Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:23]=[C:22](OC(C)C)[NH:21][N:20]=2)=[N:4][C:5]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=[N:6][CH:7]=1.Cl[C:29]1N=C(NC2C=C(C)NN=2)C(Cl)=CN=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:23]=[C:22]([CH3:29])[NH:21][N:20]=2)=[N:4][C:5]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Temperature: 160 °C
Yield: 135.2 %

Procedure:
A mixture of (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 146 mg, 1.04 mmol), 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 38; 244 mg, 1.04 mmol) and DIEA (0.39 ml) in n-BuOH (3 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 160° C. for 6 hrs. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% acetonitrile/H2O, 15 min) to give the title compound as solid (489 mg). 1H NMR: 12.02 (s, 1H), 8.50 (d, 1H), 7.87-7.97 (m, 114), 7.64 (ddd, 1H), 7.33-7.46 (m, 1H), 5.85 (s, 1H), 4.75-5.24 (m, 1H), 2.16-2.21 (m, 3H), 1.45 (d, 3H); m/z 349.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[CH:33]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[C:27]1([N:18]2[C:17]3[CH:33]=[C:13]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:6]([OH:34])=[O:5])[CH:14]=[CH:15][C:16]=3[N:20]=[C:19]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)CCOCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 15 h

Procedure:
50 mg of 3-[2-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]propanoic acid-tert-butyl ester was dissolved in 0.5 ml of trifluoroacetic acid and stirred for 15 hours. Then, it was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH2:4][N:3]3[C:2]1=[O:13].CC(C)([O-])C.[K+].C1COCC1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.O.C(OC)(C)(C)C>[CH2:25]([N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH2:4][N:3]3[C:2]1=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]c2cccc3c2n1CC=C3
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=c1n(Cc2ccccc2)c2cccc3c2n1CC=C3
Reaction time: 0.17 h

Procedure:
A mixture of 4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (I, J. Heterocyclic Chem., 19, 837-49 (1982), 1.0 g, 5.8 mmol) in DMF (10 ml) is cooled to 0° and treated with potassium t-butoxide in THF (1.98 M, 3.2 ml, 6.3 mmol) maintaining the reaction temperature at 0°. The resulting mixture is stirred at 0° for 10 minutes. Benzyl bromide (0.73 ml, 6.1 mmol) is then added while maintaining the reaction temperature at methyl t-butyl ether (MTBE) from water followed by several water washes. The MTBE phase is concentrated under reduced pressure. The concentrate is cooled to 0°, filtered and washed two times with 0° MTBE. The product is dried at 50° under reduced pressure with a nitrogen purge to give the title compound, CMR (CDCl3, 100 MHz) 153.78, 136.44, 128.69, 127.67, 127.60, 126.73, 125.86, 122.90, 122.78, 121.28, 116.92, 116.17, 108.36, 44.95 and 42.37 δ.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH:11](O)[CH2:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(=O)CC(O)CCSc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(Br)cc1
Yield: 95.1 %

Procedure:
1.50 Grams of 6-(4-bromophenylthio)-4-hydroxy-2-hexanone were dissolved in 100 mol of toluene, and 0.07 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 2.5 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 1.41 g of 6-(4-bromophenylthio)-3-hexen-2-one. (trans : cis=2.8 : 1) (purity: 95.1%). The yield was 95.1%.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[N:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1.Cl.[CH:35]([N:38]([CH:45]([CH3:47])[CH3:46])[CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])([CH3:37])[CH3:36].O>CN(C)C=O.C(Cl)Cl>[CH:45]([N:38]([CH:35]([CH3:37])[CH3:36])[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[N:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1)=[O:43])([CH3:47])[CH3:46]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(C)N(CCCC(=O)O)C(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(CCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)C(C)C
Temperature: 20 °C
Reaction time: 20 h
Yield: 49.3 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (10.7 g) is added dropwise to a suspension of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) and 4-diisopropylaminobutyric acid hydrochloride (6.7 g) in dimethylformamide (100 cc), and the mixture is stirred at a temperature in the region of 20° C. for 20 hours. The reaction mixture is then poured into water (130 cc). The solid obtained is separated by filtration and then dissolved in methylene chloride (200 cc). The organic extracts are washed with 0.1 N aqueous hydrochloric acid solution (2×35 cc), 0.5 N aqueous hydrochloric acid solution (35 cc), and then with water (2×35 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is taken up with methylene chloride (200 cc). The organic phase is washed with saturated aqueous sodium hydrogen carbonate solution (2×50 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in isopropyl ether. 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-diisopropylaminobutyrate (7.1 g), m.p. 118° C., is thereby obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]([CH3:37])=[C:14]([N:18]([CH2:22][C:23]2[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=2)[CH2:19][CH2:20][CH3:21])[CH:15]=[CH:16][CH:17]=1>>[CH3:37][C:13]1[C:14]([N:18]([CH2:22][C:23]2[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=2)[CH2:19][CH2:20][CH3:21])=[CH:15][CH:16]=[CH:17][C:12]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Reactant: Cc1ccc(B(O)O)cc1
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C)cc2)c1C

Procedure:
Prepared from 4-methylphenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(propyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][CH2:17][S:18][CH2:19][CH3:20])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1C=CC(S(O)(=O)=O)=C[CH:23]=1>COC(OC)(C)C.C(OCC)(=O)C>[CH2:19]([S:18][CH2:17][CH2:16][C@@H:9]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[O:15][C:22]([CH3:23])([CH3:21])[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:20]
Reactant: CCSCC[C@@H](NC(=O)OC(C)(C)C)C(O)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: COC(C)(C)OC
Product: CCSCC[C@@H]1C(C(=O)OC)OC(C)(C)N1C(=O)OC(C)(C)C

Procedure:
A mixture of Example 21A (1.12 g, 3.65 mmol) and catalytic 4-methylbenzenesulfonic acid (15 mg) in 2,2-dimethoxypropane (35 mL) at ambient temperature was stirred for 36 hours, diluted with ethyl acetate, washed sequentially with aqueous NaHCO3 and pH 7 buffer, dried (MgSO4), filtered, and concentrated. Flash column chromatography (silica gel, 10% acetone/hexanes) provided the desired product. MS (ESI) m/e 348 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4](=O)[CH2:3]1.[C:14]([CH2:22][C:23]#[N:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4](=[C:22]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:21])[C:23]#[N:24])[CH2:3]1
Reactant: Cc1ccc2c(c1)C(C)(C)CC2=O
Reactant: N#CCC(=O)c1ccccc1
Product: Cc1ccc2c(c1)C(C)(C)CC2=C(C#N)C(=O)c1ccccc1

Procedure:
3,3,5-Trimethyl-1-indanone are reacted with benzoylacetonitrile analogously to Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:12].O1CCOCC1.[C:19](=O)([O-:21])[O-:20].[Na+].[Na+]>O>[CH3:12][C:5]1[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([C:19]([OH:21])=[O:20])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c[nH]c2c(C)cc(Br)cc12
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c[nH]c2c(C)cc(C(=O)O)cc12
Temperature: 165 °C
Reaction time: 0.01 h
Yield: 93 %

Procedure:
A microwave tube was charged with 5-bromo-3,7-dimethyl-1H-indole (317 mg, 1.42 mmol), dioxane (3 mL), Hermann's catalyst (42.1 mg, 0.07 mmol) and a solution of sodium carbonate (450 mg, 4.24 mmol) in water (6 mL). The mixture was stirred for 20 sec, heated at 165° C. for 15 minutes in a microwave reactor at very high absorption setting. The reaction was vented before handling. The mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated and the residue was dissolved in water. The solution was acidified to pH 3 and the solid was collected to afford the title compound (250 mg, 93%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[C:32]2[C:27](=[C:28]([Cl:33])[CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43]OS(C)(=O)=O)=[CH:37][CH:36]=2)[CH:25]=1)(=O)C.[N-:49]=[N+]=[N-].[Na+].O>CN(C)C=O>[NH2:49][CH2:43][CH2:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:24]([C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[CH:25]2)=[CH:40][CH:39]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cn(Cc3ccc(OCCOS(C)(=O)=O)cc3)c3c(Cl)cccc23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NCCOc1ccc(Cn2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Cl)c32)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 21.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-7-chloro-1-{4-[2-(methanesulfonyloxy)ethoxy]-benzyl}-1H-indole (85 mg) in N,N-dimethylformamide (2 mL) was added sodium azide (12 mg), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in a mixed solvent of methanol (2 mL) and tetra hydrofuran (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.30 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in tetra hydrofuran (3 mL). To the solution were added water (0.3 mL) and triphenylphosphine (36 mg), and the mixture was stirred at room temperature for 3 days. The solvent was removed under reduced pressure, and the residue was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK C18 ODS, UG80, 5 μm, 20×50 mm, linear gradient water/methanol=90/10-10/90, flow rate 30 mL/min) to give the title compound (12 mg).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN1C(=O)CCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Fc1ccccc1-c1nc(Cl)nc2ccccc12
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(-c3ccccc3F)c3ccccc3n2)CC1
Yield: 66 %

Procedure:
A mixture of 2-chloro-4-(2-fluoro-phenyl)-quinazoline (0.8 g, 3.09 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.81 g, 4.02 mmol, 1.3 equiv; commercially available) in anhydrous NMP (8 mL) was heated by microwave irradiation to 180° C. for 40 min. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified by column chromatography on silica eluting with heptane/ethyl acetate (10:1) providing 0.86 g (66%) of the title compound. MS (ISP): 423.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[H-].[Na+].[CH2:18]([O:20][CH2:21][CH2:22]Cl)[CH3:19].O>CN(C)C=O>[CH2:18]([O:20][CH2:21][CH2:22][N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=[C:6]1[CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:15])[CH3:19]
Reactant: CN(C)CCCc1nc2ccccc2[nH]1
Reactant: CCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1c(CCCN(C)C)nc2ccccc21
Temperature: 60 °C

Procedure:
Grams 6 2-(3-dimethylaminopropyl)benzimidazole in 100 ml N,N-dimethylformamide are treated with 1.8 g 60% sodium hydride, the mixture is warmed up to 60° C. and 4 g 2-ethoxyethyl chloride are added thereto. It is maintained at 60° C. for 5 hours, then it is poured into water, extracted with diethyl ether and the extracts washed thoroughly with water, filtered on charcoal, made anhydrous on sodium sulphate and evaporated to dryness. The residue is chromatographied on silica gel column eluting with chloroform:methyl alcohol (9:1) and it gives 1-(2-ethoxyethyl)-2-(3-dimethylaminopropyl)benzimidazole.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C@H:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:7][CH:6]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:25][C:21]1[C:20]([F:26])=[C:19]([C@@H:18]2[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15][C@H:14]2[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:42])=[O:2])=[CH:10][CH:9]=2)=[O:13])[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
A mixture of (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid methyl ester (72 mg, 0.117 mmol) was dissolved in THF (3 mL) and methanol (1 mL), then 2N LiOH (1 mL) was added and stirred at room temperature for 2 hours. The mixture was concentrated and diluted with water and ethyl acetate. The organic phase was separated then concentrated to yield chiral (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid (37 mg, 52.6%) as an white powder. HRMS (ES+) m/z Calcd for C31H29Cl2F2N3O3+H [(M+H)+]: 600.1627. found: 600.1626.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[N:27]=[C:26]([NH:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[C:25]([O:35][CH3:36])=[CH:24][N:23]=2)=[N:14]1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[N:27]=[C:26]([NH:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[C:25]([O:35][CH3:36])=[CH:24][N:23]=2)=[N:14]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cnc(-c2nn(Cc3ccc(C(=O)O)cc3Cl)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
150 mg of methyl 3-chloro-4-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)benzoate (2-11-1, 0.299 mmol, 1. eq.) were dissolved in 0.364 ml of methanol. 60 mg of sodium hydroxid (1.50 mmol, 5 eq.) were added. The reaction mixture was stirred at room temperature for 3 hours. The resulting suspension was neutralised with acetic acid. The solution was diluted with ethyl acetate. The occurred precipitate was filtered off and washed with ethyl acetate and was dried in vacuo at 50° C. to yield 138 mg (0.28 mmol, 92.8%) of the analytically pure target compound.
Reaction SMILES: P([O-])([O-])([O-])=O.[O:6]=[CH:7][C@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9]>O>[OH:6][CH2:7][C:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])=[O:9]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
To 0.5 ml of a 0.1M phosphate buffer (pH 7.0) containing 0.2M mannose, an appropriate amount of the enzyme was added, after which water was added to make the total volume 1.0 ml, and reacted at a temperature of 50° C. After the reaction was terminated by the addition of a 0.5M perchloric acid solution, the amount of fructose produced was determined by the cysteine-carbazole process. The amount of the enzyme, which produces one micromole of fructose in one minute under the above-described conditions is defined as one unit.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:12]([OH:14])=O)[O:4][N:3]=1.S(Cl)([Cl:17])=O.C(Cl)(Cl)=O>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:12]([Cl:17])=[O:14])[O:4][N:3]=1
Reactant: CCOC(=O)c1c(C)noc1C(=O)O
Reactant: O=S(Cl)Cl
Agent: O=C(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)noc1C(=O)Cl

Procedure:
13.3 g of the carboxylic acid from Example b and 20 ml of thionyl chloride are refluxed in the presence of a little dimethylformamide until the evolution of gas is complete. The crude carbonyl chloride which remains in quantitative yield after evaporation is directly reacted further.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[O:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1>>[CH2:18]([C:13]1[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH:25]3[CH2:26][CH2:27][O:23][CH2:24]3)=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: NC1CCOC1
Reactant: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)NC2CCOC2)cn1
Yield: 70 %

Procedure:
As described in example 8, 6-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (200 mg, 0.57 mmol), and tetrahydrofuran-3-amine instead of isopropylamine, was converted to the title compound (140 mg, 70%) which was obtained as a light red solid after purification by chromatography (silica, dichloromethane:methanol 100:0 to 94:6). MS: m/e=328.4 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]2[Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2ccc(Cc3ccccc3)cc2c1=O
Product: CCOC(=O)c1cnc2ccc(Cc3ccccc3)cc2c1Cl
Temperature: 0 °C

Procedure:
A mixture of ethyl 6-benzyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (A, 1.96 g) and phosphorus oxychloride (10 mL) was refluxed for 15 min. The solution was poured into ice water containing concentrated ammonia solution (15 mL), and the resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to afford crude the title compound (2.77 g) as a brown oil: 1H NMR (400 MHz, CDCl3) δ 1.48 (t, J=6.8 Hz, 3H), 4.31 (s, 2H), 4.55 (q, J=6.8 Hz, 2H), 7.18-7.41 (m, 5H), 7.99 (d, J=8.8 Hz, 1H), 8.39 (s, 1H), 8.61 (d, J=8.8 Hz, 1H), and 9.38 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][N:5]2[C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17].C1(C(N2C3C(=CC([C:36]4[CH:37]=[N:38][NH:39][CH:40]=4)=CC=3)N(C(OC(C)C)=O)C[C@@H]2C)=O)CC1>>[CH:18]1([C:16]([N:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:36]4[CH:37]=[N:38][NH:39][CH:40]=4)[CH:3]=3)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6]2)=[O:17])[CH2:20][CH2:19]1
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)C2CC2)C[C@@H]1C
Reactant: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(-c3cn[nH]c3)cc21
Product: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)C2CC2)C[C@@H]1C

Procedure:
(S)-1-(4-(Cyclopropanecarbonyl)-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoxalin-1 (2H)-yl)ethan-1-one was synthesized from (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydroquinoxalin-1 (2H)-yl)ethan-1-one according to the procedure outlined above for (S)-isopropyl 4-(cyclopropanecarbonyl)-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 359 [M+1]+.