Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][CH2:14][C:13]1=[O:21].[CH3:22][CH2:23][C:24](=O)[CH2:25][CH2:26][CH3:27].C([BH3-])#N.[Na+].CO>ClCCl.C(O)(=O)C>[CH3:22][CH2:23][CH:24]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH2:17][OH:18])([CH2:19][OH:20])[CH2:15][CH2:14][C:13]1=[O:21])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(=O)CC
Reactant: COC(=O)c1ccc(N2C(=O)CCC2(CO)CO)c(N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCCC(CC)Nc1cc(C(=O)OC)ccc1N1C(=O)CCC1(CO)CO
Reaction time: 12 h
Yield: 90.7 %

Procedure:
A solution of 1-(2-amino-4-methoxycarbonylphenyl)-5,5-bis-(hydroxymethyl)pyrrolidin-2-one (0.15 g, 0.51 mmol) from Example 6 in 1 mL of dichloromethane and 0.5 mL of acetic acid was treated with 3-hexanone (0.3 g, 3 mmol) and sodium cyanoborohydride (0.1 g, 1.6 mmol). The resulting mixture was stirred at ambient temperature for 6 h after which time additional 3-hexanone (0.1 g, 1 mmol), sodium cyanoborohydride (0.05 g, 0.8 mmol) and methanol (0.5 mL) were added. Stirring was continued for 12 h. A third portion of 3-hexanone (0.17 g, 1.7 mmol) and sodium cyanoborohydride (0.055 g, 0.9 mmol) was added and stirring continued for an additional 16 h. The reaction mixture was quenched with 10 mL of a saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). The combined extracts were dried and concentrated. The residue was purified by chromatography (silica gel; 5% ethanol in ether) to give 0.175 g (90%) of 1-[2-(3-hexylamino)-4-methoxycarbonylphenyl]-5,5-bis-(hydroxymethyl)pyrrolidin-2-one as an oil.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].I[CH2:7][CH2:8][C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:18][C:9]([C:14]([F:17])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])[CH2:8][CH2:7][C:2]([CH2:7][CH2:8][C:9]([C:10]([F:11])([F:12])[F:13])([F:18])[C:14]([F:17])([F:16])[F:15])([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: FC(F)(F)C(F)(CCI)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CCC(F)(C(F)(F)F)C(F)(F)F)CCC(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 0.9 %

Procedure:
0.66 g of malononitrile and 9.7 g of 1-iodo-3,4,4,4-tetrafluoro-3-trifluoromethylbutane were dissolved in 10 ml of ethylene glycol dimethyl ether, 4.1 g of potassium carbonate was added, and the mixture was stirred at room temperature for 15 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.04 g of 2,2-bis(3,4,4,4-tetrafluoro-3-trifluoromethylbutyl)malononitrile (hereinafter, referred to as the present compound (56)).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[CH2:6]([P:10]([CH2:13][CH:14]([CH3:16])[CH3:15])([SH:12])=[S:11])[CH:7]([CH3:9])[CH3:8]>>[CH2:6]([P:10]([CH2:13][CH:14]([CH3:16])[CH3:15])([S:12][CH2:1][CH2:2][CH2:3][CH3:4])=[S:11])[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CP(=S)(S)CC(C)C
Reactant: CCCCBr
Product: CCCCSP(=S)(CC(C)C)CC(C)C

Procedure:
n-Butyl bromide was reacted with the ammonium salt of diisobutylphosphinodithioic acid to obtain n-butyl diisobutylphosphinodithioate, a colorless liquid, b.p. 97°-103° C at 0.05 mm. which on testing lasted 200 hours longer than the control. The total number of hours required to reach failure was 1.4 times that of the control.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[C:6](=O)[C:7]2[CH:8]=[N:9][C:10]([NH:15][CH3:16])=[N:11][C:12]=2[CH2:13][CH2:14]/1)[CH3:3].[CH3:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2C(N)=[CH:28][CH:27]=[N:26]2)=[CH:22][CH:21]=1>C(O)(C)C>[CH3:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2[C:3]3[N:2]=[CH:4][C:5]4[CH2:14][CH2:13][C:12]5[N:11]=[C:10]([NH:15][CH3:16])[N:9]=[CH:8][C:7]=5[C:6]=4[C:28]=3[CH:27]=[N:26]2)=[CH:22][CH:21]=1
Reactant: CNc1ncc2c(n1)CC/C(=C\N(C)C)C2=O
Reactant: COc1ccc(Cn2nccc2N)cc1
Solvent: CC(C)O
Product: CNc1ncc2c(n1)CCc1cnc3c(cnn3Cc3ccc(OC)cc3)c1-2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To a mixture of (E)-6-((dimethylamino)methylene)-2-(methylamino)-7,8-dihydroquinazolin-5(6H)-one (2.8 g, 12 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (2.69 g, 13 mmol) was added trifluoroacetic (1 mL). The reaction mixture was heated at 100° C. for 16 hours. The reaction was then cooled to room temperature followed by addition of isopropanol (20 mL). The reaction mixture was the stirred for 30 minutes and the supernatant decanted. The residue was dried under reduced pressure. The crude product was purified using flash column chromatography (SiO2, gradient from 100 hexanes to 15% EtOAc in hexanes) to give desired product (1.0 g, 22%) as solid. 1H NMR (CDCl3, 400 MHz): δ 9.32 (s, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 7.40 (d, J=8.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 5.52-5.48 (m, 1H), 5.62 (s, 2H), 3.76 (s, 3H), 3.18-3.04 (m, 5H), 3.0-2.88 (m, 2H); LCMS [M+H]: 373.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.C([Li])CCC.[Br-].[Mg+2].[Br-].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[CH:37][N:38]3[C:47]=2[CH:46]=[C:45]2[C@@:40]([CH3:50])([C@@H:41]([CH:48]=[O:49])[CH2:42][CH2:43][CH2:44]2)[CH2:39]3)=[CH:31][CH:30]=1.[Cl-].[NH4+]>C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[CH:37][N:38]3[C:47]=2[CH:46]=[C:45]2[C@@:40]([CH3:50])([C@@H:41]([CH:48]([C:6]4[N:7]=[CH:8][CH:9]=[CH:10][N:11]=4)[OH:49])[CH2:42][CH2:43][CH2:44]2)[CH2:39]3)=[CH:31][CH:30]=1
Reactant: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2C=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2C(O)c1ncccn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(tributylstannyl)pyrimidine (185 mg, 0.5 mmol) in anhydrous THF (1 mL) was added butyllithium solution (1.6 M in hexanes, 0.31 mL, 0.5 mmol) dropwise at −78° C. under nitrogen. The mixture was stirred at −78° C. for 2 hr before magnesium bromide (90 mg, 0.5 mmol) was added. After the reaction mixture was stirred at −78° C. for additional 30 min, (5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinoline-6-carbaldehyde (Example 1g, 20 mg, 0.065 mmol) was added. The mixture was stirred at −78° C. for 45 min and at RT for 5 min. Saturated aqueous ammonium chloride solution (2 mL) was added. The reaction mixture was extracted with ethyl acetate (3×1 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (50-100% ethyl acetate in heptanes and then 0-20% methanol in ethyl acetate) gave ((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)(pyrimidin-2-yl)methanol which was used as such for the subsequent step without further purification.
Reaction SMILES: [ClH:1].C(OC(=O)[N:8]([CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:9][CH2:10][N:11]([S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[CH:24][CH:25]=1)(=[O:15])=[O:14])[CH3:12])(C)(C)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][CH2:27][CH2:26][NH:8][CH2:9][CH2:10][N:11]([CH3:12])[S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[CH:24][CH:25]=1)(=[O:15])=[O:14])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CN(CCN(CCOc1ccccc1Cc1ccccc1)C(=O)OC(C)(C)C)S(=O)(=O)c1cccc2cnccc12
Agent: Cl
Solvent: ClCCl
Product: CN(CCNCCOc1ccccc1Cc1ccccc1)S(=O)(=O)c1cccc2cnccc12
Yield: 85 %

Procedure:
A 4N HCl (in 1,4-dioxane, 3 mL) solution is added to a stirred solution of [2-(2-benzyl-phenoxy)-ethyl]-{2-[(isoquinoline-5-sulfonyl)-methyl-amino]-ethyl}-carbamic acid tert-butyl ester (65.0 mg, 0.113 mmol) in anhydrous CH2Cl2 (1 mL) at ambient temperature under nitrogen. The resultant solution is stirred for 2 hours. The mixture is concentrated and the product is treated with CH3OH/EtOAc to form a white suspension. After filtration and vacuum drying, 52.5 mg (0.0957 mmol, 85% yield) of the title compound is obtained as a white solid. ESIMS: m/z 476 (M+H)+.
Reaction SMILES: P(Br)(Br)[Br:2].[CH:5]([C:8]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:9]=1[CH2:10]O)([CH3:7])[CH3:6].CCO>CCOCC>[CH:5]([C:8]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:9]=1[CH2:10][Br:2])([CH3:7])[CH3:6]
Reactant: CC(C)c1cc(C(C)C)c(CO)c(C(C)C)c1
Reactant: BrP(Br)Br
Solvent: CCO
Solvent: CCOCC
Product: CC(C)c1cc(C(C)C)c(CBr)c(C(C)C)c1
Reaction time: 1 h

Procedure:
A solution of PBr3 (2.7 9, 10 mmol) in ether (10 mL) was added slowly to a solution of 2,4,6-triisopropylbenzyl alcohol (4.68 9, 20 mmol) in 20 mL of ether at room temperature. The mixture was stirred for 1 hour, 5 mL of absolute EtOH was added, and stirring was continued for another 0.5 hour. The solvent was removed and the residue distributed between EtOAc and saturated Na2CO3. The EtOAc layer was separated, washed with brine, and dried over MgSO4. The solvent was evaporated and the pure product was isolated by column chromatography (100% CH2Cl2, 3.5 g, 59%); NMR (CDCl3):δ 1.2-1.4 (m, 18H), 2.8-3.0 (m, 1H), 3.2-3.45 (m, 2H), 4.7 (s, 2H), 7.04 (s, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O:11][CH2:12][CH:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:12]([OH:11])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:19]=[N:5]2)=[CH:7][CH:8]=1
Reactant: CCOCC(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(F)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(F)ccc2c1O
Temperature: 100 °C
Yield: 67.6 %

Procedure:
Under a nitrogen atmosphere, 3-fluoroaniline (50.0 g, 0.45 mol) and diethyl ethoxymethylmalonate (91 mL, 0.45 mol) were combined and heated at 100° C. for 3 hours. The reaction was allowed to cool to ambient temperature and it solidified. Dowtherm A (200 mL) was added and the reaction mixture was heated at 240° C. for 4 hours. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, washed with hexane and then dried in a vacuum oven to provide 71.5 g of ethyl 7-fluoro-4-hydroxy-3-quinolinecarboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[N:11][C:12]([N:14]3[CH2:19][CH2:18][N:17](CC4C=CC=CC=4)[CH2:16][CH2:15]3)=[N:13][C:6]=2[CH:5]([CH3:27])[CH2:4][NH:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[N:11][C:12]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)=[N:13][C:6]=2[CH:5]([CH3:27])[CH2:4][NH:3]1
Reactant: CC1CNN(C)C(=O)c2cnc(N3CCN(Cc4ccccc4)CC3)nc21
Agent: [Pd]
Solvent: CCO
Product: CC1CNN(C)C(=O)c2cnc(N3CCNCC3)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
Dissolved in 10 ml of ethanol was 0.2 g (0.55 mmol) of 6,9-dimethyl-2-(4-benzylpiperazino)-5-oxo-5,6,7,8-tetrahydro(9H)pyrimido[4,5-e]diazepine, followed by an addition of 20 mg of 10% Pd-C. Under reflux, the reactant was hydrogenated at atmospheric pressure for 2 hours. After cooling the reaction mixture to room temperature, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 0.1 g of the intended product (yield: 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=O)[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]2[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([SH:40])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]2[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(S)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 70.8 %

Procedure:
A mixture of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2(1H)-quinolone-3-carboxylate (6.8 g), Lawesson's reagent (8.0 g) and toluene (250 ml) was stirred under reflux for 18 hours. After cooling, the precipitated crystals were collected by filtration to give ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-mercaptoquinoline-3-carboxylate (5.0 g, 70%) which was then recrystallized from acetone. mp. 265°-266° C.
Reaction SMILES: CI.[CH2:3]([N:10]1[CH2:22][CH2:21][C:13]2[NH:14][C:15](=[O:20])[N:16]([CH3:19])[C:17](=[O:18])[C:12]=2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:23](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:3]([N:10]1[CH2:22][CH2:21][C:13]2[N:14]([CH3:23])[C:15](=[O:20])[N:16]([CH3:19])[C:17](=[O:18])[C:12]=2[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n(C)c1=O)CN(Cc1ccccc1)CC2
Temperature: 60 °C
Yield: 38.6 %

Procedure:
9.6 ml of methyl iodide were added dropwise at 40° C. over a period of 10 minutes, with stirring, to 40.7 g of 6-benzyl-3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione and 20.7 g of potassium carbonate in 230 ml of dimethylformamide. After heating for 8 hours at 60° C., the mixture was concentrated under reduced pressure, the residue was taken up with water, the pH was adjusted to 8 and the mixture was worked up by extraction with dichloromethane and water. After the combined dichloromethane phases had been concentrated under reduced pressure, the residue was purified by chromatography on silica gel with dichloromethane/ethanol (volume ratio 95:5) to give 16.5 g of 6-benzyl-1,3-dimethyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimi-dine-2,4-dione, from which 6-benzyl-1,3-dimethyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione hydrochloride was obtained as a precipitate in diethyl ether with a solution of hydrochloric acid in ether. The product was recrystallized from methanol/diethyl ether and residual methanol was removed by the addition of water to the precipitate, concentration under reduced pressure and drying of the residue under high vacuum.
Reaction SMILES: [ClH:1].[CH3:2][C:3]([NH2:19])([CH3:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1>[Pt](=O)=O.CO>[ClH:1].[CH3:18][C:3]([NH2:19])([CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(N)c1ccc(C#Cc2ccccc2)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CC(C)(N)c1ccc(CCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
A mixture of 0.45 gram of α,α-dimethyl-4-(phenylethynyl) -benzylamine hydrochloride, 61 ml. of absolute methanol, and 163 mg. of platinum dioxide catalyst is hydrogenated at 40 p.s.i. for one hour. The hydrogenation is stopped, the catalyst is removed by filtration, and the methanol is removed by evaporation. The residue is partitioned between benzene and 10% sodium hydroxide solution. The benzene phase is washed well with water, dried over magnesium sulfate, filtered, and the benzene is evaporated. The residual oil is dissolved in ether and treated with ethanolic hydrogen chloride. The precipitate is collected and recrystallized from isopropanol and ether to give α,α-dimethyl-4-phenethylbenzylamine hydrochloride, m.p. 225°-228° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([OH:12])[C:4]([CH3:13])=[N:3]1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:12][C:5]1[C:4]([CH3:13])=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(O)c(C)nn1C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(OCc2ccccc2)c(C)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a 5 ml solution of ethyl 1,3-dimethyl-4-hydroxypyrazole-5-carboxylate (2 g, 11.6 mmol) in anhydrous dimethylformamide (hereinafter, referred to as DMF) was added sodium hydride (60% dispersion in oil) (0.47 g, 11.8 mmol) under ice-cooling. Benzyl bromide (2 g, 11.7 mmol) was then added dropwise thereto, and the resulting mixture was stirred at room temperature for one hour and poured into water. The mixture was extracted with ethyl acetate. The extract was washed with water, and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed over silica gel (eluent; ethyl acetate/n-hexane=1:4) to give ethyl 4-benzyloxy-1,3-dimethylpyrazol-5-carboxylate (2.5 g, 9.1 mmol, 78%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1.C(N(CC)CC)C>C(#N)C>[NH2:8][C:6]1[N:7]=[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
6-Chloro-3-nitropyridin-2-amine (1.25 g, 7.22 mmol) was added to a solution of (R)-ethyl piperidine-3-carboxylate (2.0 g, 10.32 mmol) and triethylamine (2.87 mL, 20.65 mmol) in acetonitrile (25 mL) at room temperature. The reaction mixture was stirred for 3 h at 80° C., then was cooled and was partitioned between ethyl acetate and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 0-25% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (2 g). MS (ES+APCI) (M+H) 295.0; LCMS retention time 5.246 min (Method R1).
Reaction SMILES: NC1C=CC(N2CCOCC2=O)=CC=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][C:16]1=[O:21].[H-].[Na+].F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C:16]2=[O:21])=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: O=C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Nc1ccc(N2CCOCC2=O)cc1
Agent: [H-]
Agent: [Na+]
Product: O=C1COCCN1c1ccc([N+](=O)[O-])cc1

Procedure:
In contrast, WO-A 01/47919 also describes a preparation method for 4-(4-aminophenyl)-3-morpholinone (I). In this method, morpholin-3-one (V) is first deprotonated with sodium hydride and then reacted with 4-fluoronitrobenzene (VI) to give 4-(4-nitrophenyl)-3-morpholinone (VII). Catalytic hydrogenation of (VII) with hydrogen over palladium on activated carbon in tetrahydrofuran as a solvent affords 4-(4-aminophenyl)-3-morpholinone (I):
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C@@H:10]([OH:29])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=1[O:27][CH3:28])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:42]([Si:46]([CH3:49])([CH3:48])Cl)([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C@@H:10]([O:29][Si:46]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:49])[CH3:48])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=1[O:27][CH3:28])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 598 mg (1.175 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoic acid in 6 ml of DMF is treated, while being stirred, with 653 mg (9.4 mmol) of imidazole and 822 mg (5.287 mmol) of t-butyldimethylchlorosilane. After it has been stirred for 17 h at RT, and under argon, the reaction solution is poured onto ice-water and the whole is extracted with ethyl acetate. The organic phase is washed with 10% citric acid solution and saline (cold). The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried with Na2SO4 and evaporated. The crude product is dried under HV for approximately 2 h and, after that, is dissolved in 15.6 ml of methanol and 5.3 ml of THF, and this solution is treated with 941 mg of potassium carbonate in 5.3 ml of water. This reaction mixture is stirred at RT for approximately 3 h, then concentrated down, at approximately 30° C., to half the volume and diluted with ethyl acetate; the organic phase is washed with 10% citric acid and saline (both being cold). The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated. The crude product is chromatographed on silica gel (hexane:ethyl acetate, 2:1), and the title compound is obtained. IR(CH2Cl2) inter alia: 3436, 1708, 1603, 1494, 1166, 1100 and 837 cm-1. FAB-MS (M+H)+ =624. HPLC tRet =23.14 min (gradient II). 1H-NMR (CD3OD) inter alia: 6.76 (d, 1H); 6.59 (d, 1H); 6.07 and 5.50 (each d, in all 1H, rotamers of NH), 3.86, 3.82 and 3.81 (each s, each 3H); 3.75-3.57 (m, 2H); 2.93-2.75 (m, 2H); 2.70 (m, 1H); 1.42 (s, 9H); 0.87 (s, 6H); 0.11 and 0.08 (each s, each 3H).
Reaction SMILES: C(O)C(N)(CO)CO.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Na+].[Cl-].C=C(O[C@H:37]1[C@H:42]([OH:43])[CH:41]=[CH:40][C:39]([C:44]([O-:46])=[O:45])=[CH:38]1)C([O-])=O.[Ba+2]>>[CH:40]1[C:39]([C:44]([OH:46])=[O:45])=[CH:38][CH:37]=[C:42]([OH:43])[CH:41]=1
Reactant: C=C(O[C@@H]1C=C(C(=O)[O-])C=C[C@H]1O)C(=O)[O-]
Agent: NC(CO)(CO)CO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Ba+2]
Product: O=C(O)c1ccc(O)cc1

Procedure:
CPL enzyme assays were conducted as follows. The basic reaction mixture (final volume, 500 μl) contained 50 mM Tris pH 8.0 (at 37° C.), 10 mM EDTA, 200 mM NaCl, and 150 μM of purified barium chorismate (Siebert et al. Microbiology 140:897-904 (1994)). Following a 5-min incubation period at 37° C., reactions were initiated with tobacco leaf extract that contained 50 μg of protein. Reactions were terminated after 2 min at 37° C. with 0.3 ml of 0.75 M sodium acetate (pH 4), and the amount of pHBA that was produced in the reaction was determined. To monitor the recovery of product, each tube received 9,500 dpm of [14C]-labeled pHBA (55 mCi/mmol) as an internal standard. The mixtures were extracted with 1 ml of H2O-saturated ethyl acetate, and the organic phase was collected and taken to dryness. The amount of pHBA was then quantitatively determined by reverse phase HPLC, using the exact same column and conditions that were described in Example 9. The peak corresponding to pHBA was collected and the amount of radioactivity was determined by liquid scintillation counting. Values reported below for CPL enzyme activity are expressed as pkats per mg protein, and have been corrected for recovery of the internal standard and the small amount of pHBA that is generated from chorismate through spontaneous decomposition (Siebert et al., Plant Physiol. 112:811-819 (1996)).