Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=[O:14].[Ce+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Ce+3].Br([O-])(=O)=O.[Ba+2].Br([O-])(=O)=O>C(#N)C.O>[C:1]([C:5]1[CH:6]=[C:7]([C:11](=[O:14])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cccc(C(C)(C)C)c1
Reactant: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Agent: [Ce+3]
Agent: [O-][Br+2]([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1cccc(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a stirring solution of 1-tert-butyl-3-ethylbenzene (11.15) in acetonitrile (350 ml) and water (150 ml) at room temperature was added cerium (III) sulfate (6.05 g) and barium bromate (13.5 g). The resulting suspension was heated at reflux for 16 hrs. After cooling to room temperature, the reaction mixture was filtered. Saturated aqueous sodium thiosulphate solution was added to the filtrate, and the product was extracted into DCM (3×100 ml). Combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-(3-tert-butyl-phenyl)-ethanone as a yellow oil crude product (13.5 g). 1H NMR (CDCl3): δ 8.00 (s, 1H), 7.75 (d, 1H), 7.61 (d, 1H), 7.39 (t, 1H), 2.61 (s, 3H), 1.36 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][O:10][CH3:11])=[N+:6]([O-])[CH:7]=1.[CH2:12]([N:14](CC)CC)C.C[Si](C#N)(C)C.O>C(#N)C>[Br:1][C:2]1[C:7]([C:12]#[N:14])=[N:6][C:5]([CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COCc1ccc(Br)c[n+]1[O-]
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: O
Solvent: CC#N
Product: COCc1ccc(Br)c(C#N)n1
Yield: 58.2 %

Procedure:
A solution of 5-bromo-2-methoxymethyl-pyridine-1-oxide (5.0 g, 22.7 mmol), triethylamine (12.7 ml, 91 mmol) and trimethylsilyl cyanide (9.1 ml, 68.2 mmol) in acetonitrile (10 ml) was heated in a sealed tube to 120° C. for 18 hours. After completion of the reaction, water was added to the reaction mixture and acetonitrile was removed. The crude material was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried, filtered, and evaporated. The crude product was purified by silica gel chromatography using an ethyl acetate/hexane eluent to yield 3.0 g (58%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](OCC2C=CC=CC=2)=O)[CH:5]=[CH:4][C:3]=1[C:19]1[CH2:20][CH2:21][S:22][CH2:23][CH:24]=1.C([Li])CCC.[C:30]([O:35][CH2:36][C@@H:37]1[O:39]C1)(=[O:34])CCC.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[S:22]1[CH2:21][CH:20]=[C:19]([C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:9][C@H:36]([CH2:37][OH:39])[O:35][C:30]3=[O:34])=[CH:7][C:2]=2[F:1])[CH2:24][CH2:23]1
Reactant: O=C(Nc1ccc(C2=CCSCC2)c(F)c1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1ccc(C2=CCSCC2)c(F)c1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
4-(2-Fluoro-4-benzyloxycarbonylaminophenyl)-3,6-dihydro-2H-thiopyran (15.3 g, 44.6 mM) was dissolved in dry tetrahydrofuran (175 ml) and stirred under nitrogen at −70° C. n-Butyllithium (1.6M in hexanes, 30 ml, 175 mM) was run in over 20 minutes, keeping the temperature below −60°, and the mixture then stirred a further 10 minutes at −70° C. A solution of (R)-glycidyl butyrate (6.42 g, 44.62 mM) dissolved in dry tetrahydrofuran (10 ml) was added dropwise over 10 minutes keeping temperature below −60°, and the mixture left to warm to ambient temperature over 18 hours. Methanol (29 ml) was added, and the mixture stirred for 10 minutes only. Saturated aqueous sodium bicarbonate (200 ml) was added, and the mixture extracted with ethyl acetate (400 ml). The extract was washed with saturated aqueous sodium bicarbonate (100 ml), brine (100 ml), dried (magnesium sulfate). Filtered and evaporated. The crude product was purified on a 300 g silica sinter column, eluting with a gradient from 0% to 100% ethyl acetate in dichloromethane. Relevant fractions were combined, reduced to a small volume, and diluted with an excess of isohexane to precipitate the desired product (11.3 g). MS (ESP): 310 (MH+) for C15H16FNO3S
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4].C1(S(O[CH2:25][CH2:26][Cl:27])(=O)=O)C=CC=CC=1>[Na].CO>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH2:25][CH2:26][Cl:27])=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(O)ccc2s1
Reactant: O=S(=O)(OCCCl)c1ccccc1
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc2cc(OCCCl)ccc2s1
Reaction time: 8 h
Yield: 38.7 %

Procedure:
5-Hydroxybenzo[b]thiophene-2-carboxylic acid methyl ester (1.47 g.) was dissolved in a solution of sodium (0.163 g.) in methanol (15 ml.) and 2-(benzenesulphonyloxy)ethyl chloride (1.57 g.) was added. The resulting solution was heated under reflux for 8 hours and then allowed to cool and stood overnight. The solution was then evaporated and the residue was partitioned between water and ether. The aqueous layer was separated and washed several times with ether. The combined organic layer and ethereal extracts were washed with water, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel. Elution with chloroform gave a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80°) to give 5-(2-chloroethoxy)benzo[b]thiophene-2-carboxylic acid methyl ester, (0.74 g.), m.p. 116°-117° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:4]=1[Cl:20])=[O:28]
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2Cl)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CNC(=O)c3[nH]cnc3Cl)c2Cl)c1
Yield: 75.8 %

Procedure:
The title compound was prepared as described herein using 3-{[3-(aminomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile (40 mg, 0.129 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (35.6 mg, 0.129 mmol), EDC (29.6 mg, 0.154 mmol) and HOBT (29.5 mg, 0.193 mmol) in DMF (3.0 ml) to give the title compound as a white solid (43 mg, 76%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.62 (1H, s) 7.40 (1H, dd, J=8.5, 5.4 Hz) 7.35 (2H, br. s.) 7.12-7.22 (2H, m) 7.00 (1H, s) 4.75 (2H, d). LCMS: m/z 439 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].Cl.[CH3:15]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:15])=[O:6]
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C

Procedure:
In a 1 liter round-bottomed flask were placed 25 g (0.14 mole) 3-hydroxy-4-nitrobenzoic acid, 37% hydrochloric acid (37 ml) and methanol (300 ml). The resulting mixture was refluxed for 10 hours. The reaction mixture was cooled to room temperature and the solvent eliminated in a rotary evaporator. The resulting residue was dissolved in ethyl acetate and washed sequentially with water (1×100 ml), aqueous sodium bicarbonate (1×100 ml), water (1×100 ml) and brine (1×100 ml). The organic layer was dried over anhydrous magnesium sulfate and solvent was removed in the rotary evaporator, yielding 22.5 g of the expected methyl 3-hydroxy-4-nitrobenzoate as a yellow solid which was used as such in the next step.
Reaction SMILES: [F:1][CH:2]([F:12])[CH2:3][O:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:13][O:14][C:15]([C:17]1[S:26][C:20]2[N:21]=[C:22](Cl)[N:23]=[CH:24][C:19]=2[C:18]=1[CH3:27])=[O:16]>>[CH3:13][O:14][C:15]([C:17]1[S:26][C:20]2[N:21]=[CH:22][N:23]=[C:24]([NH:11][C:10]3[C:5]([O:4][CH2:3][CH:2]([F:1])[F:12])=[N:6][CH:7]=[CH:8][CH:9]=3)[C:19]=2[C:18]=1[CH3:27])=[O:16]
Reactant: Nc1cccnc1OCC(F)F
Reactant: COC(=O)c1sc2nc(Cl)ncc2c1C
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OCC(F)F)c2c1C

Procedure:
Prepared analogously to example 28.1 from 2-(2,2-Difluoroethoxy)pyridin-3-amine (171 mg) and Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (190 mg)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH:28]=O)([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([NH2:33])[CH2:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH2:28][NH:33][CH2:30][CH2:31][CH3:32])([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:26])([CH3:27])[O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(C=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCNCC(CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.4 %

Procedure:
A slurry of ethyl 2-(tert-butoxycarbonylamino)-2-formyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (172 mg, 0.42 mmol) and propylamine (40 μL, 0.49 mmol, 1.3 equiv) in 1,2-dichloroethane (3 mL) was treated with sodium triacetoxyborohydride (352 mg, 1.66 mmol, 4 equiv). Acetic acid (2 drops, ca 3-5 equiv) was added and the mixture stirred at room temperature for 17 hours then 60° C. for 1 hour. Once the reaction was complete, saturated aqueous sodium bicarbonate was added and the solution was extracted with dichloromethane. The organic extracts were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by flash chromatography (0-60% ethyl acetate in hexane) gave ethyl 2-(tert-butoxycarbonylamino)-2-((propylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as an oil (66 mg, 34%). 1H NMR (CDCl3, 400 MHz) δ 4.16 (m, 2H), 3.5-3.3 (m, 2H), 3.2 (br m, 2H), 2.9 (m, 1H), 1.8-1.6 (m, 4H), 1.5-1.4 (m, 2H), 1.38 (s, 9H), 1.36-1.3 (m, 3H), 1.22 (t, J=7.2 Hz, 3H), 1.18 (s, 12H), 1.05 (m, 1H), 0.75 (t, J=7.4 Hz, 3H), 0.68 (t, J=7.5 Hz, 2H). ESI+ MS: obsd m/z 457 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[S:28][C:27]([C:29](O)=O)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:54](=[N:57][OH:58])([NH2:56])[CH3:55].O>CN(C=O)C>[CH3:3][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[S:28][C:27]([C:29]5[O:58][N:57]=[C:54]([CH3:55])[N:56]=5)=[N:26][C:25]=4[C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:39])=[O:40])=[CH:36][CH:37]=4)[CH:19]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:1]
Reactant: CC(C)(c1cc(-c2cccc(-c3sc(C(=O)O)nc3-c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: CC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)c(-c3cccc(-c4cc(C(C)(C)S(C)(=O)=O)cc5cccnc45)c3)s2)n1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
To a solution of acid from step 1 in DMF (0.05M) was added CDI (1.1 eq) and, after 5 min, acetamidoxime (1.1 eq). The reaction mixture was stirred at rt for 1 h and 18 h at 110° C. The reaction mixture was cooled to rt and poured into water. The residue was purified by flash chromatography (toluene:EtOAc, 45:55) to afforded the title compound and decarboxylated analog EXAMPLE 73 (more polar product).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH2:16][CH3:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]2[C:28]([O:30][C:31](=O)[C:19]=12)=[O:29]>C(O)(=O)C>[CH2:16]([O:15][C:9]1[CH:8]=[C:7]([CH:2]([N:1]2[C:31](=[O:30])[C:19]3[CH:18]=[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]4=[CH:21][C:20]=3[C:28]2=[O:29])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14])[CH3:17]
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Solvent: CC(=O)O
Product: CCOc1cc(C(CC(=O)O)N2C(=O)c3cc4ccccc4cc3C2=O)ccc1OC
Yield: 93.5 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)-propanoic acid was prepared according to Example 2A from 3-amino-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (3.00 g, 12.5 mmol), 2,3-napthalene dicarboxylic anhydride (2.59 g, 12.5 mmol) in acetic acid (20 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propanoic acid as an off-white solid (4.9 g, 93% yield): mp, 193.0-194.0° C.; 1H NMR (DMSO-d6) δ1.32 (t, J=6.9 Hz, 3H, CH3), 3.34 (dd, J=7.1, 16 Hz, 1H, CHH), 3.57 (dd, J=8.9, 16 Hz, 1H, CHH), 3.74 (s, 3H, CH3), 4.02 (q, J=6.9 Hz, 2H, CH2), 5.71 (dd, J=7, 8 Hz, 1H, NCH), 6.91-6.98 (m, 2H, Ar), 7.09 (br s, 1H, Ar), 7.74-7.78 (m, 2H, Ar), 8.23-8.27 (m, 2H, Ar), 8.50 (br s, 2H, Ar), 12.5 (br s, 1H, OH); 13C NMR (DMSO-d6) δ14.62, 36.03, 50.28, 55.43, 63.71, 111.79, 112.28, 119.45, 124.55, 126.87, 129.27, 130.24, 131.24, 135.03, 147.74, 148.57, 167.29, 171.75; Anal Calcd for C24H21NO6: C, 68.73; H, 5.05; N, 3.34. Found: C, 68.59; H, 5.25; N, 3.17.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:31].[Na+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[CH3:31])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3ccc(Cl)cc3)cc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc(Cl)cc1)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
To a stirred solution of (S)-2-[4-(4-chloro-phenylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (60 mg) in DMF (2 ml) was added sodium hydride (6.2 mg) and stirring was continued at room temperature for 15 min. Iodomethane (24.3 mg) was then added dropwise. The reaction mixture was stirred at room temperature for 1 h. TLC at t=1 h showed the reaction was incomplete with some starting material remaining A second portion of sodium hydride (6.2 mg) was added. After stirring at room temperature for 15 min, iodomethane (24.3 mg) was added. Stirring was continued for a further hour. TLC then showed the reaction was complete. The reaction mixture was poured into sat. aq. NaCl and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in heptane) to afford (S)-2-{4-[(4-chloro-phenyl)-methyl-amino]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (49 mg, 79%) as a colourless gum. MS (ISP): 405.4 ([{37Cl}M+H]+), 403.4 ([{35Cl}M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:12]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:25][O-:26].[Na+]>CO>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:7]4[C:2]([O:26][CH3:25])=[N:3][CH:4]=[CH:5][CH:6]=4)=[N:9][N:10]=3)[CH:13]=2)=[CH:18][CH:19]=1
Reactant: C[O-]
Reactant: COc1ccc(-c2ccc3nnc(-c4cccnc4Cl)n3c2)cc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2ccc3nnc(-c4cccnc4OC)n3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
A mixture of 3-(2-chloropyridin-3-yl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (178 mg, 0.53 mmol) and sodium methoxide (518 mg, 9.6 mmol) in methanol (60 mL) was heated to reflux for 16 h under Argon. The reaction mixture was cooled to room temperature and concentrated. The residue was mixed with DCM (60 mL) and water (60 mL), and it was separated and the organic layer was washed with brine (50 mL×2) and concentrated. The residue was stirred at room temperature for 0.5 h in petroleum ether (35 mL) and ethyl acetate (5 mL) and filtered. The solids were dried in vacuo to give the title compound (150 mg, 84.0% yield). 1H NMR (DMSO-d6): 8.47 (dd, J=4.8 and 1.8 Hz, 1H), 8.32 (m, 1H), 8.10 (dd, J=7.2 and 1.8 Hz, 1H), 7.94 (dd, J=9.6 and 0.9 Hz, 1H), 7.79 (dd, J=9.6 and 1.5 Hz, 1H), 7.69 (d, J=8.7 Hz, 2H), 7.27 (dd, J=7.5 and 5.1 Hz, 1H), 7.05 (d, J=9.0 Hz, 2H), 3.95 (s, 3H), 3.80 (s, 3H). MS: m/z 333.2 [M+H+].
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 2-fluorobenzenesulfonyl chloride (380 μl). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(2-fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (891 mg).
Reaction SMILES: C(C1C=CC(CC(O)=O)=CC=1)=[O:2].C(O)C1C=CC=CC=1.[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:25][CH:24]=1)=[O:22]>>[CH2:33]([O:32][C:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]([OH:2])=[O:22])=[CH:28][CH:27]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: O=Cc1ccc(CC(=O)OCc2ccccc2)cc1
Solvent: OCc1ccccc1
Product: O=C(Cc1ccc(C(=O)O)cc1)OCc1ccccc1
Yield: 80.6 %

Procedure:
Synthesized from (4-formylphenyl)acetic acid (1 g) and benzyl alcohol (730 mg) according to an analogous synthetic method to Example 806, benzyl (4-formylphenyl)acetate (1.4 g) was used according to an analogous synthetic method to Preparation Example 53 to provide the title compound (1.2 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH2:27])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1>ClCCl.CO>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=2)[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Nc2cc(C(F)(F)F)cc(C)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 2-chlor-6-methyl-4-(trifluormethyl)pyridine (59 mg, 0.3 mmol) and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol). The reaction was heated for 16 h to reflux. Obtained as a pale-yellow solid (75 mg 69%) after column chromatography of the crude reaction product on silica gel using dichloromethane/methanol (19:1 v/v) as eluent.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH:32][C:10]([C:7]1[CH:6]=[C:5]([CH2:4][C:3]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: Cc1[nH]c2ccc(Cl)cc2c1CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c2ccc(Cl)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Yield: 62.7 %

Procedure:
A solution of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.080 g, 0.334 mmol), 2-(5-chloro-2-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.090 g; 0.368 mmol), HATU (0.127 g; 0.334 mmol) and N,N-diisopropylethylamine (0.144 mL; 0.836 mmol) in DMF (5 mL), was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and a solution of sodium hydrogen sulfate. The organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) to afford 0.090 g (62%) of the title compound as a pink solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(CCc2ccco2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(CCc2ccco2)cc1

Procedure:
Acetic anhydride (0.28 ml) was added dropwise to a solution of 2-[2-(4-aminophenyl)ethyl]furan (0.50 g) in pyridine (5 ml) at ambient temperature with stirring. After being stirred for 1 hour, the mixture was poured into water (50 ml) and the resulting precipitate was collected by filtration to give 2-[2-(4-acetamidophenyl)ethyl]furan (0.58 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.I[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:40])[CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([OH:37])=[O:36])=[C:29]([O:38][CH3:39])[CH:28]=2)[CH2:19][CH2:18]1>C(Cl)Cl>[CH3:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([NH:23][C:24](=[O:40])[CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([O:37][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:36])=[C:29]([O:38][CH3:39])[CH:28]=2)[CH2:21][CH2:22]1
Reactant: CCCCCI
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCOC(=O)COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Reaction time: 16 h

Procedure:
30 ml of diisopropylethylamine and 1.3 ml of 1-iodopentane were added to a solution of 1.84 g of N-(trans-4-methylcyclohexyl)-4-(carboxymethoxy )- 3-methoxycinnamamide (Example 172) in 50 ml of methylene chloride. The solution was stirred for 16 hours, while it was refluxed. After reaction, the reaction solution was washed three times with 200 ml of an aqueous sodium thiosulfate solution and once with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Then, the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/ether, yielding 1.56 g of N-(trans-4-methylcyclohexyl)-4-(pentyloxycarbonylmethoxy) -3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties: