Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]2[O:15]CCCO2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:18])[CH3:17].CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:16]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)[CH:10]=[O:15])[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: COc1cc(Br)cc(C2OCCCO2)c1
Reactant: CC(C)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(C=O)cc(N2CCN(C(C)C)CC2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 27.2 %

Procedure:
A mixture of 2-(3-bromo-5-methoxyphenyl)-1,3-dioxane (4.75 g, 17.4 mmol), 1-isopropyl-piperazine (3.14 mL, 21.96 mmol), sodium-tert-butoxide (3.00 g, 31.3 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.342 g, 0.55 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.167 g, 0.18 mmol) in toluene (40 mL) was stirred at 100° C. for 18 h. After this time the reaction was cooled to rt and the dark brown mixture was poured into an ice-cold solution of 1N HCl (100 mL) and stirred vigorously for 2 h at rt. After this time the reaction mixture was re-cooled to 0° C. and the pH was adjusted to 13 with 6N NaOH solution. The reaction mixture was then extracted with diethyl ether. The organic phase was concentrated, taken up in 2N HCl (50 mL) and stirred for 1 h. The resulting mixture was extracted with dichloromethane (2×150 mL). The pH of the aqueous phase was adjusted to approximately 13 with 6N NaOH solution and extracted with diethyl ether (2×150 mL). The combined organic phase was washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 3-(4-isopropylpiperazin-1-yl)-5-methoxybenzaldehyde (1.24 g, 27%) as a viscous red oil: 1H NMR (400 MHz, CDCl3): δ 9.90 (s, 1H), 7.05 (dd, J=2.15, 1.37 Hz, 1H), 6.88 (dd, J=1.95, 1.17 Hz, 1H), 6.69 (t, J=2.34 Hz, 1H), 3.85 (s, 3H), 3.25-3.28 (m, 4H), 2.64-2.78 (m, 5H), 1.10 (d, J=6.64 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[CH:35]=[C:34]([Cl:40])[C:33]([Cl:41])=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:33]1[C:34]([Cl:40])=[CH:35][C:36]2[C:37]3[CH2:38][CH2:39][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:27][CH2:28][C:29]=3[N:30]([CH2:42][C:43]([NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=3[CH3:1])=[O:44])[C:31]=2[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cc(Cl)c(Cl)cc23)CC1
Reactant: Cc1cccc(N)c1C
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(NC(=O)Cn2c3c(c4cc(Cl)c(Cl)cc42)CCN(C(=O)OC(C)(C)C)CC3)c1C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
DMAP (60 mg, 0.49 mmol), 2,3-dimethylaniline (0.065 mL, 0.53 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reaction was diluted with EtOAc followed by washing with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine. The organic layer was then dried over Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc (98:2) to give 0.13 g of impure product. Then, crystallization from EtOAc/heptane gave 96 mg (38%) of a white solid: mp 186-187.5° C.; IR (diffuse reflectance) 3290, 2977, 2939, 1692, 1681, 1662, 1538, 1471, 1450, 1412, 1366, 1338, 1282, 1235, 1163 cm−1; MS (El) m/z 515 (M+), 375, 373, 226, 225, 223, 120, 84, 76, 56, 51; Anal. Calcd for C27H31Cl2N3O3: C, 62.79; H, 6.05; N, 8.14; found: C, 62.60; H, 6.04; N, 8.07.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:25][NH:26][CH2:27][CH2:28][CH3:29].[N:30]#[C:31]Br>C(O)C>[NH2:30][C:31]1[N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][C:3]2[C:2](=[CH:24][CH:23]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:13][S:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=3)[CH:4]=2)[N:1]=1
Reactant: N#CBr
Reactant: CCCNCc1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1N
Solvent: CCO
Product: CCCN1Cc2cc(Oc3cccc(NS(=O)(=O)c4ccccc4)c3)ccc2N=C1N
Temperature: 25 °C

Procedure:
A mixture of N-[3-(4-amino-3-propylaminomethyl-phenoxy)-phenyl]-benzenesulfonamide (0.0044 mol) in ethanol (50 mL) was stirred at room temperature and cyanogen bromide (0.0064 mol) was added, then the reaction mixture was stirred and refluxed for 4 hours. After cooling, the precipitate was filtered off and was stirred in boiling CH3CN with CH3OH. The resulting solids were filtered off, washed with diisopropyl ether and dried to yield the title compound as a solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([NH:15][C:16]1([CH2:20][C:21](OCC)=[O:22])[CH2:19][CH2:18][CH2:17]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1.O.C(OCC)(=O)C>[CH2:7]([NH:15][C:16]1([CH2:20][CH2:21][OH:22])[CH2:19][CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CC1(NC(=O)c2ccccc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OCCC1(NCc2ccccc2)CCC1
Reaction time: 1 h
Yield: 60.7 %

Procedure:
LiAlH4 (3.88 g, 0.102 mol) was added to a solution of ethyl 1-(benzoylamino)-cyclobutylacetate (5.30 g, 20.3 mmol) in THF (100 mL) at room temperature. The mixture was stirred for 1 hour, then refluxed for one additional hour. The mixture was cooled in an ice-water bath, a few drops of water were added, and the mixture was allowed to stand overnight. The mixture was diluted with ethyl acetate, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Distillation of the residue gave the title compound as a colorless oil (2.53 g, 61%). 1H-NMR (400 MHz, CDCl3) δ 1.69-1.86 (2H, m), 1.88 (2H, t, J=5.5 Hz), 1.92-2.09 (4H, m), 3.73 (2H, s), 3.87 (2H, t, J=5.5 Hz), 7.22-7.35 (5H, m).
Reaction SMILES: CN(C)C=O.[C:6]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=O)[CH3:7].[Br-].[CH2:16]([O:23][C:24]([CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[N:12]1[CH:13]=[CH:14][C:9]([C:6]([CH3:7])=[CH:26][C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:25])=[CH:10][CH:11]=1
Reactant: O=C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Reactant: CC(=O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=CC(=O)OCc1ccccc1)c1ccncc1
Temperature: 70 °C
Yield: 42.4 %

Procedure:
N,N-Dimethylformamide (33 ml) was added to a mixture of 4-acetylpyridine (2.00 g, 16.5 mmol) and (benzyloxycarbonyl)methyltriphenylphosphonium bromide (8.94 g, 18.2 mmol), and the whole was stirred under ice-cooling. Potassium carbonate (9.12 g, 66.0 mmol) was added thereto, the external temperature was raised to 70° C., and the whole was stirred overnight. The reaction mixture was diluted with diethyl ether (100 ml), and the whole was washed with water (100 ml, twice) and saturated brine (50 ml) successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1.77 g (42%: mixture of E form and Z form) of benzyl 3-(4-pyridyl)-2-butenoate as a pale yellow oily matter.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]3[CH2:15][CH2:16][CH:11]2[CH2:12][CH2:13]3)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-])=O>[Pd]>[CH:11]12[N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:17]([F:20])([F:18])[F:19])[CH:6]=3)[CH:14]([CH2:13][CH2:12]1)[CH2:15][CH2:16]2
Reactant: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Agent: [Pd]
Product: Nc1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Reaction time: 12 h
Yield: 91 %

Procedure:
A flask charged with 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane 19 (7.07 g, 24.70 mmol) and 10% Pd/C (0.71 g, 6.64 mmol) was evacuated and then flushed with nitrogen. Ethanol (22 mL) was added and the reaction flask was fitted with a hydrogen balloon. After stirring vigorously for 12 h, the reaction mixture was purged with nitrogen and Pd/C was removed by filtration. The filtrate was concentrated to a dark oil under reduced pressure and the residue purified by silica gel chromatography (0-15% ethyl acetate in hexanes) to provide 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline 20 as a purple solid (5.76 g, 91% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 6.95 (dd, J=2.3, 8.8 Hz, 1H), 6.79 (d, J=2.6 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 4.89 (s, 2H), 4.09 (s, 2H), 1.61-1.59 (m, 4H) and 1.35 (d, J=6.8 Hz, 4H).
Reaction SMILES: [S:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:20])OC3C=CC=CC=3)[S:10][C:6]=2[CH:5]=1)[C:2]#[N:3].[CH3:23][C@H:24]1[O:29][C@@H:28]([CH3:30])[CH2:27][N:26]([CH2:31][CH2:32][NH2:33])[CH2:25]1>>[CH3:30][C@H:28]1[O:29][C@@H:24]([CH3:23])[CH2:25][N:26]([CH2:31][CH2:32][NH:33][C:12]([NH:11][C:9]2[S:10][C:6]3[CH:5]=[C:4]([S:1][C:2]#[N:3])[CH:22]=[CH:21][C:7]=3[N:8]=2)=[O:20])[CH2:27]1
Reactant: C[C@@H]1CN(CCN)C[C@H](C)O1
Reactant: N#CSc1ccc2nc(NC(=O)Oc3ccccc3)sc2c1
Product: C[C@@H]1CN(CCNC(=O)Nc2nc3ccc(SC#N)cc3s2)C[C@H](C)O1

Procedure:
The 2-[({2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}carbamoyl)amino]-1,3-benzothiazol-6-yl thiocyanate was prepared according to the method described in Example 9c, but using 654 mg of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate and 0.35 cm3 of 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethanamine. 783 mg of 2-[({2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}carbamoyl)amino]-1,3-benzothiazol-6-yl thiocyanate are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:1]1([N:7]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: ClCCN1CCCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCN3CCCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)pyrrolidine
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C>[C:2]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:3]=1
Reactant: Brc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2cccc(-c3nn4c(NC5CCCC5)cccc4c3-c3ccnc(NC4CCCC4)n3)c2)cc1
Temperature: 100 °C
Yield: 89 %

Procedure:
To a solution of 2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (100 mg, 0.19 mmol) in dimethylformamide (6 mL) was added phenylboronic acid (47 mg, 0.39 mmol), palladium (II) acetate (4.3 mg, 0.02 mmol), potassium carbonate (54 mg, 0.39 mmol) and triphenyl phosphine (30 mg, 0.08 mmol). The reaction was heated at 100° C. for 24 hours. After allowing the reaction mixture to cool to room temperature, ethyl acetate and water were added. The organic layer was separated and washed with water, then brine and dried (magnesium sulfate). Filtration and concentration, followed by purification with flash chromatography (4:6 ethyl acetate:hexanes) gave 2-[1,1′-biphenyl]-3-yl-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine as a yellow foam (87 mg, 89%). 1H NMR (CDCl3): δ 8.01 (d, 1H), 7.92 (s, 1H), 7.81 (d, 1H), 7.69–7.62 (m, 4H), 7.53 (t, 1H), 7.47–7.43 (m, 2H), 7.38–7.32 (m, 2H), 6.40 (d, 1H), 6.09–6.05 (m, 2H), 5.16 (m, 1H), 4.37 (m, 1H), 4.03 (m, 1H), 2.15–2.06 (m, 4H), 1.82–1.64 (m, 12H); MS m/z 515 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH:13]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10](/[CH:13]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)on1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cc(-c2ccc(Cl)cc2)on1
Temperature: 55 °C

Procedure:
A suspension of 5-(4-chlorophenyl)isoxazole-3-carbaldehyde (2.00 g, 9.63 mmol), (R)-2-methylpropane-2-sulfinamide (1.28 g, 10.6 mmol, 1.1 equiv) and anhydrous copper(II) sulfate (2.31 g, 14.5 mmol, 1.5 equiv) in 1,2-dichloroethane (19 mL) was heated at 55° C. for 2-18 hours. The reaction was then cooled to room temperature and filtered through a pad of celite, using 1,2-dichloroethane to wash through. The filtrate was concentrated in vacuo to give crude (R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide as a green solid, which was used without further purification. MS m/z 311.0 (M+H)+; Rt-1.11 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([NH2:10])=[O:9].[N:14]1([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CC(CC(C)C)=O>[CH3:6][C@H:5]1[CH2:11][CH2:12][C@H:13]([NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:11]=[CH:12][C:13]([O:9][CH2:8][CH2:7][N:23]3[CH2:24][CH2:25][CH:20]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:21][CH2:22]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:3][CH2:4]1
Reactant: COc1cccc(C=CC(N)=O)c1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCC(N2CCCCC2)CC1

Procedure:
Using 1.9 g N-(trans-4-methylcyclohexyl)-4-chloroethoxy)-3-methoxycinnamamide (Example 138), 4.56 g of 4-piperidinopiperidine, and 50 ml of methylisobutylketone, a reaction similar to that conducted in Example 142 was carried out. As a result, 1.51 g of N-(trans-4-methylcyclohexyl)-4-[2-(4-piperidinopiperidino)ethoxy]-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][CH:9]([C:15]2[C:24]([CH3:25])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[OH:26])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[Br:34]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH:9]([C:15]2[C:24]([CH3:25])=[C:23]([Br:34])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[OH:26])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:27][CH:28]=1
Reactant: BrBr
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2ccccc2c1O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)c(Br)c2ccccc2c1O
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
A solution of ethyl 2-(4-methoxybenzyloxy)-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate (102 mg, 0.268 mmol) in CHCl3 (5.0 mL) was treated with solid NaHCO3 (46 mg, 0.281 mmol). Br2 (45 mg) in CHCl3 (1.0 mL) was added dropwise over 5 min at 23° C. After 15 min, 10% Na2S2O3 (10 mL) was added. The reaction was extracted two times with CHCl3. Combined organic phases were dried (Na2SO4), filtered, and concentrated. The residue was dissolved in DCM. The solution was wet-loaded onto a 12 g “gold” ISCO silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (83 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.22 (d, J=8.6 Hz, 1H), 7.59 (dd, J=7.4, 7.4 Hz, 1H), 7.47 (dd, J=7.8, 7.8 Hz, 1H), 7.26 (d, J=8.2 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 5.47 (s, 1H), 4.67-4.56 (m, 2H), 4.26-4.08 (m, 2H), 3.81 (s, 3H), 2.60 (s, 3H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[O:29])[NH:20][O:21]CC3C=CC=CC=3)[CH:17]=2)[NH:12][C:11](=[O:30])[C:10]1=[O:31])C1C=CC=CC=1.O.[OH-].[Na+]>C(O)C.[Pd]>[OH:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[O:29])[NH:20][OH:21])[CH:17]=2)[NH:12][C:11](=[O:30])[C:10]1=[O:31]
Reactant: O=C(NOCc1ccccc1)c1ccc2[nH]c(=O)c(=O)n(OCc3ccccc3)c2c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NO)c1ccc2[nH]c(=O)c(=O)n(O)c2c1
Yield: 76.6 %

Procedure:
A suspension of 1-Benzyloxy-7-(benzyloxycarbamoyl)quinoxaline-2,3(1H,4H)-dione (250 mg, 0.6 mmol) in 50 ml of ethanol was hydrogenated at atmospheric pressure and room temperature for 1 h in the presence of 50 mg of 5% palladium on carbon. Water (20 ml) and 4 ml of 2 N sodium hydroxide was added to dissolve the product and the catalyst was removed by filtration. The filtrate was acidified with 4 ml of 4M hydrochloric acid, evaporated to about 10 ml and filtered to give a white solid. Washing with a small amount of cold water and ethanol yielded 109 mg (70%) of the title compound. 1H-NMR (DMSO-d6): 7.21 (d, J=8 Hz, 1H, ArH), 7.60 (dd, J=8 Hz, 2 Hz, 1H, ArH), 7.90 (d, J=2 Hz, 1H, ArH), 9.05 (br.s, 1H, exchangeable), 11.35 (br.s, 1H, exchangeable), 11.82 (br.s, 1H, exchangeable), 12.35 (br.s, 1H, exchangeable).
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[N:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].[OH-].[Na+]>C(Cl)Cl.O>[CH3:25][S:26]([O:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[N:11]=[CH:12][C:13]([F:16])=[CH:14][N:15]=3)[CH2:9][C@@H:4]2[CH2:3]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of 1.00 g (4.20 mmol) of (7R,8aS)-7-hydroxy-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 6) and 0.644 mL (4.62 mmol) of triethylamine in 40 mL of methylene chloride was chilled to 0° C. and 0.34 mL (4.41 mmol) of methanesulfonyl chloride in 20 mL of methylene chloride was added slowly. After 30 minutes, water was added and the pH adjusted to 10 with 1M NaOH. The layers were separated, the organic phase was washed with water (2×), dried (magnesium sulfate), filtered and evaporated to give 1.15 g (86%) of the title compound of sufficient purity for use in subsequent reactions. m/z (MH+) 317.
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9](=[NH:12])[O:10][CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N[OH:15].N>CN(C)C=O>[OH:15][N:12]=[C:9]([O:10][CH3:11])[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=N)Cc1ccccc1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: COC(Cc1ccccc1)=NO
Yield: 84.8 %

Procedure:
Methyl phenylacetimidate hydrochloride (30.9 grams; 0.167 mole) was stirred with solid hydroxylamine hydrochloride (12.8 grams; 0.184 mole) in dimethyl formamide (120 ml) while ammonia gas was added slowly without cooling. Ammonia addition (approximately 5 grams) was stopped when the temperature of the mixture peaked at 40° C. and dropped to 29° C. The slurry was then cooled in an ice bath and filtered. The filtrate (131 grams) was analyzed by GC and GC-mass spectroscopy and established to contain methyl N-hydroxyphenylacetimidate (23.4 grams; 84.8% yield).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[N:18]([CH:19]=2)[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[S:15]3)=[CH:8][CH:7]=1.[N:24]([O-])=[O:25].[Na+]>O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[N:24]=[O:25])[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[S:15]3)=[CH:10][CH:11]=1
Reactant: Clc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Nc1c(-c2ccc(Cl)cc2)nc2sc3ccccc3n12
Reaction time: 3 h
Yield: 64.8 %

Procedure:
To 700 ml of acetic acid was added 14 g of 2-(p-chlorophenyl)imidazo[2,1-b]benzothiazole and after adding thereto 5 g of sodium nitrite with stirring at room temperature, the mixture was stirred for 3 hours. Thereafter, 500 ml of water was added to the mixture and the crystals thus formed were recovered by filtration and washed with water, then n-hexane, and further with 400 ml of chloroform to provide 10 g of 2-(p-chlorophenyl)-3-nitrosoimidazo[2,1-b]benzothiazole. The product was recrystallized from chloroform to provide crystals having a melting point of 203°-206° C.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[CH:2]=1.[OH-].[K+]>C1COCC1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:2]=1
Reactant: COC(=O)CCCCCCC(=O)Nc1cccc(-c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC(=O)Nc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.2 %

Procedure:
A solution of compound 182 (0.212 g, 0.62 mmol) in THF (10 mL) was treated with potassium hydroxide (5 mL of a 3.5% aqueous solution) and stirred at room temperature for 72 h then concentrated, diluted with diethyl ether and acidified with citric acid. The acidic mixture was extracted with AcOEt, washed with H2O, dried over MgSO4, filtered, and concentrated to give title compound 183 (0.182 g, 90% yield).