Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.C(N(CC)CC)C.[C:35]1([C:41]2[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[B-]C#N.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[C:41]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:48]=[CH:47][C:44]([CH2:45][N:17]2[CH2:18][CH2:19][CH2:20][N:14]([CH2:13][C:2]3([CH3:1])[O:6][C:5]4=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]4[CH2:3]3)[CH2:15][CH2:16]2)=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(CN2CCCN(Cc3ccc(-c4ccccc4)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
A mixture of tert-butyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-homopiperazin-1-carboxylate prepared in Example 645 (346 mg, 0.91 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). To the solution, triethylamine (0.27 ml, 1.96 mmol) was added. The solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml). To the solution, 4-phenylbenzaldehyde (496 mg, 2.72 mmol), sodium cyanotrihydroborate (171 mg, 2.72 mmol) and acetic acid (0.17 ml, 2.72 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was poured into a saturated sodium hydrogencarbonate solution, then extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=5/1) to afford 2-[4-(biphenyl-4-ylmethyl)homopiperazin-1-ylmethyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (251 mg, yield 62%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14](SC#N)[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][N:11]=3)[C:6]=2[CH:22]=1.[Si:23]([O:40][C@H:41]1[C:50]2[C:45](=[CH:46][C:47]([F:51])=[CH:48][CH:49]=2)[C@H:44]([NH2:52])[CH2:43][CH2:42]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.CS(C)=O>C1COCC1>[Si:23]([O:40][C@H:41]1[C:50]2[C:45](=[CH:46][C:47]([F:51])=[CH:48][CH:49]=2)[C@H:44]([NH:52][C:14]2[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][N:11]=[C:10]([N:7]3[C:6]4[CH:22]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[N:15]=2)[CH2:43][CH2:42]1)([C:36]([CH3:39])([CH3:37])[CH3:38])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](N)c2cc(F)ccc21)(c1ccccc1)c1ccccc1
Reactant: N#CSc1nc(-n2cnc3ccc(F)cc32)ncc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](Nc2nc(-n3cnc4ccc(F)cc43)ncc2[N+](=O)[O-])c2cc(F)ccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
6-Fluoro-1-(5-nitro-4-thiocyanatopyrimidin-2-yl)-1H-benzo[d]imidazole (498 mg, 1.57 mmol, 1.1 equiv) was added to a solution of (1R,4R)-4-(tert-butyldiphenylsilyloxy)-7-fluoro-1,2,3,4-tetrahydronaphthalen-1-amine (600 mg, 1.43 mmol, 1 equiv) in THF (20 mL) containing DIEA (1.5 mL), followed by adding 2 mL of DMSO. The resulted red solution was stirred at RT for 16 h. THF was evaporated off The residue was dissolved in EtOAc, washed with water and brine, dried (Na2SO4). The organic layer was evaporated to dryness. The residue was purified on ISCO (12 g column, MeOH—CH2Cl2 0-5%) to give a yellow solid product (633 mg, 65%). MS (ESI): 677.3.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]3[CH2:34][C:33]([CH3:36])([CH3:35])[C:32]3=[O:37])[CH2:20][CH:19]2[OH:38])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]3[CH2:34][C:33]([CH3:35])([CH3:36])[C:32]3=[O:37])[CH2:20][C:19]2=[O:38])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:7]
Reactant: CC1(C)CN(c2cc(F)ccc2N2CCC(NC(=O)C3(NC(=O)c4ccco4)CCCCC3)C(O)C2)C1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC1(C)CN(c2cc(F)ccc2N2CCC(NC(=O)C3(NC(=O)c4ccco4)CCCCC3)C(=O)C2)C1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
To the solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexane carbonyl]amino]-1-[4-fluoro-2-(3,3-dimethylazetidin-2-one-1-yl)phenyl]piperidin-3-ol (0.5 g) obtained in Step 2 in 10 ml of dimethylsulfoxide, was added 0.5 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.45 g) was added to the reaction mixture, which was then stirred for about 4 hours at room temperature. The reaction mixture was diluted with 20 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 340 mg of the titled compound.
Reaction SMILES: [CH:1]1[C:6]([CH2:7]O)=[CH:5][CH:4]=[N+:3]([O-])[CH:2]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]2[CH:48]([N:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[C:43]3=[N:44][CH:45]=[CH:46][CH:47]=[C:42]3[CH2:41][CH2:40][C:39]=2[CH:55]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]2[CH:48]([N:49]3[CH2:50][CH2:51][N:52]([CH2:7][C:6]4[CH:5]=[CH:4][N:3]=[CH:2][CH:1]=4)[CH2:53][CH2:54]3)[C:43]3=[N:44][CH:45]=[CH:46][CH:47]=[C:42]3[CH2:41][CH2:40][C:39]=2[CH:55]=1
Reactant: [O-][n+]1ccc(CO)cc1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1ccc2c(c1)CCc1cccnc1C2N1CCN(Cc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 45.3 %

Procedure:
To a mixture of 188 mg (1.50 mmol) of 4-pyridylcarbinol N-oxide and 497 mg (1.50 mmol) of carbon tetrabromide in 12 mL of dry methylene chloride at room temperature and under an argon atmosphere was added in one portion 393 mg (1.50 mmol) of triphenylphosphine. After 40 minutes, 313 mg (0.997 mmol) of (-)-8-chloro-6,11-dihydro-11-(4-piperazinyl)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine was added followed by 209 mL (1.57 mmol) of triethylamine. The reaction mixture was then allowed to stir at room temperature for 3 hr, after which it was taken up in methylene chloride and washed once with 0.5M aqueous sodium bicarbonate and then brine. The organic portion was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via flash chromatography (4% methanol saturated with ammonia in methylene chloride) to provide 183 mg of (-)-8-chloro-6,11-dihydro-11-[4 -(4-pyridinylmethyl)-1-piperazinyl]-5h-benzo[5,6]cyclohepta-[1,2-b]pyridine, N-oxide as a glass: MS (CI) m/z 421 (M+ +1);
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][O:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:24][CH2:25][OH:26]>C(#N)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][O:11][N:10]([CH2:24][CH2:25][OH:26])[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCBr
Reactant: CC(C)(C)OC(=O)NC1CONC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CON(CCO)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3-Oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.2 g, prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002, 50(4) 554-557) was dissolved in acetonitrile (20 ml), then potassium carbonate (0.69 g), potassium iodide (0.175 g) and 2-bromoethanol (0.137 g) were added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and then dried over sodium sulphate. The solvent was removed in vacuo and the crude product was purified by column chromatography (eluent cyclohexane/ethyl acetate) to afford ((R)-2-(2-hydroxyethyl)-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester as a yellow solid. LCMS (method A) 1.05 min, MH+ 259; 1H-NMR (CDCl3, 400 MHz): 5.55 (br s, 1H), 4.65 (m, 2H), 4.10 (t, 1H), 3.80 (m, 1H), 3.20 (br s, 1H), 1.50 (s, 9H), 1.20 (m, 3H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:46]=[CH:47][C:48]=1[O:49][CH3:50])[O:18][C:19]1[C:24](=[O:25])[N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][CH:28]=2)[C:22]([CH2:41][CH2:42][CH3:43])=[N:21][C:20]=1[CH2:44][CH3:45]>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:46]=[CH:47][C:48]=1[O:49][CH3:50])[O:18][C:19]1[C:24](=[O:25])[N:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[NH:3][C:4](=[O:7])[O:5][N:40]=3)=[CH:31][CH:32]=2)[C:22]([CH2:41][CH2:42][CH3:43])=[N:21][C:20]=1[CH2:44][CH3:45]
Reactant: [NH3+]O
Reactant: CCCc1nc(CC)c(Oc2ccc(OC)c(OC)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2ccc(OC)c(OC)c2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogen carbonate (0.93 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[5-(3,4-dimethoxyphenoxy)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.57 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.44 g, 77%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=O)=[O:12])=[CH:3][CH:2]=1.[N:29]1([C:35]2[N:42]=[CH:41][CH:40]=[CH:39][C:36]=2[C:37]#[N:38])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[C:37]([C:36]1[C:35]([N:29]2[CH2:30][CH2:31][N:32]([C:19]([C:18]3[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=3)[CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=3[NH:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:21])[CH2:33][CH2:34]2)=[N:42][CH:41]=[CH:40][CH:39]=1)#[N:38]
Reactant: O=C(O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Reactant: N#Cc1cccnc1N1CCNCC1
Product: N#Cc1cccnc1N1CCN(C(=O)c2cccc(CONC(=O)c3ccccc3NCc3ccncc3)c2)CC1

Procedure:
Prepared by a similar procedure as described for preparation of example 405. Starting materials: 3-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 403) and 2(1-piperazinyl)-nicotinonitrile (Emka-chemie). 1H-NMR (DMSO-d6) δ 11.5 (bs, 1H), 8.48 (m, 2H), 8.43 (dd, 1H), 8.10 (dd, 1H), 7.89 (bt, 1H), 7.60-7.53 (m, 2H), 7.50 (t, 1H), 7.44 (dt, 1H), 7.38 (dd, 1H), 7.30 (m, 2H), 7.16 (m, 1H), 6.97 (dd, 1H), 6.54 (m, 1H), 6.49 (bd, 1H), 5.00 (s, 2H), 4.46 (d, 2H), 4.00-3.36 (m, 8H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([NH:25][C@H:26]3[CH2:31][CH2:30][C@@H:29]([CH3:32])[CH2:28][CH2:27]3)[N:8]=2)[CH2:2]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[CH3:33][S:34]([N:1]1[CH2:2][CH:3]([CH2:5][O:6][C:7]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[CH:17][CH:18]=3)=[CH:11][N:10]=[C:9]([NH:25][C@H:26]3[CH2:31][CH2:30][C@@H:29]([CH3:32])[CH2:28][CH2:27]3)[N:8]=2)[CH2:4]1)(=[O:36])=[O:35]
Reactant: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OCC3CNC3)n2)CC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)C1

Procedure:
Using the procedure of Example 1 Step 5, 4-((azetidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine was reacted with methanesulfonyl chloride to provide the title compound in 87% yield. 1H NMR (CDCl3, 400 MHz) 8.09 (s, 1H), 7.34 (d, 2H), 6.93 (d, 2H), 5.17 (sb, 1H), 4.50 (d, 2H), 4.08 (m, 1H), 4.01 (m, 2H), 3.87 (m, 4H), 3.82 (m, 2H), 3.17 (m, 4H), 3.05 (m, 1H), 2.66 (s, 3H), 1.85-1.55 (m, 6H), 1.80-1.40 (m, 3H), 0.94 (d, 3H); MS (ESI) m/z: Calc: 515.3 (M). Found. 516.3 (M+1).
Reaction SMILES: [CH:1]([N:4]([CH3:25])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[CH:1]([N:4]([CH3:25])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(isopropyl(methyl)amino)-2-phenylquinoxaline-6-carboxylate (109.8 mg, 0.29 mmol, 1.00 equiv, 90%) in methanol (20 mL). This was followed by the dropwise addition of a solution of sodium hydroxide (65.6 mg, 1.64 mmol, 5.00 equiv) in water (3 mL) with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The filtrate was concentrated under vacuum. The resulting solids were collected by filtration and washed with methanol and water. This resulted in 58 mg (59%) of 3-(isopropyl(methyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:19])[CH2:3]1.O[Li:34].O>>[F:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[C@@H:4]([C:18]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([O-:29])=[O:28])=[CH:31][CH:32]=2)[CH3:22])=[O:19])[CH2:3]1.[Li+:34]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2C[C@H](F)CN2Cc2cccc(C(F)(F)F)c2)cc1
Reactant: [Li]O
Solvent: O
Product: C[C@H](NC(=O)[C@H]1C[C@H](F)CN1Cc1cccc(C(F)(F)F)c1)c1ccc(C(=O)[O-])cc1
Product: [Li+]

Procedure:
The title compound (D161) (50 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from methyl 4-((S)-1-((2R,4S)-4-fluoro-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D160) (67.3 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](CNCCN)=[N:2]1.[CH2:11]([NH2:14])[CH2:12][NH2:13].BrCC1C=CSN=1.[CH3:22][N:23]=[C:24]=[O:25]>>[CH3:22][NH:23][C:24]([NH:13][CH2:12][CH2:11][NH:14][C:3]1[CH:4]=[CH:5][S:1][N:2]=1)=[O:25]
Reactant: NCCNCc1ccsn1
Reactant: CN=C=O
Reactant: NCCN
Agent: BrCc1ccsn1
Product: CNC(=O)NCCNc1ccsn1

Procedure:
N-(3-Isothiazolylmethyl)ethylenediamine, prepared by reacting ethylenediamine with 3-bromomethylisothiazole by the procedure of Example 40(a), is reacted with methyl isocyanate by the procedure of Example 24 to give, after concentrating and separating by column chromatography, the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.C(OC([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)=O)C1C=CC=CC=1>C(O)(C)(C)C.C(OCC)(=O)C>[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:30]1[CH2:31][CH2:32][NH:27][CH2:28][CH:29]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Oc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reaction time: 16 h
Yield: 92 %

Procedure:
Potassium tert-butoxide (2.81 g, 25.02 mmol) was added to a solution of 5-hydroxyindole (1.11 g, 8.34 mmol) in tert-butyl alcohol. 1-Benzyloxycarbonyl-4-piperidone (3.89 g, 16.67 mmol) was added to the purple reaction mixture at RT. After 16 h, the reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed (SiO2, 25-45% ethyl acetate/hexanes) to give 4-(5-hydroxyindol-3-yl)-1,2,3,6-tetrahydropyridine as a white solid (92%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3]1.[N+:9]([CH3:12])([O-:11])=[O:10].C(N)C1C=CC=CC=1.C(O)(=O)C>C(O)C>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:12][N+:9]([O-:11])=[O:10])=[CH:3]1
Reactant: Cn1ccc(C=O)c1
Reactant: C[N+](=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: NCc1ccccc1
Product: Cn1ccc(C=C[N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
A solution of 14.9g (0.137 mole) of 1-methylpyrrole-3-carboxaldehyde, 7.3 ml (0.137 mole) of nitromethane, 2.3 ml (.021 mole) of benzyl amine and 1.2 ml (.021 mole) of acetic acid in 20 ml of absolute ethanol is warmed briefly and stirred for 6 hours. It is then cooled and the precipitated solid is collected, giving as a yellow solid, 1-methyl-3-(2-nitrovinyl)pyrrole; m.p. 90°-92° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH2:22][CH2:23][CH2:24][OH:25])[C:16](=[O:21])[CH:17]=[C:18](Cl)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:27]([C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][C:30]=1[F:39])#[N:28].[C:40]([O-])([O-])=O.[Na+].[Na+]>C(#N)C.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>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH2:22][CH2:23][CH2:24][O:25][CH3:40])[C:16](=[O:21])[CH:17]=[C:18]([C:32]3[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[C:30]([F:39])[CH:31]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc(Cl)cc(=O)n2CCCO)CC1
Reactant: N#Cc1ccc(OB(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COCCCn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)cc1=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of {1-[4-chloro-1-(3-hydroxy-propyl)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (200 mg, 0.5 mmol), 4-cyano-3-fluorophenyl boric acid (107 mg, 0.65 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) and 0.4M Na2CO3 solution (4 mL) in ACN was stirred at 85° C. overnight. The reaction mixture was diluted with water and extracted with EA (3×). The reaction mixture was stirred at RT for 2 h and the solvent was concentrated in vacuo. The residue was purified by silica chromatography to give 240 mg of the title product (99%). [M+H] Calc'd for C25H32FN5O4, 485. Found, 485.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19]([NH2:21])=[O:20])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[CH:22]1[CH:27]=CC=C[CH:23]=1.CCCBr>C(N(CC)CC)C>[CH2:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19]([NH2:21])=[O:20])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][CH3:27]
Reactant: c1ccccc1
Reactant: NCCCCC1(C(N)=O)c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: CCCBr
Product: CCCNCCCCC1(C(N)=O)c2ccccc2-c2ccccc21

Procedure:
A solution of 9-(4-aminobutyl)-9-aminocarbonylfluorene in benzene containing one equivalent of n-propyl bromide and triethylamine is stirred for several hours. Removal of the reaction solvent and distillation of the product affords 9-(4-n-propylaminobutyl)-9-aminocarbonylfluorene.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[S:5][C:4]2[O:11][CH:12]=[CH:13][C:3]1=2.[C:14](N1C=CN=C1)([N:16]1C=CN=[CH:17]1)=O>O1CCCC1>[CH3:14][N:16]([CH3:17])[C:8]([C:6]1[S:5][C:4]2[O:11][CH:12]=[CH:13][C:3]=2[C:2](=[O:1])[CH:7]=1)=[O:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc(=O)c2ccoc2s1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(=O)c2ccoc2s1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-oxo-4H-furano[2,3-b]thiopyran-6-carboxylic acid (9.9 g, 0.05 mol) in tetrahydrofuran (50 ml) was added carbonyldimidazole (8.9 g, 0.055 mol). The mixture was stirred at ambient temperature for 3/4 hr. Anhydrous dimethylamine was bubbled into the reaction mixture at 0° C. The reaction was stirred at 0° C. for 3/4 hr. and the solvents were evaporated in vacuo. The residue was treated with H2O (150 ml) and the solid that separated was collected and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl-:9].[Cl-].[Cl-].[Al+3].ClCl>ClC(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[Cl:9]
Reactant: [Cl-]
Reactant: Clc1ccc(Cl)nn1
Agent: ClCl
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Product: Clc1cc(Cl)c(Cl)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a dry three-necked flask equipped with a refluxing condensor and a ventiduct (connected with a safety flask), 3,6-dichloropyridazine (purchased from Nanjingtianzunzezhong Chemical Agents Company) and anhydrous aluminum trichloride were added, heated by using external heat source to 120° C. to melt reactants, Cl2 gas was fed at this temperature for 3 hours, then the reaction was stopped, cooled to room temperature, trichloromethane was added to dissolve the product, the trichloromethane solution was washed with saturated sodium chloride aqueous solution for twice, the water phase was extracted with trichloromethane for twice, all trichloromethane solutions were combined together and dried over anhydrous sodium sulfate, after trichloromethane was removed by evaporation under vacuum, a reduced pressure distillation was employed to collect fraction of 110-114° C./8 mmHg or 128˜9° C./18 mmHg, a white solid was coagulated in a receiving flask Yield: 55%, m.p. 57˜58° C.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:8][C:9]([CH2:11][O:12][NH2:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=O)[C:27]([OH:29])=[O:28])[N:25]=1.CO>CN(C)C=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:13]/[O:12][CH2:11][C:9]([O:8][CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])/[C:27]([OH:29])=[O:28])[N:25]=1
Reactant: NOCC(=O)OC(c1ccccc1)c1ccccc1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1nc(/C(=N/OCC(=O)OC(c2ccccc2)c2ccccc2)C(=O)O)cs1
Yield: 76.1 %

Procedure:
16.5 g of O-diphenylmethoxycarbonylmethylhydroxylamine and 9.9 g of (2-amino-4-thiazolyl)glyoxylic acid are stirred for 3 hours at room temperature in 30 ml of dimethylformamide. The reaction mixture is introduced into 500 ml of methanol, and the resultant deposit is filtered off. 18 g of the title compound are obtained as colourless crystals. M.p.: 125°.