Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[N:10]([CH2:11][C:12]2[C:13]([O:20][CH3:21])=[N:14][C:15]([CH3:19])=[C:16]([F:18])[CH:17]=2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:22](O)=[O:23].Cl.[F:26][CH2:27][CH2:28][NH2:29].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.O>[F:18][C:16]1[CH:17]=[C:12]([CH2:11][N:10]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:22]([NH:29][CH2:28][CH2:27][F:26])=[O:23])=[CH:2]2)[C:13]([O:20][CH3:21])=[N:14][C:15]=1[CH3:19]
Reactant: NCCF
Reactant: COc1nc(C)c(F)cc1Cn1c(C)c(C(=O)O)c2ncccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1nc(C)c(F)cc1Cn1cc(C(=O)NCCF)c2ncccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
See FIG. 20(b). To the stirred solution of methyl 1-((5-fluoro-2-methoxy-6-methylpyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (0.15 g, 0.47 mmol) in dichloromethane (10 mL), were added 2-fluoroethan-1-amine hydrochloride (71 mg, 0.71 mmol), triethylamine (0.142 g, 1.41 mmol) and T3P (0.9 g, 1.41 mmol) and the mixture was stirred for 16 h at room temperature. Then the reaction mixture was poured into water and extracted with dichloromethane. The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated at reduced pressure. The residue was purified by silica gel column chromatography to yield 1-((5-fluoro-2-methoxy-6-methylpyridin-3-yl)methyl)-N-(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide as a white solid. Yield: 30 mg (18%). ES+MS m/z: 361 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.31 (d, 3H, J=2.9 Hz), 3.64-3.68 (m, 2H), 3.71-3.75 (m, 2H), 3.85 (s, 3H), 4.49-4.51 (m, 2H), 4.61-4.63 (m, 2H), 5.41 (s, 2H), 7.28-7.32 (m, 1H), 7.45 (d, 1H, J=9.0 Hz), 8.08-8.11 (m, 1H), 8.29 (s, 1H), 8.49-8.50 (m, 1H), 8.92 (t, 1H, J=5.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])[C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:29]([N:28]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:11](=[O:13])[C@H:9]([CH3:10])[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCNCCCCCC
Reactant: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccccc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)C(=O)[C@H](C)N(C(=O)OC(C)(C)C)c1ccccc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 0.81 g of the crude N-t-butoxycarbonyl-(2-cyanophenyl)alanine and 0.67 g of dihexylamine in 8 ml of N,N-dimethylformamide were added 0.55 g of 1-hydroxybenzotriazole monohydrate and 0.69 g of N-ethyl-N′-dimethylaminopropylcarbodiimide hydrochloride, followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 5% aqueous potassium bisulfate solution, a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; hexane-ethyl acetate=4:1) to give 1.01 g of N-t-butoxycarbonyl-(2-cyanophenyl)alanine dihexylamide.
Reaction SMILES: [NH2:1][C:2]1[C:3](C(N)=O)=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:7]=1.[OH-].[Na+].Cl>O1CCOCC1.ClC1C=CC=CC=1Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[N:4][CH:3]=1
Reactant: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2-c2ccccn2)ccc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2ncc(N)nc2-c2ccccn2)ccc1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 11 %

Procedure:
To a suspention of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-pyridyl)-2-pyrazinecarboxamide (52 mg) in dioxane (0.5 ml) was added an aq. NaOH (2M, 1 ml) and this solution was heated at 100° C. for 4 hours. This reaction mixture was cooled to room temperature and the pH of this solution was adjusted to 2.5 with 2N aq. HCl. This solution was evaporated under reduced pressure to give yellow solid. A suspension of this yellow solid in 1,2-dichlorobenzene (2 ml) was heated at 200° C. and stirred for 4 hours. This reaction mixture was cooled to room temperature. To this solution was added IPE and stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with IPE. The residual solid was placed on a column of silica-gel and eluted with CHCl3—MeOH—28% aq. ammonia (15:1:0.1). The eluent was evaporated and the residue was purified by recrystallization from EtOAc-IPE to give 5-[5-amino-3-(2-pyridyl)-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (5 mg) as a pale yellow crystal.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:11]=[C:10]([CH3:12])[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([F:13])[CH:4]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C1COCC1>[CH3:14][N:2]([CH3:1])[C:3]1[CH:11]=[C:10]([CH3:12])[C:6]([C:7](/[N:9]=[CH:17]/[N:18]([CH3:20])[CH3:19])=[O:8])=[C:5]([F:13])[CH:4]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(N(C)C)cc(F)c1C(N)=O
Solvent: C1CCOC1
Product: Cc1cc(N(C)C)cc(F)c1C(=O)/N=C/N(C)C
Temperature: 60 °C
Reaction time: 14 h

Procedure:
A suspension of 4-Dimethylamino-2-fluoro-6-methyl-benzamide (0.696 g, 3.55 mmol) with dimethylformamide-dimethylacetal (0.551 mL, 3.90 mmol) in THF (3 mL) was heated to 60° C. After 14 h., solvent was removed to give 4-Dimethylamino-N-[1-dimethylamino-meth-(E)-ylidene]-2-fluoro-6-methyl-benzamide as an oil, which eventually crashed out as a white solid (0.890 g, 100%).
Reaction SMILES: [CH3:1][C@@H:2]([NH:23]C(=O)OC(C)(C)C)[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:22][CH:20]([O:19][C:15]1[CH:14]=[C:13]([O:12][C:9]2[N:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([CH3:1])[NH2:23])=[CH:11][CH:10]=2)[CH:18]=[CH:17][CH:16]=1)[CH3:21]
Reactant: CC(C)Oc1cccc(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of 1,1-dimethylethyl ((1R)-1-methyl-2-{[6-({3-[(1-methylethyl)oxy]phenyl}oxy)-3-pyridinyl]amino}-2-oxoethyl)carbamate (Intermediate 31, 400 mg, 0.96 mmol) in dichloromethane (14 mL) was added TFA (6 mL) portionwise during 15 minutes at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The solvent was distilled off to afford the title compound (260 mg, 85%) as a grey oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH2:5][CH2:6][N:7]1[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[S:9][CH:8]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>CS(C)=O>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][N:7]1[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[S:9][CH:8]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCCCCCCCC1SC(c2cccnc2)N(CCCl)C1=O
Reactant: CNC
Solvent: CS(C)=O
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCN(C)C)C1=O
Temperature: 100 °C
Yield: 99.1 %

Procedure:
A 50% aqueous dimethylamine solution (1.0 ml, 11 mmol) was added to a solution of trans-isomer (128 mg, 0.35 mmol) of 3-(2-chloroethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one in dimethylsulfoxide (3 ml). The mixture, placed in a sealed tube, was heated at 100° C. for 2 hours. After removal of the solvent by evaporation under reduced pressure, the residue was dissolved in chloroform (30 ml). The solution was washed twice with saturated aqueous NaHCO3 and dried. Removal of the chloroform gave the intended trans-isomer (131 mg, 100% of theoretical) of 3-(2-dimethylaminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one in oily form. IR (CHCl3) [cm-1 ]; 2930, 2860, 1670, 1580, 1355. NMR (δ, CDCl3, ppm); 2.15 (6 H, s), 2.24 (1 H, dt, 12.87 and 5.61 Hz), 2.46 (1 H, ddd, 12.87, 7.20 and 5.94 Hz), 2.69 (1 H, ddd, 14.19, 7.20 and 5.61 Hz), 3.80 (1 H, ddd, 14.19, 5.94 and 5.61 Hz), 4.03 (1 H, ddd, 8.58, 3.96 and 1.98 Hz), 5.86 (1 H, d, 1.98 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.Cl[CH:14]([O:16]C(Cl)Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[O:16])[C:5]2[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=2[CH:12]=1
Reactant: ClC(Cl)OC(Cl)Cl
Reactant: CC1(C)COc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC1(C)COc2c(C=O)cc(Br)cc21
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To a stirred, cooled (ice-bath) solution of 5-bromo-3,3-dimethyl-2,3-dihydrobenzofuran (Intermediate 2, 0.4 g, 1.57 mmol) in anhydrous dichloromethane(4 mL), titanium tetrachloride (0.172 mL, 1.57 mmol) was added followed by dichloromethyl ether (0.14 mL, 1.57 mmol). The reaction mixture was allowed to warm to room temperature and at the end of 3 hr, the reaction mixture was poured into iced water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to a residue that on flash column chromatography using 2.5% ethyl acetate in hexane as the eluent afforded the title compound (0.25 g, 63%).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:12][C:13]1([NH2:16])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5]([NH:16][C:13]2([CH3:12])[CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: CC1(N)CC1
Reactant: CSc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(NC2(C)CC2)ncc1Br
Temperature: 90 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a stirring suspension of 5-bromo-2-chloro-4-(methylthio)pyrimidine (1.0 g, 4.18 mmol) in ethanol (6.0 mL) was added 1-methylcyclopropanamine hydrochloride (0.674 g, 6.26 mmol) and DIEA (2.188 mL, 12.53 mmol). The mixture was stirred at 90° C. for 16 h. Upon completion of the reaction as indicated by LCMS and TLC the reaction mixture was concentrated and purified by silica gel chromatography using a gradient of 0%-20% ethyl acetate in hexanes. The product fractions were combined and concentrated to afford 5-bromo-N-(1-methylcyclopropyl)-4-(methylthio)pyrimidin-2-amine (0.665 g, 58% yield) as a white solid. MS (ESI) m/z 276.2 [M+1]+.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8].[C:11](Cl)(=O)C(Cl)=O>CO>[CH3:1][S:2][CH2:3][CH2:4][O:5][CH:6]([CH3:10])[C:7]([O:9][CH3:11])=[O:8]
Reactant: CSCCOC(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Product: COC(=O)C(C)OCCSC
Yield: 96 %

Procedure:
Reaction of intermediate 9, 2-(2-(methylthio)ethoxy)propanoic acid, (13.70 g, 0.083 mol) with oxalyl chloride followed by reaction with methanol gave 14.27 g (96% yield) of the title ester as a clear oil; bp 55-60° C./0.3 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ ppm: 1.42 (3H, d, J=7.0 Hz, CH3), 2.15 (3H, s, SCH3), 2.71 (2H, t, J=6.8 Hz, CH2), 3.56 (1H, m, CH), 3.75 (3H, s, OCH3), 3.78 (1H, m, CH), 4.15 (1H, q, J=7.0 Hz, OCH).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:17]=2[OH:18])[C:12](O)=[O:13])[CH:6]=[CH:7][CH:8]=1.[CH2:31]([O:38][C:39]1[CH:53]=[CH:52][C:42]([CH2:43][O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][NH2:51])=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C.Cl>O=S(Cl)Cl.C(Cl)Cl>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:43][O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][NH:51][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:17]([OH:18])=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=3)[CH:10]=2)=[CH:52][CH:53]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: NCCCCCCOCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(NCCCCCCOCc1ccc(OCc2ccccc2)cc1)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
A stirring solution of 3,5-bis-(m-trifluoromethylphenyl)-4-hydroxybenzoic acid (0.800 g, 1.87 mmol) in SOCl2 (10 mL) was heated at reflux for 1.5 h, then cooled and concentrated in vacuo. The acid chloride was dried in vacuo overnight. The acid chloride was dissolved in CH2Cl2 (10 mL) and added to a solution of 6-(4-benzyloxy-benzyloxy)hexylamine (0.765 g, 2.44 mmol) and triethylamine (0.92 mL, 6.54 mmol) in CH2Cl2 (10 mL) at 0° C. After stirring for 4 h at 0° C., 1.0 N HCl was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), and concentrated to give 1.15 g (85%) of the amide as an oil: 1H NMR (DMSO-d6) δ9.30 (s, 1H), 8.44 (t, 1H), 7.94-7.70 (m, 10H), 7.41 (m, 4H), 7.20 (d, 2H), 6.95 (d, 2H), 5.08 (s, 2H), 4.35 (s, 2H), 3.42-3.20 (m, 4H), 1.50 (m, 4H), 1.32 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:42][N:43]([C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:42][N:43]([C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)[C:8]([C:5]1[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:27])([F:28])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(c1ccccc1)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)c1ccc(F)cc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (458 mg, 1.00 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (1.0 mL) at room temperature. The reaction was heated at reflux for 1 h then was concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and N-methyl-N-(4-fluorophenyl)aniline (0.50 mL, 3.5 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS) then quenched with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-methyl-N-(4-fluorophenyl)amide. MS m/z 570.1(M+Na); 526.0 (M+H-MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:42])[CH2:29][O:30][CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:42])([CH2:29][O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)COCc1ccc2ccccc2n1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(N2CC(O)(COCc3ccc4ccccc4n3)N=C2c2ccc(Cl)cc2)cc1

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (1 mmol) and sodium bicarbonate (2 mmol) in acetone (20 mL), 1-bromo-3-(2-quinolylmethoxy)-2-propanone from Step 1 (1.5 mmol) is added. After heating to reflux for 24 hours, the reaction mixture is filtered, washed with acetone and concentrated in vacuo. The crude product is purified by chromatography (silica gel, toluene/ethyl acetate) to give 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-[(2-quinolylmethoxy)methyl]-4,5-dihydro-1H-imidazole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:23]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCOc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 12 h
Yield: 67.9 %

Procedure:
To a solution of 3-hydroxy-4-nitrobenzaldehyde (0.80 g, 4.76 mmol), in DMF (15 mls) was added ethyl 6-bromohexanoate (1.30 g, 5.82 mmol) and potassium carbonate (1.23 g, 8.91 mmol). The mixture was stirred at 70° C., for 12 hours, cooled, poured into water and extracted twice with ethyl acetate. The combined organic fractions were washed once with water and dried over anhydrous magnesium sulfate. After the solvents were removed under reduced pressure, a red oil remained which was purified by column chromatography (70% hexane/30% ethyl acetate) to give 6-(5-formyl-2-nitro-phenoxy)-hexanoic acid ethyl ester as a yellow oil (1.00 g, 67%). 1H NMR (400 MHz, CDCl3) δ: 10.06 (s, 1H), 7.92 (d, 1H, J=8.8 Hz), 7.58 (d, 1H, J=1.2 Hz), 7.54 (dd, 1H, J=8 Hz, J=1.6 Hz), 4.20 (q, 2H, J=6.8 Hz), 4.14 (t, 2H, J=7.2 Hz), 2.36 (t, 2H, J=8.0 Hz), 1.90 (m, 2H), 1.73 (m, 2H), 1.57 (m, 2H), 1.29 (t, 3H, J=6.8 Hz) 13C NMR (400 MHz, CDCl3) δ: 173.79, 169.46, 151.87, 143.23, 133.66, 125.32, 121.93, 115.88, 69.65, 60.42, 34.12, 28.54, 25.40, 24.52, 14.25. IR (neat): 3396, 3110, 3080, 3047, 2944, 2869, 2735, 1730, 1705, 1607, 1531, 1489, 1465, 1434, 1381, 1351, 1311, 1272, 1161, 1093, 1063, 1030, 961, 863 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:15]2[CH2:20][NH:19][C:17](=[O:18])[CH2:16]2)=[CH:7][C:8]=1[O:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.CO[C:23]1C=CC([C@H]2CNC(=O)C2)=C[C:24]=1OC1CCCC1.C(OC)(=O)CC([O-])=O>>[CH2:10]([O:9][C:8]1[CH:7]=[C:6]([CH:15]2[CH2:20][NH:19][C:17](=[O:18])[CH2:16]2)[CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:14]1[CH:13]=[CH:12][CH:11]=[CH:24][CH:23]=1
Reactant: COc1ccc([C@H]2CNC(=O)C2)cc1OC1CCCC1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Agent: COC(=O)CC(=O)[O-]
Product: COc1ccc(C2CNC(=O)C2)cc1OCc1ccccc1

Procedure:
The compounds of the present invention may be prepared conventionally. Some of the known processes that can be used are described below. All starting materials are known or can be conventionally prepared from known starting materials. Preparation of Starting Material (Scheme I) Enantiomerically pure rolipram, 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, and the starting material 4-(3-benzyloxy-4-methoxyphenyl)-2-pyrrolidone were prepared as shown in scheme I and in a similar fashion as described previously (J. Demnitz, et. al., Enantiodivergent synthesis of (R)-and (S)-Rolipram, Molecules, 1998, 3, 107-119). Thus, appropriately substituted benzaldehydes were condensed with monomethyl malonate to provide the corresponding methyl cinnamyl esters after decarboxylation. Conjugate addition of nitromethane using tetramethyl guanidine as base provided methyl 4-nitro-3-(substituted-phenyl)butyrate. Racemic 4-(3-benzyloxy-4-methoxyphenyl)-2-pyrrolidone was produced in 85% yield by selective reduction of the nitro group to the corresponding amine using NiCl2 and NaBH4 (Osby, J. O.; Ganem, B., Rapid and efficient reduction of aliphatic nitro compounds to amines, Tetrahedron Lett., 1985, 26, 6413-6416) and subsequent treatment with K2CO3.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C=O)C>[C:22]1([S:19]([N:18]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH:13]=2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1ccc(CCOc2cccc(NS(=O)(=O)c3ccccc3)c2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1cccc(OCCc2ccc(C#N)cc2)c1)S(=O)(=O)c1ccccc1

Procedure:
N-{3-[2-(4-Cyanophenyl)ethoxy]phenyl}benzenesulfonamide (0.179 g; 0.47 mmol; from Example 1(iv) above), K2CO3 (0.082 g; 0.59 mmol) and ethyl bromoacetate (63 μL; 0.57 mmol) were stirred in DMF (10 mL) for 1 hour at room temperature, then 1 hour at 60° C. The mixture was filtered and the solvent removed in vacuo. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted with EtOAc. The combined organic portions were dried (Na2SO4) and the solvent evaporated to afford the sub-title compound in a quantitative yield.
Reaction SMILES: Br[C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12]C)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Cl.[OH-:15].[Na+]>>[OH:15][C:2]12[CH2:9][CH2:8][C:5]([C:10]([OH:12])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: [OH-]
Reactant: COC(=O)C12CCC(Br)(CC1)CC2
Agent: Cl
Agent: [Na+]
Product: O=C(O)C12CCC(O)(CC1)CC2
Yield: 89 %

Procedure:
Methyl 4-bromobicyclo[2.2.2]octane-1-carboxylate (17.0 g, 69.0 mmol) was refluxed in 1.5 L of 1% aqueous sodium hydroxide solution for 24 h. After cooling down, the reaction solution was acidified with hydrochloric acid (6N, 100 mL) and extracted with diethyl ether (6×500 mL). The combined organic layers were dried over magnesium sulfate and concentrated to afford the titled compound (10.4 g, 61.1 mmol, yield: 89%), which was used in the next step without further purification; MS (ESI) m/z=169.2 [M+H]−.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH:27]1([CH:33]=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=CC1CCCCC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCC2CCCCC2)CC1
Yield: 95.9 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1 g) as starting compound and cyclohexanecarboxaldehyde (0.32 g) were reacted and treated in the same manner as in Example 121 to give 1.2 g of 4-amino-5-chloro-N-((1-(5-(cyclohexylmethylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.