Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:9][CH:10]=1)C=O.[OH-].[Na+].OO.S([O-])([O-])(=O)=[O:17].[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:9][CH:10]=1)[OH:17]
Reactant: O=S(=O)([O-])[O-]
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=S([O-])S(=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: COc1ccc(O)c(O)c1

Procedure:
4-methoxycatechol was prepared by the method described in Organic Synthesis, Collective Volume 3, page 759: 60.8 g of 4-methoxysalicylaldehyde was added to a stirred solution of 16 g of sodium hydroxide in 200 ml of water. Under nitrogen gas, a solution of 60 g of 30% hydrogen peroxide in water dissolved in 200 ml of water was added drop-by-drop to the resulting solution, held at 35°-40° C. Then sodium sulfate (and a small amount of sodium hydrosulfite to decolorize the mixture) was added until the mixture was saturated. The mixture was extracted with methylene chloride. The resulting residue was extracted with ether. The ether extract was dried (Na2SO4, Na2S2O4) and the solvent was evaporated under reduced pressure, to give crude 4-methoxycatechol (10A).
Reaction SMILES: [Mg].II.[CH3:4][CH:5]([CH3:9])[CH2:6][CH2:7]Br.[CH2:10]([Si:16](Cl)([Cl:18])[Cl:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>O1CCCC1.CCCCCC>[CH2:10]([Si:16]([CH2:7][CH2:6][CH:5]([CH3:9])[CH3:4])([Cl:18])[Cl:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC[Si](Cl)(Cl)Cl
Reactant: CC(C)CCBr
Agent: II
Agent: [Mg]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC[Si](Cl)(Cl)CCC(C)C

Procedure:
Anhydrous tetrahydrofuran (125 mL) was put into a reactor with magnesium (5.0 g, 0.21 mol) which had been dehydrated and deaerated, followed by charging of argon gas. A small amount of iodine was slowly added to the mixture. 3-Methylbutylbromide (25 g, 0.17 mol) was added dropwise to the slowly stirred mixture so that the reaction mixture was gradually refluxed. After the reaction was complete, the obtained Grignard reagent was transferred to a dropping funnel. The Grignard reagent was added dropwise to a solution being stirred containing n-hexyltrichlorosilane (38 g, 0.17 mol) in anhydrous tetrahydrofuran (100 mL) in another reactor which had been dehydrated and deaerated, followed by charging of argon gas, at 60° C.-70° C. The reaction mixture was then stirred overnight at room temperature. Hexane (500 mL) was added to the reaction mixture, and the resulting mixture was filtered under pressure, followed by fractional distillation of the filtrate to provide the desired product.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:29]2[CH:28]=[CH:27][C:25]3[N:26]=[C:22]([CH3:21])[S:23][C:24]=3[CH:30]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: Cc1nc2ccc(C=O)cc2s1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2nc(C)sc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 2-methylbenzo[d]thiazole-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 397.02 g/mol.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:45])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][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][CH3:30])[CH:9]=[C:8]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:44])=[O:43])=[CH:38][CH:37]=2)[CH:7]=1>>[CH3:44][S:42]([C:39]1[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][CH2:32][O:31][C:8]2[CH:7]=[C:6]([CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][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][CH3:30])[CH:9]=2)[C:5]([OH:45])=[O:4])=[CH:41][CH:40]=1)=[O:43]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(S(C)=O)cc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(S(C)=O)cc2)cc(C(=O)O)c1
Yield: 88 %

Procedure:
Sodium hydroxide hydrolysis of 3-[3-[4-(methylsulfinyl) phenoxy]propoxy]-5-(octadecyloxy)benzoic acid methyl ester as in earlier Examples gave 3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-(octadecyloxy)benzoic acid (88% yield, mp 77°-80°).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1.C(N(C(C)C)C(C)C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:55][O:56][C:57]1[CH:75]=[CH:74][CH:73]=[CH:72][C:58]=1[CH2:59][NH:60][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[C:66]([NH2:71])[CH:67]=2)[N:62]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:55][O:56][C:57]1[CH:75]=[CH:74][CH:73]=[CH:72][C:58]=1[CH2:59][NH:60][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[C:66]([NH:71][C:9]([CH:6]3[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]3)=[O:11])[CH:67]=2)[N:62]=1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: COc1ccccc1CNc1ccc2cc(N)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1CNc1ccc2cc(NC(=O)C3CCN(C)CC3)ccc2n1
Reaction time: 1.5 h
Yield: 48.3 %

Procedure:
To a stirred solution of 1-methyl-piperidine-4-carboxylic acid hydrochloride salt (35 mg, 179 mmol) in tetrahydrofurane (3 ml) were added at room temperature N-ethyldiisopropylamine (74 mg, 0.573 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (27 mg, 0.197 mmol), N,N-diisopropyl ethyl amine (74 mg, 0.197 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.197 mmol) and the mixture was allowed to stir for 90 min. N2-(2-Methoxy-benzyl)-quinoline-2,6-diamine (example 10, step B, 50 mg, 0.179 mmol) was added and the reaction mixture was allowed to stir for 17 h, poured into sat. sodium bicarbonate solution (30 ml) and extracted with dichloromethane (2×30 ml). The combined organic layers were washed with water (30 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and crystallization (ethyl acetate/heptane) to yield the title compound as white solid (35 mg, 48%). MS: m/e=405.5 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][C@@H:21]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:2]([NH:1][C:29]([C:28]2[CH:27]=[CH:26][C:25]([C@@H:21]3[O:22][CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20]3)=[CH:33][CH:32]=2)=[O:30])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)O)cc2)C1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)N[C@@H](CO)c3ccc(F)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
A mixture of (R)-2-amino-2-(4-fluorophenyl)ethanol (68.6 mg, 0.44 mmol), (S)-4-(4-(tert-butoxycarbonyl)morpholin-2-yl)benzoic acid [CAS 1131220-40-0], (136 mg, 0.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (170 mg, 0.88 mmol), 4-dimethylaminopyridine (54.0 mg, 0.44 mmol) and triethylamine (179 mg, 0.25 ml, 1.77 mmol) in dichloromethane (9 ml) was stirred at room temperature overnight. The reaction was quenched by addition of 1M citric acid solution (5 ml). The organic layer was separated, washed with sodium bicarbonate saturated solution (5 ml), dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (silica gel, gradient heptane/ethyl acetate), to give a white foam (100 mg, 51%), MS (ISP): 445.4 (100%, [M-tBu+H]+), 389.3 (29%, [M+H]+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[O:8][C:9]([N:11]3[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[CH2:13][CH2:12]3)=[N:10][C:5]2=[CH:4][CH:3]=1.B(OC)(OC)[O:30]C.O.OO.[OH-].[Na+].Cl>C1COCC1>[OH:30][C:2]1[N:7]=[C:6]2[O:8][C:9]([N:11]3[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[CH2:13][CH2:12]3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: C[C@@H](COC1CCN(c2nc3ccc(Br)nc3o2)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](COC1CCN(c2nc3ccc(O)nc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(5-bromo[1,3]oxazolo[5,4-b]pyridin-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (484 mg) in THF (3 mL) was added 1.6M n-butyllithium-hexane solution (1.70 mL) at −78° C., and the mixture was stirred at the same temperature for 20 min. Trimethyl borate (0.355 mL) was added to the reaction mixture, and the mixture was allowed to warm to room temperature and stirred for 30 min. 30% Hydrogen peroxide water (3 mL) and 8M aqueous sodium hydroxide solution (1 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with 1M hydrochloric acid, and extracted with ethyl acetate, and the extract was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (68.1 mg).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([F:30])=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[CH:23]4)=[CH:14][N:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.C([O-])=O.[NH4+].O>[Pd].CN(C=O)C>[F:30][C:21]1[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:31][CH3:32])[CH:11]=3)[N:16]=[N:15][CH:14]=2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[C:24]([CH3:29])[NH:25]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Yield: 75.6 %

Procedure:
A solution of 7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (500 mg, 1.17 mmol), (prepared as described in Example 3), ammonium formate (740 mg, 11.7 mmol), 10% palladium on charcoal (100 mg) and water (700 μl) in DMF (10 ml) was stirred for 2 hours at ambient temperature. The mixture was filtered on diatomaceous earth and the filtrate was evaporated under vacuum. The residue was triturated with a mixture of ether and pentane (1/1). The solid was filtered, washed with pentane and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (300 mg, quant.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1F.NC1C(F)=CC([OH:21])=CC=1F>>[NH2:8][C:6]1[C:5]([F:11])=[CH:4][C:3]([OH:21])=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: Nc1c(F)cc(O)cc1F
Product: Nc1cc(F)c(O)cc1F
Yield: 72.3 %

Procedure:
This compound was prepared from 1,2,4-trifluoro-5-nitrobenzene (5.0 g, 28 mmol) in the manner described for 4-amino-3,5-difluorophenol, affording 3.0 g (72.3%) of 4-amino-2,5-difluorophenol. 1H-NMR (DMSO-d6) δ 9.04 (s, 1H), 6.67 to 6.46 (m, 2H), 4.64 (s, 2H); MS GC-MS M+=146.1, RT=1.04 min.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:36])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=4)=[O:22])=[C:17]([OH:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:37]>CO>[ClH:37].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:36])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=4)=[O:22])=[C:17]([OH:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=C(O)CS[C@H]23)cs1
Agent: Cl
Solvent: CO
Product: Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=C(O)CS[C@H]23)cs1
Yield: 84.4 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)glyoxyloylamino]-3-hydroxy-3-cephem-4-carboxylate (0.7 g) and conc.hydrochloric acid (0.23 g) in methanol (10 ml) was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo and the residue was triturated with diisopropyl ether. The precipitates were collected by filtration and washed with diisopropyl ether to give 4-nitrobenzyl 7-[2-(2-aminothiazol-4-yl)glyoxyloylamino]-3-hydroxy-3-cephem-4-carboxylate hydrochloride (0.6 g).
Reaction SMILES: O1CCN(S(F)(F)[F:8])CC1.[CH3:11][O:12][CH2:13][O:14][CH2:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>ClCCl>[F:8][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][CH2:13][O:12][CH3:11])=[N:21][CH:20]=1
Reactant: COCOCc1ccc(CO)cn1
Reactant: FS(F)(F)N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOCc1ccc(CF)cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 70% HF-pyridine complex (0.3 ml) is added to a solution of morpholinosulfur trifluoride (2 ml, 1.63×10−2 mol) in dichloromethane (32 ml) cooled to −78° C. and maintained under an inert atmosphere, followed by dropwise addition of 1 g (5.4 mmol) of compound (3) as a solution in CH2Cl2 (10 ml). The mixture is stirred for 2 hours at −78° C. and then poured into saturated NaHCO3 solution (75 ml). The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue is bulb-to-bulb distilled (P: 4.7×10−2 mb, b.p.: 110-130° C.). The title compound is isolated in the form of a colorless oil (0.3 g), which is used directly in the following step.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:9][C:10](=[O:27])[C:11]([CH3:26])=[CH:12][C:13]1[CH:18]=[C:17]2[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:16]2=[CH:15][CH:14]=1)[CH3:8].O>[Fe].C(OCC)(=O)C.CCCCCC>[CH2:7]([O:9][C:10](=[O:27])[C:11]([CH3:26])=[CH:12][C:13]1[CH:18]=[C:17]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:16]2=[CH:15][CH:14]=1)[CH3:8]
Reactant: CCOC(=O)C(C)=Cc1ccc2cc([N+](=O)[O-])ccc2c1
Agent: [Fe]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)=Cc1ccc2cc(N)ccc2c1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
Into 30 ml of benzene, 2.0 g (7 mmol) of 3-(2-nitro-benzo[d]phenyl) -2-methyl-2-propenoic acid ethyl ester were dissolved; and, with 1.73 g of iron powder (Koso Chem. Co.) and 2.5 ml of distilled water being added thereto under stirring at room temperature, temperature was raised, so that the mixture was heated to 70° C. After a reaction of 1.5 hours, insoluble matters were filtered out. The filtrate was added to 100 ml of water, and then was extracted twice with 100 ml of ethyl acetate. The resulting ethyl acetate solution was successively washed with water, an aqueous sodium hydrogencarbon ate solution, and a saturated aqueous sodium chloride solution. The washed product was dried on sodium sulfate anhydride and concentrated, whereby an oily product was obtained. This product was refined by a silica gel column chromatography (silica gel; developing solvent: ethyl acetate/hexane=1/5), whereby 1.4 g of the aimed compound were obtained as an oily product (yield: 77%).
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)O)=[O:10])[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)([Cl:29])=O.O>CCOCC>[CH3:6][O:5][C:4]1[CH:7]=[CH:8][C:1]([C:9]([CH:11]([Cl:29])[C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)=[O:10])=[CH:2][CH:3]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 35.2 %

Procedure:
One hundred grams (0.37 mole) of anisoin and 45 ml (0.55 mole) of pyridine were placed in a beaker and heated until the anisoin was completely in solution. After cooling the beaker in an ice bath, a solid was formed. This solid was broken up and then 36 ml (0.50 mole) of thionyl chloride was added with stirring, forming a liquid mixture. After 1 hr, 250 ml water was added and the organic materials extracted with ether, washed with water, dried over Na2SO4 and evaporated to afford a crude oil. Most of the oil was taken up in ether and a residual solid was filtered away. Cooling resulted in a yellow-brown solid which was filtered and collected. Recrystallization again from ether yielded 37.9 g (36%) of a solid. The product had a melting point of about 80°-81° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CS(O[CH2:21][C:22]([CH3:30])([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH3:23])(=O)=O.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:21][C:22]([CH3:30])([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH3:23])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(C)(COS(C)(=O)=O)c1ccncc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: Cc1ccc2c(c1)c1c(n2CC(C)(C)c2ccncc2)CCN(C)C1
Temperature: 100 °C
Yield: 12.4 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (145 mg, 0.727 mmol), tetra n-butyl ammonium bromide (11 mg, 0.036 mmol), and 2-methyl-2-(pyridin-4-yl)propyl methanesulfonate (200 mg, 1.20 mmol) were taken into 50% NaOH (6 mL). The reaction mixture was heated overnight at 100° C. Reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was extracted with EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography to yield 30 mg of product. 1H NMR (CDCl3, Freebase) d (ppm): 8.50 (d, 2H), 7.2-7.13 (m, 3H), 6.88 (d, 2H), 4.03 (s, 2H), 3.62 (s, 2H), 2.63 (t, 2H), 2.50 (s, 3H), 2.42 (s, 3H), 2.25 (t, 2H), 1.43 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:10]([I:11])=[C:6]2[N:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21]([OH:23])[CH3:22]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:10]([I:11])=[C:6]2[N:5]=[CH:4][CH:3]=[C:2]([O:23][CH2:21][CH3:22])[N:7]2[N:8]=1
Reactant: CCO
Reactant: Clc1ccccc1-c1nn2c(Cl)ccnc2c1I
Agent: [H-]
Agent: [Na+]
Product: CCOc1ccnc2c(I)c(-c3ccccc3Cl)nn12
Reaction time: 8 h

Procedure:
To a mixture of 7-chloro-2-(2-chlorophenyl)-3-iodopyrazolo[1,5-a]pyrimidine (I-1A-1d; 6.80 g, 17.4 mmol) in ethanol (175 ml) was added NaH (60% dispersion in oil, 439 mg, 18 mmol), portionwise. After stirring overnight, the suspended solids were isolated by vacuum filtration to afford, after drying, in vacuo, product I-11A-1a (6.87 g, 99%) as a solid: +APcI MS (M+1) 400.0; 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J=5.0 Hz, 1H), 7.58–7.40 (m, 4H), 6.67 (d, J=5.0 Hz, 1H), 4.58 (q, J=7.1 Hz, 2H), 1.58 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[C:20]([CH3:19])[CH:21]=[CH:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: Cc1cccc(B(O)O)c1
Product: CCCNC(=O)c1nnc2c(-c3cccc(C)c3)cccc2c1N

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (450 mg, 1.46 mmol) and 3-methylphenyl boronic acid (408 mg, 3.00 mmol) according to Method A to afford an off-white solid (321 mg, 69%). 1H NMR (300.132 MHz, CDCl3) δ 8.58 (t, J=5.0 Hz, 1H), 7.85 (dd, J=8.3, 1.4 Hz, 1H), 7.79 (dd, J=7.3, 1.4 Hz, 1H), 7.71 (dd, J=8.1, 7.3 Hz, 1H), 7.50 (s, 1H), 7.48 (s, 2H), 7.39 (t, J=7.9 Hz, 1H), 7.23 (s, 1H), 3.46 (q, J=6.7 Hz, 2H), 2.44 (s, 3H), 1.67 (sextet, J=7.3 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=321 (M+H). HPLC 1.90 min.
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[CH:8]=[C:9]2[C:15]([Br:16])=[CH:14][S:13][C:10]2=[CH:11][N:12]=1)(=O)=O.O.[OH-].[Li+]>CS(C)=O>[Br:16][C:15]1[C:9]2[C:10](=[CH:11][N:12]=[C:7]([OH:6])[CH:8]=2)[S:13][CH:14]=1
Reactant: O=S(=O)(Oc1cc2c(Br)csc2cn1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Oc1cc2c(Br)csc2cn1
Temperature: 75 °C
Yield: 100 %

Procedure:
A mixture of 3-bromothieno[2,3-c]pyridin-5-yl trifluoromethanesulfonate (145 mg, 0.400 mmol), lithium hydroxide monohydrate (173 mg, 4.00 mmol) and dimethyl sulfoxide (10 mL) was heated at 75° C. for 2.5 h. The solvent was removed and the residue was neutralized with aqueous 2 N HCl. The residue was then extracted with 30% n-BuOH:EtOAc (3×50 mL). The combined organic extracts were washed with water (2×10 mL) and brine (10 mL), dried over MgSO4, and concentrated in vacuo to afford 92 mg (100%) of the title compound as a yellow solid. MS (ESI): 230.01, 231.97 [M+H]+; HPLC tR=2.46 min (ZQ3: polar—5 min).
Reaction SMILES: ClC1C=CC(C2C=CN3C(=O)[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2C=CN=CC=2)=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]3[C:37](=[O:51])[N:38]([CH2:40][C:41]4[CH:46]=[CH:45][C:44](S(C)(=O)=O)=[CH:43][CH:42]=4)[N:39]=[C:33]3[C:32]=2[C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[CH:27][CH:26]=1>>[N:16]1([C:44]2[CH:45]=[CH:46][C:41]([CH2:40][N:38]3[C:37](=[O:51])[N:34]4[CH:35]=[CH:36][C:31]([C:28]5[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=5)=[C:32]([C:52]5[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=5)[C:33]4=[N:39]3)=[CH:42][CH:43]=2)[CH:10]=[CH:9][CH:18]=[N:15]1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: CS(=O)(=O)c1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)cc1
Product: O=c1n(Cc2ccc(-n3cccn3)cc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12

Procedure:
The title compound was prepared by coupling 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one with the requisite benzyl halide in a manner analogous to that in which 7-(4-chlorophenyl)-2-(4-(methylsufonyl)benzyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared. HPLC/MS: retention time=2.72 min, [M+H]+=479.
Reaction SMILES: CN(C)C=O.[CH:6]([O:9][N:10]=[C:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:13]=1)([CH3:8])[CH3:7].[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:6]([O:9][N:10]=[C:11]([N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:13]=1)([CH3:8])[CH3:7]
Reactant: c1nc[nH]n1
Reactant: CC(C)CCc1cccc(C(Cl)=NOC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCc1cccc(C(=NOC(C)C)n2cncn2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To 100 ml of N,N-dimethylformamide was added 1.5 g (5.6 mmol) of O-isopropyl-3-isopentylbenzohydroximoyl chloride, 0.8 g (11.6 mmol) of 1,2,4-triazole, and 1.6 g (11.6 mmol) of potassium carbonate. The mixture was stirred at 120° C. for 3 hours to complete the reaction. The reaction mixture was allowed to sit and cool naturally to room temperature. The cooled reaction mixture was poured into water and extracted with ethyl acetate. After being washed with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent in the organic layer was then removed under reduced pressure. The residue was purified by column chromatography, thus obtaining 1.2 g (yield: 71%) of the desired product having a refractive index of [nD20 ] 1.5317 at 20° C.