Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:13])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:14]1([CH2:20][C:21]([NH:23][C@@H:24]2[C:52](=[O:53])[N:26]3[C:27]([C:36]([O:38][CH:39]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])=[C:28](OS(C)(=O)=O)[CH2:29][S:30][C@H:25]23)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.[Cl-].[Na+].O>[C:14]1([CH2:20][C:21]([NH:23][C@@H:24]2[C:52](=[O:53])[N:26]3[C:27]([C:36]([O:38][CH:39]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)=[O:37])=[C:28]([S:13][C:10]4[S:11][CH:12]=[C:8]([C:5]5[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=5)[N:9]=4)[CH2:29][S:30][C@H:25]23)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: Sc1nc(-c2ccncc2)cs1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3nc(-c4ccncc4)cs3)CS[C@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-(4-Pyridyl)-1,3-thiazole-2-thiol sodium salt (194 g, 1 mol) prepared according to the method of Reference Example 5 was suspended in tetrahydrofuran (1.5 L) and benzhydryl 7β-[(phenylacetyl)amino]-3-[(methylsulfonyl)oxy]-3-cephem-4-carboxylate (196 g, 0.91 mol) dissolved in tetrahydrofuran (3.0 L) was added dropwise under ice-cooling over 30 min. The mixture was stirred at 0° C. for 2 hr and saturated brine (7 L) was added. The mixture was extracted with ethyl acetate (5 L). The organic layer was washed with saturated brine (5 L) and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give the title compound as crystals. The crystals were suspended in ethyl acetate (0.5 L), collected by filtration on a glass filter and washed with methanol (1 L×2). The crystals were dried in vacuo to give the title compound (412 g, 0.71 mol). yield: 78%.
Reaction SMILES: I[C:2]1([C:7]2[S:8][CH:9]=[CH:10][C:11]=2C2SC=CC=2)[CH2:6][CH:5]=[CH:4][S:3]1.[CH2:17]([O:21][P:22]([C:29]1[CH:30]=[C:31]([C:47]2[S:48][C:49]([Sn](CCCC)(CCCC)CCCC)=[C:50]([P:52]([O:59][CH2:60][CH2:61][CH2:62][CH3:63])([O:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:53])[CH:51]=2)[S:32][C:33]=1[Sn](CCCC)(CCCC)CCCC)([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH2:18][CH2:19][CH3:20].[F-].[K+]>C1(C)C=CC=CC=1>[CH2:55]([O:54][P:52]([C:50]1[CH:51]=[C:47]([C:31]2[S:32][C:33]([C:9]3[S:8][C:7]([C:2]4[S:3][C:4]([C:2]5[S:3][CH:4]=[CH:5][CH:6]=5)=[CH:5][CH:6]=4)=[CH:11][CH:10]=3)=[C:29]([P:22]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH:30]=2)[S:48][C:49]=1[C:7]1[S:8][C:9]([C:9]2[S:8][C:7]([C:2]3[S:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)=[CH:10][CH:11]=1)([O:59][CH2:60][CH2:61][CH2:62][CH3:63])=[O:53])[CH2:56][CH2:57][CH3:58]
Reactant: CCCCOP(=O)(OCCCC)c1cc(-c2cc(P(=O)(OCCCC)OCCCC)c([Sn](CCCC)(CCCC)CCCC)s2)sc1[Sn](CCCC)(CCCC)CCCC
Reactant: IC1(c2sccc2-c2cccs2)CC=CS1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(OCCCC)c1cc(-c2cc(P(=O)(OCCCC)OCCCC)c(-c3ccc(-c4ccc(-c5cccs5)s4)s3)s2)sc1-c1ccc(-c2ccc(-c3cccs3)s2)s1
Yield: 73 %

Procedure:
At room temperature, 0.1235 g (0.33 mmols) of 2-iodoterthiophene and 0.0069 g (0.006 mmols) of commercially available tetrakistriphenylphosphine palladium were dissolved in 2 ml of toluene, to which 0.1693 g (0.15 mmols) of 4,4′-bis(dibutoxyphosphoryl)-5,5′-bis(tributylstannyl)-[2,2′]-bithiophene was added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 2 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 1 hour. Subsequently, the solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturate saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate:hexane=1:10) to obtain the specified substance in the form of a red solid at a yield of 0.1143 g (yield: 73%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][CH3:36].O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: COc1cc(B(O)O)ccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)ccc1Cl
Temperature: 110 °C
Yield: 40.4 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 80 mg, 0.232 mmol), 4-chloro-3-methoxyphenylboronic acid (56.2 mg, 0.302 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16 mg, 22 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.774 mL of 1,4-dioxane and 0.387 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (65-70% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (42.3 mg, 40%). 1H NMR (DMSO-d6) δ: 11.15 (s, 1H), 7.95 (d, J=8.6 Hz, 2H), 7.91 (s, 1H), 7.78 (d, J=1.8 Hz, 1H), 7.59-7.65 (m, 1H), 7.50-7.59 (m, 3H), 6.34 (s, 1H), 3.88 (s, 3H), 2.34 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 451.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][S:13][C:12]=2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:10])=O.[C:26]([O-:29])(=[O:28])[CH3:27].[Na+].C(OCC)C>C(OC(=O)C)(=O)C>[C:26]([O:29][CH2:10][S:8][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][S:13][C:12]=2[C:22]([O:24][CH3:25])=[O:23])=[CH:3][C:2]=1[F:1])(=[O:28])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1scc(-c2ccccc2)c1-c1ccc(S(C)=O)c(F)c1
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1scc(-c2ccccc2)c1-c1ccc(SCOC(C)=O)c(F)c1
Yield: 62.5 %

Procedure:
The methyl 3-[3-fluoro-4-(methylsulfinyl)phenyl]-4-phenyl-2-thiophenecarboxylate (4.13 g, 11.04 mmol) was dissolved in acetic anhydride (45.0 mL). Powdered sodium acetate (4.0 g, 48.7 mmol) was added and the solution was refluxed for 8 hours. The solution was poured into a 500 mL round bottom flask and solvent removed at reduced pressure. The residue was taken up in ethyl acetate (200 ml) and dichloromethane (20 mL). The solution was extracted with saturated sodium bicarbonate (3×100 mL) followed by saturated ammonium chloride (2×100 mL). The solvent was removed at reduce pressure and residue taken up in ether, dried over sodium sulfate and solvent removed at reduced pressure. Methyl 3-[4-[[(acetyloxy)methyl]thio]-3-fluorophenyl]-4-phenyl-2-thiophenecarboxylate (2.9 g, 6.90 mmol) was isolated by crystallization from diethyl ether and hexanes as white crystals. (62% yield). Mp 102.9-103.7° C. 1H NMR (CDCl3/300 MHz) 7.53 (s, 1H), 7.43 (t, 1H, J=7.8 Hz), 7.22-7.28 (m, 3H), 7.04-7.08 (m, 2H), 6.92-6.98 (m, 2H), 5.42 (s, 2H), 3.81 (s, 3H), 2.11 (s, 3H). ESHRMS m/z 434.0898 (calcd for M+NH4+, 434.0896)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[OH:11].C1(C)C(C)=CC=CC=1.[Cl:20][CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[O:11][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([CH2:21][Cl:20])=[CH:23][CH:24]=1
Reactant: Oc1c(Cl)cc(Cl)c(Cl)c1Cl
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: O=C(Oc1c(Cl)cc(Cl)c(Cl)c1Cl)c1ccc(CCl)cc1

Procedure:
58 g (0.25 mole) of 2,3,4,6-tetrachlorophenol, 100 ml of absolute xylene, 47.5 g (0.25 mole) of p-chloromethylbenzoyl chloride and 0.25 ml of absolute pyridine were refluxed as described above for 4 hours. A part of the ester that formed crystallized upon the cooling of the reaction solution. The concentrated mother liquor yielded much additional crystallizate. In all, 93.15 g (97%) was isolated, with a melting point of 110° to 114° C. The raw ester was recrystallized from cyclohexane (1:15) and then melted at 143°-149° C. Another recrystallization raised the melting point to 150°-152° C.
Reaction SMILES: [CH3:1][C:2]([CH2:104][CH2:105][CH2:106][NH:107][C:108]([O:110][C:111]([CH3:114])([CH3:113])[CH3:112])=[O:109])([NH:96][C:97]([O:99][C:100]([CH3:103])([CH3:102])[CH3:101])=[O:98])[CH2:3][CH2:4][CH2:5][N:6]([C:89]([O:91][C:92]([CH3:95])([CH3:94])[CH3:93])=[O:90])[CH2:7][CH:8]([C:56]([CH2:78][CH2:79][CH2:80][NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])([CH2:66][CH2:67][CH2:68][CH2:69][NH:70][C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[N:57]([CH3:65])[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:55])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]=[N+]=[N-].[H][H]>C(O)(C)(C)C.[Pd]>[CH3:1][C:2]([CH2:104][CH2:105][CH2:106][NH:107][C:108]([O:110][C:111]([CH3:114])([CH3:113])[CH3:112])=[O:109])([NH:96][C:97]([O:99][C:100]([CH3:103])([CH3:102])[CH3:101])=[O:98])[CH2:3][CH2:4][CH2:5][N:6]([C:89]([O:91][C:92]([CH3:93])([CH3:94])[CH3:95])=[O:90])[CH2:7][CH:8]([C:56]([CH2:78][CH2:79][CH2:80][NH:81][C:82]([O:84][C:85]([CH3:86])([CH3:87])[CH3:88])=[O:83])([CH2:66][CH2:67][CH2:68][CH2:69][NH:70][C:71]([O:73][C:74]([CH3:75])([CH3:76])[CH3:77])=[O:72])[N:57]([CH3:65])[C:58]([O:60][C:61]([CH3:62])([CH3:63])[CH3:64])=[O:59])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:55])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52]
Reactant: [H][H]
Reactant: CN(C(=O)OC(C)(C)C)C(CCCCNC(=O)OC(C)(C)C)(CCCNC(=O)OC(C)(C)C)C(CCCCCCNC(=O)CCCCCCCCCCC=CCCCCCCCCCCC=CCCCCCCCCCCCN=[N+]=[N-])CN(CCCC(C)(CCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(C)(C)O
Product: CN(C(=O)OC(C)(C)C)C(CCCCNC(=O)OC(C)(C)C)(CCCNC(=O)OC(C)(C)C)C(CCCCCCNC(=O)CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCN)CN(CCCC(C)(CCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 40 °C

Procedure:
To E7 (184 mg) dissolved in tert-butanol at 40° C. was added Pd/C (50 mg) and the atmosphere changed to hydrogen. The hydrogenation was heated at 40° C. for 3 days, the catalyst filtered off and the solvent removed. The residues were purified by silica chromatography eluting initially with 100:10:0 CH2Cl2:MeOH:NH4OH to remove faster running impurities then with 100:10:1 to remove the title compound as a colourless gum, 61 mg, 34%. C91H178N813 requires 1591.3. Found ES+: MH+, 1592.3. δH (CDCl3) 1.24 (72H, br, H2N(CH2)2(CH2)32, CONH(CH2)2(CH2)4), 1.44 (66H, br, (Me)3C, CH2CH2N), 1.72 (4H, p, NCH2CH2CH2N), 1.98 (1H, br, CH), 2.14 (2H, t, CH2CO), 2.67 (2H, t, CH2NH2), 2.83 (6H, s, NMe), 2.95-3.30 (22H, m, NCH2), 5.62 (1H, br, CONH(CH2)6CH).
Reaction SMILES: [C:1]1(P)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:8]([Cl:13])(Cl)(Cl)(Cl)[Cl:9]>C1(C)C=CC=CC=1>[C:1]1([P:8]([Cl:13])[Cl:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Pc1ccccc1
Solvent: Cc1ccccc1
Product: ClP(Cl)c1ccccc1
Temperature: 70 °C

Procedure:
38.5 g (0.34 mol) phenylphosphine dissolved in 40 ml toluene was added at 25° C. to a suspension of 160 g PCl5 (0.77 mol) in 500 ml toluene. After the exothermal reaction had subsided, the whole was heated to 70° C. until gas ceased to be evolved. The low boilers were removed under vacuum. The crude product yield was 67 g; 31P-NMR: δ P=161 ppm, C6H5PCl2, 94.4 mol%. The residue was distilled under vacuum. bp 98° C./17 mbar; yield: 50.6 g (81% of the theoretical).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.[C:10]1([O:18][CH3:19])[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=1)[O:12][CH3:13]>>[CH3:13][O:12][C:11]1[C:10]([O:18][CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:9]
Reactant: O=C(O)c1ccncc1
Reactant: COc1ccccc1OC
Product: COc1cccc(C(=O)c2ccncc2)c1OC

Procedure:
In Scheme H, step d, 4-pyridinecarboxylic acid (18) is reacted with lithiated veratrole to give 4-(2,3-dimethoxybenzoyl)pyridine (12).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[C:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1>CO.C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: COC(=O)c1ccccc1C=C1CCN(C)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccccc1CC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of 2-(1-methyl-piperidin-4-ylidenemethyl)-benzoic acid methyl ester (from Intermediate B12 step 1) (130 mg; 0.53 mmol; 1 eq.) and 10% Pd/C (˜50% H2O) (34 mg) in MeOH (1 mL) and THF (1 mL) was stirred at room temperature for 3 hours under a H2 atmosphere (10 bars). The catalyst was filtered off and the solution concentrated in vacuo. Purification by column chromatography (heptane/EA) afforded the title compound (97 mg, 74%) as a white solid. UPLC/MS: (MS+) 248.2 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O)[C:4]([O:6][CH3:7])=[O:5].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CCOC(C)=O>[CH3:7][O:6][C:4]([C@@H:3]1[CH2:2][O:1][C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][N:15]3[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])=[N:8]1)=[O:5]
Reactant: COC(=O)[C@H](CO)NC(=O)c1cccc2c1ccn2C(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1COC(c2cccc3c2ccn3C(=O)OC(C)(C)C)=N1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
To a solution of tert-butyl 4-({[(1S)-1-(hydroxymethyl)-2-methoxy-2-oxoethyl]amino}carbonyl)-1H-indole-1-carboxylate (2.09 g) in THF (21.0 mL) was added Burgess Reagent (1.44 g) at ambient temperature and the mixture was stirred at 70° C. for 45 minutes. The resulting mixture was diluted with EtOAc (60 mL) and washed successively with saturated NaHCO3 aqueous solution and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=2:1) to afford tert-butyl 4-[(4S)-4-(methoxycarbonyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-indole-1-carboxylate (1.35 g) as a colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[C:4](Cl)[N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1>CC(O)C>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][CH2:19][NH:18][C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:22]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COC(=O)C(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CC(C)O
Product: COC(=O)C(C)n1cnc2c(NCCc3c[nH]c4ccccc34)nc(Cl)nc21
Temperature: 85 °C

Procedure:
A mixture of methyl 2-(2,6-dichloro-9H-purin-9-yl)propanoate (b) (600 mg, 2.2 mmol), tryptamine (420 mg, 2.6 mmol) and 2-propanol (30 mL) was heated at 85° C. in a sealed tube for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (10 to 80% ethyl acetate in hexane eluant) to afford the title compound as a white solid. MS m/z 360.1 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=3[NH:10][C:9]2=[O:21])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29]Br>CN(C)C=O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][N:10]1[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:12]=2[N:8]([C@H:5]2[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]2)[C:9]1=[O:21]
Reactant: COc1ccc(CBr)cc1OC
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ccc(C(F)(F)F)cc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-2,3-dihydro-1H-benzimidazol-2-one (200 mg) in anhydrous N,N-dimethylformamide (2 mL) was added portionwise sodium hydride (29.3 mg, 60% dispersion in mineral oil) at 5° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. After adding 3,4-dimethoxybenzylbromide (154 mg), the mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed successively with 1 N-hydrochloric acid, water, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a preparative silica gel column chromatography eluting with 5% methanol in chloroform. The obtained amorphous was recrystallized from diethyl ether to give 3-(3,4-dimethoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-2,3-dihydro-1H-benzimidazol-2-one (217.9 mg) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[CH:11].I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:11]=1)=[O:12]
Reactant: Oc1ccccc1I
Reactant: C#Cc1ccccc1C(=O)OC
Product: COC(=O)c1ccccc1-c1cc2ccccc2o1

Procedure:
The general procedure was used to convert 2-Ethynyl-benzoic acid methyl ester and 2-iodophenol to the title product. Purification by flash chromatography (10% ethyl acetate in hexanes) gave the analytically pure product as an oil (458 mg, 67% yield). 1H NMR δ 7.75-7.70 (m, 2H), 7.61-7.40 (m, 4H), 7.31-7.22 (m, 2H), 6.92 (s, 1H), 3.81 (s, 3H). 3C NMR δ 169.35, 155.10, 154.67, 131.09, 130.94, 129.61, 129.36, 128.99, 128.88, 128.64, 124.54, 122.94, 121.21, 111.09, 104.38, 52.48. Anal. Calcd. for C16H12O3: C, 76.18; H, 4.79. Found C, 75.95; H, 4.75.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:14]=[C:13]([O:12][CH3:11])[C:18]=1[O:19][CH3:20]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]ccc3c2)cc(OC)c1OC
Yield: 83.6 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (1.54 g, 7.83 mmol), 3,4,5-trimethoxyphenylboronic acid (1.83 g, 8.61 mmol) and dichlorobis(triphenylphosphine)palladium (II) (275 mg, 0.39 mmol) were combined in CH3CN (10 ml) and 1 M Na2CO3 (10 ml) and reacted in a microwave reactor for 5 min at 150° C. EtOAc was added and the mixture was washed with water, brine, dried, evaporated and purified by silica gel chromatography using 0-2% MeOH:DCM to yield 1.86 g (84%) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 9.9 (bs, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.11 (d. J=2.1 Hz, 1H), 7.41 (t, J=2.1 Hz, 1H), 6.82 (s, 2H), 6.58 (t, J=1.5 Hz, 1H), 3.96 (s, 6H), 3.92 (s, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[CH3:7][C:5]1[N:6]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[N:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=[N:17]2)[S:3][C:4]=1[CH3:8]
Reactant: Cc1nc(Br)sc1C
Reactant: C#CCCn1nc2ccccc2n1
Product: Cc1nc(C#CCCn2nc3ccccc3n2)sc1C
Yield: 17115.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-4,5-dimethylthiazole (100 mg, 0.52 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (89 mg, 0.52 mmol, Example 109(D)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 25 mg (89 mmol, 17%) of 2-(4-(4,5-dimethylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid (M.P.=96-98° C.).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:15]1([O:21][CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[CH3:22][O:21][C:15]1[CH:20]=[CH:19][C:18]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:16]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 0 °C
Yield: 44.6 %

Procedure:
Phenylacetyl chloride (30.9 g, 0.2 mol) in CH2Cl2 (100 ml) was added dropwise to a solution of AlCl3 (32 g, 0.24 mol) and anisole (21.6 g, 0.2 mol) in CH2Cl2 (400 ml) at room temperature. The reaction was complete (by TLC) after 4 hours and was poured over an ice; 10% HCl slurry. The organic layer was washed with H2O and brine, dried over MgSO4, and the solvent was removed under reduced pressure. The crude solid was chromatographed SiO2 (1500 g), eluting with toluene to afford 11 (20.2 g, 63.7%, para isomer), m.p. 74°-75.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[C:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23].C(=O)(O)[O-].[Na+].[Cl-]>C(O)(C)C.CCOCC>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:11][N:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:21]=1[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23]
Reactant: O=C(C#Cc1ccccc1Cl)c1cccnc1
Reactant: ON=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Temperature: 55 °C
Yield: 84 %

Procedure:
A mixture of 56 mg (0.25 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 60 mg (0.25 mmol) of 3-(2-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-one, and 30 mg (0.36 mmol) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. overnight with shaking. An additional 30 mg of carboximidoyl chloride and 15 mg of sodium bicarbonate was then added, and the mixture was heated for another 20 hrs. The reaction mixture was cooled, diluted with ether, and then washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 90 mg (0.21 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)carbonyl]isoxazole. 1H NMR (CDCl3): δ 7.16 (m, 1), 7.60 (m, 2), 7.92 (m, 1), 8.53 (br d, 1), and 8.74 ppm (br s, 1). MS m/z: 428.9 (M+H).