Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][N+:15]([CH3:18])=[CH:16]Cl.[Cl-]>>[CH3:14][N:15]([CH3:18])[CH:16]=[C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH:11]=[O:13]
Reactant: C[N+](C)=CCl
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Product: CN(C)C=C(C=O)c1ccc([N+](=O)[O-])cc1

Procedure:
p-Nitrophenylacetic acid is treated with Vilsmeier reagent to give 3-(dimethylamino)-2-(4-nitrophenyl)-2-propenal. This product is treated with cyanoacetiamide and sodium methoxide to give 1,2-dihydro-5-(4-nitrophenyl)-2-oxo-3-pyridinecarbonitrile. The preceding product is hydrolyzed with 1:1 concentrated hydrochloric acid-acetic acid to give 1,2-dihydro-5-(4-nitrophenyl)-2-oxo-3-pyridinecarboxylic acid. The above product is boiled with quinoline to give 5-(4-nitrophenyl)-2(1H)-pyridone. When the preceding product is treated with phosphorus oxychloride, 2-chloro-5-(4-nitrophenyl)pyridine is obtained. This product is treated with hydrazine to give 2-hydrazino-5-(4-nitrophenyl)pyridine. The above product is treated with ethyl orthoacetate to give the product of the Example.
Reaction SMILES: [C:1]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][NH2:15])=[CH:13][C:8]=2[CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]([CH3:21])=O>>[C:1]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][N:15]=[C:19]([CH3:21])[CH3:18])=[CH:13][C:8]=2[CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)N1CCc2nnc(NN)cc2C1
Reactant: CC(C)=O
Product: CCCC(=O)N1CCc2nnc(NN=C(C)C)cc2C1

Procedure:
A solution of 3.5 g of crude oily 6-butyryl-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 20 cc of acetone is heated to the boil at reflux on a water bath for 20 minutes. The title compound has a M.P. of 152°-154° (decomp., from acetone).
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:14]4[CH:15]=[N:16][NH:17][C:13]=4[N:12]=[CH:11][C:7]=3[C:8](=[O:10])[NH:9][C:4]2=[N:3][CH:2]=1.C(N1C2N=CC3C(=O)NC4N(N=CN=4)C=3C=2C=N1)C.[CH2:37](I)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CI>>[C:38]1([CH2:37][N:9]2[C:8](=[O:10])[C:7]3[CH:11]=[N:12][C:13]4[NH:17][N:16]=[CH:15][C:14]=4[C:6]=3[N:5]3[N:1]=[CH:2][N:3]=[C:4]23)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: ICc1ccccc1
Reactant: O=c1[nH]c2ncnn2c2c1cnc1[nH]ncc12
Agent: CCn1ncc2c1ncc1c(=O)[nH]c3ncnn3c12
Solvent: CI
Product: O=c1c2cnc3[nH]ncc3c2n2ncnc2n1Cc1ccccc1

Procedure:
By substituting the 4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one of Example 11 for the 8-ethyl -4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[1,5-a]pyrimidin-5(8H)-one and benzyl iodide for the methyl iodide in the procedure of Example 4, 4-phenylmethyl4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [CH3:1][Mg]Cl.[F:4][C:5]1[C:10]([C:11]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1>C1COCC1>[F:4][C:5]1[C:10]([C:11]2[CH2:16][CH2:15][CH2:14][C:13]([CH3:1])([OH:17])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: C[Mg]Cl
Reactant: O=C1C=C(c2cccnc2F)CCC1
Solvent: C1CCOC1
Product: CC1(O)C=C(c2cccnc2F)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 3.0 M solution of methylmagnesium chloride in tetrahydrofuran (4.88 mL, 14.64 mmol) was added slowly to a solution of 3-(2-fluoropyridin-3-yl)cyclohex-2-enone (2.00 g, 10.46 mmol) in THF (20 ml) at −78° C. After completion of the addition the reaction mixture was stirred overnight while it gradually warmed up to RT. It was cooled in an ice water bath and distilled water (5 ml) was added slowly. The mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate (200 ml) was added, and it was extracted EtOAc (3×100 ml). The combined organic layers were washed by brine and dried over sodium sulfate. Filtration and concentration under reduced pressure gave (rac)-3-(2-fluoropyridin-3-yl)-1-methylcyclohex-2-enol as a light yellow liquid. MS (ESI, pos. ion) m/z: 208.0 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH:13]([OH:14])[CH2:12][C:11]([CH3:16])([CH3:15])[NH:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19](O)=O.C=O.[OH-].[Na+]>O1CCOCC1>[CH:1]1([CH2:7][CH:8]2[CH:13]([OH:14])[CH2:12][C:11]([CH3:16])([CH3:15])[N:10]([CH3:19])[C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CO
Reactant: CC1(C)CC(O)C(CC2CCCCC2)C(C)(C)N1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1C(C)(C)CC(O)C(CC2CCCCC2)C1(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Into a 100 ml-flask equipped with a thermometer, a cooling tube, a dropping funnel and a magnetic stirrer were introduced 3.8 g (15 mmol) of 3-cyclohexylmethyl-2,2,6,6-tetramethyl-4-piperidinol prepared in Example B1, 70 ml of dioxane and 0.78 g (17 mmol) of formic acid, and the content of the flask was heated to 80° C. When the temperature of the content of the flask was constant, 2.44 g (30 mmol) of 37% aqueous formaldehyde dissolved in 20 ml of dioxane was added gradually through the dropping funnel, followed by heating at the temperature for 10 hours. The content of the flask was cooled to room temperature, and 5% aqueous NaOH was added so that the pH became 8, followed by extraction with 200 ml of diethylether. The extract obtained was washed with 30 ml of water 3 times, 10 g of magnesium sulfate was added and, after it was kept standing for ca. 2 hours, the solution was filtered and concentrated to give 3.95 g (yield: 98%) of the title compound as a white solid product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].COC(OC)N(C)C.[CH3:19][OH:20]>>[N:8]1[CH:9]=[CH:10][C:5]([C:1](=[O:4])[CH:2]([CH3:3])[CH:19]=[O:20])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccncc1
Reactant: CO
Agent: COC(OC)N(C)C
Product: CC(C=O)C(=O)c1ccncc1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 4-propionylpyridine (5 g, 36.99 mmol) and dimethylformamide dimethylacetal(10 mL, 75.28 mmol) was heated to reflux overnight. After cooling to room temperature, methanol generated in situ was removed from reaction mixture under reduced pressure, providing a brown color solid. The crude product was purified by column chromatography (silica gel, 3:7 EtOAc/haxane) to give the named compound (5.73 g, 81%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.C(Cl)(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][N:6]2[C:7]3[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(CCCOS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cccc2c1ccn2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.2 %

Procedure:
To a stirred solution of 4-methyl-1H-indole (1.0 g, 7.62 mmol) in DMF (20 mL), cooled at 0° C., was added NaH (60% in mineral oil; 0.40 mg, 9.91 mmol). After 45 min at 0° C., a solution of 4-(3-methanesulfonyloxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester (2.44 g, 7.62 mmol) in DMF (10 mL) was added dropwise. The mixture was warmed to rt and stirred for 18 h. The mixture was diluted with CHCl3 (100 mL) and washed with water (100 mL). The organic layer was dried and concentrated to obtain the crude residue which was purified by FCC (EtOAc/hexanes) to give 1.50 g (55%) of a colorless oil. 1H NMR (CD3OD): 7.17 (d, J=8.2, 1H), 7.13-7.09 (m, 1H), 7.07 (d, J=3.2, 1H), 6.90 (d, J=6.9, 1H), 6.49 (d, J=3.2, 1H), 4.09 (t, J=7.1, 1H), 2.68-2.57 (m, 2H), 2.55 (s, 3H), 1.90-1.79 (m, 2H), 1.64-1.55 (m, 2H), 1.44 (s, 9H), 1.40-1.21 (m, 3H), 1.13-0.98 (m, 1H).
Reaction SMILES: C1CN2C(=NCCC2)C1.[C:10](O)([C:12]([F:15])([F:14])[F:13])=[O:11].O.[CH:18]([O:20][CH2:21][CH3:22])=[CH2:19]>C1CCCCC1.CCCCC.CCCCCC.ClCCl>[CH3:22][CH2:21][O:20]/[CH:18]=[CH:19]/[C:10]([C:12]([F:15])([F:14])[F:13])=[O:11]
Reactant: C=COCC
Reactant: O=C(O)C(F)(F)F
Agent: C1CN=C2CCCN2C1
Solvent: C1CCCCC1
Solvent: CCCCC
Solvent: CCCCCC
Product: CCO/C=C/C(=O)C(F)(F)F

Procedure:
To begin with, DBN×TFA was prepared in a 250 ml 3-neck flask with a water-cooled condenser. For this purpose, dichloromethane and DBN were added to the flask, and TFA was added dropwise with stirring. Since the reaction is strongly exothermic, the flask was cooled in a water bath to prevent excessive heating. Subsequently, ethyl vinyl ether was added, and TFAH was added dropwise with stirring. The formulation turned yellow. Subsequently, stirring was continued for 1½ hours at room temperature, after which time a sample was taken for gas chromatographic (GC) analysis (sample was hydrolyzed). The ethyl vinyl ether had reacted completely. The dichloromethane was evaporated under vacuum at room temperature in a rotary evaporator, and the remaining solution was divided into partial volumes and extracted with different solvents, which formed two phases. Hexane, pentane, cyclohexane and 113 were used as two-phase extraction agents. The total yield of ETFBO isolated was 91%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[CH2:19]([N:21]([CH2:31][CH3:32])[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=1)[CH3:20].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:31]([N:21]([CH2:19][CH3:20])[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[CH:25][CH:24]=1)[CH3:32]
Reactant: CCCN1CCC(Nc2cccc(OC)c2)CC1
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCN1CCC(N(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(OC)c2)CC1
Yield: 53.6 %

Procedure:
A solution of 3.5 g (14.1 mmol) of N-(3-methoxyphenyl)-1-propyl-4-piperidinamine, 3.61 g (14.1 mmol) of N,N-diethyl-4-bromobenzamide, 129 mg (0.141 mmol) tris(dibenzylideneacetone)-dipalladium(0) (Pd2dba3), 263 mg (0.423 mmol) of (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (+BINAP) and 1.89 g (19.7 mmol) of sodium t-butoxide in 25 mL of dry toluene was heated at 110° C. under Ar in a pressure vessel for 16 h. The mixture was cooled and partitioned between CH2Cl2 and H2O. The organic layer was washed with brine, dried (K2CO3) and the solvent was evaporated. The residue was chromatographed on a Biotage Flash 75 unit using CH2Cl2:MeOH:NH4OH, 92:8:0.8 as eluent. There was obtained 3.2 g (53% yield) of N,N-diethyl-4-[3-methoxyphenyl(1-propylpiperidin-4yl)amino]benzamide as a solid. A fumarate salt was prepared out of 2-PrOH: mp 168-169° C. MS m/z=424 (M++H). 300 MHz 1H NMR (DMSO-d6) δ7.3 (t, 1H); 7.2 (d, 2H); 6.8 (d, 1H); 6.6 (m, 4H); 6.5 (s, 2H); 4.0 (m, 1H); 3.75 (s, 3H); 3.3 (q, 4H); 3.1 (d, 2H); 2.4 (m, 4H); 1.9 (d, 2H); 1.4 (m, 4H); 1.1 (t, 6H); 0.8 (t, 3H). Anal calcd. for C26H37N3O2.C4H4O4: C, 66.77; H, 7.65; N, 7.78. Found: C, 66.69; H, 7.76; N 7.68.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][CH2:9][C:2]1=2.C[Si]([C:15]#[N:16])(C)C.P(Cl)(Cl)(Cl)=O>B(F)(F)F.CCOCC.N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:15]#[N:16])=[CH:7][CH2:8][CH2:9][C:2]1=2
Reactant: O=C1CCCc2sccc21
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: N#CC1=CCCc2sccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
Boron trifluoride diethyl etherate (120 drops) was added dropwise under nitrogen at ambient temperature to a stirred mixture of 6,7-dihydrobenzo[b]thiophen-4(5H)-one (130.5 g) and trimethylsilyl cyanide (98 g), the mixture was stirred at ambient temperature for 2 hours and at 100° C. for 1 hour, then it was allowed to stand at ambient temperature for 18 hours. Pyridine (650 ml) followed by phosphorus oxychloride (125 ml) were added, the mixture was heated at 140° C. for 2 hours whilst volatile materials were removed by distillation, then it was cooled to ambient temperature and added to crushed ice (2000 ml). Ether (2000 ml) was added and the mixture was filtered through Celite. The filter pad was washed with ether (500 ml), the aqueous phase was separated, and further product was extracted from it using ether (500 ml). The ethereal solutions were combined, washed with water (500 ml), 5M hydrochloric acid (2250+500 ml), water (500 ml) and saturated aqueous sodium chloride solution (500 ml), then they were dried (MgSO4) and the solvents were removed in vacuo to give crude 6,7-dihydrobenzo[b]thiophene-4-carbonitrile (88.3 g) as an orange oil which was used without further purification.
Reaction SMILES: CC(S(/[N:7]=[CH:8]/[C:9]1[O:13][CH:12]=[N:11][CH:10]=1)=O)(C)C.[Cl:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][C:20]=1[Cl:21].[NH4+].[Cl-].Cl.O1CCOCC1>CCOCC.C1(C)C=CC=CC=1>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([CH:8]([C:9]2[O:13][CH:12]=[N:11][CH:10]=2)[NH2:7])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CC(C)(C)S(=O)/N=C/c1cnco1
Reactant: Clc1ccc([Mg]Br)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: NC(c1ccc(Cl)c(Cl)c1)c1cnco1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
A dried-flask was charged with 20 (1.211 g, 6.047 mmol) and toluene (5 mL) was added. The reaction was cooled to −78° C. and (3,4-dichlorophenyl)magnesium bromide (18.14 mL, 9.071 mmol, 0.5 M in THF) was added. The reaction was warmed to −10° C. for 15 min. Saturated NH4Cl was added and the reaction was extracted with DCM. The organic layer was separated, dried, filtered, and concentrated. The resulting residue was dissolved in DCM (10 mL) then 4 N HCl in dioxane (15.12 mL, 60.47 mmol) was added and the solution was stirred for 30 min. The reaction mixture was added dropwise to a stirred solution of ether. The resulting solid was filtered and washed with ether to afford (3,4-dichlorophenyl)(oxazol-5-yl)methanamine hydrochloride (22, 1.24 g, 4.436 mmol, 73.35% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:24][C:10]3=[CH:11][C:12]4[C:13]([CH3:23])([CH3:22])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>>[CH:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([C:26]5[O:25][CH:29]=[CH:28][CH:27]=5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:24][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:23])[C:14]1=[O:21])([CH3:19])[CH3:20]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)N1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CC(C)N1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccco4)nc3cc21

Procedure:
Furan-2-carboxylic acid[3-(5-isopropyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-isopropyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (325 mg, 0.90 mmol) and 2-furoyl chloride (102 μl, 0.99 mmol). The title compound was obtained as dark green powder (180 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[N:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:46]([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[O:47])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)NC(=O)N2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzenesulfonamide (0.10 g), potassium carbonate (0.11 mg), 1-piperidinecarbonyl chloride (29 μl) and DMF (2.0 ml) was stirred at 50° C. for 18 hrs. After the completion of the reaction, the reaction mixture was concentrated, and the residue was diluted with dichloromethane. Then, this solution was washed with 1N hydrochloric acid, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=4/1-1/1) to give the title compound (38 mg) as a colorless powder. HPLC analysis: purity 91.6% (retention time: 4.78 min). MS (ESI+): 636 (M+H), 638.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])[C:8]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:7]=2[N:6]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:5]1=[O:38])=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[O:14])[C:8]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:7]=2[N:6]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:5]1=[O:38]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(N=[N+]=[N-])C(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Yield: 56.8 %

Procedure:
A solution of 152 mg of 2-(3-azido-7-fluoro-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide in 10 mL of ethyl acetate was combined with 60 mg of palladium on carbon (10 wt %) and hydrogenated under a balloon of hydrogen gas for 16 hrs. The mixture was filtered, evaporated in vacuo and purified on flash grade silica gel using 3:7 methanol/ethyl acetate. The appropriate fractions were combined, evaporated in vacuo and dried under high vacuum to provide 82 mg of the title compound as a foam. Low resolution MS (FAB)m/e 492 (MH+); TLC (silica) 95:5 dichloromethane/methanol Rf=0.30.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[C:26]4=[N:27][C:28]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:29][C:30](=[O:31])[N:25]4[CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH3:13])[CH:8]=[CH:9][CH:10]=1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[C:26]4=[N:27][C:28]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:29][C:30](=[O:31])[N:25]4[CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH3:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(Cc1cccc(CN=[N+]=[N-])c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(Cc1cccc(CN)c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Reaction time: 2 h

Procedure:
To a nitrogen filled vessel containing a stirring solution of 9-{2-[2-(3-azidomethyl-phenyl)-1-methyl -ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (190 mg, 0.39 mmol) in methanol (25 mL) was added 10% palladium on carbon (20 mg). Mixture stirred over an atmosphere of hydrogen. After 2 h, reaction filtered through a bed of Celite and solvent removed under vacuum. Residue purified on silica and isolated as a white solid.
Reaction SMILES: [C:1](Cl)(=O)C.[F:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]([OH:16])=[O:15])[CH:9]=[C:10]([F:12])[CH:11]=1>CO>[F:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]([O:16][CH3:1])=[O:15])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1cc(F)cc(F)c1

Procedure:
A solution comprising 25 ml of acetyl chloride in 250 ml of methanol is prepared at 0° C., then, at ambient temperature, 25.5 g of 3,5-difluorophenylacetic acid are dissolved in this solution and the solution is left stirring at AT. The reaction is monitored by thin layer chromatography. After the starting material has disappeared, the medium is evaporated under reduced pressure and then the residue is dissolved in 250 ml of MTBE. The organic phase is washed three times with 100 ml of water, dried over MgSO4 and then evaporated to dryness under reduced pressure. 26.9 g of the expected compound are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:5][N:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:37].[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)C>[OH:37][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:5][N:4]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: OCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cn1
Yield: 64.5 %

Procedure:
1-{1-[2-(2-Cyanopyridin-5-yl)ethyl]piperidin-4-yl}indoline (0.103 g) was dissolved in toluene (1.5 ml). In a nitrogen atmosphere at −78° C., a 1.5 M solution (0.44 ml) of diisobutylaluminum hydride in toluene was added thereto and the resultant mixture was stirred under the same conditions for 1 hr. Then the reaction solution was poured into a 5% aqueous solution of sulfuric acid and basified with an aqueous solution of sodium hydroxide. Next, diethyl ether was added and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.066 g) as a yellow oil (yield: 64.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:26]3[NH:25][C:24](=[O:27])[O:23][C:22]([CH3:29])([CH3:28])[C:21]=3[CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:30]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:26]3[NH:25][C:24](=[O:27])[O:23][C:22]([CH3:29])([CH3:28])[C:21]=3[CH:20]=[CH:19][CH:18]=2)=[O:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(SCCCCOc2cccc3c2NC(=O)OC3(C)C)cc1OC
Reactant: OO
Product: COc1ccc(S(=O)CCCCOc2cccc3c2NC(=O)OC3(C)C)cc1OC

Procedure:
Prepared analogously to Example 2 from 8-[4-(3,4-dimethoxy-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH:12]([CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[CH:12]([NH:11][C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:20][CH3:21])[CH:17]([CH3:18])[CH3:19]
Reactant: O=C(O)Cc1ccccc1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccccc1)C(=O)OCC(C)C

Procedure:
Following General Procedure BH above and using phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by chromatography on silica gel using 9:1 toluene:EtOAc as the eluant.