Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=C(C)C=1>[C:1]([O:20][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: Cc1cccc(C)c1
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCC
Yield: 112.5 %

Procedure:
71.1 grams (0.25 mole) of purified stearic acid (melting point 70° C.) and 101.5 grams (0.375 mole) of 1-octadecanol were added to 5.5 grams of toluenesulfonic acid in 100 ml of m-xylene and charged into a Dean-Stark equipped 1-liter round bottom flask. After 4 hours of reflux under nitrogen at a pot temperature of 180° C., 6 ml of water was collected. The solvent and any excess alcohol were stripped under 29 inches of mercury vacuum at 130° C. to give 151 grams of a solid having a melting point of 58° C. The acid number of the product was 3.0. Infrared spectroscopic analysis showed formation of the ester function.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>ClCCl.Cl>[OH:20][C:17](=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])[CH2:18][CH3:19]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.41 g, 30.0 mmol) and pyridine (4.85 mL, 60.0 mmol) in dichloromethane (24 mL) at 0° C. under argon is added propionyl chloride (2.95 mL, 33.0 mmol). The mixture is stirred at 0° C. for 1 h and at room temperature for 1 h before being diluted with 2 N HCl (40 mL) and extracted with dichloromethane (80 mL). The extract is washed (brine) and dried. Solvent is removed at reduced pressure to give 5.57 g (93%) of 2 as a yellow solid, mp 43-46° C. IR 3345, 2856, 1715, 1456 cm−1; 1H NMR (CDCl3) δ 1.29 (t, J=7.5 Hz, 3H, CH2CH3), 1.76 (s, 6H, CH3, CH3), 3.14 (q, J=7.5 Hz, 2H, CH2CH3), 15.42 (bs, 1H, OH).
Reaction SMILES: CS(C)=O.[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](Cl)=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[C:18]([NH2:20])=[O:19].[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:35][CH2:34]1)=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:21][C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:34][CH2:35]1)=[O:31])[O:28][C:11]1[C:10]2[C:15](=[CH:16][C:7]([O:6][CH3:5])=[C:8]([C:18]([NH2:20])=[O:19])[CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: O=C(Nc1ccc(O)cc1Cl)NC1CC1
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(N)=O
Temperature: 70 °C
Reaction time: 23 h
Yield: 88 %

Procedure:
To dimethylsulfoxide (20 mL) were added 7-methoxy-4-chloro-quinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), followed by heating and stirring at 70° C. for 23 hours. After the reaction mixture was allowed to cool down to room temperature, water (50 mL) was added, and the produced crystals were collected by filtration to give 1.56 g of the title compound (88% yield).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH-:16].[Na+].ClCl.[OH2:20]>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:3]=1[C:2]([OH:20])=[O:16]
Reactant: Cc1nc2ccccc2cc1C(=O)O
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: ClCl
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2nc1C(=O)O
Temperature: 85 °C

Procedure:
To a reactor is added 4.03 g (18.9 mmol) of 2-methyl-3-quinolinecarboxylic acid hydrochloride and 40 ml water. The pH is adjusted to pH 10 and 16.0 g cupric hydroxide is added. The solution is warmed to 85° C. for 60 minutes; then cooled and held at 55° C. A pH controller is set to maintain the pH above 10 by the incremental addition of aqueous 50% sodium hydroxide solution. Chlorine gas is introduced at approximately 1 g/hr to give a total of 20 g after 21 hours. The reaction mixture is filtered and analyzed; 2.82 g of 2,3-quinolinedicarboxylic acid is obtained. The reaction is illustrated as follows: ##STR6##
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[OH-].[Na+].[CH2:14]=O.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([S:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:14][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: C=O
Reactant: Cn1nc(C(F)(F)F)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Cc2c(C(F)(F)F)nn(C)c2O)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
5-Hydroxy-1-methyl-3-trifluoromethylpyrazole (1.7 g (10 mmol)) synthesized in Reference Example 1 and 0.6 g (15 mmol) of sodium hydroxide were dissolved in 10 mL of DMF. While stirring the resulting solution at room temperature, 1.7 g of paraformaldehyde was charged thereto, followed by stirring at the same temperature for 1 hour. Furthermore, 1.8 g (10 mmol) of sodium p-toluenesulfinate was charged thereto at room temperature, and the obtained mixture was stirred for 2 hours. After the reaction, 5.0 g (50 mmol) of 35% hydrochloric acid was added dropwise thereto, 10 mL of water was further added, and the precipitated crystal was collected by filtration, washed twice with 5 mL of water and dried by a hot air drier to obtain 3.0 g (yield: 88.2%) of the title compound as a white crystal. The 1H-NMR spectrum agreed with that of Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][N:11]([CH3:15])[C:10]2=[O:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18].N1CCCC1.C1COCC1>CCO>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[CH:23]\[C:22]3[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)/[N:11]([CH3:15])[C:10]2=[O:16])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Solvent: C1CCOC1
Solvent: CCO
Solvent: C1CCNC1
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)/C1=C\c1ccc(C#N)cc1
Temperature: 65 °C
Yield: 86.3 %

Procedure:
A mixture of 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (1.00 kg, 3.86 mol), 4-cyanobenzaldehyde (0.70 kg, 5.79 mol), and pyrrolidine (0.27 kg, 3.86 mmol) was refluxed in EtOH (13.00 L) for 20–24 hours at a temperature of 78° C. The completeness of the reaction was followed by HPLC. Upon reaction completion, the suspension was cooled to 65° C. and THF (4.33 L) was added in 5–10 minutes. The suspension was cooled to 20–25° C. in 3–4 hours and was then filtered. The filter cake was washed with EtOH (4×2.00 L) and dried at maximum 40° C. to a constant weight. (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitril (1.24 kg, 86%) was obtained as a fluffy, yellowish crystalline solid. mp=239–241° C. 1H NMR (DMSO-d6): 8.07 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=8.4 Hz), 7.72 (1H, m), 7.59 (2H, m), 6.72 (1H, s), 3.35 (3H, s). 13C NMR (DMSO-d6): 14 Carbons (159.80, 151.48, 137.64, 133.83, 133.70, 131.80, 130.80, 130.68, 127.71, 125.51, 118.83, 114.48, 110.32, 26.72). Anal. Calcd for C18H11Cl2N3O2: C, 58.08; H, 2.97; N, 11.29; Cl, 19.05. Found: C, 58.14; H, 2.72; N, 11.14; Cl, 19.15.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[CH2:9]([Li])CCC.IC.O>O1CCCC1>[CH3:9][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccsc1
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cc1sccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Thiophenecarboxylic acid (3.84 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 41.3 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Iodomethane (3.7 ml) in tetrahydrofuran (10 ml) was added dropwise. The resulting mixture was heated to room temperature and stirred for 15 hours. The mixture was poured into water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-methyl-3-thiophenecarboxylic acid (3.98 g) as crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[OH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: O=C1COc2ccc(CO)cc2N1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
The mixture of 6.9 g of methyl 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylate and 230 ml of tetrahydrofuran is cooled to −40° C. Over 30 minutes, 88.9 ml of diisobutylaluminium hydride (1.5M in toluene) are added dropwise at −40° C. The reaction mixture is stirred at from 40° C. to −20° C. over 1.5 hours and subsequently poured cautiously onto 150 ml of 2N HCl (cold). The organic phase is removed and the water phase extracted with tetrahydrofuran (5×100 ml). The organic phases are washed with brine (1×100 ml), filtered through cottonwool and concentrated by evaporation. The title compound is obtained as beige crystals from the residue by crystallization (from ethanol). Rf (2:1 EtOAc-heptane)=0.16; Rt=2.23; m.p.: 186-187° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][N:4]=1.ClCCl>[Pd].C(O)C>[F:12][C:2]([F:1])([F:13])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: FC(F)(F)c1nnc2cnccn12
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: FC(F)(F)c1nnc2n1CCNC2
Yield: 89.8 %

Procedure:
3-(Trifluoromethyl)-1,2,4-triazolo[4,3-α]pyrazine (540 mg, 2.87 mmol, from Step A) was hydrogenated under atmospheric hydrogen with 10% Pd/C (200 mg) as a catalyst in ethanol (10 mL) at ambient temperature for 18 h. Filtration through Celite followed by concentration gave a dark colored oil. Dichloromethane was added to the above oil and the insoluble black precipitate was filtered off. Concentration of the filtrate gave the title compound as an oil (495 mg). 1H NMR (500 MHz, CDCl3) δ 2.21 (br, 1H), 3.29 (t, 2H, J=5.5 Hz), 4.09 (t, 2H, J=5.5 Hz), 4.24 (s, 2H). LC/MS (M+1) 193.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.C(N(CC)CC)C.Cl[C:21]1[N:26]=[C:25]([NH2:27])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][CH:22]=1.O>C(#N)C>[NH2:27][C:25]1[N:26]=[C:21]([N:2]2[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]2)[CH:22]=[CH:23][C:24]=1[N+:28]([O-:30])=[O:29]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
To a solution of (R)-ethyl piperidine-3-carboxylate hydrochloride salt (1.2 g, 6.21 mmol) in acetonitrile (20 mL) was added triethylamine (2.61 mL, 18.64 mmol). The mixture was stirred for 10 min at room temperature. 6-Chloro-3-nitropyridin-2-amine (753 mg, 4.31 mmol) was added and the reaction mixture was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (1.1 g). MS (ES+APCI) (M+H) 295.2.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[C:8](=[O:13])([O:11]C)[O:9][CH3:10].[CH2:14](N(CC)CC)C.C(=O)(OC)OC>CO>[CH3:10][O:9][C:8](=[O:11])[O-:13].[CH2:1]([N+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH3:14])[CH3:2]
Reactant: COC(=O)OC
Reactant: CCN(CC)CC
Solvent: CO
Product: CC[N+](C)(CC)CC
Product: COC(=O)[O-]
Temperature: 135 °C

Procedure:
Next, triethylamine and dimethyl carbonate were mixed with methanol as a solvent in a molar ratio of triethylamine/dimethyl carbonate=1/1.5, heated under a pressure of 1.5 MPa and at a temperature of 135° C. for 15 hours to carry out quaternarization until a conversion of 99.9% is achieved to obtain a reaction solution of triethylmethylammonium methylcarbonate. The conversion was measured by gas chromatography.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21]>C(Cl)(Cl)Cl>[N+:13]([C:12]1[C:7]([Cl:6])=[C:8]([C:20]([F:21])([F:22])[F:23])[CH:9]=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[NH:5][CH2:4][CH2:3][O:2][CH3:1])([O-:15])=[O:14]
Reactant: COCCN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: ClC(Cl)Cl
Product: COCCNc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of 9.8 g (0.131 mole) of 2-methoxyethylamine in 20 ml of chloroform is added dropwise at 0°-5° C. to a solution of 20 g (0.065 mole) of 2,4-dichloro-3,5-dinitro-benzotrifluoride in 40 ml of chloroform. The reaction mixture is stirred for 2 hours at 0°-5° C. and then for 18 hours at room temperature. For working up, the reaction mixture is concentrated and the residue is taken up in ether. The ethereal solution is washed twice with water and three times with sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is recrystallised from isopropanol, affording 3,5-dinitro-4-[2-methoxyethyl-amino]-2-chlorobenzotrifluoride with a melting point of 104°-105° C.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[C:11](=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH2:9]2>C(OCC)C>[CH3:1][C:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH3:4])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C[Mg]Br
Reactant: COC(=O)C=C1CCc2cc(OC)ccc2C1=O
Solvent: CCOCC
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1C
Temperature: 180 °C
Reaction time: 1 h

Procedure:
To a mixture of 12 g. of methyl magnesium bromide and 200 ml. of diethyl ether, 25 g. of 6-methoxy-2-(methoxycarbonylmethylene)-1-tetralone are added. The alkylating mixture is refluxed for one hour after it has been allowed to stand for one hour; the mixture is made acidic to litmus by the addition of 1N methanolic HC1, filtered, and evaporated. The residue, containing methyl 1-methyl-6-methoxy-3,4-dihydro-2-naphthylacetate, is added to 1 g. of 10% palladium-on-charcoal and the resulting mixture is heated to 180°C for six hours. The mixture is cooled, diluted with 200 ml. of chloroform, filtered, and evaporated to yield methyl 1-methyl-6-methoxy-2-naphthylacetate.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=C)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+]>C(Cl)(Cl)Cl.C1COCC1.[Os](=O)(=O)(=O)=O.O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:35])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:28])([F:30])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6A, 1.06 g, 2.60 mmol) in chloroform (1 mL) and THF (15 mL) were sequentially added N-methylmorpholine-N-oxide in water (0.807 mL, 3.89 mmol) and osmium tetroxide in water (0.317 mL, 0.052 mmol) at room temperature. The solution was stirred at room temperature overnight. More N-methylmorpholine-N-oxide in water (0.40 mL) was added. The mixture was stirred at room temperature for 2 hr before sodium periodate (0.666 g, 3.11 mmol) in water (4 mL) was added. The mixture was stirred at room temperature under nitrogen for 2 hr. Water (30 mL) was added and the mixture was concentrated to remove THF. The solid was filtered, washed with water (1 mL), and dried to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde as a yellow solid. The filtrate was extracted with dichloromethane (3×6 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give a yellow liquid. This liquid was combined with the yellow solid obtained above with dichloromethane (5 mL), THF (5 mL), and methanol (7 mL). The suspension obtained was treated with sodium borohydride (0.147 g, 3.89 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature for 1 hr before water (10 mL) and saturated aqueous ammonium chloride solution (5 mL) were added. The mixture was concentrated to remove organic solvents. The solid was filtered, washed with water (2×2 mL), and crystallized in methanol to give (3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol (500 mg, 1.213 mmol, 46.7% yield) as a yellow solid. The filtrate was extracted with dichloromethane (3×10 mL). The dichloromethane extracts were dried over sodium sulfate and combined with the mother liquor from the crystallization. Purification using silica gel chromatography (20 to 100% dichloromethane in heptane and then 20→100% ethyl acetate in heptane) afforded an additional crop of (3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol (205 mg, 0.497 mmol, 19.15% yield) as a yellow solid. LC/MS M+1=413.1.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:11]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)O
Temperature: 30 °C

Procedure:
Dissolve 0.1 mol (11.7 g) of valine in 50 ml of water, add 0.25 mol of sodium hydroxide in aqueous solution, heat to 30° C. and then add dropwise 0.15 mol (17.5 ml) of benzoyl chloride. Wash the aqueous solution with ether, acidify and suction off the N-benzoylvaline crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To compound 5A (9.85 g, 29.7 mmol) in CH2Cl2 (200 mL) at 0° C. was added Dess-Martin periodinane. The ice bath was removed and the reaction was warmed to rt. After 2 h, saturated aqueous Na2S2O3 and NaHCO3 (ca. 100 mL each) were added and the reaction mixture was stirred vigorously for 0.5 h. The layers were separated, and the organic layer was washed with a mixture of saturated aqueous Na2S2O3 and saturated aqueous NaHCO3 followed by brine, then dried (MgSO4), filtered and concentrated to obtain the title compound (9.23 g) as a yellow oil.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>CC(O)(C)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:21]([C:3]([S:4][C:5]3[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)=[C:2]([CH3:15])[NH:24]2)=[CH:22][CH:23]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1
Temperature: 70 °C

Procedure:
[3-(2-Oxo-propylsulfanyl)-phenyl]-acetic acid (3.69 g, 16.5 mmol) was dissolved in t-BuOH (100 mL) then 3-chlorophenylhydrazine hydrochloride (3.25 g, 18.15 mmol) was added. The reaction was heated to 70° C. for 2 hour then cooled and submitted to aqueous workup to afford a mixture of regioisomers which included the title compound. The crude material was brought forward to the next step without further purification.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.[Br:10]N1C(=O)CCC1=O>C(#N)C>[ClH:1].[Br:10][C:8]1[C:3]([F:2])=[CH:4][C:5]([NH2:9])=[N:6][CH:7]=1.[ClH:1]
Reactant: Nc1cc(F)ccn1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CC#N
Product: Nc1cc(F)c(Br)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To mono HCl salt of 4-fluoro-pyridin-2-ylamine (xviii) (3 g, 20.2 mmol) in acetonitrile at 0° C. was added in 3 portions N-bromosuccinimide (3.59 g, 20.2 mmol) over 1.5 h. The RM was stirred 1 h at 0° C. and the precipitate was filtered and dried under vacuo to give the title compound as mono HCl salt (tR 1.61 min (conditions 8), MH+=191, 193).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:24])[CH2:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Mg]Br>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([OH:24])([CH3:25])[CH2:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2cc(Cl)ncc2Br)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)Cc2cc(Cl)ncc2Br)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[2-(5-bromo-2-chloro-pyridin-4-yl)-acetyl]-piperidine-1-carboxylic acid tert-butyl ester (9.80 g) in tetrahydrofuran (6 mL) is added dropwise to an ice-cold solution of methyl magnesium bromide (1.4 mol/L in toluene/tetrahydrofuran 75:25; 74.0 mL). The reaction mixture is stirred for 30 min before the cooling bath is removed. After stirring the mixture at room temperature for 1 h, the mixture is poured into aqueous NH4Cl solution. The resulting mixture is extracted with ethyl acetate, and the combined extracts are dried (MgSO4) and concentrated. The residue containing significant amounts of starting material is azeotropically dried using toluene and resubmitted to the reaction conditions and work-up procedure described. The crude product is purified by preparative HPLC (column: Waters X-Bridge C18; mobile phase: water+0.125% NH4OH/methanol 90:10→100:0) to give the title compound. Mass spectrum (ESI+): m/z=433/435/437 (Cl+Br) [M+H]+.