Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([N:15]([CH3:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>C[O-].[Na+].CO>[OH:23][C:7]1[C:8]2[S:14][C:13]([N:15]([CH3:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(N(C)c3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(c1ccccc1)c1nc2cnc(C(=O)NCC(=O)O)c(O)c2s1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A mixture of 7-hydroxy-2-(methyl-phenyl-amino)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (87 mg, 0.26 mmol) and glycine (399 mg, 5.31 mmol) in 0.5 M sodium methoxide/methanol (10.1 mL) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (20 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (6.5 mL). The precipitate was filtered, washed with water and dried under vacuo to give the title compound as a white solid (77 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.18 (br s, 1H), 8.37 (s, 1H), 7.57 (m, 5H), 3.95 (d, J=6.2 Hz, 2H), 3.61 (s, 3H); MS: (+) m/z 359.0 (M+1).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:34][CH2:33]3)[N:22]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH3:20])[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:33][CH2:34][N:35]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:36][CH2:37]3)[N:22]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH3:20])[CH3:10]
Reactant: O=C1CCCC(=O)O1
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)CCCC(=O)O)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from glutaric anhydride and starting compound A2 as described for compound 1. After evaporating the pyridine, the residue is partitioned between ethyl acetate and 1N hydrochloric acid. The ethyl acetate solution is dried over magnesium sulfate and evaporated. Crystallisation from diethyl ether. M. p. 133-135° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10](C(C)(C)C)[CH2:9][C@:8]1(O[SiH](C)C)[CH2:16][N:17]1[C:24]2[N:20]([N:21]=[CH:22][CH:23]=2)[CH:19]=[CH:18]1)=[O:6])[CH:2]=[CH2:3].Cl.C[O-:31].[Na+]>CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:31])[CH2:9][C@H:8]1[CH2:16][N:17]1[C:24]2[N:20]([N:21]=[CH:22][CH:23]=2)[CH:19]=[CH:18]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](C(C)(C)C)C[C@@]1(Cn1ccn2nccc12)O[SiH](C)C
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cn1ccn2nccc12

Procedure:
A solution of (2S,4R)-1-allyloxycarbonyl-4-tertbutyldimethylsilyloxy-2-(imidazo[1,2-b]pyrazol-1-yl)methylpyrrolidine (4.23 g) and conc. hydrochloric acid (2.61 ml) in methanol (40 ml) was stirred at ambient temperature for 5 hours. The reaction mixture was adjusted to pH 8-9 with 28% sodium methoxide in methanol solution and the mixture was concentrated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (2:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-(imidazo [1,2-b]pyrazol-1-yl)methylpyrrolidine (3.18 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[H-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([S:22]([N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc2[nH]ccc2c1OC
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1OC
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To 4,5-dimethoxyindole (241 mg, 1.36 mmol) in 5 mL THF at 0° C. was added 82 mg (2.04 mmol, 1.5 eq) of sodium hydride, followed by benzenesulfonyl chloride (260 μL, 2.04 mmol, 1.5 eq). The reaction was warmed to room temperature over 5 h then quenched with H2O and concentrated. The residue was dissolved in CH2Cl2 and extracted with NaHCO3, H2O, aqueous NaCl, dried (Na2SO4), and concentrated. The product was purified by silica gel column chromatography (7/3 hexanes/EtOAc) to give 369 mg of 1-benzenesulfonyl-4,5-dimethoxy-1H-indole (86%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23](Cl)[C:22]3[C:17](=[CH:18][C:19]([O:31][CH3:32])=[C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:38]=[CH:37]2>C(O)(C)C.NC1C=C2C(=CC=1)N(C(OC(C)(C)C)=O)N=C2>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:38]=[CH:37]4)[C:22]3[C:17](=[CH:18][C:19]([O:31][CH3:32])=[C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1cc2c(Cl)nc(-c3cccc(OCc4ccccc4)c3)nc2cc1OC
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Solvent: CC(C)O
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(OCc4ccccc4)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline (1.55 g, 3.44 mmol) and tert-butyl 5-amino-1H-indazole-1-carboxylate (0.842 g, 3.61 mmol) in iso-propanol (100 mL) was heated at 95° C. for 2 h, upon which the an additional aliquot of tert-butyl 5-amino-1H-indazole-1-carboxylate (0.100 g, 0.43 mmol) was added. Stirring was continued at 95° C. for a further 3 h upon which a third aliquot of tert-butyl 5-amino-1H-indazole-1-carboxylate (0.050 g, 0.22 mmol) was added. Stirring was continued at 95° C. for a further 1 h upon which the mixture was allowed to cool to RT and the precipitate was collected via filtration. The solid was washed with iso-propanol and dried under vacuum to give tert-butyl 5-(2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (2.35 g, 3.44 mmol, 100%). MS 648 (M+1). HPLC retention time 7.79 mins.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:7]=1)[CH3:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>>[CH2:1]([O:3][C:4](=[O:23])[C:5]([C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:7]=1)=[CH:29][N:30]([CH3:32])[CH3:31])[CH3:2]
Reactant: CCOC(=O)Cc1nc(OC2CCN(C)CC2)ccc1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1nc(OC2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
A mixture of [6-(1-methyl-piperidin-4-yloxy)-3-nitro-pyridin-2-yl]-acetic acid ethyl ester (5.93 g, 18.3 mmol) and tert-butoxybis(dimethylamino)methane (5.7 mL, 27.5 mmol) at is heated 65° C. for a period of 6 h. The mixture is cooled to room temperature and purified by flash chromatography on silica (gradient elution with 4% MeOH/CHCl3 with 0.1% NH4OH to 6% MeOH/CHCl3 with 0.1% NH4OH) to give the title compound as a dark orange oil: 1H NMR (400 MHz, CDCl3) δ 8.03 (d, 1H, J=9.1 Hz), 7.5 (s, 1H), 6.49 (d, 1H, J=9.1 Hz), 5.00-4.96 (m, 1H), 3.97-3.82 (m, 2H), 2.69 (br s, 6H), 2.60-2.50 (m, 2H), 2.20-2.10 (m, 2H), 2.16 (s, 3H), 1.92-1.85 (m, 2H), 1.74-1.65 (m, 2H), 0.98 (t, 3H, J=7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 167.7, 163.3, 151.7, 150.8, 141.8, 135.5, 109.3, 96.8, 71.7, 59.8, 52.9, 46.3, 43.6, 31.4, 30.9, 14.4; MS (CI) m/z 379.3 (M+1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:19](=[O:20])[NH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=1)[CH2:2]2
Reactant: COc1ccc(N=C=O)cc1
Reactant: OC1CN2CCC1CC2
Product: COc1ccc(NC(=O)OC2CN3CCC2CC3)cc1
Yield: 43 %

Procedure:
3-Quinuclidinol and 4-methoxyphenyl isocyanate were used. The solid which precipitated from the reaction mixture was recrystallized from ethyl acetate to afford the title compound (43%) as a white solid: mp 159.5-160.5° C.; FAB LRMS m /z (relative intensity, %) 277 (MH+ 1, 16), 110 (100).
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[CH2:9][C@H:8]([N:10]([C:15]([C:17]2[N:18]=[N:19][N:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:21]=2[CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)[CH3:3]>Cl.CO>[OH:1][CH:2]([C@H:4]1[CH2:5][NH:6][CH2:7][C@@H:8]([N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:15]([C:17]2[N:18]=[N:19][N:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:21]=2[CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[O:16])[CH2:9]1)[CH3:3]
Reactant: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Agent: Cl
Solvent: CO
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(C)O)C2)nnn1-c1ccccc1C
Temperature: 25 °C
Reaction time: 13 h
Yield: 96.5 %

Procedure:
tert-Butyl(3R,5S)-3-(1-hydroxyethyl)-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (319 mg) was dissolved in 10% hydrogen chloride-methanol (4 ml), and the mixture was stirred at room temperature for 13 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residual aqueous layer was neutralized with 3.5M aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue and fumaric acid (27.9 mg) were dissolved in methanol (2 ml), and the solvent was evaporated under reduced pressure to give the object product (254 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=4)[CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:15]([CH3:43])[C:14]=3[CH:44]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Na+]>C(O)C.O1CCCC1>[C:1]([C:3]1[C:4]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=4)[CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:15]([CH3:43])[C:14]=3[CH:44]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Oc4ncccc4C#N)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(Oc3ncccc3C#N)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
Ethyl 3-{[(4-{[{5-[(3-cyanopyridin-2-yl)oxy]-3-methyl-1-benzofuran-2-yl}(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (234 mg) obtained in Example A197 was dissolved in ethanol (1.5 mL) and tetrahydrofuran (1.5 mL), 1N aqueous sodium hydroxide solution (0.78 mL) was added to the solution, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 mL) was added, and the mixture was neutralized with 1N hydrochloric acid (0.78 mL) under ice-cooling. The resulting precipitate was collected by filtration and dried. The obtained residue was purified by preparative HPLC “instrument: Gilson Inc., preparative HPLC system; column: Develosil ODS-UG-10, S-5 μm, 50×100 mm; solvent: SOLUTION A; 0.1% trifluoroacetic acid-containing water, SOLUTION B; 0.1% trifluoroacetic acid-containing acetonitrile, (SOLUTION A:SOLUTION B=95:5-0:100); flow rate: 150 mL/min; detection method: UV 220 nm”. To the fractionated fraction was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (73 mg, 33%) as a colorless amorphous form.
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[CH:7]=[C:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)C.[OH-].[Na+]>CO>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:23])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 93.6 %

Procedure:
A solution of (E)-5,5-bis(4-fluorophenyl)-2,4-pentadienoic acid ethyl ester (8.8 g) in methanol (30 mL) was treated with 2N sodium hydroxide solution (20 mL) and the mixture was heated at reflux for 15 minutes. The crude solid obtained from the usual work up, was crystallized from dichloromethane-hexane to yield 7.5 g of (E)-5,5-bis(4-fluorophenyl)-2,4-pentadienoic acid mp 186°-188° C. A portion was recrystallized from ether-hexane to furnish the analytical specimen, mp 187°-188° C.
Reaction SMILES: [ClH:1].[CH3:2][SiH:3]([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])[CH3:5]>>[CH3:2][Si:3]([CH:7]([CH3:9])[CH3:8])([CH:4]([CH3:6])[CH3:5])[Cl:1]
Reactant: CC(C)[SiH](C)C(C)C
Reactant: Cl
Product: CC(C)[Si](C)(Cl)C(C)C
Temperature: 100 °C

Procedure:
A thermometer, hydrogen chloride gas inlet tube, and reflux condenser were fitted to a stirrer-equipped 200 mL four-neck flask, and 100 g methyldiisopropylsilane was then introduced into the flask. This was followed by the addition of 0.01 g platinum/divinyltetramethyldisiloxane complex and heating to 100° C. Hydrogen chloride gas was then introduced into the mixture. The introduction of hydrogen chloride gas was suspended after 4 hours. Distillation at ambient pressure yielded 122 g methyldiisopropylchlorosilane (purity≥99%, bp=146° C.). The methyldiisopropylchlorosilane yield was 97%.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CNc1nc(C#N)nc2ccc(OCc3ccccn3)cc12

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.23 mmol), 2-chloromethyl-pyridine hydrochloride (0.35 mmol) and cesium carbonate (2.3 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 160° C., Rf=0.4 (CH2Cl2/MeOH=15:1) is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:51][CH3:52])[C@H:4]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][NH:34]3)=[O:32])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1)=[O:13])=[O:6])[CH3:2].[CH3:53][O:54][C@H:55]([CH3:65])[C@H:56]([NH:60][C:61]([O:63][CH3:64])=[O:62])[C:57](O)=[O:58]>>[CH3:64][O:63][C:61]([NH:60][C@H:56]([C:57]([N:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[C:31]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[C@@H:8]3[CH2:9][CH2:10][CH2:11][N:7]3[C:5](=[O:6])[C@H:4]([N:3]([CH2:1][CH3:2])[CH2:51][CH3:52])[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:20][CH:19]=2)[C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)=[CH:25][CH:26]=1)=[O:32])=[O:58])[C@@H:55]([CH3:65])[O:54][CH3:53])=[O:62]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Product: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Yield: 40.1 %

Procedure:
The product from Example 81A (0.038 g, 0.054 mmol) and (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (0.011 g, 0.059 mmol) were processed as in Example 81A to give 0.019 g (40%) of the title compound as an off-white solid. 1H NMR (500 MHz, DMSO-D6) δ ppm 0.89 (t, J=7.10 Hz, 3 H) 1.07 (t, J=7.17 Hz, 2 H) 1.13 (d, J=6.26 Hz, 3 H) 1.28 (t, J=7.25 Hz, 1 H) 1.76-1.92 (m, 4 H) 1.94-2.05 (m, 2 H) 2.07-2.23 (m, 2 H) 2.39-2.46 (m, 2 H) 2.57-2.63 (m, 2 H) 3.24 (s, 3 H) 3.34-3.42 (m, 1 H) 3.43-3.50 (m, 1 H) 3.53 (s, 3 H) 3.63-3.70 (m, 1 H) 3.75-3.87 (m, 2 H) 3.97-4.03 (m, 1 H) 4.26 (t, J=7.78 Hz, 1 H) 4.36-4.46 (m, 2 H) 4.56 (s, 4 H) 4.67 (s, 1 H) 6.64 (dd, J=9.31, 4.43 Hz, 2 H) 6.89-6.95 (m, 2 H) 7.16-7.22 (m, 4 H) 7.28 (t, J=7.17 Hz, 1 H) 7.33 (t, J=7.40 Hz, 2 H) 7.40 (d, J=7.17 Hz, 1 H) 7.49-7.57 (m, 4 H) 7.66-7.70 (m, 1 H) 9.96 (d, J=7.02 Hz, 2 H); MS ESI− m/z 876.5.
Reaction SMILES: C([NH:5][CH2:6][CH2:7][N:8]1[C:16]([CH2:17][C:18]2[C:27]([I:28])=[CH:26][C:21]3[O:22][CH2:23][CH2:24][O:25][C:20]=3[CH:19]=2)=[N:15][C:14]2[C:9]1=[N:10][C:11]([F:30])=[N:12][C:13]=2[NH2:29])(C)(C)C.[C:31](N)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[F:30][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[C:16]([CH2:17][C:18]3[C:27]([I:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[CH:19]=3)[N:8]2[CH2:7][CH2:6][NH:5][CH2:32][CH:31]([CH3:34])[CH3:33])=[C:13]([NH2:29])[N:12]=1
Reactant: CC(C)(C)N
Reactant: CC(C)(C)NCCn1c(Cc2cc3c(cc2I)OCCO3)nc2c(N)nc(F)nc21
Solvent: CN(C)C=O
Product: CC(C)CNCCn1c(Cc2cc3c(cc2I)OCCO3)nc2c(N)nc(F)nc21

Procedure:
9-(2-(tert-butylamino)ethyl)-2-fluoro-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-6-amine [DZ4-84]. S10-6 (8 mg, 0.0149 mmol) and tert-butylamine (109 mg, 157 μl) in DMF (0.5 mL) was stirred overnight at rt. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 7:2:1:0.5) to give 6 mg (77%) of DZ4-84. 1H NMR (500 MHz, CDCl3) δ 7.36 (s, 1H), 6.55 (s, 1H), 5.86 (br s, 2H), 4.29 (s, 2H), 4.17-4.23 (m, 4H), 4.04 (t, J=6.4 Hz, 2H), 2.85 (t, J=6.4 Hz, 2H), 0.99 (s, 9H); MS (ESI) m/z 527.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([S:11][CH2:12][CH2:13][CH3:14])[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:5]1=[O:52])[CH2:2][CH3:3].ClC1C=CC=C(C(OO)=[O:61])C=1>ClCCl>[CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([S:11]([CH2:12][CH2:13][CH3:14])=[O:61])[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:5]1=[O:52])[CH2:2][CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCn1c(=O)cc(S(=O)CCC)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution of 3-propyl-6-propylthio-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.6 g) in dichloromethane (10 ml) was added m-chloroperbenzoic acid (0.16 g) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with an aqueous sodium bicarbonate solution and water, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless powders (0.27 g, 44%).
Reaction SMILES: C([O:8][C:9]1[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][NH2:16])=O)=[CH:11][C:10]=1[CH2:20][CH3:21])C1C=CC=CC=1.[CH2:22]([C:25]1[S:29][C:28]([C:30]([OH:32])=O)=[CH:27][CH:26]=1)[CH2:23][CH3:24]>>[CH2:20]([C:10]1[CH:11]=[C:12]([C:13]2[O:32][C:30]([C:28]3[S:29][C:25]([CH2:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)=[N:16][N:15]=2)[CH:17]=[C:18]([CH3:19])[C:9]=1[OH:8])[CH3:21]
Reactant: CCCc1ccc(C(=O)O)s1
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Product: CCCc1ccc(-c2nnc(-c3cc(C)c(O)c(CC)c3)o2)s1

Procedure:
2-Ethyl-6-methyl-4-[5-(5-propyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-phenol is prepared in analogy to Example 29 starting from 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide and 5-propyl-thiophene-2-carboxylic acid; LC-MS: tR=0.99 min, [M+1]+=329.13.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[CH2:15][C:16]#[N:17]>C1COCC1.C(N(CC)CC)C>[C:16]([CH2:15][N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)#[N:17]
Reactant: N#CCCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-Boc piperazine (1 g) in dry THF (20 ml), triethylamine (3 ml), followed by chloroacetonitrile (5.02 ml) were added dropwise. The reaction mixture was allowed to stir at room temperature for overnight. The solvent was removed under vacuum and residue was diluted ethyl acetate (20 ml). The organic layer was concentrated to dryness under reduced pressure to afford tert-butyl 4-(cyanomethyl)piperazine-1-carboxylate, which was used for the next reaction without further purification.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:17]O>C(OCC)C>[C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([O:10][CH3:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: CCC(C(=O)O)c1ccccc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCC(C(=O)OC)c1ccccc1
Reaction time: 8 h

Procedure:
To 102 g. of 2-phenylbutyric acid dissolved in 1 liter of methanol was added 2 ml of thionyl chloride. The solution was allowed to stand at room temperature overnight. The solvent was removed in vacuo to yield an oil which was dissolved in diethyl ether, washed successively with dilute sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous potassium carbonate, and concentrated in vacuo. Distillation yielded 101 g of the title compound as a water-white oil, b.p. 62°-65°/0.5 mm, having the following elemental analysis: