Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH:10]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[C:3]2[NH:8][C:9]3[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]=3[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(Nc2ccccc2F)CCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c3c(F)cccc3c21
Yield: 155.8 %

Procedure:
Cupric acetate (2.71 g) was added to a stirred solution of 4-[(2-fluorophenyl)amino]-5,6-dihydro-2(1H)-pyridinone (1.4 g) and palladium (II) acetate (280 mg) in dry DMF (28 ml) under nitrogen. The mixture was heated at 130° for 1.5 h and the solvent was removed in vacuo. The residue was treated with hot methanol (50 ml) and the suspension was filtered and washed with hot methanol (3×50 ml). The combined filtrates were evaporated to give a gum (2.16 g) which was purified by FCC eluting with System A (200:10:1) to give the title compound (490 mg), m.p. 255°-257°.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1.[OH-].[NH4+:14]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:14])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1
Reactant: Cn1cc(Br)c2c(Cl)ncnc21
Reactant: [NH4+]
Agent: [OH-]
Product: Cn1cc(Br)c2c(N)ncnc21
Temperature: 100 °C
Reaction time: 48 h
Yield: 79.8 %

Procedure:
A suspension of 5-bromo-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (17 g, 69.0 mmol) in ammonium hydroxide (150 mL, 3852 mmol) was stirred for 2 days at 100° C. in a sealed vessel. The reaction was allowed to cool to room temperature and filtered. The collected solid was washed with Et2O to afford the product 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (12.5 g) as a white solid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]#[C:3][CH3:4].[CH:7]1[C:19]2[CH:18]([CH2:20]O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([O:6][CH2:20][CH:18]1[C:19]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:5])[C:2]#[C:3][CH3:4]
Reactant: CC#CC(=O)O
Reactant: OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC#CC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
First, 9-fluorenylmethyl 2-butynoate was prepared. A mixture of 2-butynoic acid (11.6 g, 138 mmol), 9-fluorenemethanol (35.2 g, 179 mmol), dimethylamino-pyridine-p-toluenesulfonic acid salt (16.3 g, 55 mmol), and anhydrous dichloromethane (210 mL) was cooled to 0° C. under nitrogen, and 1,3-dicyclohexylcarbodiimide (34.2 g, 166 mmol) was added. After 15 min, the reaction mixture was warmed to ambient and stirred for 12 h. The urea by product was filtered, and the filtrate was washed successively with 10% aqueous HCl, 10% aqueous NaHCO3, water, and brine. The solution was dried (Na2SO4) and concentrated to deposit a yellow oil. The product was purified by column chromatography to provide 20.0 g (54% of theory) of 9-fluorenylmethyl 2-butynoate as a yellow-green solid. 1H NMR (CDCl3): δ 1.98 (s, 3H), 4.20 (m, 1H), 4.45 (d, 2H), 7.32 (m, 4H), 7.60 (d, 2H), 7.70 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1)([O-:29])=[O:28].C(N(CC)CC)C>CN(C)C=O>[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:23]2[CH2:22][CH2:21][N:20]([C:3]3[C:4]4=[C:13]5[N:8]([CH:7]([CH3:19])[CH2:6][CH2:5]4)[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11](=[O:15])[C:12]5=[CH:14][C:2]=3[F:1])[CH2:25][CH2:24]2)=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC1CCc2c(N3CCNCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1CCc2c(N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 10 h
Yield: 60 %

Procedure:
A mixture of 9-fluoro-6,7-dihydro-5-methyl-8-(1-piperazinyl)-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (Compound [III]), hydrochloride (1.1 g), p-nitrobenzyl bromide (Compound [IV]) (1.87 g) and triethylamine (1.46 g) in N,N-dimethylformamide (50 ml) was heated with stirring at 80°-90° C. for 10 hr. After evaporation of the solvent, water was added to the residue, and the aqueous mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from a mixture of N,N-dimethylformamide and ethanol (2:1) to give 0.83 g (yield: 60%) of 8-[4-(4-nitrobenzyl)-1-piperazinyl]-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid (Compound [II]) as pale yellow needles, m.p. 230°-233° C. (decompd.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([CH3:15])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:28][CH2:29][N:30]([CH:13]([CH3:15])[CH2:12][C:8]4[C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=5[O:10][CH:9]=4)[CH2:31][CH2:32]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: COc1cccc2c(CC(C)=O)coc12
Reactant: Cc1cc(N2CCNCC2)c2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cccc2c(CC(C)N3CCN(c4cc(C)cc5cccnc45)CC3)coc12

Procedure:
6-methyl-8-{4-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl)piperazin-1-yl]quinoline was prepared by generally following the procedure outlined in example 35, step 2, starting from the 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 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, yielding a yellow oil. Yield: 40 mg (9%); (M+H): 416; 1HNMR (400 MHz, CDCl3): δ 8.86˜8.79 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H), 8.02˜7.56 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H), 7.56˜6.80 (m, 7 H), 3.89 (s, 3H), 3.50˜2.60 (m, 11H); 2.50 (s, 3H) 1.12˜114 (d, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[NH:16][C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][N:16]2[C:12]([C:10](=[O:11])[CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][C:14]([CH3:18])=[C:15]2[CH3:17])[CH2:21][CH2:20]1
Reactant: Cc1cc(C(=O)CCc2ccc(F)cc2)[nH]c1C
Reactant: BrCC1CC1
Product: Cc1cc(C(=O)CCc2ccc(F)cc2)n(CC2CC2)c1C
Yield: 64.8 %

Procedure:
The title compound was prepared as a pale yellow oil in 64.8% yield in a similar procedure to that described in Referential Example 97 by using 5-[3-(4-fluorophenyl)propionyl]-2,3-dimethylpyrrole and cyclopropylmethyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)=[O:4].[CH3:13][O:14][C:15]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17](O)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:17]([C:16]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:15]=3[O:14][CH3:13])[NH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Product: COC(=O)c1ccc2nc(-c3ccc(NS(C)(=O)=O)cc3OC)[nH]c2c1

Procedure:
Prepared analogously to Example 14 from 4-methoxycarbonyl-1,2-phenylenediamine and 2-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: Fc1cccc(OCCCBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(F)c3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.723 g of 1-(3-bromopropoxy)-3-fluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.29.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]=1.[C:13]([NH2:16])(=[O:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O>[C:13]([NH:16][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]=1)(=[O:15])[CH3:14]
Reactant: Cc1ccc2ccc(Cl)nc2c1
Reactant: CC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1ccc2ccc(C)cc2n1
Temperature: 230 °C
Yield: 78.3 %

Procedure:
Chloride 19a (0.300 g, 1.69 mmol) was diluted with molten anhydrous acetamide (8 g, 135 mmol) and K2CO3 (1.17 g, 8.45 mmol) was added. The mixture was heated in a sand bath, at reflux (˜230° C.) for 17 h. The mixture was cooled, poured into H2O (120 mL) and extracted with EtOAc (4×30 mL). The organic layers were washed with H2O (3×100 mL) and sat. aq. NaCl (50 mL), dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by flash column chromatography (SiO2, 15% EtOAc in CH2Cl2) afforded the desired compound as a white solid (0.265 g, 78%). 1H-NMR chemical shifts for this compound are consistent with those reported in the literature for the 7-isomer. H-NMR (500 MHz; CDCl3): δ 9.89-9.88 (br s, 1 H), 8.40 (d, J=8.9 Hz, 1 H), 8.15 (d, J=9.0 Hz, 1 H), 7.67 (d, J=8.3 Hz, 1 H), 7.58 (d, J=0.6 Hz, 1 H), 7.29 (dd, J=8.3, 1.4 Hz, 1 H), 2.54 (s, 3 H), 2.27 (s, 3 H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:20]1([C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: c1ccc2c(c1)CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3ccccc32)nc(N2CCOCC2)cc1=O
Temperature: 80 °C
Yield: 20.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 174 mg of 2,3-dihydro-1H-indole, and 185 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 3 ml of N,N-dimethylformamide. After silica column purification, eluent: 93/07 CH2Cl2/MeOH, the solid is taken up with 4 ml of methanol and a few drops of acetone. The suspension is heated at a temperature of 80° C., filtered while hot, and then recrystallized at a temperature of 20° C. and then of 0° C. The solid is filtered off, rinsed with diethyl ether, and then dried under a vacuum bell jar. 52 mg of 2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of white crystals, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Cl[C:6]1[N:11]=[C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=2)[C:16]#[N:17])[CH:9]=[C:8]([C:21]2([C:27]#[N:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:7]=1>>[N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=3)[C:16]#[N:17])[CH:9]=[C:8]([C:21]3([C:27]#[N:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: N#Cc1ccnc(Nc2cc(C3(C#N)CCOCC3)cc(Cl)n2)c1
Product: N#Cc1ccnc(Nc2cc(C3(C#N)CCOCC3)cc(N3CCC3)n2)c1
Yield: 17 %

Procedure:
Reaction of azetidine with 2-((6-chloro-4-(4-cyanotetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)isonicotinonitrile (50.0 mg, 0.147 mmol) following procedure of Method A afforded the target compound as a colorless solid (8.9 mg, 17%); 1H NMR (400 MHz, DMSO) δ 9.95 (br s, 1H), 8.48 (s, 1H), 8.42 (d, J=5.0 Hz, 1H), 7.23 (dd, J=5.0, 1.4 Hz, 1H), 6.89 (d, J=1.2 Hz, 1H), 5.99 (d, J=1.2 Hz, 1H), 4.06-3.98 (m, 6H), 3.70-3.59 (m, 2H), 2.41-2.28 (m, 2H), 2.08-1.96 (m, 4H); ESI-LRMS m/z [M+1]+=361.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=4)[CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2c(c1)OCCO2)c1c[nH]c2ccccc2c1=O
Reactant: FC(F)(F)c1cccc(CBr)c1
Product: O=C(c1ccc2c(c1)OCCO2)c1cn(Cc2cccc(C(F)(F)F)c2)c2ccccc2c1=O
Yield: 15.2 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 3-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-1H-quinolin-4-one 70.7 mg (0.296 mmol) and 71.1 mg (0.296 mmol) of 1-Bromomethyl-3-trifluoromethyl-benzene, to give 21 mg of desired compound. LCMS (M+H)+: 466.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:29][CH:28]=1)[C:10]([NH:12][C@@H:13]([CH:23]([CH3:25])[CH3:24])[CH2:14][O:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.CO>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:10]([NH:12][C@@H:13]([CH:23]([CH3:25])[CH3:24])[CH2:14][O:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:11])=[CH:28][CH:29]=1
Reactant: CCOC(=O)CCOC[C@@H](NC(=O)[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@@H](COCCC(=O)O)NC(=O)[C@@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
355.0 mg (0.52 mmol) of ethyl 3-((S)-2-{(R)-2-tert-butoxycarbonylamino-3-[4-(9H-fluoren-9-ylmethoxycarbonylamino)phenyl]propionylamino}-3-methylbutoxy)propionate were dissolved in a mixture of 9 ml of THF and 3 ml of MeOH. 1.29 ml (1.29 mmol) of an aqueous 1M LiOH solution were added, and the resulting reaction mixture was stirred at room temp. for 1 h. After the reaction was complete, the mixture was neutralized by adding a little aqueous 1N HCl solution, concentrated under reduced pressure and codistilled with toluene. The product obtained in this way (225.0 mg) was employed crude in the next reaction.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11]C)=[O:10])=[C:5]([CH3:17])[CH:4]=[N:3]1.[Li+].[OH-]>CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([OH:11])=[O:10])=[C:5]([CH3:17])[CH:4]=[N:3]1
Reactant: COC(=O)c1ccccc1-c1c(C)cnn1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnn(C)c1-c1ccccc1C(=O)O
Temperature: 50 °C

Procedure:
To a solution of the title compound of Step A (680 mg, 2.95 mmol) in MeOH (15 mL) was added 4 M LiOH (4 mL). The mixture was heated at 50° C. overnight. MeOH was removed and HCl added until pH=2. White solids precipitated from the reaction mixture and the precipitate was filtered, washed with EtOAc and collected to give intermediate A-31, which was used without further purification in subsequent steps. MS (ESI) mass calcd. for C12H12N2O2, 216.1. m/z found 217.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 7.95 (dd, J=7.8, 1.5 Hz, 1H), 7.67 (td, J=7.5, 1.5 Hz, 1H), 7.59 (td, J=7.6, 1.4 Hz, 1H), 7.33 (dd, J=7.6, 1.4 Hz, 1H), 7.25 (s, 1H), 3.48 (s, 3H), 1.77 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15]C)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19](#[N:21])[CH3:20].Cl>C1(C)C=CC=CC=1>[CH2:3]([O:10][CH2:11][C:12]([CH3:18])([CH3:17])[C:13](=[O:15])[CH2:20][C:19]#[N:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC#N
Reactant: COC(=O)C(C)(C)COCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(COCc1ccccc1)C(=O)CC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
To a suspension of sodium hydride (1.62 g of a 60% w/w dispersion in mineral oil, 40.5 mmol) in toluene (20 mL) at reflux was added a solution of methyl 3-(benzyloxy)-2,2-dimethylpropanoate [Eur. J. Org. Chem., 2007 (6) 934-942] (6.00 g, 27.0 mmol) and acetonitrile (2.12 ml, 40.5 mmol) in toluene, dropwise over 1 hr. The reaction mixture was heated for a further 5 hr at reflux then cooled to RT. The mixture was acidified to pH 4 with aqueous hydrochloric acid (1M) and extracted with EtOAc. The organic extract was washed with water and with brine then dried (MgSO4) and evaporated in vacuo to afford 5-(benzyloxy)-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (7.50 g, 96%): m/z 232 (M+H)+ (ES+), which was used without purification in the next step.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](C(F)(F)F)[CH:22]=3)[CH2:17][CH2:16]2)[C:11](=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[CH3:32][O:33]C1C=CC=CC=1N1CCNCC1>>[CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:33][CH3:32])[CH2:17][CH2:16]2)[C:11](=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2ccccc2OC)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 7d, using 1-(2-methoxyphenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23](O)=[O:24])=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].B>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH2:23][OH:24])=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1=C(COCC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: B
Product: CCOC(=O)C1=C(COCCO)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
was prepared by the method described in Example 1 using 2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}acetic acid (see Preparation 5 of European patent application publication No. 0100189) and borane as the starting materials.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:16](=[O:19])[NH:17][CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.[ClH:21].O1CCOCC1>>[ClH:21].[NH2:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]([NH:17][CH3:18])=[O:19]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)[C@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-(1-Methylcarbamoyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (722 mg, 2.6 mmol) was dissolved in 4M HCl-dioxane (10 mL) at 0° C. The mixture was stirred for 1 hour at 25° C., concentrated and the residue triturated with ether. Yield, 517 mg, 93%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH3:32])=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH2:16][CH3:17])[N:5]=[CH:4][C:3]([C:18]#[N:19])=[C:2]2[NH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH3:32])=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1)[CH3:14]
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(C)cc(=O)oc4c3)c2cc1OCC
Temperature: 100 °C
Yield: 71.8 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 330 mg (1.88 mM) of 7-Amino-4-methyl-coumarin in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 431 mg of 6,7-Diethoxy-4-(4-methyl-2-oxo-2H-chromen-7-ylamino)-quinoline-3-carbonitrile as a tan solid: mass spectrum (electrospray, m/e): M+H 416.0, mp=282-284° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25].O>N1C=CC=CC=1>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:24]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)=[O:25])[CH:7]=1)=[O:18]
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1)c1cccs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (240 mg, 0.86 mmol) was dissolved in pyridine (10 mL). The mixture was stirred at 0° C. for 20 min. and then thiophene-2-carbonyl chloride (113 mg, 0.77 mmol) was added dropwise. The mixture was warmed to 23° C. and stirred under nitrogen overnight. The next day, water (1 mL) was added and the mixture was stirred for 5 min. The reaction was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (Gemini, 200 mm×25 mm, gradient: CH3CN/0.05% NH3.H2O, 50-80, 10 min) to afford the desired product (72.6 mg, yield: 22%). 1HNMR: (DMSO-d6, 400 MHz): δ 11.38 (s, 1H), 10.92 (s, 1H), 8.47 (s, 1H), 8.33 (d, J=5.6 Hz, 1H), 8.26 (d, J=2.8 Hz, 1H), 7.90 (d, J=5.2 Hz, 1H), 7.62-7.51 (m, 4H), 7.22 (t, J=4.4 Hz, 1H). LCMS (ESI) (m/z): 414.3 [M+Na+].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[CH3:28][O:29][CH2:30][CH:31]([NH:33][C:34]1[NH:38][C:37]([CH3:39])=[N:36][N:35]=1)[CH3:32]>>[F:27][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:18])[N:33]([CH:31]([CH3:32])[CH2:30][O:29][CH3:28])[C:34]2[N:35]([N:36]=[C:37]([CH3:39])[N:38]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: COCC(C)Nc1nnc(C)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C(C)COC)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 40.3 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1 g) and N-(2-methoxy-1-methylethyl)-5-methyl-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.28 g, 40%).