Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.I[CH2:31][CH2:32][CH2:33][CH2:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36]>>[C:38]1([S:35]([CH2:34][CH2:33][CH2:32][CH2:31][C:13]2[CH:12]=[CH:11][C:10]([N:16]3[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:29])[CH2:17]3)=[C:9]([OH:8])[CH:14]=2)(=[O:37])=[O:36])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=S(=O)(CCCCI)c1ccccc1
Product: O=C1CN(c2ccc(CCCCS(=O)(=O)c3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and (4-iodobutane-1-sulfonyl)-benzene analogous to Example 57, steps B, C and D: (M−1)−=423. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.49-1.60 (m, 4 H) 2.40 (t, J=6.69 Hz, 2 H) 4.01 (s, 2 H) 6.46 (s, 1 H) 6.58 (s, 1 H) 7.21 (d, J=7.83 Hz, 1 H) 7.65 (t, J=7.58 Hz, 2 H) 7.71-7.77 (m, 1 H) 7.85-7.90 (m, 2 H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]3[CH:18]=2)=[CH:4][C:3]=1[I:19].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][F:30].O>CN(C)C=O.C(Cl)(Cl)Cl>[F:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]3[CH:18]=2)=[CH:4][C:3]=1[I:19]
Reactant: FCCCBr
Reactant: COc1ccc2nc(-c3ccc(O)c(I)c3)cn2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3ccc(OCCCF)c(I)c3)cn2c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 80.5 %

Procedure:
279 mg (corresponding to 0.763 mmol) of 2-(4′-hydroxy-3′-iodophenyl)-6-methoxyimidazo[1,2-a]pyridine that was dissolved in 10 mL of N,N-dimethylformamide, and 317 mg (corresponding to 2.29 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 105 μL (corresponding to 1.15 mmol) of 1-bromo-3-fluoropropane, and then the solution was stirred at room temperature for 21 hours. After the completion of the reaction, the reaction solution was poured into water, and extracted three times with chloroform. The combined chloroform layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 262 mg (corresponding to 0.614 mmol) of 2-[4′-(3″-fluoropropoxy)-3′-iodophenyl]-6-methoxyimidazo[1,2-a]pyridine (FIG. 1, Step 7).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:32][CH3:33])=O)C1C=CC=CC=1.C(OCC)(=O)C>[Pd].CO>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:32][CH3:33]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)oc1CC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1CC
Yield: 107.1 %

Procedure:
The same operation as in Example (95b) was performed using butyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (110b) (0.5 g, 1.09 mmol), 10% Pd/C (0.2 g), ethyl acetate (3 mL) and methanol (3 mL), to obtain 0.38 g of the title compound as a yellow oily substance (100%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[CH2:11]([NH2:15])[C:12]#[C:13][CH3:14]>>[CH3:14][C:13]1[CH:12]=[CH:11][N:15]=[C:2]2[CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[C:1]=12
Reactant: CC#CCN
Reactant: O=C1Cc2ccccc2C1
Product: Cc1ccnc2c1-c1ccccc1C2
Reaction time: 0.2 h
Yield: 22 %

Procedure:
The title compound is prepared from indan-2-one and but-2-ynylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2; the reaction is carried out in a microwave oven at 100° C. for 12 min. Yield: 22% of theory; LC (method 1): tR=1.98 min; Mass spectrum (ESI+): m/z=182 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[Se:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([C:23]([OH:25])=[O:24])[C:19]([SH:22])([CH3:21])[CH3:20]>CO.CN(C)C=O.O>[C:1]1([NH:7][C:11]([C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[Se:8][S:22][C:19]([CH3:21])([CH3:20])[C@H:18]([C:23]([OH:25])=[O:24])[NH2:17])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c2ccccc2[se]n1-c1ccccc1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(S[Se]c1ccccc1C(=O)Nc1ccccc1)[C@@H](N)C(=O)O

Procedure:
5 g (18,2 mmol) 2-phenyl-1,2-benzoisoselenazole-3-(2H)-one are dissolved in 250 ml methanol and 30 ml dimethylformamide. A solution of 2,71 g (18,2 mmol) D-penicillamine in 100 ml water is added while stirring. To this clear solution, so much water is added until a slight haze is to be seen. After stirring for 18 hours, the precipitate is filtered and recristallized from ethanol/water (3:2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[CH:5]=[C:6]([C:10](=O)[CH3:11])[C:7](=[O:9])[CH3:8].S(O)(O)(=O)=O.[CH3:23][O:24][C:25](=[NH:27])[NH2:26].C([O-])(O)=O.[Na+]>CCO>[CH3:23][O:24][C:25]1[NH:27][CH:5]([C:4]2[CH:13]=[C:14]([F:17])[C:15]([F:16])=[C:2]([F:1])[CH:3]=2)[C:6]([C:7](=[O:9])[CH3:8])=[C:10]([CH3:11])[N:26]=1
Reactant: CC(=O)C(=Cc1cc(F)c(F)c(F)c1)C(C)=O
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COC1=NC(C)=C(C(C)=O)C(c2cc(F)c(F)c(F)c2)N1
Temperature: 97.5 °C
Yield: 35.8 %

Procedure:
A mixture 3-(3,4,5-trifluorobenzylidene)-2,4-pentanedione (26.2 mmol), O-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and NaHCO3 (6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and heated at 95-100° C. for 6 h. The mixture was filtered and the solid filter cake was washed with ethanol (100 mL). The solvent was evaporated from the combined filtrates and the crude product was purified by flash column chromatography (EtOAc/hexane, 1/9 to 1/4), to afford the desired product as an oil (2.80 g, 36%).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:16])[CH:12]=2)[C:7]=1[CH2:17]N(C)C)(=O)C.[BH4-].[Na+].O.Cl>C(O)C>[Br:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH3:17])=[C:6]([OH:5])[CH:15]=[CH:14]2
Reactant: CC(=O)Oc1ccc2cc(Br)ccc2c1CN(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(O)ccc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Bromo-1-[(dimethylamino)methyl]-2-naphthyl acetate hydrochloride (6.4 g, 0.0179 mol) was stirred in ethanol (250 mL). Sodium borohydride (3.0 g, 0.078 mol) was added portion-wise. The mixture was heated at reflux for 2 hours, then cooled to room temperature and water (100 mL) was added. The mixture was stirred for ½ hour then acidified with 2N hydrochloric acid. The ethanol was evaporated and the mixture was extracted with ethyl acetate. The extracts were washed with 2N hydrochloric acid, then with water, dried over anhydrous magnesium sulfate and solvent evaporated to give the title compound as a solid, mp 127-129° C. 1HNMR (500 MHz, DMSO-d6): δ9.66 (s, 1H), 8.01 (s, 1H), 7.80 (d, 1H, J=9.2 Hz), 7.60 (d, 1H, J=8.7 Hz), 7.53 (d, 1H, J-9.0 Hz), 7.19 (d, 1H, J=8.9 Hz), 2.80 (s, 6H), and 2.39 ppm (s, 3H). Elemental Analysis for C11H9BrO: Calculated: C, 55.72; H, 3.83; N, 0.00. Found: C, 55.81; H, 3.82; N, 0.00.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[Mg+2].[Cl-].[CH2:24]=[O:25]>C1COCC1.CCOC(C)=O.Cl>[OH:20][C:15]1[C:16]([CH:24]=[O:25])=[CH:17][CH:18]=[CH:19][C:14]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(-c2ccccc2)c1O
Temperature: 31.5 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (20.2 g, 27.8 mL, 0.20 mol, 2.0 equiv) was added to a solution of 2-phenylphenol (13) (17.0 g, 0.10 mol, 1.0 equiv) in THF (200 mL) followed by solid magnesium chloride (14.3 g, 0.15 mol, 1.5 equiv). The reaction temperature increased from 23 to 40° C. over ˜10 min. The reaction mixture was stirred an additional 10 min during which time a light tan suspension formed. Paraformaldehyde (15.0 g, 0.5 mol, 5.0 equiv) was added and the mixture heated to reflux with formation of a yellow suspension. The mixture was refluxed for 2.5 hr, allowed to slowly cool to room temperature and stirred overnight. The mixture was diluted with EtOAc and 1N HCl (300 mL) with mild cooling to keep the reaction temperature at <25° C. The mixture was transferred to a separatory funnel and shaken with an additional 1N HCl (200 mL). The organic phase was washed with brine (300 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure giving a yellow oil that partially crystallized. The oily crystalline material was pumped on high vacuum for 1 hr to give 20.6 g (104%) of crude 14 that was used without further purification.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][NH:4]1.F[C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH3:20])[CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[CH3:20][C:18]1[CH:19]=[C:14]([N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:3][N:4]=[CH:5][CH:6]=3)[CH2:11]2)[CH:15]=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: c1cc2c(cn1)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCc3ccncc3C2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 45.7 %

Procedure:
A mixture of commercially available 1,2,3,4-tetrahydro-2,7-naphthyridine dihydrochloride (207 mg, 1.0 mmol), 5-fluoro-2-nitrotoluene (0.244 mL, 2.0 mmol), and Na2CO3 (0.53 g, 5.0 mmol) in 3.0 mL NMP was heated at 110° C. for 2.5 hours. The solids were filtered off and then rinsed with EtOAc. The EtOAc portion was washed with a H2O/brine mixture, H2O, brine, dried with anhydrous Na2SO4, and evaporated to an oil. The oil was chromatographed eluting with CHCl3/EtOAc and the resulting solid triturated with EtOAc/hexane to give the title compound as a yellow solid (123 mg, 45%). 1H NMR (CDCl3) δ: 8.48 (s, 1H), 8.44 (d, J=5.3 Hz, 1H), 8.14 (d, J=9.1 Hz, 1H), 7.15 (d, J=5.0 Hz, 1H), 6.76 (dd, J=9.2, 2.8 Hz, 1H), 6.68 (d, J=2.9 Hz, 1H), 4.58 (s, 2H), 3.71 (t, J=5.9 Hz, 2H), 3.01 (t, J=5.9 Hz, 2H), 2.68 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:7]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH2:6][CH2:5][CH2:4][O:3]1>CCO.C1COCC1.[Pd]>[C:12]([O:11][C:9]([N:8]1[C@@H:7]([C:16]([OH:18])=[O:17])[CH2:6][CH2:5][CH2:4][O:3][C:2]1([CH3:26])[CH3:1])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(=O)OCc2ccccc2)CCCOC1(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C(=O)O)CCCOC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Wet 5% Pd/C (400 mg) was added to a solution of 4-benzyl 3-tert-butyl (4R)-2,2-dimethyl-1,3-oxazepane-3,4-dicarboxylate (Preparation 49, 2.5 g, 6.87 mmol) in 50% EtOH in THF (100 mL) and stirred for 4 hours at room temperature under an H2 balloon. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure to afford the title compound (1.6 g, 85%).
Reaction SMILES: [OH:1][C:2]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:5]([CH:6]=[N:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].[H][H]>CO.Cl.[Pd]>[OH:1][C:2]1[C:14]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:13][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C=Nn2ccnc2)cc(C(C)(C)C)c1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(CNn2ccnc2)cc(C(C)(C)C)c1O

Procedure:
28.7 g of 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)imidazole are dissolved in 500 ml of methanol, whereupon 96 ml of 1N hydrochloric acid and 3 g of palladium/carbon are added and the mixture is hydrogenated at normal pressure and room temperature. After 2.2 l of hydrogen have been taken up, the catalyst is removed by filtration and the filtrate is evaporated. Eight hundred (800) ml of methylene chloride and 300 ml of water are added to the residue. The mixture is neutralized (pH=7) with saturated sodium bicarbonate solution while agitating. Then, the methylene chloride phase is separated and the aqueous phase is extracted twice with 100 ml of methylene chloride each time. The methylene chloride phases are combined, dried and evaporated. The residue is recrystallized from ethanol/water (3:1), and there is obtained 1-(4-hydroxy-3,5di-tert.-butylbenzylamino)imidazole of m.p. 178°-180°.
Reaction SMILES: [C:1]([C:6]1[S:10][C:9]([CH2:11][CH3:12])=[C:8]([CH:13]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[C:1]([C:6]1[S:10][C:9]([CH2:11][CH3:12])=[C:8]([CH:13]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:23][CH:22]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CCNC
Reactant: CCCC(=O)c1cc(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)c(CC)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC(=O)c1cc(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)c(CC)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a mixture of 4-{[(5-butanoyl-2-ethylthiophen-3-yl)(cyclohexyl)methyl]amino}benzoic acid (125 mg) synthesized in Example 289 (2), ethyl 3-(methylamino)propanoate (59.4 mg), 1-hydroxybenzotriazole monohydrate (69.4 mg) and triethylamine (63 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86.8 mg), and the mixture was stirred at room temperature for 8 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 4 hr, and concentrated under reduced pressure. The residue was dissolved in water (1 mL), and 1N hydrochloric acid (10 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (93.4 mg, 62%) as a white solid.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[NH2:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1>C1COCC1.C(N(CC)CC)C>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=C(O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.5 %

Procedure:
4-(4-Biphenylylmethoxy)phenylacetic acid (1.51 g), tert-butyl 2-aminoethyl(methyl)carbamate (826 mg), WSC (1 g), 1-hydroxybenzotriazole (798 mg), and triethylamine (2.2 ml) were added to THF (90 ml). The reaction mixture was stirred at room temperature for 20 hr and poured onto water, followed by extraction with ethyl acetate-THF (1:1). The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride sequentially, dried with sodium sulfate, and concentrated. The residue was purified by alumina column chromatography (eluent; methanol:THF=1:1) followed by recrystallization from THF-IPE gave the titled compound (888 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc([N+](=O)[O-])cc1N1CCOCC1
Temperature: 80 °C
Yield: 40.9 %

Procedure:
2-Bromo-1-methoxy-4-nitro-benzene (810 mg, 4 mmol), morpholine (420 μL, 4.8 mmol), cesium carbonate (1.8 g, 5.6 mmol), Pd2(dba)3 (75 mg, 0.02 mmol) and BINAP (75 mg, 0.03 mmol) were added to 5 mL dry dioxane under an argon atmosphere and heated to 80° C. for 6 hours. After cooling, the solvent was evaporated and the residue was purified by silica gel chromatagraphy (eluent: 5% MeOH/DCM) to afford 390 mg 4-(2-methoxy-5-nitro-phenyl)-morpholine (w): m/e: 238.09, MS (ES+): 239.3 1H NMR (500 MHz, CDCl3): 8.0 (d, J=10 Hz, 1H), 7.8 (s, 1H), 6.9 (d, J=10 Hz, 1H), 4.1 (s, 3H), 3.9 (m, 4H) and 3.2(m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:10])=[CH:4][C:3]=1[F:23].[CH2:24]([N:26]([CH2:42][CH3:43])[C:27](=[O:41])[CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:25].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:42]([N:26]([CH2:24][CH3:25])[C:27](=[O:41])[CH:28]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:10])[N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:4][C:3]=2[F:23])[CH2:31][CH2:30]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:43]
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCNCC1
Reactant: O=C(Cc1ccc(Cl)c(F)c1)N1CCCCC1c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(CC(=O)N3CCCCC3c3ccccc3)cc2F)CC1
Yield: 16.4 %

Procedure:
A solution of 2-(4-chloro-3-fluoro-phenyl)-1-(2-phenyl-piperidin-1-yl)-ethanone (0.25 g, 0.75 mmol), N,N-diethyl-2-phenyl-2-piperazin-1-yl-acetamide (0.23 g, 0.82 mmol), Pd2(dba)3 (0.01 g, 0.0075 mmol), XPhos (0.01 g, 0.015 mmol), and sodium t-butoxide (0.11 g, 1.05 mmol) in toluene (2 mL) was irradiated by microwave at 120° C. for 20 min. The solution was allowed to cool, filtered through diatomaceous earth, washing with DCM (10 mL). The filtrate was concentrated and the residue was purified by SiO2 column chromatography (2 M NH3 in MeOH:DCM) to provide the title compound (0.07 g, 16%). MS: 571.7. 1H NMR (CDCl3): 7.48-7.46 (m, 2H), 7.38-7.35 (m, 4H), 7.28-7.23 (m, 2H), 7.19-7.15 (m, 4H), 6.90-6.89 (m, 2H), 3.70 (bs, 2H), 3.49-3.40 (m, 6H), 3.31-3.12 (m, 8H), 2.70-2.69 (m, 4H), 1.60-1.59 (m, 3H), 1.10-1.04 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[C:12]1(=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:13]2[C:14](=[O:21])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]2=[O:22])=[CH:6][CH:7]=1
Reactant: OCCCc1ccc(Br)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To 3-(4-bromophenyl)propan-1-ol (4.70 g, 21.9 mmol), isoindoline-1,3-dione (3.54 g, 24.04 mmol) and triphenylphosphine (6.88 g, 26.2 mmol) in a 500 mL round-bottomed flask equipped with a stir bar, nitrogen, and addition funnel cooled in an ice water bath was added diisopropyl azodicarboxylate (5.10 mL, 26.2 mmol). The reaction was allowed to warm to room temperature over the weekend. The reaction mixture was adsorbed onto Celite®. Purification by flash column chromatography using 5-20% ethyl acetate/hexanes as eluent provided a solid which was dried overnight at 50° C. at about 25 in. Hg providing the title compound as a white solid (6.51 g, 87%): mp 88-90° C.; 1H NMR (400 MHz, CDCl3) δ 7.86-7.79 (m, 2H), 7.71 (dd, J=5.5, 3.0 Hz, 2H), 7.38-7.32 (m, 2H), 7.11-7.04 (m, 2H), 3.73 (t, J=7.1 Hz, 2H), 2.68-2.59 (m, 2H), 2.07-1.96 (m, 2H); ESIMS m/z 346 ([M+2]+).
Reaction SMILES: [NH:1]([C:8]1[N:9]=[CH:10][C:11]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][C:12]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(C)=O.CC(O)C>[C:2]1([NH:1][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][NH:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccccc3)ncc2C1
Agent: Cl
Solvent: CC(C)O
Solvent: CC(C)=O
Product: c1ccc(Nc2ncc3c(n2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
A solution of t-butyl 2-anilino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate, Intermediate 7 (2.51 g, 7.69 mmol) in acetone (20 mL) was treated with 5-6 N HCl solution in i-PrOH (6 mL) and the reaction mixture was stirred at room temperature for 27 hours. The solvent was removed in vacuo and the salt was dissolved in water. The aqueous layer was washed with EtOAc and basified with 1.0 N NaOH(aq). The alkaline mixture was extracted with CH2Cl2 (2×100 mL) and the combined CH2Cl2 extracts were dried (MgSO4), filtered, and concentrated to a yellow, crystalline solid (1.25 g, 72%).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([NH:5][CH:6]=[O:7])[CH3:4].[CH2:8](OC(Cl)=O)[CH3:9].C(=O)=O>>[CH2:8]([O:7][CH:6]=[N:5][CH:3]([CH3:4])[CH:2]=[CH2:1])[CH3:9]
Reactant: CCOC(=O)Cl
Reactant: C=CC(C)NC=O
Agent: O=C=O
Product: C=CC(C)N=COCC
Reaction time: 3 h

Procedure:
A mixture of 1.0 g. of N-(1-buten-3-yl)formamide and one equivalent of ethylchloroformate is stirred under N2 for 4 hours during which time CO2 is evolved. The solution is stirred under reduced pressure for 3 hours to remove any unreacted ethylchloroformate, and a residue of ethyl-N-(1-buten-3-yl)formimidate is obtained.