Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([N:14]=[C:15]([N:17]([CH3:19])[CH3:18])[N:16]=2)[CH:13]=1)(C)(C)C.N1(C2N=C3C=CC(N)=CN3N=2)CCOCC1>>[CH3:18][N:17]([CH3:19])[C:15]1[N:16]=[C:11]2[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][N:12]2[N:14]=1
Reactant: CN(C)c1nc2ccc(NC(=O)OC(C)(C)C)cn2n1
Agent: Nc1ccc2nc(N3CCOCC3)nn2c1
Product: CN(C)c1nc2ccc(N)cn2n1

Procedure:
Using (2-dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-carbamic acid tert-butyl ester, this compound was prepared following the same method as for the synthesis of 2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine. White solid (64 mg, 83%). MS: m/z=178 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:16])([O-:12])=[O:11]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)c2ccccc2[N+](=O)[O-])c1
Yield: 85 %

Procedure:
Using m-anisidine (2.03 g, 16.5 mmol) and 2-nitrobenzoic acid (2.51 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 3.47 g (84.9%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18](=[O:30])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][C:18]([OH:30])=[O:17])=[CH:22][C:23]=3[O:28][CH3:29])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCc1ccc(O)c(OC)c1
Reactant: ClCc1cccnc1SC1CCCC1
Product: COc1cc(CCC(=O)O)ccc1OCc1cccnc1SC1CCCC1
Yield: 58.1 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (40 mg, 0.16 mmol) obtained in Step C of Preparation Example 8 and 3-(4-hydroxy-3-methoxy-phenyl]-propionic acid ethyl ester (48 mg, 0.21 mmol) obtained in Step C of Preparation Example 38 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (36 mg, 64%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:2].[CH2:18]([Mg]Br)[CH3:19].C(I)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH3:19])#[N:2]
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1c[nH]c2ccc(-c3ccccc3C#N)cc12
Yield: 31.6 %

Procedure:
5-(2-cyanophenyl)indole (1.26 mmoles,630 mg) was dissolved in THF (20 ml) and treated with ethylmagnesium bromide (1.26 mmoles, 0.630 ml) and ethyl iodide (3.45 mmoles, 0.54 g) as in Example 24 to yield 98 mg of 5-(2-cyanophenyl)-3-ethylindole. (MS)
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH2:21][CH2:22]C.[ClH:25]>CN(C)C=O>[ClH:25].[ClH:25].[CH2:6]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCI
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1CCNCC1

Procedure:
To a dimethylformamide (7 ml) solution containing N-(tert-butoxycarbonyl)piperazine (1.0 g) were added potassium carbonate (742 mg) and then butyl iodide (1.09 g), and the mixture was stirred at room temperature for 15 hours to undergo reaction, thereby obtaining N-tert-butoxycarbonyl-N-butylpiperazine. This compound was acid-treated with hydrochloric acid to obtain N-butylpiperazine.dihydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C[Si](Cl)(C)C.CC1(C)[O:19][C:18](=O)[CH2:17][C:16](=[O:21])[O:15]1>C(Cl)Cl>[O:19]=[C:18]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:17][C:16]([OH:21])=[O:15]
Reactant: Nc1cccnc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: O=C(O)CC(=O)Nc1cccnc1
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a suspension of pyridine-3-amine (1 g, 10.6 mmol) in DCM (100 mL) was added TMSCl (1.3 mL, 10.6 mmol) at room temperature. The reaction mixture was stirred for 30 min. 2,2-Dimethyl-1,3-dioxane-4,6-dione (1.44 g, 10.6 mmol) was added and the combined mixture stirred overnight and concentrated under reduced pressure. The residue was dissolved in dilute NaHCO3 solution and washed with EtOAc. The aqueous phase was collected and acidified with cone. HCl to pH˜3 and extracted with EtOAc. The extract was dried over anhydrous Na2SO4, filtered and concentrated. The remaining solid was purified by flash chromatography (eluent CHCl3/MeOH/AcOH 8:1:0.1) to afford the title compound 39 as a white solid (0.5 g, 26% yield). 1H NMR (DMSO-d6) δ (ppm): 12.04 (bs, 1H), 9.67 (s, 1H), 8.18 (d, 1H), 8.01 (d, 1H), 7.29 (m, 1H), 2.97 (s, 2H). MS (m/z): 181.1 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH:10]([CH2:20][CH2:21]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH:24][CH3:25]>>[OH2:11].[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH:10]([CH2:20][CH2:21][N:24]([CH3:25])[CH3:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C1c2ccccc2OC(CCCl)CN1Cc1ccccc1
Product: CN(C)CCC1CN(Cc2ccccc2)C(=O)c2ccccc2O1
Product: O

Procedure:
Following the procedure of Example 1, 4-benzyl-2-(2-chloroethyl)-2,3-dihydro-1,4-benzoxazepin-5(4H)-one and dimethylamine were reacted and the free base of the title compound was obtained in the concentrated residue. Recrystallization from ethanol-water gave the product, m.p. 75°-77° C.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].[I-].[K+]>C1(C)C=CC=CC=1>[ClH:20].[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: O=C(CCCCl)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 175.5 g (0.7 mole) of 4-diphenylmethylpiperidine, 63.6 g (0.35 mole) of 4-chlorobutyrophenone, 600 ml of toluene, and a small amount of potassium iodide was refluxed for three days then allowed to stand at room temperature one day. The solvent was removed at reduced pressure, and one liter of dry ether was added after which the mixture was filtered. The filtrate was concentrated, and the residue was dissolved in 75°-90° petroleum ether treated with charcoal and filtered. The filtrate was cooled to room temperature and the resulting precipitate was filtered off, and dissolved in ether then treated with ethereal HCl. A precipitate formed which was recrystallized from methanol-butanone to give the desired product, M.P. 163.5°-164.5° C.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[C:15]([N+:18]([O-])=O)[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[C:15]([NH2:18])[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1N
Yield: 0.8 %

Procedure:
1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-1H-indazole (335 mg, 100 mmol) was dissolved in 30 ml of a 1:1 mixture of ethanol and water. To this mixture was added ammonium chloride (108 mg) and iron powder (108 mg). The mixture was then stirred at reflux for two hours, then was cooled and filtered. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (95:5 dichloromethane/methanol) to give 240 mg (78.7%) of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine as a tan solid.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:27])=[C:6]([C:8]2[C:23](=[O:24])[N:22]([O:25][CH3:26])[C:11]3[N:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:14]=[CH:15][C:10]=3[CH:9]=2)[CH:7]=1.C([N:30](CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](O)=[O:65])=[CH:62][C:61]=1[C:69]([F:72])([F:71])[F:70]>CN(C=O)C>[Cl:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:30][C:3]2[CH:2]=[CH:7][C:6]([C:8]3[C:23](=[O:24])[N:22]([O:25][CH3:26])[C:11]4[N:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:14]=[CH:15][C:10]=4[CH:9]=3)=[C:5]([Cl:27])[CH:4]=2)=[O:65])=[CH:62][C:61]=1[C:69]([F:72])([F:71])[F:70]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COn1c(=O)c(-c2cc(N)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COn1c(=O)c(-c2ccc(NC(=O)c3ccc(Cl)c(C(F)(F)F)c3)cc2Cl)cc2cnc(NCCN(C)C)nc21
Temperature: 25 °C

Procedure:
In a 6 ml maximum recovery HPLC vial equipped with a small triangular magnetic stirring bar was placed 6-(5-amino-2-chlorophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin-7(8H)-one (347 μmol). Triethylamine (344 μmol) was added, followed by aliquots of DMF stock solutions of HATU (320 μmol) and 4-chloro-3-(trifluoromethyl)benzoic acid (129 μmol), and the mixture was stirred at room temperature over night. The solutions were purified by prep. HPLC-MS. The collected fractions were transferred to centrifuge vials and lyophilized, giving 4-chloro-N-(3-chloro-4-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl) -3-(trifluoromethypbenzamide as a solid (85%).
Reaction SMILES: CC(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH2:17])[C:14]([OH:16])=[O:15])=O)(C)C.[NH:18]([C:26]([O:28]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:19]([C:23]([OH:25])=O)[CH:20]([CH3:22])[CH3:21].[NH:43](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:44](C(O)=O)[CH2:45][CH2:46][CH2:47][CH2:48][NH:49]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>CCOCC>[NH2:43][C@H:44]([C:26]([NH:18][C@H:19]([C:23]([NH:17][C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])=[O:25])[CH:20]([CH3:21])[CH3:22])=[O:28])[CH2:45][CH2:46][CH2:47][CH2:48][NH2:49]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(C)[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O

Procedure:
The protective peptide is built on 1.00 g (0.80 mmol) of H-Lys(Boc)-2-chlorotrityl resin using Fmoc-Val-OH, Fmoc-Lys(Boc)-OH and Palm-OSu. The resin is treated for 30 min with 8 ml of TFA 95% and the solution is instilled in 100 ml of Et2O. The precipitate is sucked off, washed and purified by prep. HPLC after drying. The substance is diluted in 30 ml of dioxan:water=4:6, treated overnight with 2.0 g of BioRad resin (acetate form), filtered, rotated and lyophilized. Yield: 110 mg (0.15 mmol, 19%)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:10])[CH:8]=O.C([O:13][CH:14](OCC)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)C.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[O:16][C:15](=[CH:8][N:7]([CH3:10])[CH3:6])[CH:14]=[O:13]
Reactant: CCOC(COc1ccc(Cl)c(Cl)c1)OCC
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(C)C=C(C=O)Oc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 51.7 %

Procedure:
Phosphorus oxychloride (18.4 g, 120 mmol) was added to dimethylformamide (8.8 g, 120 mmol), maintaining the temperature below 25° C. by an external ice-bath. Upon completion of the addition the reaction mixture was heated to 50° C. for 45 minutes and then cooled to room temperature. Chloroform (35 ml) was added and the resulting solution was brought to reflux. 3,4-Dichlorophenoxyacetaldehyde diethylacetal (9.61 g, 40.0 mmol) was added in portions. After heating for 3 hours at reflux the solution was cooled to room temperature and poured carefully onto a solution of potassium carbonate (115 g) in water (100 ml). The mixture was cooled in an ice-bath to around room temperature and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo yielding a brown oil, which was purified by flash column chromatography (SiO2, ethyl acetate) yielding the title compound (5.38 g, 52% yield) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](#[N:25])[CH3:24]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([OH:19])[CH2:24][C:23]#[N:25])[CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(OCCCCCOCc2ccccc2)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(OCCCCCOCc2ccccc2)c1

Procedure:
Addition of acetonitrile to 3-(5-benzyloxypentoxy)-benzaldehyde gave 3-[3-(5-benzyloxypentoxy)-phenyl]-3-hydroxypropionitrile as yellow oil. Yield (0.74 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.23-7.41 (m, 6H), 6.90-6.98 (m, 2H), 6.86 (d, J=8.0 Hz, 1H), 5.0 (t, J=6.0 Hz, 1H), 4.51 (s, 2H), 3.98 (t, J=7.0 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 2.75 (d, J=6.0 Hz, 2H), 1.75-1.84 (m, 2H), 1.67-1.73 (m, 2H), 1.53-1.62 (m, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[C:8]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][CH2:25][C:26]([OH:28])=O)=[CH:12][N:11]=1)=[O:9])([CH3:3])[CH3:2].C([N:34](CC)CC)C.ClC(OCC(C)C)=O.[OH-].N>C1COCC1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[C:8]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][CH2:25][C:26]([NH2:34])=[O:28])=[CH:12][N:11]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: COc1cc2c(CCC(=O)O)cnc(C(=O)c3cccc(OC(C)C)c3)c2cc1OC
Agent: CC(C)COC(=O)Cl
Agent: N
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2c(CCC(N)=O)cnc(C(=O)c3cccc(OC(C)C)c3)c2cc1OC
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The above carboxylic acid (70.3 mg) was dissolved in 6 ml of THF. Then at −30° C., triethylamine (0.055 ml) was added followed by isobutyl chloroformate (0.034 ml). The mixture was stirred at −20° C. for 30 minutes. Then 30% ammonia hydroxide solution (0.15 ml) was added. The mixture was stirred at room temperature overnight and then purified through a reverse preparative HPLC to give 3-[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-propionamid as a fluffy solid (47.2 mg). ES-MS calcd for C24H26N2O5 (m/e) 422.5, obsd 423.4 (M+H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>C(O)(C)(C)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
p-Cresol (190 g; 1.76 mol), potassium-tert-butoxide (220.2 g; 1.93 mol) and t-butanol (from calcium hydride; 1 l) were stirred at room temperature, under nitrogen, for 15 mins; followed by the dropwise addition of p-fluoronitrobenzene (272.7 g; 1.93 mol). After heating at reflux for 18 hours, followed by cooling, the resulting yellow precipitate was removed by filtration and washed with absolute ethanol. The combined filtrate and washings were evaporated on the Buchi and the residue taken up in benzene (4 l). The combined benzene layers were dried over magnesium sulphate and evaporated to yield a yellow residue which was recrystallised from hexane (2 l) to give 4-(4-nitrophenoxy)toluene as a yellow solid. m.p. 65°-66° C. NMR (CDCl3): 8.01 (d, 2H), 7.5 (q, 6H) and 2.31 (s, 3H). Analysis for C13H11NO3 : Calculated: C, 68.10, H, 4.84, N, 6.11; found: C, 68.13; H, 4.87; N, 6.14.
Reaction SMILES: C[O:2][C:3](=[O:45])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)C(C(=O)CO)=CC=2CC)[C:12]=1[CH2:42][CH2:43][CH3:44].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[N:61]1[C:66]([CH3:67])=[CH:65][CH:64]=[CH:63][C:62]=1[CH3:68].C[CH2:70][O:71]CC>C(Cl)Cl.O>[CH2:62]([C:63]1[CH:64]=[C:65]([C:66]2[N:61]=[CH:70][O:71][CH:67]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:42][CH2:43][CH3:44])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:45])=[O:2])[CH3:68]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(C(=O)CO)cc2CC)cccc1Oc1ccccc1C(=O)OC
Reactant: CCOCC
Reactant: Cc1cccc(C)n1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCCc1c(OCCCOc2cc(O)c(-c3cocn3)cc2CC)cccc1Oc1ccccc1C(=O)O
Temperature: 120 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
To a solution of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(2-hydroxyacetyl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (1.39 g, 2.27 mmol) in methylene chloride (20 mL) cooled to −78° C. was added triflic anhydride (0.57 mL, 3.4 mmol) and 2,6-lutidine (0.40 mL, 3.4 mmol). The resulting mixture was stirred for 1 h then poured into ether and water. The organic layer was separated and washed once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in a 2:1 mixture of formamide/N,N-dimethylformamide (9 mL) and heated at 120° C. in a sealed tube for 4 h. The mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed four times with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 89 mg (6%) of the title product as a colorless oil. 1H NMR (CDCl3) δ 7.92 (s, 1H), 7.85 (s, 1H), 7.83 (m, 2H), 7.35 (m, 6H), 7.03 (d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 6.73 (d, J=8 Hz, 1H), 6.62 (d, J=8 Hz, 1H), 6.52 (s, 1H), 6.35 (d, J=8 Hz, 1H), 5.07 (s, 2H), 4.14 (m, 4H), 3.76 (s, 3H), 2.61 (m, 4H), 2.26 (quintet, J=6 Hz, 2H), 1.48 (hextet, J=7 Hz, 2H), 1.15 (t, J=8 Hz, 3H), 0.84 (t, J=8 Hz, 3H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: OB(O)c1ccccc1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccccc2)s1
Yield: 19.3 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and phenylboronic acid (7.3 mg, 0.06 mmol) affording 3.7 mg (19%) of the title compound. MS (ESI+) calcd for C17H13N5O2S2 383.051066, found 383.050986.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:11]=O>CCCCCC>[Cl:1][CH2:11][O:10][CH2:9][C:3]1([CH3:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=O
Reactant: CC1(CO)CCCCC1
Reactant: Cl
Solvent: CCCCCC
Product: CC1(COCCl)CCCCC1

Procedure:
Under ice cooling and stirring, hydrogen chloride was blown into a mixture of 128 g of (1-methylcyclohexyl)methanol, 400 g of hexane, and 36 g of paraformaldehyde, until the is reactant alcohol disappeared on gas chromatography analysis. The excess hydrogen chloride was purged by feeding nitrogen into the reactor, after which the water layer was removed by separatory operation. The solution was dried over magnesium sulfate and the solids filtered off, yielding a hexane solution of chloromethyl[(1-methylcyclohexyl)methyl] ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:7])[C:5]2=[CH:15][CH:16]=1.Br[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:11]([N:8]1[C:9](=[O:10])[C:4]2=[CH:3][C:2]([O:1][CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[C:5]2[C:6]1=[O:7])[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)Br
Reactant: CC(C)CN1C(=O)c2ccc(O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)c2ccc(OC(C)C)cc2C1=O
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A mixture of 1 g of 4-hydroxy-N-isobutylphthalimide, 0.85 cm3 of 2-bromopropane and 1.38 g of potassium carbonate in 5 cm3 of dimethylformamide is stirred at a temperature in the region of 60° C. for 17 hours. The reaction mixture is then cooled to a temperature in the region of 20° C. and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° c. The residue is taken up in 70 cm3 of water and then extracted 3 times with 75 cm3 of ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.16 g of N-isobutyl-4-isopropyloxyphthalimide are thus obtained in the form of a white solid. (Rf=0.50, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:27][O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH2:31]>>[CH3:27][O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH:31][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: COC(=O)c1ccc(CS(=O)(=O)c2cccnc2)cc1-c1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CS(=O)(=O)c2cccnc2)cc1-c1ccccc1

Procedure:
The desired compound was prepared from 4-(3-pyridylsulfonylmethyl)-2-phenylbenzoic acid methyl ester by saponification of the methyl ester using the procedure of Example 228D, and coupling with methionine methyl ester according to the procedure of Example 186C. mp 152-154° C. 1H NMR (300 MHz, CDCl3) δ 8.95 (d, 1H), 8.87 (dd, 1H), 7.94 (ddd, 1H), 7.66 (d, 1H), 7.43 (m, 4H), 7.30 (m, 2H), 7.21 (dd, 1H), 7.10 (d, 1H), 5.91 (bd, 1H), 4.66 (ddd, 1H), 4.42 (s, 2H), 3.68 (s, 3H), 2.08 (t, 2H), 2.02 (s, 3H), 1.93 (m, 1H), 1.75 (m, 1H). MS (CI NH3) m/e 516 (M+NH4)+, 499 (M+H)+. Anal calc' for C25H26N2O5S2: C, 60.22; H, 5.25; N, 5.62. Found: C, 60.28; H, 4.94; N, 5.56.