Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:23](=[O:26])[CH2:24]Cl)[CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][NH:15][CH2:24][C:23]2=[O:26])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)NCCN(CCc1ccc(C#N)c(Br)c1)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CCN2CCNCC2=O)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-Butyl (2-{[2-(3-bromo-4-cyanophenyl)ethyl](chloroacetyl)amino}ethyl)carbamate (530 mg, 1.2 mmol) in 5 mL of DCM was added 2 mL of TFA and the mixture was stirred at RT for 3 hours, then concentrated in vacuo. The residue was redissolved in ethanol (2 mL) and added K2CO3 (169 mg, 1.22 mmol). The mixture was stirred at reflux for 1.5 hours. Then water (10 ml) was added, and the mixture was extracted with ethyl acetate (5 mL×3), dried over Na2SO4 and concentrated in vacuo to give the title product. 1H-NMR (400 MHz, CD3CN) δ 7.68-7.70 (m, 2H), 7.39 (dd, J=1.6, 7.6 Hz, 1H), 3.55 (t, J=5.6 Hz, 2H), 3.27 (s, 2H), 3.18 (t, J=5.6 Hz, 2H), 2.88-2.92 (m, 4H). MS m/z: 308 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([OH:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]O)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([O:18][CH2:27][CH2:26][NH:25][C:24](=[O:29])[O:23][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CCOCc1nc2cnc3ccccc3c2n1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3ccccc3c2n1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a stirred slurry of 2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-ol (3.80 g, 15.6 mmol), N-(2-hydroxyethyl)carbamic acid tert-butyl ester (3.9 g, 24 mmol), and triphenylphosphine (6.3 g, 24 mmol) in tetrahydrofuran (120 mL) at 0° C. was added diisopropylazodicarboxylate (4.7 mL, 24 mmol). After 1 hour, the solution was allowed to warm to room temperature. More N-(2-hydroxyethyl)carbamic acid tert-butyl ester (3.9 g, 24 mmol) and triphenylphosphine (6.3 g, 24 mmol) were added, then a solution of diisopropylazodicarboxylate (4.7 mL, 24 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred over the weekend, then concentrated under reduced pressure. Dichloromethane (150 mL) was added and the solution was washed with water (2×25 mL). The organic layer was dried over potassium carbonate, filtered, and concentrated under reduced pressure. The solid was washed with diethyl ether/hexanes twice and dried to afford 1.5 g of crude tert-butyl 2-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]oxy}ethylcarbamate, which was used without purification in Part D below.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21](O)([CH3:23])[CH3:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21]([CH3:23])=[CH2:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(C)(C)O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-hydroxypropan-2-yl)pyrrolidine-1-carboxylate (98 g) dissolved in toluene (900 mL) at −78° C. was added triethylamine (310 mL). The mixture was stirred at −78° C. for 10 minutes, and then thionyl chloride (60 mL) in toluene (100 mL) was added dropwise over 1.5 hours. The mixture was stirred at −78° C. for 2 hours and then quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(prop-1-en-2-yl)pyrrolidine-1-carboxylate. The residue was used directly without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([F:21])[CH:18]=[C:19]([Br:20])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.[Li+].[OH-].C1COCC1>O>[Br:20][C:19]1[C:13]2[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)[NH:15][C:14]=2[CH:16]=[C:17]([F:21])[CH:18]=1
Reactant: CCOC(=O)c1cnn(-c2nc3c(Br)cc(F)cc3[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3c(Br)cc(F)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
A mixture of 1-(4-bromo-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (16.0 mg, 45.0 mmol), LiOH (10.0 mg, 0.230 mmol), THF (0.5 mL), and H2O (0.17 mL) was stirred at 23° C. for 16 h. THF was removed under reduced pressure and then aqueous HCl was added. The resulting precipitate was collected and washed with water to yield the titled compound (10.0 mg, 67%). MS (ESI/CI): mass calcd. for C11H6BrFN4O2, 325.1; m/z found, 326.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.82 (s, 1H), 12.94 (s, 1H), 8.87 (s, 1H), 8.30 (d, J=0.5 Hz, 1H), 7.45 (dd, J=9.6, 2.3 Hz, 1H), 7.32 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[C:26]5[N:32]=[CH:31][N:30](COCC[Si](C)(C)C)[C:27]5=[N:28][CH:29]=4)[CH:19]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N)CN>CN(C=O)C.O>[N:32]1[C:26]2[C:27](=[N:28][CH:29]=[C:24]([C:20]3[CH:19]=[C:18]([C:16]4[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:6])[CH3:7])[CH:9]=[C:10]5[C:15]=4[N:14]=[CH:13][CH:12]=[CH:11]5)[CH:23]=[CH:22][CH:21]=3)[CH:25]=2)[NH:30][CH:31]=1
Reactant: CC(C)(c1cc(-c2cccc(-c3cnc4c(c3)ncn4COCC[Si](C)(C)C)c2)c2ncccc2c1)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(c1cc(-c2cccc(-c3cnc4[nH]cnc4c3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-phenyl}-quinoline from Step 2 (1.0 eq.), TBAF (2.0 eq.) and ethylene diamine (1.5 eq.) in DMF (0.2M) was stirred at 80° C. for 3 h. The mixture was cooled, diluted with water, filtered. The resulting solid was stirred in acetone to afford the title compound after filtration. 1H NMR (500 MHz, DMSO-d6): δ 8.94 (dd, 1H), 8.72 (s, 1H), 8.52 (dd, 1H), 8.47 (s, 1H), 8.30–8.25 (m, 2H), 8.08 (d, 1H), 7.98 (s, 1H), 7.79 (d, 1H), 7.68 (d, 1H), 7.63–7.60 (m, 2H), 2.81 (s, 3H), 1.93 (s, 6H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:6][C@@H:5]1[CH3:42])(=[O:3])[CH3:2].[ClH:43]>CO.CCOCC>[ClH:43].[ClH:43].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:35][C:36](=[O:37])[O:38][CH:39]([CH3:40])[CH3:41])[CH2:6][C@@H:5]1[CH3:42])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(CN4CCCN(C(=O)OC(C)(C)C)CC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCNCC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-({4-[(cis)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)hexahydro-1H-1,4-diazepine-1-carboxylate (for a preparation see Intermediate 11) (78 mg, 0.135 mmol) was dissolved in methanol (3 mL) and to this was added 1.25M HCl in methanol (1 mL, 1.250 mmol). The reaction vessel was sealed and heated in Emrys Optimiser microwave to 70° C. for 2 hr. After cooling the reaction was reduced in vacuo to give a colourless solid and placed under high vacuum for 1 hr. Transferred to vial using methanol, reduced, and then redissolved in ether to give a colourless solid (66 mg). LCMS (Method A): Rt=0.96, MH+=479
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:27])[C@H:10]([CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:11](OCC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=C(C)C=C(C)C=1[Mg]Br.O>O1CCCC1>[Si:1]([O:8][C@@H:9]([C@@H:10]1[CH2:16][N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11]1=[O:12])[CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](CNCc1ccc(OC)cc1)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C2=O)cc1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a solution of ethyl (2S*,3R*)-3-(t-butyldimethylsilyloxy)-2-(4-methoxybenzylaminomethyl)butanoate (6 g) in tetrahydrofuran (303 ml) was added dropwise a solution of mesitylmagnesium bromide (1M, 24.3 ml) in tetrahydrofuran at room temperature. After stirring for 30 minutes, water (10 ml) was added dropwise to the reaction mixture and the solvent was removed under reduced pressure. To the residue were added ethyl acetate and water, then the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and an aqueous sodium chloride in turn and then dried over magnesium sulfate. The resultant solution was evaporated under reduced pressure and the residue was column-chromatographed on silica gel (eluent : a mixture of hexane and ethyl acetate, 3:1) to give (3S*)-3-[(1R*)-1-(t-butyldimethylsilyloxy)ethyl]-1-(4-methoxybenzyl)azetidin-2-one (4.8 g), which contained about 2% of the corresponding (3R*), (1R*)-isomer.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:28][OH:29]>C(O)C.O.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:28][OH:29])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 66.7 %

Procedure:
To a stirred suspension of 4-(4′-bromo-biphenyl-4-yl)-4-oxo-butyric acid (0.718 g, 0.00215 mol) and potassium carbonate (0.167 g, 0.00121 mol) in absolute ethanol (15 mL) was added a solution of hydroxylamine hydrochloride (0.180 g, 0.00259 mol) in water (3 mL), and the mixture stirred at room temperature for 6 days. The mixture was rotary evaporated. The residue was dissolved in methanol, silica gel (10 g) was added, and the mixture rotary evaporated to dryness. The powder was purified by chromatography on silica gel, eluting with dichloromethane-methanol (20:1) to give 0.499 g of 4-(4′-bromo-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a white solid; mp 175-176° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:24][CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[N:27]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:32]=1.[OH-].[Na+]>C(O)C>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:32]=1
Reactant: COC(=O)c1coc(-c2cccc(N3C[C@@H]4CCCN4c4nc(SC)ncc4C3=O)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C(=O)O)co3)c1)C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
Methyl (S)-2-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxylate (172 mg, 0.381 mmol) obtained in Step 2 of Example 123 was dissolved in ethanol (3 mL), and the mixture was stirred at room temperature for 1.5 hours after adding a 2 mol/L aqueous sodium hydroxide solution (1.90 mL, 3.81 mmol). The mixture was concentrated, diluted with water, and neutralized with 1 mol/L hydrochloric acid. The precipitated solid was then filter off, and dried overnight under reduced pressure to give (S)-2-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxylic acid (110 mg, 66%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=4)[CH2:13]3)[C:9]2=[O:27])[CH2:4][CH2:3]1.CO>[Pd]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C:10]3([C:9](=[O:27])[N:8]([C@H:5]4[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]4)[CH2:12][CH2:11]3)[CH2:13]2)=[CH:19][CH:20]=1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCN(c1ccc([N+](=O)[O-])cc1)C2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCCC3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)cc1
Reaction time: 1.5 h

Procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-7-(4-nitrophenyl)-2,7-diazaspiro[4.5]decan-1-one (0.13 g, 0.00028 mol, prepared by using a procedure that was analogous to that described for the synthesis of example 43), 10% Pd/C (activated) in methanol (5 mL, 0.1 mol) was stirred under a H2 atmosphere (balloon) for 1.5 hour. The catalyst was filtered and the filtrate was concentrated in-vacuo to afford the desired product in quantitative yield. LC-MS: 344.3 (M+H)+.
Reaction SMILES: [ClH:1].C([N:15]1[CH2:18][C:17]([NH:22][CH2:23][CH2:24]CC2C=CC=CC=2)([C:19]([NH2:21])=[O:20])[CH2:16]1)(C1C=CC=CC=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[ClH:1].[CH2:23]([NH:22][C:17]1([C:19]([NH2:21])=[O:20])[CH2:18][NH:15][CH2:16]1)[CH3:24]
Reactant: NC(=O)C1(NCCCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCNC1(C(N)=O)CNC1

Procedure:
To a solution of 1-benzhydryl-3-(benzylethylamino)-azetidine-3-carboxylic acid amide hydrochloride salt (I-2A-1e; 0.66 g, 1.4 mmol) in methanol (25 ml) was added 20% Pd(OH)2 on carbon (30% water; 0.13 g). The mixture was placed on a Parr® shaker and then reduced (45 psi H2) at room temperature overnight. The mixture was diluted with methanol (200 ml) filtered through a 0.45 μm filter disk, and then concentrated to a solid. The residue was triturated from diethyl ether, collected by vacuum filtration, washed with diethyl ether and then dried, in vacuo, to afford I-2A-1g (298 mg, 98%): +APcI MS (M+1) 144.1; 1H NMR (400 MHz, CD2Cl2) δ 4.56 (br s, 4H), 3.00 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCOCC3)cc1OCC2
Yield: 44 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and morpholine, the crude product was recrystallised from methanol to give 341 as a white solid (107 mg, 44%). LCMS: RT=3.12 min, [M+H]+ 382. 1H NMR 400 MHz (DMSO-d) δ: 9.14 (1H, s), 7.90 (1H, d, J=0.63 Hz), 7.86 (1H, s), 6.36 (1H, s), 5.93-5.92 (1H, m), 4.57-4.48 (4H, m), 3.70 (4H, t, J=4.74 Hz), 3.50 (4H, t, J=4.74 Hz), 1.49 (6H, d, J=6.60 Hz)
Reaction SMILES: I[C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:12]=2[N:13]=1.[Cu](C#N)[C:30]#[N:31]>CN(C=O)C.O>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:11]2[C:12]3[N:13]=[C:5]([CH2:4][C:3]4[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=4[C:30]#[N:31])[S:6][C:7]=3[N:8]=[CH:9][N:10]=2)=[CH:16][CH:17]=1
Reactant: N#C[Cu]C#N
Reactant: FC(F)(F)c1ccc(Nc2ncnc3sc(Cc4ccccc4I)nc23)cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Cc1nc2c(Nc3ccc(C(F)(F)F)cc3)ncnc2s1
Temperature: 100 °C
Yield: 93.5 %

Procedure:
To a solution of [2-(2-iodo-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (0.20 g, 0.39 mmol) in anhydrous DMF (3.9 mL) was added copper cyanide (0.24, 2.73 mmol). The resulting suspension was heated to 100° C. in a sealed tube for 5 h. The reaction mixture was cooled to rt, diluted with H2O (20 mL) and extracted with EtOAc (2×10 mL). The organic layers were combined, washed with 10% aq. HCl (2×5 mL) and satd. aq. NaCl (2×5 mL), dried, filtered, concentrated and purified by FCC to provide the title compound as a colorless solid (0.15 g, 94%). MS (ESI): mass calcd. for C20H12F3N5S, 411.1; m/z found 412.1 [M+H]+. 1H NMR (CDCl3): 8.63 (s, 1H), 8.18 (s, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.75-7.72 (d, J=8.5 Hz, 2H), 7.65-7.61 (m, 1H), 7.52-7.49 (m, 1H), 7.48-7.44 (m, 2H), 4.66 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:3]=1.C([Mg]Cl)(C)C.C([Li])(C)(C)C.[CH3:34][C:35]([CH3:37])=[O:36].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:18]1([C:4]2[CH:3]=[C:2]([C:35]([OH:36])([CH3:37])[CH3:34])[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CC(C)=O
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 50.0 mg, 0.135 mmol) in 2 mL of THF at −78° C. under Ar was added isopropyl magnesium chloride (71 μL, 0.14 mmol, 2.0 M in THF). The resulting mixture was warmed to RT and stirred for 15 min, cooled to −78° C. again. To the mixture was added tert-butyllithium (240 μL, 0.405 mmol, 1.7 M in pentane) and the resulting mixture was stirred at −78° C. for 5 min and then acetone (0.40 mL, 0.68 mmol) was added. The reaction was warmed to RT and stirred for 1 h under Ar. The mixture was treated with 1 mL of saturated NH4Cl followed by 40 mL of EtOAc and washed with H2O (10 mL), brine (5 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-2% MeOH/DCM) gave 32.1 mg (68%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 11.88 (s, 1H), 9.58 (s, 1H), 8.29 (d, 1H, J=8.6 Hz), 7.74 (s, 1H), 7.42 (dd, 1H, J=8.6, 2.2 Hz), 7.35 (d, 1H, J=2.2 Hz), 5.87 (m, 1H), 2.23-2.34 (m, 4H), 1.73-1.90 (m, 4H), 1.79 (s, 1H, OH), 1.61 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C20H22N4O2, 351.2 (M+H). found 351.0.
Reaction SMILES: C(NC[N:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:7]1[S:8][C:9]([CH3:22])=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:16]=2)[N:11]=1)(=O)C>Cl>[CH3:22][C:9]1[S:8][C:7]([NH:6][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[N:14][N:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:16]=1
Reactant: CC(=O)NCN(c1ccccn1)c1nc(-c2cnn(CNC(C)=O)c2)c(C)s1
Agent: Cl
Product: CC(=O)NCn1cc(-c2nc(Nc3ccccn3)sc2C)cn1
Yield: 73333.3 %

Procedure:
According to Scheme 22, Step 2: A solution of N-((4-(2-((acetamidomethyl)(pyridin-2-yl)amino)-5-methylthiazol-4-yl)-1H-pyrazol-1-yl)methyl)acetamide (75 μmol, 30 mg) in 1 mL of HCl (1 N) was stirred at room temperature for 1 hour. The solution was then basified to pH 8 and the aqueous phase was extracted with AcOEt. The organic phases were dried over MgSO4, were filtered and were concentrated. The crude compound was purified by flash chromatography with silica gel using DCM/MeOH (100:0 to 95:5) and then by SCX-2 with a catch and release methodology to afford N-((4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazol-1-yl)methyl)acetamide (55 mmol, 18 mg, 73%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:4][CH:3]=1.[OH-].[K+].CO.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1oc(-c2ccc3c(c2)OCO3)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1oc(-c2ccc3c(c2)OCO3)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A mixture of methyl 3-[4-(4-chlorophenyl)-2-[3,4-(methylenedioxy)phenyl]-5-oxazolyl]propionate (1.29 g), potassium hydroxide (0.44 g), methanol (20 mL) and tetrahydrofuran (15 mL) was stirred at room temperature for 2 hrs. The reaction mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give 3-[4-(4-chlorophenyl)-2-[3,4-(methylenedioxy)phenyl]-5-oxazolyl]propionic acid (1.22 g, 98%) as a colorless powder. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 199–200° C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O[N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:8][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 5 h
Yield: 74.3 %

Procedure:
To a solution of 4.64 g (0.04 mol) of hexanoic acid and 5.75 g (0.05 mol) of N-hydroxy succinimide in 100 mL distilled DMF, 10.3 g (0.05 mol) of DCCI was added. The mixture was cooled with an ice-water bath and stirred for 5 h. The dicyclohexyl urea (DCU) precipitate was removed by filtration, and the DMF solvent was removed by vacuum rotary evaporation. The yellow oil residue was washed with water and hexane to yield a white solid, which was vacuum dried at 78° C. to give 6.34 g (74%) of N-hexanoyloxy succinimide. IR (KBr): 1816 cm−1 (ν(C═O) of ester), 1745-1786 cm−1 (ν(C═O) of imide). 1H-NMR (DMSO-d6, ppm): 0.86 (3H, —CH3), 1.31 (4H, —(CH2)2CH3), 1.62 (2H, CH2CH2COO—), 2.64 (2H, —CH2COO—), 2.80 (4H, —COCH2CH2CO—).