Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([N:23]([CH2:38][CH3:39])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=1[CH3:37])=[O:28])[CH3:22].N1CCCCC1>C(O)C>[CH2:38]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32](/[CH:35]=[C:14]2\[C:15](=[O:20])[NH:16][C:17]3[C:13]\2=[CH:12][C:11]([S:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:19][CH:18]=3)[NH:31][C:30]=1[CH3:37])=[O:28])[CH3:39]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.5 %

Procedure:
To a solution of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.34 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (92 mg, 0.34 mmol) in ethanol (4 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 25° C. for three days. An orange solid product was precipitated out, filtered, washed thrice with ethanol, and dried under high vacuum to provide to provide 99 mg (55%) of 2,4-dimethyl-5-[2-oxo-5-phenylmethanesulfonyl-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][NH2:10].[N-:11]=[C:12]=[O:13].[K+].Cl>O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][NH:10][C:12]([NH2:11])=[O:13]
Reactant: [N-]=C=O
Reactant: NCCOC1CCCCO1
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NCCOC1CCCCO1
Temperature: 0 °C
Yield: 92 %

Procedure:
A mixture of 33.2 g of 2-(tetrahydropyran-2-yloxy) ethylamine, 50 g of ice, and a solution of 35 g of potassium isocyanate in 80 ml of water is stirred well as 45.6 ml of 5N hydrochloric acid (cooled to -40°C) is added in one portion. The resulting solution is refluxed for 90 minutes, cooled, and extracted with four 150 ml portions of chloroform. The chloroform extract is dried and evaporated in vacuo to give 39.6 g of oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:34])=[C:4]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C:5]([I:28])=[C:6]([C:26]=1[I:27])[C:7]([NH:9][CH:10]([CH:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:8].[C:35]([O:38][CH:39]([CH:43]([O:49][C:50](=[O:52])[CH3:51])[CH2:44][O:45][C:46](=[O:48])[CH3:47])[C:40](Br)=[O:41])(=[O:37])[CH3:36]>>[C:35]([O:38][CH:39]([CH:43]([O:49][C:50](=[O:52])[CH3:51])[CH2:44][O:45][C:46](=[O:48])[CH3:47])[C:40]([NH:1][C:2]1[C:3]([I:34])=[C:4]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C:5]([I:28])=[C:6]([C:26]=1[I:27])[C:7]([NH:9][CH:10]([CH:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:8])=[O:41])(=[O:37])[CH3:36]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Br
Product: CC(=O)OCc1c(I)c(NC(=O)C(OC(C)=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I
Yield: 45 %

Procedure:
5-Amino-3-acetoxymethyl-N-(1,3,4-triacetoxybut-2-yl)-2,4,6-triiodobenzamide (20 g, 24.5 mmol) was acylated with 2,3,4-triacetoxybutanoyl bromide (15.9 g, 49.0 mmol) according to the procedure given in example 80a. The yield was 45%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]([OH:21])[C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=1)[O:8][C:7]([CH3:23])([CH3:22])[CH:6]=[CH:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]([OH:21])/[CH:13]=[CH:14]/[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:11]=1)[O:8][C:7]([CH3:23])([CH3:22])[CH:6]=[CH:5]2
Reactant: CC1(C)C=Cc2cc(Br)cc(C(O)C#Cc3ccccc3)c2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(C)C=Cc2cc(Br)cc(C(O)/C=C/c3ccccc3)c2O1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To a 10 mL round bottomed flask containing 100 mg (0.271 mmol, 1 equiv.) 1-(6-bromo-2,2-dimethyl-2H-chromen-8-yl)-3-phenylprop-2-yn-1-ol dissolved in 1.5 mL dry THP was added 12 mg (0.33 mmol, 1.2 equiv.) LiAlH4. The reaction was heated to reflux for 1 hr and cooled to ambient temperature. The reaction was quenched by addition of H2O followed by 15% NaOH (aq.) and then EtOAc. The organic layer was separated and then filtered through a short silica gel plug before being concentrated to yield 100 mg (99%) of the desired product (5) as a yellow oil. See Compound 6, FIG. 12F.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C#N)c(C)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2ccc(O)cc2)ccc1C#N
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.8 %

Procedure:
The product from Example 106A (5.60 g, 25.4 mmol) in CH2Cl2 (120 mL) at 78° C. was treated with 1.0 M BBr3 (in CH2Cl2, 76 mL, 76.0 mmol) dropwise over 1 hour. After stirring for 14 hours at room temperature, the mixture was warmed to 0° C. (ice bath) and treated with water (0.5 mL). After 10 minutes, additional water was added (2.0 mL), ice bath was removed, and 5.0 mL of water was added. The mixture was then treated with another 20 mL of water and allowed to stir for 45 minutes. The mixture was filtered and the filtrate extracted with CH2Cl2. The CH2Cl2 layers were combined, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to provide the title compound as an off-white powder (5.04 g, 94% yield). 1HNMR (300 MHz, CDCl3) δ 2.35 (s, 3H), 5.0 (s, 1H), 6.79-7.50 (m, 7H); MS (DCI) m/z 210 (+H)+.
Reaction SMILES: [F:1][CH:2]([F:43])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:11]([N+:28]([O-])=O)=[C:10]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:9]=2)[C:6]2[CH:37]=[CH:38][CH:39]=[C:40]([O:41][CH3:42])[C:5]=2[N:4]=1>CO.C1COCC1.[Pd]>[NH2:28][C:11]1[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[N:13][C:8]([N:7]2[C:6]3[CH:37]=[CH:38][CH:39]=[C:40]([O:41][CH3:42])[C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:43])=[N:9][C:10]=1[N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c(N2CCOCC2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c(N2CCOCC2)n1
Reaction time: 5 h
Yield: 93.3 %

Procedure:
A mixture of the above nitro compound (700 mg, 1.16 mmol) and 10% Pd on carbon in MeOH/THF (70 mL: 15 mL) was hydrogenated for 5 hrs. The reaction mixture was filtered through celite, the celite pad was washed with MeOH and CH2Cl2, and the solvents were removed under vacuum. Recrystallization from CH2Cl2/MeOH gave tert-butyl 4-{[5-amino-2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]amino}-1-piperidinecarboxylate (622 mg, 94%): mp 223-225° C.; 1H NMR (CDCl3) δ 7.92 (dd, J=8.4, 0.6 Hz, 1H), 7.54 (t, JHF=53.7 Hz, 1H), 7.32 (t, J=8.2 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 4.68 (d, J=7.6 Hz, 1H), 4.23-4.10 (m, 3H), 4.05 (s, 3H), 3.89 (m, 4H), 3.25 (m, 4H), 3.06 (br s, 2H), 2.96 (t, J=12.0 Hz, 2H), 2.11 (m, 2H), 1.47 (s, 9H), 1.50-1.40 (m, 2H); Anal. Calcd. for C27H36F2N8O4: C, 56.4. H, 6.3; N, 19.5. Found: C, 56.3; H, 6.4; N, 19.7%.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]([C:9]1[CH:25]=[C:24]2[N:12]([CH2:13][C:14]3[C:15]2=[N:16][C:17]2[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11](=[O:26])[C:10]=1[CH3:27])[CH2:7][CH3:8])=[O:4].[I-:28].[Na+]>CC(C)=O>[I:28][CH2:2][C:3]([O:5][CH:6]([C:9]1[CH:25]=[C:24]2[N:12]([CH2:13][C:14]3[C:15]2=[N:16][C:17]2[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11](=[O:26])[C:10]=1[CH3:27])[CH2:7][CH3:8])=[O:4]
Reactant: CCC(OC(=O)CCl)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(OC(=O)CI)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
To a mixture of (±)-7-[1-[(chloroacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one (100 mg, 0.26 mmol) in acetone (10 mL) was added sodium iodide (150 mg, 1.0 mmol), and the resulting solution was heated at reflux for 1 h. Upon cooling, a solid precipitate appeared. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and H2O. The organic extract was washed with H2O (3×), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. 1H NMR (CDCl3) d 8.35 (s, 1H), 8.22 (d, J=8.2 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.81 (m, 1H), 7.66 (m, 1H), 7.38 (s, 1H), 5.91 (dd, J=7.9, 6.0 Hz, 1H), 5.26 (two s, 2H), 3.84 (d, J=10.1 Hz, 1H), 3.75 (d, J=10.1 Hz, 1H), 2.36 (s, 3H), 2.10-1.83 (m, 2H), 1.03 (t, J=7.4 Hz, 3H). Anal. Calcd for C21H19IN2O3.1/2 H2O: C, 52.19; H, 4.17; N, 5.80. Found: C, 52.16; H, 4.05; N, 5.39.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C:36]1=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1COCC1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:36]4[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]4[CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=C1CCCCC1Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC4CCCCC4Cc4ccccc4)cc3)cc2)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.200 g, 0.55 mmol) and 2-benzylcyclohexanone (0.156 g, 0.83 mmol) were combined in toluene and stirred at 110° C. for 1 hour. After cooling to room temperature, THF was added, followed by sodium cyanoborohydride (0.086 g, 1.37 mmol), and the reaction was stirred at room temperature for 2 hours. The mixture was adsorbed onto silica gel and purified by silica gel chromatography to give the title compound.
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]([OH:29])=O.Cl.[CH3:31][O:32][C:33]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][NH:37][CH2:38]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:37]1[CH2:36][CH2:35][C:34]2[C:39](=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:33]=2[O:32][CH3:31])[CH2:38]1)=[O:29]
Reactant: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)O)c2cc1OC
Reactant: COc1cc2c(c(OC)c1)CCNC2
Agent: Cl
Product: COc1cc2c(c(OC)c1)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3cc(OC)c(OC)cc13)C2
Yield: 45.3 %

Procedure:
Reaction of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 118 (45.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.86 and 3.01 (2t, 2H), 3.45-4.05 (m, 23H), 4.23 and 4.77 (2s, 2H), 6.33-6.49 (m, 2H), 6.90 and 7.15 (2s, 1H), 7.48 and 7.50 (2s, 1H), 7.78 and 7.83 (2s, 2H); MS (ESI) m/z 576 ([M+H]+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]5[S:23][CH:24]=[N:25][N:26]=5)[CH:20]=4)[N:15](C(OC(C)(C)C)=O)[CH:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:23]1[CH:24]=[N:25][N:26]=[C:22]1[C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C:11]1[N:12]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nncs3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(-c2c[nH]c3ccc(-c4nncs4)cc23)nc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of tert-butyl 3-(6-morpholinopyridin-2-yl)-5-(1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (86.0 mg, 0.186 mmol) in DCM (1.0 mL) was added TFA (1.0 mL) and the reaction was stirred at RT for 1 h, then solvent was removed. The residue was diluted with DCM (60 mL) and washed with sat. NaHCO3, dried, filtered and concentrated. The residue was purified with RP-HPLC to give 4-(6-(5-(1,3,4-thiadiazol-2-yl)-1H-indol-3-yl)pyridin-2-yl)morpholine (34.0 mg, 0.094 mmol, 50.4%) as a yellow solid. MS (ESI, pos. ion) m/z: 364 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.78 (1H, br. s.), 9.52 (1H, s), 9.17 (1H, d, J=1.4 Hz), 8.16 (1H, d, J=2.5 Hz), 7.92 (1H, dd, J=8.6, 1.6 Hz), 7.53-7.65 (2H, m), 7.24 (1H, d, J=7.6 Hz), 6.66 (1H, d, J=8.4 Hz), 3.78-3.90 (4H, m), 3.57-3.69 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH3:16])=[O:4].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][Br:17])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1oc(-c2ccccc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1oc(-c2ccccc2)nc1CBr

Procedure:
4-Methyl-2-phenyl-oxazole-5-carboxylic acid methyl ester (3.2 g, 14.7 mmol, prepared according to Cynkowski, T.; Cynkowska, G.; Ashton, P.; and Crooks, P. A. J. Chem. Soc., Chem. Commun. 1995, 2335), N-bromosuccinimide (2.69 g, 15.1 mmol), and benzoyl peroxide (356 mg, 1.47 mmol) were suspended in 37 mL of benzene and the mixture heated at reflux temperature for 16 hours. The reaction mixture was cooled and diluted with ethyl acetate. The mixture was washed successively with saturated bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic solvent was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-40% ethyl acetate in hexanes to give 1.88 g of the title compound as a yellow solid. MS: (+) m/z 296.0, 298.0 (M+1, 79Br/81Br).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[Cl:16])=[O:8].Cl.[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[ClH:16].[ClH:18].[Cl:16][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:9]=1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:8])[NH:15][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(C(=O)c2ccccn2)c(Cl)c1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(C(=O)c4ccccn4)c(Cl)c3)c2cc1OC
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-amino-2-chlorophenyl 2-pyridyl ketone was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-[3-chloro-4-(2-pyridylcarbonyl)anilino]-6,7-dimethoxyquinazoline dihydrochloride salt in 45% yield, m.p. 255°-258° C.;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:6][CH2:5]2.[C:17]([Cu])#[N:18]>CN(C=O)C.O>[F:13][C:12]([F:15])([F:14])[C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17]#[N:18])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:16]
Reactant: O=C(N1CCc2cc(Br)ccc21)C(F)(F)F
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CCN2C(=O)C(F)(F)F
Temperature: 160 °C
Reaction time: 96 h

Procedure:
1-(5-Bromo-2,3-dihydro-1H-indol-1-yl)-2,2,2-trifluoroethanone (19 g, 0.0646 mol; see step (ii) above) was dissolved in DMF (50 mL). CuCN (8.68 g, 0.0969 mol) was then added and the reaction mixture was stirred at 160° C. for 4 days, before being cooled to RT, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate then concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the sub-title compound as a white solid. Yield: 13 g.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[O:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[O:15]=[C:14]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=1)[CH2:13][CH:12]([CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:26]([O:34][CH2:35][CH3:36])=[O:33])[C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(C=Cc1cc(-c2ccccc2)cs1)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(C(F)(F)F)cc1)c1cc(-c2ccccc2)cs1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 3-(4-phenylthiophen-2-yl)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one and diethyl malonate, diethyl 2-(3-oxo-1-(4-phenylthiophen-2-yl)-3-(4-(trifluoromethyl)-phenyl)propyl)malonate was obtained as yellow oil.
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]2[O:29][CH:30]=[CH:31][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[O:29][CH:30]=[CH:31][C:27]=3[CH:26]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Reactant: BrCCc1ccc2occc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3occc3c2)C1

Procedure:
A mixture containing 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (1.79 g--see Preparation 10(B)), 5-(2-bromoethyl)benzo[2,3-b]furan (1.2 g--see Preparation 17), anhydrous potassium carbonate (3 g) and acetonitrile (30 ml) was heated under reflux for 30 minutes. The mixture was partitioned between ethyl acetate (30 ml) and 10% aqueous potassium carbonate (30 ml), the layers were separated, and the aqueous layer extracted with ethyl acetate (3×50 ml). The combined ethyl acetate extracts were dried (MgSO4) and concentrated in vacuo to give a brown gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 1.4 g.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[OH-].[Na+].CCOCC>[CH2:11]([O:18][C:19]([NH:1][CH:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(C(=O)O)c1ccsc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(NC(C(=O)O)c1ccsc1)OCc1ccccc1
Reaction time: 3 h
Yield: 73.4 %

Procedure:
2-Amino-2-(3-thienyl)acetic acid (10 g) is dissolved in 1N sodium hydroxide solution, and 1N sodium hydroxide solution and a solution of benzyloxycarbonyl chloride (13 g) in ether are simultaneously added dropwise thereto at 5° to 10° C. with vigorous stirring. The mixture is stirred at the same temperature for 3 hours. After the reaction mixture is washed, the mixture is acidified and extracted with ethyl acetate. The extract is washed, dried and concentrated to remove solvent. The residue is crystallized with a mixture of ethyl acetate and diisopropyl ether, whereby 2-benzyloxycarbonylamino-2-(3-thienyl)acetic acid (13.6 g) is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH:25]([CH:28]1[NH:32][C:31](=[O:33])[N:30]([CH3:34])[C:29]1=[O:35])([CH3:27])[CH3:26]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:32]4[CH:28]([CH:25]([CH3:26])[CH3:27])[C:29](=[O:35])[N:30]([CH3:34])[C:31]4=[O:33])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CC(C)C1NC(=O)N(C)C1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C(C)C)cc3F)CC2)c(C)c1
Yield: 59.3 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and 5-isopropyl-3-methylimidazolidine-2,4-dione (69 mg) described in Preparation Example 216 and by the reaction and treatment in the same manner as in Example 536, the title compound (111 mg) was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:8])[CH3:7].[C:24]([O-])(=[O:26])C.[Na+]>CN(C)C=O>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:23])[C:17]1[CH:18]=[CH:19][C:20]([CH:24]=[O:26])=[CH:21][CH:22]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCCCCCCN(C)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCCCCCCN(C)c1ccc(C=O)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
Phosphorous oxychloride (145 g, 0.95 mol) was added dropwise at 5° C. to 280 mL of stirred N,N-dimethylformamide (DMF), and the mixture was stirred at 5° C. for 2 hours. N-(6-Acetoxyhexyl)-N-methylaniline (Example 2, 230 g, 0.93 mol) was added slowly, and the reaction mixture was heated at 90° C. for 3 hours. After cooling, the solution was poured onto 500 g of ice and the resulting mixture was neutralized to pH 5 with sodium acetate. The mixture was extracted with dichloromethane (4×200 mL), the combined extracts were dried (MgSO4), and the solvent was removed at reduced pressure. The brown residue was distilled in vacuo to provide 186 g (73%) of a yellow oil, bp 195° C. (0.15 mm).