Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH2:20][CH3:21])=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:8]2=[O:17]
Reactant: O=C(Cc1ccc(F)cc1)c1cc(Br)ccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
Intermediate 6 (3.0 g, 9.70 mmoles) was taken in a RB flask and to this triethylamine (30 ml) and propionic anhydride (3.94 g, 30.37 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (1.60 g, 47% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.33(d, J=2.4 Hz, 1H), 7.76(dd, J=8.8,2.4 Hz, 1H), 7.38(d, J=8.8 Hz, 1H), 7.24(dd, J=5.5,2.0 Hz,2H), 7.16 (dt, J=11.4,2.8 Hz, 2H), 2.61(q, J=7.6 Hz, 2H), 1.27(t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([CH:6]([NH:15][C@H:16]([C:18]([N:20]1[CH:29]2[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:23][CH2:22][C@H:21]1[C:30]([OH:32])=[O:31])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3]CC)=[O:2].[OH-].[Na+]>>[C:1]([CH:6]([NH:15][C@H:16]([C:18]([N:20]1[CH:29]2[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:23][CH2:22][C@H:21]1[C:30]([OH:32])=[O:31])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1C2CCCCC2CC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1C2CCCCC2CC[C@H]1C(=O)O

Procedure:
As described in Example 2, treat 1-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]decahydroquinoline-2-carboxylic acid (prepared as described in Example 16) with sodium hydroxide to obtain the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=2)=[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:7]=[C:6]1[CH:39]=[CH2:40])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.[Pd]>[CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=2)=[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:7]=[C:6]1[CH2:39][CH3:40])[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1nc(-c2ccccc2)c(CN(Cc2cccc(OCC)c2)Cc2ccc3c(c2)OCCO3)n1CCCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCn1c(CC)nc(-c2ccccc2)c1CN(Cc1cccc(OCC)c1)Cc1ccc2c(c1)OCCO2

Procedure:
N-[(1-butyl-2-ethenyl-4-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)-amine (8 mg) prepared in the previous example, is dissolved in 5 mL ethyl acetate and hydrogenated at room temperature under atmospheric pressure. 5% Pd/C (3 mg) is used as a catalyst. The reaction mixture is filtered through celite to provide the title compound (Compound 7). 1H NMR (CDCl3) δ 0.83(t, J=7.2 Hz, 3H), 1.10(m, 2H), 1.27(m, 2H), 1.31(t, J=7.2 Hz, 3H), 1.40(t, J=7.2 Hz, 3H), 2.66(q, 7.2 Hz, 2H) 3.30(s, 2H), 3.36(s, 2H), 3.65(s, 2H), 3.98(m, 4H), 4.23(s, 4H), 6.76(m, 4H), 7.17(t, J=7.6 Hz, 2H), 7.26(m, 1H), 7.37(t, J=7.6 Hz, 2H), 7.58(d, J=7.6 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]2[C:17](=[O:18])[CH2:16][CH2:15]N(C)[CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].CO[S:22](C(F)(F)F)(=O)=O.O.S.[Na].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>CC(C)CC(=O)C.O.CC(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]2[C:17](=[O:18])[CH2:16][CH2:15][S:22][CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCOc1cc(C2CN(C)CCC2=O)ccc1OC
Agent: S
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)CC(C)C
Solvent: CC(C)O
Product: CCOc1cc(C2CSCCC2=O)ccc1OC
Temperature: 2 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 3-(3-ethoxy-4-methoxy-phenyl)-1-methyl-piperidin-4-one (0.88 g) in 8.5 ml of 4-methyl-pentan-2-one, which is cooled to about 2° C., trifluoro-methansulfonic acid methylester (0.6 g) is added dropwise within about 9 min. Following 20 min stirring at RT a combined solution of sodium hydrogensulfide monohydrate (0.82 g) and sodium sulfide nonahydrate (0.98 g) in 8.5 ml of water is added and the stirred reaction mixture is then heated to reflux temperature for 4 h. Cooled to RT the stirring is stopped and the building up organic layer is separated. The water phase is washed three times with 2 ml each of EtOAc. The collected organic phase is washed two times with 3 ml each of water, filtered and concentrated in vacuo giving a solid residue. This is suspended in 2-propanol (4 ml) and the suspension is heated to reflux temperature giving a clear solution. The continuously stirred solution is slowly cooled down to RT inducing a spontaneous crystallization. Following stirring for 15 h at RT, the suspension is further stirred at about 2° C. for 2 h and then the crystals are filtered of, washed with 2-propanol (1 ml) and dried in vacuo at about 60° C. for 24 h yielding the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[O-2].[O-2].[Mn+4].O1CCOCC1>[C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[CH:12]=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1[nH]cnc1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=Cc1[nH]cnc1-c1ccccc1
Yield: 70.8 %

Procedure:
1,4-Dioxane (10 ml) was mixed with 1 g of (4-phenyl-1H-imidazol-5-yl)methyl alcohol and 3 g of activated manganese dioxide. The obtained mixture was treated at 80° C. for 30 minutes to conduct a reaction. The reaction mixture was passed through a hot filter and the filter cake was washed with acetone. The washings and the filtrate were combined and concentrated to give 0.7 g of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9].[I:14][C:15]1[C:23]([I:24])=[C:22]([C:25]([O-:27])=[O:26])[C:21]([I:28])=[C:20]([I:29])[C:16]=1[C:17]([O-:19])=[O:18]>CN(C=O)C>[I:14][C:15]1[C:23]([I:24])=[C:22]([C:25]([O:27][CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9])=[O:26])[C:21]([I:28])=[C:20]([I:29])[C:16]=1[C:17]([O:19][CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9])=[O:18]
Reactant: CCCCC(C)Br
Reactant: O=C([O-])c1c(I)c(I)c(C(=O)[O-])c(I)c1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCC(C)OC(=O)c1c(I)c(I)c(C(=O)OC(C)CCCC)c(I)c1I
Temperature: 76 °C
Reaction time: 22 h
Yield: 31 %

Procedure:
Cesium carbonate (1.63 g, 5.0 mmol) and 2-bromohexane (2.0 ml, 16 mmol) were added to a flask containing a stirred mixture of 2,3,5,6-tetraiodoterephthalate acid (1.4 g, 2.0 mmol) and dry DMF (20 ml). The reaction flask was immersed in an oil bath which was warmed to 76° C. over a period of 0.5 hr. After stirring under an atmosphere of N2 for 22 hrs, the reaction was allowed to cool, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up into EtOAc (200 ml), washed with saturated aqueous sodium bicarbonate (2×50 ml), water (50 ml) and brine (50 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:19; Et2O: hexanes) provided bis(2-hexyl) 2,3,5,6-tetraiodoterephthalate (0.52 g, 44%) as a light yellow solid. Mp 114°-115° C.
Reaction SMILES: [C:1]([C:6]1[CH:23]=[C:22]([C:24]([CH2:27][CH3:28])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:7]=1[O:8][C:9]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].O.CCCCCCC.C(OCC)(=O)C>Br.CC(O)=O>[C:1]([C:6]1[CH:23]=[C:22]([C:24]([CH2:27][CH3:28])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:7]=1[O:8][C:9]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(Oc2ccc(OC)cc2C(=O)O)c(C(C)(C)CC)c1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: CCC(C)(C)c1ccc(Oc2ccc(O)cc2C(=O)O)c(C(C)(C)CC)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 2-(2,4-di-tert-pentylphenoxy)-5-methoxybenzoic acid (10.0 g, 0.026 mol) in 31% HBr/HOAc (100 mL) was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and added to 500 mL water. The mixture was extracted with ethyl acetate (3×200 mL), and the combined organic extracts repeatedly washed with water to remove traces of acid. The organic extracts were dried over magnesium sulfate and concentrated to give a tan solid. Chromatography on silica gel with 1:1 heptane:ethyl acetate yielded the product in 80% yield. NMR and mass spectral data were consistent with the proposed structure.
Reaction SMILES: I[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>CCOC(C)=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[S:6][C:2]=2[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc(Oc2c(I)sc3ccccc23)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Yield: 70 %

Procedure:
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from 2-iodo-3-(4-methoxyphenoxy)benzo[b]thiophene (Part B) and (4-methoxyphenyl)boronic acid (Part C) in 70% yield following chromatography (SiO2; 5% EtOAc in hexanes).
Reaction SMILES: N[C:2]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([O:16][CH3:17])[C:6]([O:14][CH3:15])=[N:7]2.Cl.N([O-])=O.[Na+].[I-:23].[K+]>CC(C)=O>[Cl:12][C:11]1[C:2]([I:23])=[C:3]2[C:8](=[CH:9][C:10]=1[Cl:13])[N:7]=[C:6]([O:14][CH3:15])[C:5]([O:16][CH3:17])=[N:4]2
Reactant: COc1nc2cc(Cl)c(Cl)c(N)c2nc1OC
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc2cc(Cl)c(Cl)c(I)c2nc1OC
Temperature: 0 °C
Yield: 31.4 %

Procedure:
5-Amino-6,7-dichloro-2,3-dimethoxyquinoxaline (from (c) above) (38.12 g, 0.14 mol) was dissolved in acetone (2 L) and cooled to 0° C. Whilst being agitated using a mechanical stirrer, the solution was treated first with 2M hydrochloric acid (396 mL, 0.79 mol) and then dropwise with 1M aqueous sodium nitrite (208 mL, 0.208 mol), maintaining the temperature of the mixture at 0° C. After the additions were complete, the mixture was stirred for 15 minutes, then treated with 5M aqueous potassium iodide (278 mL, 1.39 mol) maintaining the temperature below 5° C. The mixture was then allowed to warm to 10° C. over 30 minutes. The acetone was removed under reduced pressure and the residue partitioned between water and ethyl acetate (total of 4 L). The organic solution was washed with 10% aqueous sodium bisulphite, saturated aqueous sodium bicarbonate, dried (MgSO4), and concentrated under reduced pressure. Purification by flash chromatography (eluting with toluene) gave 6,7-dichloro-2,3-dimethoxy-5-iodoquinoxaline (16.9 g, 32%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[C:11]([CH:14]=[N:15][CH3:16])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[NH2:17])[CH:2]([CH3:4])[CH3:3].C1(C)C=CC(S([CH:27]([N+:34]#[C-:35])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=O)=O)=CC=1.CN>CO>[CH2:1]([N:5]1[C:9]2[CH:10]=[C:11]([C:14]3[N:15]([CH3:16])[CH:35]=[N:34][C:27]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[NH2:17])[CH:2]([CH3:4])[CH3:3]
Reactant: CN=Cc1ccc2nc(N)n(CC(C)C)c2c1
Reactant: [C-]#[N+]C(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Agent: CN
Solvent: CO
Product: CC(C)Cn1c(N)nc2ccc(-c3c(-c4ccccc4)ncn3C)cc21
Temperature: 25 °C

Procedure:
Heat a mixture of 1-isobutyl-2-amino-6-(methyliminomethyl)-1H-benzimidazole (504 mg, 2.19 mmol), α-(p-toluenesulfonyl)benzylisocyanide (1.48 g, 5.47 mmol), methanol (7 mL), and methylamine (5.5 mL, 2M in tetrahydrofuran) in a sealed tube at 80° C. for 20 hours. Cool to room temperature and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with a 1:1 mixture of acetonitrile and dichloromethane containing 5% methanol to provide the desired compound.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([OH:8])[CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC(O)CCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CCC)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To an ice cooled solution of 834 mg (7.19 mmol) of 4-heptanol in 35 mL of CH2Cl2 was added 1.5 mL of triethylamine. Next, 0.7 mL (9 mmol) of methanesulfonyl chloride was added, dropwise, over 1 minute. The mixture was stirred at 0° C. for 30 minutes, then extracted with H2O (1×15 mL), 5% NH4OH (2×15 mL), 1M HCl (2×15 mL), and brine (1×15 mL), dried over MgSO4, filtered, and concentrated to an oil. Yield 1.31 g (94%). 1H NMR (300 MHz, CDCl3) d 0.96 (t, 6, J=9), 1.43 (m, 4), 1.64 (m, 4), 3.00 (s, 3), 4.73 (quintet, 1 J=5).
Reaction SMILES: CC(C)([O-])C.[K+].COP([CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC)=O.[CH3:24][NH:25][C:26](=[O:46])[C@H:27]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[NH:28][C:29](=[O:36])[C:30](=O)[CH2:31][CH:32]([CH3:34])[CH3:33].O>CN(C)C=O>[CH3:24][NH:25][C:26](=[O:46])[C@H:27]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[NH:28][C:29](=[O:36])[C:30]([CH2:31][CH:32]([CH3:33])[CH3:34])=[CH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: COP(=O)(CC(=O)OCc1ccccc1)OC
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(=O)CC(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(=CC(=O)OCc1ccccc1)CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tertiary butoxide (2.1 g., 0.0188 mol.) was suspended in dry dimethylformamide (50 mls.). To the suspension was added benzyl dimethylphosphonoethanoate (4.6 g., 0.0187 mol.) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hours. N-(4-Methyl-2-oxopentanoyl)-O-methyl-L-tyrosine N-Methylamide (3.0 g., 0.00913 mol) was added portionwise to the reaction mixture over a period of 10 minutes to yield a red solution. The red solution was stirred at room temperature for 4 hours, and then poured into water (500 mls.). The resulting mixture obtained was extracted with ethyl acetate (2×100 mls.) and the ethyl acetate extract was washed with water (2×25 mls.), brine (25 mls.) and dried over anhydrous magnesium sulfate. The ethyl acetate was removed by evaporation in vacuo to yield a crude solid product (4.2 g.). The crude product was purified by recrystallization from a mixture of ethyl acetate and hexane to yield E and Z N-[3-(benzyloxycarbonyl)-2-(2-methylpropyl)propenoyl]-O-methyl-L-tyrosine N-methylamide as a light brown crystalline solid. (m.p. 167°-9° C. Found: C, 68.3; H, 7.1; N, 6.3 %. C25H30N2O5 requires C, 68.5; H, 6.9; N, 6.4%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)[NH2:4].[CH3:14]C1C2NC=NC=2C=C(C#N)C=1>>[OH:1][N:2]=[C:3]([C:5]1[CH:13]=[C:12]([CH3:14])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)[NH2:4]
Reactant: Cc1cc(C#N)cc2nc[nH]c12
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Product: Cc1cc(C(N)=NO)cc2nc[nH]c12

Procedure:
The title compound was prepared following the procedure described for Intermediate 1, step 2, but starting from 7-methyl-1H-benzimidazole-5-carbonitrile obtained in step 2 (900 mg; 5.73 mmol) as a beige solid (985 mg, 90%). 1H NMR (DMSO-d6) δ 12.60 (br s, 1H), 9.46 (s, 1H), 8.29-7.57 (m, 3H), 5.76 (s, 2H), 2.51 (m, 3H). LC/MS (Method B): 191.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].Br[CH:38]([CH3:46])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C1(C)C=CC=CC=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH:38]([CH3:46])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:36]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(=O)OC(C)(C)C)CC2)c2ncnn12

Procedure:
To a mixture of 3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (233 g), tert-butyl 2-bromopropanoate (301 g), toluene (1.7 L) and 50% sodium hydroxide (1.7 L) was added tetrabutylammonium hydrogen sulfate (16.3 g), and the mixture was stirred with the internal temperature maintained below 30° C. for 16 hr. Water (1 L) was slowly added under ice-cooling, and phases were separated. The aqueous layer was extracted with tetrahydrofuran (1.0 L). The combined extracts were successively washed with 3M hydrochloric acid (1 L) and brine (1 L), dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as an amorphous pale-yellow solid (283 g, 96%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=3)[CH:10]=2)[CH:8]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[OH:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:7]1[CH:8]=[C:3]([OH:2])[CH:4]=[N:5][CH:6]=1)[CH:18]=[CH:17]2
Reactant: COc1cncc(-c2ccc3cc(OC)ccc3c2)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Oc1cncc(-c2ccc3cc(O)ccc3c2)c1
Yield: 7 %

Procedure:
The compound is prepared by reaction of 3-methoxy-5-(6-methoxynaphthalene-2-yl)pyridine (200 mg, 0.75 mmol, 1 eq) with aluminum trichloride (803 mg, 6.04 mmol, 8 eq) according to method F. Purification by column chromatography with dichloromethane/methanol 95/5 as the eluent yields the desired product in a yield of 7%, 13 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[C:12]([CH3:24])=[N:11][C:10]=1[CH2:25][CH2:26][CH3:27].BrB(Br)Br.C(OCC)(=O)C.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:12]([CH3:24])=[N:11][C:10]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1nc(C)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
To a solution of 3′-fluoro-4′-{[1-(4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.35 g) in methylene chloride (10 mL) was added tribromoborane (1.0 M methylene chloride solution, 20 mL) at room temperature. After being stirred at room temperature for 12 hr, 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 purified by silica gel column chromatography to give the title compound as a white solid (2.25 g, 99%).
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[CH:14][N:13]=1>CO>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc2c(c1)OCO2
Solvent: CO
Product: O=[N+]([O-])c1cnc(Nc2ccc3c(c2)OCO3)c([N+](=O)[O-])c1

Procedure:
To a stirred solution of 12.0 g. (0.0875 mole) of 3,4-methylenedioxyaniline in 100 ml. of methanol, was added with stirring 8.0 g. (0.04 mole) of 2-chloro-3,5-dinitropyridine. Within one minute the mixture had crystallized. To complete the reaction, the mixture was heated on a steam bath for 15 minutes, then cooled and filtered to give 11.0 g. of product. A small amount recrystallized from methanol melted at 187°-188° C.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[Br:12][C:13]([F:22])([F:21])[C:14](Br)([F:19])[C:15]([F:18])([F:17])[F:16].C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(OC)(C)(C)C.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Br:12][C:13]([F:22])([F:21])[C:14]([C:5]1([C:4]([O:3][CH:2]([F:11])[F:1])=[CH:10][CH:9]=[CH:8][CH2:7]1)[NH2:6])([F:19])[C:15]([F:18])([F:17])[F:16]
Reactant: Nc1ccccc1OC(F)F
Reactant: FC(F)(F)C(F)(Br)C(F)(F)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: COC(C)(C)C
Solvent: O
Product: NC1(C(F)(C(F)(F)F)C(F)(F)Br)CC=CC=C1OC(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.8 %

Procedure:
2-(Difluoromethoxy)aniline (1280 mg) and 1,2-dibromo-1,1,2,3,3,3-hexafluoropropane (8610 mg) were dissolved in tert-butylmethyl ether (30 ml) and water (30 ml), and added with tetrabutylammonium hydrogen sulfate salt (270 mg), sodium hydrogen carbonate (2030 mg) and sodium dithionite (4200 mg) in order. The mixture was stirred vigorously at room temperature for 2 days. The reaction solution was extracted twice with ethyl acetate. The organic phases were combined and washed with water, and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was removed by distillation under the reduced pressure. The resulting residues were purified by column chromatography to obtain 1-(1-bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)aniline (810 mg, 26%).