Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(O)(=O)C(O)=O.[CH:8]1[C:18]2[CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]([C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27](CC4C=CC=CC=4)[CH2:26]3)=O)[C:12]=2[CH:11]=[CH:10][CH:9]=1.C1C2CCC3C=CC=CC=3N(C(C3CCCN(CC4C=CC=CC=4)C3)=O)C=2C=CC=1.C(O)(=O)C(O)=O.Br[CH2:75][C:76]([O:78][CH2:79][CH3:80])=[O:77].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:79]([O:78][C:76](=[O:77])[CH2:75][N:27]1[CH2:28][CH2:29][CH2:30][CH:25]([CH2:23][N:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:18]=3[CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]2=3)[CH2:26]1)[CH3:80]
Reactant: O=C(C1CCCN(Cc2ccccc2)C1)N1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)CBr
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CN1CCCC(CN2c3ccccc3CCc3ccccc32)C1
Reaction time: 7 h
Yield: 86.8 %

Procedure:
A mixture of the above piperidine (2.05 g, 7 mmol), ethyl bromoacetate (1.36 g, 8.1 mmol), potassium carbonate (1.7 g, 12.3 mmol) and acetone (50 ml) was heated at reflux temperature under stirring for 7 h. The mixture was filtered and the solvent evaporated in vacuo. The oily residue was purified on silica gel (20 g) using ethyl acetate as eluent to give 2.3 g (87%) 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-ylmethyl)-1-piperidylacetic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH2:24][CH3:25])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[CH2:24]([O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1)[CH3:25]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CCOc1ccc2ccc(N)nc2n1
Solvent: CCO
Solvent: O
Product: CCOc1ccc2ccc(NC(=O)c3ccc(OC)cc3)nc2n1
Temperature: 4 °C
Yield: 75.9 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (19.8 g), N,N'-carbonyldiimidazole (21.1 g) and 2-amino-7-ethoxy-1,8-naphthyridine (18.5 g). The product produced by precipitation in water (28.9 g; m.p. 144° C.) is dissolved in boiling ethanol (280 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-ethoxy-1,8-naphthyridin-2-yl)-4-methoxybenzamide (24 g) is produced, m.p. 152° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][NH:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:34][CH:35]2[CH2:39][CH2:38][O:37][CH2:36]2)(=O)=O)=CC=1>CN(C=O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:15][CH:16]=3)=[N:9][N:10]([CH2:34][CH:35]3[CH2:39][CH2:38][O:37][CH2:36]3)[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: NS(=O)(=O)c1ccc(-c2n[nH]c3cc[nH]c(=O)c23)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(-c2nn(CC3CCOC3)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (28.7 mg) obtained in Step B of Example 100 in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 4.35 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added tetrahydrofuran-3-ylmethyl 4-methylbenzenesulfonate (27.8 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (11.8 mg).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][C:13]([CH3:24])([CH3:23])[CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][S:18][C:17]3=[O:22])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:25](=O)[CH2:26][CH2:27][CH3:28].N1CCCCC1>C(O)C>[CH:25](=[C:19]1[S:18][C:17](=[O:22])[N:16]([CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:20]1=[O:21])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC=O
Reactant: CC(C)(CCSc1cccc2nccn12)CCN1C(=O)CSC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCC(C)(C)CCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 339 mg (0.93 mmol) of 3-[5-(imidazo[1,2-a]pyridin-5-ylthio)-3,3-dimethylpentyl]thiazolidine-2,4-dione and 90 μl (1.0 mmol) of n-butyraldehyde in 5 ml of ethanol, 10 μl (0.1 mmol) of piperidine was added, followed by refluxing for 1.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=2/1→1/2) to yield 310 mg (74.2%, light yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7](Cl)=O.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28]>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=2[C:7]2[NH:29][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]=2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1ccccc1N
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1ccc(Cl)cc1-c1nc2ccccc2[nH]1)c1ccc(Cl)cc1

Procedure:
1.00 g (2.7 mmol) of 5-chloro-2-(4-chloro-phenylsulfonylamino)-benzoyl chloride and 296 mg (2.7 mmol) of o-phenylenediamine in 150 ml of toluene were heated under reflux for 1 h. A small amount of solid was filtered off with suction and the filtrate was evaporated. The residue was taken up in 50 ml of toluene, 600 mg of thionyl chloride were added and the mixture was again heated under reflux for 10 h. Subsequently it was cooled and the precipitated solid was filtered off with suction. 280 mg (25%) of the title compound having a melting point of 225-228° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[N:40]1([CH2:44]CN2C=C(C3C=CC(F)=C(C(F)(F)F)C=3)N=C2C2CCNCC2)[CH2:43][CH2:42][CH2:41]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:44][N:40]4[CH2:43][CH2:42][CH2:41]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=515, obsd.=515).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:17]=1[O:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:21][CH:20]=1>>[Cl:35][C:33]1[CH:32]=[CH:31][C:17]([O:18][C:19]2[CH:30]=[CH:29][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:21][CH:20]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:34]=1
Reactant: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(CCC)ccc23)cc1

Procedure:
The product from Example 2g (75 mg, 0.36 mmol) was reacted with the product from Example 127b (111 mg, 0.36 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (25.8 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.86 (t, J=7.35 Hz, 3H) 0.95 (t, J=7.35 Hz, 3H) 1.37-1.56 (m, 2H) 1.72-1.88 (m, 2H) 2.96 (t, J=7.54 Hz, 2H) 3.08-3.22 (m, 2H) 6.72 (d, J=6.99 Hz, 1H) 6.97 (d, J=8.82 Hz, 2H) 7.29 (d, J=8.82 Hz, 1H) 7.61 (dd, J=8.82, 2.57 Hz, 1H) 7.75 (d, J=8.82 Hz, 4H) 8.34 (t, J=5.70 Hz, 1H) 8.52 (d, J=6.99 Hz, 1H) 8.85 (d, J=8.82 Hz, 1H) 10.90 (s, 1H) 14.55 (s, 1H); MS (ESI+) m/z 475 (M+H−TFA)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH:31]=[C:30]3[C:21]([NH:22][C:23]4[C:28]([O:29]3)=[CH:27][CH:26]=[C:25]([C:32](O)=[O:33])[CH:24]=4)=[N:20][C:19]2=[O:35])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][CH2:51][NH2:52])[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:36]([O:40][C:41]([N:43]1[CH2:44][CH2:45][N:46]([CH2:49][CH2:50][CH2:51][NH:52][C:32]([C:25]2[CH:24]=[C:23]3[C:28]([O:29][C:30]4[C:21]([NH:22]3)=[N:20][C:19](=[O:35])[N:18]([CH:15]3[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17][CH2:16]3)[CH:31]=4)=[CH:27][CH:26]=2)=[O:33])[CH2:47][CH2:48]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(n2cc3c(nc2=O)Nc2cc(C(=O)O)ccc2O3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(n2cc3c(nc2=O)Nc2cc(C(=O)NCCCN4CCN(C(=O)OC(C)(C)C)CC4)ccc2O3)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.1 %

Procedure:
A solution of 3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-oxo-2,9-dihydro-3H-10-oxa-1,3,9-triaza-anthracene-7-carboxylic acid (6) (150 mg, 0.31 mmol, 1 equiv) and 4-(3-Amino-propyl)-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.62 mmol, 2.0 equiv) in DMF (5 mL) was treated with HATU(235 mg, 0.62 mmol, 2.0 equiv) and Hunig's base. The resulting solution was stirred at RT for 6 h. When TLC and LCMS showed the reaction was complete, the reaction solution was concentrated in vacuo, and the residue was directly purified by column chromatography (SiO2, 0-10% MeOH/CH2Cl2 gradient elution) to afford the desired 4-[3-({3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-oxo-2,9-dihydro-3H-10-oxa-1,3,9-triaza-anthracene-7-carbonyl}-amino)-propyl]-piperazine-1-carboxylic acid tert-butyl ester (106 mg, 220 mg, theoretical, 48%), which was treated with 4M HCl in dioxane to afford the final product 3-[1-(3-Amino-propyl)-piperidin-4-yl]-2-oxo-2,9-dihydro-3H-10-oxa-1,3,9-triaza-anthracene-7-carboxylic acid (3-piperazin-1-yl-propyl)-amide (8). For 7: C36H54N8O7, LCMS (EI) m/e 711(M++H). For 8: C26H38N8O3, LCMS (EI) m/e 511(M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl[C:24]([O:26][CH2:27][CH2:28][Cl:29])=[O:25]>ClCCl>[Cl:29][CH2:28][CH2:27][O:26][C:24]([NH:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1)=[O:25]
Reactant: Cc1cccc(N)c1CNc1cccn2c(C=O)c(C)nc12
Reactant: O=C(Cl)OCCCl
Solvent: ClCCl
Product: Cc1cccc(NC(=O)OCCCl)c1CNc1cccn2c(C=O)c(C)nc12

Procedure:
According to the procedure indicated in Example 1a, 8-(2-amino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a]pyridine (2.03 g) and 2-chloroethyl chloroformate (1.01 g) in dichloromethane (120 ml) give the title compound as a brown oil, which is used directly for further reaction in Example 3b.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[C:11]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16](O)=[O:17])(=[O:13])[CH3:12].CCN=C=NCCCN(C)C.Cl.[NH2:38][C@@H:39]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([N:55]2[CH2:59][C:58](=[O:60])[N:57]([CH2:61][C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[S:56]2(=[O:71])=[O:70])=[CH:51][CH:50]=1)[C:40]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:41]>C(Cl)Cl>[C:11]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:16]([NH:38][C@H:39]([C:40](=[O:41])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:48][C:49]1[CH:50]=[CH:51][C:52]([N:55]2[CH2:59][C:58](=[O:60])[N:57]([CH2:61][C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[S:56]2(=[O:70])=[O:71])=[CH:53][CH:54]=1)=[O:17])(=[O:13])[CH3:12]
Reactant: CCCCCNC(=O)[C@@H](N)Cc1ccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)cc1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCNC(=O)[C@H](Cc1ccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
HOBt (16 mg, 0.102 mmol), (S)-2-acetylamino-3-phenyl-propionic acid (21 mg, 0.102 mmol) and EDCl (21 mg, 0.112 mmol) are added to a solution of the title B compound, (S)-2-amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-pentyl-propionamide (50 mg, 0.102 mmol) in CH2Cl2 (3 mL) and the reaction is stirred at RT for 2.5 h, then concentrated. The residue is taken up in EtOAc, washed with 1N aqueous HCl, saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated to yield (S)-2-acetylamino-N-((S)-2-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamide as a white foam: [M+1]+=678.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([CH:10]=O)=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:14][NH2:15].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([CH2:10][NH:15][CH3:14])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cc1c(C=O)sc2ccc(F)cc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1sc2ccc(F)cc2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-fluoro-3-methyl-benzo[b]thiophene-2-carbaldehyde (5.43 g, 28.0 mmol) was added a solution of 2 M methylamine in methanol (94 mL) and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue taken up in ethanol (90 mL). The solution was cooled to 0° C. and then NaBH4 (1.06 g, 28.0 mmol) was added in one portion. The mixture was stirred 4 hr, after which time NaBH4 (0.54 g, 14.0 mmol) was added and the mixture was stirred overnight. The mixture was concentrated under reduced pressure and the residue combined with 1 M NaOH (200 mL). The mixture was extracted with diethyl ether (3×150 mL) and the combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to the title compound (5.26 g, 90%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ7.71 (dd, J=9.0, 4.8 Hz, 1H), 7.27 (dd, J=9.3, 2.6 Hz, 1H), 7.09-7.04 (m, 1H), 4.00 (s, 2H), 2.51 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][C:6]([C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>C(O)(C)C>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:10](=[O:19])[C:9]3[C:4](=[CH:5][C:6]([C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:8]=3)[N:3]=2)=[CH:36][CH:35]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(Cl)nc2c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(NCc3ccc(Cl)cc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a suspension of methyl 2-chloro-3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.10 g, 0.23 mmol) in isopropyl alcohol (2.5 mL) was added N,N-diisopropylethylamine (84 μL, 0.48 mmol) and p-chlorobenzylamine (70 μL, 0.57 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford methyl 2-[(4-chlorobenzyl)amino]-3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (46 mg, 44%). LC-MS: (FA) ES+ 456.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=O.[CH2:19]([NH2:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCOCC>[CH2:19]([NH:27][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[OH:1])([CH3:18])[CH3:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)cc1O
Reactant: CCCCCCCCN
Solvent: CCOCC
Product: CCCCCCCCNC(=O)CCCC(C)(C)c1ccc(O)cc1O

Procedure:
2.5 Parts of methyl 5-(2,4-dihydroxyphenyl)-5-methylhexanoate and 5.0 parts of n-octylamine are sealed into a glass Carius tube for 3 days at 120° C. The cooled reaction mixture is taken up in ether, washed first with dilute hydrochloric acid until free of the excess oxtylamine, and then with water. After removing the ether, the residual oil, on dilution with 40°-60° C. petroleum ether containing a little ether yields 5-(2,4-dihydroxyphenyl)-5-methylhexanoic acid-n-octylamide m.p. 110°-113° C. with the following percentage composition by weight.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14])[CH2:2][CH3:3]>CCO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[O:13][CH3:14])[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1OC
Solvent: CCO
Product: CCCOc1ccc(CO)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Crude 4-(propyloxy)-3-methoxybenzaldehyde (2.55 g) was dissolved in EtOH (30 mL) and cooled to 0° C. NaBH (0.499 g, 13.2 mmol) was added portionwise. After the addition was completed, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added and the resulting mixture was extracted with diethyl ether (3×100 mL). The combined organic layers were dried over anhydrous MgSO4. Removal of the solvent gave a pale yellow oil which was purified by silica gel column chromatography (hexanes/EtOAc, 4:1) to give 4-(propyloxy)-3-methoxybenzyl alcohol (2.38 g, 92% over two steps) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[C:10]3[CH:17]=[CH:18][C:19]([C:21]([O:23]C)=[O:22])=[CH:20][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO.[OH-].[Na+].Cl>O>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[C:10]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccccc1)c1ccncc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(c1)nc(-c1ccccc1)c1ccncc12
Yield: 86.1 %

Procedure:
methyl 5-phenylbenzo[c][2,6]naphthyridine-8-carboxylate (147 mg, 0.468 mmol) was reacted with EtOH (3 ml) and 6 N NaOH (1 ml) at 60° C. for 2 hours. Water was added and the mixture acidified using 6N HCl. The solid was filtered and washed with water. The material was triturated in AcOEt/hexanes, filtered and dried to afford 5-phenylbenzo[c][2,6]naphthyridine-8-carboxylic acid as an off-white solid (121 mg, 86% yield). LCMS (ES): >95% pure, m/z 301[M+1]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](#[N:12])[CH3:11]>>[N:12]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:4][CH2:3][CH2:2][CH2:9][CH2:11][CH2:10]1
Reactant: CC#N
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(N2CCCCCC2)cc1

Procedure:
A solution of 4-fluoro-benzaldehyde (2.59 mL, 24.2 mmol) and hexamethyleneimine (8.2 mL, 72 mmol) in acetonitrile (40 mL) was heated at reflux for 16 hours. The product was preabsorbed onto silica gel and purified by flash silica gel chromatography, using ethyl acetate (10-15%) in hexane as the eluant, to give the product, 5.0 g (100%). MS: m/z 204 (MH+). 1H NMR (CDCl3): 1.53-1.59 (m, 4 H), 1.78-1.82 (m, 4 H), 3.53 (t, 4 H), 6.70 (d, 2 H), 7.70 (d, 2 H) and 9.70 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>CN(C)C=O>[N:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:21][CH:22]=1
Reactant: ClCc1ccncc1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccncc1
Yield: 79.8 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (401 mg), N,N-dimethylformamide (6 ml), potassium carbonate (0.68 g) and 4-(chloromethyl)pyridine (406 mg) according to the similar method described in Production Example 4 was obtained 500 mg of 2-(4-pyridylmethyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (7)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.8 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)aniline (10 g) in pyridine (50 mL) was added acetic anhydride (5.6 g) at 0° C., and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (12.9 g, yield quant.) as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:51])([CH2:49][CH3:50])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=3)=[CH:33][CH:32]=2)[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>O1CCOCC1.CO>[CH3:2][C:3]([CH3:51])([CH2:49][CH3:50])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([NH:44][S:45]([CH3:48])(=[O:46])=[O:47])[C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=3)=[CH:35][CH:36]=2)[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NS(C)(=O)=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(CC(NS(C)(=O)=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride (4N, 2 mL) in dioxane was added to a solution of N-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}methanesulfonamide in methanol (4 mL) at ambient temperature. The solution was stirred at 50° C. for 2 hr. Concentration of the solution afforded the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.51 (d, J=2.5 Hz, 1H), 8.00 (d, J=8.0 Hz, 2H), 7.91 (dd, J=4.2, 8.7 Hz, 1H), 7.67 (td, J=3.0, 8.5 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.13 (s, 1H), 4.95 (t, J=8.1 Hz, 1H), 3.59 (dd, J=8.1, 14.8 Hz, 1H), 3.41 (dd, J=8.1, 14.8 Hz, 1H), 2.66 (s, 3H), 2.48 (dd, J=14.7, 19.7 Hz, 2H), 1.96 (s, 3H), 1.20 (q, J=7.2, 14.7 Hz, 2H), 0.83 (t, J=7.2 Hz, 3H), 0.79 (s, 3H), 0.79 (s, 3H).