Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27]([O:29]C)=[O:28])[CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:14]([CH3:15])([CH3:16])[CH3:17])[C@H:9]([C:27]([OH:29])=[O:28])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(butylthio)pyrrolidine-2-carboxylate (430 mg, 0.738 mmol) in THF (4 mL) and MeOH (4.00 mL) was added pre-made solution of lithium hydroxide monohydrate (61.9 mg, 1.476 mmol) in water (4 mL). The formed cloudy solution was stirred at room temperature for 5 h. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated, to afford the desired product (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (409 mg, 0.611 mmol, 83% yield) as a white foam. LC-MS (retention time: 3.49 min, method B), MS m/z 569 (M+H).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CCO>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[S:8][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=2)[CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1cccnc1
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 47.4 %

Procedure:
To a suspension of thionicotinamide (30.0 g, 217.1 mmol) in EtOH (400 mL) at room temperature was added ethyl bromopyruvate (90% technical, 30.6 mL, 219 mmol). The reaction mixture was heated to reflux and stirred for 2.5 days. The reaction mixture was cooled to room temperature and the precipitate that formed upon cooling was collected via vacuum filtration. The cake was rinsed twice with hexanes. This solid was added to a separatory funnel containing ethyl acetate and saturated aqueous NaHCO3. The biphasic mixture was separated and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified using silica gel chromatography, (0 to 100% ethyl acetate/hexanes) to afford the desired product as a tan solid (24.1 g, 47%): mp 73-75° C.; 1H NMR (300 MHz, CDCl3) δ 9.19 (dd, J=2.6, 1.0 Hz, 1H), 8.69 (dd, J=4.6, 1.6 Hz, 1H), 8.34 (dt, J=7.9, 1.6 Hz, 1H), 8.22 (s, 1H), 7.41 (ddd, J=7.9, 4.6, 1.0 Hz, 1H), 4.47 (q, J=6.9 Hz, 2H), 1.43 (t, J=6.9 Hz, 3H); ESIMS m/z 236.1 (M+2).
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:32][N:33]1[CH2:46][CH2:45][C:36]2[NH:37][C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][C:43]=3[C:35]=2[CH2:34]1>CN(C=O)C.[Cu]I>[CH3:32][N:33]1[CH2:46][CH2:45][C:36]2[N:37](/[CH:2]=[C:3](/[C:5]3[CH:15]=[CH:14][C:8]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:7][CH:6]=3)\[CH3:4])[C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][C:43]=3[C:35]=2[CH2:34]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1ccc(C(=O)N(C)C)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(C(=O)N(C)C)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
4-(1-Bromoprop-1-en-2-yl)-N,N-dimethylbenzamide (264 mg, 1 mmol) was dissolved in DMF (2 mL). Potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added under nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Ice water (5 mL) was added and the resulting solid mass was filtered to obtain the crude compound which was purified on silica gel chromatography (100-200 mesh) using 0-7% MeOH: DCM as eluent. Yield: 60 mg. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.76 (d, 2H), 7.50 (d, 2H), 7.30 (s, 1H), 7.10 (m, 3H), 4.75 (d, 1H), 4.40 (d, 1H), 3.84 (m, 1H), 3.60 (m, 1H), 3.18 (m, 2H), 3.10 (d, 6H), 3.05 (s, 3H), 2.42 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=[O:27]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][N:28]([C:26]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])=[O:27])[CH2:33][CH2:32]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 68.5 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (4.43 g, 18.79 mmol), N,N-diisopropylethylamine (4.68 ml, 26.84 mmol) and 4-dimethylaminopyridine (0.33 g, 2.68 mmol) were added to a suspension of tert-butyl 4-chlorocarbonylpiperazine-1-carboxylate (3.34 g, 13.42 mmol) in toluene (70 ml), and the resulting mixture was stirred at 100° C. for 4.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/methylene chloride/ethyl acetate=45/45/10) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-tert-butoxycarbonylpiperazine-1-carboxylate (4.12 g, yield 69%) as a colorless oil.
Reaction SMILES: O.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:15]2[CH:16]=[C:17]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36](/[CH:40]=[CH:41]/[C:42]5[S:43][CH:44]=[C:45]([CH:47]6[CH2:50][CH2:49][CH2:48]6)[N:46]=5)[CH:35]=4)=[O:32])=[C:25]([CH:29]=3)[C:26](O)=[O:27])[S:18][C:14]=2[N:13]2[C:51]([CH3:54])=[N:52][N:53]=[C:12]2[CH2:11][N:10]=1.Cl.C(N=C=[N:60][CH2:61][CH2:62][CH2:63]N(C)C)C.C(N)C=C>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:15]2[CH:16]=[C:17]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36](/[CH:40]=[CH:41]/[C:42]5[S:43][CH:44]=[C:45]([CH:47]6[CH2:48][CH2:49][CH2:50]6)[N:46]=5)[CH:35]=4)=[O:32])=[C:25]([C:26]([NH:60][CH2:61][CH:62]=[CH2:63])=[O:27])[CH:29]=3)[S:18][C:14]=2[N:13]2[C:51]([CH3:54])=[N:52][N:53]=[C:12]2[CH2:11][N:10]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1nnc2n1-c1sc(CCc3ccc(CC(=O)Nc4cccc(/C=C/c5nc(C6CCC6)cs5)c4)c(C(=O)O)c3)cc1C(c1ccccc1Cl)=NC2
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C=CCN
Product: C=CCNC(=O)c1cc(CCc2cc3c(s2)-n2c(C)nnc2CN=C3c2ccccc2Cl)ccc1CC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
A mixture of 0.1 g (0.13 mmol) of (E)-5-[2-[4-(2-chlorophenyl)-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]ethyl]-2-[2-[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenylamino]-2-oxoethyl]-benzoic acid monohydrate, 0.03 g (0.16 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 0.02 mL (4 mmol) of allylamine and 15 mL of dry CH2Cl2 was stirred at room temperature under nitrogen for 18 hours and concentrated to dryness. The residue was purified by thick layer chromatography using ethyl acetate/CH3OH (5:1) as the eluent. The product was isolated and partitioned between CH2Cl2 and dilute NH4OH. The organic phases were concentrated and the residue triturated with hot ethyl acetate and filtered. The filtrates were concentrated and the solid triturated with diethyl ether and filtered to give 60 mg (57%) of (E)-4-[ 2-[4-(2-Chlorophenyl)-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepin-2-yl]ethyl]-N-[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]-phenyl]-2-[(2-propenylamino)carbonyl]benzeneacetamide as a tan powder: mp 127°-132° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15](SC(=O)N(C)C)=[C:16](Cl)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.BrCC1N=NC(Cl)=CC=1>>[CH2:13]1[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH:10]=[CH:9][N:8]=[CH:14]1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: Clc1ccc(CBr)nn1
Product: C1=Cc2ccccc2CC=N1

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 3-bromomethyl-6-chloropyridazine to give 3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro)-1H-benzo[d]azepine. Use a method similar to the General Procedure 14 to give the title compound as an off-white powder. MS (APCI+) m/z: 340 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH3:17].[CH2:18]([O:25][C:26]([NH:28][C@@H:29]([C:32](O)=[O:33])[CH2:30][OH:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH2:17][C:30](=[O:31])[C@@H:29]([CH2:32][OH:33])[NH:28][C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1F
Reactant: O=C(N[C@H](CO)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(F)c(CNCC(=O)[C@@H](CO)NC(=O)OCc2ccccc2)c1
Yield: 85.8 %

Procedure:
According to the procedure of Preparation 4(c), except using tert-butyl 4-fluoro-3-(methylaminomethyl)benzoate (4.00 g, 16.7 mmole), N-(benzyloxycarbonyl)-D-serine (4.00 g, 16.7 mmole), HOBt.H2O (2.3 g, 17 mmole), DCC (2.4 g, 11.6 mmole), and 1:1 DMF/CH2Cl2 (100 mL), the title compound (6.60 g, 79%) was prepared as a sticky foam following flash chromatography on silica gel (50% EtOAc/hexanes): MS (ES) m/e 461.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[CH:12]2)[NH:4][CH:3]=1.[H-].[Na+].[Br:24][C:25]1[CH:32]=[C:31](F)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>CN(C=O)C>[Br:24][C:25]1[CH:32]=[C:31]([N:4]2[C:5]3=[N:6][CH:7]=[CH:8][C:9]([N:11]4[CH:15]=[C:14]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:13]=[CH:12]4)=[C:10]3[C:2]([CH3:1])=[CH:3]2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: Cc1c[nH]c2nccc(-n3cnc(-c4ccccc4)c3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-n3cnc(-c4ccccc4)c3)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
Compound (97c) (0.140 g) was dissolved in DMF (1.7 mL), and sodium hydride (0.024 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring for 10 min. Then, 2-bromo-4-fluorobenzonitrile (0.112 g) was added to the reaction solution, followed by stirring at 50° C. for 30 min. Ice water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (97d) (0.160 g, 69%) as a white solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12]O>>[C:2]1([C:1]2[O:9][CH2:12][CH2:11][N:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=C(O)c1ccccc1
Product: c1ccc(C2=NCCO2)cc1

Procedure:
The methods (1) to (6) will be described more specifically. For example, as the method (1), potassium hydroxide or acetic anhydride is reacted to 2-chloroethylformamide to provide 2-oxazoline, and the case where 2-bromoethylbenzamide is used provides 2-phenyl-2-oxazoline (see, for example Non-patent Document 1). As the method (2), thionyl chloride is reacted to 2-formamide ethanol to provide 2-oxazoline, and N-(2-hydroxyethyl)benzamide is heated with phosphorous pentoxide to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 2). As the method (3), benzoic acid and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 3). As the method (4), benzonitrile and 2-aminoethanol are heated with calcium chloride at 110 to 120° C. to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 4 and Patent Document 1). As the method (5), methyl benzimidate and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 5). Vinylbenzamide is simply heated to provide 2-phenyl-2-oxazoline. As the method (6), N-allylbenzamide is heated with sulfuric acid to provide 5-methyl-2-phenyl-2-oxazoline (see, for example, Non-patent Document 6).
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH3:18][N:19]([CH3:43])[C:20]1[N:25]=[CH:24][C:23]2[O:26][C:27]3[C:32]([C:33]([CH3:35])(O)[C:22]=2[CH:21]=1)=[CH:31][C:30]([C:36]1[C:37]([F:42])=[N:38][CH:39]=[CH:40][CH:41]=1)=[CH:29][CH:28]=3.C(=O)(O)[O-].[Na+]>ClCCCl>[F:42][C:37]1[C:36]([C:30]2[CH:31]=[C:32]3[C:27](=[CH:28][CH:29]=2)[O:26][C:23]2[CH:24]=[N:25][C:20]([N:19]([CH3:18])[CH3:43])=[CH:21][C:22]=2[C:33]3=[CH2:35])=[CH:41][CH:40]=[CH:39][N:38]=1
Reactant: CN(C)c1cc2c(cn1)Oc1ccc(-c3cccnc3F)cc1C2(C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C=C1c2cc(-c3cccnc3F)ccc2Oc2cnc(N(C)C)cc21
Temperature: 60 °C

Procedure:
PPTS (0.082 g, 0.327 mmol) was added in one portion to a suspension of 3-(dimethylamino)-7-(2-fluoropyridin-3-yl)-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol (0.23 g, 0.66 mmol) in DCE (8 mL) and the reaction was heated to 60° C. The resulting solution was stirred until judged complete by LC/MS. The solution was allowed to cool and then poured into saturated aqueous sodium bicarbonate. The layers were seperated and the aqueous layer was extracted with DCM and the combined organic extracts were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to afford 7-(2-fluoropyridin-3-yl)-N,N-dimethyl-5-methylene-5H-chromeno[2,3-c]pyridin-3-amine which was used directly for the next reaction without further purification. MS m/z=334.2 [M+H].
Reaction SMILES: O.CO[CH:4](OC)[CH2:5][O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:16]>ClC1C=CC=CC=1>[CH3:16][C:8]1[C:7]2[O:6][CH:5]=[CH:4][C:12]=2[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][CH:9]=1
Reactant: COC(COc1cc([N+](=O)[O-])ccc1C)OC
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1ccc([N+](=O)[O-])c2ccoc12
Temperature: 25 °C
Yield: 38 %

Procedure:
Add Amberlyst® 15 ion-exchange resin (36 g) to chlorobenzene (700 mL). Heat the reaction mixture to reflux and azeotrope out water, to dry the resin. Dissolve 2-(2,2-dimethoxyethoxy)-1-methyl-4-nitrobenzene (34.8 g, 144 mmol) in chlorobenzene (125 mL) and add dropwise to the stirring, refluxing reaction mixture under nitrogen over 15 minutes. Continue refluxing for 1.5 hours. Cool to room temperature, filter to remove the resin and concentrate under reduced pressure. Dissolve the residue in hexane, diethyl ether (1:1), wash with 0.5 M aqueous sodium hydroxide, aqueous saturated sodium chloride, dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Chromatograph on flash silica using hexane, ethyl acetate (9:1) and recrystallize from hexane, toluene (1:1) to obtain the desired compound as a yellow solid (9.7 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[S:14]([NH:17][C:18]1[N:23]=[C:22]([N:24]2[CH2:29][C@H:28]([CH3:30])[N:27](C(OC(C)(C)C)=O)[C@H:26]([CH3:38])[CH2:25]2)[CH:21]=[CH:20][C:19]=1[O:39][CH3:40])(=[O:16])=[O:15]>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[S:14]([NH:17][C:18]1[C:19]([O:39][CH3:40])=[CH:20][CH:21]=[C:22]([N:24]2[CH2:29][C@H:28]([CH3:30])[NH:27][C@H:26]([CH3:38])[CH2:25]2)[N:23]=1)(=[O:16])=[O:15]
Reactant: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(-c2ccc(C)s2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(-c2ccc(C)s2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
1,1-Dimethylethyl (2R,6S)-4-[6-({[2-chloro-4-(5-methyl-2-thienyl)phenyl]sulfonyl}amino)-5-(methyloxy)-2-pyridinyl]-2,6-dimethyl-1-piperazinecarboxylate (D16) (0.170 g) was dissolved in 4N HCl/dioxane (5 mL) added and the reaction stirred at rt for 24 hours. The reaction mixture was evaporated and triturated with ethyl acetate/ether ×3 to give a white solid which was dried at 50° C. under high vac to give the compound as a white solid (E8)(0.066 g). MS (ES+) m/e 507/509 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:21]1[CH2:26][CH2:25][S:24][CH2:23][C:22]1=[O:27]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:22](=[O:27])[CH2:23][S:24][CH2:25][CH2:26][OH:21])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CSCCO1
Reactant: NCCCCCOc1cc(CN2CCCCC2)ccn1
Product: O=C(CSCCO)NCCCCCOc1cc(CN2CCCCC2)ccn1
Yield: 78 %

Procedure:
Following a procedure similar to that described in Example 68, but using 5-(4-piperidinomethyl-2-pyridyloxy)pentylamine and 1,4-oxathian-2-one as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 78% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].B(O)(O)[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:41]4[C:42]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:38]=[CH:39][CH:40]=4)[CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4cccc5ccccc45)c3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (433 mg, 0.907 mmol) (see Ex. 3, part F) and 1-naphthyleneboronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3(aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (52.5 mg) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes). Rf=0.16 in 1:9 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ 8.11-8.05 (m, 2H), 7.90-7.82 (m, 3H), 7.56-7.39 (m, 6H), 6.80-6.72 (m, 4H), 4.22-4.19 (m, 4H), 2.98 (t, 2H), 2.35 (s, 3H) 1.47 (s, 3H), 1.22 (t, 6H); MS (EI) 436.5 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[NH:12][CH:13]([CH3:30])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[F:35][C:2]([F:1])([F:36])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[N:12]=[C:13]([CH3:30])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1
Reactant: CC1Nn2c(nn(Cc3ccc(C(F)(F)F)cc3)c2=O)C(c2ccc(Cl)cc2)=C1c1ccc(Cl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: Cc1nn2c(=O)n(Cc3ccc(C(F)(F)F)cc3)nc2c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (28 mg, 0.053 mmol), prepared as described in Example 469 in CH2Cl2 (0.5 mL) at RT was added DDQ (15 mg, 0.064 mmol). The reaction was stirred at RT for 1 h. LC-MS showed the completion of the reaction. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by using silica gel column chromatography using an automated system eluting with a gradient of (0% to 80% EtOAc for 20 min.) to give the title compound, 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (23 mg, 84% yield) as a yellow solid in 84% yield. HPLC retention time: 4.18 min; MS [M+H]+: found 529. 1H NMR (CDCl3, 400 MHz) δ 7.61 (d, 2H), 7.52 (d, 2H), 7.35 (dd, 2H), 7.27 (dd, 2H), 7.16 (dd, 2H), 7.02 (dd, 2H), 5.28 (s, 2H), 2.29 (s, 3H).