Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[CH:16][N:17]2[C:22]=1[C:21](=[O:23])[NH:20][C:19]([CH3:24])=[N:18]2)=[O:13])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[CH:16][N:17]2[C:22]=1[C:21](=[O:23])[N:20]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:19]([CH3:24])=[N:18]2)=[O:13])[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccn2nc(C)[nH]c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccn2nc(C)n(Cc3ccccc3)c(=O)c12
Temperature: 95 °C
Yield: 71 %

Procedure:
Benzyl bromide (0.112 ml, 0.945 mmol) was added to a solution of 2-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid ethyl ester (0.19 g, 0.86 mmol) and Cs2CO3 (0.34 g, 1.06 mmol) in dioxane (5 mL) and the reaction mixture was heated to 95° C. for 3 h. The reaction mixture was quenched with saturated NaCl (100 mL), extracted with CHCl3 (3×50 mL), the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 1/1 hexane/EtOAc to afford the title compound as a solid (0.19 g, 70%): 1H NMR (CDCl3) δ 7.22–7.35 (m, 6H), 7.00–7.01 (m, 1H), 5.28 (s, 2H), 4.38 (q, 2H, J=7.19 Hz), 2.38 (s, 3H), 1.38 (t, 3H, J=7.09 Hz); MS (ESI+) 312 (M++H).
Reaction SMILES: [O:1]=[C:2]([C@H:23]([CH3:70])[C@@H:24]([O:61][C:62]([O:64][CH2:65][C:66]([Cl:69])([Cl:68])[Cl:67])=[O:63])[C@@H:25]([CH3:60])[CH2:26]/[CH:27]=[CH:28]/[C:29](/[CH3:59])=[CH:30]\[CH2:31][C@H:32]([O:51][Si](CC)(CC)CC)/[C:33](/[CH3:50])=[CH:34]/[C:35]1[N:36]=[C:37]([CH2:40][O:41][C:42]([O:44][CH2:45][C:46]([Cl:49])([Cl:48])[Cl:47])=[O:43])[S:38][CH:39]=1)[C:3]([CH3:22])([CH3:21])[C@@H:4]([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O.Cl.P([O-])([O-])([O-])=O>C(Cl)Cl.C(OCC)(=O)C>[O:1]=[C:2]([C@H:23]([CH3:70])[C@@H:24]([O:61][C:62]([O:64][CH2:65][C:66]([Cl:67])([Cl:68])[Cl:69])=[O:63])[C@@H:25]([CH3:60])[CH2:26]/[CH:27]=[CH:28]/[C:29](/[CH3:59])=[CH:30]\[CH2:31][C@H:32]([OH:51])/[C:33](/[CH3:50])=[CH:34]/[C:35]1[N:36]=[C:37]([CH2:40][O:41][C:42]([O:44][CH2:45][C:46]([Cl:47])([Cl:48])[Cl:49])=[O:43])[S:38][CH:39]=1)[C:3]([CH3:22])([CH3:21])[C@@H:4]([O:13][Si:14]([CH2:19][CH3:20])([CH2:15][CH3:16])[CH2:17][CH3:18])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC[Si](CC)(CC)O[C@@H](C/C=C(C)\C=C\C[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)OC(C)(C)C)O[Si](CC)(CC)CC)/C(C)=C/c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC[Si](CC)(CC)O[C@@H](CC(=O)O)C(C)(C)C(=O)[C@H](C)[C@@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C/C=C/C(C)=C\C[C@H](O)/C(C)=C/c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reaction time: 10 h

Procedure:
A solution of tert-butyl (3S,6R,7S,8S,10E,12Z,15S,16E)-5-oxo-3,15-bis(triethylsilyloxy)-17-(2-(2,2,2-trichloroethoxycarbonyloxymethyl)thiazol-4-yl)-4,4,6,8,12,16-hexamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-heptadeca-10,12,16-trienoate (2.8 g) in 12 mL of CH2Cl2 is treated with 2,6-lutidine (0.86 mL) and triethylsilyl trifluoromethanesulfonate (0.98 g) at 0° C. for 30 minutes, then at ambient temperature for 10 hours. The mixture is diluted with 50 mL of ethyl acetate and poured into 20 mL of 1 N HCl. The organic phase is separated, washed with pH 7 phosphate buffer, dried with Na2SO4, filtered, and concentrated. The residue is dissolved in 5 mL of THF and treated with 0.5 mL of 0.1 N HCl in methanol. The reaction is monitored by thin-layer chromatography, with additional aliquots of methanolic HCl being added to achieve complete reaction. When complete, the reaction is poured into 15 mL of pH 7 phosphate buffer and extracted with ethyl acetate. The extract is washed with brine, dried with Na2SO4, filtered, and evaporated. The product is purified by flash chromatography on SiO2 (1:1 hexanes/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[S:25]1[C:29]([CH:30]=O)=[CH:28][C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]1=2>>[S:25]1[C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[CH:28]=[C:29]1[CH2:30][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[N:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: O=Cc1cc2ccccc2s1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Clc1cccc2c(-c3cccc(NCc4cc5ccccc5s4)c3)c(-c3ccccc3)nnc12

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and benzo[b]thiophene-2-carbaldehyde according the procedure of Example 5 Step 5. MS (ES) m/z 478.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.Cl.[NH2:18]O>CO>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=2)[O:14][N:18]=1)=[O:16]
Reactant: NO
Reactant: COC(=O)C(=O)CC(=O)c1cccc(Br)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2cccc(Br)c2)on1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.4 %

Procedure:
To a suspension of 2,4-dioxo-4-(3-bromophenyl)-butyric acid methyl ester (10.3 g, 36.1 mmol) in anhydrous MeOH (100 mL) was added hydroxylamine hydrochloride (3.8 g, 54.2 mmol). The mixture was then refluxed for 90 min. The reaction mixture was then cooled to room temperature, and ice/water mixture (200 mL) was added. The mixture was stirred for 20 minutes, filtered through a Buchner funnel and washed with cold water. The light yellow solid was dried in vacuum oven to provide the title compound (8.9 g, 87% yield).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].CCCCCCCCCCCCCC(NCC(N[C@H](C(N[C@H](C(N[C@H](C(N1[C@H](C(N2[C@H](C(N[C@H](C(N3[C@H](C(N4[C@H](C(N[C@H](C(N[C@H](C(N5[C@H](C(N)=O)CCC5)=O)C[O:100][P:101](O)([OH:103])=[O:102])=O)CCC(N)=O)=O)CCC4)=O)CCC3)=O)C)=O)CCC2)=O)CCC1)=O)C)=O)CCC(O)=O)=O)CCCCN)=O)=O>>[CH2:11]([O:12][P:101]([OH:103])([OH:102])=[O:100])[C@H:9]1[O:10][C@@H:2]([OH:1])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: CCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](COP(=O)(O)O)C(=O)N1CCC[C@H]1C(N)=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=P(O)(O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
HEK 293 cells were grown in 10 cm plates with Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal calf serum (FCS). On the day of the experiment, cells were incubated with low glucose medium supplemented with 0.5% FCS for 1 hour, followed by the addition of the conjugate L803-mts or its respective controls LE803-mts and LS803-mts at various concentrations, for additional 2.5 hours. A vehicle control of DMSO (0.1% DMSO) was also tested. Cells were thereafter washed twice with ice-cold GS buffer (50 mM Tris, pH=7.8, 100 mM NaF, 10 mM EDTA with protease inhibitors: 20 μg/ml leupeptine, 10 μg/ml aprotinine, 10 mg/ml pepstatin A, 1 mM benzamidine), scraped with the same buffer, and frozen in liquid nitrogen (as described in Eldar-Finkelman et al., 1996). Glycogen synthase activity was assayed according to the method of Thomas et al. (1968), based on the incorporation of uridine 5-diphosphate [14C] glucose (UDPG) into glycogen. Aliquots of cell lysates (15 μl) were incubated with 15 μl reaction mixture (66.6 mM Tris, pH=7.8, 32.5 mM KF, 0.8 μCi/μl [14C]-UDPG (400 μM), 13 mg/ml glycogen rabbit liver, Sigma) for 20 minutes at 30° C. (as described in Eldar-Finkelman et al., 1996). The reactions were then spotted on ET31 (Whatman) papers, washed with 66% ice-cold ethanol, and counted for radioactivity. Glycogen synthase assays were measured in the presence of 0.1 mM glucose-6-phosphate (G6P). Similar results were obtained when G6P was absent in the assays (data not shown).
Reaction SMILES: [O-2].[Zn+2:2].[C:3]([OH:7])(=[O:6])[CH:4]=[CH2:5].[C:8]([O:12]CC)(=[O:11])[CH:9]=[CH2:10]>C1(C)C(C)=CC=CC=1.C(O)CCC.C1(C)C(C)=CC=CC=1.C(O)CCC.O>[C:3]([O-:7])(=[O:6])[CH:4]=[CH2:5].[Zn+2:2].[C:8]([O-:12])(=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)OCC
Reactant: C=CC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Solvent: CCCCO
Solvent: Cc1ccccc1C
Product: C=CC(=O)[O-]
Temperature: 95 °C

Procedure:
A zinc acrylate polymer was prepared by the reaction of zinc oxide and naphthenic acid (acid value 200 mgKOH/g) with a carboxylic acid functional acrylic copolymer based on the monomers; Acrylic acid (18.4 mol %), ethyl acrylate (80.35 mol %) and, methoxy polyethyleneglycol methacrylate (MPEG350) (1.25 mol %). These components were mixed at a 1:1:1 molar ratio (Zinc oxide:Naphthenic acid:polymer carboxylic acid groups) in xylene/n-butanol (4:1 weight ratio) and heated and stirred at 95° C. until a clear solution was obtained resulting in a solution of zinc acrylate polymer of 45 wt % in xylene/n-butanol/water (43.3:10.8:0.9 wt %).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]=[CH2:12])[CH2:5][OH:6].[N+:13]([O-])([OH:15])=[O:14].[OH-].[Na+]>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([C:7]([N+:13]([O-:15])=[O:14])=[CH:8][C:9]=1[CH2:10][CH:11]=[CH2:12])[CH2:5][OH:6]
Reactant: O=[N+]([O-])O
Reactant: C=CCc1ccc(CO)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C=CCc1cc([N+](=O)[O-])c(CO)cc1O
Reaction time: 0.33 h
Yield: 43.7 %

Procedure:
8.40 g of 3-hydroxy-4-(2-propenyl)benzylalcohol (Tetrahedron, 56 (2000), 1873) was dissolved in 70 ml of acetic acid. Thereafter, 4.14 g of concentrated nitric acid and 0.6 ml of fuming nitric acid were added to the reaction solution while cooling on ice, and the obtained mixture was stirred at the same temperature for 20 minutes. Thereafter, the reaction solution was adjusted to be pH 6 with addition of a 5 N sodium hydroxide aqueous solution, while cooling on ice. It was then extracted with ethyl acetate. The extract was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 4.68 g of 3-hydroxy-6-nitro-4-(2-propenyl)benzylalcohol.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CN1CCNCC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN(C)CC3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using the product of Example 75 step i) and 1-methyl-piperazine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C@@H:10]12[C:19](=O)[O:18][C:16](=[O:17])[C@@H:11]1[CH2:12][CH:13]=[CH:14][CH2:15]2.[BH4-].[Na+].Cl>O.CC(O)C>[OH:18][CH2:19][CH:10]1[CH:11]([C:16]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:17])[CH2:12][CH:13]=[CH:14][CH2:15]1
Reactant: NCCN1CCCCC1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C(NCCN1CCCCC1)C1CC=CCC1CO
Temperature: 140 °C
Reaction time: 6 h

Procedure:
N-(2-Aminoethyl)piperidine (2.11 g) was added to cis-4-cyclohexene-1,2-dicarboxylic anhydride (2.50 g) and stirred for 6 hours at 140° C. The reaction mixture was suspended into a mixed solution of 2-propanol (125 ml) and water (21 ml) and then sodium borohydride (3.12 g) was added thereto at room temperature. After being stirred for 68 hours at room temperature, the reaction mixture was acidified with dilute hydrochloric acid and then concentrated. The residue was adjusted to pH 9 with saturated sodium hydrogencarbonate aqueous solution and 1N sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate anhydride, and concentrated, thereby yielding a crude (3.34 g) containing the entitled compound as brown syrup.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:15]=O)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:19])[CH3:18]>>[CH2:17]([N:19]([CH2:15][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH3:18]
Reactant: CCN
Reactant: COC(=O)C[C@@H](C=O)NC(=O)OC(C)(C)C
Product: CCN(CC(CC(=O)OC)NC(=O)OC(C)(C)C)CC(CC(=O)OC)NC(=O)OC(C)(C)C

Procedure:
The product from Example 16A and ethylamine were processed as described in Example 7B to provide the title compound.
Reaction SMILES: [CH:1]([S:4]Cl)([CH3:3])[CH3:2].[C:6]1([NH:12][P:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[CH:1]([S:4][N:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[P:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)SCl
Reactant: O=P(Nc1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)SN(c1ccccc1)P(=O)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 11.1 parts of isopropyl sulphenyl chloride in 100 parts of carbon tetrachloride is added to a suspension of 30.9 parts of N,P,P-triphenylphosphinic amide and 10.0 parts of triethylamine in 150 parts of carbon tetrachloride at room temperature. The mixture is stirred for a further 1 hour. The triethylamine hydrochloride is filtered off and the filtrates evaporated under reduced pressure to give a white solid. This is recrystallised from methylated spirits to yield 16.5 parts of N-isopropylthio-N,P,P-triphenylphosphinic amide as a colourless solid m.p. 148°-150°C. Found, C, 67.2; H. 6.2; N, 4.0; P, 8.1 percent, C21H22NOPS requires C, 68.7; H, 6.0; N, 3.8; P, 8.45 percent. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [OH-].[K+].Cl.[CH2:4]([NH2:6])[CH3:5].[CH2:7]([N:14]1[CH2:19][CH2:18][C:17](=O)[C:16]([CH3:22])([CH3:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([BH3-])#N.[Na+]>CO>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([NH:6][CH2:4][CH3:5])[C:16]([CH3:22])([CH3:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCN
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Product: CCNC1CCN(Cc2ccccc2)CC1(C)C
Reaction time: 0.5 h

Procedure:
Potassium hydroxide (4.6 g, 83.0 mmol) was added to the stirred solution of ethylamine hydrochloride (6.8 g, 83.0 mmol) in methanol (70 ml) and stirring was continued for 30 min at 30° C. 1-benzyl-3,3-dimethyl-4-piperidone (3.5 g, 16.6 mmol)), was added to the resulting mixture and stirred for 6 hr. Sodium cyanoborohydride (1.0 g, 16.6 mmol) was added to it and reaction mixture was stirred for 15 hr. The reaction mixture was concentrated to dryness, triturated with water, extracted with chloroform, dried (Na2SO4) and concentrated to give 1-benzyl-4-ethylamino-3,3-dimethylpiperidine. Yield 3.8 g (88%), C16H26N2, m/z 247 (M+1), PMR (CDCl3): 0.9 (s, 3H), 1.06 (s, 3H), 1.18-1.38 (m, 5H), 1.64-2.8 (m, 6H), 2.94 (m, 1H), 3.44 (dd, 2H), 7.2 (m, 5H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[H-].[Na+].[CH3:14][N:15]1[C:20]([CH3:21])=[CH:19]C(=O)[O:17][C:16]1=O>O1CCCC1>[CH3:14][N:15]1[C:20]([CH3:21])=[CH:19][C:3]([OH:5])=[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:16]1=[O:17]
Reactant: Cc1cc(=O)oc(=O)n1C
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
At room temperature, 1 ml of a solution of 0.71 g diethyl malonate in tetrahydrofuran was added to a mixture of 0.19 g of sodium hydride and 4 ml of tetrahydrofuran and the mixture was stirred for 20 minutes. At room temperature, 3 ml of a solution of 0.59 g 3,4-dimethyl-2H-1,3-oxazine-2,6(3H)-dione in tetrahydrofuran was added to the mixture, followed by stirring for 2 hours under heat refluxing condition. The reaction mixture was concentrated under reduced pressure. To the residue, 10 ml of water and 12 ml of 2 mol/L hydrochloric acid were added, followed by extraction with ethyl acetate. The organic layer was dried with magnesium sulfate, then filtered and concentrated to obtain 0.57 g of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate represented by the formula:
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH2:18]([C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)=[CH:26]1)[CH2:10][C:9]([OH:42])=[O:8])[CH2:16][OH:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 20 h
Yield: 83.6 %

Procedure:
A suspension of 10% Pd/C (wet DeGussa type, 15 mg) and N-(1(S)-benzyl-2-hydroxyethyl)-3 (R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester (68 mg, 0.12 mmol) in EtOAc (5 mL) was stirred under H2 for 20 hours. The catalyst was filtered onto Celite and rinsed with MeOH. The filtrate was concentrated under reduced pressure to give a yellow oil, which was purified via flash column chromatography with a 1% HOAc/2-5% MeOH/CH2Cl2 stepwise gradient elution to provide 47 mg (82%) of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid as a white solid.
Reaction SMILES: CO.[CH2:3]([O:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])[CH2:4][CH2:5][CH3:6].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.C[O-].[Na+]>O>[C:24]1([CH3:23])[CH:29]=[CH:28][C:27]([S:30][C:13]2[C:8]([O:7][CH2:3][CH2:4][CH2:5][CH3:6])=[C:9]([N+:20]([O-:22])=[O:21])[CH:10]=[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(S)cc1
Reactant: CCCCOc1cc([N+](=O)[O-])c(OCCCC)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCOc1cc(Sc2ccc(C)cc2)c(OCCCC)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 110 parts of methanol was added 51 parts of 2,5-dibutoxy-4-chloronitrobenzene, and the mixture was warmed to 50° C. A methanol (50 parts) solution of 21.5 parts of p-thiocresol and 9.8 parts of sodium methylate was added dropwise thereto over a period of about one hour to carry out a reaction therebetween. After completion of the dropwise addition, the reaction was further continued under reflux for 5 hours. After completion of the reaction, 85 parts of water was added to the reaction mixture to precipitate a crystal. The crystal was recovered by filtration and recrystallized from methanol to obtain 58.5 parts of 4-tolylthio-2,5-dibutoxynitrobenzene (m.p.: 44° to 45° C.).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]1([C:14]([CH2:19][CH2:20][Cl:21])([CH2:17][CH3:18])[C:15]#[N:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.C12CCC(CC1)CN2.C1(C(C2C=CC=CC=2)(CCBr)C#N)C=CC=CC=1>>[ClH:21].[C:8]1([C:14]([CH2:19][CH3:20])([CH2:17][CH2:18][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:15]#[N:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC(C#N)(CCCl)c1ccccc1
Reactant: C1CCNCC1
Agent: C1CC2CCC1CN2
Agent: Cl
Agent: N#CC(CCBr)(c1ccccc1)c1ccccc1
Product: CCC(C#N)(CCN1CCCCC1)c1ccccc1

Procedure:
When equivalent quantities of piperidine hydrochloride and 2-phenyl-2-(2-chloroethyl)butyronitrile are substituted for the 2-azabicyclo[2.2.2]octane hydrochloride and 2,2-diphenyl-4-bromobutyronitrile used in Example 12, and the procedure described therein substantially repeated, there is obtained 2-phenyl-2-ethyl-4-piperidino-butyronitrile hydrochloride melting at about 200° - 203° C.
Reaction SMILES: N.O1CCOCC1.C([N:10](CC)CC)C.[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C@@H:27]2[C:32]([C:33]#[N:34])=[C:31]([CH3:35])[N:30]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:29](=[O:46])[NH:28]2)=[C:21]([S:23](Cl)(=[O:25])=[O:24])[CH:22]=1)#[N:16]>C(#N)C>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C@@H:27]2[C:32]([C:33]#[N:34])=[C:31]([CH3:35])[N:30]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:29](=[O:46])[NH:28]2)=[C:21]([S:23]([NH2:10])(=[O:25])=[O:24])[CH:22]=1)#[N:16]
Reactant: CCN(CC)CC
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: N
Solvent: CC#N
Solvent: C1COCCO1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(N)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
At room temperature, a 0.5 M solution of ammonia in dioxane (25.79 ml, 12.9 mmol; 10 eq.) and triethylamine (130 mg, 1.3 mmol; 1 eq.) were added to 5-cyano-2-{(4S)-5-cyano-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (3.10 g, content 20%, 1.29 mmol), and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure, water/acetonitrile (˜10:1) was added to the residue and the solution was lyophilized. The substance obtained was dissolved in acetonitrile and then purified by preparative HPLC (column: Waters Sunfire C18, 5 μm; column dimensions: 250 mm×20 mm; detection: 240 nm; temperature: 28° C.; flow rate: 25 ml/min; injection volume: 500 μl; mobile phase: acetonitrile/0.2% trifluoroacetic acid 45:55). The title compound was obtained as a solid (0.155 g, 26% of theory).
Reaction SMILES: Br[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[O:15]>>[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:18][CH:17]=1)(=[O:15])[CH3:13]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Product: CCOC(=O)C(Oc1ccc(C(C)=O)cc1)C(=O)OCC

Procedure:
Diethyl bromomalonate was reacted with 4-hydroxyacetophenone to give diethyl 4-acetylphenoxymalonate by the procedure described for the preparation of isopropyl 4-acetylphenoxyacetate.