Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.Cl.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1N
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1NCCN(C)C
Temperature: 25 °C
Yield: 48.2 %

Procedure:
2-Anisidine (5.9 ml, 0.05 mole) and 2-dimethylaminoethyl chloride hydrochloride (5.0 g, 0.035 mole) were dissolved in ethanol (75 ml) and treated with sodium carbonate (7.42 g, 0.07 mole). The mixture was heated under reflux for 7 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate evaporated in vacuo. The residue was dissolved in H2O and 10% NaOH solution was added until basic. The mixture was extracted into Et2O, dried (Na2SO4) and evaporated in vacuo to give an orange oil. This was purified by flash column chromatography, eluting with ethyl acetate to afford the title compound as a pale orange oil (3.28 g, 48%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][NH:11][C:12]2([C:17]([O:19]C)=O)[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH2:23]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[CH3:24].CC(O)=O.[BH3-]C#N.[Na+]>CO>[F:8][C:6]1[CH:5]=[C:4]([CH:9]2[N:28]([CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:29])[C:17](=[O:19])[C:12]3([CH2:13][CH2:14][CH2:15][CH2:16]3)[NH:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C1(NCC(=O)c2cc(F)cc(F)c2)CCCC1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CN1C(=O)C2(CCCC2)NCC1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of methyl 1-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}cyclopentanecarboxylate from Step A (10.0 g, 33.6 mmol), glycine ethyl ester hydrochloride (46.9 g, 336 mmol), and AcOH (5.78 mL, 101 mmol) in MeOH (300 mL) was stirred at ambient temperature for 10 min. NaCNBH3 (2.54 g, 40.4 mmol) was added and the pH of the mixture was checked and adjusted to pH ˜5 as necessary by addition of AcOH. The reaction mixture was heated to 50° C. for 18 h then allowed to cool. The reaction mixture was carefully quenched with saturated aqueous NaHCO3 (250 mL) and then extracted with CH2Cl2 (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=353 (M+1).
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:38][CH2:39][CH2:40]O)[C:5]=2[N:4]=1.C[CH2:44][N:45](CC)[CH2:46]C.CS(Cl)(=O)=O.N(C)C>C1COCC1>[F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:38][CH2:39][CH2:40][N:45]([CH3:46])[CH3:44])[C:5]=2[N:4]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OCCCO)cccc43)n2)CC1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)CCCOc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate from the previous step and 0.34 g (3.3 mmol) of Et3N in 20 mL of THF was cooled to 0° C. and 0.32 g (2.8 mmol) of methanesulfonyl chloride was added dropwise. After 1 hr, 6 g of 40% aqueous Me2NH was added, and the resulting mixture was stirred at room temperature for 36 hrs. The THF was removed under vacuum and the residue was diluted with water and extracted into CH2Cl2. Drying and removal of the solvent gave tert-butyl 4-[4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-1H-benzimidazol-1-yl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate as an oil: 1H NMR (CDCl3) δ 7.87 (dd, J=8.4. 0.6 Hz, 1H), δ 7.48 (t, JHF=53.5 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 4.31 (t, J=6.7 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.53 (m, 4H), 2.51 (t, J=7.2 Hz, 2H), 2.26 (s, 6H), 2.13 (pentet, J=7.0 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C1CNCCN1
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 25 °C

Procedure:
The pyridine intermediate was prepared by treating a suspension of 5-bromo-2-(piperazin-1-yl)pyridine (7.0 g, 28.9 mmol) with di-tert-butyldicarbonate (6.30 g, 28.9 mmol) and the resulting mixture stirred for 2 h. The solvent was removed under reduced pressure to give the desired product (8.76 g as a beige solid after recrystallisation from aqueous ethanol, m.p. 88-90°. δH (CDCl3) 8.18 (1 H, d, J 2.5 Hz), 7.52 (1H, dd, J 9.0, 2.5 Hz), 6.52 (1H, d, J 9.0 Hz), 3.50 (8H, m) and 1.47 (9H, s). The 5-bromo-2-(piperazin-1-yl)pyridine was prepared by heating a mixture of 2,5-dibromopyridine (10.0 g, 42.4 mmol) and piperazine (7.98g, 92.8 mmol) as a melt at 125° for 3 h. On cooling to room temperature the mixture was triturated with methanol-dichloromethane to afford the desired product (7.0g) as a beige solid. δH (CDCl3) 8.18 (1H, d, J 2.1 Hz), 7.25 (1H, dd, J 9.1, 2.1 Hz), 6.52 (1H, d, J 9.1 Hz), 3.47 (4H, m), 2.97 (4H, m) and 1.75 (1H br s).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:14](Cl)[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.CCOC(C)=O>[CH2:16]([O:15][CH2:14][N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(COCn2ccnc2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To 2-phenylimidazole (500 mg, 3.47 mmol) in 10 mL THF at 0° C., was added 60% NaH (146 mg, 3.64 mmol). The mixture was stirred at 0° C. for 15 min, then BOM-Cl (80%, 656 μL, 3.82 mmol) was added. The mixture was stirred at rt for 1 h, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 630 mg of Intermediate 15.1 as a colorless oil.
Reaction SMILES: C1(C2NN=C(N[C:10]3[N:15]=[C:14]([NH:16][C@H:17](C4C=CC(F)=CC=4)C)[C:13]([CH2:26]O)=C[C:11]=3[F:28])C=2)CC1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:41]=[N+:42]=[N-:43].[Na+]>C(Cl)Cl>[N:41]([CH:13]([C:14]1[N:15]=[CH:10][C:11]([F:28])=[CH:17][N:16]=1)[CH3:26])=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CO)c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(N=[N+]=[N-])c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A round-bottom flask containing 1-(5-fluoropyrimidin-2-yl)ethanol (Method 74, 0.79 g, 5.55 mmol) was charged with triethylamine (0.67 g, 6.66 mmol) and anhydrous DCM (10 ml). The solution was cooled to 0° C., and methanesulfonyl chloride (0.70 g, 4.1 mmol) was added dropwise. The resulting mixture was allowed to stir at room temperature for 2 hours, at which point the volatile components were removed using a rotary evaporator. The residue was dissolved in DMF (15 ml) and treated with sodium azide (0.72 g, 11.1 mmol). The resulting mixture was stirred at room temperature for 60 hours. It was then partitioned between EtOAc and brine. The organic layer was obtained, dried (Na2SO4), and evaporated to dryness. The crude material was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexanes) to afford the title compound as a colourless oil (0.60 g, 65% yield over two steps). GC-MS, 167 (M), 138 (M-N2), 125 (M-N3); 1H NMR (CDCl3) δ 8.60 (s, 2H), 4.60 (m, 1H), 1.65 (d, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][C:54]=1[CH3:55])[NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][C:50]4[CH:52]=[CH:53][C:54]([CH3:55])=[C:48]([F:47])[CH:49]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(N)cc1F
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2ccc(C)c(F)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-fluoro-4-methylaniline (Aldrich) to give the title product. LC-MS (ES+) 772 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][C:52](=[O:54])[CH3:53])=[C:46]([CH:50]=2)[C:47](O)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]>C(Cl)Cl>[O:11]1[CH2:10][CH2:9][N:8]([C:5]2[N:4]=[CH:3][C:2]([NH:1][C:47](=[O:48])[C:46]3[CH:50]=[C:42]([CH2:41][C:35]4[C:36](=[O:40])[C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[C:33](=[O:56])[C:34]=4[CH3:55])[CH:43]=[CH:44][C:45]=3[O:51][C:52](=[O:54])[CH3:53])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(N4CCOCC4)nc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.5 %

Procedure:
3-Amino-6-morpholinopyridine (0.269 g, 1.500 mmol), triethylamine (0.197 g, 1.950 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.165 g, 0.975 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.281 g, 0.750 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.239 g, 0.446 mmol, 59%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH:13](Br)[CH3:14].[N-:16]=[N+:17]=[N-:18].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[N:16]([CH:13]([C:3]1[N:4]=[C:5]2[S:11][CH:10]=[C:9]([CH3:12])[N:6]2[C:7](=[O:8])[C:2]=1[Br:1])[CH3:14])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1csc2nc(C(C)Br)c(Br)c(=O)n12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reaction time: 0.12 h
Yield: 97.5 %

Procedure:
To a suspension of 6-bromo-7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (6.85 g, 19.4 mmol) in N,N-dimethylformamide (30.1 mL) was added sodium azide (1.45 g, 22.4 mmol). The mixture slowly turned clear after 5-10 min. After 50 min, a solution of sodium bicarbonate (4.7 g, 56 mmol) in water (90 mL) was added dropwise with stirring. The mixture was stirred at room temperature for 1 h and the solid precipitates were filtered off. The solid was then washed with water (30 mL×3), and dried to give 7-(1-azidoethyl)-6-bromo-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one as an off-white solid (5.94 g, 97.2%). LCMS calculated for C9H9BrN5OS (M+H)+: m/z 313.96, 315.96. Found: 313.75, 315.75. 1H NMR (400 MHz, DMSO-d6) δ 7.15 (q, J=1.3 Hz, 1H), 4.83 (q, J=6.8 Hz, 1H), 2.67 (d, J=1.4 Hz, 3H), 1.48 (d, J=6.8 Hz, 3H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[CH2:41][CH2:42][NH2:43]>>[Cl:37][C:38]1[CH:39]=[C:40]([CH2:41][CH2:42][NH:43][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([CH3:34])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:44]=[CH:45][CH:46]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCCc4cccc(Cl)c4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 3-chlorophenethylamine, m.p. 174-176°C. MS [(+)ESI, m/z]: 574 [M+H]+ Anal. Calcd for C36H32CIN3O2: C, 75.31; H,5.62; N, 7.32. Found: C, 75.19; H, 5.55; N, 7.22.
Reaction SMILES: C(OC(O[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:8]=[CH2:9])=O)C.C([Mg]Br)(C)C.[I:21]I.Cl>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.O1CCCC1.C(OCC)C>[I:21][C:8](/[CH:7]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH2:9]
Reactant: C=C=C(CCCCCC)OC(=O)OCC
Reactant: II
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(I)/C=C/CCCCC
Temperature: -50 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To an ethyl ether solution (12 ml) containing 3-[(ethoxycarbonyl)oxy]-1,2-nonadiene (424 mg, 2.0 mmol) and tetraisopropoxytitanium (0.89 ml, 3.0 mmol) was added at −78° C. an ethyl ether solution containing isopropylmagnesium bromide (6.0 mmol). The reaction liquid was heated to −50° C. over 30 minutes and stirred for 1 hour. The reaction liquid was given dropwise a tetrahydrofuran solution (4 ml) containing iodine (761 mg, 3.0 mmol). After heating to 0° C. over 1.5 hours, the reaction liquid was given 3N hydrochloric acid (4 ml) and separated into layers. The organic layer was washed with a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate, dried with anhydrous magnesium sulfate, and freed of solvent by vacuum distillation. The residues were purified by silica gel chromatography. There was obtained 385 mg of (E)-2-iodo-1,3-nonadiene as an iodinated compound (yield: 77%).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN[C@H]3CCN(Cc4ccccc4)C3)cc2)nc1
Yield: 43.6 %

Procedure:
Using a method similar to Example 334, and using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.300 g, 1.24 mmol), (3S)-1-benzylpyrrolidin-3yl amine (0.21 mL, 1.22 mmol), and sodium borohydride (0.108 g, 2.85 mmol) in methanol (12 mL) provides 0.214 g (43%) of the title compound as a white foam (chromatography solvent: ethyl acetate→19:1 ethyl acetate:methanol): high resolution mass spectrum (electrospray): m/z calc for C24H27N4O2 403.2134, found 403.2144; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.9, 8.8 Hz), 7.48-7.42 (m, 2H), 7.40-7.27 (m, 5H), 7.17-7.12 (m, 2H), 7.02 (d, 1H, J=9.3 Hz), 3.79 (d, 1H, J=13.2 Hz), 3.76 (d, 1H, J=13.7 Hz), 3.69 (d, 1H, J=12.7 Hz), 3.67 (d, 1H, J=12.7 Hz), 3.44-3.36 (m, 1H), 2.92 (dd, 1H, J=7.3, 9.8 Hz), 2.69 (t, 2H, J=6.8 Hz), 2.44 (dd, 1H, J=6.3, 10.2 Hz), 2.25-2.14 (m, 1H), 1.77-1.67 (m, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[OH:11][NH2:12]>C(O)C.C(OCC)(=O)C>[NH2:2][C:1](=[N:12][OH:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: NO
Reactant: CC(C)(C)OC(=O)CC#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)CC(N)=NO
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
tert-Butyl cyanoacetate (1.0 g) was dissolved in ethanol (10 mL), and aqueous hydroxyamine solution (50%, 0.5 mL) was added dropwise under ice-cooling. After stirring at room temperature for 5 hr, the mixture was diluted with ethyl acetate, and washed with brine, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and ethyl acetate-hexane was added. The resulting precipitate was collected by filtration to give the object product (820 mg, 67%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>C(OCC)(=O)C>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CN(C)c1ccc(C(=O)O)cc1
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(=O)Cl)cc1
Yield: 77.9 %

Procedure:
4-Dimethylaminobenzoic acid (250 g, 1.51 moles) was suspended in 2 L of ethyl acetate and thionyl chloride (359.3 g, 3.02 moles) was added. After the completion, the solvent was evaporated. Crystallization from ethyl acetate gave 216 g of 4-dimethylaminobenzoyl chloride (78%).
Reaction SMILES: [Br:1][CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3](O)=[O:4].C1C=CC=CC=1.[CH3:16][C:17]([NH2:25])([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH3:16][C:17]([NH:25][C:3](=[O:4])[CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[Br:1])([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)C(Br)C(=O)O
Reactant: CC(C)(N)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)(NC(=O)C(Br)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.8 %

Procedure:
Into a 200 ml four-necked flask, there were charged α-bromo-tert-butylacetic acid (9.8 g) and benzene (50 ml), and pyridine (50 ml) and α,α-dimethylbenzylamine (6.9 g) were dropwise added thereto while stirring at room temperature. Dicyclohexylcarbodiimide (10.8 g) was further added thereto, and the reaction was continued at 60°-70° C. for 6 hours, followed by cooling. The solvent was distilled off under reduced pressure, and the residue was extracted with hot benzene. The benzene extract was concentrated by distillation, and the residue was recrystallized from ethanol to give N-(α,α-dimethylbenzyl)-α-bromo-tert-butylacetamide (10.8 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:23])[CH:9]=2)[N:4]=1.ClC1C2C(=CC=C(F)C=2)N=C(CCl)[N:26]=1.COC1C=CC(NC)=CC=1>CC(O)C.Cl.C(Cl)Cl>[NH2:26][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:23])[CH:9]=2)[N:4]=1
Reactant: Fc1ccc2nc(CCl)nc(Cl)c2c1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccc(F)cc23)cc1
Agent: CNc1ccc(OC)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc(N(C)c2nc(CN)nc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
(2-Chloromethyl-6-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A suspension of 4-chloro-2-chloromethyl-6-fluoroquinazoline (265 mg, 1.15 mmol) and (4-methoxy-phenyl)-methyl-amine (175 mg, 1.26 mmol) in i-PrOH (10 mL) was treated with HCl (12 M, 4 drops) and stirred overnight at rt. The reaction was diluted with CH2Cl2 and washed with 5% NaOH. The organics were dried (MgSO4), concentrated and purified by gradient MPLC (SiO2, EtOAc/hexanes, 0-100%, 20 min) to provide 258 mg (68%) of the title compound. 1H NMR (DMSO-d6) δ 7.83 (dd, 1H), 7.62 (ddd, 1H), 7.25-7.33 (m, 2H), 7.02-7.10 (m, 2H), 6.47 (dd, 1H), 4.75 (s, 2H), 3.81 (s, 3H), 3.54 (s, 3H); LC-MS (ESI+; 332 ([M+H]+)).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)c(OC)nc1C
Yield: 82 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CC(C)([O-])C.[K+].[CH3:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=[S:23])[CH2:21]Br)=[CH:18][CH:17]=1>CC(O)(C)C.C1C=CC=CC=1>[CH3:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=[S:23])[CH2:21][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccc(C(=S)CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)C(CC(=S)c1ccc(C)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
2.28 g (19.7 mmol) of methyl acetoacetate were dissolved in 40 ml of 2-methyl-2-propanol, and 2.21 g (19.7 mmol) of potassium t-butoxide were added to the resulting solution under a nitrogen atmosphere. The mixture was then stirred at room temperature for 1 hour, after which a solution of 4.82 g (19.7 mmol) of 4-methylthiophenacyl bromide in 30 ml of benzene was added dropwise to the resulting mixture. The mixture was then stirred at 60° C. for 3 hours, after which it was cooled. It was then poured into ice-water and extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was applied to a silica gel chromatography column and eluted with a 1:4 by volume mixture of ethyl acetate and hexane, to give 4.42 g (yield 80%) of the title compound as a slightly yellow powder.