Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][C:3]=2[O:2]1.[CH2:14]([NH2:17])[CH2:15][NH2:16]>>[NH2:16][CH2:15][CH2:14][NH:17][C:6]([C:5]1[CH:10]=[CH:11][C:12]2[O:13][CH2:1][O:2][C:3]=2[CH:4]=1)=[O:8]
Reactant: NCCN
Reactant: COC(=O)c1ccc2c(c1)OCO2
Product: NCCNC(=O)c1ccc2c(c1)OCO2
Yield: 41.9 %

Procedure:
7 g (0.039 mol) of methyl 3,4-methylenedioxybenzoate and 8.5 ml (0.126 mol) of ethylenediamine are heated to 100° (bath temperature) for 2.5 hours. After cooling, the excess ethylenediamine is removed in a high vacuum. The residue is acidified with dilute hydrochloric acid and extracted with chloroform. The aqueous phase is made alkaline with sodium hydroxide solution and then extracted several times with chloroform. After evaporating the solvent and recrystallizing the residue from chloroform/hexane, there are obtained 3.4 g of N-(2-aminoethyl)-1,3-benzdioxol-5-carboxamide, m.p. 120°-123°. The hydrochloride melts at 210°-213°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH2:56]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:56][CH2:55][CH2:54][N:53]([CH3:57])[CH3:52])=[O:21])[CH:17]=2)[NH:12][N:11]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C)CCNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 37 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (250 mg, 0.70 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (292 mg, 0.77 mmol) and N,N-dimethyl ethylene diamine (153 μL, 1.4 mmol); (243 mg, 37% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.7 (m, 2H), 8.0 (d, 1H), 7.6–7.8 (m, 4H) 7.4 (m, 2H), 3.3–3.6 (m, 4H), 2.3 (s, 6H), ES-MS (m/z) 349 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH2:14][CH3:15])=[C:4]([CH2:16][O:17][CH3:18])[CH:3]=1.C([Li])CCC.[C:24](=[O:26])=[O:25].[ClH:27]>C1COCC1>[ClH:27].[CH2:14]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:24]([OH:26])=[O:25])=[CH:3][C:4]=1[CH2:16][O:17][CH3:18])[CH3:15]
Reactant: O=C=O
Reactant: CCC1CCCCN1c1ccc(Br)cc1COC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1CCCCN1c1ccc(C(=O)O)cc1COC
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 1-[4-bromo-2-(methoxymethyl)phenyl]-2-ethylpiperidine (1.42 g, 4.55 mmol) in anhydrous THF was added n-butyl lithium (2.4 mL, 6.82 mmol) in drops at −78° C. After 1 hour at −78° C., the reaction mixture was poured onto crushed dry-ice (100 g). Once the excess carbon dioxide was escaped, the reaction mixture was acidified with 2N HCl. The precipitate was filtered off and dried to afford the title compound as a solid (1.0 g, 70%). HPLC (Method A), Rt: 2.5 min (purity: 97.7%). LC/MS, M+(ESI): 278.0. 1H NMR (CD3OD, 400 MHz) δ 8.20 (1H, d), 8.07 (1H, s), 7.92 (1H, d), 5.05 (2H, m), 3.89 (1H, bs), 3.69 (4H, m), 2.39 (1H, d), 2.02-2.14 (2H, m), 1.72-1.95 (3H, m), 1.46 (2H, m), 0.88 (3H, t).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[H-].[Na+].CS(O[C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C@H:14]([C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][O:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=3)=[O:42])[CH2:34][CH2:33]2)=[O:31])[CH2:13]1)(=O)=O.[Cl-].[Na+]>CN(C)C=O>[C:1]([S:3][C@@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C@H:14]([C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH2:38][CH2:39][O:40][C:41]([O:43][CH2:44][C:45]3[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=3)=[O:42])[CH2:36][CH2:37]2)=[O:31])[CH2:13]1)(=[O:4])[CH3:2]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(O)=S
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
51 μl of thioacetic acid were added to a suspension of 26 mg of sodium hydride (as a 55% W/W dispersion in mineral oil) in 1.4 ml of anhydrous dimethylformamide, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, a solution of 340 mg of (2S,4R)-4-methanesulfonyloxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine {prepared as described in step (b1) above} in 2 ml of anhydrous dimethylformamide was added to the mixture, and the resulting mixture was stirred at 80°-90° C. for 4 hours, after which the reaction mixture was allowed to cool to room temperature. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The residue was purified in a similar manner to that described in step (a), above, to afford the title compound (166 mg). The infra-red absorption spectrum and nuclear magnetic resonance spectrum of the product thus obtained were identical with those of the compound obtained as described in step (a), above.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:20][CH2:19][CH:18]([OH:21])[CH2:17][C:10]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COc1ccc(CC(O)CO)c(OCc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(CC(O)COS(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
To a solution of (±)-3-[2-(benzyloxy)-4-methoxyphenyl]propane-1,2-diol (30.50 g, 0.106 mol) in anhydrous pyridine (600 mL) cooled to 0° C. under a nitrogen atmosphere was added p-toluenesulfonyl chloride (22.18 g, 0.116 mol). The reaction mixture was allowed to stir at 0° C. for 12 h. The reaction mixture was quenched by the addition of water (10 mL). The reaction mixture was diluted with ethyl acetate (750 mL) and the organic layer was washed with aqueous hydrogen chloride (6 N, 4×400 mL), saturated aqueous sodium chloride (300 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) gave 42.84 g (91%) of (±)-3-[2-(benzyloxy)-4-methoxyphenyl]-2-hydroxypropyl 4-methylbenzenesulfonate as a colorless oil. Rf=0.28 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C24H26O6S: C, 65.14; H, 5.92. Found: C, 64.59; H, 5.72.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:13]CC2C=CC=CC=2)=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]=2[CH:12]=1.[CH:21](Br)([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[OH:13][C:3]1[C:2]([O:1][CH:21]([CH3:23])[CH3:22])=[CH:12][C:6]2[CH:7]=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1
Reactant: O=c1ccc2cc(O)c(OCc3ccccc3)cc2o1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2ccc(=O)oc2cc1O
Reaction time: 2.5 h

Procedure:
50.0 g (186 mmol) 6-hydroxy-7-phenylmethoxy-2H-1-benzopyran-2-one, 36.3 ml (387 mmol) isopropylbromide, 51.5 g (373 mmol) potassium carbonate and 5.0 g potassium iodide are agitated in 500 ml DMF for 14 h at 80° C. After filtration the filtrate is evaporated and the product recrystallized from isopropanol, yield: 57.7 g (100%) 6-(1-methyl-ethoxy)-7-(phenylmethoxy)-2H-1-benzopyran-2-one. Of this 50.0 g (161 mmol) are agitated in 100 ml of glacial acetic acid and 90 ml concentrated hydrochloric acid for 2.5 h at 70° C. This is followed by evaporation and purification using column chromatography on silica gel (eluent: chloroform and methanol 98/2 H 95/5): 24.65 g (69%), fusion point 121°-122° C. (from isopropanol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[N:4]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(O)C>[Br:10][CH2:9][C:5]1[N:4]=[C:3]([CH2:2][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=1
Reactant: BrCc1cccc(CBr)n1
Reactant: C1COCCN1
Solvent: CCO
Product: BrCc1cccc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
2,6-Bis(bromomethyl)pyridine (265 mg) was suspended in 2 mL of ethanol, thereto 87 mg of morpholine was added at ice temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (methylene chloride-ethanol-triethylamine=400:20:1 (v/v, the same hereinafter)) to give 90 mg of 4-(6-bromomethylpyridin-2-ylmethyl)morpholine as a white powder.
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.[C:21](#[N:23])[CH3:22]>>[O:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([CH2:22][C:21]#[N:23])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC#N
Reactant: COC(=O)c1cccc(Oc2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Product: N#CCC(=O)c1cccc(Oc2ccccc2)c1
Yield: 65 %

Procedure:
A solution of sodium methoxide (from 1.2 g sodium in 25 ml methanol) was added dropwise over 2 hours to a refluxing solution of methyl-3-phenoxybenzoate (11 g) in acetonitrile (100 ml) under a nitrogen atmosphere while distilling off methanol and excess acetonitrile. After complete removal of methanol the reaction mixture was poured onto ice-water (200 g) and acidified with 50% HCl. The solid was filtered off and dried to give the title compound (7.5g, 65%) as a white solid of m.p. 95°-96° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:10]([C:12]([CH3:14])=[CH2:13])[N:11]=1)=[O:5].[H][H]>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)=[C:10]([CH:12]([CH3:13])[CH3:14])[N:11]=1)=[O:5]
Reactant: [H][H]
Reactant: C=C(C)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Yield: 71.9 %

Procedure:
Into a solution of Compound 68a (63.6 mg, 0.15 mmol) in EtOAc (2.0 mL) was added 5% Pd/C (50 mg). The mixture was stirred at room temperature under 1 atmosphere of hydrogen for 2 hours. The mixture was filtered through a short plug of silica, the filtrate was concentrated, the residue was purified by column chromatography on silica gel (eluted with 10-70% ethyl acetate in hexanes) to give Compound 69 (46 mg, 72%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[CH:17]=[CH:16]3)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:38][C:39](Cl)=[O:40])[CH:35]=[CH:36][CH:37]=1>ClCCl>[Cl:12][C:10]1[C:9]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[CH:17]=[CH:16]3)=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][C:39](=[O:40])[CH2:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH3:30])[CH:33]=2)[CH:11]=1
Reactant: COC(=O)c1cc(-c2ccc3c(ccn3C)c2)c(Cl)cc1N
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc3c(ccn3C)c2)c(Cl)cc1NC(=O)Cc1cccc(OC)c1
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a suspension of methyl 2-amino-4-chloro-5-(1-methyl-1H-indol-5-yl)benzoate (Intermediate 45) (150 mg, 0.427 mmol) in dichloromethane (20 mL) at 0° C. was added triethylamine (0.131 mL, 0.940 mmol) and [3-(methyloxy)phenyl]acetyl chloride (Acros Organics, 79 mg, 0.427 mmol) was added dropwise. The reaction mixture was stirred from 0° C. to RT for 1 h before being quenched with 1N HCl. The organic layer was separated and washed successively with sat. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by chromatography using a cyclohexane to cyclohexane/EtOAc 80:20 as eluant. The appropriate fractions were combined and concentrated in vacuo to give the title compound methyl 4-chloro-5-(1-methyl-1H-indol-5-yl)-2-({[3-(methyloxy)phenyl]acetyl}amino)benzoate (150 mg, 0.324 mmol, 76% yield) as a white amorphous solid. LCMS: (M+H)+=463; Rt=4.23 min.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.[Cl:13][C:14]1[C:21]([CH3:22])=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:13][C:14]1[C:21]([CH3:22])=[C:20]([N:6]2[CH2:7][CH2:8][C@:4]([CH2:1][CH3:3])([OH:12])[C@@H:5]2[CH2:9][CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(Cl)c2C)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (201 mg), 2-chloro-4-fluoro-3-methylbenzonitrile (294 mg) and lithium carbonate (250 mg), the title compound was obtained as pale-yellow oil (yield: 95.6 mg, yield: 31%).
Reaction SMILES: [O:1]=[CH:2][CH:3]=[C:4]1[O:10][CH:9]2[N:6]([C:7](=[O:11])[CH2:8]2)[CH:5]1[C:12]([O:14]CC1C=CC=CC=1)=[O:13].P([O-])([O-])([O-])=O.[Na+:27].[Na+].[Na+]>O1CCCC1.[Pd]>[O:1]=[CH:2][CH:3]=[C:4]1[O:10][CH:9]2[N:6]([C:7](=[O:11])[CH2:8]2)[CH:5]1[C:12]([O-:14])=[O:13].[Na+:27]
Reactant: O=CC=C1OC2CC(=O)N2C1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CC=C1OC2CC(=O)N2C1C(=O)[O-]

Procedure:
Benzyl 3-oxoethylidene-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate (II) (50 mg, 0. 17m mol) was dissolved in tetrahydrofuran (5 ml) and 0.2 M sodium phosphate adjusted to pH 6.85 (5 ml), and hydrogenated at ambient temperature and pressure for ten minutes with 10% palladium on carbon (40 mg). The reaction mixture was rapidly filtered and evaporated to dryness while the temperature was maintained below 10° C. The residue was immediately redissolved in D2O to give a solution of the title compound (III). δH(250 MHz, D20) inter alia E isomer 3.25 (1H, d, J 17.4 Hz, 6β-H), 3.65 (1H, dd, J 17.4 and 2.9 Hz, 6 α-H), 5.73 (1H, d, J 1.2 Hz, 2-H), 5.79 (1H, dd, J 8.3 and 1 Hz, 8-H), 5.94 (1H, d, 2.7 Hz, 5-H), 9.55 (1H, d, J 8.3 Hz, 9-H), Z isomer 3.29 (1H, d, J 17.3 Hz, 6β-H), 3.65 (1H, dd, J 17.4 and 2.9 Hz, 6 α-H), 5.27 (1H, s, 2-H), 5.50 (1H, d, J 8.2 Hz, 8-H), 6.00 (1H, d, J2.7 Hz, 5-H), and 9.70 (1H, d, J 8.2 Hz, 9-H). The E and Z isomers were assigned on the relative positions of their 8-proton resonance (Gerald Brooks+Eric Huit J.Chem.Soc. Perkin Trans. I (1983) 2513) and were in the ratio E-Z (2:1). Material prepared by the above hydrogenation with water substituting for the phosphate solution and adjustment of the pH of the reaction mixture to 6.5 with 0.1 M NaOH gave (III) (Yield 35% from NaOH consumed), λmax. (H2O) 262 nm; vmax.(KBr) 3 400, 1 792 (br), and 1 640 cm−1 (br), and 1 640 cm−1 (br); thin layer chromatography on silica 60 eluted with butan- 1-ol-ethanol-water (4:1:1) and visualised with Schiffs reagent gave a blue zone (Rf:0.52). Addition of a known weight of fumaric acid to the crude product solution followed by evaporation and nmr analysis indicated a yield of 20% by comparison of the intensity of the fumarate protons with the intensity of the aldehydic proton of (M). When this solution was allowed to stand at room temperature for 3.5 hours, (III) was seen to have decomposed to a yield of 3.2%.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36]>C(Cl)Cl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([N:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -35 °C
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
A solution of Boc-Phe-OH (5.48 g) and NMM (2.09 g) in methylene chloride (50 ml) was cooled to -20° C. To this solution was added dropwise isobutyl chloroformate (2.82 g) maintaining the temperature between -22° C. to -20° C. in 7 minutes. After stirring the mixture for 20 minutes at the same temperature, the solution was cooled to -35° C. and HNMeBzl (2.50 g) was added dropwise to the solution. The reaction mixture was stirred for 2 hours during which period the temperature was gradually raised to -2° C. The solution was washed successively with water (twice), diluted sodium hydrogencarbonate solution (twice), water 0.5N hydrochloric acid (twice), and sodium chloride solution, and dried over magnesium sulfate. After evaporation, the solidified residue was pulverized in hot diisopropyl ether (10 ml), and after cooling, n-hexane (30 ml) was added to the mixture. The crystalline solid was filtered, washed with n-hexane (5 ml×2), and dried to give Boc-Phe-NMeBzl (6.49 g).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].[CH3:14][NH:15][CH3:16]>C1COCC1>[CH3:14][N:15]([CH3:16])[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3]
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc2c(c1)COC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5-chlorocarbonylphthalid (32 g, 0.16 mole) in THF (300 ml) is added to dimethylamine (40% v/v in water, 300 ml) and ice (100 g). The mixture is stirred for 1 hour. THF is evaporated off in vacuo and precipitated crystals are filtred off at 5° C. and washed with water (100 ml).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH2:12][C:13]([O:15]CC)=O)=[CH:4][CH:3]=1>CC(O)=O.CCOC(C)=O.[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:12][C:13](=[O:15])[NH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1COc2ccc(Br)nc2N1
Temperature: 90 °C

Procedure:
Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90° C. for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52%); MS (ES) m/z 229.0 (M+H)+.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[C:14]([F:15])=[CH:13][C:12]([N:16]4[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]4=[O:26])=[CH:11][C:10]=3[F:27])[CH2:5][CH2:4]2)[CH2:2]1.[N-:28]=[N+:29]=[N-:30].[Na+].C(O)(=O)C>CN(C)C=O>[N:28]([CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][C:12]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:11][C:10]=2[F:27])[CH2:5][CH2:4]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCC(O)(CN=[N+]=[N-])CC3)c(F)c2)C(=O)O1
Yield: 65 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3,5-difluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.30 mmol) with sodium azide (2.10 mmol) and glacial acetic acid (7.0 mmol) in dimethylformamide (15 ml) at a temperature 40° C. for 14 hours and by purifying the compound by silica gel column chromatography in 65% yield.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1ccc(Cl)cc1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
0.202 g (0.291 mmol) of (2R*,4S*)-2-benzyl-1-(4-chlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.054 g (1.43 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR76## is obtained (0.136 g, 81%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.17, FD-MS: M+ =469, 471; IR: 3675, 1625, 1595, 1570 cm-1.
Reaction SMILES: N[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].N(OCCC(C)C)=O.C(I)[I:19]>>[I:19][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(C)c1N
Reactant: ICI
Agent: CC(C)CCON=O
Product: Cc1ccnc(C)c1I

Procedure:
In a manner similar to that described in Example 5 (Step 1), commercially available 3-amino-2,4-dimethylpyridine was treated with isoamyl nitrite and CH2I2 to provide 3-iodo-2,4-dimethylpyridine (16A).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:14]=2)=[C:10]([CH3:26])[CH:9]=[C:8]([OH:27])[C:3]=1[C:4](OC)=[O:5].[BH4-].[Na+]>C(O)C.O>[CH3:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:24])[CH3:25])[CH:14]=2)=[C:10]([CH3:26])[CH:9]=[C:8]([OH:27])[C:3]=1[CH2:4][OH:5]
Reactant: COCOc1ccc(Cc2c(C)cc(O)c(C(=O)OC)c2C)cc1C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCOc1ccc(Cc2c(C)cc(O)c(CO)c2C)cc1C(C)C
Temperature: 80 °C

Procedure:
To a solution of methyl 2,4-dimethyl-6-hydroxy-3-(4′-methoxymethoxy-3′-iso-propylbenzyl)benzoate in ethanol-water (3.0 mL, 95:5) at room temperature was added NaBH4. The reaction mixture was heated at 80° C. for 4 h and cooled to room temperature. The reaction mixture was quenched with aqueous NH4Cl and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 30% acetone in hexanes to afford 2,4-dimethyl-6-hydroxy-3-(4′-methoxymethoxy-3′-iso-propylbenzyl)benzyl alcohol: 1H NMR (300 MHz, CD3OD): δ 6.97 (d, J=2.4 Hz, 1 H), 6.92 (d, J=13.2 Hz, 1 H), 6.68 (dd, J=13.2, 2.4 Hz, 1 H), 6.59 (s, 1 H), 5.17 (s, 2 H), 4.78 (s, 2 H), 3.96 (s, 2H), 3.47 (s, 3 H), 3.30 (m, 1 H), 2.24 (s, 3 H), 2.19 (s, 3 H), 1.18 (d, J=10.8 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=acetone-hexanes (3:7); Rf=0.40.