Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6]
Reactant: O=C([O-])CCCO
Reactant: BrCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCCO)OCc1ccccc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
Sodium 4-hydroxybutyrate (25 g, 0.2 mol) and benzyl bromide (37 g, 0.22 mol) were dissolved in a mixed solvent of DMF (40 ml) and ethyl acetate (50 ml), and the reaction mixture was heated and refluxed for 4 hours. Then, the reaction mixture was allowed to cool to room temperature, diluted with a proper amount of ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily product. The resulted product was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=4/1) to give 34.9 g of benzyl 4-hydroxybutyrate. Yield: 90%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:37][C:38]([O:41][C:42](/[N:44]=[N:45]/[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:43])([CH3:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[CH2:19]([N:26]1[CH2:31][CH2:30][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])([N:44]([C:42]([O:41][C:38]([CH3:40])([CH3:39])[CH3:37])=[O:43])[NH:45][C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCOC(=O)C1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.1 %

Procedure:
A solution of diisopropylamine (8.8 ml, 0.063 mol) in ether (400 ml) at -70° C. under nitrogen was treated with 1.6M n-butyllithium in hexane (37.5 ml, 0.060 mol) and stirred for 10 minutes. A solution of ethyl 1-benzylpiperidin-4-ylcarboxylate (13.6 g, 0.055 mol) in ether (70 ml) was added over 5 minutes and the resulting mixture then stirred at -70° C. for 40 minutes, before adding a solution of di-tert-butylazodicarboxylate (13.5 g, 0.058 mol) in ether (80 ml). The reaction mixture was allowed to warm to room temperature over 0.5 h, then stirred for a further 2 h before adding dilute potassium carbonate solution (150 ml). The ether layer was separated, dried (Na2SO4) and concentrated in vacuo to leave an orange oil. This was chromatographed on silica gel eluting initially with 20% ether/60-80 petrol, then with neat ether to afford the title compound (D26) (14.2 g, 54%) as a yellow oil.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([C@H:13]2[C@H:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([C:23]3[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][CH:28]=3)=[O:31])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)c2ccc(C#N)cc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CN(C(=O)c2ccc(C#N)cc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of rac-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (1.08 g, 2.28 mmol) in CH2Cl2 (25 ml) was added TFA (5 ml) at RT. Stirring was continued one hour. The reaction mixture was then concentrated under vacuo, the crude dissolved in CH2Cl2, washed with aq.NaHCO3 and the organic phase was dried over Na2SO4. Purification by flash chromatography (SiO2, CH2Cl2/MeOH 95:5) yielded 0.72 g (85%) of the title compound as light yellow foam. ES-MS m/e: 374.0 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[CH:9]=[C:10]2[CH2:31][C:15]3([CH2:30][C:17]4([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH2:16]3)[O:14][C:11]2=[CH:12][N:13]=1.[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34].O1CCOCC1>CO>[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([C:8]2[CH:9]=[C:10]3[CH2:31][C:15]4([CH2:30][C:17]5([CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]5)[CH2:16]4)[O:14][C:11]3=[CH:12][N:13]=2)=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 M aqueous Na2CO3 solution (0.30 mL) is added to a mixture of 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (0.10 g), 4-(methanesulfonyl)phenylboronic acid (0.08 g), 1,4-dioxane (1.5 mL), and methanol (0.5 mL) at room temperature. The mixture is sparged with Ar for 10 min prior to addition of PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (20 mg). The resulting mixture is heated to reflux temperature and stirred at this temperature for 2 h. After cooling to room temperature, water and methanol are added and the resulting mixture is filtered. The filtrate is concentrated and the residue is chromatographed on reversed phase (HPLC, methanol/water) to give the title compound. LC (method 2): tR=1.72 min; Mass spectrum (ESI+): m/z=485 [M+H]+.
Reaction SMILES: C[C@H]1C[O:29][C@@:5]2([O:9][C@H:8]3C[C@H]4[C@@H]5CC=C6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H:7]3[C@@H]2C)[CH2:4]C1.C(OCC)(=O)C[C:33](OCC)=[O:34].[CH2:42]([C:44]1([CH2:48][OH:49])[CH2:47][O:46][CH2:45]1)[CH3:43].C([Sn](=O)CCCC)CCC>>[CH2:42]([C:44]12[CH2:47][O:46][C:45]([CH2:4][C:5]([O:9][CH2:8][CH3:7])=[O:29])([O:49][CH2:48]1)[O:34][CH2:33]2)[CH3:43]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCC1(CO)COC1
Agent: CCCC[Sn](=O)CCCC
Product: CCOC(=O)CC12OCC(CC)(CO1)CO2
Temperature: 140 °C

Procedure:
Into a 4 l three necked flask equipped with a stirrer, a distilling column, a nitrogen in- and outlet, a heating jacket, a thermocouple, and a vacuum pump were charged 1920 g of diethyl malonate (12 moles), 464 g of 3-ethyl-3-hydroxymethyl oxetane (4 moles), and 2,5 g of dibutyl tin oxide. The reaction mixture was heated to 140° C. upon which temperature the ethanol distillation began. The reaction temperature was gradually increased to 200° C. during 6 hours. During this time 171 g of ethanol were collected as distillate. The temperature was lowered to 100° C. and the pressure was lowered to 29 mbar by application of vacuum. The excess diethylmalonate was distilled off. The pressure was further lowered to 0.03 mbar and the temperature was gradually increased to 156° C. Three fractions of distillate were collected. The third fraction (100–104° C./0.03 mbar) consisted of 379 g, which according to GC analysis contained 75% of 4-ethyl-1-(ethoxycarbonylmethyl)-2,6,7-trioxabicyclo[2.2.2]octane having the following structure
Reaction SMILES: Cl.Cl.[CH:3]([NH:6][NH2:7])([CH3:5])[CH3:4].[C:8]([O:18]CC)(=O)[CH2:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=O.[Na]>O.C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:10]1[CH:9]=[C:8]([OH:18])[N:6]([CH:3]([CH3:5])[CH3:4])[N:7]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: CC(C)NN
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)n(C(C)C)n1
Temperature: 140 °C
Yield: 28.4 %

Procedure:
A solution containing 29 g of isopropylhydrazine dihydrochloride in 150 ml of water was added dropwise to a stirred solution of 41.7 g of diethyl oxalacetate, sodium salt in 300 ml of acetic acid and 150 ml of toluene. The mixture was heated at 140° C. for 5 h. The mixture was left to cool to room temperature and then the solvent was evaporated under reduced pressure and the residue azeotroped with toluene. The residue was partitioned between dichloromethane and water. The dichloromethane extract was washed with brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was triturated with diethyl ether to give a white solid which was filtered then washed three times with cold diethyl ether and dried to give 11.1 g of 5-hydroxy-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid which was used without further purification.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:16]([NH:18][CH2:19][C:20]([O:22]C)=O)=[O:17])=[C:4]2[CH:3]=[CH:2]1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C[Al](C)C.O>O1CCCC1>[CH2:24]([NH:31][C:20]([CH2:19][NH:18][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12)=[O:17])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
To a solution of methyl ({[3-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)thiophen-2-yl]carbonyl}amino)acetate (50 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added a pre-mixed solution of benzylamine (25 uL, 0.23 mmol) and trimethylaluminum (2.0 M toluene, 91 uL, 0.18 mmol). The solution was stirred at room temperature for 10 minutes then water was added resulting in precipitation. The precipitate was collected by filtration and dried under vacuum to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (benzylcarbamoyl-methyl)-amide (55 mg, 90%) (ESI) 406 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.31 (1H, s) 8.46 (1H, t, J=6.08 Hz) 8.39 (1H, t, J=5.69 Hz) 8.03 (1H, d, J=5.37 Hz) 7.81 (1H, d, J=5.42 Hz) 7.51 (1H, d, J=5.42 Hz) 7.33 (1H, dd, J=3.20, 2.71 Hz) 7.28 (4H, d, J=0.05 Hz) 7.16-7.25 (1H, m) 6.85 (1H, d, J=5.47 Hz) 6.44 (1H, dd, J=3.47, 1.90 Hz) 4.30 (2H, d, J=5.95 Hz) 3.89 (2H, d, J=5.71 Hz)
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])([CH3:3])[CH3:2].C([Li])CCC.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.C(OCC)(=O)C.Cl>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:32])=[O:31])[CH:9]=[C:8]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2[nH]cc(CCC(=O)O)c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of propionic acid (27) (96.3 mg, 0.510 mmol) in tetrahydrofuran (10 ml), n-butyl lithium (1.40 ml, 2.24 mol) was added next and stirred for 30 minutes at −78° C. Benzene sulfonyl chloride (277 mg, 1.5 mmol) was added next, and the reaction was stirred for 16-24 hours, allowing temperature to rise from −78° C. to ambient conditions. The reaction was then diluted with ethyl acetate, and 1M HCl was added to adjust the pH to 1-2. The layers were then separated, and the organic layer was placed over magnesium sulfate and concentrated under reduced pressure. The crude material was then purified by flash chromatography with silica, eluting with 5% methanol in dichloromethane to yield the desire product (22) as a white solid. (M−1=386.4)
Reaction SMILES: [NH2:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].O.[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:16][C:15](=[O:24])[NH:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: NC1(CO)CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC1(CO)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-amino-1-cyclopentanemethanol (1.15 g, 10 mmol) and NaHCO3 (0.84 g, 10 mmol) in acetone (14 mL)/water (14 ml) at room temperature was added benzyl succinimidyl carbonate (2.5 g, 10 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (DCI) m/z 250 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9](Cl)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1([F:25])[O:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21](B(O)O)[C:15]=2[O:14]1>>[F:25][C:13]1([F:12])[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[C:18]([C:9]3[N:10]=[C:3]4[CH:2]=[CH:7][CH:6]=[CH:5][N:4]4[N:8]=3)[C:16]=2[O:17]1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: OB(O)c1cccc2c1OC(F)(F)O2
Product: FC1(F)Oc2cccc(-c3nc4ccccn4n3)c2O1

Procedure:
2-Chloro-8-(2,2-difluoro-1,3-benzodioxol-4-yl-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro[1,2,4]triazolo[1,5-a]pyridine (0.71 g, 3.0 mmol) and 2,2-difluorobenzo[1,3]dioxole-4-boronic acid (0.64 g, 3.2 mmol) in a manner analogous to Example 2c. Product was isolated as a foam (0.63 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.84 (d, J=7.5 Hz, 1H), 7.78-7.67 (m, 2H), 7.33-7.23 (m, 2H), 7.36 (d, J=6 Hz, 1H), MS=310 (MH)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[C:13]1=[O:30].[CH2:31](I)[CH3:32]>C(#N)C>[CH2:10]([N:1]([CH2:31][CH3:32])[C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])[CH3:11].[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[C:13]1=[O:30]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CCI
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: CC#N
Product: CCN(CC)[C@H](C(=O)O)C(C)C
Temperature: 80 °C

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-amino-3-methylbutanoate (92 mg) was dissolved in acetonitrile (18 mL). Ethyl iodide (74 mg) was added. The mixture was stirred at 80° C. and allowed to react overnight. The solvent was removed by rotary evaporation in vacuo. White solid (30 mg) was obtained after the crude product was purified by silica gel column (eluted with acetic ether:petroleum ether=1:1). 1H NMR (CDCl3, ppm) δ 7.86-7.90 (m, 2H), 7.76-7.79 (m, 2H), 4.97-5.08 (m, 1H), 4.38-4.43 (m, 1H), 4.05-4.30 (m, 3H), 3.15-3.25 (m, 1H), 2.95-3.05 (m, 1H), 2.80-2.95 (m, 2H), 2.45-2.58 (m, 4H), 2.10-2.20 (m, 1H), 1.90-2.10 (m, 2H), 1.00-1.20 (m, 7H), 0.95-0.98 (m, 3H), 0.87-0.91 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]([CH2:14][C:15](OC)=[O:16])=[CH2:13].OC1C=CC=CN=1>CO.C1(C)C=CC=CC=1>[CH3:21][O:20][C:11]([CH:12]1[CH2:14][C:15](=[O:16])[N:8]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:13]1)=[O:19]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: COc1ccc(CN)cc1
Agent: Oc1ccccn1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Temperature: 20 °C
Yield: 85.7 %

Procedure:
In a 250 ml three necked flask fitted with a magnetic stirrer and reflux condenser, under inert atmosphere, 10 g (73 mmol, 1 eq) of 4-methoxy-benzylamine and 12.7 g (81 mmol, 1.1 eq) of dimethyl itaconate are dissolved in 100 ml of MeOH. The mixture is brought to reflux for 10 h, and cooled down slowly to 20° C. over 4 h and concentrated to dryness. In a 250 ml three necked flask fitted with a magnetic stirrer and Rashig column and distillation arm, under inert atmosphere, the crude intermediate and 0.69 g (7.30 mmol, 0.1 eq) of 2-hydroxypyridine are dissolved in 200 ml of toluene. The mixture is brought to reflux and the methanol formed distilled off for 8 h, until no more methanol is collected. Temperature in the pot reached 112° C. The mixture is cooled down and concentrated to dryness to give the crude ester. It is purified by column chromatography on silicagel (AcOEt/n-Hexane: 1/1 (v/v)) to afford the pure ester a1 (16.48 g, 85.9%).
Reaction SMILES: [CH:1]1([CH2:4][C@:5]2([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][C:17](B4OC(C)(C)C(C)(C)O4)=[CH:16][CH:15]=3)[CH3:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Br[C:35]1[CH:36]=[CH:37][C:38]([C:41]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]2)=[N:39][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH2:4][C@:5]2([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][C:17]([C:35]4[CH:36]=[CH:37][C:38]([C:41]5([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]5)=[N:39][CH:40]=4)=[CH:16][CH:15]=3)[CH3:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: NC(=O)C1(c2ccc(Br)cn2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@@](CC2CC2)(CC(C)(C)O)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)nc2)cc1)N1CC[C@@](CC2CC2)(CC(C)(C)O)OC1=O
Temperature: 100 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (3.3 mg) was added to a solution of (S)-6-(cyclopropylmethyl)-6-(2-hydroxy-2-methylpropyl)-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (150 mg), 1-(5-bromopyridin-2-yl)cyclopropanecarboxamide (94 mg), and Na2CO3 (348 mg, 3.28 mmol) in ethanol (8 mL), toluene (12 mL), and H2O (4 mL) at room temperature. The reaction mixture was heated to 100° C. for 2 h. After cooling to room temperature, the formed mixture was concentrated to afford an oil which was diluted with H2O (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was concentrated to afford an oil which was purified by preparative TLC and preparative HPLC to give the title compound. Yield: 30 mg (19% of theory); LC (method 4): tR=0.95 min, Mass spectrum (ESI+): m/z=492 [M+H]+; 1H NMR (CDCl3, 400 MHz) δ 0.01 (d, 2H), 0.40-0.50 (m, 2H), 0.69 (m, 1H), 1.27 (m, 2H), 1.33 (s, 3H), 1.39 (s, 3H), 1.61 (d, 3H), 1.78 (m, 1H), 1.82 (m, 2H), 1.89-2.05 (m, 4H), 2.21 (m, 1H), 2.80 (m, 1H), 3.19 (m, 1H), 5.51 (1H), 5.85 (m, 1H), 7.29 (m, 1H), 7.48 (d, 2H), 7.58 (d, 2H), 7.82 (1H), 7.89 (d, 1H), 8.79 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:20]=[CH:19][C:15]3[O:16][CH2:17]O[C:14]=3[CH:13]=1)[N:6]=[CH:5]2.[CH:21](Cl)(Cl)Cl.CO>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:20]=[CH:19][C:15]3[O:16][CH2:17][CH2:21][C:14]=3[CH:13]=1)[N:6]=[CH:5]2
Reactant: Nc1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Reactant: ClC(Cl)Cl
Solvent: CO
Product: Nc1ccc2nc(-c3ccc4c(c3)CCO4)ncc2c1
Yield: 73 %

Procedure:
This compound was synthesized in 73% yield, according to the procedure described in example 1 for the synthesis of 6-amino-2-(1,3-benzodioxol-5-yl)-quinazoline. C16H13N3O, MW: 263.30. TLC(CHCl3/MeOH 9/1) Rf=0.65.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:30]1C[CH:31]1[CH2:33][N:34]1[C:42]2[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=2[C:36]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=2)=[N:35]1>C(Cl)Cl>[Cl:21][C:20]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:22])[C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][CH:31]([OH:30])[CH2:33][N:34]2[C:42]3[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=3[C:36]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)=[N:35]2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cncc2Cl)CC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(Oc3c(Cl)cncc3Cl)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A solution of 103 mg (0.30 mmol) of 4-(3,5-dichloro-pyridin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (2 mL) was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in MeOH and stirred over 100 mg of sodium bicarbonate for 1 h. The solid was filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 90 mg (54%) of a white solid. MS (electrospray): exact mass calculated for C28H30Cl2F3N5O3, 611.17; m/z found, 612.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 8.44 (s, 2H), 7.77 (d, J=8.41 Hz, 1H), 7.72 and 7.68 (A and B of AB quartet, J=8.41 Hz, 2H), 7.65 (d, J=8.41 Hz, 1H), 4.88 and 4.76 (A and B of AB quartet, J=15.65 Hz, 1H), 4.66 (br s, 1H), 4.55 (br s, 1H), 4.26-4.08 (m, 2H), 4.08-3.98 (m, 2H), 3.91-3.69 (m, 2H), 3.03-2.92 (m, 1.6H), 2.91-2.85 (m, 0.8H), 2.85-2.75 (m, 1.6H), 2.52-2.40 (m, 3H), 2.35-2.24 (br m, 1H), 2.22 (s, 1.5H), 2.17 (s, 1.5H), 2.03-1.90 (m, 4H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:24][S:25]([O:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:41])[NH2:40])[CH:35]=2)[CH:30]=1)(=[O:27])=[O:26].C(OCC)C>N1C=CC=CC=1>[CH3:24][S:25]([OH:28])(=[O:27])=[O:26].[C:1]([O:8][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:40])[NH2:41])[CH:35]=2)[CH:30]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)O
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCC(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Product: CS(=O)(=O)O
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
To a solution of 2.1 g of caproic acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate formed upon addition of ethyl ether to the reaction mixture was collected by filtration, washed with ethyl ether, dissolved in methanol at room temperature, and filtered to remove the insolubles. The filtrate was concentrated under reduced pressure and the residue was recrystallized from an ethanol-ether mixture to obtain 2.1 g of 6-amidino-2-naphthyl caproate methanesulfonate.