Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:14])[C@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[S:23]([NH:26][C:27]1[CH:35]=[C:34]([I:36])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30])(=[O:25])=[O:24]>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[S:23]([NH:26][C:27]1[CH:35]=[C:34]([I:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:13][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:14])=[O:30])(=[O:25])=[O:24]
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Agent: Cl
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
(R)-2-(tert-Butoxycarbonylamino)-3-phenyl-propionic acid was treated as in EXAMPLE 2, Part A, to produce (R)-2-amino-3-phenyl-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled with 2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=9.27 min. MS (ESI−): mass calcd. for C22H17F2IN2O5S, 585.99; m/z found, 584/586 [M−H]. 1H NMR (500 MHz, CDCl3): 11.32 (s, 1H), 8.11 (s, 1H), 7.50-7.46 (m, 1H), 7.38-7.28 (m, 4H), 7.16-7.15 (m, 2H), 7.00-6.96 (m, 3H), 6.51 (d, J=7.6, 1H), 5.07-5.03 (m, 1H), 3.34 (dd, J=14.0, 5.6, 1H), 3.25 (dd, J=14.3, 5.3, 1H).
Reaction SMILES: C[Si](C)(C)[N:3]1[CH2:7][C@H:6]([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][C@H:4]1[C:13]([O:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Cl:22][CH2:23][C:24](F)=[O:25].[Si](F)(C)(C)C>ClCCl>[Cl:22][CH2:23][C:24]([N:3]1[CH2:7][C@H:6]([O:8][Si:9]([CH3:10])([CH3:11])[CH3:12])[CH2:5][C@H:4]1[C:13]([O:15][Si:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:25]
Reactant: O=C(F)CCl
Reactant: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1[Si](C)(C)C
Agent: C[Si](C)(C)F
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)CCl
Temperature: 25 °C
Yield: 95 %

Procedure:
Into a solution of trimethylsilyl (2S,4R)—N-trimethylsilyl-4-(trimethylsilyloxy)-pyrrolidine-2-carboxylate (5.22 g, 15.0 mmol) in 15 ml of anhydrous dichloromethane was drop wise added a solution of chloroacetyl fluoride in 5 ml of dichloromethane with vigorous stirring at room temperature. Exothermic reaction occurred with liberation of Me3SiF. The reaction mixture was stirred at room temperature for 2 h and then the reaction mixture was evaporated to dryness at reduced pressure, which gave 5.02 g (yield 95%) of trimethylsilyl (2S,4R)—N-chloroacetyl-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate as off-white solid: 1H-NMR (CDCl3) δ 0.02 (m, 9H), 0.19 (m, 9H), 1.80-2.4 (m, 2H), 3.3-3.8 (m, 2H), 3.8-4.0 (m, 2H), 4.2-4.6 (m, 2H): 13C-NMR (CDCl3) δ −0.32 (CSi), −0.05 (CSi), 37.91, 41.81, 55.30, 59.21, 70.31, 165.13, 171.78.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:16][CH3:17])[C:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[CH:7][C:6]=2[N:15]=1.C([O-])([O-])=O.[K+].[K+].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[S:30][CH:31]=[CH:32][N:33]=1>CN(C=O)C>[CH2:16]([N:4]1[C:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[CH:7][C:6]=2[N:15]=[C:3]1[CH2:2][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[CH3:17]
Reactant: CCn1c(CCl)nc2cnc(C(F)(F)F)cc21
Reactant: c1c[nH]c(-c2nccs2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cnc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-Chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine (1 g, 3.8 mmol) in anhydrous DMF (15 mL) were added K2CO3 (2.68 g, 19 mmol), and 2-(1H-imidazol-2-yl)-thiazole (555 mg, 3.8 mmol) and stirred at room temperature for 48 h. The crude residue after usual work up was purified eluting with 5% MeOH—CH2Cl2 containing few drops of NH4OH to afford1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine (800 mg, 80%); 1H NMR (CD3OD): δ 8.83 (s, 1H), 8.14 (s, 1H), 7.71 (d, J=2.7 Hz, 1H), 7.53 (d, J=2.7 Hz, 1H), 7.45 (d, J=0.9 Hz, 1H), 7.19 (d, J=0.9 Hz, 1H), 6.30 (s, 2H), 4.54 (q, J=5.4 Hz, 2H), 1.46 (t, J=5.4 Hz, 3H); m/z 379 [M+1]
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CC[N:30](CC)CC.ClC(OCC)=O.[NH4+].[OH-].[NH4+].[Cl-]>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:30])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C(=O)O)cc2)CC(C)(C)C1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C(N)=O)cc2)CC(C)(C)C1
Yield: 35.1 %

Procedure:
To a cold (−15° C.) solution of 4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoic acid (0.100 g, 0.274 mmol) (26) in THF were added Et3N (0.042 mL, 0.302 mmol) and ethyl chloroformate (0.029 mL, 0.302 mmol) sequentially. The resultant solution was stirred at that temperature for 0.5 h. An aqueous 28% NH4OH solution was added slowly to the above mixture at −15° C. and stirred the resultant mixture at room temperature for 15 h. Reaction mixture was poured into sat. NH4Cl solution (30 mL) and then extracted with EtOAc (2×40 mL). The combined organic layer was washed with brine (1×25 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 column chromatography using CHCl3 and MeOH (100:00 to 9:1) as an eluent to afford 0.035 g (35%) of the title compound (95) as white crystalline solid. Around 25 mg of starting material was also recovered from this reaction. mp 209° C.-210° C. 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 7.87 (s, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.27 (s, 1H), 7.15 (d, J=8.0 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 1.91 (s, 2H), 1.85 (s, 2H), 1.24 (s, 2H), 0.87 (s, 6H), 0.85 (s, 6H). LCMS (ESI): m/z 362.31 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:15])=[C:8](C(O)=O)[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[I-:16].[K+].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:15])=[C:8]([I:16])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: [I-]
Reactant: CCOC(=O)c1c(C)[nH]c(C(=O)O)c1C
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)[nH]c(I)c1C
Temperature: 25 °C
Yield: 80.9 %

Procedure:
3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 4-ethyl ester 6c (3.65 g, 17.3 mmol) was dissolved in the solvent mixture of 100 mL of dichloromethane and 10 mL of water followed by addition of potassium iodide (11.5 g, 69.2 mmol) and iodine (4.39 g, 17.3 mmol). Upon completion of the addition, the reaction mixture was heated to reflux for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled to room temperature and then 20 mL of water and 10 mL of sodium thiosulfate (2 M) were added. The mixture was extracted with dichloromethane (30 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-iodo-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6d (4.1 g, yield 80.8%) as an orange solid.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:19]/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22])[C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:5][CH:4]=1.[CH2:30]([N:37]=[C:38]=[O:39])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>ClCCl>[CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:19]/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22])[C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:38]([NH:37][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:39])=[CH:7][CH:8]=1
Reactant: CC(C)=CCC/C(C)=C/CN(C(=O)c1ccccc1N)c1ccc(N(C)C)cc1
Reactant: CCCCCCCN=C=O
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)N(C/C=C(\C)CCC=C(C)C)c1ccc(N(C)C)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of N-(4-dimethylaminophenyl)-N-geranyl-2-aminobenzamide (0.8 g) in dichloromethane (10 ml) was added under ice-cooling heptyl isocyanate (0.56 g) and the mixture was stirred overnight while returning slowly to room temperature. After distilling off the solvent, the 10 residue was purified by a silica gel column chromatography (hexane:ethyl acetate=3:1) to give N-(4-dimethylaminophenyl)-N-geranyl-2-(3-heptylureido)benzamide (0.98 g, 89%) as an oily product.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14]O)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:11]1[S:12][CH:13]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[CH:10]=1
Reactant: CC1(c2csc(CO)c2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2csc(CCl)c2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-methanol (256 mg, 1.28 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.23 mL, 1.64 mmol) followed by DMAP (16 mg, 0.13 mmol) and Ms-Cl (0.12 mL, 1.55 mmol). After stirring at 0° C. for 30 min and at rt for 1 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 2-(5-chloromethyl-thiophen-3-yl)-2-methyl-[1,3]dioxolane (TLC:rf (1:1 EA-Hept)=0.61). A solution of the crude material in DMF (3 mL) was treated at rt with a solution of (4-nitro-2H-[1,2,3]triazole (124 mg, 1.07 mmol) in DMF (2.0 mL) pre-treated for 30 min with DIPEA (0.40 mL, 2.34 mmol). The resulting mixture was stirred for two weeks at rt. Water (10 mL), followed by EA (10 mL) were added. The org. extract was washed with water (10 mL), dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (hept to 1:1 hept-EA) gave the title compound as a yellow oil: TLC:rf (1:1 hept-EA)=0.48.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:17]([Li])CCC.IC>C1COCC1>[O:4]=[C:3]([CH2:5][CH3:17])[CH2:2][C:1]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6]
Reactant: [Li]CCCC
Reactant: CC(=O)CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Following the procedure of Weiler, J. Am. Chem. Soc. 1974, 96, 1082, benzyl acetoacetate, 7.68 g (40 mmol) was added dropwise to a 0° C. suspension of sodium hydride (2.1 g of 50% dispersion, 42 mmol) in THF (100 mL). After stirring for 10 minutes n-butyl lithium (16 mL of 2.5 M in hexane) was added and the mixture was aged for an additional 10 minutes. At this time iodomethane (2.74 mL, 44 mmol) in THF (4 mL) was added dropwise and the mixture aged 1 hour while slowly warming to room temperature. Work-up was achieved by quenching at 0° C. with 1N HCl, extracting with ether, washing the ether with aqueous NaHCO3, brine, and drying with MgSO4. Removal of the solvent yielded benzyl 3-oxopentanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([O:7]C)=O.[C-]#[N:30].[K+].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([NH2:30])=[O:7]
Reactant: COC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(Cl)c1
Reactant: [C-]#N
Agent: N
Agent: [K+]
Solvent: CO
Product: Cn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(N)=O)cc1Cl
Temperature: 110 °C

Procedure:
A mixture of methyl 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.14 g, 0.32 mmol, Example #E.1), methanol (15 mL), potassium cyanide (0.02 g, 0.3 mmol), and ammonia (10 mL, 7 M in MeOH, 70 mmol) was heated, in a sealed flask, for about 18 h at about 110° C. After cooling to rt the mixture was concentrated in vacuo. The residue was dissolved in DCM (100 mL) and washed with water (2×40 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Table 2, Method a,) to give 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide as an off white solid (0.018 g, 0.05 mmol, 16%): LC-MS (Table 1, Method b) Rt=4.5 min; m/z 400 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.63-2.72 (1H, m) 2.75-2.86 (1H, m) 3.18-3.28 (1H, m) 3.75-3.75 (1H, m) 3.83 (3H, s) 4.78 (1H, br.d, J=5.5 Hz) 6.23 (1H, br. s) 6.91 (1H, s) 7.08 (1H, ddd, J=8.0, 5.0, 1.0 Hz) 7.32-7.49 (2H, m) 7.56-7.65 (2H, m) 7.77 (1H, d, J=8.5 Hz) 7.94 (1H, d, J=1.5 Hz) 8.46-8.51 (1H, m).
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:6]=[C:5]([C:22]([F:25])([F:24])[F:23])[N:4]=1)[NH2:2].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33].Cl>ClCCl>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[N:6]=[C:5]([C:22]([F:25])([F:24])[F:23])[N:4]=[C:3]([NH:1][NH:2][C:32](=[O:34])[CH3:33])[C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:16][CH:17]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(-c2nc(C(F)(F)F)nc(NN)c2-c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NNc1nc(C(F)(F)F)nc(-c2ccc(C)cc2)c1-c1ccccc1
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of 4-hydrazino-6-(4-methylphenyl)-5-phenyl-2-(trifluoromethyl)pyrimidine (0.23 g, 0.66 mmol) (synthesized according to the procedure described in example 22) in dichloromethane (5 ml) and pyridine (0.06 g, 0.8 mmol), acetyl chloride (0.6 g, 0.7 mmol) was added dropwise at room temperature over a period of ten minutes under stirring. Stirring was continued for two hours and the resultant reaction mass was poured onto ice-water mixture and neutralised with hydrochloric acid. The reaction mixture was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (0.2 g, 77.9%, HPLC purity 99.4%), mp: 147-152° C.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32]1(Br)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([N:21]2[CH2:20][C:19]3[C:23](=[CH:24][C:16]([N:13]4[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:15][CH2:14]4)=[CH:17][CH:18]=3)[C:22]2=[O:25])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: BrC1CCCCCC1
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Product: O=C1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)ccc2CN1C1CCCCCC1
Yield: 19.5 %

Procedure:
In the same manner as in Example 51, the title compound (12 mg) was prepared from the compound (50 mg) obtained in Example 50 and cycloheptyl bromide (32 mg).
Reaction SMILES: ClC(OC(Cl)C)=O.[N:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH:22]1[CH2:27][CH2:26][N:25](CC2C=CC=CC=2)[CH2:24][CH2:23]1)[C:15]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=[O:16]>ClCCCl>[N:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:15]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=[O:16]
Reactant: O=C(c1ccco1)N(c1cnccn1)C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C(c1ccco1)N(c1cnccn1)C1CCNCC1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
A solution of 1-chloroethyl chloroformate (9.7ml, 90 mmol) in 1,2-dichloroethane (25ml) was added to an ice-chilled solution of N-(2-pyrazinyl)-N-(1-phenylmethyl-4-piperidinyl)-2-furanamide (45 mmol) and 1,2-dichloroethane (125ml). The reaction mixture was stirred under reflux for 5 hours, then cooled and concentrated under vacuum. The crude carbamate residue was dissolved in methanol (150ml) and the reaction solution was heated under reflux for 2 hours. The reaction solution was cooled, decolorizing carbon (10g, Darco G-60) was added to the mixture, then the suspension was heated and stirred under reflux for 15 minutes. The suspension was filtered through Celite and the filtrate was concentrated under vacuum. The residue was suspended in hot isopropanol (100ml), then cooled and filtered. The pale maize colored powder was dried under vacuum (85° C., 0.01mm Hg, 2 hours) to yield N-(2-pyrazinyl)-N-(4piperidinyl)-2-furanamide (8.9g, 72%) as the hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:15][OH:16]>ClCCl.[O-2].[Mn+4].[O-2]>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([C:11]([F:14])([F:12])[F:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH:15]=[O:16]
Reactant: Cc1c(CO)[nH]c2c(C(F)(F)F)cccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1c(C=O)[nH]c2c(C(F)(F)F)cccc12
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of (3-methyl-7-(trifluoromethyl)-1H-indol-2-yl)methanol (1.03 g, 4.4 mmol) and manganese (IV) oxide (1.95 g, 22.4 mmol) in dichloromethane (15 mL) was stirred overnight. The mixture was filtered through celite and evaporated to afford the title compound (510 mg, 51%). 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.95 (s, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.62 (d, J=7.1 Hz, 1H), 7.20 (t, J=7.7 Hz, 1H), 2.65 (s, 3H)
Reaction SMILES: FC(F)C1NC2C=CC=CC=2N=1.FC(F)C1N(C2N=C(N3CCOCC3)C=C(N3CCOCC3)N=2)C2C=CC([N+]([O-])=O)=CC=2N=1.[F:46][CH:47]([F:78])[C:48]1[N:52]([C:53]2[N:58]=[C:57]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)[CH:56]=[C:55]([N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)[N:54]=2)[C:51]2[CH:71]=[C:72]([N+:75]([O-])=O)[CH:73]=[CH:74][C:50]=2[N:49]=1>>[NH2:75][C:72]1[CH:73]=[CH:74][C:50]2[N:49]=[C:48]([CH:47]([F:46])[F:78])[N:52]([C:53]3[N:58]=[C:57]([N:59]4[CH2:64][CH2:63][O:62][CH2:61][CH2:60]4)[CH:56]=[C:55]([N:65]4[CH2:70][CH2:69][O:68][CH2:67][CH2:66]4)[N:54]=3)[C:51]=2[CH:71]=1
Reactant: O=[N+]([O-])c1ccc2nc(C(F)F)n(-c3nc(N4CCOCC4)cc(N4CCOCC4)n3)c2c1
Agent: FC(F)c1nc2ccccc2[nH]1
Agent: O=[N+]([O-])c1ccc2c(c1)nc(C(F)F)n2-c1nc(N2CCOCC2)cc(N2CCOCC2)n1
Product: Nc1ccc2nc(C(F)F)n(-c3nc(N4CCOCC4)cc(N4CCOCC4)n3)c2c1
Yield: 88 %

Procedure:
In accordance with the procedure of the Example 1 except that 2-difluoromethylbenzimidazole in (1) of the Example 1 was replaced by 2-difluoro-6-nitrobenzimidazole, a mixture of 2-(2-difluoromethyl-5-nitrobenzimidazol-1-yl)-4,6-dimorpholinopyrimidine with 2-(2-difluoromethyl-6-nitrobenzimidazol-1-yl)-4,6-dimorpholinopyrimidine was obtained. In accordance with the procedure of (3) of the Example 8, using 0.92 g (2.0 mmol) of this mixture, 0.76 g (yield: 88%) of the titled compound was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([N:27]([CH2:30][CH3:31])[CH2:28]C)C.C([O-])([O-])=O.[K+].[K+].CC1NC1>O.CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([N:27]2[CH2:28][CH:30]2[CH3:31])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Agent: CC1CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N1CC1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.2 %

Procedure:
To 50 ml of DMF was added 5.0 g (0.0126 mol) of product of Example 28 , followed by 1.27 g (0.0126 mol) of triethylamine and 1.74 g (0.0126 mol) of K2CO3. To this mixture was added 0.922 g (0.0161 mol) of propyleneimine. This reaction mixture was stirred under N2 for 48 hours at room temperature. The reaction mixture was then poured into H2O and extracted with diethyl ether. The ether phase was then washed with H2O, and dried over MgSO4. The dry ether phase was then concentrated in vacuo to a crude yield of 4.8 g of a brown oil. This oil was kugelrohr distilled at 105° C./53 Pa, to yield 4.0 g of a yellow oil (76%), nD25 1.4763.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.Cl>CN(C)C=O.CCCCCC>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A slurry of hexane-washed sodium hydride (3 g, 75 mmol) in dimethyl formamide (80 mL) was stirred as a solution of N-(t-butoxycarbonyl)4-hydroxypiperidine (10 g, 50 mmol) in dimethyl formamide (10 mL) was added dropwise. Slight heating was used to initiate reaction, but the reaction needed to be cooled in an ice bath to control the reaction rate. Approximately 30 min after the addition was complete, solid 4-fluoro-1-nitrobenzene (7.4 g, 52 mmol) was added at once. The reaction was stirred for about 3 hours. The reaction was poured into ice water. The pH of the resulting liquid was adjusted to neutrality with 1 N hydrochloric acid. The resulting solid was isolated by filtration, washed with water, and dried under reduced pressure to give 16 g of 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-1-nitrobenzene, NMR (CDCl3, TMS) δ1.45 (s, 9), 1.72 (m, 2), 1.98 (m, 2), 3.38 (m, 2), 3.68 (m, 2), 4.62 (m, 1), 6.98 (m, 2), 8.19 (m, 2).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][S:21][CH2:22][CH2:23]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:23][CH2:22][S:21][CH3:20])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CSCCO
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(O)cc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CSCCOc1ccc2oc(C(=O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
Cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methanone (0.76 g) synthesized in Example A82(3) was dissolved in tetrahydrofuran (15 mL), and 2-(methylthio)ethanol (0.26 mL), tributylphosphine (1.5 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.46 g) were added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 12 hr. Hexane (15 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (0.73 g, 76%) as a pale-yellow oil.