Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][N:33]([CH2:35][C:36](O)=[O:37])[CH3:34].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:36](=[O:37])[CH2:35][N:33]([CH3:34])[CH3:32])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.2 %

Procedure:
A solution of 8-(4-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione (45 mg, 0.11 mmol) in N,N-dimethylformamide (1.0 mL) at 25° C. was treated with dimethylamino-acetic acid (11 mg, 0.11 mmol), O-benzotriazol-1-yl-N,N.N′N′-tetramethyluronium hexafluorophosphate (45 mg, 0.12 mmol), and N,N-diisopropylethylamine (56 μL, 0.32 mmol). The resulting solution was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in chloroform and then was washed with a saturated aqueous sodium chloride solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water/0.075% trifluoroacetic acid over 30 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford N-{4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-2-dimethylamino-acetamide (24 mg, 44.3%) as an off-white solid: LR-MS for C27H29FN6O3 (M+H)+ at m/z=505.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]([CH3:17])[CH3:16])[C:13]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([CH:15]([CH3:17])[CH3:16])[C:13]=2[CH:18]=1
Reactant: CC(C)n1c([C@H](C)NC(=O)OC(C)(C)C)nc2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1c([C@H](C)N)nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
[(S)-1-(6-Fluoro-1-isopropyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (1.0 g, 3.11 mmol) was dissolved in DCM (10 mL) and TFA (5 mL) added. The reaction mixture was stirred at RT for 30 minutes. The resultant mixture was concentrated in vacuo and the residue dissolved in DCM (40 mL) and stirred vigorously with saturated aqueous NaHCO3 (20 mL), for 10 minutes. The layers were separated and the organic fraction washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (0.5 g, 72%). 1H NMR (CDCl3, 400 MHz): δ 7.65 (1H, dd, J=8.83, 5.01 Hz), 7.20 (1H, dd, J=9.40, 2.46 Hz), 6.97 (1H, ddd, J=9.58, 8.80, 2.43 Hz), 4.92-4.82 (1H, m), 4.37-4.28 (1H, q, J=6.68 Hz), 1.64 (6H, d, J=6.98 Hz), 1.58 (3H, d, J=6.65 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[N:22]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[C:23]=S.C(N=C=NC(C)C)(C)C>C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]2[N:14]=[C:23]([NH:22][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[NH:15][C:11]2=[N:10][C:9]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: S=C=Nc1cccnc1
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Product: Fc1cnccc1-c1cc2nc(Nc3cccnc3)[nH]c2nc1-c1cccnc1
Temperature: 50 °C
Yield: 33 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.1 g, 0.356 mmol) and 3-isothiocyanatopyridine (0.06 mL, 0.534 mmol) in ethanol (2 mL), 1,3-diisopropylcarbodiimide (0.083 mL, 0.534 mmol) was added. The mixture was heated at 50° C. for 2 h. After cooling at room temperature, the solvent was evaporated. The crude mixture was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (0.045 g, 33% of yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:12]=1[CH2:13][NH2:14].[BH4-].[Na+].Cl.C([O-])(O)=O.[Na+]>CO>[CH3:10][C:11]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:12]=1[CH2:13][NH:14][CH2:5][C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(C)c(CN)c(C)c1
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: Cc1cc(C)c(CNCc2cccc(O)c2)c(C)c1
Reaction time: 8 h

Procedure:
3-Hydroxy-benzaldehyde (1.22 g, 0.01 mol) and 2,4,6-trimethyl-benzylamine (1.19 g, 0.01 mol) were added to methanol (10 mL) and the resulting mixture was stirred overnight. Sodium borohydride (0.45 g, 0.012 mol) was then added, and stirring was continued one hour. The resulting mixture was acidified with 2N HCl and then neutralized with saturated aqueous NaHCO3 solution to yield a gummy solution. The gummy solution was extracted with EtOAc (3×100 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield a white solid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)=[O:10]>>[CH:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:16])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCCCCCCO
Product: CCCCCCCOC(=O)c1ccc(C=O)cc1

Procedure:
The title compound was prepared through a condensation between 1-heptanol and 4-formylbenzoic acid. 1H NMR (500 MHz, CDCl3): δ 10.10 (s, 1H), 8.20 (d, J=8.2, 2H), 7.95 (d, J=8.2, 2H), 4.35 (t, J=6.8, 2H), 1.75-1.85 (m, 2H), 1.40-1.50 (m, 2H), 1.25-1.40 (m, 6H), 0.89 (t, J=7.0, 3H).
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[O:11][C:10]([CH3:12])=[N:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:3]([OH:5])=[O:4]>C(O)(=O)C.[Zn]>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH2:6][CH2:2][C:3]([OH:5])=[O:4])=[CH:18][CH:17]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(CC(Cl)C(=O)O)o1
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1

Procedure:
Zinc dust (0.87 g) was added portionwise under stirring at 80°-90° C. into a suspension of 2-chloro-3-[4-(4-chlorophenyl)-2-methyl-5-oxazolyl]-propionic acid (1.0 g) in acetic acid (10 ml). After heating for 40 minutes, undissolved materials were filtered off and water was added to the filtrate. The resulting crystalline precipitate was collected by filtration to give 4-(4-chlorophenyl)-2-methyloxazole-5-propionic acid, yield 0.83 g (94.3%). Recrystallization from ethanol gave colorless needles, m.p. 211°-212° C. The IR and NMR spectra of this compound were in agreement with those of the compound obtained in Example 5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH:24]([F:26])[F:25])=[CH:20][CH:21]=3)[C:16]([C:27]3[N:28]=[C:29]4[C:35]([C:36](=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][N:33](COCC[Si](C)(C)C)[C:30]4=[N:31][CH:32]=3)=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[C:38]([NH:37][C:36]([C:35]1[C:29]2[C:30](=[N:31][CH:32]=[C:27]([C:16]3[C:17]4[C:22](=[CH:21][CH:20]=[C:19]([O:23][CH:24]([F:26])[F:25])[CH:18]=4)[N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[N:15]=3)[N:28]=2)[NH:33][CH:34]=1)=[O:42])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CCN(C(=O)OC(C)(C)C)CC4)c4ccc(OC(F)F)cc34)nc12
Solvent: CCOC(C)=O
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(C4CCNCC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
In a round-bottomed flask, 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (65 mg, 0.091 mmol) was dissolved in dichloromethane (0.5 ml) and trifluoroacetic acid (0.28 ml, 3.63 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.5 ml) and ethylenediamine (0.37 ml, 5.48 mmol) was added. The reaction was stirred at room temperature for 1 h then water and ethyl acetate were added. The resulting suspension was filtered and washed with hot water and ethyl acetate. The product collected was dried under high vacuum to provide 37 mg (80%) of 2-(5-difluoromethoxy-1-piperidin-4-yl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as an off-white powder. MS: (M+H)+=484; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.06 (s, 1H), 8.37 (s, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.96 (d, J=9.1 Hz, 1H), 7.89 (s, 1H), 7.38 (dd, J=9.1, 2.3 Hz, 1H), 7.18 (t, J=74.8 Hz, 1H), 4.73-4.93 (m, 1H), 3.12 (d, J=12.8 Hz, 2H), 2.63-2.81 (m, 2H), 2.01-2.19 (m, 2H), 1.89-2.01 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:16]=[C:17]([Cl:28])[CH:18]=[C:19]3[C:23]=1[N:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:21]=[CH:20]3)[C:9](=[O:29])[CH2:8]2)=[O:4].[OH-].[Li+].O.CO>O1CCCC1>[Cl:28][C:17]1[CH:18]=[C:19]2[C:23](=[C:15]([CH2:14][N:10]3[C:11]4[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=4)[CH2:8][C:9]3=[O:29])[CH:16]=1)[N:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:21]=[CH:20]2
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2Cc1cc(Cl)cc2cnn(CC(C)C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)Cn1ncc2cc(Cl)cc(CN3C(=O)Cc4cc(C(=O)O)ccc43)c21
Temperature: 100 °C

Procedure:
A mixture of compound 65 (0.021 g, 0.05 mmol), lithium hydroxide (0.09 g, 0.208 mmol) in a mixture of tetrahydrofuran (1.5 mL), water (0.5 mL) and methanol (0.5 mL) was heated at 100° C. under microwave conditions for 10 minutes. Then, the reaction was quenched by adding water and diluted with ethyl acetate. The organic layer was separated, washed with Brine, dried (MgSO4), filtered and the solvent was evaporated.
Reaction SMILES: [CH3:1][Si:2]([CH3:34])([CH3:33])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[CH:9]=1.[C:35]1([C:41]2[CH:46]=[CH:45][C:44](B3OC(C)(C)C(C)(C)O3)=[CH:43][N:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:1][Si:2]([CH3:34])([CH3:33])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:44]3[CH:43]=[N:42][C:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:46][CH:45]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2c(I)cnn12
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 90 °C
Yield: 81.8 %

Procedure:
A mixture of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (751 mg, 1.22 mmol), 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (444 mg, 1.58 mmol), PdCl2(dppf)CH2Cl2 (99.6 mg, 0.122 mmol), and K3PO4 (777 mg, 3.66 mmol) in dioxane/H2O (7/0.7 mL) was degassed and then heated at 90° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc and washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.2 in 20% EtOAc/Hexanes) to afford 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone as a pale yellow solid (643 mg). HPLC-MS TR=3.12 min (UV 254 nm, 5 min method); mass calculated for formula C35H49N5O3Si2 643.3, observed LCMS m/z 644.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](Cl)=[N:9][N:8]=1.Br[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:9][N:8]=1
Reactant: Brc1nccs1
Reactant: COC(=O)CCCc1nnc(Cl)c2cc(OC)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Zn]
Product: COC(=O)CCCc1nnc(-c2nccs2)c2cc(OC)ccc12
Yield: 26.1 %

Procedure:
Operating analogously at what described in example 48 starting from 4-(4-chloro-6-methoxy-phthalazin-1-yl)-butyric acid methyl ester (12.5 g, 0.0424 mole), prepared as described in example 114, zinc (17.3 g), 2-bromothiazole (24.3 g, 0.1484 mole), palladium acetate (0.476 g, 2.12 mmole), triphenylphosphine (1.67 g, 6.36 mmole), 3.8 g of the title compound were obtained (yield: 12.6%). m.p.: 136-137° C.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C.ClCCCl>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:12][CH2:11][C@H:10]([N:13]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[NH:15][C:14]4=[O:22])[CH2:9][CH2:8]3)[CH2:6][CH2:5]2)[CH:24]=1
Reactant: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCNCC2)CC1
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCN(Cc3cccnc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.10 g of trans-1,3-dihydro-1-{4-(1-piperazinyl)-1-cyclohexyl}-2H-benzimidazol-2-one, 0.037 mL of 3-pyridinecarboxaldehyde, 15 mL of 1,2-dichloroethane, 0.10 mL of glacial acetic acid and 0.11 g of sodium triacetoxyborohydride was stirred at room temperature for 24 h. The reaction mixture was poured into 10 mL dichloromethane and 10 mL saturated aqueous NaHCO3 and the layers separated. The aqueous layer was extracted with 2×10 mL of dichloromethane and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Preparative thin layer chromatography on silica gel, eluting with 90:10:2 chloroform: methanol: conc. NH4 OH gave 0.050 g of trans-1,3-dihydro-1-{4-[4-(3-pyridinylmethyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: mp=250° C.; 1H NMR (400 MHz, CDCl3) 9.71 (br s, 1H), 8.54 (dd, 2H), 7.68 (d, J=7.9, 1H), 7.26 (t, 1H), 7.15-7.02 (m, 4H), 4.26 (m, 1H), 3.54 (s, 2H), 2.66 (br dd, 4H), 2.27 (q, 2H), 2.10 (d, 2H), 1.97 (d, 2H), 1.92 (q, 2H): Analysis calculated for C23H29N5O.0.45 CHCl3C: 63.25, H: 6.67, N: 15.73 found C: 62.96, H: 6.74, N: 15.54.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH3:18])[C:8]([CH3:17])=[C:9]([CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH3:18])[C:8]([CH3:17])=[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(CCC(=O)O)cc(C(C)(C)C)c(O)c1C

Procedure:
Under nitrogen, a solution of methyl 3-(5-tert.-butyl-2,3-dimethyl-4-hydroxyphenyl)propionate (71.5 g) in 150 ml of ethanol was treated with a solution of 98% sodium hydroxide (12.1 g) in 15 ml of water, and the mixture was heated under reflux for 3 hours. The cold solution was diluted with water to about 1200 ml and then acidified with concentrated hydrochloric acid. The precipitated solid was filtered off and washed with water. Recrystallization from 600 ml of acetonitrile gave the acid, m.p. 191° to 193° C.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]23[N:16]([CH2:17][CH:18]=[CH2:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12][CH2:11][CH:10]3[OH:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br.C1OCCOCCOCCOCCOCCOC1>C1COCC1>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH2:26][O:20][C@H:10]2[CH2:11][CH2:12][C@H:13]3[N:16]([CH2:17][CH:18]=[CH2:19])[C@:9]2([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:15][CH2:14]3)[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1
Reactant: C=CCN1C2CCC(O)C1(c1ccccc1)CC2
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1[C@@H]2CC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@]1(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% in oil, 67 mg, 1.67 mmol) was washed twice with THF and treated with a solution 1S,2S,5S)-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octan-2-ol (Description 57; 116 mg, 0.47 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (430 mg, 1.4 mmol), 18-crown-6 (33 mg, 1.25 mmol) in THF (2 ml). The reaction mixture was stirred at room temperature overnight, quenched with saturated aqueous NH4Cl and extracted into diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:26][CH2:27][CH2:28][CH3:29])[NH:7][C:6](=[O:30])[CH:5]=1)([CH3:3])[CH3:2].[Cl:31]Cl>>[Cl:31][C:5]1[C:6](=[O:30])[NH:7][C:8]([C:10]2[CH:15]=[C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:26][CH2:27][CH2:28][CH3:29])=[N:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc(C(C)C)cc(=O)[nH]1
Reactant: ClCl
Product: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc(C(C)C)c(Cl)c(=O)[nH]1

Procedure:
The compound of example 221 was prepared by reacting the compound of example 1 with chlorine gas in the same manner as that of example 207. 1H NMR (CDCl3) 8.86 (1H, d), 7.88 (1H, dd), 7.16 (1H, d), 4.27 (2H, t), 3.49 (1H, m), 3.09 (4H, t), 2.50 (4H, t), 2.27 (3H, s), 2.03 (2H, m), 1.26 (6H, d), 1.16 (3H, t).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)(OC[C@@H]1OC1)(=O)=O.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CS(C)=O>[CH2:42]([NH:49][CH2:11][CH:12]1[O:25][C:16]2=[C:17]3[C:21](=[CH:22][CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:24])[CH2:18]3)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCc2ccccc2)CO3)N1
Temperature: 77.5 °C
Reaction time: 3 h

Procedure:
(S)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (2.0 g, 5.3 mmole), prepared in the same manner as the (R) enantiomer described above with substitution of (S)- for (R)-glycidyl tosylate, and benzylamine (2.9 ml, 26.7 mmole) were placed in 20 ml of fresh DMSO under nitrogen. The mixture was then heated to 75-80° C. with stirring for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The DMSO layer was extracted with ethyl acetate and the combined ethyl acetate extracts were washed with water to remove trace DMSO, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant to yield the free base (1.4 g, 4.5 mmole, 83%) of the expected product as a solidified oil under reduced pressure. The free base was dissolved in 20 ml of ethanol, treated with 0.25 M ethanolic fumaric acid (10 ml) and precipitated with diethyl ether to give the title compound as a pale yellow solid fumarate salt, predominantly in the (R)-configuration, m.p. 195-196° C. This sample, from which the pharmacological results reported in this application were obtained, was determined by chiral HPLC to contain 9% of the (S)-enantiomer.
Reaction SMILES: C([NH:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH2:19][O:20][CH3:21])[CH:7]=1)(C)(C)C.Cl>CO>[NH2:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH2:19][O:20][CH3:21])[CH:7]=1
Reactant: COCc1cc(NC(C)(C)C)c([N+](=O)[O-])cc1C(=O)OC
Agent: Cl
Solvent: CO
Product: COCc1cc(N)c([N+](=O)[O-])cc1C(=O)OC
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a mixed liquid of 6.80 g of methyl 4-(tert-butylamino)-2-(methoxymethyl)-5-nitrobenzoate and 68.0 mL of methanol was added 37.0 mL of 6 M hydrochloric acid, followed by stirring overnight under the heating and refluxing condition. The solvent was evaporated under reduced pressure, and then 111 mL of methanol and 1.00 mL of concentrated sulfuric acid were added thereto, followed by stirring overnight under the heating and refluxing condition. Ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added thereto, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 4.73 g of methyl 4-amino-2-(methoxymethyl)-5-nitrobenzoate as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]([O:22][CH3:23])[C:11](=[O:21])[CH:12]=[C:13]2[C:17](=[O:18])[O:16][C:15](C)(C)[O:14]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CO>[CH3:15][O:16][C:17](=[O:18])[C:13]([OH:14])=[CH:12][C:11](=[O:21])[N:10]([CH2:9][C:8]1[CH:24]=[CH:25][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)[O:22][CH3:23]
Reactant: CON(Cc1ccc(NC(C)=O)cc1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(NC(C)=O)cc1)OC
Yield: 35 %

Procedure:
N-(4-Acetylaminobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (35% yield); mp 125° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.18 (3H, s, COCH3), 3.68 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.79 (2H, s, NCH2), 6.46 (1H, s, CH), 7.16 (1H broad s, NH), 7.29 (2H, d, J=8.6 Hz, aromatics), 7.48 (2H, d, J=8.6 Hz, aromatics). Anal. Calcd for C15H18N2O6: C, 55.89; H, 5.62; N, 8.69. Found: C, 55.95; H, 5.70; N, 8.59.