) are combined and rotoevaporated to a thick syrup, typically giving a 40% yield.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1)[C:10]([OH:12])=O.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:31][CH:32]1[C:55](=[O:56])[N:34]2[C:35]([C:52]([OH:54])=[O:53])=[C:36]([CH2:39][O:40][C:41](=[O:51])[C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)[CH2:37][S:38][C@H:33]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1)[C:10]([NH:31][CH:32]1[C:55](=[O:56])[N:34]2[C:35]([C:52]([OH:54])=[O:53])=[C:36]([CH2:39][O:40][C:41](=[O:51])[C:42]3[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[CH:46][CH:47]=3)[CH2:37][S:38][C@H:33]12)=[O:12]
Reactant: NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccc([N+](=O)[O-])cc3)CS[C@H]12
Reactant: CON=C(C(=O)O)c1csc(N)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccc([N+](=O)[O-])cc3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.33 h
Yield: 42.9 %

Procedure:
Phosphorus oxychloride (0.56 g) was at a time added under 5° C. to a mixture of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (0.6 g) and dry ethyl acetate (6 ml), and the mixture was stirred for 20 minutes at 4° to 6° C. Bis(trimethylsilyl)acetamide (0.3 g) was at a time added thereto at the same temperature and the mixture was stirred for 10 minutes at the same temperature.To the resulting mixture was at a time added phosphorus oxychloride (0.56 g) and the mixture was stirred for 30 minutes at the same temperature, to which was added dropwise dimethylformamide (0.24 g) and the resulting mixture was stirred for 30 minutes at 4° to 6° C. Thus obtained solution was at a time added with stirring at -15° C. to a solution of 7-amino-3-(4-nitrobenzoyl)oxymethyl-3-cephem-4-carboxylic acid (1.1 g) and trimethylsilylacetamide (3.5 g) in dry ethyl acetate (20 ml), and the resulting mixture was stirred for 2 hours at -5° to -10° C. The reaction mixture was adjusted to pH 7-7.5 with a saturated aqueous solution of sodium bicarbonate under 0° C., stirred for 1 hour at pH 7 under 5° C., adjusted to pH 2.5 and filtered. The organic layer in the filtrate was separated, and water (20 ml) was added thereto. The mixture was adjusted to pH 6.5 with sodium bicarbonate. The aqueous layer was separated and washed with diethyl ether. Remaining solvent in the aqueous layer was removed by passing nitrogen gas, and the aqueous layer was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and dried to give pale yellow powder of 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(4-nitrobenzoyl)oxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.7 g), mp 151° to 163° C. (dec.).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1Br.[F:17][C:18]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:22]=[CH:21][C:19]=1[NH2:20].C([O-])([O-])=O.[K+].[K+]>[Cu]I>[CH3:1][N:2]([CH3:16])[C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH:20][C:19]1[CH:21]=[CH:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[CH:24][C:18]=1[F:17]
Reactant: CN(C)C(=O)Cc1cc(C2CC2)ccc1Br
Reactant: Nc1ccc(-c2ccc(F)cc2)cc1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)C(=O)Cc1cc(C2CC2)ccc1Nc1ccc(-c2ccc(F)cc2)cc1F

Procedure:
A mixture of N,N-dimethyl-2-bromo-5-cyclopropylphenylacetamide (1.0 g), 2-fluoro-4-(4-fluorophenyl)aniline (1.5 g), K2CO3 (490 mg), KI (590 mg), Cu (113 mg), CuI (337 mg) in xylenes (10 mL) is heated to reflux for 48 hours. After cooling, the reaction is filtered through silica gel and the filtrate concentrated to a brown oil. The oil is purified by flash chromatography using 10%, then 20%, then 30%, then 40% EtOAc in hexane to give the title product as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[N:6]=[C:5]2[CH3:11]
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nn(COCC[Si](C)(C)C)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of 5-bromo-3-methylindazole 104 (2 g, 9.48 mmol) in anhydrous DMF (20 mL), cooled in ice bath, was added-sodium hydride (60% w/w, 0.57 g, 14.25 mmol) and (2-trimethylsilylethoxy)methyl chloride (2.5 mL, 14.16 mmol) in a dropwise manner. The reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. Ethyl acetate (200 mL) was added. The organic layer was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-bromo-3-methyl-N-(2-trimethylsilanylethoxymethyl)indazole 116 (2.95 g, 8.65 mmol) as a mixture of the 1H- and 2H-indazole regioisomers.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=3)=[N:13][CH:14]=2)=CC=1>C(O)(C(F)(F)F)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=2)=[N:13][CH:14]=1
Reactant: COC(=O)c1cnc(-c2ccc(OCc3ccc(OC)cc3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc(-c2ccc(O)cn2)s1

Procedure:
A solution of methyl 2-(5-(4-methoxybenzyloxy)pyridin-2-yl)thiazole-5-carboxylate (1.10 g) in TFA (10 mL) was stirred at 80° C. for 2 hours. After the reaction was complete, the mixture was evaporated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:2 to pure EA) to provide the subtitle compound. MS ESI+: m/z=237 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>Br>[CH3:12][C@@H:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][NH:4]1
Reactant: C[C@@H](NCCO)c1ccccc1
Agent: Br
Product: C[C@H]1NCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
11.0 g(66.58 mmole) of (R)-(+)-N-(2-hydroxyethyl)-α-methylbenzylamine produced in Example 8(1) above was suspended in 52 ml of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126° C. for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature and 47 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 55 ml of acetone, and 50 ml of ethyl acetate and 70 ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 30 ml of ethyl acetate and then dried to obtain 10 g of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 60 ml of ethanol and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in 50 ml of acetone, diluted with 70 ml of ether and then allowed to stand at 0° C. for 12 hours. The resulting solid product was filtered, collected and washed with 30 ml of ethyl acetate to obtain 3.1 g of the second crop of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O>[Pt]=O.C(OCC)(=O)C>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)C(=O)CCC2
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of platinum oxide (1.6 g), 0.1M aqueous ferric chloride (1 ml), 7-nitro-1-tetralone (15.8 g) and ethyl acetate (400 ml) in a hydrogenation bottle was hydrogenated at 3.5 bar for 3 h. The catalyst was removed by filtration through diatomaceous earth with methanol wash and the filtrate was evaporated to give crude 7-amino-1-tetralone (13.2 g, 100%) as a brown solid; NMR (80 MHz, DMSO-d6) 1.76-2.17(m, 2H, CH2), 2.34-2.90(m, 4H, 2XCH2), 5.10 (br s, 2H, NH2), 6.76(dd, 1H, J=8.3, 2.8 Hz), 7.0(d, 1H, J=8.3 Hz), 7.07 (d, 1H, J=2.8 Hz).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([N:12]1[CH2:16][CH:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[O:14][C:13]1=[O:26])[CH3:11])(C(C)(C)C)(C)C.[F-]>O1CCCC1>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][CH:15]1[O:14][C:13](=[O:26])[N:12]([CH:10]([CH3:11])[CH2:9][OH:8])[CH2:16]1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)N1CC(COc2cccc(F)c2)OC1=O
Agent: [F-]
Solvent: C1CCOC1
Product: CC(CO)N1CC(COc2cccc(F)c2)OC1=O
Yield: 96.5 %

Procedure:
A procedure similar to that described in Preparation 5(b) was repeated, except that 0.93 g of 3-(2-t-butyldimethylsilyloxy-1-methylethyl)-5-(3-fluorophenoxymethyl)oxazolidin-2-one (prepared as described in Preparation 72), 9 ml of anhydrous tetrahydrofuran and 7.2 ml of tetrabutylammonum fluoride (26% w/v in tetrahydrofuran) were used, to give 0.63 g of the title compound having an Rf value of 0.18 (on silica gel thin layer chromatography, using ethyl acetate as the developing solvent).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].[O:12]1CCCC1>>[OH:12][CH2:11][CH2:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: C=Cc1cccnc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ncccc1CCO
Reaction time: 8 h

Procedure:
Dimethyl sulfide-borane complex (15.9 mL, 32 mmol) was added to a solution of 2-nitro-3-vinylpyridine (2.4 g, 15.9 mmol) (Yamaka et. al., Heterocycles, 1992, 34, 2379-2384) in tetrahydrofuran (30 mL) under argon. The reaction was stirred at 200C for 2 h, and concentrated in vacuo. The concentrate was redissolved in tetrahydrofuran and stirred overnight with 20% aqueous sodium hydroxide (20 mL) and 30% hydrogen peroxide solution (20 mL). Methylene chloride was added and the mixture extracted with saturated sodium bicarbonate, and the organic phase dried over sodium sulfate. The crude product was purified (silica gel, 0-50% ethyl acetate in hexane gradient elution) to produce the title compound (0.300 g). MS 169 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14](O)[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:32])CC>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14]([F:32])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1F
Temperature: 25 °C

Procedure:
To a solution of (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate (1.0 equiv.) in dichloromethane (0.3 M solution) was added DAST at −78° C. The reaction mixture was slowly warmed up to room temperature for 15 h. After quenched with saturated sodium bicarbonate aqueous solution, ethyl acetate and water were added for work-up. The (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-fluoropiperidine-1-carboxylate was obtained by silica column chromatography (30% EtOAc in hexanes, 40%). LCMS (m/z): 253.1; LC Rt=4.08 min. The enantiomerically pure (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-fluoropiperidine-1-carboxylate and (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-fluoropiperidine-1-carboxylate were resolved by chiral HPLC (for analysis: Rt=9.4 min and 12.6 min respectively; n-heptane:isopropanol=90:10 (v:v), Chiralpak AS 250×4.6 mm at 1 mL/min. For preparative separation, n-heptane:isopropanol=90:10 (v:v), Chiralpak AS 50×500 mm at 90 mL/min).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:20])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30].O>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:19][C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH2:28][C:29]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:30])[CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1
Reactant: O=C(CBr)N1CCOCC1
Reactant: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@H]1COCc2nc3c(N)nc4ccc(OCC(=O)N5CCOCC5)cc4c3n21
Temperature: 75 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (500 mg, 1.85 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (1.80 g, 5.55 mmol) and 2-bromo-1-morpholin-4-yl-ethanone (462 mg, 2.03 mmol). After stirring overnight at 75° C., the brown mixture was poured into 150 mL of H2O and stirred for 30 minutes. The reaction mixture was extracted with CHCl3 (3×75 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give an off-white solid. Chromatography (SiO2, 0-20% CMA/CHCl3) gave an off-white solid which was crystallized from acetonitrile to give 272 mg of the title compound as an off-white solid, mp 226-228° C.