Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9]>[Ru].O>[CH3:7][C:4]1([CH3:8])[CH:5]([OH:6])[C:2]([CH3:10])([CH3:1])[CH:3]1[OH:9]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Agent: [Ru]
Solvent: O
Product: CC1(C)C(O)C(C)(C)C1O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A 2 liter Parr autoclave was charged with 100 grams of 2,2,4,4-tetramethylcyclobutane-1,3-dione, 600 grams of dionized water, and 50 grams of 2% ruthenium on alumina (surface area=10 m2/g, purchased from BASF Catalysts). The autoclave was pressure purged three times with nitrogen and three times with hydrogen, and the pressure was increased to 3.5 MPa (500 psig) with hydrogen. The autoclave was heated to 100° C. with stirring at approximately 1000 rpm and held for 6 hours at 3.5 MPa (500 psig). Analysis of the product by gas chromatography indicated that 98.5% conversion of the 2,2,4,4-tetramethylcyclobutane-1,3-dione was obtained with 100% selectivity to 2,2,4,4-tetramethycyclobutane-1,3-diol with a cis:trans ratio of 2.15:1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[C:12]([S:14]C#N)[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][C:9]=1[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:4])([CH3:3])[CH3:2].S.[Na].[BH4-].[Na+].CO>CC(O)=O.O>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[C:12]([SH:14])[C:11]([C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:10][C:9]=1[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cc(SC#N)c(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Agent: S
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(S)c(C(C)(C)C)cc1NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to General Method 14b using (2-tert-butoxycarbonylamino-4-tert-butyl-5-thiocyanato-phenyl)-carbamic acid tert-butyl ester (prepared in Example SS-2; 18 g, 43 mmol), sodium hydrogen sulfide (7.2 g, 128 mmol), sodium borohydride (9.7 g, 256 mmol), MeOH (150 mL), H2O (50 mL), and AcOH (10 mL). The crude product was used without purification.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[NH2:26][C@H:27]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].[OH-].[Na+].Cl>COCCO.CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][C@H:27]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Solvent: CO
Product: N#Cc1nc(C(=O)N[C@@H](CC(=O)O)Cc2ccccc2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 56.5 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (40 mg, 0.125 mmol), (R)-3-amino-4-phenyl-butyric acid HCl salt (270 mg, 1.25 mmol) (PepTech Corporation), and NaOMe (101 mg, 1.88 mmol) in 2-methoxyethanol (10 mL) was refluxed for 1.5 h. The resulting mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and water. Hydrochloric acid (1 M) was added with vigorous stirring until pH ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (5-40% EtOAc/hexanes+2% AcOH). The compound isolated was then dissolved in MeOH (2 mL) and treated with 2 M NaOH (2 mL) for 2 h. Hydrochloric acid (1 M) was added to acidify the mixture, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography (5-40% EtOAc/hexanes+2% AcOH) to give 33 mg of the title compound. MS: (+) m/z 468.06 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([NH:10][S:11](Cl)(=[O:13])=[O:12])[CH3:9].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([O:7][S:11](=[O:13])(=[O:12])[NH:10][CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCNS(=O)(=O)Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCNS(=O)(=O)Oc1ccccc1
Yield: 70.8 %

Procedure:
A solution of 18.8 g (0.2 mole) of phenol and 38.4 g (0.27 mole) of ethylaminosulfonyl chloride (Preparation 23) in 150 ml of toluene was stirred and heated at reflux for 16 hr. The solution was cooled and then treated with 250 ml of a 20% sodium bicarbonate solution. The layers were separated and the organic layer was washed successively with 250 ml of a 20% sodium bicarbonate solution, two 300-ml portions of water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the oily residue was purified by chromatography (4.5×105 cm glass column; 550 g of silica gel; ethyl acetate-hexanes, 1:16). Fractions containing the product were combined and the solvents evaporated under reduced pressure to give 28.5 g (71%) of the title compound as a colorless liquid. Elemental analysis suggested that the product contained water.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]#[N:12].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][CH2:2][C:3]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]#[N:12])=[O:4]
Reactant: N#C[C@@H]1CCCN1
Reactant: O=C(Br)CBr
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#C[C@@H]1CCCN1C(=O)CBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
To a cold solution (−10° C.) of bromoacetyl bromide (2.0 g, 10.0 mmol) in CH2Cl2 (30 mL), a solution of (S)-pyrrolidine-2-carbonitrile (480 mg, 5.0 mmol) and pyridine (1.4 g, 210 mmol) together with a catalytic amount of DMAP (50 mg) in CH2Cl2 (10 mL) was added over a 30 minute period. After stirring for about 10 minutes, the reaction temperature was gradually increased to room temperature. Stirring at room temperature was continued overnight. The residue was diluted with CH2Cl2 (60 mL), washed with ice water and cold 10% sodium bicarbonate aqueous solution to give crude product (1.01 g; yield of 93%). Column chromatography purification of the crude product resulted in pure 1-(2-bromo-acetyl)-(S)-pyrrolidine-2-carbonitrile (892 mg; 82.6% yield).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.Cl>CCO.[OH-].[OH-].[Pd+2]>[NH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: O=[N+]([O-])c1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2c(c1)CNC2
Reaction time: 1 h

Procedure:
Part B. To a solution of the isoindoline (5.40 g, 21.3 mmol) made above in EtOH (266 mL) under N2 was added 20% Pd(OH)2/C (3.00 g, 4.25 mmol). The reaction mixture was hydrogenated at 45 psi for 1 h. TLC analysis indicated that the nitro functionality was reduced and the Bn group was still intact. Therefore, concentrated HCl (1.6 mL, 19.1 mmol) was added to the reaction mixture and hydrogenation (50 psi) was continued overnight. The mixture was filtered through Celite®, washed with MeOH, and the filtrate was concentrated to one fourth of the volume. The precipitate was filtered off to provide the 5-aminoisoindoline.HCl (1.32 g, 36% yield): 1H NMR (500 MHz, CDCl3) δ 9.88 (s, br, 2H), 7.00 (d, 1H), 6.54 (m, 2H), 5.44 (s, br, 2H), 4.32 (s, 2H), 4.28 (s, 2H); ESI MS m/z 135 (M−HCl+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH3:9])[C:3]=1[C:10]#[N:11].[CH3:12][N:13]=[C:14]=[O:15]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCCC1>[CH3:12][NH:13][C:14]([NH:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH3:9])[C:3]=1[C:10]#[N:11])=[O:15]
Reactant: CN=C=O
Reactant: CCSc1nsc(N)c1C#N
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CCSc1nsc(NC(=O)NC)c1C#N
Reaction time: 48 h

Procedure:
A solution of 35.0 g of 5-amino-4-cyano-3-(ethylthio)-isothiazole, 11.9 g of methyl isocyanate, 50 drops of dibutyltin diacetate in 175 ml of dried tetrahydrofuran was heated under reflux during 15 hours. Thin-layer chromatographic analysis of the reaction mixture indicated the reaction was 50% complete. An additional 11 ml of methyl isocyanate and 10-15 drops of dibutyltin diacetate were added. The reaction mixture was heated with stirring for 2 days. Thin-layer chromatographic analysis of the reaction mixture indicated the reaction to be complete. The reaction mixture was cooled, and the solid collected by filtration. The filtrate was evaporated to give a second crop, which was recrystallized from ethanol/dimethylformamide. The total yield of pure 1-methyl-3-(4-cyano-3-(ethylthio)-5-isothiazolyl)urea was 37.6 g; m.p. 246° (phase change) - 263°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)(=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCc2cc([N+](=O)[O-])ccc21
Reaction time: 17 h

Procedure:
A mixture of 5-nitroindoline (I, 12.012 g) in pyridine (100 ml) and acetic anhydride (50 ml) is stirred for 17 hr under argon. The mixture is then concentrated under reduced pressure to give the title compound, mp 175°-177°; NMR (CDCl3, 300 MHz) 8.28, 8.10, 8.01, 4.23, 3.31 and 2.28 δ; CMR (CDCl3, 75.47 MHz) 23.95, 27.01, 49.11, 115.73, 119.93, 124.27, 132.4, 143.4 and 169.8 δ; IR (CHCl3) 1680, 1600, 1480, 1470, 1390, 1340 and 1320 cm-1.
Reaction SMILES: [CH3:1][C:2]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:5].BrC1C(C)=C(C=CC=1)C(NCCCCCC(O)=O)=O.Cl.[NH2:45][OH:46]>>[OH:46][NH:45][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]=1[CH3:1])=[O:13]
Reactant: Cc1c(C(=O)NCCCCCC(=O)O)cccc1-c1ccccc1
Reactant: NO
Agent: Cc1c(Br)cccc1C(=O)NCCCCCC(=O)O
Agent: Cl
Product: Cc1c(C(=O)NCCCCCC(=O)NO)cccc1-c1ccccc1
Yield: 20.3 %

Procedure:
The procedure of the step 3 in Example 80 was repeated except that 6-(2-methyl-3-phenyl-benzamido)hexanoic acid (38 mg, 0.116 mmol)) instead of 6-(3-bromo-2-methylbenzamido)hexanoic acid and hydroxylamine hydrochloride (16 mg, 0.23 mmol) instead of 1,2-phenylenediamine were used and purified by a preparative HPLC (C18, 20% H2O/CH3CN, 20 ml/min) to obtain the title compound (8 mg, 20%).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]#[CH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:15][CH:16]([Cl:20])[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[CH:1]([N:4]([CH2:5][C:6]#[CH:7])[C:17](=[O:18])[CH:16]([Cl:20])[Cl:15])([CH3:3])[CH3:2]
Reactant: C#CCNC(C)C
Reactant: O=C(Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#CCN(C(=O)C(Cl)Cl)C(C)C
Temperature: 25 °C
Yield: 84.7 %

Procedure:
118 g of isopropylpropargylamine and 123 g of triethylamine are dissolved in 670 ml of toluene. While cooling and at room temperature, a solution of 180 g of dichloroacetyl chloride in 450 ml of toluene is dripped into this solution. The mixture is allowed to react for 1 hour before being filtered, and the filtrate is washed with water. The residue remaining after removal of the solvent is washed with petroleum ether. There is obtained 214 g (84% of theory) of N-isopropyl-N-propargyldichloroacetamide; b.p. (0.013 mbar): 80°-82° C.; m.p.: 58°-59° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:16][CH:15]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:18][CH:19]=2)=[CH:6][C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1
Reactant: CC(C)Oc1cnc(Cl)c(Cl)c1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC(C)CCc1ccc(Oc2cc(OC(C)C)cnc2Cl)cc1

Procedure:
2,3-Dichloro-5-isopropoxypyridine (514 mg, 2.496 mmol) and N-[3-(4-hydroxy-phenyl)-1-methylpropyl]acetamide (517 mg, 2.496 mmol) were reacted with sodium hydride in DMF in analogy to example 2c. Yield: 29 mg (3%), M+H+: 377.09. The isomer N-{3-[4-(2-chloro-5-isopropoxypyridin-3-yloxy)phenyl]-1-methylpropyl}acetamide was formed as further compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2O.P(Cl)(Cl)([Cl:25])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[Cl:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1c(-c2ccccc2)c(C(F)(F)F)nc2ccc(Br)cc12
Product: FC(F)(F)c1nc2ccc(Br)cc2c(Cl)c1-c1ccccc1

Procedure:
A solution of 6-bromo-3-phenyl-2-(trifluoromethyl)quinolin-4-ol (8.29 g, 22.5 mmol, Intermediate 34, step a) in phosphoryl trichloride (25 mL, 269 mmol) was heated at 110° C. for 2 hours, and concentrated in vacuo. Dichloromethane and ice-water were added, and the mixture was basified at 4° C. with conc. NH4OH until pH ˜10. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (120 g silica gel column, 2-9% EtOAc in heptane) to give the title compound as a light yellow solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:22]([O:24]CC3C=CC([N+]([O-])=O)=CC=3)=[O:23])=[C:8]([C:10]3[CH:14]=[C:13]([CH3:15])[N:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:11]=3)[CH2:9][C@H:5]12)[CH3:3].C(=O)([O-])O.[Na+:41]>O1CCCC1.O.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:22]([O-:24])=[O:23])=[C:8]([C:10]3[CH:14]=[C:13]([CH3:15])[N:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:11]=3)[CH2:9][C@H:5]12)[CH3:3].[Na+:41]
Reactant: Cc1cc(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)nn1-c1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)nn1-c1ccccc1
Reaction time: 0.12 h
Yield: 85.3 %

Procedure:
p-Nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-(5-methyl-1-phenylpyrazol-3-yl)carbapen-2-em-3-carboxylate (122 mg) in tetrahydrofuran (THF) (10 ml) and water (10 ml) was treated with sodium hydrogen carbonate (42 mg) (10 ml) and 3% Pd—C catalyst (50 mg) and the mixture was hydrogenated at atmospheric pressure for 5-10 min. The mixture was filtered through Kieselguhr, washing the filter cake with water and ethyl acetate. Combined filtrate and washings were reduced in volume using a rotary evaporator, a little NaCl was added and the mixture was chromatographed on a Diaion HP20SS column (2×10 cm), eluting with water (200 ml), followed by water/THF mixtures: 2% THF (10 ml); followed by 3% THF (100 ml), followed by 4% THF, followed by 6% THF. Fractions were monitored by uv and hplc. Fractions containing the product were combined and evaporated to lower volume and then freeze-dried to give sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-(5-methyl-1-phenylpyrazol-3-yl)carbapen-2-em-3-carboxylate (80 mg) νmax(KBr)/cm−1 1786, 1756, 1588, 1501, 1412, 1383, 1359, 1288 1246, 1223, and 1145; λmax(H2O)/nm 300.0 (ε/dm3 mol−1 cm−1 13,232), 236.5 (ε 7,027); δ(D2O) 1.26 (3H, d, J 6.4 Hz), 2.20 (3H,s), 3.1-3.29 (2H, m), 3.46 (1H, dd, J 2.9 & 5.9 Hz), 4.16-4.28 (2H, m), 6.61 (1H,s), 7.39-7.57 (5H,m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[Cl:14][S:15](O)(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:14][S:15][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)c1ccc(OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(OC)c(SCl)c1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 4-methoxybenzoate (15.7 g; 87.2 mmol) in CCl4 (60 ml) was cooled to −15° C., and chlorosulfonic acid (17.5 ml; 263 mmol) was added dropwise over a period of 15 min, resulting in a temperature increase to −10° C. After the addition had ended, the reaction mixture was stirred at room temperature for 2 h and then heated at 50° C. until no more starting material could be detected by thin-layer chromatography. With ice-cooling and vigorous stirring, the reaction mixture was added to a suspension of ice (50 g) in CCl4 (100 ml). The mixture was stirred vigorously for 3 min. The organic phase was separated off and the aqueous phase was extracted with CH2Cl2 (3×100 ml). The combined organic extracts were washed with saturated NaCl solution (3×), dried over Na2SO4 and concentrated. Trituration of the oily brown residue with diethyl ether resulted in 5c precipitating as a crystalline white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])([O-])=O.[K+].[K+]>C1(C)C(C)=CC=CC=1.CCOC(C)=O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:10]1[CH2:11][CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH:9]1[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:25]
Reactant: COC(=O)C1CCNC(CCc2ccccc2)C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCC(C(=O)OC)CC1CCc1ccccc1

Procedure:
To a suspension of methyl 2-(2-phenylethyl)piperidine-4-carboxylate in xylene were added ethyl bromoacetate and K2CO3, followed by heating under reflux for 8 hours. The reaction mixture was diluted with EtOAc, the organic layer was washed with water and brine in this order, dried over MgSO4, and then filtered. The filtrate was concentrated under reduced pressure. To the residue was added hexane, and the insolubles were removed by filtration, followed by concentration under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 1-(2-ethoxy-2-oxoethyl)-2-(2-phenylethyl)piperidine-4-carboxylate as a pale brown oil.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([C:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]I)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH2:8].[Cl-].[NH4+]>[Cu](I)I.C1COCC1>[CH2:6]([C:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:1][CH2:2][CH2:3][CH3:4])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH2:8]
Reactant: C=CCC(CCCCCI)(C(=O)OCC)C(=O)OCC
Reactant: [Li]CCCC
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(CCCCCCCCC)(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.7 %

Procedure:
To a THF suspension (2.1 ml) containing copper iodide (0.228 g, 1.2 mmol) was added dropwise at −10° C. butyl lithium (2.4 mmol in 0.88 ml of 2.68M hexane solution). The reaction liquid was heated to 0° C. over 30 minutes and then given diethyl allyl(5-iodopentyl)malonate (0.40 g, 1 mmol), followed by stirring at 0° C. for 5 hours. After addition of a saturated aqueous solution of ammonium chloride, the reaction product was purified as in Referential Example 1. Thus there was obtained 0.234 g of diethyl allyl(nonyl)malonate (yields: 75%). Characteristic Values of diethyl allyl(nonyl)malonate
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].Cl>O.C(O)C>[ClH:1].[F:18][C:19]([F:28])([F:29])[O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Agent: Cl
Solvent: CCO
Solvent: O
Product: FC(F)(F)Oc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol), 3-trifluoromethoxyaniline (19 μl, 0.144 mmol), and 2N HCl (75 μl) in water:ethanol (2:1, 5 ml) was refluxed for 24 h. The mixture was cooled to room temperature and the resulting precipitate was filtered, washed with water, water:ethanol (2:1) and dried to give a yellow solid (23 mg, 59%). 1H NMR (CDCl3): 8.88-8.85 (m, 1H), 8.59-8.55 (m, 1H), 7.93-7.87 (m, 1H), 7.59 (s, 1H), 7.48 (t, J=8.3 Hz, 1H), 7.45 (dd, J=1.2, 7.5 Hz, 1H), 7.36 (s, 1H), 7.30-7.29 (m, 1H), 7.16-7.10 (m, 1H), 7.05 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[O:18])=[CH:19][CH:20]=1)([O-:11])=[O:10]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 99.6 %

Procedure:
Using p-toluidine (1.19 g, 11.0 mmol) and 4-nitrobenzoic acid (1.77 g, 10.5 mmol), the procedure of Reference Example 16 was repeated to obtain 2.68 g (99.6%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[Cl:7].[CH2:12]([N:14]1[C:18](B2OC(C)(C)C(C)(C)O2)=[C:17]([CH3:28])[CH:16]=[N:15]1)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:18]1[N:14]([CH2:12][CH3:13])[N:15]=[CH:16][C:17]=1[CH3:28]
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Reactant: CCn1ncc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCn1ncc(C)c1-c1cc(C(=O)OC)sc1Cl
Temperature: 70 °C
Yield: 94 %

Procedure:
A mixture of methyl 4-bromo-5-chloro-2-thiophenecarboxylate (230 mg, 0.9 mmol), 1-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (425 mg, 1.8 mmol), PdCl2(dppf) (65.9 mg, 0.09 mmol), and sodium carbonate (2N aq, 1.35 mL, 2.7 mmol) in THF (5 mL) was heated to 70° C. in a sealed tube. Afte 5 h, the reaction mixture was concentrated under vacuum and purified on silica (EtOAc/Hex, 40-60%) to afford the title compound (241 mg, 92%) as a light yellow solid: LC-MS (ES) m/z=285 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH3:25])[CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH3:25])[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CN(c1ccc([N+](=O)[O-])cc1F)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1ccc([N+](=O)[O-])cc1F)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
tert-Butyl 4-((2-fluoro-4-nitrophenyl)(methyl)amino)piperidine-1-carboxylate (2.83 mmol, 1 g) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum and purified by SCX chromatography to afford the intermediate N-(2-fluoro-4-nitrophenyl)-N-methylpiperidin-4-amine (600 mg).