Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[C:37]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](O)=[O:40].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:35][C:36]1[C:37]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:38]([C:39]([N:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:1]([N:8]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:7]3)[CH2:2]2)=[O:40])[CH:42]=[CH:43][CH:44]=1
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1cccc(F)c1-n1nccn1)N1CC[C@H]2CN(c3cnc4ccccc4n3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline (Intermediate 3) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 50) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C23H20FN7O, 429.46; m/z found 430.1 [M+H]+. 1H NMR (CD3OD): 8.27-8.14 (m, 1H), 8.08-7.58 (m, 5H), 7.48-6.45 (m, 4H), 4.83-4.54 (m, 1H), 4.25-3.97 (m, 3H), 3.74-3.63 (m, 1H), 3.43-3.37 (m, 1H), 3.19-3.06 (m, 2H), 2.27-1.82 (m, 2H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][CH2:20][C@@H:19]2[C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:12][C:11]=1[F:32])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:24][C:22]1([CH3:25])[CH2:23][C@H:18]([O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([NH:6][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][N:34]=3)(=[O:8])=[O:9])=[C:11]([F:32])[CH:12]=2)[C@@H:19]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH2:20][CH2:21]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC(C)(C)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC(C)(C)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 92.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-5,5-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (100 mg, 0.159 mmol) prepared in Example 72e, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (70 mg, 92%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[N:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH3:16]>CN(C)C=O.O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]([CH2:15][CH3:16])[C:10](=[O:11])[C:5]2=[N:4][CH:3]=1
Reactant: O=c1[nH]ccn2c(Br)cnc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccn2c(Br)cnc2c1=O
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 20.1 %

Procedure:
3-Bromo-7H-imidazo[1,2-a]pyrazin-8-one (prepared as described in Example 5, 1.6 g, 7 mmol) was suspended in N,N-dimethylformamide (15 ml) then treated with sodium hydride (420 mg of a 60% dispersion in mineral oil, 10.5 mmol). The resulting mixture was heated at 60° C. for 20 min then treated with iodoethane (840 μl, 10.6 mmol). After stirring for 40 min the reaction was cooled, diluted cautiously with water (150 ml) and then extracted with dichloromethane (2×100 ml). The organics were combined, washed with water, dried over anhydrous magnesium sulphate, filtered and concentrated under high vacuum. The residue was triturated with diethyl ether and the resulting solid collected by filtration and recrystallized from ethyl acetate/methanol to furnish 3-bromo-7-ethyl-7H-imidazo[1,2-a]pyrazin-8-one as a white solid (0.34 g): δH (400 MHz, DMSO) 1.23 (3H, t, J 7), 3.94 (2H, q, J 7), 7.31 (1H, d, J 6), 7.41 (1H, d, J 6), 7.62 (1H, s); m/z (ES+) 244 and 242 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5](=[O:16])[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1.[CH2:17](I)[CH3:18]>CN(C)C=O.ClCCl>[CH2:17]([O:3][C:4]1[C:5](=[O:16])[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1)[CH3:18]
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc(C(C)C)ccc(CO)c1=O
Temperature: 70 °C
Yield: 37.5 %

Procedure:
60% oily sodium hydride (256 mg, 6.4 mmol) was added to a solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (1.13 g, 5.82 mmol) in dimethylformamide (5 ml) with stirring. Then, ethyl iodide (0.7 ml, 8.75 mmol) was added and the reaction mixture was heated at 70° C. for 3 hours. The reaction solution was diluted with dichloromethane, washed with water, and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (2:3)] to give 485 mg of 2-ethoxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one as a pale yellow amorphous powder (yield: 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[NH:10][C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24]C(C)(C)C)=[O:23])[CH:17]=3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[NH:10][C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)O)c2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
At room temperature, tert-butyl 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureido)phenoxy)picolinate (1.4 g, 2.76 mmol) was dissolved in dichloromethane (20 mL). To the resulted solution, trifluoroacetic acid (20 mL) and triethylsilane (0.5 mL) were added. The resulted mixture was heated to 50° C. and stirred for 16 hours. The solvent was removed under reduced pressure, and water (50 mL) and ethyl acetate (70 mL) were added. The resulted mixture was separsted and the organic phase was removed. The aqueous layer was filtered and the solid was washed with water (30 mL×2). The solid was dried under vacumn to give the title compound (1.1 g, purity 97%, yield 90%) as a light green solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH:12][CH:13]=[C:14]1[C:19](=[O:20])OC(C)(C)OC1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:24]([C:19](=[O:20])[CH:14]=[CH:13][NH:12]2)=[CH:25][C:26]=1[O:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OCc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 45 °C
Yield: 82 %

Procedure:
5-((3-Benzyloxy-4-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g, 26 mmol) was rapidly added to phenyl ether (150 ml) heated at reflux. The mixture maintained a vigorous reflux for 5 minutes, and was allowed to cool to 45° C. then poured into petroleum ether. The resulting solid was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10 and 85/5) to give 7-benzyloxy-6-methoxy-1,4-dihydroquinolin-4-one (6 g, 82%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=4)[CH:15]=3)[CH:10]=[CH:9]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][NH2:34].O>CS(C)=O>[CH3:33][NH:34][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=4)[CH:15]=3)[CH:10]=[CH:9]2)[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3ccn(-c4cc(Cl)ncn4)c3c2)c1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)ncn1
Temperature: 100 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
1-(6-Chloropyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (200 mg, 0.57 mmol) and potassium carbonate (788 mg, 7.5 mmol) were dissolved in DMSO (5 mL). Methylamine hydrochloride (192 mg, 2.85 mmol) was added at room temperature. The reaction mixture was stirred at 100° C. for 15 hours. After cooling to room temperature, water was added and the reaction mixture was stirred for 1 hour. Thus prepared solid was filtered, washed with water, and dried in the air. N-Methyl-6-(6-(3-nitrophenyl)-1H-indol-1-yl)pyrimidin-4-amine (193 mg) was yielded as white solid.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>>[CH2:13]([NH:19][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC1CO1
Reactant: NCCCCCN
Product: CCCCCCCCCC(O)CNCCCCCNCC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and 1,5-pentanediamine affords N,N'-(1,5-pentylene)-bis[2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = H, X = (CH2)5, Z = H).
Reaction SMILES: [N:1]1(N)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:13]1[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl>CCO>[CH:8]1[C:9]2[C:17]3[CH2:18][CH2:19][NH:13][CH2:14][CH2:15][C:16]=3[N:1]3[C:10]=2[C:5]([CH2:4][CH2:3][CH2:2]3)=[CH:6][CH:7]=1
Reactant: O=C1CCCNCC1
Reactant: NN1CCCc2ccccc21
Agent: Cl
Solvent: CCO
Product: c1cc2c3c(c1)c1c(n3CCC2)CCNCC1
Temperature: 20 °C
Yield: 25.2 %

Procedure:
To a solution of 3,4-dihydro-1(2H)-quinolinamine (1.0 g, 14 mmol) and hexahydro-4H-azepin-4-one hydrochloride (1.0 g, 14 mmol) in EtOH (13 mL) was added concentrated HCl (1.2 mL). The reaction was stirred at reflux for 14 h, then cooled to 20° C. A brown precipitate was filtered from the reaction mixture, affording the title compound (800 mg, 45%) as a brown solid. 1H NMR (CD3OD, 300 MHz) δ 2.14-2.23 (m, 2H), 2.91 (t, 2H, J=6.0 Hz), 3.16-3.21 (m, 2H), 3.27-3.33 (m, 2H), 3.39-3.50 (m, 4H), 4.04 (t, 2H, J=5.7 Hz), 6.70 (d, 1H, J=6.9 Hz), 6.87-6.93 (m, 1H), 7.22 (d, 1H, J=8.0 Hz) ppm. MS (ESI): 227.2 (base, M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([OH:13])[CH:3]=1.[CH2:14]([S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])=[O:17])[CH3:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([O:13][C:22]2[CH:23]=[CH:24][C:19]([S:16]([CH2:14][CH3:15])(=[O:18])=[O:17])=[CH:20][C:21]=2[Cl:26])[CH:3]=1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)CCc1ccc(Cl)cc1O
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2CCC(=O)O)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 3 step viii) using the product from step ii) and the product from example 4 step i).
Reaction SMILES: ClC1C=C([N:8]2[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]2)C=CN=1.Br[C:17]1[CH:18]=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:21][CH:22]=1>>[CH3:15][C@H:10]1[NH:11][C@@H:12]([CH3:14])[CH2:13][N:8]([C:17]2[CH:18]=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:21][CH:22]=2)[CH2:9]1
Reactant: C[C@@H]1CN(c2ccnc(Cl)c2)C[C@H](C)N1
Reactant: CCOC(=O)c1cncc(Br)c1
Product: CCOC(=O)c1cncc(N2C[C@@H](C)N[C@@H](C)C2)c1

Procedure:
The title compound was prepared in a similar manner to cis-1-(2-chloro-4-pyridinyl)-3,5-dimethylpiperazine using ethyl 5-bromo-3-pyridinecarboxylate and cis-2,2-dimethylpiperazine as the starting materials (D19). MS (ES+) m/e 264 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.O[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[O:18][CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:19][O:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[O:6][C@@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: O[C@H]1CCOC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O[C@@H]2CCOC2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
To a stirred solution of (3S)-tetrahydrofuran-3-ol (403 mg, 4.57 mmol), methyl 4-hydroxy-3-methoxy-benzoate (1.00 g, 5.49 mmol) and triphenylphosphane (1.44 g, 1.27 mL, 5.49 mmol) in THF (13 mL) at 0° C. was added DIAD (1.11 g, 1.06 mL, 5.49 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h, then at 55° C. for 4 h. The mixture was diluted with EtOAc and was washed with sat. aq. NaHCO3 (×2) and brine (×2). The organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield (R)-methyl 3-methoxy-4-(tetrahydrofuran-3-yloxy)benzoate (0.97 g, 84%) as a viscous liquid. ESI-MS m/z calc. 252.1. found 253.3 (M+1)+; Retention time: 1.72 minutes (3 min run).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([OH:12])=[CH:5]2.[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:22])=[CH:11][CH:10]=2
Reactant: Oc1cnc2ccc(I)cc2c1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc2ncc(O)cc2c1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A stirred solution of 6-iodoquinolin-3-ol (1.76 g, 6 mmol) in THF (10 mL) was treated with 2-tert-butoxy-2-oxoethylzinc chloride (39 ml, 19 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.8 g, 0.6 mmol). After the addition, it was heated to reflux (75° C.) under N2. After 3 h, TLC 89368-3-1 showed no sign of starting material. Reaction was stop. The reaction was cooled to rt. Solvent was removed. The residue was stirred in EtOAc/10% EDTA (50 mL/50 mL) solution mixture. After 1 h, the organic layer was separated. The aqueous layer was extracted with more EtOAc (2×25 mL). The combined organic layers were washed with water, brine, dried over MgSO4, and removed solvent. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO2, hex:acetone=80%:20%, Flow=30 mL/min). to afford the desired product as brownish liquid. MS m/z: 260.3 (M+H). Calc'd. for C15H17NO3—259.2.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:9]([C:24]([OH:26])=[O:25])=[CH:10][S:11][C:12]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.[CH:27]1([CH2:30][C:31](N(OC)C)=[O:32])[CH2:29][CH2:28]1.O>O1CCCC1>[CH:27]1([CH2:30][C:31]([C:10]2[S:11][C:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)=[C:8]([O:7][CH3:6])[C:9]=2[C:24]([OH:26])=[O:25])=[O:32])[CH2:29][CH2:28]1
Reactant: CON(C)C(=O)CC1CC1
Reactant: COc1c(C(=O)O)csc1Cc1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(Cc2cccc(C(F)(F)F)c2)sc(C(=O)CC2CC2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.1 %

Procedure:
2M butyl lithium in hexanes (1.75 ml) was added slowly to a solution of 4-methoxy-5-[(3-trifluoromethylphenyl)methyl]thiophene-3-carboxylic acid (500 mg) in tetrahydrofuran (30 ml) at −78° C. The resultant red solution was stirred for 20 minutes and then 2-cyclopropyl-N-methoxy-N-methylacetamide (229 mg) in tetrahydrofuran (3 ml) was added. The mixture was stirred for 20 minutes at −78° C. and was then allowed to warm to room temperature. After 5 hours water was added and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated. Purification of the residue by chromatography, eluting with 10:10:1 isohexane:ether:acetic acid, gave the sub-title compound (177 mg).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([C:24]4[N:25]=[N:26][N:27]([CH3:29])[N:28]=4)[CH:20]=[C:21]([F:23])[CH:22]=3)[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:9][CH:10]([CH:12]([C:17]2[CH:18]=[C:19]([C:24]3[N:25]=[N:26][N:27]([CH3:29])[N:28]=3)[CH:20]=[C:21]([F:23])[CH:22]=2)[C:13]([F:16])([CH3:15])[CH3:14])[CH2:11]1
Reactant: Cn1nnc(-c2cc(F)cc(C(C3CN(C(c4ccccc4)c4ccccc4)C3)C(C)(C)F)c2)n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Agent: [OH-]
Solvent: CCO
Product: Cn1nnc(-c2cc(F)cc(C(C3CNC3)C(C)(C)F)c2)n1

Procedure:
A solution of 370 mg (0.78 mmol) of 5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-2-methyl-2H-tetrazole in 20 mL of EtOH was shaken in presence 200 mg of Pd(OH)2 under 50 Psi pressure hydrogen for 24 h. Then it was filtered to remove the solid and washed with CH2Cl2. The combined organic layer was concentrated and washed with hexanes/ethyl ether to afford the title compound as a white solid; Mass Spectrum: m/e=308 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2[C:27](O)=[O:28].Cl.[OH:31][C:32]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:33]=1[CH2:34][CH2:35][NH:36][CH2:37]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[N:7]=[C:6]2[C:27]([N:36]1[CH2:35][CH2:34][C:33]2[C:38](=[CH:39][CH:40]=[CH:41][C:32]=2[OH:31])[CH2:37]1)=[O:28]
Reactant: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)O)c2cc1OC
Reactant: Oc1cccc2c1CCNC2
Agent: Cl
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)N3CCc4c(O)cccc4C3)c2cc1OC
Yield: 9.3 %

Procedure:
Reaction of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 119 (9.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.80 and 2.90 (2t, 2H), 3.52-4.07 (m, 17H), 4.42 and 4.94 (2s, 2H), 6.29-7.17 (m, 4H), 7.48 and 7.51 (2s, 1H), 7.78 and 7.84 (2s, 2H), 9.50 and 9.52 (2s, 1H); MS (ESI) m/z 532 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.Cl[C:13]1[N:22]=[C:21]([NH:23][CH2:24][CH2:25][O:26][CH3:27])[C:20]2[C:19](=[O:28])[N:18]([CH3:29])[CH:17]=[N:16][C:15]=2[CH:14]=1>>[CH3:27][O:26][CH2:25][CH2:24][NH:23][C:21]1[C:20]2[C:19](=[O:28])[N:18]([CH3:29])[CH:17]=[N:16][C:15]=2[CH:14]=[C:13]([C:2]2[CH:11]=[CH:10][C:5]3[N:6]=[C:7]([CH3:9])[O:8][C:4]=3[CH:3]=2)[N:22]=1
Reactant: Cc1nc2ccc(Br)cc2o1
Reactant: COCCNc1nc(Cl)cc2ncn(C)c(=O)c12
Product: COCCNc1nc(-c2ccc3nc(C)oc3c2)cc2ncn(C)c(=O)c12

Procedure:
5-(2-Methoxyethylamino)-3-methyl-7-(2-methylbenzo[d]oxazol-6-yl)pyrido[4,3-d]pyrimidin-4(3H)-one was synthesized, as described in Example 9, from 6-bromo-2-methylbenzo[d]oxazole and 7-chloro-5-(2-methoxyethylamino)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one. After purification by preparatory LC/MS, it was partially decomposed to N-(2-hydroxy-4-(5-(2-methoxyethylamino)-3-methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)phenyl)acetamide. The two compounds are separated again by preparatory TLC.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH:20][C:31](=[O:33])[CH3:32])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(N)c3)n2)n1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 56.7 %

Procedure:
To a stirred and cooled solution of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-phenylamine (example 327) (0.400 g, 0.986 mmol) in EtOAc (4 mL) and sat. NaHCO3-sol. (2 mL) was added acetyl chloride (0.080 mL, 1.085 mmol) and the mixture was stirred at 23° C. for 1 h. Diluted with EtOAc, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by trituration with diethyl ether to give the title compound as a white solid (0.250 g, 57%). MS (ISP) 484.2 [(M+H)+].
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][NH:36][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CNCCCN
Product: CNCCCNC(=O)Nc1snc(OCc2c(F)cc(C)c(F)c2F)c1C(N)=O

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N-methyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCl, m/z): 432 [M+H]+.