Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:15]([C:13]1[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([NH:1][C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=2)[CH:14]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc(OC(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-phenethylbenzoate 0.10 g were added 1-bromo-4-(trifluoromethoxy)benzene 0.13 mL, cesium carbonate 0.23 g, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg at room temperature, and it was stirred at 110° C. for 6 hours. After the reaction mixture was cooled to room temperature, palladium acetate 1.6 mg, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg were added at room temperature, and it was stirred at 110° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 4-phenethyl-2-(4-(trifluoromethoxy)anilino)benzoate.
Reaction SMILES: [CH2:1]=[C:2]([O:5][Si](C)(C)C)[CH:3]=[CH2:4].[CH3:10][S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:10][S:11]([CH:14]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:5][CH2:15]1)(=[O:13])=[O:12]
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: C=CS(C)(=O)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
A solution containing (buta-1,3-dien-2-yloxy)(trimethyl)silane (12.5 ml, 70.7 mmol) in toluene (50 ml), was treated with (methylsulfonyl)ethene (4.1 ml, 47.1 mmol) and heated under reflux for 76 hours. After which time, the reaction mixture was cooled to room temperature and concentrated in-vacuo to give a yellow oil. The oil was dissolved in CH2Cl2 (120 ml) and filtered through Celite®. The filtrate was concentrated in-vacuo and the resulting residue was then dissolved in MeOH (8 ml) with cooling (ice/water). It was then treated with TFA (2.0 ml). The reaction mixture was stirred at 0° C. for a further 10 minutes and then at room temperature for 25 hours. The reaction mixture was concentrated in-vacuo and the residue was purified by flash column chromatography (0-10% MeOH/CH2Cl2) 100 g SNAP cartridge on the Biotage Isolera to give the title compound 1.2 g (14%) as a thick yellow oil. LC-MS 94%, 0.39 min (3.5 minute LC-MS method), m/z=177.0 (ELS visible only). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 3.24-3.32 (m, 1H) 2.94 (s, 3H) 2.62-2.70 (m, 2H) 2.50-2.56 (m, 2H) 2.38-2.45 (m, 2H) 2.07-2.18 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[CH:33](=O)[CH2:34][CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH2:33][CH2:34][CH3:35])=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 76.8 %

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (81e) (38 mg, 0.080 mmol), 1-propanal (7 μL, 0.097 mmol) and sodium (triacetoxy)borohydride (80 mg, 0.38 mmol), to obtain 31.9 mg of the title compound as a white solid (77%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Br:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15](Br)[C:14]=1[CH2:22][N:23](CC1C=CC(OC)=CC=1)[C:24]([NH:26]C1C(Cl)=CC=CC=1Cl)=[O:25].[NH4+].[OH-]>[Cu](I)I.O>[Br:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]2[C:14]=1[CH2:22][NH:23][C:24](=[O:25])[NH:26]2
Reactant: COc1ccc(CN(Cc2c(Br)cc(OC)cc2Br)C(=O)Nc2c(Cl)cccc2Cl)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)c2c(c1)NC(=O)NC2
Temperature: 25 °C

Procedure:
To a flask containing dry, finely ground potassium carbonate (22.17 g, 0.160 mol) under a nitrogen atmosphere was added anhydrous DMF (800 ml), N-[(2,6-dibromo-4-methoxyphenyl)methyl]-N′-(2,6 dichlorophenyl)-N-[(4-methoxyphenyl)methyl]urea (32.25 g, 0.0535 mol) (INTERMEDIATE 21) and copper iodide (6.80 g, 0.0353 mol). After refluxing one hour the solution was cooled to RT and poured into a solution containing 700 mL NH4OH (28%) and water (8 L). The precipitated product was filtered, washed with water (5×500 mL), hexanes (4×500 mL) and air dried to give 1-(2,6-dichlorophenyl)-3-(4-methoxyphenyl)methyl]-5-bromo-7-methoxy-3,4-dihydro-2(1H)-quinazolinone. 1H NMR(CDCl3, 500 MHz): δ 3.67 (s, 3H), 3.83 (s, 3H), 4.44 (s, 2H), 4.68 (s, 2H), 5.59 (d, 1H, J=2.3 Hz), 674 (d, 1H, J=2.3 Hz), 6.91 (d, 2H, J=8.7 Hz), 7.34-7.37 (m, 3H), 7.50 (d, 2H, J=8.0 Hz), MS(ES) 521 (M+1); LC 1:4.15 min.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].[CH:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C([BH3-])#N.[Na+].Cl>CO.[Cl-].[Na+].O.CCOCC.O>[CH2:2]([O:9][NH:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCC=O
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CCCCCCCNOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
O-Benzylhydroxylamine hydrochloride (1a) (13.37 g, 83.74 mmol) was dissolved in 31 mL of methanol and 14 mL of water at 0° C. and the apparent pH adjusted to 4.7 using 6N potassium hydroxide. Heptanal (10.2 mL, 76 mmol) was added, and the pH was maintained at 4.7 while the reaction warmed to room temperature. After the pH change stabilized, the mixture was again cooled to 0° C. and 3.54 g (56.31 mmol) of sodium cyanoborohydride was added. The pH was then lowered to just below 3 and maintained there by the addition of 2N hydrogen chloride in methanol. When the pH change had stabilized, the solution was stirred at pH 3 for 3 h at room temperature. The mixture was then poured into ether (100 mL) and brine (50 mL), and enough 6N potassium hydroxide was added to bring the pH to 9. The aqueous layer was extracted with ether (3×50 mL) and the ether solutions were combined and dried over magnesium sulfate. The solvents were then removed, and the resulting oil distilled at 110°-112° C. (0.1 mm) to give 3.6 g (22%) of (3a): 1H NMR (CDCl3): δ 0.7-1.05 (m, 3H), 1.05-1.73 (m, 10H), 2.92 (t, 2H), 4.7 (s, 2H), 5.3-5.7 (m, 1H), 7.4 (s, 5H): HRMS calcd. for C14H23NO: 221.1778. Found: 221.1721.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[CH3:25][C:26]1[S:27][CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[N:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:34]5[CH:35]=[CH:36][C:31]([C:29]6[N:30]=[C:26]([CH3:25])[S:27][CH:28]=6)=[CH:32][CH:33]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: Cc1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cs1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(-c2ccc(-c3ccc(-n4c(C[C@@H]5CCN(C(=O)C6CC6)C5)n[nH]c4=O)cc3)cc2)cs1
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.256 mmol) in 1,4-dioxane (1.5 mL) was treated with 2-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-thiazole (0.281 mmol), dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium (II)-dichloromethane adduct (10 mg) and 2M aq potassium carbonate (0.767 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave at 150° C. for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over sodium sulfate, treated with Si-Thiol (Silicycle, 20 mg), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (25-55% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions from the HPLC were combined, adjusted to pH˜5 with the addition of saturated aq sodium bicarbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting product was then purified by flash chromatography (3-10% methanol/dichloromethane) to afford the title compound as an amorphous white solid (40%). MS(ES)+ m/e 486.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:21]([O:20][CH:19]([O:23][CH2:24][CH3:25])[CH2:18][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)([CH3:1])[CH3:3])=[CH:15][CH:14]=1)[CH3:22]
Reactant: CCOC(CBr)OCC
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Product: CCOC(COc1ccc(C(C)(C)c2ccccc2)cc1)OCC

Procedure:
Synthesized according to Scheme 1, Step 1 from (4-(2-phenylisopropyl)phenol) and 2-bromo-1,1-diethoxyethane to give 1-(2,2-diethoxyethoxy)-4-(2-phenylpropan-2-yl)benzene as a yellow-orange oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.19-7.29 (m, 4H), 7.14-7.19 (m, 1H), 7.13 (d, J=9.0 Hz, 2H), 6.82 (d, J=8.5 Hz, 2H), 4.82 (t, J=5.3 Hz, 1H), 3.98 (d, J=5.0 Hz, 2H), 3.70-3.81 (m, 2H), 3.57-3.68 (m, 2H), 1.65 (s, 6H), 1.24 (t, J=7.0 Hz, 6H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][C:27]([C:30]3([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)O1>>[CH3:7][N:6]1[C:2]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3([C:33]([F:34])([F:35])[F:36])[CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[C:3]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[N:4]=[CH:5]1
Reactant: CC1(C)OB(c2ccc(C3(C(F)(F)F)CC3)cc2)OC1(C)C
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(C2(C(F)(F)F)CC2)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4,4,5,5-tetramethyl-2-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]-1,3,2-dioxaborolane according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H15F3N4, 369. Found, 369.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:9]=3[C:8]([N:20]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:21]3)=[N:7][C:6]=2[CH:31]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:17])[F:18])=[CH:15][C:9]=3[C:8]([N:20]3[CH2:25][CH2:24][N:23]([CH3:34])[C@@H:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:21]3)=[N:7][C:6]=2[CH:31]=1
Reactant: COCCC[C@H]1CN(C2=Nc3cc(F)ccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCCC[C@H]1CN(C2=Nc3cc(F)ccc3Nc3ccc(C(F)(F)F)cc32)CCN1C
Yield: 77.3 %

Procedure:
Combine (S)-8-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.144 g, 0.330 mmol), formaldehyde (37 μL, 0.461 mmol, 37%), and sodium triacetoxyborohydride (0.105 g, 0.495 mmol) in dichloroethane (5 mL) and stir at room temperature overnight. Dilute the mixture with saturated sodium bicarbonate and extract three times with methylene chloride. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the crude product. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (S)-8-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-4-methyl-piperazin 1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.115 g, 0.255 mmol, 77%) as a yellow oil. Mass spectrum (APCI): m/z=451.3 (M+1). Isolate clean product as the corresponding dihydrochloride in the following manner: dissolve the yellow foam in ethanol (5 mL) and add a solution of about 5 equivalents of HCl in ethanol (5 mL). Evaporate the mixture to obtain (S)-8-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine dihydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:51]=[CH:50][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:23]3[C:31]([O:32][CH3:33])=[CH:30][C:29]([CH3:34])=[C:28]4[C:24]=3[CH:25]=[CH:26][N:27]4C(OC(C)(C)C)=O)([O:15][CH2:16][C:17]3[O:18][C:19]([CH3:22])=[N:20][N:21]=3)[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(OCC3OC(C)=NN=3)C(F)(F)F)N(COCC[Si](C)(C)C)C=2C=1)#N.Cl[Sn](Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[F:14][C:11]([F:12])([F:13])[C:10]([C:8]1[NH:7][C:6]2[CH:50]=[CH:51][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)([C:23]1[C:31]([O:32][CH3:33])=[CH:30][C:29]([CH3:34])=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2)[O:15][CH2:16][C:17]1[O:18][C:19]([CH3:22])=[N:20][N:21]=1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(OCc1nnc(C)o1)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(OCc1nnc(C)o1)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C)c2[nH]ccc2c1C(OCc1nnc(C)o1)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate compound and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 35-K) (38 mg, 0.051 mmol) in dichloromethane (1.0 mL) at 0° C. was added a 1.0M solution of SnCl4 in dichloromethane (0.51 mL, 0.51 mmol). This mixture was stirred at 0° C. for 30 min and then warmed to room temperature and stirred for an additional 1.0 hr. The crude reaction mixture was diluted with ethyl acetate and a saturated sodium bicarbonate solution and the layers were passed over Celite® and then separated. The organic phase was washed with brine solution, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified using FCC eluting with ethyl acetate/heptane (0-100%) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.00 (br.s., 1H) 11.10 (br. s., 1H) 8.30 (s, 1H) 7.82-7.93 (m, 1H) 7.49-7.64 (m, 1H) 7.36 (t, J=2.91 Hz, 1H) 6.76 (s, 1H) 6.68 (br. s., 1H) 4.47-4.82 (m, 2H) 3.11 (s, 3H) 2.40 (s, 3H) 1.24 (s, 3H). HRMS calcd. for C24H19F3N6O3 (M+H)+ 497.1535. found 497.1504.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:20][CH2:21][S:22][CH3:23])[C:10]([O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[CH3:19][N:16]1[CH2:15][CH2:14][CH:13]([O:12][C:10](=[O:11])[C@H:9]([CH2:20][CH2:21][S:22][CH3:23])[NH2:8])[CH2:18][CH2:17]1
Reactant: CSCCC(NC(=O)OC(C)(C)C)C(=O)OC1CCN(C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](N)C(=O)OC1CCN(C)CC1

Procedure:
A solution of the 1-methylpiperidin-4-yl 2-tert-butoxycarbonylamino-4-methylsulfanylbutyrate (3.8 g; 11 mmol) in dichloromethane (5 ml) and TFA (10 ml) was stirred at ambient temperature for 2 hours. After evaporation to dryness, the residue was redissolved in dichloromethane and treated with a solution of 3.8 M HCl in ether (6 ml) at 0° C. The resulting precipitate was triturated with ether and filtrated to give L-methionine (N-methylpiperidin-4-yl) ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][C:10](=[O:12])[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH2:20][CH2:21][C:22]1([CH3:33])[O:26][C:25]2=[N:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][N:24]2[CH2:23]1)(=O)=O.[I-].[Na+]>O.CN(C=O)C>[CH3:33][C:22]1([CH2:21][CH2:20][N:9]2[N:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[O:11][C:10]2=[O:12])[O:26][C:25]2=[N:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][N:24]2[CH2:23]1
Reactant: CC1(CCOS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Reactant: O=c1[nH]nc(-c2ccncc2)o1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CCn2nc(-c3ccncc3)oc2=O)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
A mixture of 5-(pyridin-4-yl)-3H-[1,3,4]-oxadiazol-2-one (150 mg, 0.92 mmol), sodium hydride (41 mg, 1.03 mmol) and DMF (1.5 ml) was stirred at room temperature for 1 hour. To the reaction mixture, 2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)ethyl methanesulfonate prepared in Example 42 (200 mg, 0.69 mmol) and sodium iodide (140 mg, 0.93 mmol) were added in this order followed by stirring at 50-60° C. for 6 hours. The reaction mixture was allowed to return to room temperature. To the solution, water was added, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water three times, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=25/1) to afford 3-[2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)ethyl]-5-(pyridin-4-yl)-3H-[1,3,4]oxadiazol-2-one (137 mg, yield 56%) as a white powder.
Reaction SMILES: [Mg].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](O)=[C:14](Br)[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH2:28][CH3:29])=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)=[CH:13][CH:14]=2)([OH:30])[CH2:28][CH3:29])=[CH:25][CH:26]=1
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: Oc1ccc(OCCCN2CCCCC2)cc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(Cl)cc1)c1ccc(OCCCN2CCCCC2)cc1

Procedure:
To a Grignard reactant prepared from 1.82 g. of magnesium turnings and 22.3 g. of 4-[3-(piperidin-1-yl)-propoxy]-bromophenol in 100 ml. of dry tetrahydrofuran a solution of 8.4 g. of p-chloropropiophenone in 30 ml. of tetrahydrofuran is added dropwise, under slight reflux. The reaction mixture is slightly boiled for an additional hour, whereupon it is cooled and decomposed with a saturated aqueous ammonium chloride solution. The aqueous phase is extracted with tetrahydrofuran, the tetrahydrofuran phase is washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. Crystallization of the residue from a mixture of n-hexane and ethyl acetate yields 12.2 g. of the named compound, melting at 104° to 105° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11].[H-].[Na+].[Br:14][CH2:15][CH2:16][CH2:17]Br>C1COCC1.[Cl-].[Na+].O>[Br:14][CH2:15][CH2:16][CH2:17][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]([CH3:1])[C:3]1=[O:11]
Reactant: BrCCCBr
Reactant: Cn1c(=O)[nH]c2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCBr)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
Add portion wise 3-methyl-1,3-dihydro-benzoimidazol-2-one (400 mg, 27.0 mmol) to a suspension of sodium hydride (1.296 g, 32.4 mmol of 60% dispersion in oil) in anhydrous THF (200 mL) under nitrogen over 15 min, then continue to stir for 30 min. Add 1,3-dibromopropane (11.0 mL, 108 mmol) and stir overnight. Then heat at reflux for 3 days. Cool the suspension to room temperature, pour into brine (400 mL), extract with diethyl ether (300 mL), dry over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40 min) to give the title compound as a colourless oil (2.15 g, 30%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:10][C:11]1[CH:16]=[C:15]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: OB(O)c1ccnc(Cl)c1
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: O
Solvent: COCCOC
Product: Cc1oc(-c2ccnc(Cl)c2)cc1C=O
Reaction time: 8 h
Yield: 53.9 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 2-chloropyridine-4-boronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 50% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.2 g, 55%) as a yellow solid.