Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([NH2:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Br[C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([NH:12][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1Br
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1Br
Temperature: 100 °C

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanamine (5.0 g, 18 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (7.0 g, 25 mmol) and N,N-diisopropylethylamine (9.4 mL, 54 mmol) in ethanol (100 mL) was heated at 100° C. (flushed with nitrogen) overnight. The reaction mixture was cooled, poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified on silica gel (eluting with 0-65% ethyl acetate in hexane) to afford the desired product. LCMS calculated for C20H24BrClN5O2 (M+H)+: m/z=480.1, 4821. found: 480.0, 482.1.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6].[Br:20][C:21]1[CH:28]=[C:27](F)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:27]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Br:20])[CH:28]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: COC(=O)c1cccc2[nH]c3ccccc3c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1ccccc1n2-c1ccc(C#N)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
In a 250 ml round-bottomed flask under argon, 391 mg of a suspension of sodium hydride at 60% in petroleum jelly are added at ambient temperature, in 4 stages, in ½ hour, to a solution of 2.0 g of 9H-carbazole-4-carboxylic acid methyl ester obtained according to the preceding stage and of 1.95 g of 2-bromo-4-fluorobenzonitrile in 50 ml of dimethylformamide. The mixture is stirred at ambient temperature for 3 hours. The reaction medium is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and cyclohexane (50:50). 3.2 g of 9-(3-bromo-4-cyanophenyl)-9H-carbazole-4-carboxylic acid methyl ester are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1.[BH4-].[Na+]>CO>[OH:2][CH2:3][CH2:4][O:5][C:6]1([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:7]1
Reactant: COC(=O)COC1(c2nccs2)CCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(OCCO)(c2nccs2)C1
Reaction time: 1 h

Procedure:
To an ambient solution of tert-butyl 3-(2-methoxy-2-oxoethoxy)-3-(thiazol-2-yl)pyrrolidine-1-carboxylate (2.05 g, 5.99 mmol) in methanol (29.9 ml) was added NaBH4 (0.680 g, 17.96 mmol). The reaction was stirred for 1 hour and was then quenched by the addition of water (20 mL) and ethyl acetate (20 mL). The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×20 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound, which was used in the subsequent step without further purification. MS ESI(+) m/z 314.9 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=3[CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32].O>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][C:16]1([CH3:21])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]2[CH:11]=[C:10]([C:8]([C:4]3[CH:3]=[C:2]([CH:32]=[CH:31][C:30]([O:34][CH3:35])=[O:33])[CH:7]=[CH:6][CH:5]=3)=[O:9])[CH:19]=[CH:18][C:17]1=2
Reactant: C=CC(=O)OC
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)c3cccc(I)c3)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C=Cc1cccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Temperature: 55 °C

Procedure:
A solution of 2 g (4.8 mmol) of 3-iodophenyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-methanone in 30 ml of DMF is introduced into a three-necked flask under a stream of nitrogen, followed by successive addition of 1.7 g of potassium carbonate, 1.4 g of tetrabutylammonium chloride and 600 μl (6.2 mmol) of methyl acrylate. The reaction medium is degassed by bubbling a stream of argon through it, and 22 mg (0.1 mmol) of palladium acetate are introduced. The reaction medium is heated at 55° C. for six hours and then poured into water, the mixture is extracted with ethyl acetate and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and heptane (90/10). After evaporation of the solvents, 1.39 g (77%) of the expected methyl ester, with a melting point of 103-4° C., are collected.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1.C(Cl)(=O)C.[I-:17].[Na+]>C(#N)C>[I:17][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Cl)ccnc1C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: COC(=O)c1c(I)ccnc1C
Temperature: 80 °C
Yield: 22.4 %

Procedure:
To a solution of methyl 4-chloro-2-methylnicotinate (6.00 g, 32.3 mmol) in acetonitrile (80 mL) was added acetyl chloride (3.45 mL, 48.5 mmol) followed by sodium iodide (48.5 g, 323 mmol). The reaction mixture was heated at 80° C. for 16 hrs. The reaction mixture was evaporated to dryness and the residue was adjusted to pH 6 by adding saturated potassium carbonate solution. The product was extracted with dichloromethane (250 mL). The organic phase was washed with brine (2×100 mL), dried over Na2SO4, and concentrated under reduced pressure to afford methyl 4-iodo-2-methylnicotinate (2.00 g, 7.22 mmol, 22% crude yield) as colorless semisolid which was carried on without further purifications. LC/MS (ESI) m/e 278.0 [(M+H)+, calcd for C8H9INO2 278.0]; LC/MS retention time (method C): tR=2.13 min.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[CH3:21][O:22]/[N:23]=[C:24](/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)\[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=1>>[CH3:21][O:22]/[N:23]=[C:24](/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)\[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:34][C:18]2[CH:17]=[CH:16][C:15]([CH:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH2:9][C:10]([OH:12])=[O:11])=[CH:20][CH:19]=2)=[CH:29][CH:28]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: CCOC(=O)CC(c1ccccc1)c1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(CC(=O)O)c3ccccc3)cc2)cc1)c1ccccc1
Yield: 18.2 %

Procedure:
Compound 112 was synthesized from ethyl 3-(4-hydroxyphenyl)-3-phenylpropanoate (0.6 g, 2.2 mmol) and (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.6 g, 2.2 mmol) by following the procedure described in scheme 36. (0.2 g, yield: 18.2%); purity: 98.55%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:29]3[CH2:30][CH2:31][N:26]([C:24]4[CH:25]=[C:16]([Cl:15])[CH:17]=[C:18]5[C:23]=4[N:22]=[CH:21][CH:20]=[CH:19]5)[CH2:27][CH2:28]3)[C:7]=2[CH:14]=1
Reactant: Clc1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1ccc2occ(CCI)c2c1
Product: COc1ccc2occ(CCN3CCN(c4cc(Cl)cc5cccnc45)CC3)c2c1

Procedure:
8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline was prepared by generally following the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-chloro-8-piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yield a brown solid. MP: 72° C.; Yield: 130 mg (30%); (M+H): 422; 1HNMR (400 MHz, CDCl3): δ□8.86˜8.84 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H); 8.05˜8.02 (dd, J1=1.7 Hz,J2=1.7 Hz, 1H); 7.60˜6.88 (m, 7H); 3.86 (s, 3H); 3.69˜2.57 (m, 12H).
Reaction SMILES: C([O:8][C:9]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([CH2:12][C:13]1[O:18][C:17]([CH3:20])([CH3:19])[O:16][C:15](=[O:21])[CH:14]=1)[C:10]#[CH:11])(=O)C(OCC)=O.C([O-])([O-])=O.[K+].[K+].Cl>CO>[CH:22]1([C:9]([OH:8])([C:10]#[CH:11])[CH2:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[O:16][C:15](=[O:21])[CH:14]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C#CC(CC1=CC(=O)OC(C)(C)O1)(OC(=O)C(=O)OCC)C1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Temperature: 23 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To the optically pure (+)-1-cyclopentyl-1-[(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)methyl]prop-2-ynyl ethyl oxalate (2.5 g, 15.1 mmol) in 50 ml of MeOH was added K2CO3 (2.0 g). The mixture was stirred at 23° C. for 8 h. After complete conversion, the mixture was neutralized with 1N HCl at cold temperature. The aqueous solution was extracted with MTBE (×3) and the organic layer was washed with brine and dry over MgSO4. After removal of MTBE, 1.75 g of the desired product (+ enantiomer) was produced with 95.5% ee and 96% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([I:12])=[N:10][NH:11][C:4]=2[CH:3]=1.[H-].[K+].[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([I:12])=[N:10][N:11]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:4]=2[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(Cl)cc2[nH]nc(I)c12
Agent: O=C([O-])O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask containing 6-chloro-3-iodo-4-methyl-1H-pyrazolo[4,3-c]pyridine (2.06 g, 7.02 mmol) in THF (60 mL) was cooled to 0° C. and potassium hydride (1.126 g, 14.04 mmol) was added. The reaction was stirred for 30 min followed by addition of trityl chloride (2.94 g, 10.53 mmol). The reaction mixture was warmed to room temperature and stirred for 4 h. The reaction was poured into sat. sodium bicarbonate and extracted with EtOAc. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-10% DCM/EtOAc) to give 6-chloro-3-iodo-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. for C26H19ClIN3 [M+1]+ 536. found 536.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>O1CCOCC1>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:28][CH2:27][CH2:26][O:25][CH3:24])[CH:12]=3)[CH:7]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(Cl)cc21
Reactant: COCCN
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(NCCOC)cc21
Temperature: 100 °C
Yield: 72.6 %

Procedure:
To a suspension of Example A6 (0.500 g, 1.507 mmol) in dioxane (10 mL) was added 2-methoxyethylamine (2 mL, 23.22 mmol) and the mixture was heated at 100° C. for 40 h. Solvent from the reaction mixture was evaporated and the residue was diluted with water (50 mL) and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried, and the solvent evaporated to provide 3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-7-(2-methoxyethylamino)-1,6-naphthyridin-2(1H)-one (405 mg, 73% yield) as an orange-yellow solid. MS (ESI) m/z: 371.2 [M+H]+.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[NH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[CH:27][CH:28]=1>>[N+:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:36])[CH:24]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ccc3ccccc3c2[N+](=O)[O-])c1
Yield: 69 %

Procedure:
1-Nitronaphthalen-2-yl triflate (5.94 g, 18.5 mmol) and tert-butyl 3-aminophenylcarbamate were used in a process similar to Example 1(1) to give the titled compound (4.83 g, yield 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([Br:18])[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl.[CH2:20]([N:27]([CH2:31][CH2:32]Cl)[CH2:28][CH2:29]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH2:20]([N:27]1[CH2:31][CH2:32][N:1]([C:2]2[CH:14]=[C:13]3[C:5]([C:6]4[CH:7]=[C:8]([Br:18])[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=4[NH:12]3)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N)ccc12
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N3CCN(Cc4ccccc4)CC3)ccc12
Temperature: 80 °C

Procedure:
7-Amino-3-bromo-9H-carbazole-1-carboxamide 470B (400 mg, 1.315 mmol), N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (707 mg, 2.63 mmol) and sodium carbonate (697 mg, 6.58 mmol) were mixed in DMF (8 mL) in a sealed microwave vial. The vial was degassed and filled with N2. The mixture was heated at 80° C. for 16 hrs in an oil bath. The mixture was then heated in microwave at 200 C for 1 hr. The mixture was purified using preparative HPLC to give titled product. MS (ESI) m/z 463.07 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16](O)[C:15]3[C:10](=[C:11]([O:23][CH3:24])[C:12]([O:21][CH3:22])=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([Cl:27])[C:15]3[C:10](=[C:11]([O:23][CH3:24])[C:12]([O:21][CH3:22])=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2c(O)nc(-c3ccc(Cl)cc3)nc2c(OC)c1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(Cl)nc(-c3ccc(Cl)cc3)nc2c(OC)c1OC

Procedure:
18.2 g of 2-(4-chlorophenyl)-hydroxy-6,7,8-trimethoxyquinazoline were heated at 100° C. for 3 h in 120 ml of phosphorus oxychloride. The excess phosphorus oxychloride was distilled off and the oily residue was stirred with ice water. The solid was filtered off with suction and dried under reduced pressure. Yield: 15.0 g. M.p.: 159° C.
Reaction SMILES: [C:1](C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1O)(=O)[C:2]1C=CC=CC=1.[OH:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([N+:41]([O-:43])=[O:42])[C:31]=1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C:26]([OH:28])=[O:27]>>[OH:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([N+:41]([O-:43])=[O:42])[C:31]=1[C:32](=[O:40])[C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1)[C:26]([O:28][CH2:1][CH3:2])=[O:27]
Reactant: Cc1ccc(C(=O)c2c(O)cc(C(=O)O)cc2[N+](=O)[O-])cc1
Reactant: O=C(O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Product: CCOC(=O)c1cc(O)c(C(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1

Procedure:
By replacing in Example 6, step A, 4-benzoyl-3hydroxy-5-nitrobenzoic acid with 3-hydroxy-4-(4'-methylbenzoyl)-5-nitrobenzoic acid and following the procedure described, ethyl 3-hydroxy-4-(4'-methylbenzoyl)-5-nitrobenzoate is obtained with a melting point of 145°-147° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[C:3]=1[F:13].CS(C)=O.[CH:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>O>[F:13][C:3]1[C:4]([O:11][CH3:12])=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:24]1[CH2:25][CH2:26][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23]1
Reactant: COc1c([N+](=O)[O-])ccc(F)c1F
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1c([N+](=O)[O-])ccc(N2CCN(C(C)C)CC2)c1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
A pressure flask was charged with 1,2-difluoro-3-(methyloxy)-4-nitrobenzene (3.5 g, 18.5 mmol), dimethylsulfoxide (100 mL), isopropyl piperazine (5.41 mL, 22.2 mmol) and potassium carbonate (5.1 g, 37.04 mmol). The resulting slurry was warmed to 70° C. and stirred overnight. The next morning, the orange solution was poured into water and extracted with diethyl ether. The organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and purified via chromatography on SiO2 (0 to 10% MeOH/CH2CL2 with 0.2% NH3) to afford 1-[2-fluoro-3-(methyloxy)-4-nitrophenyl]-4-(1-methylethyl)piperazine as a yellow solid (5.7 g, quant. yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.10 (d, J=6.60 Hz, 6 H), 2.71 (s, 4 H), 2.76 (s, 1 H), 3.29 (s, 4 H), 4.03 (s, 3 H), 6.64 (dd, J=9.53, 8.07 Hz, 1 H), 7.70 (dd, J=9.35, 2.02 Hz, 1 H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[N:5]([CH2:8][CH3:9])[C:6]=1Br.[Li]CCCC.CCCCCC.C[Si](Cl)(C)C.CN([CH:39]=[O:40])C>C1COCC1.CO.O>[CH2:8]([N:5]1[CH:6]=[C:2]([CH:39]=[O:40])[N:3]=[C:4]1[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:9]
Reactant: CCn1c(-c2cccc3ccccc23)nc(Br)c1Br
Reactant: CN(C)C=O
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(C=O)nc1-c1cccc2ccccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4,5-dibromo-1-ethyl-2-naphthalen-1-yl-1H-imidazole (3.80 g, 10 mmol) in anhydrous THF (60 ml) at −78° C. under nitrogen is added a solution of n-BuLi in hexane (1.6 M, 6.88 ml, 11 mmol, 1.1 eq.) dropwise. The resulting mixture is stirred at −78° C. for 1 hr, followed by dropwise addition of TMSCl (1.188 g, 11 mmol, 1.1 eq.). The resulting solution is stirred at −78° C. After 1 hr, n-BuLi in hexane (1.6 M, 6.88 ml, 11 mmol, 1.1 eq.) is added dropwise. The resulting mixture is stirred at −78° C. for 1 hr followed by the addition of anhydrous DMF (3.65 g, 50 mmol, 5.0 eq.). The resulting solution is stirred at −78° C. for 10 min, and then warmed to rt and stirred for additional 10 min. Water (30 ml) is added to quench the reaction, followed by the addition of MeOH (3 ml). The resulting mixture is stirred at rt for 4 hr. The organic solvent is evaporated under reduced pressure and the residue is extracted with EtOAc (50 ml×3). The combined organic layers are washed with water and brine, and dried over Na2SO4. Concentration and purification through silica gel chromatography (hexanes/EtOAc, from 8:1 to 4:1) affords the title compound. LCMS 251 (M+1).
Reaction SMILES: [N:1]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[C:17]5[N:31](C6CCCCO6)[N:30]=[CH:29][C:18]=5[C:19](=[O:28])[N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:21]=4[CH:22]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1(C2C(C3C=CC4C5NN(C6CCCCO6)CC=5C(=O)N(CC(F)(F)F)C=4C=3)=CC=CN=2)CCCCC1.[ClH:75]>O>[ClH:75].[N:1]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[C:17]5[NH:31][N:30]=[CH:29][C:18]=5[C:19](=[O:28])[N:20]([CH2:23][C:24]([F:26])([F:25])[F:27])[C:21]=4[CH:22]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1c2cnn(C3CCCCO3)c2c2ccc(-c3cccnc3N3CCCCC3)cc2n1CC(F)(F)F
Agent: Cl
Agent: O=c1c2c(c3ccc(-c4cccnc4N4CCCCC4)cc3n1CC(F)(F)F)NN(C1CCCCO1)C2
Solvent: O
Product: O=c1c2cn[nH]c2c2ccc(-c3cccnc3N3CCCCC3)cc2n1CC(F)(F)F
Yield: 86 %

Procedure:
The product is obtained according to the procedure described in Step 1.7. starting with 7-[2-(piperidin-1-yl)pyrid-3-yl]-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-[2-(piperidin-1-yl)pyrid-3-yl]-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one, in the form of a white powder (hydrochloride, 1.3 H2O; yield 86%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:18])([F:17])[F:19])=[N:14][N:15]=4)[CH:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Reactant: O=Cc1ccc(F)cc1
Product: Fc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 4-fluorobenzaldehyde was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:28])[N:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>C1COCC1>[CH3:30][N:31]1[CH2:32][CH2:33][N:34]([C:37]2[CH:42]=[CH:41][C:40]([NH:43][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:28])[N:25]=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:29])=[CH:39][CH:38]=2)[CH2:35][CH2:36]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6ccnn6C)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
A small screw cap test tube was charged with 2-Methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 50 mg, 0.129 mmol) and THF (1 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (50.53 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with ˜1 mL of i-prOH yielding 32% (45 mg, 0.076 mmol) of the title compound.