Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(COC2C=CC=CC=2C(O)=O)C=CC=CC=1.C(Cl)(=O)OCC.N[C@@H:25]1[CH2:30][CH2:29][N:28]([CH:31](C)[CH2:32][C:33](C2C=CC=CC=2)(C2C=CC=CC=2)[C:34]([N:36](C)C)=[O:35])[CH2:27][C@H:26]1O>ClC(Cl)Cl.C(N(CC)CC)C>[N:28]1([CH2:31][CH2:32][CH2:33][C:34]([NH2:36])=[O:35])[CH2:29][CH2:30][CH2:25][CH2:26][CH2:27]1
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](N)[C@H](O)C1
Agent: CCOC(=O)Cl
Agent: O=C(O)c1ccccc1OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: NC(=O)CCCN1CCCCC1
Reaction time: 8 h

Procedure:
To a stirred and cooled (ice bath) solution of 4 parts of 2-(phenylmethoxy)benzoic acid in 90 parts of trichloromethane were added first 1.47 parts of N,N-diethylethanamine and then 1.6 parts of ethyl carbonochloridate at <5° C. After stirring for 1 hour in an ice bath, the thus obtained mixture was added dropwise to a cooled solution of 5.94 parts of trans-4-amino-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide in 90 parts of trichloromethane at a temperature below 5° C. Upon completion, stirring was continued overnight at room temperature. The organic layer was washed with water, a sodium carbonate solution in water and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was C solidified in 2,2'-oxybispropane. The product was filtered off and dried in vacuo at 60° C. yielding 3.7 parts (40.7%) of trans-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-4-[[2(piperidinebutanamide: mp 149.0° C. (compound 29).
Reaction SMILES: [N:1]1([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[C:26]([F:30])=[CH:25][C:21]=1[C:22](Cl)=[O:23]>O1CCOCC1>[N:1]1([CH:6]=[C:7]([C:22](=[O:23])[C:21]2[CH:25]=[C:26]([F:30])[C:27]([Cl:29])=[CH:28][C:20]=2[Cl:19])[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Reactant: COC(=O)C=CN1CCCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C(=CN1CCCC1)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 56.7 %

Procedure:
First a solution of 15.5 g of methyl 3-(1-pyrrolidinyl)acrylate in 25 ml of dioxane is added dropwise, and then 10.5 g of triethylamine are added to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 80 ml of anhydrous dioxane, while cooling in ice and stirring. The mixture is stirred at room temperature for 1 hour, heated to boiling under reflux for 30 minutes, and the solvent is removed by distillation in vacuo, and the residue is taken up in methylene chloride/H2O. The phases are separated and the aqueous solution is again extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate, and the methylene chloride is removed in vacuo. The crystalline residue is recrystallized from cyclohexane. 19.6 g of methyl 3-(1-pyrrolidinyl)-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 74°-76° C. are obtained.
Reaction SMILES: [ClH:1].C([O:6][C:7](=[O:33])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:32])[CH2:14][NH:15][S:16]([C:19]1[C:28]2[C:23](=[C:24]([N:29]([CH3:31])[CH3:30])[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])(C)(C)C.CCOCC>O1CCOCC1>[ClH:1].[CH3:30][N:29]([CH3:31])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[CH:22]=[CH:21][CH:20]=[C:19]2[S:16]([NH:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:7]([OH:33])=[O:6])=[O:32])(=[O:17])=[O:18]
Reactant: CN(C)c1cccc2c(S(=O)(=O)NCC(=O)N3CCC[C@H]3C(=O)OC(C)(C)C)cccc12
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN(C)c1cccc2c(S(=O)(=O)NCC(=O)N3CCC[C@H]3C(=O)O)cccc12
Reaction time: 1 h
Yield: 99 %

Procedure:
A cold (0° C.), saturated solution of hydrogen chloride in dioxane (400 mL) was added to N-(5-dimethylamino-1-naphthalenesulfonyl)-glycyl-L-proline tert-butyl ester (7.20 g, 15.6 mmol). The mixture was stirred at about 0° C. for about 2 hours and at room temperature for about 2 hours before ether (100 mL) was added. After refrigeration for about 1 hour, the mixture was suction-filtered and afforded 8.30 g (99%) of the title compound as a dense, white solid, m.p. 115°-135° C. (sealed tube); 1H NMR (D2O) δ 8.53 (d, J=8.8 Hz, 1H), 8.30 (d, J=8.7 Hz, 1H), 8.10 (d, J=7.4 Hz, H), 7.95 (d, J=7.8 Hz 1H), 7.74-7.67 (m, 2H), 3.84-3.67 (m, 2H), 3.61 (s, 6H), 3.32-3.17 (m, 2H), 1.96-1.87 (m, 1H), 1.77-1.67 (m, 3H); --C NMR (D2O) ppm 178.17, 178.03, 170.68, 170.34, 141.10, 137.84, 137.61, 133.07, 132.88, 131.39, 130.65, 129.57, 129.24, 128.50, 128.41, 128.11, 122.13, 61.88, 49.52, 49.27, 46.82, 33.44, 31.34, 26.84, 24.32; IR (KBr, cm-1) 3432, 3070, 2960, 1736, 1654, 1440, 1328, 1178, 1146, 1120, 872, 772, 586; MS m/z (MH+ -HCl) calcd 406.1437, obsd 406.1450.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[OH:36][CH2:37][CH:38]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:38][CH2:37][OH:36])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: O=CCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(CCO)CC3)cc2C2=CCCCC2)n1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 14, step (b)), and hydroxy-acetaldehyde according to the procedure in Example 21. 1H-NMR (400 MHz, CD3OD): δ 8.18 (d, 1H), 8.02 (s, 1H), 7.22 (dd, 1H), 7.14 (d, 2H), 5.82 (m, 1H), 3.94 (m, 2H), 3.74 (m, 2H), 3.30 (m, 2H), 3.18 (t, 2H), 2.92 (m, 1H), 2.30 (m, 4H), 2.20-1.98 (m, 4H), 1.96-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C24H29N5O2, 420.2 (M+H). found 420.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:15]2[CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[CH:12]=[CH:11][C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.Br[C:37]1[CH:49]=[CH:48][C:47]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]([CH3:51])([CH3:50])[C:39]=2[CH:38]=1.C(=O)([O-])[O-].[K+].[K+].S(=O)(O)[O-].[Na+].CCCCCCCCCCCC>[Cu].CO.C1(C)C=CC=CC=1>[CH3:50][C:40]1([CH3:51])[C:41]2[CH:42]=[C:43]([N:9]3[C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:2]([CH3:35])([CH3:1])[C:15]4[CH:14]=[C:13]([C:16]5[CH:21]=[CH:20][C:19]([N:22]([C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)[C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)=[CH:18][CH:17]=5)[CH:12]=[CH:11][C:10]3=4)[CH:44]=[CH:45][C:46]=2[C:47]2[C:39]1=[CH:38][CH:37]=[CH:49][CH:48]=2
Reactant: CC1(C)c2ccccc2Nc2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc21
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: CO
Product: CC1(C)c2ccccc2-c2ccc(N3c4ccccc4C(C)(C)c4cc(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)ccc43)cc21
Temperature: 200 °C
Reaction time: 35 h
Yield: 33.4 %

Procedure:
[4-(9,9-Dimethylacridan-2-yl)phenyl]-diphenylamine (2.02 g), 2-bromo-9,9-dimethyl-9H-fluorene (1.37 g), a copper powder (0.036 g), potassium carbonate (0.94 g), sodium bisulfite (0.078 g), and dodecane (4 ml) were added to a nitrogen-substituted reaction vessel and stirred at 200° C. for 35 hours. The mixture was allowed to cool to a room temperature, and toluene (30 ml) and methanol (30 ml) were added. Precipitated insoluble matter was removed by filtration and concentrated under reduced pressure to obtain a black crude product. The crude product was purified by column chromatography (carrier: silica gel; eluent: hexane/toluene), crystallized with diisopropyl ether/methanol, and then crystallized with ethyl acetate/diisopropyl ether/hexane to obtain a pale yellowish white powder of {4-[10-(9,9-dimethyl-9H-fluorene-2-yl)-9,9-dimethylacridan-2-yl]phenyl}-diphenylamine (0.96 g; yield 33%).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[C:5](=[O:15])[NH:4][N:3]=1.O.C(O)C.S(=O)(=O)(O)O>[Pd].C(O)(=O)C>[CH3:1][C:2]1[C:14]2[N:13]3[C:8]([CH2:9][CH2:10][CH2:11][CH2:12]3)=[CH:7][C:6]=2[C:5](=[O:15])[NH:4][N:3]=1
Reactant: Cc1n[nH]c(=O)c2cc3ccccn3c12
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c(=O)c2cc3n(c12)CCCC3

Procedure:
4-Methylpyridazino[4,5-b]indolizin-1-one (5.08 g, 25.5 mmol) was hydrogenated at room temperature and 55 psi using a Parr apparatus in a mixture containing 100 mL each of water, ethanol and acetic acid, 3 mL of concentrated sulfuric acid, and 10% Pd on charcoal (500 mg). A white precipitate was observed. The precipitate and catalyst were filtered through Solka Floc and the solids were washed with methanol and methylene chloride. The washes were evaporated to give 6,7,8,9-tetrahydro-4-(methyl)pyridazino[4,5-b]indolizin-1-one (XI). The reduction filtrate was evaporated in vacuo to remove most of the volatiles, then filtered to isolate additional XI. The aqueous phase was then washed with methylene chloride to extract the remaining XI. The product from all three fractions was combined and dried in vacuo to give 3.2 g (67%) of XI.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].[CH2:28]([CH2:31][OH:32])[CH2:29][NH2:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:25])([CH3:26])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:30][CH2:29][CH2:28][CH2:31][OH:32])=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: NCCCO
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NCCCO)C1(C)C

Procedure:
The product from Example 173 and propanolamine (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.19 (s, 3H), 1.23 (s, 3H), 1.26-1.45 (m, 3H), 1.49-1.57 (m, 2H), 1.57 (s, 9H), 1.57-1.67 (m, 3H), 1.96-2.08 (m, 1H), 2.62-2.68 (m, 3H), 2.72-2.83 (m, 1H), 2.95-3.06 (m, 1H), 3.13-3.26 (m, 1H), 3.37-3.43 (m, 2H), 4.42 (t, J=5.3 Hz, 1H), 7.56 (t, J=5.7 Hz, 1H), 8.50 (s, 1H). (ESI+) m/z 452 (M+H)+. Anal. calcd. for C24H41N3O3S: C, 63.82; H, 9.15; N, 9.30. Found: C, 63.12; H, 8.91; N, 9.25.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.N1C=CC=CC=1>[CH3:25][S:26]([NH:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
To a stirred solution of (E)-5-amino-1-(2-pyridyl)-2-styryl-1H-benzimidazole (162 mg, 0.52 mmol) in dichloromethane (3 ml) and pyridine (1 ml) was added a solution of methanesulfonyl chloride (63 mg, 0.55 mmol) in dichloromethane (2 ml) dropwise. The reaction mixture was stirred for 2 h at room temperature and then partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate solution (50 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 ml). The combined extracts were washed with brine (50 ml), dried (sodium sulfate) and concentrated in vacuo to give brown oil. It was purified by column chromatography (silica gel, 20 g; n-hexane/ethyl acetate (5/1)). Recrystallization of the residue from ethyl acetate afforded 70 mg (34%) of the titled compound as off white solids.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:33]([O-:36])(=[O:35])[CH3:34].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[C:33]([O:36][CH2:12][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:35])[CH3:34]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(Br)c2ncccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)OCc1ccc(Br)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 8-bromo-5-methylquinoline (5.4 g, 24.3 mmol), N-bromosuccinimide (5.2 g, 29.2 mmol), and 2,2′-azobis(2-methylpropionitrile) (AIBN) (0.40 g, 24.3 mmol) in carbon tetrachloride (80 mL) was heated at reflux for 3 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered, using hexane for rinsing. The filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (50 mL), and then sodium acetate (4.0 g, 48.8 mmol) was added. The resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with a mixture of ethyl acetate and hexane (3:7). The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate as eluent to afford the title product as a pale yellow solid (4.8 g).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[CH:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[C:20]([O:19][C:17]([CH:4]1[CH2:3][C:2](=[O:1])[O:6][CH:5]1[C:7]([OH:9])=[O:8])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)O
Yield: 97.3 %

Procedure:
4.92 g of 2-benzyl 3-tert-butyl (2RS,3RS)-5-oxotetrahydrofuran-2,3-dicarboxylate in 50 ml of ethyl acetate was catalytically reduced with 500 mg of a 10% palladium-carbon catalyst at room temperature under atmospheric pressure of hydrogen for 3 hours. The catalyst was filtered off, and the filtrate was evaporated to dryness under reduced pressure to give 3.44 g of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]4([CH2:25][CH2:24]4)[C:16]3=[O:26])[CH2:8][CH2:7]2)[N:5]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][N:3]1[CH2:33][C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[C:37]([O:39]C(C)(C)C)=[O:38].C(O)=O.C([O-])=O.[ClH:53]>O1CCOCC1>[ClH:53].[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]4([CH2:25][CH2:24]4)[C:16]3=[O:26])[CH2:8][CH2:7]2)[N:5]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:4][N:3]1[CH2:33][C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[C:37]([OH:39])=[O:38]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)C5(CC5)c5ccccc54)CC3)C2=O)c1
Agent: Cl
Agent: O=C[O-]
Solvent: C1COCCO1
Solvent: O=CO
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)C5(CC5)c5ccccc54)CC3)C2=O)c1
Yield: 65 %

Procedure:
tert-Butyl 3-((4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.27 g, 0.435 mmol) and formic acid (4 mL) were stirred at room temperature for 20 hours. The reaction was evaporated to dryness and the residue purified by PTLC (10% methanol/dichloromethane) to give product as an oil; 1H NMR (DMSO-d6); 61.52 (m, 2H); 1.59 (m, 2H); 1.68 (d, J=13.6 Hz, 2H); 1.87 (m, 2H); 2.57-2.62 (m, 4H); 2.91 (m, 4H); 3.82 (t, J=6.4 Hz, 2H); 4.60 (s, 2H); 4.62 (s, 2H); 6.76 (t, J=7.2 Hz, 1H); 6.86 (d, J=8.4 Hz, 2H); 6.96-7.03 (m, 2H); 7.17-7.23 (m, 4H); 7.48-7.55 (m, 2H); 7.87-7.89 (m, 2H); 8.15 (s, 1H). The formate salt was dissolved in 4M hydrochloric acid in 1,4-dioxane (5 mL) and then evaporated under vacuum. The residue was dissolved in acetonitrile (5 mL) and water (5 mL) and lyophilized to give product as a white solid (0.17 g, 65%); HPLC rt 10.65 min; 1H NMR (DMSO-d6); δ1.54 (m, 2H); 1.62 (m, 2H); 1.90 (d, J=14.4 hz, 2H); 2.11 (m, 2H); 2.92-2.98 (m, 2H); 3.22 (m, 2H); 3.46-3.70 (m, 4H); 3.85 (t, J=7.2 hz, 2H); 4.64 (s, 2H); 4.65 (s, 2H); 6.79 (t, J=7.6 hz, 1H); 7.00-7.06 (m, 4H); 7.19-7.29 (m, 4H); 7.49-7.58 (m, 2H); 7.87-7.89 (m, 2H); 10.6 (br s, 1H); 13.1 (br s, 1H); MS for C34H36N4O4 m/z 565 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH2:23][CH:24]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)[C:25]([NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[CH2:40]([O:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][CH:24]([NH:23][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:13][CH:12]=2)[C:25](=[O:26])[NH:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:34][CH:35]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)NC(=O)C(N)Cc1ccc(OCc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.589 g (3.026 mmol) 4-tert-butylbenzoic acid (Aldrich, Milwaukee Wis.) 1.06 mL (6.5 mmol) N,N-diisopropylethylamine, and 1.15 g (3.026 mmol) O-Benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)-uronium hexafluorophosphate in 6 mL dry DMF was stirred in an ice bath for 35 minutes, when 1.00 g (3.026 mmol) of 2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (Example 1, Step B) was added. The resulting solution was warmed to 25° C. and stirred for 60 minutes. The mixture was poured into 20 mL diethyl and washed sequentially with 25 mL each of saturated aqueous sodium bicarbonate solution and twice with brine. The mixture was then dried over anhydrous sodium sulfate and concentrated at reduced pressure giving a pale amber solid that was purified by column chromatography on silica gel with 30% ethyl acetate in hexane to give N-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-4-tert-butyl-benzamide as a white solid; mp 124-131° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][O:11][C:10](=[O:13])[C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1>CN(C=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[C:10](=[O:13])[O:11][CH2:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[CH:7][CH:6]=2)=[CH:15][CH:16]=1
Reactant: Cc1cccc(CCl)n1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)COC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4cccc(C)n4)cc3)COC2=O)cc1
Temperature: 80 °C
Yield: 2.4 %

Procedure:
To a solution of 4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)furan-2(5H)-one (300 mg, 1.06 mmol) in DMF (10 mL) were added K2CO3 (294 mg, 2.12 mmol), 2-(chloromethyl)-6-methylpyridine (225 mg, 1.59 mol) at RT. The reaction mixture was then heated at 80° C. for 16 h, quenched with ice and then extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 3-(4-methoxyphenyl)-4-(4-((6-methylpyridin-2-yl)methoxy)phenyl)furan-2(5H)-one (10 mg) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.44 (d, J=7.2 Hz, 1H), 7.79 (m, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.38-7.27 (m, 3H), 7.16 (d, J=7.2 Hz, 2H), 6.99-6.92 (m, 2H), 5.41 (s, 2H), 5.33 (s, 2H), 2.79 (s, 3H). MS: M+H: m/z=388.2.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:12][CH3:13].[NH2:15][CH2:16][CH:17]([NH2:19])[CH3:18]>>[CH2:12]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH3:11])[C:4]=1[CH2:3][C:2]1[NH:15][CH2:16][CH:17]([CH3:18])[N:19]=1)[CH3:13]
Reactant: CC(N)CN
Reactant: CCc1cccc(CC)c1C=C(Br)Br
Product: CCc1cccc(CC)c1CC1=NC(C)CN1

Procedure:
rac-2-(2,6-Diethyl-benzyl)-4-methyl-4,5-dihydro-1H-imidazole was prepared from 2-(2,2-dibromo-vinyl)-1,3-diethyl-benzene and 1,2-diaminopropane in analogy to Example 1 e): orange crystals; MS (EI): 230.2 (M+. ), 215.2 ((M-CH3)+.), 201.2 (((M-CH3CH2)+.), 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]([CH3:42])[CH2:28][CH2:29][CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:30][CH2:29][CH2:28][N:27]([CH3:42])[CH3:26])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2c1
Yield: 39.5 %

Procedure:
A mixture of 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.051 g (0.2 mmole) of toluene-4-sulfonic acid 3-dimethylamino-propyl ester, 1 mL of dimethylformamide and 0.160 g (0.5 mmole) of cesium carbonate was heated at 100 degrees for 30 minutes. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 30:70-100:0) to give 0.018 g of 4-(3-chloro-phenyl)-2-[6-(3-dimethylamino-propoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.31) as a white powder. MH+/Z=456
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C@H:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:7]([CH3:14])[O:6][C:4]1=[O:5].C(=O)(O)[O-:16].[Na+]>C(Cl)Cl>[NH2:2][C@@H:3]([C@H:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@H:7]([OH:6])[CH3:14])[C:4]([OH:16])=[O:5]
Reactant: CCOC(=O)[C@H]1[C@H](N)C(=O)O[C@@H]1C
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]([C@H](N)C(=O)O)[C@@H](C)O

Procedure:
56.0 g of 2(S)-amino-3(S)-ethoxycarbonyl-4(R)-pentanolide hydrochloride are dissolved in methylene chloride and the pH is adjusted to 7.5 with sodium bicarbonate solution. The methylene chloride phase is separated off, the aqueous phase is saturated with sodium chloride and extracted repeatedly with methylene chloride, and the organic phases are concentrated by evaporation. 106 ml of 2N sodium hydroxide solution are added dropwise to the residue in 120 ml of ethanol at 0° C. within a period of 6 hours. The solution is then concentrated to half its volume, adjusted to pH 3.9 with 103 ml of 2N hydrochloric acid, and completely concentrated by evaporation. The residue is crystallised from isopropanol/diisopropyl ether, stirred up with methanol and filtered over silica gel. [α]36520 =+14.5° (1% in H2O), m.p. 150°-151° C.