Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.N1C=CC=CC=1.[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:31])[N:28]5[C:44]([CH:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:45])=[CH:23][CH:22]=4)[CH2:14][CH2:15]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1C(=O)C1CCCCC1

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-quinolin-2-one (1 g) synthesized in the same manner as in WO2006/112464 (Example 11) in dichloromethane (30 ml) was added pyridine (0.37 ml), with stirring under ice-cooling, cyclohexanecarbonyl chloride (0.46 ml) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=9:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1-(cyclohexanecarbonyl)-3,4-dihydroquinolin-2(1H)-one (1.2 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:7](=[S:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:7]([S:10][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=2)=[N:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCCCc1n[nH]c(=S)n1Cc1ccc([N+](=O)[O-])cc1
Product: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc([N+](=O)[O-])cc1
Yield: 90 %

Procedure:
Reaction of 5-n-butyl-2,4-dihydro-4-(4-nitrobenzyl)-3H-1,2,4-triazole-3-thione with 4-chlorobenzyl chloride according to the procedure of Example 4, Step A (with reaction time shortened to 4.5 hours) gave a 90% yield of the title compound as an oil, homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB m/e 417 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:36][CH2:35][CH2:34][O:33][CH3:32])=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: COCCN
Product: COCCNCc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 2-methoxyethanamine (36.4 mg; 0.48 mmol) to give Example 114 as a white solid. 1H NMR: (CDCl3, 400 MHz) δ 8.73-8.69 (2H, m), 8.05 (2H, d, J=8.0 Hz), 7.66-7.52 (2H, m), 7.46 (2H, d, J=8.0 Hz), 7.40-7.33 (3H, m), 7.18 (1H, t, J=9.1 Hz), 3.88 (2H, s), 3.53 (2H, t, J=5.1 Hz), 3.36 (3H, s), 2.82 (2H, t, J=5.1 Hz). LC/MS (Method C): 472 (M+H)+. HPLC (Method F) Rt 3.07 min (Purity: 96.5%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][N:7]([CH3:13])[C:8]=1[S:9]([NH2:12])(=[O:11])=[O:10])[CH:2]=[CH2:3].C1(N[C:21](=O)[O-:22])C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([NH2:34])[N:27]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([NH:34][C:21]([NH:12][S:9]([C:8]2[N:7]([CH3:13])[N:6]=[CH:5][C:4]=2[CH:1]=[CH:2][CH3:3])(=[O:11])=[O:10])=[O:22])[N:27]=1
Reactant: O=C([O-])Nc1ccccc1
Reactant: COc1cc(OC)nc(N)n1
Reactant: C=CCc1cnn(C)c1S(N)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC=Cc1cnn(C)c1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Reaction time: 0.5 h

Procedure:
The sulfonamide from Example 4 (150 mg, 0.7 mmol) and the phenylcarbamate of 4,6-dimethoxy-2-aminopyrimidine (202 mg, 0.7 mmol) were dissolved in 5 ml of acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (112 mg, 0.7 mmol) was added and the reaction was stirred for 30 minutes. Addition of 5 ml of 5% hydrochloric acid resulted in a solid, which was collected and dried to afford 280 mg of the desired product, m.p. 154°-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.C([O-])(=O)C.[NH4+:17].O.[OH-].[Na+]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH2:17])[CH2:7][CH2:6][CH2:5]2
Reactant: [NH4+]
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: NC1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
6-Bromo-3,4-dihydro-2H-naphthalen-1-one (9.5 g, 42.2 mmol) was suspended in 2-propanol (250 ml); then, NaBH3 CN (13.3 g, 211 mmol) was added, followed by ammonium acetate (65.1 g, 844 mmol). The reaction mixture was then stirred at RT for 4 hours. It was subsequently heated up to reflux and stirring was continued for 22 hours. The reaction mixture was then cooled down to RT and poured into cold H2O (500 ml); the pH was adjusted to >10 with sodium hydroxide solution and the mixture was extracted with CH2Cl2 (2×25 ml). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (9.842 g) which was purified by flash chromatography (silica gel, 100 g, 2% to 10% MeOH in CH2Cl2) to yield the title compound (8.08 g, 85%) as light red oil. MS: 226.0 (MH+, 1Br).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]1[N:21]=[C:20]([C:22]#[N:23])[C:19]([C:24](OC)=[O:25])=[C:18]([NH:28][C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>[Pd].CCO>[O:25]=[C:24]1[C:19]2[C:18]([NH:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)=[N:17][C:16]([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]3[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:21][C:20]=2[CH2:22][NH:23]1
Reactant: COC(=O)c1c(C#N)nc(N2CCCCC2CNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cccc(Nc2nc(N3CCCCC3CNC(=O)OC(C)(C)C)nc3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
A mixture of methyl 2-(2-((tert-butoxycarbonylamino)methyl)piperidin-1-yl)-4-cyano-6-(m-tolylamino)pyrimidine-5-carboxylate (310.1 mg, 0.645 mmol), palladium on carbon (72.4 mg, 0.680 mmol) in EtOH (8 mL), and 1N HCl (4 mL) was stirred at RT for 16 h. The mixture was filtered to remove the catalyst. The filtrate was treated with saturated aq NaHCO3 (20 mL) for 3 h. The mixture was concentrated under reduced pressure and the residue was extracted with EtOAc (2×40 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL), and brine (20 mL), were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (213.4 mg, 73%). 1H-NMR (DMSO-d6) δ ppm 1.28 (s, 9H), 1.35 (br s, 1H), 1.49-1.56 (m, 2H), 1.67-1.69 (m, 3H), 2.31 (s, 3H), 3.06 (br s, 1H), 3.24 (br s, 2H), 4.16 (s, 2H), 4.67 (br s, 1H), 5.08 (br s, 1H), 6.77 (br s, 1H), 6.87 (d, 1H, J=7.0 Hz), 7.23-7.25 (m, 1H), 7.53 (br s, 2h), 8.07 (s, 1H), 8.55 (s, 1H). [M+H] calc'd for C24H33N6O3, 453. found, 453.5.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>CO>[NH:10]([C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: NN
Reactant: Cc1ccnc(Cl)n1
Solvent: CO
Solvent: O
Product: Cc1ccnc(NN)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of 2-chloro-4-methylpyrimidine (6.06 g, 47.1 mmol) in MeOH (40 mL) was added hydrazine monohydrate (10 mL, 206 mmol). The solution was stirred for 16 h at room temperature and then purified by reverse phase HPLC to provide 4.43 g of the title compound. (76%) as a white solid. MH+125.
Reaction SMILES: O1CCCCC1[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:9]12[CH3:10])[C@@H:22]1[C@H:17]([CH2:18][CH:19]=[CH:20][CH2:21]1)[CH2:16][CH2:15]3.Cl.O.CCOCC>CO>[OH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:9]12[CH3:10])[C@@H:22]1[C@H:17]([CH2:18][CH:19]=[CH:20][CH2:21]1)[CH2:16][CH2:15]3
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC=CC[C@@H]43)[C@@H]1CC[C@@H]2OC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC=CC[C@@H]43)[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.5 %

Procedure:
To a solution of 0.25 g of 17β-tetrahydropyranyloxy-5α-estr-2-en, Compound 4, in 8 ml of methanol is added 1N hydrochloric acid (0.2 ml) and the reaction mixture is stirred at room temperature for 6 hr. Evaporation of the solvent under vacuum produces a residue of white crystals. The residue is treated with water (15 ml) and ether (25 ml). The ether phase is separated, and the water is extracted once more with 12 ml of ether. The combined ether phase is washed with water, sodium chloride solution, and dried over sodium sulfate. Evaporation of the solvent produces 0.19 g of 17β-hydroxy-5α-estr-2-ene. The structure of the Compound 5, is confirmed by the following spectral data:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([Cl:23])=[C:6]([NH:8][CH:9]([CH3:22])[C:10]([O:12][CH:13]2[CH:17]([O:18][C:19](=[O:21])[CH3:20])[CH2:16][O:15][CH2:14]2)=[O:11])[CH:7]=1.[C:25]1(=O)[O:30][C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C(O)(=O)C>O>[Cl:23][C:5]1[CH:4]=[C:3]([F:24])[C:2]([N:1]2[C:28](=[O:29])[C:27]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]3[C:25]2=[O:30])=[CH:7][C:6]=1[NH:8][CH:9]([CH3:22])[C:10]([O:12][CH:13]1[CH:17]([O:18][C:19](=[O:21])[CH3:20])[CH2:16][O:15][CH2:14]1)=[O:11]
Reactant: CC(=O)OC1COCC1OC(=O)C(C)Nc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC1COCC1OC(=O)C(C)Nc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Yield: 89.8 %

Procedure:
A mixture of 1.62 g of 4-acetoxytetrahydrofuran-3-yl 2-[(5-amino-2-chloro-4-fluorophenyl)amino]propionate, 0.80 g of phthalic anhydride, and 10 ml of acetic acid was heated under reflux for 3 hours while stirring. Water was added to the reaction mixture, and the semi-solid formed was collected by filtration, dissolved in ethyl acetate, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane=2:3) to give 1.98 g of the title compound (Table 1, Compound No. 32).
Reaction SMILES: CCCCCC.[CH3:7][O:8][C:9]([NH:11][C@@H:12]([CH:33]([CH3:35])[CH3:34])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:22][CH:23]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:24]([CH3:26])[CH3:25])=[O:21])=[O:14])=[O:10]>COC(C)(C)C>[CH3:7][O:8][C:9]([NH:11][C@@H:12]([CH:33]([CH3:35])[CH3:34])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:22][C@H:23]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:24]([CH3:26])[CH3:25])=[O:21])=[O:14])=[O:10]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NC(C(=O)C(F)(F)F)C(C)C)C(C)C
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)F)C(C)C)C(C)C
Yield: 30 %

Procedure:
Hexane (13 ml) was added to a solution of (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoroacetyl)propyl]pyrrolidine-2-carboxamide (0.85 g; SSS:SSR 53:47; hydrate:ketone 1:1) in tert-butyl methyl ether (8.5 ml) until cloudiness persisted. The solution was then warmed to give a clear solution, seeded with substantially pure crystalline SSS diastereoisomer and allowed to stand. A white solid crystallised which was collected by filtration to give (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[(S)-2-methyl-1-(2,2,2-trifluoroacetyl)propyl]-pyrrolidine-2-carboxamide as a crystalline solid in 30% yield, SSS:SSR 95:5; hydrate:ketone 80:20; NMR similar to that of the product of Example 2.
Reaction SMILES: [CH3:1][O-].[Na+].[N:4]#[C:5][NH2:6].[Cl:7][C:8]1[CH:15]=[C:14]([N:16]=[C:17]=[S:18])[CH:13]=[C:12]([Cl:19])[C:9]=1[C:10]#[N:11].CI>CO>[C:5](/[N:6]=[C:17](\[S:18][CH3:1])/[NH:16][C:14]1[CH:15]=[C:8]([Cl:7])[C:9]([C:10]#[N:11])=[C:12]([Cl:19])[CH:13]=1)#[N:4]
Reactant: N#CN
Reactant: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CS/C(=N\C#N)Nc1cc(Cl)c(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 6.4 %

Procedure:
Sodium methoxide (0.5M in methanol) (5.7 ml, 2.85 mmol, Eq: 1.22) was added to cyanamide (108 mg, 2.58 mmol, Eq: 1.1). After 15 minutes, the solution was added to a solution of 2,6-dichloro-4-isothiocyanatobenzonitrile (537 mg, 2.34 mmol, Eq: 1.00) in methanol (5 mL). After 1 hr, methyl iodide (704 mg, 310 μl, 4.96 mmol, Eq: 2.11) was added and the reaction was stirred overnight at room temperature. The resulting suspension was filtered and dried to give 43 mg of desired product as a gray solid. The filtrate was concentrated and chromatographed (40 g Analogix, 50% EtOAc/hex to 75% EtOAc/hex) to give 191 mg of desired product as a yellow solid. The solids were combined to give 234 mg (35%) of desired product.
Reaction SMILES: [CH3:1][C:2]([CH3:23])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=O)[CH2:8][CH:7]=1.[OH-].[K+].O.NN>C(O)COCCO>[CH3:1][C:2]([CH3:23])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:8][CH:7]=1
Reactant: COc1ccc(C(=O)CC2CC=C(CCC=C(C)C)CC2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc(CCC2CC=C(CCC=C(C)C)CC2)cc1
Temperature: 125 °C

Procedure:
To a solution of ketone 2E (R=4-Methyl-3-pentenyl) (10 g) in diethylene glycol (30 mL) is added potassium hydroxide (4.3 g) and hydrazine hydrate (4.5 mL). The solution is sequentially heated to 100° C., 125° C., and 150° C., all for 30 minutes each, then cooled to room temperature. The reaction mixture is extracted between ethyl ether and water, and the combined organic layers are washed with brine and dried over magnesium sulfate. The solution is concentrated in vacuo, and the product is purified by silica gel filtration using 20:1 hexanes:ethyl acetate as an eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]2[CH:23]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])[CH:22]3[CH2:36][CH2:37][N:19]2[CH2:20][CH2:21]3)[CH:12]=1>CC(C)=O.C(O)(C)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C@@H:18]2[C@H:23]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])[CH:22]3[CH2:36][CH2:37][N:19]2[CH2:20][CH2:21]3)[CH:12]=1
Reactant: O=C(NC1C2CCN(CC2)C1Cc1cccnc1)c1cc2ccccc2o1
Agent: O=C(O)c1ccc(Cl)cc1
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=C(N[C@@H]1C2CCN(CC2)[C@@H]1Cc1cccnc1)c1cc2ccccc2o1
Temperature: 25 °C
Yield: 94 %

Procedure:
Solid p-chlorobenzoic acid (46.8 mg, 0.299 mmol) was added in one portion to a solution of the earlier eluting isomer of N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl]benzofuran-2-carboxamide from Example 15 (108 mg, 0.299 mmol) in acetone (10 mL). This mixture was warmed to near reflux for 30 min and cooled to ambient temperature. No precipitate formed, so the solution was concentrated to about 20% of its former volume (hot plate), at which point crystals began to form. The mixture was cooled and diluted with isopropanol (2 mL). This mixture was concentrated by slow evaporation of solvent at ambient temperature, and the resulting solids were collected and dried. This produced 145 mg (94% yield) of light yellow crystals, mp 150-152° C. 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.38 (d, 1H), 7.93 (d, 2H, p-chlorobenzoic acid), 7.67 (m, 2H), 7.57 (d, 1H), 7.45 (m, 1H), 7.36 (d, 2H, p-chlorobenzoic acid), 7.30 (m, 1H), 7.27 (s, 1H), 7.16 (m, 1H), 7.00 (d, 1H, amide), 6.90 (broad s, quaternary ammonium), 4.62 (m, 1H), 3.85 (dd, 1H), 3.36 (m, 1H), 2.95-3.25 (m, 5H), 2.16 (s, 1H), 1.70-2.10 (m, 4H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=O.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.FC(F)(F)C(O)=O>CC(C)=O>[CH:20]1([N:26]2[C:4]([C:6]3[CH:11]=[CH:10][C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:8][CH:7]=3)=[C:3]([CH3:19])[NH:2][C:27]2=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(N)C(=O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: Cc1[nH]c(=O)n(C2CCCCC2)c1-c1ccc(Oc2ccccc2)cc1
Reaction time: 0.83 h

Procedure:
2-Amino-4'-phenoxypropiophenone hydrochloride (459 mg, 1.65 mmol) was suspended in acetone (30 ml) under ice-cooling, and cyclohexyl isocyanate (278 mg, 2.22 mmol) was added thereto. Triethylamine (476 mg, 4.71 mmol) was added, and the mixture was stirred for 50 minutes under ice-cooling. After addition of trifluoroacetic acid (1.5 ml), the mixture was stirred for 3 days at room temperature. The solvent was removed by evaporation in vacuo, and the residue was extracted with dichloromethane. The extract was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. Evaporation of the solvent provided a crude product, which was purified by column chromatography (chloroform/ethanol=50/1 (v/v)) and recrystalization (ethyl acetate) to give the title compound. Yield: 520 mg (90%), m.p. 198° C.
Reaction SMILES: [CH:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:5]#N)([CH3:3])[CH3:2].[OH-:18].[K+].C(O)C[OH:22]>O>[CH:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:5]([OH:22])=[O:18])([CH3:3])[CH3:2]
Reactant: OCCO
Reactant: CC(C)C(C#N)c1ccc(OC(F)(F)F)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: CC(C)C(C(=O)O)c1ccc(OC(F)(F)F)cc1
Temperature: 140 °C

Procedure:
A mixture of α-isopropyl-4-trifluoromethoxyphenylacetonitrile (2.0 g), potassium hydroxide (3.0 g) in ethylene glycol (35 ml) and water (3 ml) is heated at 140° C. for 8 hours. The solution is poured into water and extracted with ether (2×10 ml). The aqueous layer is acidified with dilute hydrochloric acid and extracted with ether (3×10 ml), washed with water (1×25 ml), dried (Na2SO4) and evaporated to an oil (1.23 g); ir (neat) 1700 cm-1.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:13][CH:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[CH3:12][C:7]1[C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[CH:9][CH:8]=1.[CH3:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc2c(c1)CCCC2C
Reactant: Cc1cccc2c1CCCC2C
Product: Cc1ccc2c(C)cccc2c1
Product: Cc1cccc2c(C)cccc12

Procedure:
For example, in the case where 1,5-dimethyltetraline and/or 1,6-dimethyltetraline are/is reacted in a gas phase using a platinum-alumina catalyst to obtain 1,5-dimethylnaphthalene and/or 1,6-dimethylnaphthalene can be prepared efficiently by setting up the catalyst calcination temperature to 300° to 400° C., the catalyst reduction temperature to 400° to 500° C., and the reaction temperature to 350° to 450° C.; or the catalyst calcination temperature to 400° to 500° C., the catalyst reduction temperature to 300° to 400° C., and the reaction temperature to 350° to 450° C.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:33][NH2:34].C(O)C>C(OCC)(=O)C>[CH3:33][NH:34][C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:21]=[CH:22][C:23]([O:26][C:27]([F:29])([F:28])[F:30])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 90 °C
Yield: 98 %

Procedure:
A mixture of 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188, 40 mg, 0.08 mmol) and 8M methyl amine solution in ethanol (408 uL, 3.26 mmol) and was heated to 90° C. in a sealed tube for 48 h. The reaction mixture was transferred to a round bottom flask and concentrated in vacuo to give a crude residue which was diluted with ethyl acetate and washed with water, sat. NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure to give a crude residue which was purified by flash column chromatography using Amine-Silica to yield the desired product as a white solid (39 mg, 98%). MS (ESI): 485.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1>CCO.CN(C=O)C.CN(C=O)C.CCO.[Pd]>[CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.8 %

Procedure:
A solution of tert-butyl 3-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-1-carboxylate (I138) (0.527 g, 0.906 mmol) in EtOH (10 mL) was added to a solution of 10% Pd/C (0.500 g) in DMF (6 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and washed through with EtOAc (80 mL). The solvent was removed in vacuo to afford a yellow oil. This was taken up in DMF/EtOH (1:1, 10 mL) and a slurry of 10% Pd/C (0.500 g, 1 eq) in DMF was added. The reaction was stirred under an atmosphere of H2 at room temperature for an additional 24 hours. The reaction was filtered through a pad of celite and washed through with EtOAc (80 mL). The solvent removed in vacuo to afford a yellow oil which was purified by column chromatography on silica gel (0-45% EtOAc in petroleum benzine 40-60° C.) to yield the title compound (I139) (0.126 g, 24%) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.30-7.17 (m, 6H), 3.91-3.72 (m, 2H), 3.75 (s, 2H), 3.68 (s, 3H), 3.66-3.52 (m, 1H), 3.47-3.21 (m, 3H), 3.17-3.04 (m, 4H), 2.23 (d, J=20.4 Hz, 1H), 1.97 (dd, J=21.1, 10.2 Hz, 1H), 1.48 (d, J=3.1 Hz, 9H). LCMS Method C: rt 6.91 min; m/z 585 [M+H], 607 [M+N]+.