Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)([O-])=O.[N+]([C:12]1[CH:16]=[CH:15]S[CH:13]=1)([O-])=O.Cl.[Sn].C(C(C)=O)=C.N>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)(Cl)Cl.C(O)C>[CH3:15][C:16]1[CH:12]=[CH:13][N:1]=[C:4]2[S:5][CH:6]=[CH:7][C:8]=12
Reactant: O=[N+]([O-])c1ccsc1
Reactant: O=[N+]([O-])c1cccs1
Agent: C=CC(C)=O
Agent: Cl
Agent: N
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccnc2sccc12
Temperature: 30 °C
Reaction time: 1 h

Procedure:
25 g of a mixture of 85% of 2-nitrothiophene and 15% of 3-nitrothiophene and 375 ml of a 37% aqueous solution of hydrochloric acid were mixed together and then, at 30° C. over about one hour, 50 g of tin in granules were introduced in small portions. The mixture was stirred at 30° C. until the metal had disappeared (4 hours in all) and 50 ml of ethanol, 22 g of anhydrous ferric chloride and 0.5 g of anhydrous zinc chloride were added. Then at 60° C. over about one hour, 30 ml of methyl vinyl ketone and 60 ml of ethanol were introduced with stirring at 80° C. for two hours and at 20° C. for 16 hours. The reaction mixture was poured onto ice and carbon tetrachloride and concentrated ammonia were added to pH 9. After filtering on hyflosupercel and decanting, the aqueous phase was extracted with carbon tetrachloride, then dried and concentrated to dryness by distilling under reduced pressure. The 9.8 g of residue were chromatographed over silica under nitrogen pressure and eluted with a gradient of 100% of methylene chloride to 100% of ethyl acetate to obtain 7.55 g of 4-methyl thieno[2,3-b]pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C2CCCCO2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[O:23])[CH:17]=1.[BH4-].[Na+].[C:26]([OH:38])(=O)[CH2:27][C:28]([CH2:33][C:34](O)=O)(C(O)=O)O>COCCOC.O1CCCC1>[CH3:15][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][CH:26]2[CH2:27][CH2:28][CH2:33][CH2:34][O:38]2)[CH:17]=1
Reactant: Cc1cc(OC2CCCCO2)cc(C)c1-c1cccc(C=O)c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1cc(O)cc(C)c1-c1cccc(COC2CCCCO2)c1
Reaction time: 3 h
Yield: 36 %

Procedure:
2′,6′-Dimethyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-carbaldehyde (9.05 g, 29.2 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (50 mL) and tetrahydrofuran (50 mL), and sodium borohydride (0.567 g, 15.0 mmol) was added under ice-cooling. The mixture was stirred at the same temperature for 3 hrs. 10% Aqueous citric acid solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15%-50% ethyl acetate/hexane) to give the title compound (3.24 g, yield 36%) as colorless crystals.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][O:21][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
N6-benzoyl-2′-deoxyadenosine (20.95 g) was dissolved in 200 ml of DMF. Imidazole (15.7 g) was dissolved to the resultant solution by addition. Then, 20.8 g of tert-butyldimethylsilyl chloride was added. DMF (100 ml) was further added and the solution was stirred at room temperature. After 8 hours, extraction using chloroform was carried out and the organic layer was washed by a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. After concentration of the extract, the target compound was purified by column chromatography (methanol/chloroform) to obtain 16.1 g of the titled compound (yield; 61%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH2:26][CH2:25][CH2:24][CH2:23][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCCCCc1ccccc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCCCc3ccccc3)CC1)O2

Procedure:
Compound 149 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione and (4-bromobutyl)benzene and conditions outlined in procedure V. M.p.=145-147° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.93-7.88 (m, 1H), 7.84-7.73 (m, 2H), 7.62-7.52 (m, 1H), 7.35-7.1 (m, 5H), 3.06 (s, 2H), 2.76-2.64 (m, 2H), 2.62-2.54 (m, 2H), 2.4-2.2 (m, 4H), 2.04-1.9 (m, 2H), 1.87-1.7 (m, 2H), 1.68-1.4 (m, 4H); LCMS: 434 [M+H].
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:8]=[C:9]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:19][CH:18]=2)=[O:15])[N:10]([CH3:12])[N:11]=1)([CH3:6])([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.N=C=N.C1C=CC2N(O)N=NC=2C=1.[C:52](O)(=[O:59])[C:53]1[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=1.C(O)C(N)(CO)CO>C(Cl)Cl>[C:3]([C:7]1[CH:8]=[C:9]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:52]([C:53]4[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=4)=[O:59])[CH2:26][CH2:25]3)=[CH:19][CH:18]=2)=[O:15])[N:10]([CH3:12])[N:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)c1ccncc1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: N=C=N
Agent: NC(CO)(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(CN2CCN(C(=O)c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 75 mg (0.17 mmol) of 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-piperazin-1-ylmethyl-phenyl)-urea dihydrochloride in methylene chloride (5 mL) is added DIEA (0.103 mL, 0.6 mmol), PS-carbodiimide (266 mg, 0.34 mmol), HOBT (23 mg, 0.17 mmol) and then isonicotinic acid (21 mg, 0.17 mmol). The reaction mixture is shaken at room temperature overnight. Next, PS-trisamine (150 mg) is added and the reaction mixture shaken at room temperature for 2 hr. The mixture is filtered and evaporated to afford a yellow oil, that is chromatographed using methylene chloride to 92:8 methylene chloride:methanol in a gradient. The title compound is collected as a white solid weighing 12 mg (0.03 mmol, 18%). ES+(m/z)=476 [M+H]).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:8][N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH:16]=3)[NH:11][CH2:10]2)[O:6][CH:7]=1>C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:8][N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]4[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:24][CH:25]=4)[CH:16]=3)[N:11]=[CH:10]2)[O:6][CH:7]=1
Reactant: O=C1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2NCN1Cc1nc(CO)co1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2ncn1Cc1nc(CO)co1

Procedure:
3-((4-(Hydroxymethyl)oxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one Compound 177-B (120 mg) was stirred in ethyl acetate (20 mL) in the presence of palladium on carbon (10%, 120 mg) for 16 hours, then filtered through Celite® and purified by reverse-phase (ACN/H2O with 0.1% TFA) followed by neutralization on resin column to produce 44 mg of 3-((4-(hydroxymethyl)oxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one Compound IV-24 as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][N:17]([C:20]([C:22]4[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=4[C:24]([O:26]C)=[O:25])=[O:21])[CH2:16][CH2:15]3)[C:5]=2[CH:4]=[N:3]1.[OH-].[Na+]>O1CCOCC1>[CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][N:17]([C:20]([C:22]4[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=4[C:24]([OH:26])=[O:25])=[O:21])[CH2:16][CH2:15]3)[C:5]=2[CH:4]=[N:3]1
Reactant: COC(=O)c1ccccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1ncc2c1-c1ccccc1OC21CCN(C(=O)c2ccccc2C(=O)O)CC1
Temperature: 80 °C
Yield: 7 %

Procedure:
A mixture of methyl 2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzoate (500 mg, 1.17 mmol), NaOH (5.0 mL of 1.0 M, 5.0 mmol), and 1,4-dioxane (5 mL) was heated at 80° C. for 1.5 h. The mixture was cooled to rt before it was concentrated in vacuo. The solid residue was taken up in water and was washed with ethyl acetate which was discarded. The aqueous layer was acidified with 1N HCl and was extracted with ethyl acetate (2×). The combined organics were washed with brine, dried over sodium sulfate, and were concentrated in vacuo to give 2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzoic acid (33 mg, 75%) as a white solid. ESI-MS m/z calc. 403.2, found 404.2 (M+1)+; Retention time: 2.31 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 13.22 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.65 (t, J=7.4 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.36 (br s, 2H), 7.28 (t, J=7.7 Hz, 1H), 7.08 (dd, J=13.8, 6.3 Hz, 2H), 4.39 (br s, 1H), 4.10 (s, 3H), 3.30-3.12 (m, 2H), 2.05-1.86 (m, 4H), 1.85-1.74 (m, 1H).
Reaction SMILES: N(OCC(C)C)=O.N[C:9]1[CH:32]=[C:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:30]=[CH:29][C:10]=1[O:11][C:12]1[C:21]([Br:22])=[C:20]2[C:15]([CH:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:18][O:19]2)=[CH:14][C:13]=1[Cl:28]>CN(C)C=O>[Br:22][C:21]1[C:12]([O:11][C:10]2[CH:9]=[CH:32][C:31]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[CH:30][CH:29]=2)=[C:13]([Cl:28])[CH:14]=[C:15]2[C:20]=1[O:19][CH2:18][CH2:17][CH:16]2[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1N)c2Br
Agent: CC(C)CON=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1)c2Br
Temperature: 68 °C
Reaction time: 0.08 h
Yield: 8.8 %

Procedure:
N,N-dimethylformamide (20 mL) was heated in an oil bath set to 70° C. Isobutyl nitrite (0.90 mL, 7.6 mmol) was added, and to the resulting stirred solution at 68° C. was added a solution of ethyl 7-(2-amino-4-(tert-butoxycarbonyl)phenoxy)-8-bromo-6-chlorochroman-4-carboxylate (1.6 g, 6.0 mmol) in N,N-dimethylformamide (6 mL), dropwise over 5 minutes. The resulting solution was stirred at 70° C. for 30 minutes. The resulting red solution was cooled to ambient temperature and partitioned between water (600 mL) and ethyl acetate (50 mL). The organic layer was washed with 1M hydrochloric acid (10 mL) and brine (10 mL), then dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 95/5 to 85/15 hexanes/ethyl acetate, to afford ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate as an orange oil (0.27 g, 17% yield).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:39][O:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c(OC)c1
Yield: 85.7 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with (2,4-dimethoxyphenyl)boronic acid (147 mg, 0.81 mmol), sodium carbonate (86 mg, 0.81 mmol) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 20%, dichloromethane-ethyl acetate) to give 95 mg (87% yield) of the title compound. Purity 87%.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH3:13])[C:7]=1[C:14]#[N:15])=[O:4].S(=O)(=O)(O)[OH:17]>>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH3:13])[C:7]=1[C:14](=[O:17])[NH2:15])=[O:4]
Reactant: CCSc1nsc(NC(=O)NC)c1C#N
Reactant: O=S(=O)(O)O
Product: CCSc1nsc(NC(=O)NC)c1C(N)=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 4.0 g of 1-methyl-3-(4-cyano-3-(ethylthio)-5-isothiazolyl)urea in 6 ml of concentrated sulfuric acid was heated at 160° for 1.5 hours. After this time the reaction mixture was poured into 120 ml of ice-water, and this mixture was stirred for 45 minutes. The white precipitate was collected by filtration. The solid was recrystallized from ethanol to give 4.0 grams of 1-methyl-3-(4-carbamoyl-3-(ethylthio)-5-isothiazolyl)urea, m.p. 205°. The nmr spectra was consistent with the assigned structure.
Reaction SMILES: [CH3:1][CH2:2]/[C:3](/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=1)\[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:30][C:31]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:32]=1[C:33](O)=[O:34]>>[CH3:30][C:31]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:32]=1[C:33]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:2][CH3:1])=[CH:10][CH:9]=1)=[O:34]
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCN(C)C)cc1)c1ccccc1
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Product: CCC(=C(c1ccc(OCCN(C)C)cc1)c1ccc(OC(=O)c2c(C)cc(C)cc2C)cc1)c1ccccc1

Procedure:
This was prepared using 4-OH tamoxifen (Example 19) and 2,4,6-trimethylbenzoic acid following the procedure described in Example 30.
Reaction SMILES: [S:1]=[C:2]1[NH:6][N:5]=[C:4]([S:7][CH2:8][C:9]([O:11]CC)=[O:10])[NH:3]1.[OH-].[Na+]>>[S:1]=[C:2]1[NH:6][N:5]=[C:4]([S:7][CH2:8][C:9]([OH:11])=[O:10])[NH:3]1
Reactant: CCOC(=O)CSc1n[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CSc1n[nH]c(=S)[nH]1
Yield: 75 %

Procedure:
A solution of 2.19 g. (10 mmol) of ethyl [(4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)thio]acetate in 50 ml. of 5% sodium hydroxide was heated at reflux for 1 hour. After thorough cooling, the mixture was filtered, and the filtrate was washed with ethyl acetate. The aqueous layer was separated, acidified to pH 1 and extracted with ethyl acetate. The extract was evaporated in vacuo to dryness. The residue was crystallized from chloroform to give 1.43 g. (75% yield) of [(4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)thio]acetic acid.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1.I[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]3[S:40][C:39]([NH:41][CH3:42])=[N:38][N:37]=3)[CH:34]=2)[NH:29][CH:28]=1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.CC(O)C.O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]3[S:40][C:39]([NH:41][CH3:42])=[N:38][N:37]=3)[CH:34]=2)[NH:29][CH:28]=1
Reactant: CNc1nnc(-c2ccc3[nH]cc(I)c3c2)s1
Reactant: CC1(C)OB(c2ccc(F)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: CNc1nnc(-c2ccc3[nH]cc(-c4ccc(F)cc4F)c3c2)s1
Temperature: 120 °C

Procedure:
A mixture of potassium phosphate (0.089 g, 0.42 mmol), 2,4-difluorophenylboronic acid pinacol ester (0.040 g, 0.17 mmol, Aldrich), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5 mg, 7 μmol), 5-(3-iodo-1H-indol-5-yl)-N-methyl-1,3,4-thiadiazol-2-amine (0.05 g, 0.14 mmol), and IPA/H2O (70%, 0.5 mL) was heated in a microwave at 120° C. for 10 min. The aqueous layer was removed and the organic layer was purified by preparative HPLC (10-90% MeCN/water/0.1% NH4OH) to give 5-(3-(2,4-difluorophenyl)-1H-indol-5-yl)-N-methyl-1,3,4-thiadiazol-2-amine as a tan solid. MS (ESI, pos. ion) m/z: 343 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (1H, s), 7.64-7.73 (2H, m), 7.56-7.61 (2H, m), 7.06-7.14 (2H, m), 3.14 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[F:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30](=O)[CH2:31]Br>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:31]=[C:30]([C:29]3[CH:34]=[CH:35][CH:36]=[C:27]([F:26])[CH:28]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3cccc(F)c3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 77.5 °C
Yield: 50.3 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (30 mL), 3-fluorophenacyl bromide (0.97 g, 4.48 mmol) was added. After heating the reaction mixture at 75-80° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (481 mg, 50%) as a white solid: mp 194-196° C. Anal. Calc'd. for C22H16N2SO2FCl: C, 61.90, H, 3.78, N, 6.56, S, 7.51. Found: C, 61.71, H, 3.59, N, 6.42, S, 7.69.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+]([O-])=O.CC(C)([O-])C.[K+].C(Cl)(Cl)Cl.[F:23][C:24]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][OH:26]>>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[O:26][CH2:25][C:24]([F:31])([F:23])[C:27]([F:30])([F:29])[F:28]
Reactant: Cc1c[n+]([O-])cc(C)c1[N+](=O)[O-]
Reactant: OCC(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1c[n+]([O-])cc(C)c1OCC(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 18 h
Yield: 80.6 %

Procedure:
To a solution of 3,5-dimethyl-4-nitropyridine-1-oxide (2.0 g) in 2,2,3,3,3-pentafluoropropanol (10 g) was added at 0° C. little by little potassium t-butoxide (2 g) over 15 minutes. The mixture was stirred at 60° C. for 18 hours. To the reaction mixture was added chloroform, which was subjected to filtration with celite. The filtrate was chromatographed on a column of silica gel (80 g), eluted with ethyl acetate-hexane (1:1), then with 20% methanol-ethyl acetate, and recrystallized from ether-hexane to yield 2.6 g of 3,5-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as crystals, m.p. 89°-91° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][CH3:36])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:21]3[C:22](=[O:24])[O:23][C:18]([CH:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][CH3:36])[CH:29]=4)[CH2:19][C:20]=3[OH:25])[N:10]=2)[CH:7]=1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Reactant: O=Cc1nc2ncc(Br)cn2n1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Br)cn4n3)C(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to Example A(224) where 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.15 (t, J=7.54 Hz, 3H), 1.30-1.90 (brm, 8H), 2.00-2.40 (brm, 3H), 2.50 (q, J=10.74 Hz 2H), 2.75 (m, 2H); 2.90 (m, 2H), 3.50 (m, 3H), 6.64 (d, J=5.26 Hz, 1H), 6.70 (d, J=5.26 Hz, 1H), 7.00 (s, 1H), 8.75 (s, 1H), 9.19 (s, 1H). Anal. Calcd. For C26H29O4N4Br C, 57.68; H, 5.40; N, 10.35. Found: C, 57.50; H, 5.50; N, 10.30.
Reaction SMILES: [NH2:1][C:2](=[S:13])[CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>CCO.CCOC(C)=O>[C:18]1([C:16]2[N:1]=[C:2]([CH2:3][NH:4][C:5](=[O:12])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:13][CH:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=S)CNC(=O)c1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NCc1nc(-c2ccccc2)cs1)c1ccccc1
Temperature: 80 °C
Yield: 88.2 %

Procedure:
A mixture of N-(2-amino-2-thioxoethyl)benzamide (300 mg, 1.54 mmol) and 2-bromoacetophenone (305 mg, 1.54 mmol) in EtOH (10 mL) was heated to 80° C. for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The concentrated reaction mixture was diluted with EtOAc and the organic layer was washed with H2O and brine, and concentrated under reduced pressure to yield N-((4-phenylthiazol-2-yl)methyl)benzamide (0.4 g, yield 88%) as a white solid, which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 8.69 (br s, 1H), 8.04-8.01 (dd, J=7.8 Hz, 1.5 Hz, 2H), 7.99-7.97 (m, 2H), 7.64 (s, 1H), 7.56-7.52 (m, 4H), 7.48-7.44 (m, 2H), 5.34 (d, J=6 Hz, 2H). MS (ESI) m/z: Calculated for C17H14N2OS: 294.08. found: 295.0 (M+H)+.