Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([C@@H:7]2[O:11][C@H:10]([CH2:12][O:13][P:14]([O:17][P:18]([O:21][CH2:22][C@H:23]3[O:27][C@@H:26]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH2:37])[C:31]=5[N:30]=[CH:29]4)[C@H:25]([OH:38])[C@@H:24]3[OH:39])([OH:20])=[O:19])([O-:16])=[O:15])[C@@H:9]([OH:40])[C@H:8]2[OH:41])[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH:2]=1>O>[CH:34]1[N:35]=[C:36]([NH2:37])[C:31]2[N:30]=[CH:29][N:28]([C@@H:26]3[O:27][C@H:23]([CH2:22][O:21][P:18]([O:17][P:14]([O:13][CH2:12][C@H:10]4[O:11][C@@H:7]([N:5]5[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH2:2][CH:1]=[CH:6]5)[C@H:8]([OH:41])[C@@H:9]4[OH:40])([OH:16])=[O:15])([OH:20])=[O:19])[C@@H:24]([OH:39])[C@H:25]3[OH:38])[C:32]=2[N:33]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Solvent: O
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
The physicochemical properties of the present Enzyme are further described below. The activity of the present Enzyme is measured as follows. That is, into a quartz cell are placed 0.1 ml of 2.5 mM aqueous solution of lithocholic acid 3α-sulfate (Sigma), 0.2 ml of 15 mM aqueous solution of β-NAD (Oriental Yeast), 1.0 ml of 0.1M tris-hydrochloric acid buffer solution (pH 8.0) and 1.55 ml of distilled water, and after equilibrating at 30° C., 0.05 ml of β-hydroxysteroid dehydrogenase (Sigma) solution (10 U/ml) and 0.1 ml of a solution of the present Enzyme are sequentially added thereto and the reaction is effected at 30° C., and the increase of the absorbance at 340 nm in the initial stage of the reaction is determined. Under these conditions, the enzyme activity producing 1 μmol of NADH per minute is defined as 1 unit.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:28][C:29](=O)[CH2:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: COC(=O)Cc1cn[nH]c1
Product: COc1ccc(N2CCN(C(=O)Cc3cn[nH]c3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 14 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (1H-pyrazol-4-yl)-acetic acid methyl ester with heating for 17 days to afford the title compound as an off-white solid (20 mg, 14%). LC/MS (Method B) 3.42 min, [M+1]+ 461.
Reaction SMILES: [N:1]1([CH2:10][C:11](OC)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CN1CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCN1CCc2ccccc21
Yield: 87.1 %

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 780 mg of methyl indolin-1-ylacetate (prepared as described in Preparation 8), 200 mg of lithium aluminum hydride and 12 ml of anhydrous tetrahydrofuran were used, to give 580 mg of the title compound having Rf=0.31 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [F-:1].[Na+].[CH2:3]([N:7]1[C:12](=[O:13])[N:11]([CH2:14][CH:15]([OH:18])[CH2:16]Cl)[C:9](=[O:10])[N:8]1[CH2:19][CH:20]1[O:22][CH2:21]1)[CH:4]1[O:6][CH2:5]1>CC(C)=O>[CH2:3]([N:7]1[C:12](=[O:13])[N:11]([CH2:14][CH:15]([OH:18])[CH2:16][F:1])[C:9](=[O:10])[N:8]1[CH2:19][CH:20]1[O:22][CH2:21]1)[CH:4]1[O:6][CH2:5]1
Reactant: O=c1n(CC(O)CCl)c(=O)n(CC2CO2)n1CC1CO1
Reactant: [F-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=c1n(CC(O)CF)c(=O)n(CC2CO2)n1CC1CO1
Reaction time: 6 h

Procedure:
2.1 g (50 mMoles of sodium fluoride were added to a solution of 1.5 g (5 mMoles) of 1,2-diglycidyl-4-(3-chloro-2-hydroxypropyl)-urazole in 100 ml of acetone and the mixture boiled for 6 hours. After the solvent had been distilled off and the residue taken up in 50 ml of methylene chloride, followed by filtration, removal of the methylene chloride by distillation and drying in an oil pump vacuum at 40° C., 1,2-diglycidyl-4-(3-fluoro-2-hydroxypropyl)-urazole, refractive index nD20 :1.4955 (colorless liquid), was obtained in a yield of 1.5 g (100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Br)cc2c1ccn2C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of methyl 6-bromo-1-cyclopropyl-1H-indole-4-carboxylate (0.43 g, 1.462 mmol) in MeOH (12 mL) and THF (3 mL) was added 3 M NaOH (1.949 mL, 5.85 mmol). The reaction was stirred for 18 h at RT, at which time the volatiles were removed in vacuo. The residue was diluted with water and slowly acidifed with 1 N HCl to pH 4-5, then extracted with EtOAc (2×). The combine organics were wash with brine, dried over magnesium sulfate, filtered, and concentrated to give 6-bromo-1-cyclopropyl-1H-indole-4-carboxylic acid (0.376 g, 1.315 mmol, 90% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92-1.01 (m, 2H) 1.05-1.12 (m, 2H) 3.51 (tt, J=7.07, 3.66 Hz, 1H) 6.89 (d, J=2.53 Hz, 1H) 7.52 (d, J=3.03 Hz, 1H) 7.80 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.01 Hz, 1H) 13.05 (br. s., 1H). MS(ES) [M+H]+ 280.1.
Reaction SMILES: C([NH:8][CH2:9][C:10](O)=[O:11])(OC(C)(C)C)=O.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[CH:18][CH:17]=1>C(Cl)Cl.CO>[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([N:22]([C:10](=[O:11])[CH2:9][NH2:8])[CH3:23])=[CH:18][CH:17]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(N(C)C(=O)CN)cc1

Procedure:
BOC-glycine and methyl-4-methylaminobenzoate according to 1.2., followed by BOC-cleavage 3.1. to give 4-(Aminoacetyl-methyl-amino)-benzoic acid methyl ester as an orange gum (Rf 0.1 CH2Cl2:MeOH 9:1), MS: 222 (MH+).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].Cl[CH2:8][C:9]([CH3:11])=[CH2:10].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]([OH:6])([C:4]#[C:5][CH2:10][C:9]([CH3:11])=[CH2:8])[CH3:3]
Reactant: C=C(C)CCl
Reactant: C#CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(C)CC#CC(C)(C)O
Yield: 7.4 %

Procedure:
The coupling reaction was conducted in the manner described in the procedure of Example VI using the following reagents: 1.00 mL (10.3 mmoles) of 2-methyl-3-butyn-2-ol, 1.10 mL (11.1 mmoles) of 3-chloro-2-methylpropene, 2.40 g (17.3 mmoles) of anhydrous potassium carbonate, and 84 mg (0.85 mmoles) of cuprous chloride. Isolation of the product in the usual manner afforded 105 mg (7.4% yield) of the named alcohol. When this yield is compared with that reported in Example VII, it is evident that, in the absence of a polar solvent, the phase-transfer catalyst is desirable since it markedly accelerates the coupling. However, the presence of such a catalyst is not essential to achieve the desired transformation.
Reaction SMILES: Cl[CH:2]=[C:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].C[Si]([C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)(C)C>C1(C)C=CC=CC=1>[N:23]1([CH:2]=[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:24]=[CH:25][N:26]=[CH:22]1
Reactant: CC(C)(C)C(=O)C(=CCl)Oc1ccc(Cl)cc1
Reactant: C[Si](C)(C)c1ncc[nH]1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)C(=Cn1ccnc1)Oc1ccc(Cl)cc1
Yield: 59.1 %

Procedure:
13 g (0.05 mols) of 1-chloro-2-(4-chlorophenoxy)-4,4-dimethyl-1-penten-3-one and 7 g (0.05 mole) of trimethylsilylimidazole in 50 ml of toluene were heated under reflux for 5 hours. Thereafter, the reaction mixture was concentrated by distilling off the solvent in vacuo and the oily residue was separated by column chromatography (silica gel; ethyl acetate: chloroform=1:2). 9 g (58% of theory) of 1-(imidazol-1-yl)-2-(4-chlorophenoxy)-4,4-dimethyl-1-penten-3-one of melting point 94°-95° C. were obtained. ##STR54##
Reaction SMILES: NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH3:44][C@H:45]([O:49][C:50]1[N:58]=[C:57]2[C:53]([N:54]=[C:55]([O:59][CH3:60])[NH:56]2)=[C:52]([NH2:61])[N:51]=1)[CH2:46][CH2:47][CH3:48].Br[CH2:63][CH2:64][CH2:65][CH2:66][CH:67]1[CH2:72][CH2:71][N:70]([C:73]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[CH2:69][CH2:68]1>>[NH2:61][C:52]1[N:51]=[C:50]([O:49][C@@H:45]([CH3:44])[CH2:46][CH2:47][CH3:48])[N:58]=[C:57]2[C:53]=1[N:54]=[C:55]([O:59][CH3:60])[N:56]2[CH2:63][CH2:64][CH2:65][CH2:66][CH:67]1[CH2:68][CH2:69][N:70]([C:73]([O:75][CH2:76][C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)=[O:74])[CH2:71][CH2:72]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt and phenylmethyl 4-(4-bromobutyl)-1-piperidinecarboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]#[N:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[CH3:31][S:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:19]([CH2:18][NH:17][C:15](=[O:16])[C@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[NH:9][CH:8]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:5]1[CH:6]=[CH:7][C:2]([C:36]2[CH:37]=[CH:38][C:33]([S:32][CH3:31])=[CH:34][CH:35]=2)=[CH:3][CH:4]=1)#[N:20]
Reactant: CC(C)C[C@H](NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1)C(=O)NCC#N
Reactant: CSc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CSc1ccc(-c2ccc(C(N[C@@H](CC(C)C)C(=O)NCC#N)c3ccc(S(C)(=O)=O)cc3)cc2)cc1
Temperature: 85 °C

Procedure:
A heterogeneous mixture of N2-{(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}-N1-(cyanomethyl)-L-leucinamide from step 4 (72 mg, 0.15 mmol), 4-(methylthio)phenylboronic acid (37 mg, 0.22 mmol) in ethylene glycol dimethyl ether (1 mL) and 2M aqueous sodium carbonate was degassed under vacuum and purged with nitrogen. To this mixture was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (19 mg, 0.023 mmol), followed by degassing and purging with nitrogen. The reaction mixture was heated at 85° C. for 16 hours with efficient stirring. The reaction mixture was partitioned between EtOAc and aqueous NH4OAc 25% w/v. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography using EtOAc and hexane as eluant to give the title compound as a colorless gum.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[CH:4]=1.C1OCCOCCOCCOCCOCCOC1.[C-:29]#[N:30].[K+].ClCCl>C(#N)C>[CH3:10][S:9][C:5]1[CH:4]=[C:3]([CH2:2][C:29]#[N:30])[CH:8]=[CH:7][CH:6]=1
Reactant: CSc1cccc(CCl)c1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CSc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
To a solution of 1-chloromethyl-3-methylsulfanyl-benzene (26.9 g, 0.156 mol) and 18-crown-6 (2 g, 7.8 mmol) in dry acetonitrile (100 mL) was added potassium cyanide and stirred at room temperature for 48 hours. A precipitate was formed while adding dichloromethane (400 mL). The suspension was filtered, washed with water (2×150 mL), dried (Na2SO4) concentrated and distilled under reduced pressure to give a colorless oil (22.9 g, 91%). MS: 161.9 (M+1−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6](/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:7]([NH2:9])[CH3:8].[CH3:26][CH:27]1[CH2:33][C:32](=[O:34])[O:31][C:29](=[O:30])[CH2:28]1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6](/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:7]([NH:9][C:32]([CH2:33][CH:27]([CH3:26])[CH2:28][C:29]([OH:31])=[O:30])=[O:34])[CH3:8]
Reactant: CC(N)C(/C=C/c1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Reactant: CC1CC(=O)OC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CC(=O)O)CC(=O)NC(C)C(/C=C/c1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
20 mg of (1RS,2RS,3E)-2-(3,4-dichlorobenzyl)-1-methyl-4-(2-naphthyl)-3-butenylamine was dissolved in 1 ml of methylene chloride, and 10 mg of 3-methylglutaric anhydride and 4 μl of triethylamine were added thereto. The mixture was stirred at room temperature for 3 hours. A saturated sodium carbonate aqueous solution and methylene chloride were added to the reaction solution, and the mixture was stirred for 30 minutes. Then, the organic layer was collected by separation, washed with 1N hydrochloric acid and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-200, 2 g; chloroform/methanol=20/1) to obtain 16 mg (yield: 74%) of the above-identified compound as colorless oily substance.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[CH2:4][CH2:5][C:6]([OH:8])=O)[CH3:2].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C=O)C.C(OCC)(=O)C.O>[CH2:9]([CH:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH3:10]
Reactant: CCC(CC)CCC(=O)O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)CCC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Ethylhexanoic acid (47.0 g) was dissolved in DMF (190 mL). To the solution were added piperidine (34.0 mL), HOBt.H2O (52.7 g) and WSC.HCl (66.1 g). The mixture was stirred at RT overnight. To the reaction mixture were added ethyl acetate (300 mL) and 1 N hydrochloric acid (100 mL) at ice temperature. The aqueous layer was removed and the organic layer was washed with saturated aqueous sodium bicarbonate (150 mL×2) and brine (100 mL×2), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (59.8 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C:18]4([OH:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]4[OH:24])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C:18]4([OH:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]4[OH:24])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4(O)CCCCC4O)n3)c3cc(Cl)cnc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC1CCCCC1(O)Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Reaction time: 1 h

Procedure:
To a solution of (1R,2S,3S)-3-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol, 31c, (0.11 g, 0.21 mmol) in THF was added TBAF (0.23 g, 0.84 mmol). The reaction was aged at room temperature 1 hour, quenched with 1N HCl (1 ml), and purified via reverse phase chromatography (5-70% MeCN/H2O with 0.1% TFA). The product was desalted on an SPE bicarbonate cartridge, concentrated to dryness, and then triturated from MeOH to provide 18 mg of compound 632.
Reaction SMILES: C(OC([O:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[C:8]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)C>O1CCCC1>[OH:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[C:8]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)OC1=C(C(=O)OCC)C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(O)C(=O)c2ccccc2C1=O

Procedure:
To the tetrahydrofuran solution under water cooling was added a solution of ethyl 3-ethoxycarbonyloxy-1,4-dihydro-1,4-dioxo-2-naphthoate, obtained by the procedure of Referential Example 22(1) using 3.41 g of ethyl 3-hydroxy-1,4-dihydro-1,4-dioxo-2-naphthoate, in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 100 ml of ethanol, and the resulting crystals were collected by filtration and recrystallized from chloroform - ethanol to give the title compound, m.p. 224°-227° C., yield of 3.70 g.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5]O[C:3]=1[CH3:9].[NH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+]>CO>[C:12]([CH2:11][N:10]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:9])([OH:14])=[O:13]
Reactant: NCC(=O)O
Reactant: Cc1occc(=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(O)c(=O)ccn1CC(=O)O
Temperature: 60 °C
Reaction time: 48 h

Procedure:
3-hydroxy-2-methyl-4-pyrone (15 g) in methanol (250 ml) is added to an aqueous mixture (200 ml) containing glycine (7.7 g) and sodium hydroxide (10 g) with pH adjusted to 11.0, heated to 60° C. and kept with stirring under reflux conditions for 48 h. The mixture is rotary evaporated to oily residue which is made up to 100 ml with water and extracted (2×) with equal volumes of ethyl acetate. The aqueous fraction acidified with HCl to pH 1.8 to give an almost white precipitate with a yellowish hue, the desired compound. After filtration and drying the powdery compound is insoluble in water, but it is soluble in dilute base (pH 9). The mass spectrum showed a molecular ion mass M+=186.2 consistent with 1-carboxymethyl-3-hydroxy-2-methyl-pyrid-4-one. The compound reacts with iron to form the purple coloured iron-ligand complex indicating the presence of the 3-hydroxypyrid-4-one chelating moiety. TLC showed single a band separate and of lower rf than the 3-hydroxy-2-methyl-4-pyrone control. HPLC analysis of a mixture of 3-hydroxy-2-methyl-4-pyrone control and synthetic end product showed two sharp peaks with retention times of control=5.8 min. and sample=15.2 min.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]12([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=3[O:41][CH3:42])[C:35](Cl)=[O:36])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.O>ClCCl>[C:22]12([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=3[O:41][CH3:42])[C:35]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([N:8]4[CH2:9][CH2:10][CH2:11][CH2:12]4)=[O:7])=[CH:13][CH:14]=3)=[O:36])[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]3)[CH2:31]1)[CH2:29]2
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(C(=O)N3CCCC3)cc2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 72.7 %

Procedure:
1.7 g (9 mmoles) of N-p-aminobenzoyl pyrrolidine and 1 g (10 mmoles) of triethylamine are dissolved in 30 ml of dichloromethane. With stirring, 2.8 g (9 mmoles) of 3-(1-adamantyl)-4-methoxybenzoyl chloride dissolved in 60 ml of dichloromethane are added. The reaction mixture is stirred for 16 hours, at which point water is added and the reaction mixture is extracted with dichloromethane. The extract is washed with water, extracted with methylene chloride and dried on MgSO4. The solvents are evaporated and the residue (yellow foam) is crystallized in ethyl acetate to give 3.0 g (73% yield) of N-[4-[3-(1-adamantyl)-4-methoxy benzamido]-benzoyl]pyrrolidine which melts at 239°-242° C.
Reaction SMILES: [OH:1][C@H:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1.Cl[C:23]1[N:24]=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([C:33]#[N:34])[C:27]=2[CH3:35].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:1][C@H:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:23]2[N:24]=[CH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[C:28]([C:33]#[N:34])[C:27]=3[CH3:35])[C:6](=[O:10])[CH2:5]1
Reactant: Cc1c(C#N)ccc2cc(Cl)ncc12
Reactant: Cc1c([C@@H](O)CN2CCNC(=O)C2)ccc2c1COC2=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c([C@@H](O)CN2CCN(c3cc4ccc(C#N)c(C)c4cn3)C(=O)C2)ccc2c1COC2=O
Temperature: 100 °C

Procedure:
A mixture of 4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (26 mg, 0.089 mmol), 3-Chloro-8-methylisoquinoline-7-carbonitrile [I-12] (18 mg, 0.089 mmol), Pd2(dba)3 (16 mg, 0.017 mmol), Xantphos (21 mg, 0.036 mmol), and Cs2CO3 (40 mg, 0.12 mmol) in dioxane (4 mL) was sealed in a microwave tube and purged three times with nitrogen. It was heated to 100° C. for 10 minutes in a microwave reactor. LC showed formation of the desired product, which was purified by silica gel flash chromatography. LC-MS (IE, m/z): 457 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Si:13]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Si:13]([O:20][CH:21]1[CH2:22][CH2:23][N:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]3[CH:12]=[CH:11][N:10]=[N:9]3)[CH:3]=2)[CH2:25][CH2:26]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Reactant: Brc1cccc(-n2ccnn2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2cccc(-n3ccnn3)c2)CC1
Temperature: 100 °C

Procedure:
A dioxane (5 mL) solution of 1-(3-bromophenyl)-1H-1,2,3-triazole (224 mg, 1.00 mmol) and 4-{[tert-butyl(dimethyl)silyl]oxy}piperidine (323 mg, 1.50 mmol) was degassed with bubbling nitrogen in a vial. 2-(Dicyclohexylphosphino)-2′-(dimethylamino)biphenyl (20 mg, 0.051 mmol), palladium(II)acetate (11 mg, 0.050 mmol), and sodium tert-butoxide (384 mg, 4.0 mmol) were then added. The reaction mixture was degassed again, and the vial was sealed. It was heated to 100° C. for 20 hours and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.83 (s, 1H), 7.38-7.31 (m, 2H), 7.02 (d, J=7.9 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 3.97-3.89 (m, 1H), 3.53 (ddd, J=12.4, 7.5, 3.5 Hz, 2H), 3.16 (ddd, J=12.5, 7.8, 3.5 Hz, 2H), 1.95-1.81 (m, 2H), 1.72-1.64 (m, 2H), 0.90 (s, 9H), 0.08 (s, 6H); LC-MS: m/z 359.1 (M+H).