Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[C:7]1([C:13]2[O:17][C:16]([C:18]3[C:19]([NH2:30])=[N:20][CH:21]=[C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:23]=3)=[N:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([S:3]([N:27]1[CH2:28][CH2:29][N:24]([C:22]2[N:23]=[C:18]([C:16]3[O:17][C:13]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:14][N:15]=3)[C:19]([NH2:30])=[N:20][CH:21]=2)[CH2:25][CH2:26]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ncc(N2CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethanesulfonyl chloride (37.51 mg, 27.64 μL, 0.2917 mmol) was added to a solution of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-piperazin-1-yl-pyrazin-2-amine (116 mg, 0.2652 mmol) and triethylamine (53.67 mg, 73.93 μL, 0.5304 mmol) in dichloromethane (5 mL) at 0° C. and the resulting solution stirred at room temperature for 1.5 hours. The mixture was diluted with dichloromethane, washed with water and the aqueous layer extracted further with dichloromethane. The organics were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel by flash column chromatography (3% MeOH/DCM) to afford the title compound still impure. This was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (25.2 mg, 18% Yield).
Reaction SMILES: [Te].[BH4-].[Na+].[CH3:4][O:5][C:6]([C:8]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:41])[CH:17]([NH:27][C:28](=[O:40])[C:29]([NH2:39])([CH3:38])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:12][CH2:11]2)[CH:9]=1)=[O:7].C(Cl)Cl.C(OCC)(=O)C>C(O)C>[CH3:4][O:5][C:6]([CH:8]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:41])[CH:17]([NH:27][C:28](=[O:40])[C:29]([NH2:39])([CH3:38])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:12][CH2:11]2)[CH2:9]1)=[O:7]
Reactant: COC(=O)C1=CC2(CCN(C(=O)C(COCc3ccccc3)NC(=O)C(C)(N)CC(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Agent: [Te]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)C1CC2(CCN(C(=O)C(COCc3ccccc3)NC(=O)C(C)(N)CC(=O)OC(C)(C)C)CC2)c2ccccc21
Yield: 90.9 %

Procedure:
To a suspention of Tellurium (52.6 mg, 0.412 mmol) in ethanol (2.0 ml) was added sodiumborohydride (36.6 mg, 0.99 mmol) and the mixture was refluxed for 10 minutes. A solution of the title compound from Example 3, Step E (100 mg, 0.165 mg) in ethanol (1.0 ml) was cannulated into the reaction mixture at room temperature. The reaction mixture was then stirred over night, filtered and concentrated. The residue was dissolved in ethyl acetate and 1 N KOH was added. The aqueous layer was then extracted with ethyl acetate (3×1 vol). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. Flash chromatography (silica gel, methylene chloride/ethyl acetate 2:1) gave the title compound (91 mg, 0.15 mmol) as a clear glass.
Reaction SMILES: [C:1]([CH2:8][C:9](=[O:19])[CH:10]([NH2:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:20][Mg]Br>C(Cl)Cl>[C:1]([CH2:8][C:9]([CH3:20])([OH:19])[CH:10]([NH2:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)CC(=O)C(N)Cc1ccccc1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(C)(O)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Grignard Addition A solution of Boc-3-amino-4-phenyl-2-butanone (0.5 g, 1.9 mmol) in 100 mL methylene chloride was cooled to −78° C. and treated with methyl magnesium bromide (1.39 mL of a 3.0M solution, 4.2 mmol). The reaction was warmed to ambient temperature and stirred for 14 hours. The reaction was charged with additional methyl magnesium bromide (1.39 mL of a 3.0 M solution, 4.2 mmol) and stirred at ambient temperature for 5 hours. The reaction was quenched with ammonium chloride solution and partitioned between water and ethyl acetate. The organics were washed with water (3×), brine, dried over sodium sulfate, filtered and evaporated in vactio. Purification by flash column chromatography (20-35% ethyl acetate/hexanes) gave Boc-3-amino-2-methyl-4-phenylbutan-2-ol as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 5H), 4.52 (m, 1H), 3.69 (m, 1H), 3.09 (dd, J=14.1, 3.3 Hz, 1H), 2.61 (t, J=12.0 Hz, 1H), 2.39 (s, 1H), 1.30 (m, 15H). Step B: Deprotection
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.Cl.[NH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N#N.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1ccc(I)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of 1,4-diiodobenzene (33 g, 100 mmol) and tert-butyl 2-aminoacetate hydrochloride (25 g, 150 mmol) in DMF (100 mL) was purged with N2. Cut (19 g, 100 mmol) was added, followed by K2CO3 (35 g, 250 mmol). The reaction mixture was stirred overnight at 90° C. and allowed to cool to rt. The mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:25 v/v)) to obtain compound 56a as a red oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C12H16INO2: 334.2 (M+H). Found 334.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19])O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[CH2:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[NH2:1]
Reactant: COc1cccc(C(O)c2c(F)cccc2F)c1N
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Cc2c(F)cccc2F)c1N
Temperature: 40 °C
Yield: 69.7 %

Procedure:
The reaction mixture composed of 5.8 g of (2-amino-3-methoxyphenyl)(2,6-difluorophenyl)methanol, 11 ml of triethylsilane (3 eq.), 10 ml of trifluoroacetic acid (3.9 eq.) in 90 ml of dichloromethane is heated for 6 hours at 40° C. After one night at room temperature, the reaction medium is slowly hydrolyzed in the cold state with 6N sodium hydroxide, the organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by filtration on silica H, eluting with dichloromethane, in order to obtain 3.8 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:28]([O-])([O-])([O-])[O:29][CH2:30][C:31]([F:34])([F:33])[F:32]>>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:12]2[C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=[C:28]2[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[CH:15][CH:16]=1)#[N:27]
Reactant: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: [O-]C([O-])([O-])OCC(F)(F)F
Product: COC(=O)c1cccc2nc(OCC(F)(F)F)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 25 %

Procedure:
The title compound was prepared as pale yellow crystals from methyl 3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate and 2,2,2-trifluoroethyl orthocarbonate according to the procedure for Working Example 3. Yield: 25%, m.p. 143-145° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:16]>>[CH2:1]([O:8][CH:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:16]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccocc1OCc1ccccc1
Reactant: N
Product: O=C1C=CN=CC1OCc1ccccc1
Reaction time: 72 h

Procedure:
This method is adapted from that of Bartulin et al., J. Heterogyclic Chem. 29: 1017-1019 (1992), which is hereby incorporated by reference. A 3-benzyloxy-4-pyrone, prepared as in Method B, is added to an ethanolic solution of aqueous ammonia. The reaction mixture is stirred for approximately 3 days, concentrated under reduced pressure, triturated with acetone, and the solid recrystallized from ethanol to yield the corresponding 3-benzyloxypyrid-4-one. To a solution of this pyrid-4-one in aqueous ethanol containing one equivalent of sodium hydroxide was added an equivalent of n-alkyl bromide. The reaction mixture was heated under reflux for 24 hours after which it was cooled, concentrated under reduced pressure, and extracted with an appropriate solvent. After washing, the organic phase with water, it is dried over magnesium sulfate. The product is obtained upon concentration of the solution under reduced pressure. Crude 1-alkyl-3-benzyloxypyrid-4-one in acetic acid containing 40% hydrobromic acid is then heated on a steam bath for 30 minutes. The 1-alkyl-3-hydroxypyrid-4-one precipitates and is subsequently recrystallized from benzene in good yield with a narrow melting point and appropriate NMR spectrum. ##STR6##
Reaction SMILES: Cl.Br[C:3]1[CH:14]=[N:13][C:6]2[NH:7][C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[CH3:15][N:16]([CH2:21][C:22]1[O:23][C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[C:26]=1[CH3:27])[C:17](=[O:20])[CH:18]=[CH2:19].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.C(Cl)Cl.CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:15][N:16]([CH2:21][C:22]1[O:23][C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[C:26]=1[CH3:27])[C:17](=[O:20])/[CH:18]=[CH:19]/[C:3]1[CH:14]=[N:13][C:6]2[NH:7][C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Reactant: O=C1CNCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCC(=O)N3)oc2ccccc12
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
A suspension of 7-bromo-1,3,4,5-tetrahydropyrido[2,3-e][1,4]diazepin-2-one hydrochloride (0.29 g, 1.0 mmol) and N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.29 g, 1.3 mmol) in propionitrile (5 mL) and DMF (1.3 mL) was de-oxygenated with Ar for 10 min. The mixture was treated with (i-Pr)2EtN (0.56 mL, 3.2 mmol) and was de-oxygenated with Ar for 5 min. Pd(OAc)2 (24 mg, 0.11 mmol) and P(o-tol)3 (64 mg, 0.21 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight, then allowed to cool. The resulting precipitate was isolated by filtration, dissolved in CH2Cl2/MeOH and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2 to 96:4) gave the title compound (0.18 g, 47%) as a white solid: MS (ESI) m/e 391 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:12]([OH:29])[CH2:13][CH:14]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:10][CH:11]([CH:12]([OH:29])[CH2:13][CH:14]([S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: [H][H]
Reactant: CC(C)CCC(CC(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)S(=O)(=O)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCC(CC(O)C(N)Cc1ccccc1)S(=O)(=O)c1ccccc1

Procedure:
To a solution of (4-benzenesulfonyl-1-benzyl-2-hydroxy-7-methyl-octyl)-carbamic acid benzyl ester in ethanol is added 10 mole % palladium hydroxide on carbon. The mixture is then shaken on a Parr shaker under 50 psi of hydrogen for approximately 18 h. The catalyst is filtered off and the solution concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:24]=[CH:23][C:17](/[CH:18]=[CH:19]/B(O)O)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:24]=[CH:23][C:17](/[CH:18]=[CH:19]/[C:2]2[CH:11]=[CH:10][C:5]3[N:6]=[C:7]([NH2:9])[S:8][C:4]=3[CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(/C=C/B(O)O)cc1
Reactant: Nc1nc2ccc(Br)cc2s1
Product: COc1ccc(/C=C/c2ccc3nc(N)sc3c2)cc1

Procedure:
Compound (E)-6-(4-methoxystyryl)benzo[d]thiazol-2-amine (W201) was prepared using the general procedure for Suzuki coupling reaction between 6-bromobenzo[d]thiazol-2-amine (69 mg, 0.3 mmol) and (E)-4-methoxystyrylboronic acid (53 mg, 0.3 mmol), as a white solid (80 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J=1.6 Hz, 1 H), 7.46 (s, 2 H), 7.45 (d, J=8.8 Hz, 2 H), 7.36 (dd, J=8.4, 1.6 Hz, 1 H), 7.24 (d, J=8.0 Hz, 1 H), 7.03 (d, J=2.0 Hz, 2 H), 6.89 (d, J=9.2 Hz, 1 H), 3.71 (s, 3 H); MS (ESI) m/z 283 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.I[CH:24]([CH3:26])[CH3:25]>CN(C=O)C.CCOC(C)=O>[CH:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1)([CH3:26])[CH3:25]
Reactant: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Reactant: CC(C)I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Temperature: 65 °C
Reaction time: 48 h
Yield: 48.3 %

Procedure:
To a solution of 1-(4-aminophenyl)-7,8-methylenedioxy-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (110 mg, 0.373 mmol) in DMF (3 mL) was added 2-iodopropane (290 μL, 2.91 mmol). The mixture was stirred at 65° C. for two days, diluted with EtOAc (45 mL), washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography to afford the title compound as a tan solid (60 mg, 0.18 mmol, 48%), mp: 144°-146° C. 1H NMR (CDCl3) 8.20 (s, 1H), 7.41 (d, J=8.5, 2H), 6.81 (s, 1H), 6.74 (s, 1H), 6.56 (d, J=8.5, 2H), 6.02 (s, 2H), 3.80 (s, 1H), 3.69 (m, 1H), 3.42 (s, 2H), 1.24 (d, J=6.0, 6H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[NH:37][C:38](=[NH:47])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][OH:46])=[CH:41][CH:40]=1>CN(C)C=O>[F:12][C:2]([F:1])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:9][N:47]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][OH:46])=[CH:41][CH:40]=3)[N:37]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(-c2noc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-trifluoromethylbenzoic acid (6 g, 0.032 mol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (6.05 g, 0.0315 mol) and 1-hydroxy-benzotriazole hydrate (4.82 g, 0.032 mol) in N,N-dimethylformamide (30 mL) is stirred at room temperature for 30 minutes. N-Hydroxy-4-hydroxymethylbenzamidine (6.97 g, 90%, 0.038 mol) is added and the reaction mixture is heated at reflux for 3 hrs, then allowed to come to room temperature and solvent is removed under reduced pressure. An aqueous solution (100 mL) of sodium bicarbonate is added to the residue and the aqueous layer is extracted with ethyl acetate (2×100 mL). Combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate, 65:35) to give 4-[5-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-3-yl]phenylmethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH2:5][N:6]1[CH2:10][CH2:9][N:8]=[C:7]1[SH:11].[OH-].[K+].O.[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23]Br>CN(C)C=O>[C:21]([CH2:22][CH2:23][S:11][C:7]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:14]=[C:13]([F:15])[CH:12]=2)[CH2:10][CH2:9][N:8]=1)([O:20][CH3:19])=[O:25]
Reactant: Fc1cc(F)cc(CN2CCN=C2S)c1
Reactant: COC(=O)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCSC1=NCCN1Cc1cc(F)cc(F)c1
Temperature: 95 °C

Procedure:
1-(3,5-difluorobenzyl)-2-mercaptoimidazoline, prepared as in example 8, and potassium hydroxide in equimolar proportions in dimethylformamide and water are stirred under argon at ambient temperature, and one mole of methyl-3-bromopropionate is added. The reaction mixture is heated at 95° C. overnight, cooled, and extracted three times with ether, and the combined ether extracts are concentrated. Purification by flash chromatography on silica gel gives 2-(2-carbomethoxyethylthio)-1-(3,5-difluorobenzyl)imidazoline.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[H-].COCCO[Al+]OCCOC.[Na+].[H-].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][CH:37]([NH:50][C:51]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:38]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[O:48][CH3:49])=O)=[CH:28]1>C1(C)C=CC=CC=1.O1CCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][CH:37]([NH:50][C:51]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:38][NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[O:48][CH3:49])=[CH:28]1
Reactant: COc1ccccc1CNC(=O)C(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COCCO[Al+]OCCOC
Agent: COCCO[AlH2-]OCCOC
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Red-Al®, [a 3.4M, solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 moles), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, 3-(1H-indol-3-yl)-N-(2-methoxybenzyl)-2-(N-triphenylmethylamino)propanamide (228.6 g, 0.404 mols) produced supra, in anhydrous tetrahydrofuran (1.0 liter) under a nitrogen atmosphere. The reaction mixture became a purple solution. The reaction was quenched after at least 20 hours by the slow addition of excess saturated Rochelle salt solution (potassium sodium tartrate tetrahydrate). The organic layer was isolated, washed with brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No further purification was done and the product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]1.C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cc(Cl)ncc2[N+](=O)[O-])C1
Yield: 107.1 %

Procedure:
A solution of 2,4-dichloro-5-nitropyridine (from AstaTech, 0.500 g, 2.59 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (0.52 g, 2.6 mmol) and triethylamine (1.1 mL, 7.9 mmol) in isopropyl alcohol (10 mL) was heated at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was re-dissolved in EtOAc (40 mL) and washed with saturated aq. NaHCO3 and water (3×3 mL). The combined aqueous phases were extracted with EtOAc (3 mL). The combined organic layers were washed with brine (3 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to afford the sub-title compound (0.99 g), which was used in the subsequent reaction without further purification. LCMS (ESI) calc. for C15H22ClN4O4[M+H]+: m/z=357.1. found 357.0.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH3:10])[C:3]([N:5]=[C:6]=[S:7])=[O:4].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH2:8][CH2:9][CH3:10])=[S:7])=[CH:28][CH:27]=1
Reactant: CCCC(C)C(=O)N=C=S
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCC(C)C(=O)NC(=S)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
2-Methylpentanoyl isothiocyanate prepared according to the method 2 was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 57%).
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][S:11]/[C:10]/2=[N:14]\[C:15]([N:17]2[CH:21]=[CH:20][N+](C)=[CH:18]2)=[O:16])=[CH:5][CH:4]=1.[CH3:23]NCC#C.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][S:11]/[C:10]/2=[N:14]\[C:15](=[O:16])[N:17]([CH3:18])[CH2:21][C:20]#[CH:23])=[CH:7][CH:8]=1
Reactant: C#CCNC
Reactant: C[n+]1ccn(C(=O)/N=C2\SCCN2c2ccc(Cl)cc2)c1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C#CCN(C)C(=O)/N=C1\SCCN1c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
1-({[(2Z)-3-(4-Chlorophenyl)-1,3-thiazolidin-2-ylidene]amino}carbonyl)-3-methyl-1H-imidazol-3-ium iodide (97 mg, 0.216 mmol, Example 25B), N-methylprop-2-yn-1-amine (0.020 mL, 0.238 mmol) and diisopropylethylamine (0.041 mL, 0.238 mmol) were heated in acetonitrile at 65° C. After 1 hour, the mixture was concentrated and the residue was purified by chromatography over silica using dichloromethane:methanol 95:5 as eluant to provide the title compound.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[NH:13][C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC([O-])(C)C.[K+].Br[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1>C(#N)C.C(OC(=O)C)C.O>[N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:18][CH:17]=3)[N:13]([CH2:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CCCCO1
Reactant: Cc1[nH]c(-c2ccc(OC(F)(F)F)cc2)nc1C(=O)NN1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(OC(F)(F)F)cc2)n1CC1CCCCO1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a suspension of 100 mg of 5-methyl-2-(4-trifluoromethoxy-phenyl)-1H-imidazole-4-carboxylic acid piperidin-1-ylamide in 3 ml of acetonitrile was added 33 mg of potassium tert-butylate and the reaction mixture was stirred at room temperature for 2 minutes. After such time, 0.034 ml of 2-(bromomethyl)-tetrahydro-2H-pyran (as R3—(CH2)m—Br) was added and the reaction mixture was stirred at 100° C. for 26 hours under argon atmosphere. The reaction mixture was then diluted with ethylacetate/water, the aqueous phase removed, and the organic phase was washed with 2×H2O followed by brine, dried (MgSO4), and after filtration concentrated in vacuo and purified by column chromatography (50 g SiO2, CH2Cl2/MeOH: 24/1) to give 44 mg of the title compound as a pale yellow solid, MS (ISP) 467.2 (M+H)+.