Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]([N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N+:43]([C:46]1[CH:54]=[C:53]2[C:49]([CH:50]=[CH:51][NH:52]2)=[CH:48][CH:47]=1)([O-:45])=[O:44]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:18])[CH2:9][C:10](=[O:11])[N:12]([CH3:13])[CH2:14][C:15]([N:52]1[C:53]2[C:49](=[CH:48][CH:47]=[C:46]([N+:43]([O-:45])=[O:44])[CH:54]=2)[CH:50]=[CH:51]1)=[O:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CC(=O)O)C(=O)CN(C)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(=O)n1ccc2ccc([N+](=O)[O-])cc21)C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30 %

Procedure:
To a mixture of {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid (13.8 g, 53 mmol) and TFFH (21.0 g, 79.5 mmol) in anhydrous THF (125 mL) was added DIEA (27.7 mL, 159 mmol) at room temperature under nitrogen. The solution was stirred at room temperature for 20 min. A solution of 6-nitroindole (8.6 g, 53 mmol) in THF (75 mL) was added and the reaction mixture was heated at 60° C. for 18 h. The solvent was evaporated and the crude mixture was re-partitioned between EtOAc and water. The organic layer was separated, washed with water (×3), dried over Na2SO4 and concentrated. Diethyl ether followed by EtOAc was added. The resulting solid was collected via filtration, washed with diethyl ether and air dried to yield methyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester (6.42 g, 30%). 1H NMR (400 MHz, DMSO-d6) δ 1.37 (m, 9H), 2.78 (m, 3H), 2.95 (d, J=1.5 Hz, 1H), 3.12 (d, J=2.1 Hz, 2H), 4.01 (d, J=13.8 Hz, 0.6H), 4.18 (d, J=12.0 Hz, 1.4H), 4.92 (d, J=3.4 Hz, 1.4H), 5.08 (d, J=11.4 Hz, 0.6H), 7.03 (m, 1H), 7.90 (m, 1H), 8.21 (m, 1H), 8.35 (d, J=3.8 Hz, 1H), 9.18 (m, 1H); HPLC ret. time 3.12 min, 10-99% CH3CN, 5 min run; ESI-MS 405.5 m/z (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[O:28][C:29](=[O:31])[CH3:30])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@H:18]([O:32][C:33](=[O:35])[CH3:34])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:36][C:37](=[O:39])[CH3:38])[CH2:11][CH2:10]1)[CH3:8])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C1C[O:52]CC1>>[CH2:1]([O:3][C:4](=[O:40])[CH:5]([OH:52])[CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[O:28][C:29](=[O:31])[CH3:30])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@H:18]([O:32][C:33](=[O:35])[CH3:34])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:36][C:37](=[O:39])[CH3:38])[CH2:11][CH2:10]1)[CH3:8])[CH3:2]
Reactant: CCOC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](OC(C)=O)C[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](OC(C)=O)[C@]12C
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOC(=O)C(O)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](OC(C)=O)C[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](OC(C)=O)[C@]12C
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
A solution of 3α,7α,12α-triacetoxy-5β-cholanic acid-ethyl ester (5 mmol) in dry THF (100 ml) was cooled to -78° C. and lithium diisopropylamide (LDA, 5.98 g, 7.5 mmol) was added thereto. After 15 minutes, a solution of trans-2-(phenylsulfonyl)-3-phenyloxaziridine (Davis reagent, 2.06 g, 6.73 mmol) in THF (10 ml) was added. The mixture was stirred at -60° C. for 3 hours. Normal workup, followed by purification over silica gel gave two diastereomers of 3α,7α,12α-triacetoxy-23-hydroxy-5β-cholanic acid-ethyl ester. The absolute stereochemistry of the diastereomers was not determined.
Reaction SMILES: S(Cl)(Cl)=O.C1(CCC(O)=O)C=CC=CC=1.C1(CCC(Cl)=O)C=CC=CC=1.[C:27]1([CH2:33][CH2:34][C:35]([N:37]=[C:38]=[S:39])=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][C:56]=1[F:62]>C(O)C.C1(C)C=CC=CC=1>[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:38]([NH:37][C:35](=[O:36])[CH2:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[S:39])=[CH:57][C:56]=1[F:62]
Reactant: O=C(CCc1ccccc1)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)CCc1ccccc1
Agent: O=C(O)CCc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCc4ccccc4)cc3F)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-phenylpropanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-phenylpropanoyl isothiocyanate was prepared using the resultant 3-phenylpropanoyl chloride as a starting compound according to the description of the literature. 3-Phenylpropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (57 mg, yield 71%).
Reaction SMILES: C1(O)C2C(=CC=CC=2)C=CC=1.BrCCCCCCCCCO.[C:23]1([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][OH:43])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C1(OCCCCCCCCC(O)=O)C2C(=CC=CC=2)C=CC=1.Cl.Cl.[CH2:68]([O:75][C:76](=[O:84])[CH2:77][C@@H:78]([NH2:83])[CH2:79][N:80]([CH3:82])[CH3:81])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>>[CH2:68]([O:75][C:76](=[O:84])[CH2:77][C@@H:78]([NH:83][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH2:79][N:80]([CH3:81])[CH3:82])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCCOc1cccc2ccccc12
Agent: Cl
Agent: O=C(O)CCCCCCCCOc1cccc2ccccc12
Agent: OCCCCCCCCCBr
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCOc1cccc2ccccc12

Procedure:
The title compound, m/e=429.5 ([M+H]+), was produced in analogy with example 18, steps 1 to 4. Thus, naphthalen-1-ol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-(naphthalen-1-yloxy)-nonan-1-ol, which was oxidized in step 2 to 9-(naphthalen-1-yloxy)-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-(naphthalen-1-yloxy)-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: CC(S[C@H:5]1[C@H:15]2[C@H:16]3[C@:20]([CH3:23])([CH2:21][CH2:22][C@@H:14]2[C@:13]2([CH3:29])[C:7](=[CH:8][C:9]([CH2:11][CH2:12]2)=[O:10])[CH2:6]1)[C@@:19]1([O:28][C:26](=[O:27])[CH2:25][CH2:24]1)[CH2:18][CH2:17]3)=O.[OH-].[Na+].C[O-].[Na+]>>[CH3:29][C:13]12[CH:14]3[CH2:22][CH2:21][C:20]4([CH3:23])[C:19]5([O:28][C:26](=[O:27])[CH2:25][CH2:24]5)[CH2:18][CH2:17][CH:16]4[CH:15]3[CH:5]=[CH:6][C:7]1=[CH:8][C:9](=[O:10])[CH2:11][CH2:12]2
Reactant: CC(=O)S[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC[C@@]34CCC(=O)O4)[C@H]12
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC12CCC(=O)C=C1C=CC1C2CCC2(C)C1CCC21CCC(=O)O1

Procedure:
The 7β-acetylthio derivative can be converted into the spironolactone by treating the 7β-acetylthio derivative with a base such as sodium hydroxide or sodium methoxide to give the starting material, 17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone, followed by the addition reaction with thioacetic acid. (This method is hereinafter referred to as "elimination-addition method".)
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:22]1[CH:29]2[CH:23]1[CH2:24][CH2:25][O:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=12.C[Si](C)(C)[O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[O:36]=[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]1[C@@H:29]1[C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[O:26][CH2:25][CH2:24][C@H:23]1[OH:22]
Reactant: C[Si](C)(C)Oc1ccccn1
Reactant: c1ccc2c(c1)OCCC1OC21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=c1ccccn1[C@@H]1c2ccccc2OCC[C@H]1O
Temperature: 0 °C

Procedure:
6.40 g (20 mmol) of tetrabutylammonium fluoride trihydrate are added to a mixture of 3.24 g (20 mmol) of 4,5-epoxy-2,3,4,5-tetrahydro-1-benzoxepin and 10 g (60 mmol) of 2-trimethylsilyoxy-pyridine, and the mixture is heated at 80°-90° C. with stirring. After a reaction time of 5 hours, the mixture is slowly stirred into ice-water, and the precipitated solid is filtered off with suction and recrystallized from methanol with the addition of small amounts of dioxane. Crystals of melting point 232°-234° C. are obtained.
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[CH2:27]([SH:30])[CH2:28][SH:29].B(F)(F)F.CCOCC>C(Cl)Cl>[S:29]1[CH2:28][CH2:27][S:30][CH:1]1[CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: SCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C1SCCS1
Yield: 74.4 %

Procedure:
In 20 ml of anhydrous methylene chloride was dissolved 1.0 g of N-benzyloxycarbonyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 4-(b), and 300 mg of 1,2-ethanedithiol and 0.8 ml of boron trifluoride ethyl etherate were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 900 mg of the titled compound as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH:10](O)([CH3:12])[CH3:11]>>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([O:8][CH:10]([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: Cc1cc(O)ncc1Br
Reactant: CC(C)O
Product: Cc1cc(OC(C)C)ncc1Br

Procedure:
The title compound was prepared from 5-bromo-2-hydroxy-4-methylpyridine and isopropanol in analogy to Example 9c): colorless liquid.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)[NH2:2].[C:15](Cl)(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>>[O:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]3[N:4]([C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:2][N:1]=3)[N:5]=2)[CH2:14][CH2:13]1
Reactant: NNc1ccc(N2CCOCC2)nn1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccc(-c2nnc3ccc(N4CCOCC4)nn23)cc1

Procedure:
39 Grams of 3-hydrazino-6-morpholinopyridazine is added portionwise to 30 grams of benzoyl chloride. The mixture is heated at a temperature of 130°-140° C. for 1 hour. The mixture is then cooled and the residue of the reaction mixture is neutralized by the addition of aqueous sodium bicarbonate solution. The resulting aqueous mixture is then extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The 6-morpholino-3-phenyl-s-triazolo[4,3-b]pyridazine product is obtained as a residue from the evaporation. The product is crystallized twice from isopropanol and found to melt at 195°-196° C. 15 Grams of the named product are obtained. The structure of the product is confirmed by infrared spectroscopy and by nuclear magnetic resonance analysis.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:19]([CH:23]=2)[C:20](Cl)=[O:21])=[CH:3][CH:2]=1.[NH:38]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(OCC)(=O)C.CCCCCC>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][N:38]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:20](=[O:21])[C:19]1[CH:23]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:4]2[CH:5]=[CH:6][C:1]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:2][CH:3]=2)[CH:16]=[CH:17][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:44]
Reactant: O=C(Cl)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1OCc1ccccc1
Reactant: CCOC(=O)CNCC(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1OCc1ccccc1
Yield: 74 %

Procedure:
The reaction of 5-[[6-([1,1'-biphenyl]-4-yloxy)hexyl]oxy]-2-(phenylmethoxy)benzoic acid chloride with diethyl iminodiacetate under conditions described in Example 80 gave, after purification by HPLC using 25% ethyl acetate-hexane, N-(2-ethoxy-2-oxoethyl)-N-[5-[[6-([1,1'-biphenyl]-4-yloxy)hexyl]oxy]-2-(phenylmethoxy) benzoyl]glycine ethyl ester (74% yield, mp 60°-62° ). The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][CH:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:21].S(Cl)([Cl:24])=O.O.[OH-].[NH4+]>ClCCl>[Cl:24][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:21]
Reactant: CCCCCC(O)Nc1cc(OC)cc2c(C)ccnc12
Reactant: O=S(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(NCCCCCCCl)c2nccc(C)c2c1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a stirred solution of 7.8 g (0.027 mole) of 6-[(6-methoxy-4-methyl-8-quinolinyl)amino-1-hexanol in 90 ml of dichloromethane at 5° was added dropwise a solution of 1.9 ml (0.03 mole) of thionylchloride in 25 ml of dichloromethane. The mixture was allowed to warm to room temperature overnight, poured into iced water, and made basic with concentrated ammonium hydroxide. The resulting emulsion was filtered and the layers then separated. The organic portion was washed, dried, and concentrated to afford 7.9 g (96%) of crude product which was used in the next step without further purification. TLC(silica--thyl acetate) indicated that the product, Rf=0.65, was slightly contaminated with the starting hexanol, Rf=0.4.
Reaction SMILES: [N:1]([CH:4]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=2[N:6]([CH3:22])[C:5]1=[O:23])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[NH2:1][CH:4]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=2[N:6]([CH3:22])[C:5]1=[O:23]
Reactant: CN1C(=O)C(N=[N+]=[N-])N=C(c2cccnc2)c2cc(Cl)ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN1C(=O)C(N)N=C(c2cccnc2)c2cc(Cl)ccc21

Procedure:
As illustrated in the scheme above and following General Procedure 7, 3-azido-7-chloro-1,3-dihydro-1-methyl-5-(3-pyridinyl)-2H-1,4-benzodiazepin-2-one (1.47 g, 4.49 mmol) and PS—PPh3 (16.4 g of 1.37 mmol/g, 22.4 mmol) were combined. After workup and purification by “catch and release,” the title compound was obtained as a slightly brown solid (1.46 g, quantitative). 1H-NMR (CDCl3): δ 8.76 (d, J=2.4 Hz, 1H), 8.72 (dd, J=1.6 Hz, J=5.2 Hz, 1H), 8.06 (dt, J=2.4 Hz, J=7.6 Hz, 1H), 7.58 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.40 (dd, J=4.8 Hz, J=8.0 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 4.51 (s, 1H), 3.46 (s, 3H), 2.41 (br s, 2H). MS (ESI) (M+H)+=301.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:25]1[CH:26]=[C:27]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>>[C:10]([C:9]1[CH:12]=[C:5]([CH2:4][O:3][C:25]2[CH:26]=[C:27]3[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:32][N:28]3[C:29](=[O:31])[N:30]=2)[CH:6]=[N:7][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)#[N:11]
Reactant: N#Cc1cc(CO)cnc1Oc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1cnc(Oc3cccc(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)nicotinonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo-[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[O-]CC.[Na+].Cl.[CH2:17]([N:24]1[CH:28]=[CH:27][N:26]=[C:25]1C[Cl:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O)C>[ClH:30].[CH2:17]([N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:3][CH2:2][C:1]([OH:9])=[O:8])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCc1nccn1Cc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCc1nccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diethyl malonate (57.8 g) in absolute ethanol (100 ml) was added to a stirred solution of sodium ethoxide in absolute ethanol (prepared from sodium (8.31 g) and absolute ethanol (150 ml)). The mixture was stirred at ambient temperature for 30 minutes. The mixture was cooled in ice water and a solution of 1-benzyl-2-chloromethylimidazole hydrochloride (25.0 g) in absolute ethanol (210 ml) was added over 30 minutes. The mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. Ice cold 2 M hydrochloric acid (200 ml) was added to the residue and the solution washed with ethyl acetate. The aqueous layer was neutralised with sodium carbonate and extracted with ether to give a residue which was warmed at 95° C. for 18 hours with concentrated hydrochloric acid (100 ml). The mixture was evaporated to dryness to give 3-(1-benzylimidazol-2-yl)propionic acid hydrochloride as a glasslike product.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:5][CH:3]1O.CN(C=O)C.C(Br)(=O)C([Br:42])=O>ClCCl>[F:1][C@@H:2]1[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:5][CH:3]1[Br:42]
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1F
Reactant: O=C(Br)C(=O)Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: F[C@H]1C(Br)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-Deoxy-2-fluoro-3,4,6-tri-O-benzyl glucopyranose (450 mg) was dissolved in dichloromethane (5.0 mL) and dry DMF (180 μL) was added. The reaction solution was cooled to 0° C. and oxalyl bromide (102 μL) was added. The resulting solution was stirred for 3-5 hours at 0° to 5° C. The solution was then diluted with dichloromethane (50 mL) and washed with water (2×50 mL), dried over sodium sulfate, filtered and evaporated to obtain the title compound.
Reaction SMILES: [OH:1][C@H:2]([CH2:24][N:25]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[C@@H:3]([NH:11][C:12](=[O:23])[O:13][C@H:14]1[CH2:22][C@H:17]2[O:18][CH2:19][C:20](=[O:21])[C@H:16]2[CH2:15]1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[BH4-].[Na+].[NH4+].[Cl-]>CCO>[OH:1][C@H:2]([CH2:24][N:25]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:26]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)(=[O:28])=[O:27])[C@@H:3]([NH:11][C:12](=[O:23])[O:13][C@H:14]1[CH2:22][C@H:17]2[O:18][CH2:19][C@@H:20]([OH:21])[C@H:16]2[CH2:15]1)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(S(=O)(=O)N(CC(C)C)C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@@H]2C[C@@H]3C(=O)CO[C@@H]3C2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(CC(C)C)C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@@H]2C[C@@H]3[C@H](O)CO[C@@H]3C2)cc1
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
A solution of keto-inhibitor 19a (10 mg, 17 μmol) in EtOH was cooled to −25° C. and NaBH4 (6 mg) was added at once. The solution was stirred for 30 min then saturated NH4Cl aq. solution was added. The aqueous phase was extracted with EtOAc (4×), the combined organic layer was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using hexanes:EtOAc (2:1, 1:1, then 1:2) as the eluent to afford the desired inhibitor 22 (8 mg, 80%). TLC: Rf=0.22 (hexanes/EtOAc=1:2); 1H NMR (CDCl3, 400 MHz) δ 7.70 (d, J=8.8 Hz, 1H), 7.32-7.17 (m, 5H), 6.98 (d, J=8.8 Hz, 1H), 5.07 (m, 1H), 4.96 (d, J=7.2 Hz, 1H), 4.38 (, t, J=6.8 Hz, 1H), 4.22 (m, 1H), 3.87 (s, 3H), 3.88-3.74 (m, 3H), 3.54 (dd, J=3.2, 9.6 Hz, 1H), 3.10 (dd, J=7.8, 15.0 Hz, 1H), 3.05-2.82 (m, 4H), 2.78 (dd, J=6.8, 13.6 Hz, 1H), 2.42 (dd, J=10.8 Hz, 1H), 2.18-2.04 (m, 2H), 1.94-1.76 (m, 3H); TLC: Rf=0.39 (hexanes/EtOAc=1:5); 1H NMR (CDCl3, 500 MHz) δ 7.70 (d, J=8.8 Hz, 2H), 7.32-7.19 (m, 5H), 6.97 (d, J=8.8 Hz, 2H), 5.07 (m, 1H), 4.89 (d, J=7.2 Hz, 1H), 4.38 (t, J=6.8 Hz, 1H), 4.21 (m, 1H), 3.87 (s, 3H), 3.88-3.74 (m, 4H), 3.54 (dd, J=3.2, 9.6 Hz, 1H), 3.10 (dd, J=7.8, 15.0 Hz, 1H), 3.05-2.82 (m, 5H), 2.78 (dd, J=6.8, 13.4 Hz, 1H), 2.42 (br.s, 1H), 2.18-2.04 (m, 2H), 1.94-1.76 (m, 3H), 0.90 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 163.0, 155.3, 137.6, 129.9, 129.6, 129.5, 128.6, 126.5, 114.3, 84.9, 78.1, 76.3, 73.0, 72.2, 58.7, 55.6, 55.3, 53.7, 47.3, 39.1, 35.4, 31.3, 27.2, 20.1, 19.9; HRMS-ESI (m/z): [M+Na+] calcd for C30H42N2O2SNa 597.2610. found 597.2608.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1C(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O>[CH2:1]([S:8][C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)nn(C)c1SCc1ccccc1
Agent: Cl
Solvent: O
Product: Cc1cc(SCc2ccccc2)n(C)n1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 2.0 g of ethyl 5-benzylthio-1,3-dimethylpyrazole-4-carboxylate, 9 ml of concentrated hydrochloric acid and 6 ml of water is refluxed for 11 hours. The reaction mixture is cooled to room temperature, extracted with chloroform. The extract is washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate. Chloroform is evaporated under reduced pressure to yield 1.5 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH:17]=[C:16]([CH:18]=[CH:19][C:20]3[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[NH:23][CH:24]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>[Pd]>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[NH:23][CH:24]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COC(=O)c1cc(C=Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)c[nH]1
Reactant: [H][H]
Agent: [Pd]
Product: COC(=O)c1cc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)c[nH]1
Yield: 95 %

Procedure:
Upon reduction of methyl 4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]-pyrimidin-6-yl)ethenyl]pyrrole-2-carboxylate with hydrogen and palladium-on-carbon catalyst (200 mg) analogously to that described in Example 8, there is obtained methyl 4-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]pyrrole-2-carboxylate (380 mg, 95%): mp 236-238° C.: 1H NMR (DMSO-d6) δ 11.59 (s, 1H), 11.21 (s, 1H), 10.60 (s, 1H), 6.81 (s, 1H), 6.62 (s, 1H), 6.42 (s, 1H), 3.70 (s, 3H), 3.23 (br d, 1H, J=10.5 Hz), 2.82 (m, 1H), 2.57-2.43 (m, 3H), 1.87 (dd, 1H, J=15.2, 8.0 Hz), 1.68-1.43 (m, 3H), 1.18 (s, 9H).