Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>>[CH2:15]([N:17]([CH2:18][CH3:19])[C:12]([C:8]1[CH:9]=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:14])[CH3:16]
Reactant: CCNCC
Reactant: O=C(O)c1cnoc1-c1ccccc1
Product: CCN(CC)C(=O)c1cnoc1-c1ccccc1

Procedure:
The title compound was prepared from 5-(phenyl)isoxazole-4-carboxylic acid (9.5 mg, 0.050 mmol) and diethylamine (4.4 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (4.6 mg). MS (pos) m/z 245.2 (M+1).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1)(=O)=O.[ClH:17].Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]([C:29]2[S:39][C:38]3[N:40]4[C:31](=[CH:32][N:33]=[C:34]4[CH:35]=[CH:36][CH:37]=3)[CH:30]=2)=[O:28])[CH2:21][CH2:20]1.[CH2:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH3:42]>C(O)C>[O:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8][C@H:7]1[CH2:6][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]([C:29]2[S:39][C:38]3[N:40]4[C:31](=[CH:32][N:33]=[C:34]4[CH:35]=[CH:36][CH:37]=3)[CH:30]=2)=[O:28])[CH2:21][CH2:20]1.[ClH:17].[CH2:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH3:42]
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: CS(=O)(=O)OC[C@@H]1COc2ccccc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCC1CCN(C[C@@H]2COc3ccccc3O2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
A solution of the above crude (S)-2-methanesulfonyloxymethyl-1,4-benzodioxane, 1.05 g (2.71 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride, and 1.20 ml (8.64 mM) of triethylamine in 30 ml of ethanol was refluxed for 3 days. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=4/1 to 3/1) to provide the title compound and triethylamine hydrochloride as a mixture. This mixture was diluted with ethyl acetate and washed serially with aqueous solution of sodium hydrogen carbonate, water, and saturated aqueous solution of NaCl. The organic layer was dried over MgSO4 and the solvent was distilled off to provide the title compound.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:66](O)(=[O:69])[CH2:67][OH:68]>CN(C=O)C>[OH:69][CH2:66][C:67]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:7][CH:8]=3)[N:14]=[C:15]([N:23]([CH2:24][CH2:25][OH:26])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH2:22]1)=[O:68]
Reactant: O=C(O)CO
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CO)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (100 mg, 0.23 mmol, Example 1) was dissolved in DMF (5 mL). N-Ethyldiisopropylamine (0.081 mL, 0.47 mmol) was added followed by O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (115 mg, 0.30 mmol) and glycolic acid (0.025 mL, 0.23 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude dissolved in DMF and acetonitrile, filtered and purified by prep. HPLC. The fractions containing the title compound were pulled together and freezed-dried over the weekend yielding 2-hydroxy-1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (21.0 mg, 18.49%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[C:5]([F:18])=[CH:4][N:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([CH2:27][S:28][CH3:29])[CH:26]=1)[NH2:23]>>[CH2:16]([O:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[C:6]1[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:23][C:22]2[CH:24]=[C:25]([CH2:27][S:28][CH3:29])[CH:26]=[C:20]([F:19])[CH:21]=2)[N:7]=1)[CH3:17]
Reactant: CSCc1cc(N)cc(F)c1
Reactant: CCOc1cc(F)ccc1-c1nc(Cl)ncc1F
Product: CCOc1cc(F)ccc1-c1nc(Nc2cc(F)cc(CSC)c2)ncc1F

Procedure:
Intermediate 36.2 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-4-(2-ethoxy-4-fluorophenyl)-5-fluoropyrimidine and 3-fluoro-5-[(methylsulfanyl)-methyl]aniline. The residue was purified by chromatography (hexane to hexane/ethyl acetate 7:3) to give the desired product.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[CH3:19][CH:20]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:21](Cl)=[O:22]>O1CCCC1>[CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:21](=[O:22])[C@H:20]([CH3:19])[CH2:24][C:25]([F:28])([F:27])[F:26]
Reactant: CC(CC(F)(F)F)C(=O)Cl
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](CC(F)(F)F)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a mixture of (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (3.22 g) and tetrahydrofuran (35 ml) at -70° C., under nitrogen was added 1.625M n-butyllithium (12.31 mL) and the mixture was stirred for 15 min. 2-Methyl-4,4,4-trifluorobutyryl chloride (3.5 g) was added to the reaction mixture which was stirred for 15 min at -70° C. and then at 0° C. for 1 hour. The reaction was quenched with ammonium chloride and extracted with ethyl acetate. The organic phase was washed (saturated NaHCO3, brine) and dried (MgSO4). Evaporation and flash chromatography, eluting with 5:95 then 1:9 ethyl acetate:petroelum ether, afforded the two diastereomeric products. Recrystallization from hexane at 20° C. gave (4R,5S)-4-methyl-3-((2R)-2-methyl-4,4,4-trifluorobutyryl)-5-phenyl-2-oxazolidinone (2.376 g, 42%) as colorless needles; mp 72.5°-73.5° C.; TLC, Rf =0.43, 1:9 ethyl acetate:petroleum ether; MS(CI): 316 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[N:15]1([S:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)(=[O:14])=[O:13])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(CCS(=O)(=O)N2CCOCC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1
Yield: 34.3 %

Procedure:
A solution of 370 mg (1.11 mmol) of 4-[2-(4-nitro-phenyl)-ethanesulfonyl]-morpholine (as prepared in the previous step) in MeOH (20 mL) was treated with 10% Pd/C (Degussa type E101-NE/W, Aldrich, 50% by weight water) and H2 (1 atm) at RT for 3 h. The mixture was filtered through Celite, the filter cake was washed with MeOH, and solvents were evaporated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50-70% EtOAc-hexane afforded 103 mg (34%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C12H18N2O3S, 271.1 (M+H). found 270.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][C:24]([CH3:30])=[N:25]3)[C:9]([CH2:15][S:16][CH2:17][CH3:18])([C:11]([F:14])([F:13])[F:12])[OH:10])=[C:4]([F:31])[C:3]=1[O:32]C.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][C:24]([CH3:30])=[N:25]3)[C:9]([CH2:15][S:16][CH2:17][CH3:18])([C:11]([F:12])([F:14])[F:13])[OH:10])=[C:4]([F:31])[C:3]=1[OH:32]
Reactant: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1ccc(Cl)c(OC)c1F)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1ccc(Cl)c(O)c1F)C(F)(F)F
Reaction time: 22 h

Procedure:
Analogously to example 10 44 mg (0.087 mmol) 4-chloro-2-fluoro-α-[(ethylsulfanyl)methyl]-3-methoxy-β-[(2-methylquinolin-5-yl)amino]-α-(trifluoromethyl)benzeneethanol in 1.7 ml dichloromethane are treated with 0.87 ml of a 1 M solution of boron tribromide in dichloromethane at −20° C. The typical work up after 22 hours at room temperature and chromatography on silica gel (acetone in hexane 50%) yields 30 mg of the desired product.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[CH3:5][N:6]([CH3:14])[C@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1>>[CH3:5][N:6]([CH3:14])[CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:3]([NH:2][CH3:1])=[S:4])[CH2:9][CH2:8]1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Reactant: CN=C=S
Product: CNC(=S)NC1CCC(N(C)C)CC1
Temperature: 25 °C

Procedure:
0.90 g of Methyl-isothiocyanate are added to a solution of 1.74 g of trans-4-dimethylamino-cyclohexanamine in 50 ml of EtAc. The mixture obtained is stirred at RT, solvent is evaporated and 1-(4-dimethylaminocyclohexyl)-3-methyl-thiourea is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH3:11])=[C:4]([CH2:12][CH3:13])[CH:3]=1.[N:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])=[C:15]=[O:16]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:11])[C:15]([NH:14][C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([C:20]#[N:21])[CH:18]=2)=[O:16])=[C:4]([CH2:12][CH3:13])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CCNC
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: CCc1cc(Br)ccc1CCN(C)C(=O)Nc1cccc(C#N)c1
Yield: 62.8 %

Procedure:
A solution of 36C (250 mg, 1.03 mmol) and 3-isocyanatobenzonitrile (164 mg, 1.03 mg) in CH2Cl2 (10 mL) was refluxed for 30 min. The solution was concentrated in vacuo and purified by flash chromatography (0% to 100% EtOAc in hexanes) to afford 36D (250 mg, 63%) as a yellow solid. MS (ESI) m/z 386.04/388.05 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[S:5][C:4]=1[C:16]([O:18]C)=O.[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH3:28]>>[C:8]([C:7]1[C:3]([O:2][CH3:1])=[C:4]([C:16]([NH:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH2:27][CH3:28])=[O:18])[S:5][C:6]=1[C:12]([O:14][CH3:15])=[O:13])([O:10][CH3:11])=[O:9]
Reactant: CCN1CCCC1CN
Reactant: COC(=O)c1sc(C(=O)OC)c(C(=O)OC)c1OC
Product: CCN1CCCC1CNC(=O)c1sc(C(=O)OC)c(C(=O)OC)c1OC

Procedure:
The above compound was prepared from trimethyl 3-methoxy-2,4,5-thiophene tricarboxylate and (±) 2-(aminomethyl)-1-ethyl-pyrrolidine as in Example 5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:43]([CH3:44])=[CH:42][N:41]=[C:40]([CH3:45])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:43]([CH3:44])=[CH:42][N:41]=[C:40]([CH3:45])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)cn1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)ncc3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K17) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (250 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([OH:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4].[Br:22]N1C(=O)CCC1=O>ClCCl.C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([Br:22])=[C:9]([OH:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(O)nc(-c2ccc(Cl)c(OC)c2F)n1
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(O)c1Br
Yield: 63.8 %

Procedure:
6-Hydroxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester(150 mg, 0.48 mmol) was combined with N-bromosuccinimide (180 mg, 1.0 mmol) in 7 mL dichloromethane plus 2 mL acetonitrile and heated to reflux for 2 hours. After cooling the volatiles were removed under vacuum and the residue was taken up in 15 mL dichloromethane plus 5 mL water. The organic phase was separated and washed with 10 mL 5% sodium bisulfite solution, washed with 10 mL brine, dried and evaporated to give 120 mg (63% yield) of 6-hydroxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-bromopyrimidine-4-carboxylic acid methyl ester: mp 192-195° C.; MS m/z 390/392; 1H NMR (DMSO-d6): δ 7.47 (m, 3H), 3.95 (d, 3H), 3.91 (s, 3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[N+:12]([O-])([OH:14])=[O:13].O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)c1ccccc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
To a solution of the 1-(2-fluoro-phenyl)-propan-1-one (99 mmol) in concentrated sulfuric acid (80 ml) cooled down to −30° C. was added slowly fuming nitric acid (8 ml) over 20 min and the solution was stirred at −30° C. for 15 min. The mixture was slowly poured into a stirred mixture of 200 ml of water and 400 g ice. The aqueous phase was extracted with ethyl acetate, the organic layer was extracted again with water and aqueous NaHCO3 1M. The organic layer was dried over Na2SO4, evaporated and the residue was purified by chromatography on silica using a mixture of heptane and ethylacetate as eluent to afford the pure nitro intermediate J. MS (ISP): m/z=198.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([N:16]2[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCO
Product: CC1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45.1 %

Procedure:
A flask was charged with 2,6-dichloro-3-nitropyridine (1.00 g, 5.00 mmol), absolute ethanol (25 mL), and 4-methylpiperidine (0.65 mL, 5.5 mmol) and stirred 15 h at RT. The solvents were removed in vacuo and purification of the resulting residue by silica gel preparative TLC eluting with 10% ethyl acetate in hexane yielded 577 mg (45%) of the title compound as a yellow glass. LC-MS (ESI, m/z): Calcd. for C11H15ClN3O2, 256.1/258.1 (M+H); found: 256.1/258.1.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+].C=O.O>O1CCCC1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (0.50 g, 1.1 mmol) is dissolved in 2 mL of anhydrous tetrahydrofuran, add potassium tert-butoxide (161 mg, 1.4 mmol) and paraformaldehyde (66 mg, 2.2 mmol) in one portion, the result mixture is heated to reflux for 2 h under nitrogen atmosphere. The reaction mixture is cooled to room temperature, add 15 mL of water, extract with toluene, the organic extracts are washed with saturated Na2CO3 aqueous solution and brine, dry over anhydrous Na2SO4, evaporate the solvent under vacuum to obtain the crude product which is purified by column chromatography to obtain (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl). Spectroscopic data as Example 23, Method 1.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[C:6]([O:9][C@@H:10]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[C@@H:31]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:30][C@H:11]1[O:12][C:13]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=2[CH3:26])=[C:16]([CH:27]([CH3:29])[CH3:28])[NH:15][N:14]=1)(=[O:8])[CH3:7].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([O:9][C@@H:10]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[C@@H:31]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:30][C@H:11]1[O:12][C:13]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:4]=[CH:3]/[CH2:2][CH2:1][OH:5])=[CH:21][C:20]=2[CH3:26])=[C:16]([CH:27]([CH3:29])[CH3:28])[NH:15][N:14]=1)(=[O:8])[CH3:7]
Reactant: C=CCCO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 90 °C
Yield: 50.6 %

Procedure:
Add 3-buten-1-ol (6.1 mL, 70 mmol) to a solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (15 g, 23.5 mmol) in acetonitrile (200 mL) and triethylamine (50 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (1.43 g, 4.7 mmol) and palladium acetate (526 mg, 2.35 mmol). After refluxing at 90° C. for 2 hours, cool and concentrate to remove the solvent under reduced pressure. Purify the resulting residue by flash chromatography (silica gel, gradient ethyl acetate/hexanes from 20-80% over 20 min, 330 g column) to provide the title compound (7.5 g, 11.9 mmol). MS (m/z): 631.2 (M+1), 629.2 (M−1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1.N1C=CC=CC=1.Cl.[NH2:34][OH:35]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([CH:25]=[N:34][OH:35])=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(COCc2ccccn2)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=Cc1ccc2c(c1)ncn2-c1cccc(COCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of compound 12a (220 mg, 0.64 mmol) and pyridine (0.08 mL, 1.5 equiv) in ethanol (2 mL) was added hydroxylamine hydrochloride (500 mg) and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (100 mL), washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using a mixture of ethyl acetate and pet-ether as the eluent to afford compound 14a (180 mg, 78%) as a solid. Mp 154-154.8° C. In analogy herewith, the following compounds were prepared: 1-[3-(1-Methyl-1H-imidazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14b) from 12b. Mp 209.8-211.7° C. and 1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14c) from 12c. Mp 145.8-147.7° C. O-Methyl 1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14h) from 12c and O-methyl hydroxylamine. LC-ESI-HRMS of [M+H]+ shows 377.1724 Da. Calc. 377.172525 Da, dev. −0.3 ppm 1-[3-(2-Methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14e) from 12e. LC-ESI-HRMS of [M+H]+ shows 362.1603 Da. Calc. 362.161625 Da, dev. −3.7 ppm O-Methyl 1-[3-(2-methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14i) from 12e and O-methyl hydroxyl amine. LC-ESI-HRMS of [M+H]+ shows 376.1755 Da. Calc. 376.177325 Da, dev. −4:9 ppm 1-[3-(1,3-Thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14j) from 12g. LC-ESI-HRMS of [M+H]+ shows 365.1074 Da. Calc. 365.107225 Da, dev. 0.5 ppm O-Methyl 1-[3-(1,3-thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14g) from 12g and O-methyl hydroxylamine. LC-ESI-HRMS of [M+H]+ shows 379.1238 Da. Calc. 379.122825 Da, dev. 2.6 ppm and 1-[3-(Pyridin-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14d) 1-[3-(Pyrimidin-4-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14f) are prepared likewise.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][O:12][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][NH:37]3)O1>>[NH:37]1[C:38]2[C:34](=[C:33]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([CH2:11][O:12][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:8][C:6]=4[N:7]=3)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CN(C)C(=O)COCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(C)C(=O)COCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethoxy)-N,N-dimethyl-acetamide was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 333. NMR: CDCl3: 3.02 (6 H, s, Me), 3.96-3.99 (4 H, m, CH2), 4.09-4.13 (4 H, m, CH2), 4.31 (2 H, s, CH2), 4.95 (2 H, s, CH2), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar), 9.03 (1 H, s, Ar) and 10.30 (1 H, s, NH). MS: (ESI+): MH+ 453.20
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:21]1([O:27][N:28]2[C:33]([CH3:35])([CH3:34])[CH2:32][CH:31]([OH:36])[CH2:30][C:29]2([CH3:38])[CH3:37])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([O:27][N:28]2[C:29]([CH3:37])([CH3:38])[CH2:30][CH:31]([O:36][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:32][C:33]2([CH3:35])[CH3:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 69 %

Procedure:
The title compound is prepared in 69% yield from the reaction of octadecanoyl chloride with 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine following the procedure in Example 17. Purification (Waters Prep. 500A HPLC, 100:1 heptane:ethyl acetate) yields a white solid, m.p. 44°-47° C.