Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][OH:21].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CCO.ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H]2CO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
A solution of 10.0 g (50.2 mmol) of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 6.00 ml=6.15 g (60.2 mmol) of (S)-(−)-pyrrolidin-2-yl-methanol in 100.0 ml of EtOH was treated with 100.0 ml of 1,2-dichloroethane, followed by 7.53 ml (60.2 mmol) of borane-pyridine complex (8 molar). Then, 7.46 ml=7.84 g (130.5 mmol) of acetic acid was added to this solution. After stirring at RT for 16 hours, the reaction mixture was poured into crashed ice; then, the pH was adjusted to 9-10 with sodium carbonate solution and the mixture was extracted twice with EtOAc; the combined organic phases were washed with water, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 10.4 g (73%) of the title compound as light yellow oil. MS: 285.1 (MH+).
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([CH3:14])([CH3:13])[O:11][B:10]([OH:15])[C:9]=2[CH:16]=1)([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:50][C:51]1[CH:52]=[C:53]([C:59]2([C:76]([F:79])([F:78])[F:77])[O:63][N:62]=[C:61]([C:64]3[N:65]4[C:69]([C:70]([C:73](O)=[O:74])=[CH:71][CH:72]=3)=[CH:68][CH:67]=[CH:66]4)[CH2:60]2)[CH:54]=[C:55]([Cl:58])[C:56]=1[Cl:57]>C1COCC1.CC(=O)OCC>[OH:15][B:10]1[C:9]2[CH:16]=[C:5]([C:2]([NH:1][C:73]([C:70]3[C:69]4[N:65]([CH:66]=[CH:67][CH:68]=4)[C:64]([C:61]4[CH2:60][C:59]([C:53]5[CH:54]=[C:55]([Cl:58])[C:56]([Cl:57])=[C:51]([Cl:50])[CH:52]=5)([C:76]([F:79])([F:77])[F:78])[O:63][N:62]=4)=[CH:72][CH:71]=3)=[O:74])([CH3:4])[CH3:3])[CH:6]=[CH:7][C:8]=2[C:12]([CH3:14])([CH3:13])[O:11]1
Reactant: CC(C)(N)c1ccc2c(c1)B(O)OC2(C)C
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(2-aminopropan-2-yl)-3,3-dimethylbenzo[c][1,2]-oxaborol-1(3H)-ol (100 mg), HATU (277 mg, 0.73 mmol) and DIPEA (0.2 mL, 1.1 mmol) in THF (5 mL) can be added 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.37 mmol). The reaction mixture can be stirred at rt overnight. EA can be added and the mixture can be washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue can be purified by prep-HPLC to give the final title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])[F:11])[NH2:5].C(N(CC)CC)C.[CH3:20][C:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.O>C(Cl)Cl>[F:12][CH:10]([F:11])[O:9][C:8]1[CH:7]=[CH:6][C:4]([NH:5][C:24]([C:21]2([CH3:20])[CH2:23][CH2:22]2)=[O:25])=[CH:3][C:2]=1[F:1]
Reactant: CC1(C(=O)Cl)CC1
Reactant: Nc1ccc(OC(F)F)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1(C(=O)Nc2ccc(OC(F)F)c(F)c2)CC1
Yield: 83.9 %

Procedure:
To a solution of 3-fluoro-4-difluoromethoxyaniline (1.8 g) in methylene chloride (50 ml), triethylamine (1.1 g) was added, and a solution of 1-methylcyclopropanecarbonyl chloride (1.2 g) in methylene chloride was dropwise added thereto while stirring and ice-cooling. After stirring at room temperature for 1 hour, the reaction mixture was admixed with water and extracted with ether. The extract was washed with 1 N hydrochloric acid, sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The oily residue (2.5 g) was chromatographed on silica gel and eluted with a mixture of hexane and acetone to give N-(4-difluoromethoxy-3-fluorophenyl)-1-methylcyclopropanecarboxamide (2.2 g). nD24 1.5061.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][CH2:58][CH2:59][CH2:60][NH2:61])[CH:52]=1>CN(C=O)C>[C:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:61][CH2:60][CH2:59][CH2:58][CH2:57][C:53]3[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=3)=[O:18])=[CH:19][CH:20]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCOc2ccc(C(=O)O)cc2)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1c(OCCOc2ccc(C(=O)NCCCCc3cccnc3)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a cold (0° C.) solution of 1.22 g of 4-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)ethoxy]benzoic acid in 15 mL of anhydrous DMF was added to 0.8 mL of diphenylphosphoryl azide and 1.05 mL of anhydrous triethylamine. The resulting mixture was stirred at 0° C. for one hour and then 0.56 g of 3-pyridine butanamine was added. The mixture was stirred in ice bath for 1 hour and at room temperature for 6 hours. The solvent was removed in vacuo, the residue was dissolved in methylene chloride and washed with sodium bicarbonate solution. The extract was dried (over magnesium sulfate) and concentrated in vacuo to an oil which was purified by HPLC using 7% methanol-ethyl acetate to give an oil which was triturated with ethyl acetate-ether and filtered to yield 1.0 g, mp 93° , (60% yield) of 4-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)-ethoxy]-N-[4-(3-pyridinyl)butyl]benzamide, the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)C(=O)C2C=CC(CCC)=CC=2)=[CH:4][CH:3]=1.F[C:28]1[CH:29]=[C:30]([CH:48]=[CH:49][C:50]=1O)[C:31](N(C1C=CC(F)=CC=1)C1C=CC(O)=CC=1)=O.O[C:53]1C=CC(N(C2C=CC(O)=CC=2)C(=O)C2C=CC=C(C)C=2C)=CC=1.FC1C=C(C=CC=1O)C(N(C1C=CC(O)=CC=1)C1C=CC(O)=CC=1)=O.FC1C=C(C=CC=1O)C(N(C1C=CC(O)=CC=1)C1C=CC=CC=1)=O.FC1C(C)=C(C=CC=1)C(N(C1C=CC(O)=CC=1)C1C=CC(O)=CC=1)=O>>[CH2:31]([O:26][C:23]1[CH:22]=[CH:21][C:20]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH3:53])=[CH:7][CH:6]=2)=[CH:25][CH:24]=1)[C:30]1[CH:48]=[CH:49][CH:50]=[CH:28][CH:29]=1
Reactant: CCCc1ccc(C(=O)N(c2ccc(O)cc2)c2ccc(O)cc2)cc1
Reactant: O=C(c1ccc(O)c(F)c1)N(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: Cc1cccc(C(=O)N(c2ccc(O)cc2)c2ccc(O)cc2)c1C
Agent: Cc1c(F)cccc1C(=O)N(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C(c1ccc(O)c(F)c1)N(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C(c1ccc(O)c(F)c1)N(c1ccccc1)c1ccc(O)cc1
Product: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
The following compounds where synthesized as described herein above and characterized and summarized in Table 1: N,N-bis(4-hydroxyphenyl)-4-propylbenzamide (II); 3-fluoro-N-(4-fluorophenyl)-4-hydroxy-N-(4-hydroxyphenyl)benzamide (IV); N,N-bis(4-hydroxyphenyl)-2,3-dimethylbenzamide (V); 3-fluoro-4-hydroxy-N,N-bis(4-hydroxyphenyl)-benzamide (VII); 3-fluoro-4-hydroxy-N-(4-hydroxyphenyl)-N-phenylbenzamide (XI); and 3-fluoro-N,N-bis(4-hydroxyphenyl)-2-methylbenzamide (XII).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:3]=1.[NH2:18][CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1>O>[ClH:1].[ClH:1].[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:4]2[N:3]=[C:2]([NH:18][CH:19]3[CH2:20][C:21]([CH3:28])([CH3:27])[NH:22][C:23]([CH3:26])([CH3:25])[CH2:24]3)[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=2)=[CH:12][CH:13]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(C)c1cc(Cl)nc(-c2ccc(Cl)cc2)n1
Solvent: O
Product: CC(C)c1cc(NC2CC(C)(C)NC(C)(C)C2)nc(-c2ccc(Cl)cc2)n1
Product: Cl
Temperature: 150 °C

Procedure:
A mixture of 534 mg of 4-chloro-2-(4-chlorophenyl)-6-isopropylpyrimidine and 1.8 g of 4-amino-2,2,6,6-tetramethylpiperidine was heated at 150° C. for 2 hours with stirring. After cooling, 20 ml of water were added and the mixture was stirred at room temperature. The white precipitate was filtered off with suction, dried in vacuo and taken up in 20 ml of ethyl acetate. By addition of hydrogen chloride, the title compound was precipitated, filtered off with suction and dried in vacuo. Yield: 0.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=[O:9])=[C:4]([NH:11][C:12]([C:14]([O:16]CC)=O)=[O:13])[CH:3]=1>CN(C)C=O.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([OH:9])[C:14](=[O:16])[C:12](=[O:13])[NH:11]2
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)ccc2n(O)c1=O
Yield: 77.3 %

Procedure:
A solution of 2 g (7.3 mmol) 4-chloro-2-ethoxalylamino-1nitrobenzene in 50 ml dimethyIformamide was hydrogenated at atm. pressure by using Ra-Ni (0.2 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with water to give a crude product. Recrystallization (dimethylformamide-water) gave 1.2 g (78%) 6-chloro-1-hydroxyquinoxaline-2,3(1H,4H)-dione M.p. >300° C. 1H-NMR (DMSO-d6): 11.8 (2H, broad s), 7.2 (3H, m). MS (m/e): 212 (M+, 60%).
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[CH3:16][Si:17](Cl)([CH2:19][CH2:20][Si:21](Cl)([CH3:23])[CH3:22])[CH3:18]>O1CCCC1>[F:8][C:9]1[CH:10]=[C:11]([N:12]2[Si:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][Si:17]2([CH3:18])[CH3:16])[CH:13]=[CH:14][CH:15]=1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Reactant: Nc1cccc(F)c1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of freshly distilled diisopropylamine (22.9 mL) in dry tetrahydrofuran (175 mL) at -78° C. under N2 is treated with n-butylithium (1.6 M in hexanes, 109 mL) dropwise over 15 minutes, and the resulting mixture is stirred at -78° C. for 45 minutes and is then added over ten minutes via cannula to a solution of 3-fluoroaniline (8.00 mL) in dry tetrahydrofuran (166 mL) at -78° C. under N2. The resulting reaction mixture is stirred at -78° C. for 50 minutes and is then treated with a solution of 1,1,4,4-tetramethyl-1,4-dichlorodisilethylene (18.3 g) in dry tetrahydrofuran (85 mL). The mixture is allowed to slowly warm to ambient temperature over four hours with stirring and is then washed with water (2×200 mL) and saline (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (CDCl3, 400 MHz) 7.12, 6.65, 6.58, 0.86, 0.24 δ.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.[CH2:27]([NH2:30])[CH:28]=[CH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([NH:11][C@H:12]([C:17]([NH:30][CH:27]=[CH:28][CH3:29])=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: C=CCN
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC=CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Cbz-leucine (3.0 g, 11.3 mmol) was dissolved in DMF (50 ml), then NMM (1.3 g, 12.4 mmol) was added, followed by allyl amine (0.65 g, 0.85 mmol), and HBTU (4.3 g, 11.3 mmol) and the reaction was stirred overnight at RT. The reaction was diluted with water, extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 40% EtOAc: hexanes): MS(ES) M+H+ =305.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[CH2:22]1[CH2:32][CH2:31][N:30]2[C:25](=NCC[CH2:29]2)[CH2:24][CH2:23]1.C1(S(N=C=O)(=O)=[O:40])C=CC=CC=1.Cl>CS(C)=O>[O:11]=[C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:29]([NH:30][C:25]2[CH:24]=[CH:23][CH:22]=[CH:32][CH:31]=2)=[O:40])(=[O:19])=[O:20])=[CH:14][CH:13]=1
Reactant: NS(=O)(=O)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CS(C)=O
Product: O=C(Nc1ccccc1)NS(=O)(=O)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 4-(1,3-dioxobenzo[c]azolidin-2-yl)benzenesulfonamide in 660 uL of DMSO was added 60 mg (0.40 mmol) of DBU followed by 36 μl (0.33 mmol) of phenylsulfonylisocyanate. After stirring for 0.5 h, the mixture was poured into 1N HCl, cooled, and the precipitate was collected by filtration and dried under vacuum to give 137 mg (100%) of the titled compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: O[C@@H]1CCNC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CC[C@@H](O)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3R)-pyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 7.88 (dd, J=7.83, 1.01 Hz, 1 H), 7.79-7.69 (m, 2 H), 7.52 (td, J=7.52, 1.14 Hz, 1 H), 7.44 (d, J=8.59 Hz, 1 H), 7.33-7.27 (m, 1 H), 7.23 (dd, J=8.59, 1.77 Hz, 1 H), 6.02 (s, 1 H), 5.04 (s, 2 H), 4.55-4.42 (m, 2 H), 3.89-3.76 (m, 2 H), 3.59-3.42 (m, 4 H), 3.37 (s, 2 H), 2.35 (s, 3 H), 2.16-1.97 (m, 2 H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:19][CH2:18][CH2:17][C:9]3[CH:10]=[C:11]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
55 mg (78%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-(4-chlorophenyl)piperazine (38 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[CH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[CH:14]=[C:15]([CH:18]=[O:19])[S:16][CH:17]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:13]2[CH:14]=[C:15]([CH:18]=[O:19])[S:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCCCc1ccccc1
Reactant: O=Cc1cc(Br)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cc(C#CCCCc2ccccc2)cs1
Temperature: 50 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
5-Phenylpent-1-yne (18.1 g, 126 mmol) was dissolved in tetrahydrofuran (100 ml), and then 4-bromothiophen-2-carboxaldehyde (18.7 g, 98 mmol) in tetrahydrofuran (200 ml), triethylamine (150 ml, 1.07 mmol), copper(I) iodide (962 mg, 5.05 mmol), and dichlorobis(triphenylphosphine)palladium (3.54 g, 5.04 mmol) were added thereto, and the mixture was stirred at 50° C. for 4 hours under a nitrogen atmosphere. After the reaction solution was filtered, the filtrate was evaporated under reduced pressure. To the residue was added ether, and the solution was washed with water and a saturated aqueous sodium chloride solution, respectively. After the ether layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=100:1-10:1) to afford the title compound (19.4 g, 78% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:32]=[CH:31][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1>>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]([C:21]2[CH:31]=[CH:32][C:18]([NH:1][C:2]3[N:7]=[C:6]([C:8]4[N:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]5=[N:10][CH:9]=4)[CH:5]=[CH:4][N:3]=3)=[CH:19][CH:20]=2)=[O:23])=[CH:25][CH:26]=1
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Reactant: Cc1ccc(C(=O)c2ccc(Br)cc2)cc1
Product: Cc1ccc(C(=O)c2ccc(Nc3nccc(-c4cnc5ccccn45)n3)cc2)cc1
Yield: 17 %

Procedure:
The title compound was prepared from 2-amino-4-(imidazo[1,2-a]pyridin-3-yl)pyrimidine and 4-bromo4′-methylbenzophenone following the general method of Example 2. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 98:2, as the eluent affording 52 mg (17% yield) of the title compound as a yellow solid: mp 238.9-239.2° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.15-10.13 (m, 2 H), 8.64 (s, 1 H), 8.50 (d, J=5.3 Hz, 1 H), 7.96 (d, J=8.5 Hz, 2 H), 7.79-7.74 (m, 3 H), 7.63 (d, J=7.8 Hz, 2 H), 7.53-7.49 (m, 2 H), 7.35 (d, J=7.7 Hz, 2 H), 7.16 (t, J=6.8 Hz, 1 H), 2.40 (s, 3 H); 13C NMR (400 MHz, DMSO-d6) δ 194.4, 159.4, 157.7, 157.4, 148.4, 145.1, 142.7, 139.4, 135.5, 131.5, 130.1, 129.9, 129.8, 129.3, 127.5, 121.3, 118.2, 117.8, 114.2, 108.6, 21.5; MS (TSP) m/z 406 (M+1).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].[NH2:19][C@H:20]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)[C@H:21]([OH:25])[C:22]([OH:24])=[O:23].O1CCOCC1>O>[Br:32][C:28]1[CH:27]=[C:26]([C@@H:20]2[C@@H:21]([C:22]([OH:24])=[O:23])[O:25][C:2](=[O:4])[NH:19]2)[CH:31]=[CH:30][CH:29]=1
Reactant: N[C@H](c1cccc(Br)c1)[C@H](O)C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1N[C@H](c2cccc(Br)c2)[C@@H](C(=O)O)O1
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To triphosgene (36.5 mg, 0.123 mmol) and Na2CO3 (65.2 mg, 0.615 mmol) in Water (2.000 mL) at 0° C. was added dropwise a solution of (2S,3R)-3-amino-3-(3-bromophenyl)-2-hydroxypropanoic acid (20 mg, 0.077 mmol) in Water (0.5 mL)/1,4-Dioxane (0.5 mL). After 15 min, the ice bath was removed and stirring was continued for one hour. ethylacetate (1 ml) was added to the reaction mixture and after five minutes the ethylacetate layer was discarded and the aqueous layer was acidified to pH 2 and extracted with ethylacetate (5 mL×3). The combined organics were dried over magnesium sulfate, filtered and concentrated providing (4R,5S)-4-(3-bromophenyl)-2-oxooxazolidine-5-carboxylic acid (14.2 mg, 0.047 mmol, 61.3% yield) as a white solid. Mass spec.: 287.79 (MH)+.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:22]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=O)=O)=CC=1.[C:34]([O-])(=[O:36])[CH3:35].[Na+]>CS(C)=O.CCOC(C)=O>[C:34]([O:11][CH2:12][C:13]12[CH2:18][CH2:17][C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:22]=3)([CH2:19][CH2:20]1)[O:15][CH2:14]2)(=[O:36])[CH3:35]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4cccc(Oc5ccccc5)c4)(CC2)OC3)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 70 °C
Reaction time: 72 h

Procedure:
A mixture of (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate (0.1 g, 0.215 mmol) and sodium acetate (0.212 g, 2.58 mmol) in DMSO (5 mL) was stirred at 70° C. in a seal tube for 3 days. The reaction was diluted with EtOAc (5 mL) and washed with water (3×5 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl acetate. The mixture of the above acetate (0.076 g, 0.216 mmol) and 1 M NaOH (0.65 mL, 0.647 mmol) in THF/MeOH (1:1 of a 2 mL solution) was stirred at rt for 18 h. The reaction was diluted with EtOAc (5 mL) and washed with water (3×5 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 50% EtOAc:hexanes) to afford the title compound (0.05 g, 75% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.39-7.26 (m, 3H), 7.21-7.14 (m, 2H), 7.14-7.08 (m, 1H), 7.05-7.00 (m, 2H), 6.88 (ddd, J=8.1, 2.5, 1.0 Hz, 1H), 3.99-3.89 (m, 2H), 3.38 (s, 2H), 2.16-2.00 (m, 4H), 1.84-1.71 (m, 3H), 1.71-1.57 (m, 2H).
Reaction SMILES: [C:1]([CH:3]([CH:7]([CH3:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[C:4]([OH:6])=O)#[N:2].[NH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][N:17]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[C:18]1[C:24]#[N:25].C(N(CC)CC)C>S(Cl)(Cl)=O.C(OCC)(=O)C>[Cl:23][C:20]1[CH:19]=[C:18]([C:24]#[N:25])[N:17]([CH2:16][CH2:15][CH:14]([NH:13][C:4](=[O:6])[CH:3]([C:1]#[N:2])[CH:7]([CH3:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:26])[C:21]=1[CH3:22]
Reactant: CC(C(C#N)C(=O)O)C(C)(C)C
Reactant: Cc1c(Cl)cc(C#N)n1CCC(C)N
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cc(C#N)n1CCC(C)NC(=O)C(C#N)C(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.54 g (3.5 mmol) 2-cyano-3,4,4-trimethylpentanoic acid in 15 mL thionyl chloride was heated at reflux for 30 min. The thionyl chloride was stripped and the residue was dried in vacuo. The residue was then dissolved in 20 mL methylene chloride and a solution of 0.66 g (3.13 mmol) of 1-(3-aminobutyl)-4-chloro-5-methyl-1H-pyrrole-2-carbonitrile and 0.59 mL (4.2 mmol) triethylamine was added dropwise. The mixture was stirred at room temperature overnight. Solvent was stripped and the residue was taken up in ethyl acetate which was washed with water and brine. Drying (MgSO4) and removal of solvent gave an oil which was chromatographed (40% ether in hexanes) on silica gel to give the title compound as a mixture of diastereomers, mp 111–118° C. 1H NMR (CDCl3) δ 1.0 (m, 3H), 1.2–1.3 (2m, 6H), 1.4 (d, 1H), 1.6 (m, 2H), 1.9 (m, 2H), 2.2 (m, 3H), 4.1 (2m, 2H), 5.7 (m, 1H), 6.65 (2s, 1H).