Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+:15]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH2:8][CH:9]([C:1]3[CH:6]=[CH:5][N:15]=[CH:3][CH:2]=3)[C:10](=[O:13])[NH:11][N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1NN=C(c2ccccc2)CC1c1ccncc1
Reaction time: 8 h
Yield: 50 %

Procedure:
To a 200 ml, three-necked, round-bottomed flask equipped with a magnetic stir bar, 150 ml pressure-equalizing addition funnel, reflux condenser and a glass stopper, was added 21 g (135 mmole) of 4-bromopyridine and 70 of anhydrous THF. The system was oven-dried and flushed with argon before use. 135 ml (135 mmole) of THF solution of phenylmagnesium bromide (1M) was placed in the pressure-equalizing addition funnel. Then, the grignard solution was added dropwise over a period of 10 minutes. After the addition, the reaction was stirred for 15 minutes for completion. The solution of Grignard reagent was then obtained. A solution of 4-pyridylmagnesium bromide obtained above was added to a hot suspension of 6-phenylpyridazinone compound 7.8 g (45 mmole) in dry toluene (50 ml). The mixture was refluxed for 8 h, left overnight at ambient temperature, then decomposed with a saturated solution of ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with 100 ml of ethyl acetate. The solvent was removed and the residue was crystallized from ethanol. The crystals were collected by filtering and dried over a medium frit sintered glass funnel in vacuo to give 5.6 g of white crystals. Yield was 50%, confirmed by ESI-MS. ESI-MS: m/z 252.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:21][O:22]C1C=C([N+]([O-])=O)C=CC=1S(Cl)(=O)=O>>[CH3:21][O:22][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:12])=[O:11]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccccc1C
Yield: 79 %

Procedure:
(RK2-063-03)I This compound was prepared according to the procedure for compound 11a except using 2-methoxy-4 nitrobenzenesulfonyl chloride. Recrystallization from DCM/Hexanes obtained the required product as brown crystals (202 mg, 79%). Mp=127-129° C.; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.8 Hz, 1H), 7.85-7.88 (m, 2H), 7.14-7.11 (m, 2H), 7.06-7.04 (m, 2H), 6.76 (br s, 1H), 4.13 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [CH:1]([NH:3][CH:4]([C:8]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])=O.Cl.[OH-].[Na+].[CH2:23]=O>CC(O)C.C(O)=O.O.CCOCC>[ClH:18].[CH3:1][N:3]([CH:4]([C:8]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])[CH3:23]
Reactant: C=O
Reactant: CCCC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CCOCC
Solvent: CC(C)O
Product: CCCC(N(C)C)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
The product of Example 7 (8.3 g), diethyleneglycoldimethyl ether (50 ml), water (20 ml) and concentrated hydrochloric acid (20 ml) were mixed and heated under reflux for sixteen hours. The mixture was poured into water, aqueous NaOH was added and the product extracted into ether. Evaporation gave a dark oil. A sample of this oil (7.9 g), water (0.7 ml) and formic acid (6.5 ml) were mixed and formaldehyde (6.5 ml) added. The mixture was heated under reflux for three hours and then concentrated hydrochloric acid (10 ml) and propan-2-ol (10 ml) were added. Evaporation to dryness gave N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine hydrochloride (m.p. 195°-196°) as a white solid (Formula I R1 =propyl; R2 =H; R3, R4 =Me; R5 =4--Cl and R6 =3--Cl).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].[CH2:12]([OH:14])[CH3:13]>>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[NH:11])[O:14][CH2:12][CH3:13]
Reactant: CCO
Reactant: N#CCc1ccccc1F
Agent: Cl
Product: CCOC(=N)Cc1ccccc1F
Reaction time: 48 h
Yield: 91.5 %

Procedure:
Dry hydrogen chloride gas (29.8 g, 0.817 mol) was bubbled through a solution of 2-fluorophenylacetonitrile (100 g, 0.743 mol) (Aldrich) in absolute ethanol (37.6 g, 0.817 mol) at 0° C. After uptake of hydrogen chloride was complete, the reaction was kept at 0° C. for 48 hours. The solid was triturated in ether (3×200 mL) and the white solid was collected by suction filtration. Drying for several days under vacuum in a desiccator containing sodium hydroxide pellets and phosphorus pentoxide gave 148 g (91%) of ethyl 2-(2-fluorophenyl)acetimidate hydrochloride, mp. 96°-99° C.; nmr (DMSO-d6)L δ11.58 (br s, 2H, NH2), 6.95-7.50 (complex multiplets, 4H, ArH), 4.40 (q, 2H, OCH2), 4.06 (s, 2H, CH2), 1.24 (t, 3H, CH3); ms: m/e 181 (M+), 162 (M-F+), 153 (M-C2H4 +), 136 (M-OEt+), 109 (C7H6F+).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][O:7][CH:8](OC)[CH2:9][CH:10](OC)OC.C(OC(=O)C)(=O)C>>[CH3:6][O:7][CH:8]=[CH:9][CH:10]=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: COC(CC(OC)OC)OC
Reactant: N#CCC#N
Solvent: CC(=O)OC(C)=O
Product: COC=CC=C(C#N)C#N

Procedure:
A solution of 2.0 g. (31 m moles) of malononitrile and 5 g. (31 m moles) of 1,1,3,3-tetramethoxypropane in 12 ml. of acetic anhydride is heated to reflux for 24 hrs. The reaction mixture is distilled separating the lower boiling by-products and solvent from the product. The product fraction is diluted with water and the resulting precipitate is filtered and recrystallized from isopropanol-water, 1.0 g., m.p. 74°-76°C.
Reaction SMILES: [C:1]([C@:4]1([CH2:38][OH:39])[O:10][C@@:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)O)=[CH:14][CH:13]=2)([OH:9])[C@:7]([C:27](=[O:29])[CH3:28])([OH:26])[C@@:6]([C:31](=[O:33])[CH3:32])([OH:30])[C@@:5]1([C:35](=[O:37])[CH3:36])[OH:34])(=[O:3])[CH3:2].O=S(Cl)[Cl:42]>C(Cl)Cl>[C:1]([C@:4]1([CH2:38][OH:39])[O:10][C@@:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[Cl:42])=[CH:14][CH:13]=2)([OH:9])[C@:7]([C:27](=[O:29])[CH3:28])([OH:26])[C@@:6]([C:31](=[O:33])[CH3:32])([OH:30])[C@@:5]1([C:35](=[O:37])[CH3:36])[OH:34])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)[C@]1(O)[C@](O)(C(C)=O)[C@](CO)(C(C)=O)O[C@](O)(Oc2ccc(C(O)c3ccccn3)cc2)[C@@]1(O)C(C)=O
Solvent: ClCCl
Product: CC(=O)[C@]1(O)[C@](O)(C(C)=O)[C@](CO)(C(C)=O)O[C@](O)(Oc2ccc(C(Cl)c3ccccn3)cc2)[C@@]1(O)C(C)=O
Reaction time: 1 h

Procedure:
Tetraacetyl-(p-(pyridinylhydroxymethyl)phenoxy)-β-galactose (600 mg, 1.1 mmol) is dissolved in 15 ml of CH2Cl2. SOCl2 (143 mg, 88 μl, 1.2 mmol) is added dropwise and the solution is left stirring for 1 hour. The solvent is evaporated under vacuum. The product is obtained pure and quantitatively.
Reaction SMILES: NC1C=CC(CC(OCCCC)=O)=CC=1.[N:16]1([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH2:33]CC)=[O:30])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.S([O-])([O-])(=O)=O>>[N:16]1([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=2)[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: CCCCOC(=O)Cc1ccc(N2CCNCC2)cc1
Agent: CCCCOC(=O)Cc1ccc(N)cc1
Agent: O=S(=O)([O-])[O-]
Product: CCOC(=O)Cc1ccc(N2CCNCC2)cc1

Procedure:
In analogous manner, with the use of n-butyl 4-aminophenylacetate, there is prepared n-butyl 4-(piperazin-1-yl)-phenylacetate; yield 52% of theory of sulphate; m.p. 197°-199° C.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.O.Cl.C(OCC)(=O)C>[C:30]1([NH:29][C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:16][CH2:15]2)=[O:14])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Part A: To a solution of N-Boc-isonipecotic acid (4.85 g, 21.2 mmol) in tetrahydrofuran (80 mL) at 25° C. was added carbonyl diimidazole (3.80 g, 23.3 mmol), and the reaction mixture was stirred for 1.00 h at 25° C. To the resulting mixture was added aniline (2.10 mL, 23.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) (3.20 mL, 21.2 mmol), and the solution was stirred at 25° C. for another 90 h. The reaction mixture was diluted with water, 1.00 N hydrochloric acid (80 mL), and ethyl acetate. The phases were separated, and the organic phase was washed with water (×2) and brine, dried over anhyd. sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% diethyl ether/methylene chloride) furnished tert-butyl 4-(phenylcarbamoyl)-piperidine-1-carboxylate (4.25 g) as a white solid; 1H NMR (300 MHz, CDCl3) δ 7.48 (d, 2H, J=8.0 Hz), 7.29 (t, 2H, J=8.0 Hz), 7.20 (br s, 1H), 7.08 (t, 1H, J=8.0 Hz), 4.16 (m, 2H), 2.75 (m, 2H), 2.35 (m, 1H), 1.89-1.61 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10]([NH:12][N:13]=[C:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+]>C(O)(=O)C.CO>[C:5]([O:9][C:10]([NH:12][NH:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NNC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Sodium cyanoborohydride (6.4 g, 0.101 mol) was added portion-wise to a suspension of 1-cyclopentylidenehydrazine-2-carboxylic acid tert-butyl ester (20 g, 0.101 mol) in a mixture of acetic acid and methanol (288 mL, 1:1). The resulting solution was stirred at RT for 2 h. The reaction mixture was neutralized with 1 N aq NaOH and extracted with CH2Cl2. The organic layer was washed with saturated NaHCO3, dried (Na2SO4) and concentrated under reduced pressure to give 1-cyclopentylhydrazine-2-carboxylic acid tert-butyl ester (18.4 g) as an oil.
Reaction SMILES: N#N.N#N.C1(C[C:12]2(CC3C=CC=CC=3)[CH2:21][CH2:20][CH2:19][C:18]3[N:17]=[C:16]([NH2:22])[C:15]([NH2:23])=[C:14]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:13]2=3)C=CC=CC=1.[C:36](Cl)(=O)[CH:37]([CH3:39])[CH3:38]>>[C:37]1([CH2:39][N:22]([CH2:14][C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:12]=2)[C:16]2[C:15]3[N:23]=[C:36]([CH:37]([CH3:39])[CH3:38])[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:14]=3[C:13]3[CH2:12][CH2:21][CH2:20][CH2:19][C:18]=3[N:17]=2)[CH:38]=[CH:27][CH:26]=[CH:25][CH:36]=1
Reactant: CC(C)CNc1c(N)c(N)nc2c1C(Cc1ccccc1)(Cc1ccccc1)CCC2
Reactant: CC(C)C(=O)Cl
Agent: N#N
Product: CC(C)Cn1c(C(C)C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3c(c21)CCCC3
Yield: 136.7 %

Procedure:
Using the general method of Example 65, N2, N2 -bis(phenylmethyl)-5,6,7,8-tetrahydro-N4 -(2-methylpropyl)quinolin-2,3,4-triamine (0.86 g, 2.1 mmole) was reacted with isobutyryl chloride (0.217 mL, 2.1 mmole) to provide 0.67 g of the desired product as a yellow foam.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C([O-])=O.[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:26]=1[CH:39]1[CH2:43][CH2:42][NH2+:41][CH2:40]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH:1]1([NH:7][C:8]([N:41]2[CH2:42][CH2:43][CH:39]([C:26]3[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:30][C:25]=3[O:24][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:40]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: c1ccc(COc2ccc(C3CC[NH2+]C3)c(OCc3ccccc3)c2)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCC1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
In a 10 ml round-bottomed flask, 0.25 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidinium trifluoroacetate is dissolved in 5 ml of tetrahydrofuran in the presence of 0.25 ml of N,N-diisopropylethylamine. 0.1 g of cyclohexyl isocyanate is added and the reaction mixture is stirred for 30 minutes at ambient temperature. The reaction mixture is extracted with ethyl acetate and the organic phases are then combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (7/3 heptane/ethyl acetate). 0.23 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid cyclohexylamide is obtained. Yield=66%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([CH2:11][C:12]#[N:13])=[N:3]1.[C:14](=O)([O:20]C(C)(C)C)[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:8])([F:9])[F:10])[C:4]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:3]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Cn1cc(C(F)(F)F)c(CC#N)n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1cc(C(F)(F)F)c(CCNC(=O)OC(C)(C)C)n1
Reaction time: 3 h

Procedure:
The [1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]acetonitrile (4.76 mmol, 0.90 g), the di-terbutyl carbonate (9.52 mmol, 2.08 g) and nickel chloride hexahydrate (4.77 mmol, 1.13 g) are added to methanol (10 ml) at room temperature. Sodium borohydride (13.1 mmol, 0.49 g). is added portionwise to the reaction mixture. The reaction mixture is allowed to room temperature and stirred for three hours.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: C1COCCN1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2sccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine 3, (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 as a white solid (11.04 g, 100%). 1H NMR (400 MHz, d6-DMSO) 3.74 (4H, t, J=4.9 Hz), 3.90 (4H, t, J=4.9 Hz), 7.40 (1H, d, J=5.6 Hz), 8.30 (1H, d, J=5.6 Hz).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:18]=[C:12]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[N:21]=1.FC1C=C(F)C=CC=1N1CCN2N=C(COC3C=CC=CC=3)C=C2C1=O>>[Br:19][C:20]1[N:21]=[C:22]([N:14]2[CH2:15][CH2:16][N:11]3[N:10]=[C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:18]=[C:12]3[C:13]2=[O:17])[CH:23]=[CH:24][CH:25]=1
Reactant: Brc1cccc(Br)n1
Reactant: O=C1NCCn2nc(COc3ccccc3)cc21
Agent: O=C1c2cc(COc3ccccc3)nn2CCN1c1ccc(F)cc1F
Product: O=C1c2cc(COc3ccccc3)nn2CCN1c1cccc(Br)n1

Procedure:
The compound was prepared from 2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one and 2,6-dibromopyridine using the method described in the preceding example 43 (5-(2,4-difluoro-phenyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one). 1H NMR (500 MHz, CDCl3) δ ppm 4.48-4.55 (m, 2H), 4.58-4.63 (m, 2H), 5.13 (s, 2H), 6.98 (t, J=7.4 Hz, 1H), 7.01 (d, J=7.8 Hz, 2H), 7.08 (s, 1H), 7.28-7.34 (m, 3H), 7.60 (t, J=7.9 Hz, 1H), 8.09 (d, J=8.1 Hz, 1H).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6]1)([OH:3])=[O:2].[Br:14]Br>C(Cl)Cl>[Br:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][CH2:6][CH:5]([CH2:4][C:1]([OH:3])=[O:2])[C:9]=2[CH:10]=1
Reactant: O=C(O)CC1COc2ccccc21
Reactant: BrBr
Solvent: ClCCl
Product: O=C(O)CC1COc2ccc(Br)cc21
Reaction time: 0.42 h

Procedure:
To a solution of 3-(carboxymethyl)-2,3-dihydro-benzofuran (reference example 16, 1.26 g, 7.7 mmol) in CH2Cl2 (24 mL) is added, dropwise, a solution of Br2 in CH2Cl2 (7 mL, 1 M). On complete addition the solution is stirred for a further 25 min. The reaction mixture is concentrated under vacuum to give the title compound (1.86 g) as a tan solid. 1H NMR (CDCl3) d 2.67 (dd, J=16, 8 Hz, 1H), 2.85 (dd, J=16, 6 Hz, 1H), 3.88 (m, 1H), 4.29 (t, J=8 Hz, 1H), 4.79 (t, J=8 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 7.26 (m, 2H). MS m/z 256/258 Br pattern (M+).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C(C)=CC=CN=1.N[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C=CCCCC.C1(C)C=CC=CC=1>>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cc1cccnc1N
Solvent: C=CCCCC
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)c1ccccc1
Temperature: 130 °C
Reaction time: 0.04 h

Procedure:
Under the same reaction procedure and conditions as in Example 1 (benzaldehyde 0.5 mmol, 2-amino-3-picoline 0.1 mmol, aniline 0.3 mmol, 1-hexene 2.5 mmol, toluene 0.87 mmol), various kinds of acids 0.03 mmol as shown in the following table 4, were added to each 500 ml pressure reactor. The mixture was stirred at normal temperature for 2-3 minutes and then combined with Rh(PPh3)3Cl 0.01 mmol. While the reactor was stopped with a stopper, the reactants were heated at 130° C. for 1 hour with stirring. After completion of the reaction, gas chromatography was conducted to determine the yields of heptanophenone, products from various acids and the results are given in Table 4, below.
Reaction SMILES: I[CH2:2][CH2:3][OH:4].C(=O)(O)[O-].[Na+].[C:10]([C@@H:13]1[CH2:17][C@H:16]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:15][NH:14]1)(=[O:12])[NH2:11]>CN(C)C=O>[C:10]([C@@H:13]1[CH2:17][C@H:16]([S:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:15][N:14]1[CH2:2][CH2:3][OH:4])(=[O:12])[NH2:11]
Reactant: OCCI
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(CCO)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
0.175 ml of 2-iodoethanol and 0.16 g of sodium bicarbonate were added, whilst ice-cooling, to a solution of 0.5 g of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine [prepared as described in Preparation 1-(5)] dissolved in 5 ml of dry dimethylformamide, and the mixture was stirred at the same temperature for 1 hour, at room temperature for 2.5 hours, and at 40° C. for 19 hours. The reaction mixture was then poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was subject to column chromatography through silica gel (Wako Pure Chemicals, Ltd.; wako gel C-100). 0.465 g of the title compound was obtained as crystals from the fractions eluted with a 95:5 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][C:4]2[O:19][CH2:20][O:21][C:3]=2[CH:2]=1.[H][H]>C(O)C.[Pd]>[CH:1]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:12])=[CH:5][C:4]2[O:19][CH2:20][O:21][C:3]=2[CH:2]=1
Reactant: O=C(/C=C/C=C/c1ccc2c(c1)OCO2)N1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(CCCCc1ccc2c(c1)OCO2)N1CCCCC1
Yield: 78.5 %

Procedure:
Piperine (2 g, 7 mmol) was hydrogenated in ethanol (50 ml) over 5% Pd—C under a pressure of hydrogen at 10 psi for 30 mins to give tetrahydropiperine (1.59 g, 78% yield) as an oil2.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:5][C:6](=[O:14])[CH:7]=[C:8]([S:12][CH3:13])[C:9]=1[C:10]#[N:11].Br[CH2:16][C:17]([NH2:19])=[O:18].Cl>CN(C=O)C>[C:10]([C:9]1[C:8]([S:12][CH3:13])=[CH:7][C:6](=[O:14])[NH:5][C:4]=1[S:3][CH2:16][C:17]([NH2:19])=[O:18])#[N:11]
Reactant: NC(=O)CBr
Reactant: CSc1cc(=O)[nH]c(S)c1C#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(=O)[nH]c(SCC(N)=O)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
NaH (2.60 g, 65.0 mmol) was added to a solution of 2-mercapto-4-methylsulfanyl-6-oxo-1,6-dihydro-pyridine-3-carbonitrile (12.5 g, 63 mmol) in DMF (300 mL) cooled in an ice water bath. The mixture was stirred for 30 min then 2-bromoacetamide was added (8.80 g, 64 mmol) as a solid in one portion. The mixture was slowly warmed to room temperature and stirred for 15 h then poured onto ice water. The mixture was acidified with 2N HCl, filtered, and the resulting precipitate was washed with diethyl ether then hexanes to provide 11.3 g (70%) of 2-(3-cyano-4-methylsulfanyl-6-oxo-1,6-dihydro-pyridin-2-ylsulfanyl)-acetamide as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[C:4](=[O:13])[CH:3]=1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>CN(C)C=O>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[C:4](=[O:13])[CH:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ccn(-c2ccsc2)c(=O)c1
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccn(-c2ccsc2)c(=O)c1
Temperature: 100 °C

Procedure:
A mixture of 4-methyl-1-(3-thienyl)pyridin-2(1H)-one (0.73 g, 3.8 mmol), tert-butoxybis(dimethylamino)methane (3 mL, 15 mmol), and N,N-dimethylformamide (4 mL) is heated in a 100° C. oil bath for 3 hours and then concentrated to dryness under reduced pressure. A quantitative yield of 4-(2-dimethylamino-vinyl)-1-thiophen-3-yl-1H-pyridin-2-one is assumed, and the material is carried on without further purification.
Reaction SMILES: [CH3:1][CH2:2][C:3]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:11])[NH:9][C:7](=[O:8])[NH:6]C1=O.[OH-].[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]>CN(C)C=O>[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:9]1[C:10](=[O:11])[C:3]([C:2]2[CH:1]=[CH:10][CH:3]=[CH:2][CH:1]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:6][C:7]1=[O:8])([OH:27])=[O:26]
Reactant: O=C(O)CCCCBr
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)CCCCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O

Procedure:
The DppE amide of 1-(4-carboxybutyl)-5-ethyl-5-phenyl barbituric acid (DPPE-phenobarbital) was prepared as outlined in FIG. 2. The sodium salt of phenobarbital (compound A) (2 mmoles) formed by treating phenobarbital with sodium hydroxide was reacted with the methyl ester of 5-bromovaleric acid (2.200 mmoles) in 5 ml of N,N-dimethyl formamide, for 4 hrs at 96° C., to form the methyl ester of 1-(4-carboxybutyl)-5-ethyl-5-phenyl barbiturate (compound B). The product was purified by column chromatography at a yield of about 77%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17](=O)[CH2:18][CH3:19])(C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[CH2:18]([C:17]1[NH:7][C:8]2[C:9]([CH:16]=1)=[CH:10][CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)[CH3:19]
Reactant: CCC(=O)Cc1ccc(OC)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCc1cc2ccc(OC)cc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 166.9 %

Procedure:
To a solution of [5-methoxy-2-(2-oxo-butyl)-phenyl]-carbamic acid t-butyl ester 73b (1.36 g, 4.65 mmole) in 10 ml THF was added 4 ml TFA. The reaction mixture was stirred at room temperature for 5 h, quenched with 50 ml H2O and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (10-15% EtOAc in hexane) to give pale yellow solid (1.36 g, 73%). 1H NMR (CDCl3) δ7.75 (1H, bs), 7.49 (1H, d, J=8.6 Hz), 6.81 (1H, s), 6.73 (1H, d, J=8.6 Hz), 3.83 (3H, s), 2.75 (2H, q, J=7.5 Hz), 1.32 (3H, t, J=7.5 Hz). ESIMS (MH+): 272.10.