Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.O>CN(C=O)C>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CCNC1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 120 °C
Yield: 83.9 %

Procedure:
2,6-Dichloro-4-phenyl-quinoline-3-carbonitrile (30 mg, 100 μmol, Eq: 1.00), pyrrolidine (14.3 mg, 16.6 μl, 201 μmol, Eq: 2) and triethylamine (30.4 mg, 41.9 μl, 301 μmol, Eq: 3) were dissolved in DMF (0.5 ml) and the reaction mixture was heated to 120° C. for 20 min in a microwave. Then water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried with Na2SO4 and evaporated to dryness. The remaining residue was purified by column chromatography (silica gel, DCM/heptane 1:1) to afford the title compound as yellow solid (28 mg). MS (ESI): 334.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[F:13][C:14]([F:22])([F:21])[C:15]([F:20])([F:19])[C:16](O)=O>>[CH3:8][C:5]1[S:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]2[C:6]=1[NH:7][C:16]([C:15]([F:20])([F:19])[C:14]([F:22])([F:21])[F:13])=[N:1]2
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: COC(=O)c1sc(C)c(N)c1N
Product: COC(=O)c1sc(C)c2[nH]c(C(F)(F)C(F)(F)F)nc12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 3,4-diamino-5-methylthiophene-2-carboxylate (1.0 g) in pentafluoropropionic acid (8.9 g) was stirred at 100° C. for 6 hr. The reaction solution was concentrated to dryness and the residue was suspensed in water. The mixture was made basic with aqueous solution of K2CO3, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from isopropyl ether-hexane gave colorless plates (0.86 g, 51%). m.p. 156°-157° C.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].N1C=C(C#C[C:23]2[CH:24]=[C:25]([CH:47]=[CH:48][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])N2C=CN=CC=12>>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:48]2[CH:47]=[C:25]([CH:24]=[CH:23][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])[N:7]2[C:6]=1[CH:11]=[CH:10][CH:9]=[N:8]2
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Reactant: C#Cc1cnc2cccnn12
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized in a manner similar to that described for Example 14, from 3-ethynylimidazo[1,2-b]pyridazine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (Prepared as described in Example 2). The product was obtained as a solid: 533 m/z (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([P:10](Cl)(Cl)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([Mg]Br)=[CH2:15].O1CC[CH2:20][CH2:19]1>>[CH:19]([P:10]([CH:14]=[CH2:15])([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:11])=[CH2:20]
Reactant: C=C[Mg]Br
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccc(P(=O)(Cl)Cl)cc1
Product: C=CP(=O)(C=C)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-Nitrophenylphosphonic dichloride (2.14 g, 8.91 mmol) in tetrahydrofuran at −78° C. was added vinylmagnesium bromide (2.34 g, 17.8 mmol). The solution was stirred at −78° C. for one hour then quenched by the addition of ammonium chloride solution. The mixture was extracted with dichloromethane. The combined organic layers were dried and concentrated. 4-(Divinyl-phosphinoyl)nitro benzene was isolated as a brown-yellow oil (1.69 g, 85%). MS=224 (MH)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1>C(OC(=O)C)(=O)C>[Br:5][C:6]1[S:7][C:8]([N+:1]([O-:4])=[O:2])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])O
Reactant: Brc1cccs1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Nitric acid (24.00 g, 1.42 sp gr, 0.381 mol) in acetic anhydride (50 ml) at 0° C. was added dropwise to a cooled (0° C.) rapidly stirred solution of the compound of step 5.1 (24.77 g, 0.152 mol) in acetic anhydride (50 ml). At the end of the addition the stirring was continued for 0.5 hr and the mixture was refrigerated overnight. The mixture was poured into ice water (400 ml) and the precipitate was filtered off, dissolved in ether (2×200 ml), and washed with water until free of acid. The solvent was removed in vacuo and the residue was purified by column chromatography [silica gel/petroleum fraction (bp 40°-60° C.), dichloromethane, 5:1] and was recrystallised from ethanol/dimethoxyethane, 100:1 to give a pale yellow solid which was dried in vacuo (P2O5) to give 66% yield of 20.89 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH3:17][C:18](=[O:23])[CH2:19][C:20](=[O:22])[CH3:21]>Cl.O.C(O)C>[C:2]1([NH:1][N:8]=[C:19]([C:18](=[O:23])[CH3:17])[C:20](=[O:22])[CH3:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)C(=NNc1ccccc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
Aniline (20 g, 0.215 mol) was dissolved in a mixture of concentrated hydrochloric acid (64 ml) and water (64 ml). To the resulting mixture was added dropwise at 0° C. a solution of sodium nitrite (16.3 g, 0.24 mol) in water (80 ml). The resulting diazonium salt was added to a mixture of sodium acetate (53 g, 0.64 mol), ethanol (225 ml) and pentane-2,4-dione (21.5 g, 0.22 mol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The precipitate was filtered off and washed with water (2×150 ml), 50% aqueous ethanol (2×50 ml), heptane (50 ml) and dried in vacuo at 50° C. for 18 h affording 39.3 g (90%) of 3-(phenylhydrazono)-pentane-2,4-dione as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:13]/[C:14](/[CH3:20])=[CH:15]\[C:16]([O:18][CH3:19])=[O:17].[C:21]([O:27][CH2:28][C:29]([CH3:41])([CH3:40])[CH2:30][N:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32])(=[O:26])[CH2:22][C:23]([CH3:25])=O>CC(O)C>[CH3:25][C:23]1[NH:13][C:14]([CH3:20])=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:4]([C:3]2[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=2[Cl:1])[C:22]=1[C:21]([O:27][CH2:28][C:29]([CH3:41])([CH3:40])[CH2:30][N:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32])=[O:26]
Reactant: CC(=O)CC(=O)OCC(C)(C)CN(C)Cc1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN(C)Cc2ccccc2)C1c1cc([N+](=O)[O-])ccc1Cl
Yield: 38.8 %

Procedure:
A mixture of 185 mg of 2-chloro-5-nitrobenzaldehyde, 118 mg of methyl 3-aminocrotonate and 292 mg of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate in 1 ml ml of 2-propanol was reacted and then purified in the same way as in Example 9 to yield 215 mg of the desired compound (148).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:25](=[O:30])[C:26]([OH:29])([CH3:28])[CH3:27].[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])[CH3:32]>C(#N)C.C(Cl)Cl>[C:31]([O:34][CH2:35][C:36]([NH:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:25](=[O:30])[C:26]([OH:29])([CH3:27])[CH3:28])=[O:37])(=[O:33])[CH3:32]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(O)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1c(C(=O)C(C)(C)O)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C

Procedure:
To a solution of 4.0 g of the product of Example 100 in 25 mL of acetonitrile was added 7.5 mL acetoxy acetylchloride and the reaction mixture was stirred at room temperature. After 50 min the reaction mixture was diluted with CH2Cl2 and washed two times with aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate then concentrated. The residue was suspended in 150 mL of methanol at 60–65° C. After cooling to room temperature the methanol was decanted away and the solid rinsed three times with fresh methanol. The solids were then dried in vacuo to afford the title compound. HPLC/MS: 540.9 (M+1), 542.8 (M+3); Rt=4.07 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[CH3:12][N:13]1[C:22]2[CH2:21][CH2:20][CH2:19][C:18](=O)[C:17]=2[CH:16]=[CH:15][C:14]1=[O:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][CH:18]2[CH2:19][CH2:20][CH2:21][C:22]3[N:13]([CH3:12])[C:14](=[O:24])[CH:15]=[CH:16][C:17]2=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN)cc1
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCNC2CCCc3c2ccc(=O)n3C)cc1
Temperature: 25 °C
Reaction time: 39 h
Yield: 80.4 %

Procedure:
A mixture of 2-(4-methoxyphenyl)ethylamine (5.6 g), 5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (5.5 g), and a catalytic amount of para-toluenesulfonic acid was heated in refluxing toluene (90 ml), with azeotropic removal of water, for 39 hrs. The solution was cooled and concentrated in vacuo. Sodium borohydride (1.1 g) was added to a solution of the residue in ethyl alcohol (90 ml), and the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo, the residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was washed with diethyl ether to afford 7.8 g (81%) of product. Recrystallization from ethyl acetate/hexanes provided the analytical sample, mp 97°-99° C.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[OH:9])=[N+:2]=[N-:3].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:9][C@@H:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[N:1]=[N+:2]=[N-:3])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: [N-]=[N+]=N[C@@H]1CCC[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CCC[C@H]1Oc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Trans-1-azidocyclopentan-2-ol 1.27 g was dissolved in DMF and treated with sodium hydride (400 mg. 60%) at room temperature for 1h. 4-Fluoronitrobenzene (1.41 g) was added and the mixture stirred at 50° C. for 4 h and then left at room temperature overnight. The reaction was quenched with water and extracted with ether. The organic solution was washed with water, dried (MgSO4) and evaporated. Purification by flash chromatography (SiO2-20% DCM/hexane) gave trans-2-(4-nitrophenoxy) cyclopentylazide. 1H nmr (CDCl3) 8.22 (2H, d); 6.98 (2H, d); 5.63 (1H, m); 4.07 (1H, m); 2.20 (2H, m); 1.87 (4H, m).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[H][H].C(Cl)(Cl)(Cl)[Cl:14]>CS(C)=O>[Cl:14][CH:5]([C:3]#[N:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC#N
Reactant: [H][H]
Reactant: ClC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(Cl)C#N
Yield: 82.5 %

Procedure:
To a suspension of NaH in 400 mL of DMSO at 20° C. were added dropwise 79.1 g of ethyl cyanoacetate (700 mmol). The solution was stirred for 1 h at 20° C. until no more hydrogen evolved from the reaction system. 156 mL (1.5 mol) of CCl4 were added carefully. Occasional cooling was applied so as to maintain the temperature between 20°-25° C. The mixture was carefully quenched with HOAc, extracted with CH2Cl2, dried over MgSO4, concentrated, and distilled to give 85.2 g of the title compound (82.5%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:36][CH3:37])=[C:32]([CH:35]=1)[CH:33]=O)([CH3:27])[C:23]([F:26])([F:25])[F:24].C(OC(N1CCC[C@H](NCC2C=C(C(F)(F)C)C=CC=2OC(F)(F)F)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:33][C:32]2[CH:35]=[C:28]([C:22]([CH3:27])([CH3:21])[C:23]([F:26])([F:24])[F:25])[CH:29]=[CH:30][C:31]=2[O:36][CH3:37])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(C(C)(C)C(F)(F)F)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Product: COc1ccc(C(C)(C)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 12 and Compound 71 in the same manner of Compound 26.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:21]=[CH:22][C:23]1[CH:31]=[CH:30][C:28]([OH:29])=[C:25]([O:26][CH3:27])[CH:24]=1.CN(C)C=O>O>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([CH:31]=[CH:30][C:28]=1[O:29][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8])[CH:22]=[O:21]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1nc(-c2ccccc2)sc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyl-1,3-thiazole (1.0 g), potassium carbonate (0.57 g), vanillin (0.62 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzaldehyde as colorless crystals (1.28 g, 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 133-134° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:25])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCCCCCBr
Solvent: Cc1ccccc1
Product: O=C(Cl)CCCCCCCCCCCBr

Procedure:
A solution of 30 mmols (8.4 g) of 12-bromododecanoic acid and 10 ml of toluene in 5 ml of thionyl chloride was stirred at 80° C. for 1 hour. Excess thionyl chloride and toluene were distilled out under reduced pressure to obtain 12-bromododecanoyl chloride(acid chloride 9d). A solution of 25 mmols (8.2 g) of hydroxy ester 9c obtained in the above (9-5) was stirred with 30 mmols (3.0 g) of triethylamine in 100 ml of THF. A solution of said acid chloride 9c in THF, was added dropwise thereto followed by stirring for 8 hours. The reaction mixture was extracted with ether, washed with dilute aqueous hydrochloric acid solution, dried, concentrated and then purified by column chromatography to obtain the desired bromo ester 9e (12.1 g, yield 82% [α]23D=+2 35 (chloroform)).
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(Cl)Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:30]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[N:29]([C:44](Cl)=[O:45])[CH2:28][CH2:27]2>O>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH:7][C:44]([N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=2)[CH:30]1[C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)=[O:45])([CH3:3])[CH3:2]
Reactant: CC(C)N(CCN)C(C)C
Reactant: COc1ccc(C2c3cc(OC)c(OC)cc3CCN2C(=O)Cl)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C2c3cc(OC)c(OC)cc3CCN2C(=O)NCCN(C(C)C)C(C)C)cc1
Reaction time: 4 h

Procedure:
To a mixture of 2.5 parts of 2-diisopropylaminoethylamine and 12 parts of triethylamine in approximately 225 parts of chloroform is added portionwise, at room temperature, a solution of 5.0 parts of 6,7-dimethoxy-1-(4-methoxyphenyl)-3,4-dihydro-2(1H)-isoquinolinecarbonyl chloride in about 75 parts of chloroform. The reaction mixture is stirred for 3 to 5 hours, allowed to stand overnight and then poured into water. The chloroform layer is separated, dried over anhydrous calcium sulfate and stripped of solvent under reduced pressure. The resultant oil is triturated with n-hexane to give a solid. Crystallization of that solid from ethyl ether affords N-(2-diisopropylaminoethyl)-6,7-dimethoxy-1-(4-methoxyphenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxamide as a low melting solid. That compound is characterized by infrared absorption maxima in chloroform at about 1640 and 3400 cm-1.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH3:11][NH:12][S:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=O)(=[O:15])=[O:14].N>>[CH3:11][NH:12][S:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:18]([C:19]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:17]=1)(=[O:14])=[O:15]
Reactant: NC(=NO)c1cccnc1
Reactant: CNS(=O)(=O)c1cccc(C(=O)O)c1
Agent: N
Product: CNS(=O)(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and the product of Example 57A. 1H NMR (300 MHz, CD3OD) δ 2.60 (s, 3H), 7.65 (ddd, J=8.1, 5.0, 0.8 Hz, 1H), 7.87 (t, J=8.1 Hz, 1H), 8.15 (ddd, J=8.0, 1.9, 1.0 Hz, 1H), 8.48 (ddd, J=7.8, 1.7, 1.0 Hz, 1H), 8.58 (dt, J=8.1, 1.9 Hz, 1H), 8.67 (t, J=1.5 Hz, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.31 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 317 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C=O.[CH:15]1([C:21]([NH2:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C:24](=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:24][NH:23][C:21]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:22])[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: NC(=O)C1CCCCC1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: CCO
Product: O=C(NCN1CCN(c2ccccn2)CC1)C1CCCCC1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (16 mg, 0.1 mmol, Aldrich), paraformaldehyde (30 mg, 1 mmol), cyclohexanecarboxylic acid amide (64 mg, 0.5 mmol, Aldrich), and 42 mg of potassium carbonate (0.3 mmol) in 2 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 30 mg (66%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ 1.05-1.40 (m, 5H), 1.59-1.68 (m, 5H), 2.15 (m, 1H), 2.48 (m, 4H), 3.45 (t, J=4 Hz, 4H), 3.95 (d, J=5 Hz, 1H), 6.62 (t, J=6 Hz, 1H), 6.81 (d, J=6 Hz, 1H), 7.53 (t, J=6 Hz, 1H), 8.01 (t, J=5 Hz, 1H), 8.10 (d, J=5 Hz, 1H); MS (ESI/APCI−) m/e 301 (M−H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)=[O:4].[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CCOCC>C(#N)C>[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CCc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of methyl 3-(4-bromoacetylphenyl)propionate (380 mg) in acetonitrile (4 ml) was added dropwise over 15 minutes to a stirred solution of 1-(4-pyridyl)piperazine (450 mg) in acetonitrile (10 ml) and the mixture stirred overnight. The mixture was then filtered and the filtrate concentrated in vacuo to give an oil. Purification by flash chromatography on silica eluting first with dichloromethane then 5% v/v methanol/dichloromethane gave a solid. Trituration with ether gave the title compound, 172 mg, as a solid: m.p. 141°-143° C.; NMR (d6DMSO) δ 8.15(2H,d), 7.92(2H,d), 7.37(2H,d), 6.83(2H,d), 3.89(2H,s), 3.59(3H,s), 3.37(4H,t), 2.93(2H,t), 2.69(2H,t), 2.65(4H,t); m/e 368(M+H)+ ; calculated for C21H25N3 O3.0.25H2O: C, 67.8; H, 6.9; N, 11.3. found: C, 67.8; H, 6.9; N, 11.1%.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:11]([CH:26]2[CH2:28][CH2:27]2)[CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH:26]1([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=2[CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:27][CH2:28]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)OCc2ccccc2)c(C2CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(O)cc1C1CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of benzyl (4-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropylphenyl)acetate (586 mg) in tetrahydrofuran (6.89 mL) was added a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (2.23 mL) under ice-cooling, followed by stirring at room temperature overnight. To a reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (2-cyclopropyl-4-hydroxyphenyl)acetate (398 mg).
Reaction SMILES: [C:1]([C:3]1[NH:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1)#[N:2].[H-].[Na+].C[N:13](C=O)C>>[NH2:13][N:4]1[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:3]1[C:1]#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1c[nH]c(C#N)c1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cc(C#N)n(N)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
To a stirred solution of 2,4-dicyano-pyrrole (3.00 g, 25.6 mmol) in DMF (300 mL) was added sodium hydride (60% in mineral oil, 1.54 g, 38.4 mmol). The mixture was stirred for 15 min. Diphenylphosphinyl amino ester (8.96 g, 38.4 mmol) was added. The mixture was vigorously stirred while heating at 80° C. for 2 h and then cooled to rt. The mixture was filtered using DCM washings. The filtrate was concentrated to dryness to provide desired product (2.00 g, 59%). LTQ LC-MS: [M+H]+ 133.0, RT 0.96 min. The product was used in the next step without further purification.