Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([CH2:23][C:24]1[N:28]([CH3:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=1)[C:6](=[O:22])[O:7][CH2:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.Cl>O1CCCC1>[CH:20]1[C:21]2[CH:9]([CH2:8][O:7][C:6](=[O:22])[N:5]([CH2:23][C:24]3[N:28]([CH3:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[N:25]=3)[CH2:4][CH:3]=[O:2])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: COC(CN(Cc1nc2ccccc2n1C)C(=O)OCC1c2ccccc2-c2ccccc21)OC
Agent: Cl
Solvent: C1CCOC1
Product: Cn1c(CN(CC=O)C(=O)OCC2c3ccccc3-c3ccccc32)nc2ccccc21
Temperature: 75 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A solution of the product of Example 59B (0.2 g) in tetrahydrofuran (0.2 mL) was treated with 30% HCl (0.2 mL), stirred at 75° C. for 6 hours, cooled to 25° C. and concentrated. The residue was partitioned between 10% NaHCO3 and ethyl acetate, the organic phase layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound (175 mg).
Reaction SMILES: C1(C(Cl)=O)CCC1.C1(C(Cl)=O)CCCCC1.[C:17]([NH:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH:34]2[CH2:37][CH2:36][CH2:35]2)=[O:33])=[C:27]([O:38][C:39]([CH:41]2[CH2:44][CH2:43][CH2:42]2)=[O:40])[CH:26]=1)=[O:24])([CH3:20])([CH3:19])[CH3:18]>>[CH:41]1([C:39]([O:38][C:27]2[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=2[O:31][C:32]([CH:34]2[CH2:35][CH2:36][CH2:37]2)=[O:33])[CH:23]([OH:24])[CH2:22][NH:21][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:40])[CH2:44][CH2:43][CH2:42]1
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C2CCC2)c(OC(=O)C2CCC2)c1
Agent: O=C(Cl)C1CCC1
Agent: O=C(Cl)C1CCCCC1
Product: CC(C)(C)NCC(O)c1ccc(OC(=O)C2CCC2)c(OC(=O)C2CCC2)c1

Procedure:
When cyclobutanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis-(cyclobutanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(cyclobutanecarbonyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=2[S:21][CH3:22])[C:10]([O:12]C2CCCC2)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)C>O.CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=2[S:21][CH3:22])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ccc(C(=O)OC2CCCC2)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CSc1ccc(C(=O)O)cc1OC1CCCC1
Yield: 92.5 %

Procedure:
A solution of cyclopentyl 3-cyclopentyloxy-4-(methylthio)benzoate (0.5 g, 1.5 mmol) in water (30 mL) and methanol (10 mL) containing sodium hydroxide (1 g, 25 mmol) is heated under reflux for 3 hours. The solution is then poured into water (60 mL) and acetic acid is added dropwise with stirring to between pH 5-6. The solid which separates is collected by filtration, washed with water (5×10 mL) and dried giving 3-cyclopentyloxy-4-(methylthio)benzoic acid (0.35 g, 88.6%) as a cream solid m.p. 158-160° C.
Reaction SMILES: [CH2:1]([S:19][C:20]([CH3:30])([CH3:29])[C:21]([CH2:23][C:24]([O:26]CC)=O)=[O:22])[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].[CH3:31][O:32][C:33]1[C:34]([NH2:39])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:24](=[O:26])[CH2:23][C:21](=[O:22])[C:20]([S:19][CH2:1][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])([CH3:29])[CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCSC(C)(C)C(=O)CC(=O)OCC
Reactant: COc1ccccc1N
Product: CCCCCCCCCCCCCCCCCCSC(C)(C)C(=O)CC(=O)Nc1ccccc1OC
Yield: 83 %

Procedure:
A mixture of 8.0 g of ethyl (2-n-octadecylthio-2-methylpropionyl)acetate obtained in Step 1 above and 3.2 g of o-anisidine was stirred in an oil bath at 140° C for 3 hours under a reduced pressure of 60 mmHg, and then the excess o-anisidine was removed under a reduced pressure of 1mmHg. The reaction mixture was recrystallized from ethanol to obtain 7.9 g (yield 83%) of Coupler (4) having a melting point of 59° to 61° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.C(NC(C)C)(C)C.[Li].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[C:25]([C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1>C1COCC1>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([CH:4]2[CH2:5][CH2:6][CH2:7][N:8]=[C:3]2[O:2][CH3:1])[CH:25]([C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:23]=1
Reactant: COC(=O)C(=Cc1ccc(F)cc1)C(=O)C(C)C
Reactant: COC1=NCCCC1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C(=O)C(C)C)C(c1ccc(F)cc1)C1CCCN=C1OC
Temperature: -60 °C
Yield: 106.5 %

Procedure:
6-Methoxy-2,3,4,5-tetrahydropyridine (102.7 g, 0.91 mole) was added over 25 min to a solution of lithium diisopropylamine (1.8 M, 505 mL, 0.91 mole) in THF (1.2 L) stirring at −60° C. under nitrogen. After stirring at −60° C. for 1 h, methyl 3-(4-fluorophenyl)-2-isobutyrylacrylate (175 g, 0.70 mole) was added over 75 min keeping the temperature below −50° C. The reaction was quenched with saturated ammonium chloride (750 mL) after the reaction had stirred at −60° C. for 35 min. After the reaction mixture had warmed to room temperature, ethyl acetate was added and the mixture transferred to a separatory funnel. The mixture was extracted with ethyl acetate (2×1 L). The combined organic layers were washed with 50% saturated ammonium chloride solution, water, and brine; dried over magnesium sulfate; and concentrated in vacuo to afford methyl 2-[(4-fluorophenyl)-(2-methoxy-3,4,5,6-tetrahydro-pyridin-3-yl)-methyl]-4-methyl-3-oxo-pentanoate (271 g).
Reaction SMILES: C[I:2].[I-].[CH3:4][N+:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:23])[NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:22])[CH:16]=2)[CH:6]=1.[CH3:24]OC1C=C(C=CC=1O)CCN>>[I-:2].[CH3:4][N+:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:23])[NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:24])[CH:16]=2)[CH:6]=1
Reactant: COc1cc(CCN)ccc1O
Reactant: C[n+]1cccc(C(=O)NCCc2ccc(O)c(O)c2)c1
Reactant: CI
Agent: [I-]
Product: COc1cc(CCNC(=O)c2ccc[n+](C)c2)ccc1O

Procedure:
N-nicotinoyl-3-methoxytyramine was prepared by following the procedure used for the preparation of compound 7. The isolated crude amine was quaternized directly with methyl iodide following the method used for the preparation of compound 6a. Crystallization from methanol gave a yellow crystalline compound, m.p. 192°-194° C. with overall yield of 84%, calculated on the basis of 3-methoxytyramine starting material. NMR (D2O) closely similar to that of 6a except for the singlet at δ 3.66 for OCH3.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:14])[C:5](=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.C(=O)([O-])[O-:16].[K+].[K+].Cl.[H][H]>[C].[Pd].O>[C:2]([NH:6][C@H:5]([C:4]([OH:3])=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:16])[CH3:1]
Reactant: CC1=NC(=Cc2ccccc2)C(=O)O1
Reactant: O=C([O-])[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 2 h
Yield: 157.7 %

Procedure:
In 100-ml tightly-sealed glass vessel were charged 9.36 g of 2-methyl-4-benzylidene-5-oxazolone and 40 ml of water. 4.15 g of potasium carbonate was then added thereto and the resulting mixture was stirred at 40°-45° C. for two hours. Concentrated hydrochloric acid was added to the resulting solution to adjust its pH at 6.8 and 0.2 g of 5%-palladium-carbon was added thereto. The gas phase in the vessel was purged with nitrogen and then with hydrogen, and thereafter the reaction mixture in the vessel was subjected to catalytic reduction at 40°-45° C. under atmospheric pressure. The reaction time during which hydrogen absorption was completed was 100 minutes. It was observed that one mole of hydrogen was absorbed to one mole of 2-methyl-4-benzylidene-5-oxazolone during this period. After the gas phase in the vessel was purged with nitrogen upon completion of the reaction, the catalyst was filtered and washed with a small amount of water. The filtrate and the washings were combined, to which concentrated hydrochloric acid was added at a temperature lower than 30° C. to adjust pH of the resulting mixture at 1. The mixture was cooled to 0°-5° C. The crystal was filtered, washed with a cold water and dried to obtain 9.81 g of N-acetylphenylalanine having a melting point 150°-151° C. as a white crystal. Its yield was 94.7%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])=O.[NH4+].[CH3:30][N+:31]([O-:33])=[O:32]>CC(O)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=[CH:30][N+:31]([O-:33])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 23 °C
Yield: 24.1 %

Procedure:
A mixture of 79.5 g (1.25 mol) of 3,4-dibenzyloxybenzaldehyde (11) (available from Aldrich Chemical Co.), 47 g CH3CO2NH4, 47 g CH3NO2, and 400 ml CH3CO2H is refluxed for two hours. The mixture is cooled to 23° C. to precipitate the product. The yellow solid is isolated by filtration, washed with ethanol, and air dried. Recrystallization from CH3CO2H--C2H5OH gives 67.2 g (74.5%) of (12): mp 118°-119° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[N:6][CH:7]=1.O=[CH:27][C:28]([OH:30])=[O:29].FC(F)(F)C(O)=O>CN(C=O)C>[CH3:14][C:12]1[CH:13]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][CH2:27][C:28]([OH:30])=[O:29])[CH:7]=[N:6][CH:5]=2)[CH:9]=[C:10]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:11]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(N)c2)c1
Reactant: O=CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(NCC(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-[3-(5-aminopyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (20.0 mg, 0.058 mmol), oxoacetic acid (4.29 mg, 0.058 mmol) in DMF (0.579 mL, 0.1 M), and trifluoroacetic acid (8.92 μL, 0.116 mmol). was stirred for 1 hour at room temperature. Si-cyanoborohydride (123 mg, 0.116 mmol, 0.94 g/mmol) was added to the reaction mixture and stir for 12 hours at room temperature. The reaction mixture was filtered, concentrated in vacuo and the residue was purified by reverse phase liquid chromatography (5:95 to 95:5, acetonitrile:water+0.1% v/v formic acid) afforded N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]glycine as the formic acid salt. MS APCI calc'd for C19H17F3N5O2 [M+H]+ 404. found 404. 1H NMR (600 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.96 (d, J=2.6 Hz, 1H), 7.89 (s, 1H), 7.53 (s, 1H), 7.26 (d, J=4.9 Hz, 1H), 7.11 (s, 1H), 7.05 (s, 2H), 3.91 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[N:9]=2)[C:5]([O:23][CH3:24])=[CH:4][N:3]=1.[C@H:25]1([NH2:32])[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1.[OH-].[K+]>O1CCOCC1>[NH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:32][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=4)[N:9]=3)[C:5]([O:23][CH3:24])=[CH:4][N:3]=2)[CH2:26][CH2:27]1
Reactant: COc1cnc(Cl)cc1-c1cccc(NCc2cccc(F)c2)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cnc(N[C@H]2CC[C@H](N)CC2)cc1-c1cccc(NCc2cccc(F)c2)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a scintillation vial was added 2′-chloro-N-(3-fluorobenzyl)-5′-methoxy-2,4′-bipyridin-6-amine (30 mg, 0.087 mmol), trans-cyclohexane-1,4-diamine (45 mg, 0.394 mmol), 1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium(0) (11.4 mg, 8.73 μmol), KOH (45 mg, 0.802 mmol) and Dioxane (0.3 mL). The resulting mixture was stirred at 100° C. for 18 h. The mixture was concentrated in vacuo and then diluted with water. The resultant solid was filtered and washed with water (×3). The solid was then purified by reverse phase preparative HPLC and then lyophallized to yield N2′-(trans-4-aminocyclohexyl)-N6-(3-fluorobenzyl)-5′-methoxy-2,4′-bipyridine-2′,6-diamine (6.5 mg), LCMS (m/z): 422.3 (MH+), retention time=0.54 min as a TFA salt. 1H-NMR (400 MHz, METHANOL-d4, 25° C.) 1.40-1.66 (m, 4H) 2.05-2.25 (m, 4H) 3.10-3.25 (m, 1H) 3.55-3.64 (m, 1H) 3.86 (s, 3H) 4.57 (s, 2H) 6.69 (d, J=8.4 Hz, 1H) 6.92-7.00 (m, 1H) 7.10 (d, J=10.0 Hz, 1H) 7.17 (d, J=7.6 Hz, 1H) 7.28-7.33 (m, 2H) 7.48-7.52 (m, 2H) 7.53-7.58 (m, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27]([CH2:30]Br)=[N:28][CH:29]=1.CCCCCC>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([CH2:30][N:6]2[CH2:7][CH2:8][C:3]([CH3:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5]2)=[N:28][CH:29]=1
Reactant: BrCc1ncc(Br)cn1
Reactant: CCOC(=O)C1(C)CCNCC1
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)C1(C)CCN(Cc2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a solution of ethyl 4-methylpiperidine-4-carboxylate hydrochloride (0.08 g, 0.48 mmol) in EtOH (5.0 mL) was added DIPEA (0.22 mL, 1.20 mmol) at rt and the mixture stirred at rt for 10 minutes followed by addition of 5-bromo-2-(bromomethyl)pyrimidine (0.10 g, 0.40 mmol). The reaction was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 20% EtOAc:hexane to obtain the desired product as a yellow solid (0.10 g, 73% yield). 1H NMR (DMSO-d6): δ 1.09 (s, 3H), 1.13 (t, J=7.20 Hz, 3H), 1.45 (m, 2H), 2.00 (m, 2H), 3.12 (m, 2H), 3.32 (m, 2H), 3.62 (q, J=7.20 Hz, 2H), 4.08 (m, 2H) and 8.94 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].CCN(C(C)C)C(C)C.CN1CCCC1=O>O>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:3]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: Clc1ccnc(-c2ccccc2)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(-c3ccccc3)c2)cc1
Yield: 31.8 %

Procedure:
4-Chloro-2-phenylpyridine 1.0 g (5.5 mM), paranitrophenol (1.68 g, 12 mM), Hunig's base (diisopropylethylamine, 5 ml) and 1-methylpyrrolidone (10 ml) were stirred at 160° C. for 20 hours. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed 5 times with water. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to obtain 490 mg of 4-(4-nitrophenoxy)-2-phenylpyridine as a light yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[N:14](C(OC(C)(C)C)=O)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4]([CH:6]1[NH:14][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)C1Cc2cccnc2N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)C1Cc2cccnc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.6 %

Procedure:
In a 100 mL round-bottomed flask, tert-butyl 2-(ethylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (402 mg, 1.38 mmol, Eq: 1.00) was combined with DCM (8 mL) to give a colorless solution. TFA (2 mL, 26.0 mmol, Eq: 18.8) was added and the reaction was stirred at rt for 6 h. The reaction mixture was concentrated in vacuo, saturated aqueous NaHCO3 (30 mL) was added and the resulting mixture was extracted with DCM (20 mL×3). The organic layers were dried over Na2SO4 and concentrated in vacuo to give 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethylamide as an off-white solid (210 mg), m/z=192 (M+H).
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([O:12][C:13]2[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)=[O:17])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(O)c1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 63.6 %

Procedure:
To a solution of 4-fluoro-3-nitroaniline (1.0 g, 6.40 mmol) and 3-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide (1.80 g, 6.40 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.32 g, 9.60 mmol), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off and washed with ethyl acetate (150 mL). The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (1.70 g, 64%) as a red-orange powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>>[Br:1][C:2]1[C:3]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:4][N:5]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:6]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1ccc(-c2n[nH]cc2Br)cc1
Product: COc1ccc(Cn2cc(Br)c(-c3ccc([N+](=O)[O-])cc3)n2)cc1

Procedure:
Following the procedure described for Intermediate 3 with 4-bromo-3-(4-nitrophenyl)-1H-pyrazole and p-methoxybenzylchloride provided the title product. ESMS [M+H]+: 388.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:26])=[C:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:42])[C:31]([O:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)([CH3:33])[CH3:32])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:27]([O:29][C:30](=[O:42])[C:31]([O:34][C:35]1[CH:40]=[CH:39][C:38]([O:15][CH2:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:26])=[CH:37][CH:36]=1)([CH3:33])[CH3:32])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Yield: 44 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethyl ester (prepared as described in E above), 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (American Home Products U.S. Pat. No. 3,795,691) (7.06 g, 31.5 mmol) and Cs2CO3 (13.3 g, 41.0 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between EtOAc (250 mL) and H2O (250 mL), and the aqueous phase extracted with EtOAc (2×100 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, hexanes to 10% EtOAc/hexanes) to provide 2-(4-{2-[2-(4-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (6.81 g, 44%) as a off-white solid: Rf=0.48 in 35% EtOAc/hexanes; mp 78-79° C.; 1H NMR (300 MHz, CDCl3) δ 7.85-7.82 (m, 2H), 7.57-7.53 (m, 2H), 6.83-6.75 (m, 4H), 4.22 (q, J=7.0 Hz, 2H), 4.18 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.7 Hz, 2H), 2.36 (s, 3H), 1.52 (s, 6H), 1.27 (t, J=7.0 Hz, 3H) and by-product 2-(4-Bromophenyl)-5-methyl-4-vinyloxazole (1.81 g, 22%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.92-7.87 (m, 2H), 7.58-7.55 (m, 2H), 6.54 (dd, J=17.3, 10.8 Hz, 1H), 5.94 (dd, J=17.0, 1.8 Hz, 1H), 5.30 (dd, J=10.8, 1.8 Hz, 1H), 2.41 (s, 3H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:49])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[CH3:48])[CH:21]=[CH:22][C:16]=2[O:15]1>O.C(OCC)(=O)C>[CH3:13][C:14]1([CH3:49])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[CH3:48])[CH:21]=[CH:22][C:16]=2[O:15]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A mixture of hydroxylammonium chloride (6.1 g), sodium hydrogen carbonate (8.80 g) and dimethyl sulfoxide (50 mL) was stirred at 40° C. for 30 min, 4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (4.28 g) was added, and the mixture was stirred at 90° C. for 23 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (50 mL). N,N′-carbonyldiimidazole (1.7 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.57 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3.64 g, 76%).