Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:13][CH2:14][C@@H:15]1[CH2:17][O:16]1)([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1.[CH3:18][NH:19][CH3:20]>C(O)(C)C>[CH3:18][N:19]([CH3:20])[CH2:17][C@H:15]([OH:16])[CH2:14][O:13][C:2]([CH3:12])([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1
Reactant: CC(C)(Cn1ccc([N+](=O)[O-])n1)OC[C@@H]1CO1
Reactant: CNC
Solvent: CC(C)O
Product: CN(C)C[C@H](O)COC(C)(C)Cn1ccc([N+](=O)[O-])n1
Yield: 86.2 %

Procedure:
Compound (S)-1-dimethylamino-3-[1,1-dimethyl-2-(3-nitro-pyrazol-1-yl)-ethoxy]-propan-2-ol was prepared by reacting 1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-3-nitro-1H-pyrazole (0.39 g, 1.62 mmol), isopropyl alcohol (6 mL), and dimethylamine (3 mL, 6 mmol, 2 M in dioxane) under microwave conditions at 130° C. for 15 min. The mixture was extracted with dichloromethane and water. The organic layer was separated and the solvent evaporated under reduced pressure to yield (S)-1-dimethylamino-3-[1,1-dimethyl-2-(3-nitro-pyrazol-1-yl)-ethoxy]-propan-2-ol (0.4 g, 87%). This compound was reduced under the following conditions. The mixture of (S)-1-dimethylamino-3-[1,1-dimethyl-2-(3-nitro-pyrazol-1-yl)-ethoxy]-propan-2-ol (0.39 g, 1.66 mmol), ethyl acetate (30 mL), ethanol (30 mL) was added to a Parr bottle with 10% Pd/C (0.22 g) and subjected hydrogen gas (20 psi) for 2 h under the Parr Shaker Apparatus conditions. Work up by filtration via a glass membrane filter paper, solvent was removed under reduced pressure to afford (S)-1-[2-(3-amino-pyrazol-1-yl)-1,1-dimethyl-ethoxy]-3-dimethylamino-propan-2-ol as an oil (0.37 g, 97.5%).
Reaction SMILES: C(Cl)(=O)C.[N+:5]([C:8]([CH3:38])([CH3:37])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[CH:13][C:12]=1[C:30]1[N:31]([CH3:36])[N:32]=[CH:33][C:34]=1[Cl:35])([O-])=O>CO.[Zn]>[NH2:5][C:8]([CH3:38])([CH3:37])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=2)=[CH:13][C:12]=1[C:30]1[N:31]([CH3:36])[N:32]=[CH:33][C:34]=1[Cl:35]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)Cl
Solvent: CO
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)N
Temperature: 23 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Acetyl chloride (97 μl, 1.4 mmol) was added dropwise to a solution of N-(4-(2-nitro-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide (68 mg, 0.136 mmol) in MeOH (2.0 mL). Zinc dust (89 mg, 1.4 mmol) was added, and the mixture was stirred at 23° C. After 1 hr, the mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in ammonium hydroxide (35%), diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was dissolved in methanol, a solution of acetyl chloride (15 μl) in methanol was added, and the solution was evaporated to dryness. The residue was dissolved in water—acetonitrile 1:1 and lyophilized to afford the product (57 mg, 83%) as the hydrochloride. LCMS m/z (%)=469.4 (M+H 37Cl 58.9%), 467.4 (M+H 35Cl 83.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (s, 3 H), 1.20 (s, 3 H), 3.66 (s, 3 H), 3.87 (d, J=9.60 Hz, 1 H), 4.02 (d, J=9.85 Hz, 1 H), 7.31 (d, J=9.09 Hz, 1 H), 7.67 (s, 1 H), 7.72 (d, J=2.53 Hz, 1 H), 7.80 (t, J=7.71 Hz, 1 H), 7.92-8.08 (m, 5 H), 8.27 (d, J=8.08 Hz, 1H), 8.30 (s, 1 H), 10.58 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[C:12](O)(=O)[CH3:13]>Cl>[CH3:5][N:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:2]=2[N:1]=[C:12]1[CH3:13]
Reactant: CNc1cccc(OC)c1N
Reactant: CC(=O)O
Agent: Cl
Product: COc1cccc2c1nc(C)n2C
Yield: 87.5 %

Procedure:
A suspension of 2-amino-3-methoxy-N-methylaniline (671 mg) and acetic acid (265 mg) in 4N hydrochloric acid (3.5 ml) was refluxed for 10 hours. Insoluble material was filtered off, and the filtrate was adjusted to pH 7 with saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel flash chromatography (dichloromethane:methanol=40:1, v/v) to give 1,2-dimethyl-4-methoxy-lH-benzimidazole (680 mg). mp: 122.5-124° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[F:18].[H][H]>C(O)(=O)C.[C].[Pd]>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[F:18]
Reactant: [H][H]
Reactant: Oc1ccc(-c2cc(F)c(F)c3ccoc23)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1ccc(-c2cc(F)c(F)c3c2OCC3)cc1
Yield: 59 %

Procedure:
The compound (568 mg, 2.31 mmol) of Step 1 was dissolved in acetic acid (25 mL), and a catalytic amount of 10% palladium-carbon was added thereto, and stirred in a hydrogen atmosphere of 4 atm overnight. The insoluble material was filtered off, and the solvent was distilled away under reduced pressure. The resulting residue was purified by reversed-phase HPLC in the same manner as in Step 2 of Example 1 to thus obtain the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([CH:14]=1)[NH2:13]>CN(C=O)C>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([NH2:13])[CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
Morpholine (1 equivalent) and 5-chloro-2-nitroaniline (1 equivalent) were dissolved in DMF, and TEA (2 equivalents) was added. The reaction mixture was heated at 120° C. overnight. The reaction mixture was then cooled to room temperature, most of the DMF was distilled off, and water was added to the residue to obtain the crude product as a precipitate. The solid was dried and purified by chromatography on silica gel (2-10% MeOH/CH2Cl2) to afford the desired product, 5-morpholin-4-yl-2-nitro-phenylamine.
Reaction SMILES: [OH-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.Cl.[CH3:13]O>>[CH3:13][C:4]1[NH:3][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methanol (2 ml) and a 10% aqueous solution of sodium hydroxide (0.2 ml) were added to optically active 6-(2-benzoyloxy-1-pentane)sulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methyl-benzimidazole isomer with shorter retention time as obtained in Production Example 34 (277 mg) and the mixture was stirred for 90 minutes at room temperature. A 10% aqueous solution of sodium hydroxide (0.36 ml) was further added thereto and stirring was continued for 50 minutes under heating at 50° C. The solution was allowed to cool for 70 minutes to room temperature and 1N hydrochloric acid (1.4 ml) was added thereto and the resulting solution was cooled with ice. Deposited crystals were collected by filtration, washed three times with water (2 ml) and twice with chloroform (1ml), and dried by heating under reduced pressure to obtain optically active 1-(2,4-dichlorobenzyl)-6(2-hydroxy-1-pentane)sulfonyl-carbamoyl)-2-methylbenzimidazole with longer retention time on CHIRALPAK AD (79) (143 mg).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.Cl.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH2:33])[CH3:32])=[N:27][CH:26]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:33][CH:31]([C:28]2[CH:29]=[CH:30][N:25]=[CH:26][N:27]=2)[CH3:32])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(N)c1ccncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)c1ccncn1
Yield: 54 %

Procedure:
This compound (41 mg, 56% yield) as a yellow crystalline solid was prepared according the procedures described for Example 318, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (55 mg, 0.19 mmol), (1-(pyrimidin-4-yl)ethanamine dihydrochloride (73 mg, 0.37 mmol) (ChemBridge Corporation) and DIEA (0.26 mL, 1.48 mmol) in 2 mL of DMSO (heated in a microwave at 160° C. for 30 min)1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (1H, br.), 9.15 (1H, s), 8.69 (1H, d, J=5.1 Hz), 7.87 (1H, d, J=7.2 Hz), 7.67 (2H, d, J=4.3 Hz), 7.57 (1H, d, J=8.0 Hz), 7.32 (1H, t, J=7.7 Hz), 6.99 (1H, br.), 6.87 (1H, s), 5.27 (1H, m), 3.48 (2H, m), 3.06 (2H, m), 2.69 (3H, s), 1.69 (3H, d, J=6.8 Hz). m/z (ESI, +ve) 400.1 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH2:15][CH2:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccc2c1NCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cccc2cc[nH]c12

Procedure:
A reaction vessel is charged with 2.23 liters of methylene chloride to which is added one mole of the 7-benzoylindoline obtained in Example 1. To this mixture is added 3.0 moles of activated manganese dioxide. This reaction mixture is agitated and heated at reflux for 24 hours to produce 7-benzoylindole. The produce is then filtered through a filter that will retain the manganese dioxide. The reaction vessel is rinsed with 0.2 liter of hot methylene chloride and the filter cake washed with this rinse. The 7-benzoylindole product obtained has a melting point of 100°-104.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:34]1([N:37]2[CH2:41][CH2:40][CH2:39][CH:38]2[CH2:42][NH2:43])[CH2:36][CH2:35]1>O>[CH:34]1([N:37]2[CH2:41][CH2:40][CH2:39][CH:38]2[CH2:42][NH:43][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[CH:11][C:3]=2[O:2][CH3:1])[CH2:36][CH2:35]1
Reactant: COc1cc(N)c(S(=O)(=O)N(C)C)cc1C(=O)O
Reactant: NCC1CCCN1C1CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(N)c(S(=O)(=O)N(C)C)cc1C(=O)NCC1CCCN1C1CC1
Temperature: 0 °C

Procedure:
68.5 g of 2-methoxy-4-amino-5-dimethylsulphamoyl benzoic acid (0.25 mole), 740 ml of water and 25.4 g of triethylamine (0.25 mole) are placed in a 2 liter flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The solution is cooled to about 0° C, and 34.1 g of isobutyl chloroformate (0.25 mole) is poured in drop by drop. The mixture is reacted for 40 minutes at room temperature then cooled, and 42 g of 1-cyclopropyl-2-aminomethylpyrrolidine is added drop by drop, while the temperature is kept between 0° and +5° C. The medium is reacted for 3 hours at room temperature, then the solution is evaporated dry under vacuum. The residue is dissolved in 250 ml of water and 50 ml of hydrochloric acid. The solution is extracted twice with 125 ml of methylene chloride, which is eliminated. The aqueous phase is made alkaline with 70 ml of soda lye.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C@@H:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[NH:15][C:14]=4[C@@H:7]2[CH2:6][C@@H:5]([CH2:10]3)[CH2:4]1.C1(C2NC3C(=CC=[C:31](C=3)[O:32]C)C=2CCN=1)C.COCC[C@@H]1[C@@H]2N3CCC4C5C=CC=CC=5NC=4[C@]2(C(OC)=O)CC(C3)C1.CC[C@@H]1[C@@H]2N3CCC4C5C=CC=CC=5NC=4[C@]2(C(OC)=O)C[C@@H](C3)C1>>[CH3:1][CH2:2][C@@H:3]1[C@@H:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:17]5[CH:18]=[C:19]([O:32][CH3:31])[CH:20]=[CH:21][C:16]=5[NH:15][C:14]=4[C@@H:7]2[CH2:6][C@@H:5]([CH2:10]3)[CH2:4]1
Reactant: CC[C@H]1C[C@H]2C[C@H]3c4[nH]c5ccccc5c4CCN(C2)[C@@H]13
Reactant: COc1ccc2c3c([nH]c2c1)C(C)=NCC3
Agent: CC[C@H]1C[C@@H]2CN3CCc4c([nH]c5ccccc45)[C@](C(=O)OC)(C2)[C@H]13
Agent: COCC[C@H]1CC2CN3CCc4c([nH]c5ccccc45)[C@](C(=O)OC)(C2)[C@H]13
Product: CC[C@H]1C[C@H]2C[C@H]3c4[nH]c5ccc(OC)cc5c4CCN(C2)[C@@H]13

Procedure:
Ibogamine (20-40 mg/kg), harmaline (10-40 mg/kg) and desethycoronaridine (10-40 mg/kg) were obviously tremorigenic for 3-4 h and no attempt was made to compare these drugs quantitatively. However, visual observations and videotape recordings of 18-methoxycoronaridine (40 mg/kg) and both R- and S-enantiomers of both ibogamine (40 mg/kg) and coronaridine (40 mg/kg) indicated very little if any tremorigenic activity. The effects of these latter drugs were therefore assessed using the automated testing procedure developed to quantitate tremors. Ibogains (40 mg/kg) and saline (1 ml/kg) were used as positive and negative controls, respectively. While ibogaine produced a significant increase in movements indicative of tremors, the 18-methoxycoronaridine and the ibogamine and coronaridine enantiomers had no effects that differed significantly from the effects of saline.
Reaction SMILES: [La:1].[Tb].[O-2].[La+3].[O-2].[O-2].[La+3].[O-2].[Tb+3].[O-2].[O-2].[Tb+3].[N+:13]([O-:16])([OH:15])=[O:14]>>[N+:13]([O-:16])([O-:15])=[O:14].[La+3:1].[N+:13]([O-:16])([O-:15])=[O:14].[N+:13]([O-:16])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: [La]
Agent: [La+3]
Agent: [O-2]
Agent: [Tb+3]
Product: O=[N+]([O-])[O-]

Procedure:
The lanthanum and terbium raw materials may be lanthanum oxide and terbium oxide. Lanthanum oxide is added to concentrated nitric acid to form lanthanum nitrate, which is then preferably diluted. Terbium oxide is added to concentrated nitric acid to form terbium nitrate solution, which is then preferably diluted. The diluted lanthanum nitrate solution and the diluted terbium nitrate solution are then combined to form a single rare earth solution. Hydrated cerium nitrate is then added to the rare earth solution. The molar ratio of the rare earth elements in the rare earth solution is thus about x mole La:y mole Ce:z mole Tb where x=0.39 to 0.73, y=0.17 to 0.45 and z=0.10 to 0.17. The molar ratio of the rare earth elements is preferably about 0.6 mole La:0.225 mole Ce:0.165 mole Tb.
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[C-:8].[C:14]1([C:20]2[S:21][CH:22]=[C:23]([C@@H:25]([N:36]=[C:37]=[S:38])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>C1COCC1>[C:14]1([C:20]2[S:21][CH:22]=[C:23]([C@@H:25]([NH:36][C:37]3[S:38][CH:8]=[N:7][C:9]=3[C:10]([O:12][CH3:13])=[O:11])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(C[C@H](N=C=S)c2csc(-c3ccccc3)n2)cc1
Reactant: [C-]#[N+]CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ncsc1N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of potassium tert-butoxide (89 mg, 0.75 mmol) in THF (3 mL) is added methyl isocyanoacetate (65 μL, 0.68 mmol) followed by (S)-2-phenyl-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)thiazole, 43, (250 mg, 0.68 mmol). The reaction mixture is stirred at room temperature for 2 hours then poured into sat. NaHCO3. The mixture is extracted with EtOAc (3×25 mL) and the combined organic layers are washed with brine and dried (Na2SO4) and concentrated in vacuo. The crude residue is purified over silica to afford 323 mg (˜100% yield) of the desired product as a slightly yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.09-8.13 (m, 2H), 7.95-7 98 (m, 3H), 7.84 (d, J=1.2 Hz, 1H), 7.44-7.50 (m, 3H), 7.28-7.31 (m, 2H), 7.96 (d, J=0.6 Hz, 1H), 4.71-4.78 (m, 1H), 3.92 (s, 3H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H), 3.45 (dd, J=13.8 and 6.0 Hz, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:13](=O)[CH3:14]>>[CH2:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)[CH3:14]
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: CC=O
Product: CCNc1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 8, react 4-(1H-imidazol-1-yl)benzenamine with acetaldehyde to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH3:26])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].Cl>ClCCl.CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH3:26])=[C:19]([CH2:23][CH2:24][N:27]4[CH2:28][CH2:29][CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: Cc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-methylphenyl]acetaldehyde (118 mg, 0.305 mmol) (D97) in Dichloromethane (DCM) (20 mL) stirred at room temperature was added ethyl 4-piperidinecarboxylate (192 mg, 1.220 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (129 mg, 0.610 mmol) was added. The reaction mixture was continuously stirred for 1 day. The reaction was quenched with water, and DCM was evaporated in vacuo. Sodium hydroxide (12.20 mg, 0.305 mmol) and i-PrOH was added. The reaction mixture was continuously stirred for 2 hours. 1M HCl solution was added until PH=6-7. i-PrOH was evaporated in vacuo. The aqueous layers were extracted by EA/THF for 3 times. The combined organic layers were concentrated, and purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-methylphenyl]ethyl}-4-piperidinecarboxylic acid (E58) (80 mg) as a off-white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.55 (2H, m), 1.81 (2H, m), 2.05 (2H, t), 2.18 (1H, tt), 2.41 (3H, s), 2.45 (2H, m), 2.87 (4H, m), 4.83 (1H, dt), 7.30 (1H, m), 7.41 (3H, m), 7.94 (1H, dd), 8.08 (1H, d). MS (ES): C26H30ClN3O3S requires 499.2. found 500.2 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17]([C:19]3[CH:28]=[C:27]4[C:22]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][C:26]4=[O:29])=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.C[Li].O.[C:35](=O)([O-])O.[Na+]>C1COCC1.C(OCC)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[C:17]([C:19]3[CH:28]=[C:27]4[C:22]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][C:26]4([CH3:35])[OH:29])=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:12]1
Reactant: CC1(C)CCC(=O)c2cc(-c3cccc(N4CCN(CCCCCO)CC4)n3)ccc21
Reactant: O=C([O-])O
Agent: [Li]C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CCC(C)(O)c2cc(-c3cccc(N4CCN(CCCCCO)CC4)n3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
50 mg (0.12 mmol) of 7-{6-[4-(5-hydroxypentyl)piperazin-1-yl]pyridin-2-yl}-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one are dissolved in 5 ml of THF, cooled to 0° C., and 224 μl (0.36 mmol) of methyllithium in diethyl ether (5%) are added. The reaction mixture is stirred at 0° C. for 30 min and warmed to room temperature. Water added to the reaction mixture, sodium hydrogencarbonate solution added, and the mixture extracted with ethyl acetate, dried and evaporated. The crude product is purified by means of column chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([O:12][CH3:13])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:15]([CH2:22][CH:23]1[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]1)[C:16](=O)[C:17]([F:20])([F:19])[F:18]>C(O)CCC>[F:29][C:26]1([F:30])[CH2:27][CH2:28][CH:23]([CH2:22][C:15]2[N:11]3[CH:10]=[C:9]([O:12][CH3:13])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]3=[N:1][C:16]=2[C:17]([F:18])([F:19])[F:20])[CH2:24][CH2:25]1
Reactant: COC(=O)c1cc(N)ncc1OC
Reactant: O=C(C(Br)CC1CCC(F)(F)CC1)C(F)(F)F
Solvent: CCCCO
Product: COC(=O)c1cc2nc(C(F)(F)F)c(CC3CCC(F)(F)CC3)n2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
Methyl 2-amino-5-methoxyisonicotinate (20 mg, 0.110 mmol) obtained in step 3 was suspended in n-butanol (1.10 mL), and the suspension was stirred overnight at 130° C. after adding 3-bromo-4-(4,4-difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (53 mg, 0.165 mmol) obtained in step 2 of Example 36, and molecular sieve 4A (20 mg). The reaction mixture was allowed to cool to room temperature, filtered through Celite (registered trademark) after adding a sodium hydrogen carbonate aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=15/1) to give methyl 3-(4,4-difluorocyclohexylmethyl)-6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridine-7-carboxylate (23.0 mg, yield 52%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH2:10]O)[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[CH:6][C:5]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])(=[O:3])[CH3:2].N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:41])(=O)=O.Cl.[Cl-].[Na+]>CN(C)C=O>[C:1]([C:4]1[CH:9]=[C:8]([CH2:10][Cl:41])[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[CH:6][C:5]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(CO)c(OCCCCC#N)cc1OCCCCC#N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(=O)c1cc(CCl)c(OCCCCC#N)cc1OCCCCC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 124 (688 mg) was dissolved in 50 ml of dimethylformamide. To this solution were added 0.29 ml of collidine followed by 0.252 g of lithium chloride. The reaction was cooled by means of an external ice bath and 0.507 ml of methane sulfonyl chloride were added. After stirring for 2 hours, the reaction was allowed to warm to room temperature. The mixture was poured into cold dilute hydrochloric acid to which sodium chloride had been added and the solution was extracted with ethyl acetate. The organic layer was washed twice with cold hydrochloric acid/sodium chloride, dried over sodium sulfate, and concentrated in vacuo. Concentration of the solution provided a residue which was crystallized from methylene chloride/hexane to provide 180 mg of the desired title product, m.p.=100°-110° C. (decomposition).
Reaction SMILES: [C:1]([CH2:9][N+:10]([O-:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:14](=[N:20]O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15]([C:14]1[C:9]([N+:10]([O-:12])=[O:11])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][N:20]=1)=[O:16])[CH3:19]
Reactant: O=C(C[N+](=O)[O-])c1ccccc1
Reactant: CCOC(=O)C(Cl)=NO
Product: CCOC(=O)c1noc(-c2ccccc2)c1[N+](=O)[O-]

Procedure:
4-Nitro-5-phenyl-isoxazole-3-carboxylic acid ethyl ester is prepared from benzoylnitromethane and ethyl chlorooximinoacetate, using the condition described in Dal Piaz, V.; Pinzauti, S.; Lacrimini, P. Synthesis 1975, 664; 1H NMR (CDCl3, 400 MHz) δ 7.93 (d, 2H), 7.65 (t, 1H), 7.58 (t, 2H), 4.53 (q, 2H), 1.44 (t, 3H); HPLC-MS calculated for C12H10N2O5 (M+H+) 263.1. Found 263.1.