Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:22][OH:23])([CH2:24][OH:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:13]([C:18]([F:20])([F:19])[F:21])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(O)c(C(F)(F)F)c1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(CCC(CO)(CO)NC(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Compound 9-6 (360 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (263 mg) and 1-bromooctane (0.198 ml) were added, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (490 mg) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21](O)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.S(=O)(=O)(O)O.CCOCC>C(O)C.O>[C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:19])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCc1ccccc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: O=C(OCCc1ccccc1)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2

Procedure:
2-Phenyl-4-quinolone-6-carboxylic acid (1.5 grams) obtained in Example 2 is stirred for fifteen hours at 110° C. with 50 ml of phenethyl alcohol and 1 ml of concentrated sulfuric acid. After cooling, 1.5 liters of ether is added to the mixture, the mixture is cooled with ice, oil which separates out therefrom is taken out. The mixture is then dissolved in 5 ml of ethanol. Then 3 ml of water is added thereto, and crystal which separates out therefrom are collected by filtration, and washed with a 5% sodium bicarbonate solution, then with water, and finally with methanol, and dried to give 0.9 gram of phenethyl 2-phenyl-4-quinolone-6-carboxylate, colorless powder, melting point 282°to 284° C.
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4](=[O:10])[C:5]([O:7]CC)=O)#[N:2].[C:17]1([CH2:23][C:24]#[N:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]CC.[Na+].[Na]>C(O)(=O)C.O>[C:17]1([CH:23]([C:5](=[O:7])[C:4](=[O:10])[CH:3]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:1]#[N:2])[C:24]#[N:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(=O)C(C#N)c1ccccc1
Reactant: N#CCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: N#CC(C(=O)C(=O)C(C#N)c1ccccc1)c1ccccc1

Procedure:
Ethyl 3-cyano-3-phenylpyruvate (50.0 g., 0.23 mol.) and 41.0 g. (0.35 mol.) of phenylacetonitrile were added to an alcoholic solution of sodium ethoxide [prepared from 13.4 g. (0.58 g. -atom) of sodium and 360 ml. of absolute ethanol] and the resulting yellow solution was refluxed for 1.75 hours. The cooled solution was diluted with 700 ml. of water and acidified by slow addition of acetic acid. After further cooling in ice, the suspension was filtered and the solid was washed with water and dried to give 2,5-diphenyl-3,4-dioxoadiponitrile, m.p. 284°-286° (dec.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1>O1CCCC1>[Cl:1][CH2:2][CH2:3][C:4]([N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)=[O:5]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)CCCl
Solvent: C1CCOC1
Product: O=C(CCCl)N1CCc2ccccc2C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A solution of 3-chloropropanoyl chloride (10.5 g) in tetrahydrofuran (400 mL) was cooled down to 6° C. followed by the addition of a solution of 3,4-dihydro-1H-isoquinoline (10.0 g). The resulting mixture was stirred at 10° C. for 30 min, filtered and concentrated in vacuo. The residue was subjected to a standard aqueous work up procedure followed by purification by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give the product as a colourless oil (10 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[S:22](Cl)(=[O:24])=[O:23])[C:18](=[O:26])[CH2:17][CH2:16]2>CC(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[S:22](=[O:23])(=[O:24])[NH:4][CH2:1][CH2:2][CH3:3])[C:18](=[O:26])[CH2:17][CH2:16]2
Reactant: CCCN
Reactant: O=C1CCc2cc(Cl)c(S(=O)(=O)Cl)cc21
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCNS(=O)(=O)c1cc2c(cc1Cl)CCC2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1.95 g (33 mmoles) of n-propylamine and 3.04 g (30 mmoles) of triethylamine in 50 ml of acetone is added to a solution of 7.95 g (30 mmoles) of 5-chloro-6-chlorosulfonyl-1-indanone in 50 ml of acetone, and the whole is stirred for 6 hours at room temperature, thereafter for 1 hour at boiling temperature. The solution is largely concentrated, 200 ml of water are added, and the mixture is then acidified with 2N hydrochloric acid to a pH of 2. The precipitate is filtered off with suction and washed with water. The product melts at 122° to 123° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([N:12]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH:5]=1.[OH-].[Na+].Cl>CO>[CH2:20]([O:19][C:17]([N:12]([CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[CH:7]=1)[C:3]([OH:27])=[O:2])=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C=CCCN(C(=O)OCc1ccccc1)c1cc(OC)cc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCCN(C(=O)OCc1ccccc1)c1cc(OC)cc(C(=O)O)c1

Procedure:
This ester (118 mg, 0.32 mmol) is dissolved in 2 ml MeOH and treated with 2 ml 1N NaOH for 18 h. The mixture is acidified with 1 N HCl and extracted with EtOAc. The organic phase is dried with sodium sulfate and evaporated to yield the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:12][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccccc2)C1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a solution of 1-Boc-3-aminoazetidine 1a (1.2 g, 6.98 mmol) and Et3N (2.4 mL, 17.3 mmol) in CH2Cl2 (70 mL) at 0° C. was added benzoyl chloride 1b (0.89 mL, 7.68 mmol). The reaction was kept at 0° C. for 3 h, quenched with aq. NaHCO3, and the resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 40% EtOAc/heptane) gave compound 1c (1.9 g).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:8]2[C:9]([O:11][C:12](=O)[NH:13][C:7]2=[CH:6][CH:5]=1)=O)([O-:3])=[O:2].Cl[C:17]1[CH:28]=[C:21]2[C:22](OC(=O)[NH:26][C:20]2=[CH:19][CH:18]=1)=[O:23].N1C2C(=CC=CC=2)C(=O)C1=O.FC1C=C2C(=CC=1)NC(=O)C2=O>CN(C=O)C>[N+:1]([C:4]1[CH:15]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:13]=[C:12]1[C:22](=[O:23])[C:21]3[C:20]([N:26]1[C:9]2=[O:11])=[CH:19][CH:18]=[CH:17][CH:28]=3)([O-:3])=[O:2]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: O=C1Nc2ccc(F)cc2C1=O
Agent: O=C1Nc2ccccc2C1=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2c1nc1ccc([N+](=O)[O-])cc1c2=O
Yield: 24 %

Procedure:
Using the procedure in Example 12, and substituting NMP for DMF, 5-nitroisatoic anhydride for 5-chloroisatoic anhydride and isatin for 5-fluoroisatin gave 495 mg (24%) of the title compound: mp 349° C. (dec); 1H NMR(CDCl3)δ 7.46-7.54 (m, 1H), 7.84-8.00 (m, 3H), 8.18-8.22 (m, 1H), 8.62-8.68 (m, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][Cl:32]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:29][CH2:30][CH2:31][Cl:32])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCl

Procedure:
Using 5 g of of N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 131), 120 ml of methylisobutylketone, 3.5 g of potassium carbonate, and 2.4 ml of 1-bromo-3-chloropropane, a reaction similar to that conducted in Example 106 was carried out. As a result, 5.63 g of N-(trans-4-methylcyclohexyl)-4-(3-chloropropoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39].C([O-])([O-])=O.[Na+].[Na+]>CC#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:34]5[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[CH:33]=5)[CH:3]=4)[NH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc5[nH]ccc5c4)c3c2)cc(OC)c1OC
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (65 mg, 0.14 mmol) in CH3CN (1 mL) in a Personal Chemistry microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol), bis(triphenylphosphine)-palladium(II)dichloride (7.0 mg, 0.010 mmol), and 1 M Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The organic layer was separated, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL) and acetone (2 mL), and 2 M NaOH (1.5 mL) was added. The resulting mixture was stirred at 65° C. for 30 min, after which it was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue purified via preparatory HPLC to give the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 11.78 (s, 1H), 11.03 (s, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.36 (d, J=1.8 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.45 (s, 2H), 7.32 (m, 1H), 6.92 (s, 2H), 6.45 (m, 1H), 3.85 (s, 6H), 3.70 (s, 3H); HPLC retention time: 2.04 minutes; MS ESI (m/z): 400.4 (M+1)+, calc. 399.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([OH:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:37])[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(CN(C)CC(O)Cc2ccccc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-(methylamino)-3-phenylpropan-2-ol (Eur. J Med. Chem.—Chim. Ther. 1979, 14, 165-70)(63 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5.0 mL) was stirred for 24 hours at room temperature. The solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (94 mg) as a white solid.
Reaction SMILES: COC(=O)C([C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:16])(=[O:15])=[O:14])=[C:9](OC)[CH:8]=1)(C)C.[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1C2C(=CC=CC=2)[CH2:27][CH2:26][C:25]1=[O:34].COC(=O)CN1C2C(=CC(S)=CC=2)CCC1=O>>[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:7]2[C:8](=[CH:9][C:10]([S:13]([Cl:16])(=[O:14])=[O:15])=[CH:11][CH:12]=2)[CH2:27][CH2:26][C:25]1=[O:34]
Reactant: COC(=O)C(C)(C)c1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: COC(=O)CN1C(=O)CCc2ccccc21
Agent: COC(=O)CN1C(=O)CCc2cc(S)ccc21
Product: COC(=O)CN1C(=O)CCc2cc(S(=O)(=O)Cl)ccc21
Yield: 28 %

Procedure:
Compound 49B was prepared analogously to compound 21B using the product prepared from compound 49A. Yield was 28%. MS m/z 318 (M+1). Step 3. Preparation of (6-Mercapto-2-oxo-3,4-dihydro-2H-quinolin-1-yl}-acetic acid methyl ester (Compound 49C).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([CH3:28])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:32].[H-].[Na+].Cl[CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)[C:7]2=[O:32]
Reactant: COc1ccc(COc2cc3c(c(Cl)c2OCc2ccc(OC)cc2)CCNC3=O)cc1
Reactant: ClCCN1CCCC1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(COc2cc3c(c(Cl)c2OCc2ccc(OC)cc2)CCN(CCN2CCCC2)C3=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To the solution of 5-chloro-6,7-bis((4-methoxybenzyl)oxy)-3,4-dihydroisoquinolin-1(2H)-one (1.017 g, 2.241 mmol) in N,N-dimethylformamide (DMF) (10 ml) was added sodium hydride (0.179 g, 4.48 mmol). Stirred at rt for 10 min. 1-(2-Chloroethyl)pyrrolidine (0.329 g, 2.465 mmol) (first freed as free base with MP-carbonate resin) was added and the mixture was heated at 40° C. for 12 h. Mixture extracted with EtOAc, washed with water, NaCl, dried over magnesium sulfate. Chromotagraphed eluting with 0-10% methanol:dichloromethane to give 5-chloro-6,7-bis((4-methoxybenzyl)oxy)-2-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroisoquinolin-1(2H)-one (420 mg, 0.762 mmol, 34.0% yield). LCMS (M+H)+: 551.0
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH2:4][CH:3]1[C:16](OCC)=O.O.Cl.Cl.Cl>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH2:4][CH:3]1[C:16]1[NH:2][CH2:3][CH2:4][N:5]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2Cl)CCN1C
Agent: Cl
Solvent: O
Product: CN1CCN(Cc2ccccc2Cl)CC1C1=NCCN1

Procedure:
Yield: 62% (from 1-methyl-4-(2-chlorobenzyl)-2-ethoxycarbonylpiperazine) Melting point: 140°-142° C. (decomposition) (trihydrochloride monohydrate)
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:41]1[CH:46]=[CH:45][CH:44]=[N:43][C:42]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(OCC)(=O)C>O1CCCC1.CCO.CCCCCC>[CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27][N:50]2[CH2:51][CH2:52][N:47]([C:42]3[N:41]=[CH:46][CH:45]=[CH:44][N:43]=3)[CH2:48][CH2:49]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN3CCN(c4ncccn4)CC3)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 41 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and 1-(2-pyrimidyl)piperazine (1.13 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a kelly green compound CC-50. Mol. Wt.: 560.6025 (C32H28N6O4); Rf: 0.32 (ethyl acetate:n-hexane=1:2); Yield: 41%; Mp.: 267-268° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 560.2172 (C32H28N6O4+); found, 560.2170; 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 2.20 (s, 3H, —CH3), 3.05 (br, 8H, —CH2—), 3.11 (s, 2H, —CH2N—), 3.22 (br, 8H, —CH2—), 6.66 (d, J=4.8 Hz, 1H, Ar—H), 7.16 (d, J=7.8 Hz, 1H, Ar—H), 7.87-7.91 (m, 2H, Ar—H), 8.01 (d, J=6.0 Hz, 2H, Ar—H), 8.08-8.19 (m, 2H, Ar—H), 8.32 (d, J=7.2 Hz, 1H, Ar—H), 8.82 (d, J=8.7 Hz, 1H, Ar—H), 10.19 (s, 1H, Ar—NH—), 10.54 (s, 1H, Ar—NH—); 13C-NMR (125 MHz, DMSO-d6) δ (ppm): 20.98, 42.53, 43.01, 52.46, 61.44, 110.28, 111.11, 124.77, 126.32, 126.89, 127.44, 127.92, 128.14, 128.90, 129.18, 130.18, 132.26, 134.06, 134.48, 142.39, 157.65, 158.07, 161.24, 166.12, (NCO), 169.08 (NCO), 181.35 (CO), 183.39 (CO).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:25][N:26]=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CN.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14](=[O:15])[NH:26][CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Agent: CN
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
N-tert-butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid (3.0 g; 9.0 mmol) was dissolved in methylene chloride (25 ml) and EDAC (1.8 g; 9.0 mmol) and HOAt (1.3 g; 9.0 mmol) was added. The mixture was stirred for 15 min, then methyl amine (33% in ethanol; 2.3 ml; 18 mmol) and DIEA (1.6 ml; 9.0 mmol) was added and the mixture was stirred overnight. Methylene chloride (100 ml) was added and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and a aqueous solution of sodium hydrogensulfate (10%, 50 ml), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica (90 g) using a mixture of aqueous ammonia/ethanol/methylene chloride (1:7:92) as eluent to afford 2.8 g of 4-benzyl-4-methylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1.C1CCC(C(O)=O)CC=1.[N+:28]([O-:33])([N+]([O-])=O)=[O:29].O>C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[CH3:14][C:9]1[CH:8]=[C:7]([C:6]2[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[O:3][C:2]=2[N+:28]([O-:33])=[O:29])[CH:12]=[CH:11][C:10]=1[CH3:13]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: Cc1ccc(-c2c(Br)oc3ccccc23)cc1C
Agent: O=C(O)C1CC=CCC1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(-c2c([N+](=O)[O-])oc3ccccc23)cc1C
Reaction time: 16 h

Procedure:
To a solution of 12.4 g (0.041 mole) of 2-bromo-3-(3',4'-dimethylphenyl)benzofuran in 400 ml of acetic acid is added 7.8 g (0.062 mole) of cyclohexene-4-carboxylic acid and a solution of 5 g (0.062 mole) of dinitrogen tetroxide in 25 ml of acetic acid. After stirring for about 16 hours the mixture is poured into cold water to give a gummy solid. The solid is collected, washed with water and dissolved in diethyl ether. The ether solution is washed with water, 10% sodium bicarbonate solution and saturated sodium chloride solution, then dried. Evaporation provides a residue which is dissolved in carbon tetrachloride and chromatographed on silica gel, eluting with carbon tetrachloride and combining the fractions consisting of chiefly one component according to thin layer chromatography. The solid is recrystallized from aqueous ethanol, then from isopropanol to provide yellow solid 3-(3',4'-dimethylphenyl)-2-nitrobenzofuran, m.p. 125°-133° C. which is about 90% pure, containing about 10% of monobromo-3-(3',4'-dimethylphenyl)-2-nitrobenzofuran.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][N:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][NH:29][C:28]=3[CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][N:5]([C:8]([CH3:13])([CH3:12])[C:9]([N:29]2[CH2:30][CH2:31][CH2:32][C:33]3[N:25]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)[N:26]=[CH:27][C:28]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(C)(C)C(=O)O
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(C)(C)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 68 %

Procedure:
The title compound was from prepared from 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2×1 M NaHSO4. The organic layer was concentrated and the residue was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 80 mg (68%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.44 (m, 2H), 7.16 (m, 2H), 3.08 (m, 2H), 2.74 (t, J=6.6 Hz, 2H), 2.21 (s, 3H), 1.91 (s, 6H), 1.76 (ddd, J=5.8, 6.2, 10.5 Hz, 2H); MS: (ES) m/z calculated for C21H21ClF4N5O [M+H]+ 470.1, found 470.1.