Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](=[C:3]([C:17]([CH3:19])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-:2].C(N(CC)CC)C.FC(S(O[Si:35]([CH3:38])([CH3:37])[CH3:36])(=O)=O)(F)F>C(Cl)Cl>[N+:1](=[C:3]([C:17]([O:18][Si:35]([CH3:38])([CH3:37])[CH3:36])=[CH2:19])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a suspension of p-nitrobenzyl α-diazoacetoacetate (236 mg, 1 mmole) and triethylamine (0.15 ml, 1.08 mmole) in CH2Cl2 (2 ml) was added at 0°-5° C. trimethylsilyl trifluoromethylsulfonate (0.22 ml) under a nitrogen atmosphere and the mixture was stirred for 30 minutes. To this clear yellow solution was added dry hexanes (30 ml) and the reaction mixture was stirred for 10 minutes. After removing the oily deposit, the hexanes solution was evaporated in vacuo to yield yellow solid which was redissolved in dry hexanes (50 ml). The insoluble material was filtered over Celite and the filtrate was evaporated in vacuo to obtain 277 mg (0.90 mmole, yield 90%) of the title compound as yellow crystals: ir (film) νmax : 2100 (N2), 1705 (ester), 1520 and 1345 cm-1 (NO2); 1Hmr (CDCl3) δ: 0.27 (9H, s, --SiMe ), 4.23 (1H, d, J=2 Hz, vinyl proton), 4.93 (1H, d, J=2 Hz, vinyl proton), 5.32 (2H, s, --CO2CH2Ar), 7.48 (2H, "d", J=9 Hz, aromatic protons) and 8.23 ppm (2H, "d", J=9 Hz, aromatic protons).
Reaction SMILES: [CH2:1]([N:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1)[CH3:22]>C(N(CC)CC)C.[Cu]I.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>[CH2:1]([N:8]([CH3:9])[C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:28]3[CH:29]=[CH:30][C:25]([C:24]([O:23][CH2:21][CH3:22])=[O:32])=[CH:26][CH:27]=3)=[CH:17][CH:18]=2)[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccc(C2(N(C)Cc3ccccc3)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(C)Cc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Using General Procedure F; benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-methylamine (Intermediate 132, 70.0 mg, 0.28 mmol) and ethyl-4-iodo benzoate (Reagent A, 77.0 mg, 0.28 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (18.0 mg, 0.10 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (65 mg, 0.10 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 86 mg (75%) of the title compound as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:43])[N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH2:28][CH2:27]1>>[Cl:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])[N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:28][CH2:27]1
Reactant: NCCCCC1CCN(C(c2ccccc2Cl)c2ccccc2Cl)CC1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(C(c2ccccc2Cl)c2ccccc2Cl)CC1

Procedure:
Batch size: 1.6 g (10.7 mmol) 3-(3-pyridyl)-acrylic acid, 1.9 g (15.0 mmol) oxalyl chloride and 3.9 g (10.0 mmol) 4-{1-[bis-(2-chlorophenyl)-methyl]-piperidine-4-yl}-butylamine. In the purification, chromatographic purification is done twice over silica gel with CHCl3/CH3OH (97/3 and 97/3 to 95/5) and crystallization is from 25 ml acetic acid after drawing off the solvent. Colorless crystals with a MP of 129-131° C. were recovered; yield: 0.6g (11%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16](=[O:18])[CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16](=[O:18])/[CH:17]=[CH:21]/[N:22]([CH3:24])[CH3:23])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C

Procedure:
1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)ethanone (10.8 g, 40.75 mmol) in dimethoxy-N,N-dimethylmethanamine (15.0 mL) was heated to reflux for 3 days. The mixture was concentrated and used for next step without further purification. MS (ESI) m/z 321.1 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.N1C=CC=CC=1.[NH2:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24]>C(O)=O>[OH:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[NH:14][CH:1]=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: O=CO
Solvent: c1ccncc1
Product: O=CNc1cc([N+](=O)[O-])ccc1O
Reaction time: 18 h

Procedure:
To a stirred mixture of formic acid (20.7 g, 0.449 mol), acetic anhydride (32.0 g, 0.313 mol) and pyridine (37 g, 0.468 mol) is added at ambient temperature 2-amino-4-nitrophenol (24.0 g, 0.156 mol) in 15 mL of formic acid. Stirring is continued for 18 h. The solid formed is separated by suction filtration, washed with aqueous sodium bicarbonate, water, DCM and hexanes. After air drying for 18 h, N-(2-hydroxy-5-nitrophenyl)-formamide is obtained as a light green solid: (M−H)−=181.1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[N:10]([CH2:12][CH2:13][OH:14])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CN=C1.CO>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:15])[N:10]([CH2:12][CH2:13][O:14][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCO)C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
Subsequently, to a solution of N-(2-hydroxyethyl)-N-methylcarbamic acid benzyl ester (2.82 g, 13.5 mmol) in dimethylformamide (85 ml) were added t-butyldiphenylsilyl chloride (4.21 ml, 16.2 mmol) and imidazole (1.10 g, 16.2 mmol) in an ice bath. The resulting mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, methanol was added thereto and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (9:1) as the eluant to afford N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-methyl-carbamic acid benzyl ester (5.7 g, yield 94%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:19][N:20]1[CH:24]=[C:23](Br)[CH:22]=[C:21]1[CH:26]=[O:27]>>[CH3:19][N:20]1[CH:24]=[C:23]([C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)[CH:22]=[C:21]1[CH:26]=[O:27]
Reactant: Cn1cc(Br)cc1C=O
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Product: Cc1cc2c(cc1-c1cc(C=O)n(C)c1)C(C)(C)CCC2(C)C
Yield: 59.2 %

Procedure:
In a similar manner to Example 3(b), by reaction of 3 g (12.1 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid with 1.9 g (10.1 mmol) of N-methyl-4-bromo-2-pyrrolecarboxaldehyde, 1.85 g (59%) of the expected product are obtained in the form of a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].CC1(C)O[C:16](=O)[CH2:15][C:13](=O)[O:12]1>>[O:12]=[C:13]1[C:3]2[C:4](=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=2[Cl:1])[NH:5][CH:16]=[CH:15]1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: O=c1cc[nH]c2cc(Cl)cc(Cl)c12

Procedure:
Kokai Pat. No. Hei 1(1989)-246263 describes a method for producing 5,7-dichloro-4-(2-fluorophenoxy)-quinoline whereby a mixture of 3,5-dichloroaniline and Meldrum's acid is heated to give 4-oxo-5,7-dichloro-1,4-dihydroquinoline, which is reacted with phosphorus oxychloride to give 4,5,7-trichloroquinoline, which is then reacted with 2-fluorophenol to give the final compound.
Reaction SMILES: P([O-])([O-])([O-])=O.[OH:6][CH:7]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[OH-].[Na+]>O>[OH:6][C@H:7]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(O)CCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)[C@H](O)CCc1ccccc1
Yield: 43.1 %

Procedure:
A 3 L three-neck, round-bottom flask equipped with a mechanical stirrer, an electrode connected to a pH control unit and an addition tube connected to a peristaltic pump, was charged with 450 ml of deionized water, 50 ml of 0.05M aqueous phosphate buffer (pH 7.0) and 52.0 g of racemic ethyl 2-hydroxy-4-phenylbutanoate. The mixture was stirred for a few minutes to make certain that the pH remained constant at 7.0. Then, 1.0 g (30,000 units) of Pseudomonas lipase enzyme (P-30, Amano International) was added and the hydrolysis was allowed to proceed at pH 7.0 and room temperature, with stirring. The pH was kept constant by adding 1.0N aqueous sodium hydroxide solution via the paristaltic pump, which was activated by the pH control unit. The reaction was discontinued at 55% conversion when 137.5 ml of 1.0N aqueous sodium hydroxide solution had been added (at the 25 hour mark). The reaction mixture was then extracted with 3×200 ml (600 ml total) of diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed at 45° C. under 70 mm Hg of vacuum to provide 22.4 g of ethyl (2R)-2-hydroxy-4-phenylbutanoate (43% yield; 96% of theory), which was 99% enantiomerically pure (α)D25 -8.4° (c 1.15, EtOH). The aqueous layer was acidified to pH 2 with 3N hydrochloric acid and extracted with 3×200 ml of diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed at 45° C. and 70 mm Hg to give 22.7 g of (2S)-2-hydroxy-4-phenylbutanoic acid (50% yield; 91% of theory), which was 73% enantiomerically pure. (α)D25 +5.7°, m.p. 109°-110° C.
Reaction SMILES: [CH3:1][Mg+].[Br-].FC(F)(F)S(O[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)(=O)=O.[NH4+].[Cl-]>C1COCC1.O>[CH2:10]([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)[CH3:1]
Reactant: O=S(=O)(OCC1CCc2ccccc2O1)C(F)(F)F
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
MeMgBr (45.6 mL, 137 mmol, 3M in ether) was added to a mixture of the title compound from Step 2 (13.5 g, 45.6 mmol) and CuBr-Me2S (1.61 g, 7.74 mmol) in THF (150 mL) at −5° C. The reactions was stirred at rt for 2 h. It was then poured onto a solution of NH4Cl (55 g, 1.04 mol) in water (200 mL) and extracted with DCM (3×150 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6.66 g, 90%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.09-7.02 (m, 2H), 6.82-6.78 (m, 2H), 3.93-3.87 (m, 1H), 2.84-2.72 (m, 2H), 2.02-1.96 (m, 1H), 1.81-1.61 (m, 3H), 1.04 (t, J=7.2 Hz, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[N:8][C:7]=1[C:16]([O:18][CH3:19])=[O:17]>>[Cl:3][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[N:8][C:7]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1nnc2ccccc2c1O
Reactant: O=S(Cl)Cl
Product: COC(=O)c1nnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (8.15 g, 5 ml) was added dropwise under inert atmosphere to methyl 4-hydroxycinnoline-3-carboxylate (0.50 g, 2.45 mmol). The mixture was heated to reflux for 1.5 h, cooled to room temperature and excess thionyl chloride was removed under vacuum. Toluene (5 ml) was added to the residue. The mixture was stirred at room temperature overnight. The solids were collected by filtration and dried under vacuum. The title compound was isolated as a brown solid (248 mg, 1.11 mmol, 45%). LCMS: m/z 223 [M+H]+.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([CH2:11][C:12]([OH:14])=O)[N:5]=1.[CH3:15][C:16]1([CH3:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH2:17]1.CN(C)CCCN=C=NCC>CN(C)C=O.N1C=CC=CC=1>[Cl:10][C:8]1[CH:9]=[C:4]([O:3][CH3:2])[N:5]=[C:6]([CH2:11][C:12]([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([CH3:25])([CH3:15])[CH2:17]2)=[O:14])[N:7]=1
Reactant: CC1(C)CNc2ccccc21
Reactant: COc1cc(Cl)nc(CC(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: [Na]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc(Cl)nc(CC(=O)N2CC(C)(C)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41 %

Procedure:
0.5 g of the sodium salt of (4-methoxy-6-chloropyrimidin-2-yl)acetic acid (example 8b, step 3b), 0.33 g of 3,3-dimethyl-2,3-dihydro-1H-indole (CAS 1914-02-9), 0.4 ml of pyridine and 5 ml of dimethylformamide are placed in a three-necked flask so as to obtain a homogeneous brown solution. 512 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide are added at ambient temperature and the mixture is stirred at ambient temperature for 20 hours. The resulting product is concentrated in a rotary evaporator under vacuum, 40 ml of water are added, extraction is carried out with 3 times approximately 25 ml of dichloromethane, washing is carried out with 50 ml of saturated NaCl solution, drying is carried out over MgSO4, and the resulting product is filtered through a VF filter. The compound obtained is purified by chromatography on silica gel (40-63 μm), elution being carried out with a 98/2 dichloromethane/methanol mixture. The fractions containing the expected compound are combined and evaporated under reduced pressure. 2-(4-Chloro-6-methoxypyrimidin-2-yl)-1-(3,3-dimethyl-2,3-dihydroindol-1-yl)ethanone is isolated: 0.3 g of a yellow oil; yield 41%, which is used as it is in the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].Br[CH2:11][C:12](=O)[C:13]([O:15]CC)=[O:14].C(=O)(O)[O-].[Na+]>O.C(#N)C>[CH3:4][C:3]1([CH3:5])[CH:2]([C:7]([OH:9])=[O:8])[NH:1][C:12]([C:13]([OH:15])=[O:14])=[CH:11][S:6]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(S)[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1(C)SC=C(C(=O)O)NC1C(=O)O
Yield: 34.5 %

Procedure:
To a solution of L-penicillamine (298 mg, 2.0 mmol) in water (5 mL) and acetonitrile (5 mL) was added ethyl 3-bromopyruvate (0.25 mL, 390 mg, 2.0 mmol) slowly. To the resulted mixture was added sodium bicarbonate aqueous solution till the pH about 5. Acetonitrile was removed under vacuum and some more water was added. The solution was extracted with methylene chloride. The water phase was separated and freeze-dried under high vacuum. The residue was chromatographed (silica gel, methylene chloride-methanol-acetic acid 100:5:0.3 to 100:10:0.3) to give 150 mg of product (yield 31%). 1HNMR (300 Hz, D3COD) δ (ppm) 6.17 (s, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.79 (s, 1H), 1.48 (s, 3H), 1.31 (t, J=7.1 Hz, 3H), 1.29 (s, 3H). 13CNMR (75 Hz, D3COD) δ (ppm) 173.8, 164.0, 128.0, 102.4, 64.1, 62.2, 41.2, 28.3, 25.2, 14.7 ppm. MS (ESI) m/z 268 (M+Na, 100), 246 (M+1, 5).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[CH2:16][NH:15][C@H:14]([CH3:17])[CH2:13][N:12]1[C@H:18]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[CH3:10][C@H:11]1[CH2:16][N:15]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[C@H:14]([CH3:17])[CH2:13][N:12]1[C@H:18]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:36][CH:37]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)N(Cc3ccc(O)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.05 %

Procedure:
4-Hydroxybenzaldehyde (488 mg, 4.0 mmol) was dissolved in a solution of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (759 mg, 2.0 mmol, Example 2) and acetic acid in tetrahydrofuran (10 mL). Sodium triacetoxy borohydride (848 mg, ˜4 mmol) was added portionwise over 5 min, then the reaction mixture sealed under nitrogen and stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue partitioned between water (6 mL) and ethyl acetate (20 mL). The aqueous solution was further extracted with ethyl acetate (2×10 mL) and the combined extract and washings diluted with an equal volume of ether. The organic solution was extracted with 3M-HCl and the acidic aqueous solution carefully neutralized, initially with 5M-NaOH, then saturated NaHCO3. At pH 4 the solution was filtered through a 0.45 mM syringe filter to remove a small quantity of an off-white gummy solid. The pH of the filtrate was adjusted to 8.5 to precipitate a flocculent white solid which was filtered off, washed well with cold water and dried overnight at 2 mm Hg at room temperature to yield 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(4-hydroxybenzyl)-1-piperazinyl)-benzyl)-N,N-diethylbenzamide (73.05%). Calc. for C31H39N3O2 1.5H2O C, 72.62; H, 8.26; N, 8.20. Found C, 72.58; H, 7.83; N, 8.40% 1H NMR (1% NaOD in D2O, 300 MHz); □□0.75 (br m, 3H); 0.81 (br d, J=7.3 Hz, 6H); 0.94 (br m, 3H); 1.71 (m, 1H); 1.84 (m, 1H); 2.29 (m, 2H); 2.49 (br m, 2H); 2.91 (m, 3H); 3.22 (m, 2H); 3.57 (br m, 2H); 5.02 (s, 1H); 6.39 (d, J=7.5 Hz, 2H); 6.80 (d, J=7.3 Hz, 2H); 7.01 (m, 7H); 7.17 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:11]=[CH:10][C:9]=2[N+:18]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:11]=[CH:10][C:9]=2[NH2:18])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1c([N+](=O)[O-])cnn1CCC(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cl)cc1-c1c(N)cnn1CCC(C)C
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(5-Chloro-2-methoxyphenyl)-1-isopentyl-4-nitro-1H-pyrazole (632 mg, 1.95 mmol, 1.00 eq), iron (642.5 mg, 11.50 mmol, 5.90 eq), and ammonium chloride (500.7 mg, 9.36 mmol, 4.80 eq) in 5.0 mL ethanol and 10 mL water was stirred at 75° C. for 2 hours. The reaction mixture was concentrated, 10 mL of saturated bicarbonate solution was added, and the aqueous layer was extracted with dichloromethane (20 mL*3). The combined dichloromethane layers were dried with magnesium sulfate, filtered and concentrated. The reddish yellow oil was used as is for the next step LCMS (ESI) m+H=293.8.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:4].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:23]([N:2]([CH3:1])[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:4])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNC(=O)NC1CCN(Cc2ccc3ccccc3c2)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CN(C(=O)NC1CCN(Cc2ccc3ccccc3c2)CC1)C(=O)c1ccccc1

Procedure:
1-Methyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (1.4 g.) (prepared by reacting 4-amino-1-(naphth-2-ylmethyl)piperidine with methyl isocyanate) in toluene (30 cm3) was acylated using benzoyl chloride (0.92 g) in presence of pyridine (0.6 g) to give the title compound: m.p. of HCl, hemihydrate salt=164°-166° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[NH:7][C:8]1[NH:9][C:10](=[O:17])[C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1.C(=O)([O-])[O-].[Na+:27].[Na+]>C(O)C.O>[CH3:1][CH:2]([CH3:22])[CH2:3][O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[NH:7][C:8]1[NH:9][C:10](=[O:17])[C:11]([C:14]([O-:16])=[O:15])=[CH:12][N:13]=1.[Na+:27]
Reactant: CC(C)COc1ccccc1Nc1ncc(C(=O)O)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)COc1ccccc1Nc1ncc(C(=O)[O-])c(=O)[nH]1
Yield: 57.8 %

Procedure:
A mixture of 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylic acid (20 g) and sodium carbonate (7.0 g) in ethanol (100 ml) and water (100 ml) is heated until the solution is completed. After allowing to stand the solution overnight, the precipitate is collected by filtration, washed with water and dried to give sodium 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (12.4 g). M.p. 231°-233° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]O)([O-:15])=[O:14].[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH2:28][N:27]1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][N:30]1[C:29](=[O:31])[CH2:28][N:27]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:26]1=[O:25])([O-:15])=[O:14]
Reactant: CCOC(=O)CN1CC(=O)NC1=O
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CC(=O)N(Cc2ccc(Cl)c([N+](=O)[O-])c2)C1=O
Yield: 78.1 %

Procedure:
A solution of 5.2 mL of diethyl azodicarboxylate in 30 mL of tetrahydrofuran was added to a solution of 5.13 g of 3-nitro-4-chlorobenzyl alcohol, 4.70 g of ethyl 2,4-dioxoimidazolidine-1-acetate and 8.68 g of triphenylphosphine in 30 mL of tetrahydrofuran at 0° C. The reaction mixture was poured over water and the mixture was extracted with ethyl acetate several times. The extracts were combined, washed with a saturated saline solution, dried over sodium sulfate and concentrated. The concentrate was purified by a silica gel column and recrystallized from a mixed solvent of ethanol and water to give 7.01 g of ethyl 3-(3-nitro-4-chlorobenzyl)-2,4-dioxoimidazolidine-1-acetate.