Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:30])=[N:6][C:7]2[N:8]([N:27]=[CH:28][CH:29]=2)[C:9]=1[N:10]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:2]=[CH2:3].CSC.B.[OH-:35].[Na+].OO>O1CCCC1>[C:13]([O:12][C:11](=[O:17])[N:10]([C:9]1[N:8]2[N:27]=[CH:28][CH:29]=[C:7]2[N:6]=[C:5]([Cl:30])[C:4]=1[CH2:1][CH2:2][CH2:3][OH:35])[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=1)([CH3:15])([CH3:14])[CH3:16]
Reactant: C=CCc1c(Cl)nc2ccnn2c1N(C(=O)OC(C)(C)C)c1ccc(OCC)cc1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCCO)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a tetrahydrofuran (23 mL) solution containing tert-butyl (6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)carbamate (3.0 g, 7.0 mmol), borane-dimethyl sulfide complex (2 mol/L tetrahydrofuran solution, 5.6 mL, 23 mmol) was added over 30 min with ice-cooling. This mixture was stirred at room temperature for 2 hr and then again cooled on ice. Here, 1 mol/L aqueous sodium hydroxide (11.2 mL, 11.2 mmol) was added over 20 min, and hydrogen peroxide (30% aqueous solution, 0.81 mL, 8.4 mmol) was added. The resultant mixture was stirred for 1 hr. After the reaction, the reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (20% ethyl acetate-hexane) to obtain the title compound (2.02 g, yield 65%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][C@@H:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=2)[CH3:18])=[O:15])=[CH:9][CH:8]=1.[H][H]>CCOC(C)=O.[Pd]>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]([C@H:17]([NH:16][C:14](=[O:15])[CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:3]3[CH:4]=[N:5][O:6][C:2]=3[CH3:1])=[CH:8][CH:9]=2)[CH3:18])=[N:20][CH:21]=1)[CH3:26]
Reactant: [H][H]
Reactant: C=Cc1ccc([C@@H](C)NC(=O)Cc2ccc(-c3cnoc3C)cc2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc([C@@H](C)NC(=O)Cc2ccc(-c3cnoc3C)cc2)nc1
Reaction time: 24 h

Procedure:
To a solution of 0.11 g (0.32 mmol) 2-[4-(5-methylisoxazol-4-yl)phenyl]-N-[(1R)-1-(5-vinylpyridin-2-yl)ethyl]acetamide in 1.30 ml EtOAc was added 0.010 g of 10% palladium on carbon. The reaction flask was equipped with a hydrogen balloon. After 24 h at room temperature, the reaction mixture was filter through celite, washed three times with methanol, and concentrated in vacuo. Purification by automated flash chromatography (40 g silica gel cartridge 20-100% EtAOc/hex over 15 min) afforded N-[(1R)-1-(5-ethylpyridin-2-yl)ethyl]-2-[4-(5-methylisoxazol-4-yl)phenyl]acetamide 1H NMR (CDCl3, 400 MHz) 8.35 (s, 1H); 8.31 (d, 1H, J=1.56 hz); 7.47 (dd, 1H, J=2.19 Hz, 7.96 Hz); 7.36 (d, 4H, J=2.29 Hz); 7.13 (d, 1H, J=7.88 Hz); 6.97 (br d, 1H J=7.88 Hz); 5.10 (m, 1H); 3.62 (s, 2H); 2.63 (q, 2H, J=7.60 Hz, 15.11 Hz); 2.57 (s, 3H); 1.43 (d, 3H, J=6.69); 1.24 (t, 3H, J=7.60). HRMS (ES) exact mass calcd for C21H23N3O2: 350.1864, Found: 350.1856.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8](C(OC(C)(C)C)=O)[N:7]=1)[CH3:3].[F:22][C:23]([F:35])([F:34])[S:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:3][CH:2]([N:4]([CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)[C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([S:24][C:23]([F:34])([F:22])[F:35])=[CH:26][CH:27]=1)=[O:33])[CH3:1]
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Reactant: CC(C)NCc1nn(C(=O)OC(C)(C)C)c2ncccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(Cc1n[nH]c2ncccc12)C(=O)Nc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To crude tert-butyl 3-[(propan-2-ylamino)methyl]-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (75 mg, 0.26 mmol) in 2 mL CH2Cl2 was added 4-(trifluoromethylthio) phenylisocyanate (57 mg, 0.26 mmol). The reaction was allowed to stir at ambient temperature for 16 h. To the reaction solution was added trifluoroacetic acid (1.0 mL, 1.35 mmol). The solution was allowed to stir at ambient temperature for 1 h, concentrated, and purified on a Gilson reverse phase preparatory instrument. The aqueous fractions were partitioned between saturated Na2CO3 and ethylacetate. The organics were washed with water and brine, dried over Na2CO3, filtered, and purified by silica gel chromatography to give 1-(1-methylethyl)-1-(1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-3-{4-[(trifluoromethyl)sulfanyl]phenyl}urea. 1H NMR (400 MHz, CDCl3): δ 11.69 (s, 1 H); 8.62 (dd, J=4.6, 1.5 Hz, 1 H); 8.54 (s, 1 H); 8.22 (dd, J=8.1, 1.5 Hz, 1 H); 7.51 (d, J=3.1 Hz, 4H); 7.24-7.21 (m, 1 H); 4.71 (s, 2 H); 4.61-4.51 (m, 1 H); 1.24 (d, J=6.8 Hz, 6 H. LCMS [M+H]+=410.1.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][C:3]([OH:5])=O.[C:8](=[O:13])([O:10][CH2:11][CH3:12])[NH2:9].P(Cl)(Cl)(Cl)=O>O>[C:3]([NH:9][C:8]([O:10][CH2:11][CH3:12])=[O:13])(=[O:5])[CH2:2][C:1]([NH:9][C:8]([O:10][CH2:11][CH3:12])=[O:13])=[O:7]
Reactant: CCOC(N)=O
Reactant: O=C(O)CC(=O)O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)NC(=O)CC(=O)NC(=O)OCC
Temperature: 80 °C
Yield: 43.1 %

Procedure:
With a mortar and pestle 10.40 g (0.100 mole) of malonic acid and 18.00 g (0.210 mole) of ethyl carbamate were ground to a fine powder. This powder was placed in a flask, and 16.0 mL (0.167 mole) of phosphorus oxychloride was added. This mixture was heated at 80° C. until the evolution of gas ceased. After this reaction mixture had cooled to ambient temperature, 210 mL of water was added. When the stiff glassy mixture became fluid, it was extracted with ethyl acetate. The combined extracts were washed in succession with saturated aqueous solutions of sodium bicarbonate and sodium chloride and were then dried over anhydrous magnesium sulfate and filtered. The solution was filtered through a short column of silica gel, which was eluted with ethyl acetate. The solvent was then evaporated under reduced pressure, leaving a crystalline mass of malonyldiurethane weighing 10.62 g. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].C[Si]([C:40]#[N:41])(C)C.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[CH:47]=O>C1COCC1>[C:40]([CH:47]([NH:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[C:46]1[CH:49]=[CH:50][C:51]([O:52][CH3:53])=[C:44]([O:43][CH3:42])[CH:45]=1)#[N:41]
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#Cc1ccc(N)cc1F
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)Nc2ccc(C#N)c(F)c2)cc1OC

Procedure:
After adding 541 mg of 2-fluoro-4-aminobenzonitrile [CAS No. 53312-80-4], 500 mg of MS3A, 493 mg of Yb(OTf)3 and 1.1 ml of trimethylsilyl cyanide to a solution of 795 mg of 3,4-dimethoxybenzaldehyde in 20 ml of THF under a nitrogen atmosphere, the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure to give a crude product of 4-{[cyano-(3,4-dimethoxyphenyl)methyl]amino}-2-fluorobenzonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:8][S:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[S:4][CH2:3]1.[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)CCl>[CH3:15][C:14]([C:10]1[CH:11]=[CH:12][C:5]2[S:4][CH2:3][C:2]([CH3:13])([CH3:1])[CH2:8][S:7][C:6]=2[CH:9]=1)=[O:16]
Reactant: CC1(C)CSc2ccccc2SC1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)SCC(C)(C)CS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13.3 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepine were dissolved in 110 ml of ethylene chloride under argon and treated portionwise at -10° C. in succession with 10.1 ml of acetyl chloride and 19 g of aluminum chloride. Thereafter, the reaction mixture was stirred at room temperature for 21/2 hours, poured on to ice and extracted with ether. The extract was washed with dilute sodium hydroxide solution and water, dried and evaporated to dryness. There were obtained 15.6 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl methyl ketone in the form of brownish crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:8]([O:10][CH3:11])[CH:9]=1)([O-])=O.[OH-].[Na+]>C(O)C>[CH3:11][O:10][C:8]1[CH:9]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=1[S:12]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(N)ccc1S(=O)(=O)c1ccncc1
Temperature: 0 °C
Yield: 82.7 %

Procedure:
A stirred solution of 5-nitro-2-(4-pyridylsulfonyl)anisole (3.00 g, 10.2 mmol) and stannous chloride dihydrate (11.49 g, 51.0 mmol) in absolute ethanol (35 mL) was heated at reflux for 1 hour. The reaction mixture was poured into ice water, and the aqueous solution basified with 15% NaOH and extracted with ethyl acetate (2×200 mL). The combined organic portions were dried (MgSO4) and the solvent removed in vacuo to yield the title benzeneamine as a pale yellow solid (2.23 g, 83%); mp 150°-152° C. 1H-NMR (250 MHz, d6-DMSO): 3.62 (s, 3H, OCH3) 6.18 (d, 1H, J=1.8 Hz, aromatic) 6.24 (d, 1H, J=1.9 Hz, aromatic) 6.28 (s, 2H, NH2) 7.58 (d, 1H, J=8.8 Hz, aromatic) 7.70 (dd, 2H, J=4.5, 1.5 Hz, aromatic) 8.79 (dd, 2H, J=4.4, 1.6 Hz, aromatic). MS (CI, CH4): 265 (M+1).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]3[N:47]=[CH:48][N:49]=[C:23]23)[CH2:18][CH2:17]1>C(OCC)(=O)C>[OH:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]3[N:47]=[CH:48][N:49]=[C:23]23)[CH2:20][CH2:21]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(CCO)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCN(CCO)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
A mixture of hydroxylammonium chloride (417 mg), sodium hydrogen carbonate (672 mg) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-[1-(2-hydroxyethyl)piperidin-4-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (200 mg) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (81 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (76 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=5/95→30/70 (volume ratio)] and crystallized from acetonitrile to give the title compound as colorless crystals (51 mg, 23%).
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:20][CH2:21][CH3:22])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@H:6]([CH2:18]O)[CH2:5]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:21]([O:20][C:4]1([O:3][CH2:1][CH3:2])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[C@H:6]([CH2:18][N:46]2[C:42](=[O:52])[C:43]3=[CH:51][CH:50]=[CH:49][CH:48]=[C:44]3[C:45]2=[O:47])[CH2:5]1)[CH3:22]
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@H](CO)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A suspension of 4,4-diethoxy-1-(1-(S)-phenyl-ethyl)-(S)-2-hydroxymethyl-piperidine (20 g, 65 mmol), triphenylphosphine (18.76 g, 72 mmol) and phthalimide (10.52 g, 72 mmol) in tetrahydrofurane (200 ml) cooled to 0° C. was added diethyl azodicarboxylate (11.34 ml, 72 mmol) over the course of 1 hour. The reaction mixture was stirred at 0° C. for another 2 hours before the volatiles were removed in vacuo. The residue was dissolve in hot heptane-toluene (3:2) (100 ml) before it was cooled on an ice bath. The precipitate was filtered off and washed with heptane. The filtrate was concentrated in vacuo and the residue subjected to column chromatography using a mixture of toluene/ethyl acetate/heptane (3:1:3) as eluent. The solvent was evaporated in vacuo and the residue was crystallized by addition of light petrol ether (250 ml). The precipitate was filtered off, which afforded 24 g (85%) of 4,4-diethoxy-1-(1-(S)-phenyl-ethyl)-2-(S)-phthalimidomethyl-piperidine as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Cl[CH2:13][CH:14]=O.CCOCC>CCO>[OH:10][C:6]1[CH:7]=[CH:8][N:9]2[CH:13]=[CH:14][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: O=CCCl
Reactant: COc1ccnc(N)c1C#N
Solvent: CCOCC
Solvent: CCO
Product: N#Cc1c(O)ccn2ccnc12
Temperature: 150 °C

Procedure:
To a mixture of compound D3 (2 g, 13.404 mmol) in EtOH (5 ml) was added chloroacetaldehyde (1.58 g, 20.11 mmol). The reaction mixture was subjected to microwave heating at 150° C. for 45 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue thus obtained was then treated with Et2O and a solid precipitated. The solid thus obtained was filtered off, washed with EtOAc and dried in vacuo to yield compound D21 (1.5 g, 70%).
Reaction SMILES: Cl[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])=[C:5]2[O:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:17][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[C:2]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:3][O:4][C:5]=12
Reactant: C1COCCN1
Reactant: Cc1ccncc1-c1ccnc2c(Cl)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccncc1-c1ccnc2c(N3CCOCC3)noc12
Temperature: 90 °C
Yield: 75 %

Procedure:
To a suspension of 3-chloro-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine (0.0069 g, 0.028 mmol) and morpholine (0.025 ml, 0.281 mmol) in DMSO (Volume: 0.100 ml) was added cesium carbonate (0.027 g, 0.084 mmol). The vial was sealed, heated at 90° C. for 4 hr, and then allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with CH2Cl2. The solvent was concentrated to afford a yellow liquid, which was further dried under high vacuum overnight. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 70-100% EtOAc in hexanes over 14 min, tr=4 5 min) gave 7-(4-methylpyridin-3-yl)-3-morpholinoisoxazolo[4,5-b]pyridine (6.5 mg, 0.021 mmol, 76% yield) as a white solid. ESI MS (M+H)+=297.2. HPLC Peak tr=1.56 minutes. Purity=97%. HPLC Conditions: C.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][S:15][C:14]2[CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=[CH:21][C:13]1=2)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.NN>CO.[Ni]>[NH2:22][C:19]1[CH:20]=[CH:21][C:13]2[N:12]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:17][CH2:16][S:15][C:14]=2[CH:18]=1
Reactant: CN(CCN1CCSc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN(CCN1CCSc2cc(N)ccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a solution of tert-butyl methyl(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (0.8811 g, 2.493 mmol) in MeOH (20 mL) was added Raney-Nickel (slurry in water; ˜0.5 g, 2.493 mmol) followed by hydrazine hydrate (1.213 mL, 24.93 mmol). The mixture was then immersed in a preheated oil bath and refluxed for 5 minutes. The solution was cooled to room temperature and filtered through a pad of Celite. The filter pad was washed with MeOH, and the crude material was concentrated. The crude material was then filtered through a silica plug (70% EtOAc/hexanes). The collected fractions were concentrated to give brown oil (0.78 g, 98%). 1H NMR (CDCl3) δ 6.64-6.58 (m, 1H), 6.45 (d, J=2.4 Hz, 1H), 6.39 (d, J=8.4 Hz, 1H), 3.53-3.50 (m, 2H), 3.39-3.28 (m, 4H), 3.01-2.98 (m, 2H), 2.90 (s, 3H), 1.45 (s, 9H); ESI-MS (m/z, %): 326, 324 (MH+, 95), 268 (100).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=O)[CH3:2].[CH3:11][CH:12]([NH2:16])[CH2:13][O:14][CH3:15]>C1(C)C=CC=CC=1.CCOCC.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=[N:16][CH:12]([CH3:11])[CH2:13][O:14][CH3:15])[CH3:2]
Reactant: COCC(C)N
Reactant: CCC1CCCC(C)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC1CCCC(C)C1=NC(C)COC
Yield: 50.2 %

Procedure:
163 g of titanium tetrachloride in 800 ml of toluene were added dropwise to a solution of 229 g (1.64 mole) of 2-ethyl-6-methylcyclohexanon and 435 g (4.9 mole) of 1-methyl-2-methoxyethylamine in 1000 ml toluene and 110 ml of ether over a period of two hours with stirring and at a temperature of between 0°-10° C. After distilling off the ether the reaction mixture was refluxed for 61/2 hours. After cooling the precipitate was filtered off and the filtrate concentrated in a rotary evaporator at 50° C. Distillation of the residue under reduced pressure gave 174 g 2-ethyl-6-methyl-N-(1-methyl-2-methoxy-ethyl)-cyclohexylidene-amine, m.p. 109°-113° C./15 Torr.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:43][CH:44]([CH3:53])[C@H:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)O>ClCCl>[CH3:43][CH:44]([CH3:53])[C@H:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[O:2][C:1](=[O:3])[CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: CC(C)[C@@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O[C@@H](c1ccccc1)C(C)C
Yield: 29.6 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (298 mg, 0.73 mmol), 4-N,N-dimethylaminopyridine (100 mg, 0.82 mmol, 1.3 eq), 1,3-dicyclohexylcarbodiimide (242 mg, 1.17 mmol, 1.8 eq) in dichloromethane (10 mL) was treated with (R)-2-methyl-1-phenyl-1-propanol (100 mg, 0.64 mmol, 1.3 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 96.2 mg (30%) of L-isoleucine, N-[1-(2-(2-methyl-1-(R)-phenyl-1-propoxy)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:28])[CH2:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=2[O:26][CH3:27])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29]I>>[C:1]1([CH:7]([O:14][C:15](=[O:28])[CH:16]([C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=2[O:26][CH3:27])[CH3:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc([N+](=O)[O-])cc1CC(=O)OC(c1ccccc1)c1ccccc1
Reactant: CI
Product: COc1ccc([N+](=O)[O-])cc1C(C)C(=O)OC(c1ccccc1)c1ccccc1
Yield: 46 %

Procedure:
Using the compound obtained in Example 342 as a starting material and also using methyl iodide (1 eq.) as a reagent, the same procedure of Example 1a gave the titled compound (yield, 46%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C:1]12[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]1[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: O=C1NC2C=CC=CC2(Cc2ccccc2)C(=O)O1

Procedure:
Following the procedure set forth in Step (2) of Preparation A, isatoic anhydride was reacted with benzyl bromide to give 1-benzyl-isatoic anhydride.
Reaction SMILES: C1([N:7]=[C:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)C=CC=CC=1.C(O)[CH2:17][OH:18].C1(NC(=O)NC2C=CC=CC=2)C=CC=CC=1.[C:36]1([CH3:43])[C:37](C)=[CH:38][CH:39]=[CH:40][CH:41]=1>>[C:36]1([CH:43]2[N:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:8](=[NH:7])[CH2:17][O:18]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: OCCO
Reactant: Cc1ccccc1C
Reactant: C(=Nc1ccccc1)=Nc1ccccc1
Agent: O=C(Nc1ccccc1)Nc1ccccc1
Product: N=C1COC(c2ccccc2)N1c1ccccc1

Procedure:
194 g of diphenyl carbodiimide, 31 g of ethylene glycol and 0.05 g of Sn(II)-(2-ethyl hexoate) are dissolved in 200 g of xylene. The reaction solution is heated to reflux temperature, diphenyl urea being precipitated. Concentration of the xylene solution gives 102 g (86% of the theoretical) of 2-phenyl imino-3-phenyl oxazolidine. Mp: 115° to 117° C.