Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[OH:14])(=O)[CH3:2].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24]Br)=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C>CN(C=O)C>[CH3:2][C:1]1[C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=2[O:14][C:24]=1[C:22](=[O:23])[C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2c(C)c(C(=O)c3ccc(C)cc3)oc2c1
Temperature: 60 °C

Procedure:
0.72 g (3.75 mmol) of N-(4-acetyl-3-hydroxy-phenyl)acetamide and 0.81 g (4.1 mmol) of 2-bromo-4-methylacetophenone were dissolved in 5 ml DMF and 1,55 g (11.25 mmol) of potassium carbonate were added. The suspension was heated to 60° C. for 1 h and ethylacetate was added. The organic phase was washed three times with water, one time with a NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was further purified by crystallisation (ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:34][NH:35][O:36][CH3:37].Cl.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:35]([O:36][CH3:37])[CH3:34])=[O:9]
Reactant: COc1ncc(Br)cc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ncc(Br)cc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of 5-bromo-2-methoxynicotinic acid (15.0 g, 64.65 mmol) in anhydrous DMF (150 mL), HOBT (9.0 g, 66.61 mmol) and EDCI (25.0 g, 130.41 mmol) were added. The reaction mixture was stirred at room temperature for 2 hour. And then MeNHOMe.HCl (20.0 g, 205.04 mmol) and Et3N (60 mL, 415.06 mmol) was added to the mixture. The mixture was stirred at 20° C. overnight. The reaction mixture was concentrated in vacuo. Then H2O was added, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using column chromatography (eluted with petroleum ether:EtOAc=2:1) to provide 5-bromo-N,2-dimethoxy-N-methylnicotinamide (16.5 g, yield: 92%). 1H-NMR (CDCl3, 400 MHz) δ 8.23 (d, J=2.4 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 3.95 (s, 3H), 3.53 (s, 3H), 3.33 (s, 3H). MS (M+H)+: 275/277.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])[C:29]([O:31]CC)=[O:30])[C@@:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:39])([F:40])[F:41])[C:29]([OH:31])=[O:30])[C@@:7]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCCCCC[C@H]1c2ccc(O)cc2SC[C@@]1(C)c1ccc(O)cc1)CCCC(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@@]1(c2ccc(O)cc2)CSc2cc(O)ccc2[C@@H]1CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O
Yield: 90.6 %

Procedure:
Ethyl 10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoate (2.08 g, 3.297 mmol) and sodium hydroxide (527 mg, 13.19 mmol) were added to an ethanol/water mixture (40/10 ml), followed by heating under reflux for 4 hours. The reaction mixture was acidified with 2N hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane/dichloromethane=1/4/1) to give 10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methythiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid (1.8 g, Yield 91%) as a foam.
Reaction SMILES: [CH3:1][NH:2][NH2:3].Br[C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]>>[CH3:11][C:5]([N:2]([CH3:1])[NH2:3])([CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CNN
Product: CCOC(=O)C(C)(C)N(C)N
Yield: 97 %

Procedure:
According to the procedure described in the synthesis method of Compound XIV-1, methylhydrazine (7.12 g, 150 mmol) was reacted with ethyl 2-bromo-2-methylpropanoate (19.51 g, 100 mmol) to obtain the title compound (15.54 g, 96%).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:15])=[N:7][N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:16]1([CH2:22][CH2:23][C:24](Cl)=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([C:5]1[C:6]([NH:15][C:24](=[O:25])[CH2:23][CH2:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:7][N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCC1CCCCC1
Reactant: Cc1cnc2c(C(C)(C)C)c(N)nn2c1
Product: Cc1cnc2c(C(C)(C)C)c(NC(=O)CCC3CCCCC3)nn2c1

Procedure:
The product from Example 178A and 3-cyclohexylpropionyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81-0.93 (m, 2H), 1.09-1.28 (m, 4H), 1.43-1.51 (m, 11H), 1.58-1.73 (m, 5H), 2.24-2.33 (m, 5H), 8.38 (d, J=2.0 Hz, 1H), 8.74 (s, 1H), 9.60 (br s, 1H); MS (DCI) m/z 343 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14](F)[CH:13]=[C:12]([N:17]([CH3:19])[CH3:18])[N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:20][NH:21][CH3:22].C(O)C>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([N:21]([CH3:22])[CH3:20])[CH:13]=[C:12]([N:17]([CH3:19])[CH3:18])[N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2nc(F)cc(N(C)C)n2)CC1
Reactant: CNC
Solvent: CCO
Product: CC(=O)N1CCN(c2nc(N(C)C)cc(N(C)C)n2)CC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
1-Acetyl-4-(6-(dimethylamino)-4-fluoropyrimidin-2-yl)piperazine (1.0 g) was dissolved in 12% dimethylamine-ethanol solution (30 ml) in an autoclave, and the mixture was stirred at 100° C. for 5 hr. The reaction mixture was concentrated under reduced pressure and chloroform was added to the reside. The chloroform solution was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (1.3 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([CH3:12])[CH:6]=[CH:5][C:3]=1N.[OH:13]S(O)(=O)=O.N([O-])=O.[Na+]>O>[CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([CH3:12])[CH:6]=[CH:5][C:3]=1[OH:13]
Reactant: Cc1ccc(N)c(C)c1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(O)c(C)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2,4-dimethyl-3-nitroaniline (105.6 g) is added to a reaction mixture containing 300 ml of H2SO4 and 300 ml of H2O. The reaction mixture is stirred at a temperature of 105°-108° C. for one half hour and then cooled to 0° C. A solution of sodium nitrite (52.6 g) in H2O (124 ml) is added dropwise. After addition is complete the reaction mixture is poured into a 50% aqueous H2SO4 solution (2,000 ml) and refluxed for one and one half hours. The reaction mixture is cooled over the weekend to ambient temperature, and filtered leaving a yellow and black solid which is washed with H2O, dried and boiled with hexanes (8 l). The hexane extract is concentrated and filtered to obtain 65.4 grams of a yellow solid, M.P. 99°-101° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:19])[C:9]2[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: COc1ccnc(Nc2ccc(I)cc2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccnc(N(C)c2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of 4-iodoaniline (220 mg) and 2-chloro-4-methoxypyrimidine (145 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125° C. for 21 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=10/1) to obtain N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg). (2) Under an argon atmosphere, N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg) was added to a suspension of sodium hydride (11 mg) in anhydrous DMF (5 ml), and the resulting mixture was stirred at room temperature for 5 minutes. Methyl iodide (0.0096 ml) was added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 23 hours. Water was added thereto and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=3/1) to obtain N-(4-iodophenyl)-4-methoxy-N-methylpyrimidin-2-amine (46 mg).
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=O)[CH:9]([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@@H:49]([NH2:51])[CH3:50])[S:48][C:44]=2[CH:43]=1>C1(C)C=CC=CC=1>[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@@H:49]([NH:51][C:12]([C@@H:8]([NH:7][C:5](=[O:6])[O:4][CH:1]([CH3:2])[CH3:3])[CH:9]([CH3:10])[CH3:11])=[O:14])[CH3:50])[S:48][C:44]=2[CH:43]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2s1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: CC(C)OC(=O)N[C@H](C(=O)N[C@@H](C)c1nc2ccc(F)cc2s1)C(C)C
Yield: 80.8 %

Procedure:
In 250 ml of toluene, 13.4 g (0.066 mol) of N-isopropoxycarbonyl-L-valine was dissolved. Thereto was added 14.3 g (0.144 mol) of N-methylmorpholine. Then was dropwise added at −10° C., 8.6 g (0.063 mol) of isobutyl chlorocarbonate. Thereto was added 22 g (0.06 mol) of (S)-1-(6-fluoro-2-benzothiazolyl)ethylamine p-toluenesulfonate. A reaction and a post-treatment were conducted in the same manner as in Reference Example 1, and the suspension of a solid in toluene was filtered at 70° C. to collect the solid. The solid was washed with water and toluene and dried to obtain 18.5 g (yield: 81.1%) of isopropyl {(S)-1-[(S)-1-(6-fluorobenzothiazol-2-yl)ethylcarbamoyl]-2-methylpropyl}carbamate. The compound obtained was confirmed for the structure by IR analysis and NMR analysis in comparison with its authentic material and identified.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)c2ccc(C(F)(F)F)cc2)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl- 6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 4-Trifluoromethylbenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro- 1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(4-trifluoromethylbenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH2:27])=[N:8][N:9]([C:11]2[N:20]=[CH:19][C:18]3[CH2:17][CH2:16][C:15]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:14]=4[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+].CO.Cl>O>[NH2:27][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][N:9]([C:11]2[N:20]=[CH:19][C:18]3[CH2:17][CH2:16][C:15]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:14]=4[C:13]=3[N:12]=2)[N:8]=1
Reactant: CCOC(=O)c1cn(-c2ncc3c(n2)-c2ccc(OC)cc2CC3)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCc1cnc(-n3cc(C(=O)O)c(N)n3)nc1-2
Temperature: 100 °C
Yield: 103.8 %

Procedure:
A mixture of 3-Amino-1-(8-methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester(3, 3.15 g, 8.63 mM), 1 N NaOH (15 mL), and methanol (20 mL) was heated at 100° C. for 3 hr then cooled to room temperature and diluted with water (100 mL). the pH was adjusted with 1 N HCl to approximately 3-4 and the resulting precipitate was isolated via filtration, washed with water (2×80 mL) and dried in vaccuo to give 3-Amino-1-(8-methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (4, 3.02 g, 100% yield). ES-MS MH+ 338.4 1H NMR (300 MHz, ppm, DMSO-d6): 8.81 (s, 1H), 8.57 (s, 1H), 8.2 (d, 1H), 7.0 (dd, 1H), 6.95 (s, 1H), 3.85 (s, 3H), 2.93 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[O:5][CH:6]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)CCC>>[N:28]1[CH:29]=[CH:30][C:25]([C:2]2[CH:3]=[C:4]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])[O:5][CH:6]=2)=[CH:26][CH:27]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)co1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2ccncc2)co1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from (R)-3′-(4-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-(tri-n-butylstannyl)pyridine. The title compound (21 mg) was obtained as a pale solid, m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][NH2:13])=O)=[CH:5][CH:4]=1.Cl[C:15]1[N:16]=[N:17][C:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[CH:19][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[N:16]3[N:17]=[C:18]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[CH:19]=[CH:20][C:15]3=[N:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)NN)cc1
Reactant: Clc1ccc(-c2cccs2)nn1
Product: COc1ccc(Cc2nnc3ccc(-c4cccs4)nn23)cc1

Procedure:
The title compound was prepared as described in Example 17 from 4-methoxy-phenylacetic acid hydrazide (1.39 mmol) and 3-chloro-6-thiophen-2-yl-pyridazine (0.32 mmol) as a pale orange solid. 1H NMR (CD3OD) δ 8.17 (1H, d, J=9.8 Hz), 7.92 (1H, dd, J=3.8 Hz, 1.2 Hz), 7.88 (1H, d, J =9.9 Hz), 7.74 (1H, dd, J=5.0 Hz, 1.0 Hz), 7.40 (2H, d, J=8.8 Hz), 7.23 (1H, dd, J =5.0 Hz, 3.8 Hz), 6.88 (2H, d, J=8.9 Hz,), 4.51 (s, 2H), 3.75 (3H, s). ESI-MS (m/z): Calcd for C17H14N4OS: 322.1; found 323.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]3[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:16]=3[NH2:42])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:43](OCC)(OCC)(OCC)[CH3:44].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:15]4[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH2:33][C:34]5[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=5)[C:16]=4[N:42]=[C:43]3[CH3:44])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2N)cc1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c3c2nc(C)n3Cc2cc(-c3ccc(F)cc3)no2)cc1
Yield: 23.6 %

Procedure:
N4-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3,4-triamine (6.00 g, 10.6 mmol), triethyl orthoacetate (2.9 mL, 16 mmol), concentrated hydrochloride acid (0.2 mL), and toluene (30 mL) were combined and treated according to the method described in Part E of Example 18 with the modification that no additional triethyl orthoacetate was added. 1-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N,N-bis(4-methoxybenzyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.48 g) was obtained as a yellow solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Cl.O>CN(C)C=O>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C=Cc1ccc(O)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(OCc2ccccn2)cc1
Reaction time: 1 h
Yield: 51 %

Procedure:
To a suspension of sodium hydride (60% active, 125 mg) in dimethylformamide (2 ml) at ambient temperature was added ethyl 4-hydroxycinnamate (250 mg) under nitrogen atmosphere, and the mixture was stirred for 1 hour. 2-Picolyl chloride hydrochloride (256 mg) was added to the mixture at the same temperature, and allowed to stand for 16 hours. The reaction mixture was poured into water, extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give ethyl 4-(2-pyridylmethoxy)cinnamate (188 mg) as colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][OH:21])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:11]=2[CH:20]=[O:21])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CO)CCCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC1(c2ccc(C(F)(F)F)cc2C=O)CCCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (2-(1-methoxycycloheptyl)-5-(trifluoromethyl)phenyl)methanol (167 mg; 0.552 mmol) in methylene chloride (3.0 mL) was added Dess-Martin reagent (290 mg; 0.683 mmol). Reaction was stirred at room temperature for 5 hours. The reaction was diluted with ethyl acetate and quenched with aqueous 1N sodium hydroxide. After partitioning off the aqueous layer, the organic layer was washed with water and brine. It was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over a Bakerbond 1 g silica cartridge (Mallinkrodt Baker Inc. Phillipsburg, N.J.) (eluted with 0-5% heptane) to yield 167 mg of a cloudy oil. 1H NMR (400 MHz, CDCl3) δ ppm 10.91 (s, 1H), 811 (d, J=2.07 Hz, 1H), 7.73 (dd, J=8.71, 8.30 Hz, 1H), 7.48 (d, J=7.88 Hz, 1H), 2.96 (s, 3H), 2.25 (m, 2H), 2.09 (m, 2H), 1.94-1.57 (m, 8H).
Reaction SMILES: [N+:1]([C:4]1[C:5](F)=[C:6]([F:14])[C:7]([F:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].[OH-:16].[Na+]>>[F:13][C:7]1[C:6]([F:14])=[C:5]([OH:16])[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1cc([N+](=O)[O-])c(O)c(F)c1F

Procedure:
The solid 5-nitro-2,3,4-trifluorobenzoic acid (1.00 g, 0.00452 mol) was dissolved in 10 wt. % aqueous sodium hydroxide solution. The mixture was clear deep orange. After standing under ambient conditions for several minutes, the mixture was quenched with concentrated aqueous hydrochloric acid until strongly acidic (pH 0). A white solid precipitated which was isolated by vacuum filtration and dried with suction to afford 0.40 g of an off-white solid. This solid was recrystallized from chloroform (20 ml) to afford 0.22 g of an off-white crystalline powder; 22% yield; MS (APCl−) 218 (M−1, 100).
Reaction SMILES: [CH3:1][C:2]1[C:19]([C:20]#[N:21])=[C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:16]([O-])=O)[O:9][C:5]2=[C:4]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]2)[C:3]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[O:9][C:5]2[C:6](=[C:19]([C:20]#[N:21])[C:2]([CH3:1])=[C:3]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:4]=2[N:22]2[CH2:26][CH2:25][C@H:24]([N:27]([CH3:28])[CH3:29])[CH2:23]2)[N:7]=1
Reactant: [H][H]
Reactant: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3ccccc3[N+](=O)[O-])nc2c1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3ccccc3N)nc2c1C#N
Yield: 55 %

Procedure:
10% Palladium-carbon (150 mg) was added to an ethyl acetate (30 ml) solution of 5-methyl-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2-nitrophenyl)-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-211) (128 mg, 0.27 mmol), followed by stirring at the same temperature under atmospheric pressure of hydrogen for 1.5 hours. The catalyst was removed by filtration with washing with ethyl acetate, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Elution with a mixed solvent of chloroform/methanol (99:1→96:4, v/v) gave the entitled compound (65 mg, 55%) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9](O)=[O:10])[NH:6][N:5]=1)([O-:3])=[O:2]>C1COCC1>[N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)[nH]n1
Temperature: -5 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A 3-L three-neck round-bottomed flask equipped with a mechanical stirrer, addition funnel and nitrogen inlet was purged with nitrogen and charged with 3-nitropyrazole-5-carboxylic acid (28.0 g, 178 mmol) and THF (420 mL) and cooled to −5° C. using an ice/acetone bath. Borane-THF complex solution (1.0 M, 535 mL, 535 mmol) was added at a rate that maintained the internal reaction temperature below 5° C. After the addition was complete the cooling bath was removed and the reaction was stirred at room temperature for 18 h. After this time the reaction was cooled to −5° C. using an ice/acetone bath, water (70 mL) and 4N hydrochloric acid (70 mL) was added and the reaction was stirred at reflux for 1 h in order to destroy the borane complex with pyrazole. The reaction was cooled to room temperature and concentrated under reduced pressure to a volume of approximately 30 mL. Ethyl acetate (175 mL) was added and the mixture stirred for 15 min. The aqueous layer was separated and extracted with ethyl acetate (4×200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2×50 mL), brine (50 mL) and dried over sodium sulfate, the drying agent was removed by filtration, and the filtrate concentrated under reduced pressure to afford (3-nitro-1H-pyrazol-5-yl)methanol 113a in a 94% yield (24.0 g) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 13.90 (br s, 1H), 6.87 (s, 1H), 5.58 (t, 1H, J=5.4 Hz), 4.53 (d, 2H, J=5.1 Hz); MS (ESI+) m/z 144.0 (M+H)