Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:20](=[O:22])[CH3:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Product: CC(=O)Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-ylamine and acetic acid as starting materials, MS (LC/MS): 317.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:30][CH:31]=O)[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S@:14](=[O:29])[CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:34][NH:35][CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:30][CH2:31][N:35]([CH3:36])[CH3:34])[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S@:14](=[O:29])[CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC
Reactant: N#Cc1cc2ccccc2c2c1[S@](=O)CCN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C2=O
Agent: Cl
Product: CN(C)CC[C@H](CN1CC[S@@](=O)c2c(C#N)cc3ccccc3c2C1=O)c1ccc(Cl)c(Cl)c1
Yield: 92.6 %

Procedure:
By the method described in Example 79, Intermediate 78c (10 mg, 0.021 mmol) and dimethylamine hydrochloride (5 mg, 0.06 mmol) were converted to 10 mg of the title compound.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.Cl.[CH3:13][O:14][C:15](=[O:21])[C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:13][O:14][C:15]([C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)=[O:21]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (6.00 g, 17.3 mmol) and L-proline methyl ester hydrochloride (2.88 g, 17.4 mmol) in DMF (125 mL) was treated with a solution of triethylamine (7.8 mL, 55.5 mmol) in DMF (75 mL). After stirring at room temperature under N2 for 3 h, the cloudy mixture was diluted with H2O (300 mL) and extracted with EtOAc (2×300 mL). The combined organic layers were washed with H2O (2×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1 to 98:2) gave the title compound (3.66 g, 67%) as a pale yellow oil: MS (ESI) m/e 314 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[CH:9]=[C:8]([Br:20])[CH:7]=1.CN(C)C1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([Br:20])[CH:7]=1
Reactant: Brc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Oc1cc(Br)cc(Br)c1
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Aluminium chloride (11.7 g, 87.6 mmol) was added in portions to a solution of 1,3-dibromo-5-benzyloxybenzene (10.0 g, 29.2 mmol; see step (i) above) and N,N-dimethylaniline (35.4 g, 292 mmol) in CH2Cl2 (100 mL) at room temperature under a nitrogen atmosphere. After 30 min, the mixture was partitioned with 1N HCl (300 mL) and EtOAc (5×150 mL). The combined organic extracts were washed with saturated NaHCO3 (150 mL) and brine (150 mL) then, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with Hex:EtOAc (9:1) afforded the sub-title compound (6.1 g, 82%) as a white solid.
Reaction SMILES: Br[C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]([OH:14])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1)[C:7]2=[O:15].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[F:23])[CH2:16][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[C:9]([OH:14])[C:10](=[O:13])[N:11]([CH3:12])[C:2]=2[C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[C:7]1=[O:15]
Reactant: Cn1c(Br)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1c(-c2cccnc2)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (35 mg, 0.08 mmol; Example 80), tetrakis(triphenylphosphine)palladium(0) (5 mg), pyridine-3-boronic acid (15 mg, 0.13 mmol), aq sodium carbonate (2 M, 0.5 mL), and dioxane (1.5 mL) was heated in a microwave oven at 100° C. for 15 minutes. The product mixture was concentrated under vacuum, and the residue was partitioned between water and dichloromethane. The organic extract was separated, concentrated under vacuum. The residue was subjected to preparative reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provide the titled compound.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:34]1[N:35]=[CH:36][S:37][CH:38]=1)\[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])=[C:12]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:13][S:14](=O)[C@H:9]12)=[O:6].O.O.Cl[Sn]Cl.C(Cl)(=O)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:34]1[N:35]=[CH:36][S:37][CH:38]=1)\[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])=[C:12]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(N)=O)CS(=O)[C@H]12)c1cscn1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Solvent: O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(N)=O)CS[C@H]12)c1cscn1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
The 1-oxide derivative (85 mg) from Example 4 was dissolved in dimethylformamide (2 ml, followed by addition of SnCl2.2H2O (84 mg) and cooling with ice. Acetyl chloride (0.38 ml) was added dropwise to the mixture. Then the ice bath was removed to raise the temperature to 20° C. After stirring for 15 minutes, the reaction mixture was added to cold water (10 ml). The mixture was extracted three times with ethyl acetate (15 ml×3). The ethyl acetate layers, combined together, were washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (0.5 ml) and the solution was added dropwise to petroleum ether (30 ml) with stirring. Resulting crystals were filtered, and dried under reduce pressure to give the title compound (35 mg).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[S:15]([O:20]C)([O:18][CH3:19])(=[O:17])=[O:16]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:19][N+:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[N:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2.[CH3:19][O:18][S:15]([O-:20])(=[O:17])=[O:16]
Reactant: c1ccc2nc3ccccc3nc2c1
Reactant: COS(=O)(=O)OC
Solvent: O=[N+]([O-])c1ccccc1
Product: COS(=O)(=O)[O-]
Product: C[n+]1c2ccccc2nc2ccccc21
Reaction time: 2 h
Yield: 53.8 %

Procedure:
5-methyl phenazinium methosulfate was prepared by quaternizing 36.0 g (200 mmoles) of phenazine with 25.2 g (200 mmoles) of dimethyl sulfate in 300 ml of nitrobenzene in a 500 ml 3-neck, round-bottom flask. The mixture was gradually heated to 80 degrees Celsius and then held at that temperature for 2 hours. After cooling, the methosulfate salt was filtered off and washed with ethanol for a 53.8% yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:11])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[CH:20]([Si:23](OS(C(F)(F)F)(=O)=O)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[O:11][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: OC1CCc2ccc(Br)cc21
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](OC1CCc2ccc(Br)cc21)(C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
To 6-Bromo-2,3-dihydro-1H-inden-1-ol (300 mg, 1.41 mmol) in CH2Cl2 (4 mL) was added 2,6-lutidine (151 μL, 1.41 mmol) followed by triisopropylsilyltriflate (378 μL, 1.41 mmol) at room temperature. The reaction was stirred for 30 min then added to 1N HCl and extracted. The organic layer was washed with saturated sodium bicarbonate then brine and dried over MgSO4. The solvent was removed in vacuo and the crude material purified by column chromatography.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17](Cl)=[O:18].Cl.[C:21]1([C:27]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH2:34]3)[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])([OH:36])[CH:29]([OH:45])[CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:46]1([C:27]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:35]3[CH:31]([CH2:32][N:33]([C:17](=[O:18])[CH2:16][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][CH3:8])[CH2:34]3)[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])([OH:36])[CH:29]([OH:45])[CH2:28]2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: COc1ccccc1CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1CC2C(C1)C(O)(c1ccccc1OC)C(O)CC2(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4.2 cm3 of triethylamine and then 2.4 g of (2-methoxyphenyl)-acetyl chloride in 50 cm3 of methylene chloride are added to a solution of 4.5 g of (3aRS, 4RS, 5RS, 7aRS )-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindole-4,5-diol hydrochloride in 100 cm3 of methylene chloride, cooled to 0° C. The reaction mixture is stirred at room temperature for 90 minutes; it is washed with twice 10 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid which has crystallised out is taken up in 100 cm3 of diisopropyl ether and then filtered off and washed with 50 cm3 of a saturated solution of sodium bicarbonate and then 50 cm3 of diisopropyl ether. 4.35 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)-acetyl]-perhydroisoindole-4,5-diol are obtained in the form of a light beige solid which melts at 278° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:27]([O:29][CH3:30])=[O:28]>C(O)C.[Pd].O>[CH3:30][O:29][C:27]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)=[O:28]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CCN(C(=O)OC)CC1=O
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A solution of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (Iselin, B. M. and Hoffmann, K., Helv. Chim. Acta, 1954, 37, 178) (14.0 g; 47 mmol) in aqueous ethanol (300 ml; 50%) was hydrogenated (ca. 300 kPa) in a PARR hydrogenation apparatus by using a 10% Pd-C catalyst (1.4 g). The reaction mixture was filtered and evaporated to dryness in vacuo. To an ice cooled solution of the residue in water (50 ml) was added with stirring an iced solution of potassium carbonate (19.4 g; 140 mmol) in water (20 ml) followed by addition of methyl chloroformate (11.3 g; 120 mmol). Stirring was continued at 0° C. for 30 minutes and at 25° C. for 30 minutes. The mixture was extracted with three 100 ml portions of ether. The combined and dried (Na2SO4) ether phases were evaporated in vacuo to give 10.0 g of crude product. Ball-tube distillation at 40-130 Pa (oven temperature 170° C.) gave IVa (9.0 g; 84%) as a colourless oil, which slowly crystallized, m.p. 36°-38° C. IR (film): 2980-2850 (several bands, m-s), 1700 (s), 1655 (s), 1620 (m) cm-1. 1H NMR (CCl4): δ12.3 (1 H, s), 4.13 (q, J 7 Hz) and 4.0-3.9 (m) (a total of 4 H), 3,62 (3 H, s), 3,43 (2 H, t, J 6 Hz), 2.4-2.1 (2 H, m), 1.30 (3 H, t, J 7 Hz).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@H:4]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:7].[OH-].[Li+]>CO.O>[CH:20]1([CH2:19][C@H:4]([CH2:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:7])[C:3]([OH:26])=[O:2])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)[C@@H](CC(=O)NCCNc1ccc(F)cc1)CC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(C[C@@H](CC1CCCCC1)C(=O)O)NCCNc1ccc(F)cc1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
(R)-2-cyclohexylmethyl-N-[2-(4-fluoro-phenylamino)-ethyl]-succinamic acid methyl ester (220 mg, 0.60 mmol, 1.0 eq.) was dissolved in a mixture of MeOH (4.5 mL) and H2O (3 mL) and placed in a 0° C. ice bath. Lithium hydroxide (30 mg, 1.25 mmol, 2.1 eq.) was added in one portion and allowed to stir for 8 hours, slowly warming to 23° C. After the reaction was judged complete by LC/MS, methanol was removed by evaporation. Ethyl acetate (75 mL) was added to the resulting solution and was extracted with 1 M HCl (50 mL). The aqueous phase was extracted 2×75 mL of ethyl acetate and the combined organic phases were washed with saturated sodium bicarbonate (50 mL), saturated sodium chloride (50 mL) dried over magnesium sulfate, filtered and evaporated to provide 183 mg of (R)-2-cyclohexylmethyl-N-[2-(4-fluoro-phenylamino)-ethyl]-succinamic acid an yellow oil (0.52 mmol, 86%) and was used directly in the following reaction.
Reaction SMILES: BrCCBr.[Mg].[CH3:6][N:7]1[CH2:12][CH2:11][CH:10](Cl)[CH2:9][CH2:8]1.[CH3:14][C:15]1[CH:31]=[CH:30][C:18]2[N:19]3[CH2:29][CH2:28][C:27]4[C:20]3=[C:21]([CH:24]=[CH:25][CH:26]=4)[CH:22]=[N:23][C:17]=2[CH:16]=1>O1CCCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH3:14][C:15]1[CH:31]=[CH:30][C:18]2[N:19]3[CH2:29][CH2:28][C:27]4[C:20]3=[C:21]([CH:24]=[CH:25][CH:26]=4)[CH:22]([CH:10]3[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]3)[NH:23][C:17]=2[CH:16]=1
Reactant: Cc1ccc2c(c1)N=Cc1cccc3c1N2CC3
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1ccc2c(c1)NC(C1CCN(C)CC1)c1cccc3c1N2CC3
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a 1 L three-necked flask, 1,2-dibromoethane (0.3 ml) was added to a refluxing slurry of magnesium chips (4.1 gm) in tetrahydrofuran (80 ml) to initiate a Grignard reaction. A solution of N-methyl-4-chloropiperidine (28 ml) in tetrahydrofuran (30 ml) was added in portions to maintain a fast reflux. The resultant slurry was refluxed for 1 hour and cooled to about 0° C. A solution of 9-methyl-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (10.0 gm) in tetrahydrofuran (50 ml) was added dropwise. After 1.5 hours of stirring, the mixture was diluted with ethyl acetate (400 ml) and with saturated ammonium chloride solution (600 ml). The organic phase was separated. The aqueous phase was basified with 50% sodium hydroxide solution and then it was extracted twice with ethyl acetate (400 ml). The combined ethyl acetate solution was washed with water (2×300 ml) and brine (2×300 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to a solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[CH2:19][C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si](C(C)(C)C)(C)C)/[C:9]1=[O:32])=O)(C)(C)C.[Cl:33][C:34]1[C:35]([F:47])=[C:36](/[CH:40]=[N:41]/[CH2:42][Si](C)(C)C)[CH:37]=[CH:38][CH:39]=1.C(O)(=O)C.O>CN(C)P(N(C)C)(N(C)C)=O>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:32])[C:10]3([CH:18]([CH2:19][C:20]([CH3:30])([CH3:31])[CH2:21][OH:22])[CH2:42][NH:41][CH:40]3[C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[C:35]=3[F:47])[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)(C/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21)CO[Si](C)(C)C(C)(C)C
Reactant: C[Si](C)(C)C/N=C/c1cccc(Cl)c1F
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(=O)O
Product: CC(C)(CO)CC1CNC(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of E/Z-3-[4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 31 (2.5 g, 5.2 mmol) in hexamethylphosphoramide (30 mL) was added [1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine prepared in Example 5 (2.9 g, 12 mmol), acetic acid (0.75 g, 12 mmol) and H2O (0.25 g, 14 mmol) sequentially. The reaction mixture was stirred at room temperature for 24 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSO4, then concentrated. The residue was dissolved into dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, dried over MgSO4, then concentrated. The residue was dissolved into tetrahydrofuran (5 mL), and saturated aqueous NaHCO3 solution was added (5 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4, then concentrated. The residue was purified by chromatography (3% MeOH in EtOAc) to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(3-hydroxy-2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a white solid (Yield, 0.25 g, 11%).
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=[O:2].[CH2:7]=O.[CH3:9][C:10]1([CH3:15])[NH:14][CH2:13][O:12][CH2:11]1>>[CH3:5][C:4]([N+:1]([O-:3])=[O:2])([CH3:7])[CH2:6][N:14]1[C:10]([CH3:15])([CH3:9])[CH2:11][O:12][CH2:13]1
Reactant: CC1(C)COCN1
Reactant: C=O
Reactant: CC(C)[N+](=O)[O-]
Product: CC1(C)COCN1CC(C)(C)[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 2 h

Procedure:
2-Nitropropane 89 g (1 mole) and 37% formaldehyde 88 g (1 mole) were mixed together and heated to 65° C. There was then added dropwise Oxazolidine A 101 g (1 mole) and after the addition was complete, heating of the reaction mixture at 60°-70° C was continued for 2 hours. Water was then removed by distillation at about 8-12 mm Hg pressure. There was obtained N-(2-methyl-2-nitropropyl)-4,4-dimethyl-1,3-oxazolidine. It analyzed carbon 53.65% (calc. 53.47), hydrogen 9.07% (calc. 8.98) and nitrogen 13.47% (calc. 13.87). The compound was effective against bacteria and fungi at a concentration of 500 μg/ml or less as shown in Table 1.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.C[O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:34][N:35]=[C:36]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[N:37]=2)=[CH:29][N:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C1COCC1.O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([CH2:20][N:41]4[CH2:42][CH2:43][CH:38]([C:36]5[N:37]=[C:33]([C:30]6[CH:31]=[CH:32][C:27]([OH:26])=[N:28][CH:29]=6)[NH:34][N:35]=5)[CH2:39][CH2:40]4)=[CH:22][CH:23]=3)[C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: COc1ccc(-c2nc(C3CCNCC3)n[nH]2)cn1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccc(O)nc6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-methyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (293 mg, 1 mmol) and 2-methoxy-5-(5-piperidin-4-yl-2H-[1,2,4]triazol-3-yl)-pyridine (0.58 g) in CH2Cl2 (5 mL) and THF (23 mL) was treated with Ti(OiPr)4 (0.82 mL) and stirred overnight at rt. The mixture was treated with NaBH(OAc)3 (395 mg) and stirred for 2 hours at rt. The reaction was diluted with CH2Cl2 and water and filtered through Celite. The phases were separated and the organic phase was washed with brine. The Celite pad was washed with MeOH and the combined organic portions were concentrated in vacuo. Purification was achieved by preparative HPLC to give the title compound.
Reaction SMILES: [Na].[CH3:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C@@H:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1Br>C(O)C>[CH2:12]([O:11][C:9](=[O:10])[C:3]([CH:19]1[CH2:18][CH2:17][CH:16]=[CH:15]1)([CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:13]
Reactant: Br[C@@H]1CCC[C@H]1Br
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C(=O)OCC)C1C=CCC1
Reaction time: 3 h

Procedure:
52.4 g of sodium, cut into small pieces, was introduced into a three-necked flask equipped with dropping funnel, reflux condenser, and KPG agitator. Under an argon atmosphere, 790 ml of absolute ethanol was added dropwise thereto within 3 hours so that the reaction mixture was boiling vigorously. Within 1.5 hours, 157 g of diethyl methylmalonate was added dropwise to the hot, slightly turbid alcoholate solution. The mixture was agitated for another hour and then 205 g of trans-1,2-dibromocyclopentane was added dropwise within one hour to the cooled-off solution. Thereafter the solution was refluxed for 17 hours. After concentration of the reaction solution on a forced circulation evaporator, the residue was combined with ether and dilute hydrochloric acid, the organic phase was washed neutral with saturated sodium chloride solution, dried over sodium sulfate, and distilled under vacuum, thus obtaining 170 g, bp1.5 90°-105° C.