Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10](O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)([Br:16])=O>C1(C)C=CC=CC=1>[Br:16][C:10]1[N:11]=[N:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1ccc(-c2ccccc2)nn1
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2)nn1
Temperature: 90 °C
Yield: 31.8 %

Procedure:
6-Phenylpyridazin-3-ol (5.0 g, 29.06 mmol) is dissolved in toluene (100 mL) and heated to 90° C. Phosphorous oxybromide (25 g, 87.19 mmol) is added in several portions and the reaction is heated for 30 minutes. The resulting yellow solution is cooled to room temperature, poured onto ice water, and extracted with ethyl acetate. The organic layers are further washed with water and 1M sodium hydroxide, dried over magnesium sulfate, filtered, and evaporated to a yellow solid. Recrystallization from CHCl3 gives 2.17 g of 3-bromo-6-phenylpyridazine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[NH:17][N:16]=2)[CH:9]=1)=[O:6].[O-]CC.[Na+]>C(O)C>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[NH:17][N:16]=1
Reactant: O=C(CCCCl)Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCCN1c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
4-Chloro-N-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]butyramide (1 g, 2.8 mmol) was added in portions at 0° C. to a stirred solution of sodium ethoxide [from sodium (0.15 g, 6.7 mmol)] in ethanol (10 ml), then the mixture was heated under reflux for 3 hours, cooled to ambient temperature and added to ice-water (50 ml). The resulting solid was collected by filtration, washed with water (10 ml) and dried in vacuo to give 4-[3-(2-oxopyrrolidin-1-yl)benzyl]-2H-phthalazin-1-one (0.77 g) as an off-white solid, m.pt. 206–207° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 2.00 (m, 2H) (—CH2CH2CH2—), 2.55 (m-partially obscured by DMSO peak, 2H) (—NCH2—), 3.75 (t, 2H) (—COCH2—), 4.3 (s, 2H) (ArCH2—), 7.05 (d, 1H) (ArH), 7.25 (t, 1H) (ArH), 7.5 (d, 1H) (ArH), 7.7 (s, 1H) (ArH), 7.75–8.0 (m, 3H) (3×ArH), 8.25 (d, 1H) (ArH); m/z (M+H)+. 320, 100% purity.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]([C:13]3[C:18]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[CH:14]=3)=[N:11][N:10]=[N:9]2)C=CC=CC=1.N([O-])=O.[Na+].O.[ClH:46]>CO.CN(C=O)C.S(=O)(=O)(O)O.[Pd].Cl[Cu]>[Cl:46][C:15]1[CH:14]=[C:13]([C:12]2[NH:11][N:10]=[N:9][N:8]=2)[C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2ccc([N+](=O)[O-])cc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cl
Agent: Cl[Cu]
Agent: [Pd]
Agent: O=N[O-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2ccc(Cl)cc2-c2nnn[nH]2)cc1
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A solution of N-triphenylmethyl-5-(4'-methyl-4-nitrobiphen-2-yl)tetrazole (0.115 g, 0.224 mmol) in MeOH/DMF (2 mL/12 mL) was submitted to hydrogenation at 40 psi H2 with 10% Pd on carbon (50 mg) at room temperature for 1 hour. The reaction was filtered through celite and the filtrate was concentrated in vacuo. The triphenyl methyl group had been lost during the hydrogenation. The crude 4-amino compound was dissolved in glacial acetic acid (3 mL) and added slowly to a cooled (0° C.) solution of NaNO2 (28.8 mg, 0.417 mmol) in conc. sulfuric acid (1 mL). The diazonium solution was stirred well for 2 hours then slowly added to a cooled (0° C.) solution of CuCl (0.449 g; 20 equiv) in conc. HCl. This mixture was stirred for 30 minutes and then poured over H2O and extracted with Et2O/EtOAc. The combined organic extracts were washed with H2O and brine, dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography on a silica column eluting with Hex/EtOAc/HOAc (80:20;1) to afford 27 mg (45% for 2 steps) of 5-(4-chloro-4'-methyl-biphen-2-yl)tetrazole. The free tetrazole was dissolved in CH2Cl2 (3.5 mL) and NEt3 (0.035 mL, 2.5 equiv) and Ph3CCl (27 mg, 1.0 equiv) were added. After 30 minutes the reaction was diluted with Et2O washed with 10% citric acid, 1N NaOH and brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo to afford 51.2 mg (100%) of crude N-triphenylmethyl-5-(4-chloro-4'-methyl-biphen-2-yl)tetrazole. 1H NMR (300 MHz, CDCl3) δ 2.26 (s, 3H), 6.91 (d, 6H), 6.94 (ABq, 4H), 7.20-7.25 (comp, 7H), 7.43 (dd, 1H), 7 99 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.C(O)C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Nc1ccccc1
Solvent: CCO
Product: Nc1ccc2ccc(Nc3ccccc3)nc2n1
Temperature: 120 °C
Yield: 60.8 %

Procedure:
A suspension of 2-amino-7-chloro-1,8-naphthyridine (9 g) in aniline (19.6 g) is heated for 19 hours at 120° C. The suspension obtained is filtered, washed with diethyl ether (3×15 cc) and air-dried. The crude solid obtained (14 g; m.p. 190° C.) is then dissolved in boiling ethanol (700 cc). After cooling for 2 hours at 4° C., the crystallized product is separated by filtration, washed with ethanol (25 cc) and air-dried. 2-Amino-7-anilino-1,8-naphthyridine (7.2 g), m.p. approximately 250° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.C[O:13][C:14](=O)[CH2:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18].C(N)CN>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:18][CH:17]([CH3:19])[C:16](=[O:20])[CH2:15][C:14]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=1)=[O:13]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: COC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: NCCN
Product: COC(=O)c1ccc(NC(=O)CC(=O)C(C)C)cc1

Procedure:
To a solution of methyl-4-aminobenzoate (250 g, 1.65 moles) in toluene (2.4 L) was added methyl-4-methyl-3-oxopentanoate (237.7 g, 1.648 moles) and ethylene diamine (1.15 ml, 0.016 moles). The reaction mixture was refluxed for about 20-25 hours. The solvent was removed under reduced pressure to obtain a solid residue. The residue was dissolved in ethyl acetate (2.4 L). The organic phase was washed with an acid (e.g., 20% w/w hydrochloric acid 0.5 L) followed by de-ionized water. It was further washed with a 10% sodium bicarbonate solution, followed by de-ionized water and saturated brine. The solvent was removed under reduced pressure. To this was added hexane while stirring and the solid precipitated out completely. The solid was filtered and washed with hexane. The solid was dried to yield the title product in 99.45% purity.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f45) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.C([O-])=O.[NH4+]>CO.O.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: Nc1cc(Cl)ccc1Br
Temperature: 50 °C
Yield: 75.6 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (140 g, 0.59 mol) was dissolved in 2.5 L of MeOH with gentle heating (50° C.) in a hot water bath. A solution of ammonium formate (303 g, 4.81 mol) in 500 mL of water was added. Zinc powder (155 g, 2.36 mol) was added in small portions, resulting in heat evolution and refluxing of the solvent. Subsequent additions were made cautiously as to avoid build up of excess unreacted zinc. The reaction was cooled to room temperature and filtered through a large plug of CELITE® filter aid. The filtrate was then concentrated until a biphasic mixture of red oil and water was evident. The product was extracted with five 200 mL portions of diethyl ether. The organics were combined and dried over sodium sulfate, decanted, and concentrated in vacuo to a reddish-brown oil. The oil was redissolved in 150 mL of dichloromethane/hexanes and filtered through a plug of silica gel. The filtrate was concentrated to an orange oil. Addition of hexanes (200 mL) and cooling in a dry ice bath resulted in precipitation of 2-bromo-5-chloroaniline as a pale yellow solid (92.1 g, 75%) that was collected via vacuum filtration.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.Cl.[CH3:20][C@H:21]1[CH2:26][NH:25][CH2:24][C@H:23]([CH3:27])[NH:22]1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.C(Cl)CCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]([N:25]3[CH2:24][C@H:23]([CH3:27])[NH:22][C@@H:21]([CH3:20])[CH2:26]3)=[O:17])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@H]1CNC[C@H](C)N1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: C[C@H]1CN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)C[C@H](C)N1

Procedure:
The title compound (D18) was prepared using a similar procedure to Description 4 step 1from 1-(4-cyanophenyl)-piperidine4-carboxylic acid (D3), (2S, 6S)-2,6-dimethylpiperazine dihydrochloride (J. W. Mickleson, K. L. Belonga and E. J. Jacobsen, J. Org. Chem., 1995, 60(13), 4177-4183), EDC, HOBT and N-methyl morpholine in DMF.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[C:3]1[CH3:19].[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([CH3:26])([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([CH3:19])=[C:4]2[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)[CH3:25])[CH3:21]
Reactant: Cc1cccc(-c2c(C)n(C)c3ccc(O)cc23)c1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1cccc(C)c1)c(C)n2C

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 1,2-dimethyl-3-(3-methyl-phenyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [OH:1][C:2]1([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:29][O:30][C@:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:35]([F:38])([F:37])[F:36])[C:32](Cl)=[O:33]>ClCCl.CN(C1C=CN=CC=1)C>[C:10]1([CH2:9][O:8][C:6]([N:4]2[CH2:3][C:2]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([O:1][C:32](=[O:33])[C@:31]([O:30][CH3:29])([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:35]([F:37])([F:38])[F:36])[CH2:5]2)=[O:7])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCCC1C1(O)CN(C(=O)OCc2ccccc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CO[C@@](C(=O)OC1([C@H]2CCCCN2C(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1)(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 8.1 %

Procedure:
To a solution of 1,1-dimethylethyl 2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (368 mg, 0.94 mmol), prepared using procedures similar to those described in Reference 5, in dichloromethane (5 mL) was added DMAP (115 mg, 0.94 mmol) and the resulting solution was cooled to 0° C. (R)-(−)-α-Methoxy-α-trifluoromethylphenylacetyl chloride (105 μL, 0.56 mmol) was added to the solution by syringe and the mixture was allowed to warm to room temperature then stirred an additional 12 hours. The solution was then partitioned with saturated aqueous sodium bicarbonate and the organic phase dried over anhydrous magnesium sulfate then filtered and concentrated to an oily residue. Silica gel flash chromatography using hexanes:ethyl acetate 3:1 as eluent afforded the less polar 1,1-dimethylethyl (2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (27.5 mg, 5% yield), the more polar 1,1-dimethylethyl (2S)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (105 mg, 19% yield) and starting material (253 mg, 69% recovery).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:29](Cl)(=[O:33])[CH2:30][CH2:31][CH3:32].[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37]>CN(C)C=O.C(#N)C>[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37].[C:29]([O:26][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Reactant: CCCC(=O)Cl
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCC(=O)OC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 3 h
Yield: 69.4 %

Procedure:
A solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1pyridyl)propyl]-3-hydroxy-1-isoindolinone (8 g) in anhydrous dimethylformamide (75 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (1.2 g) in anhydrous dimethylformamide (15 cc) at a temperature close to 20° C. in the course of 15 minutes and agitation is continued for 3 hours. Then, 2.6 g of butyryl chloride is added in the course of 10 minutes, and agitation is continued for a further 20 hours. The suspension obtained is poured into distilled water (400 cc) and extracted with methylene chloride (4×200 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in acetonitrile (120 cc). A solution of oxalic acid (2.3 g) in acetonitrile (60 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 8.1 g of 3-butyryloxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH:22]([O:24]C(=O)C)[CH3:23])[CH2:17][CH2:16]1)=[N:8][N:7]=[CH:6]2.CCOCC>[OH-].[Na+].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH:22]([OH:24])[CH3:23])[CH2:17][CH2:16]1)=[N:8][N:7]=[CH:6]2
Reactant: COc1cc2cnnc(N3CCC(CC(C)OC(C)=O)CC3)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: COc1cc2cnnc(N3CCC(CC(C)O)CC3)c2cc1OC
Yield: 45.1 %

Procedure:
6,7-Dimethoxy-1-[4-(2-acetoxypropyl)piperidino]phthalazine (1 g) was heated at 90° in a mixture of 5 N sodium hydroxide (5 ml) and ethanol (5 ml) for 30 hours. The mixture was then evaporated in vacuo and the residue suspended in water (25 ml) from which it was extracted with chloroform (2×25 ml). The combined chloroform extracts were washed with water (20 ml) and evaporated in vacuo to give a crude oily product, which solidified on trituration with ether (20 ml). Recrystallization from acetonitrile gave 6,7-dimethoxy-1-[4-(2-hydroxypropyl)piperidino]phthalazine (400 mg), m.p. 154°-6°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:31]=[C:32]1[O:36][N:35]=[C:34]([CH:37]2[CH2:42][CH2:41][CH:40]([C:43](O)=[O:44])[CH2:39][CH2:38]2)[NH:33]1>>[O:31]=[C:32]1[O:36][N:35]=[C:34]([CH:37]2[CH2:38][CH2:39][CH:40]([C:43]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]4[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]5[N:17]=[C:18]([C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[O:19][C:20]=5[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=4)[CH2:3][CH2:2]3)=[O:44])[CH2:41][CH2:42]2)[NH:33]1
Reactant: O=C(O)C1CCC(c2noc(=O)[nH]2)CC1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(C2CCN(C(=O)C3CCC(c4noc(=O)[nH]4)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 1,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclohexanecarbonyl]-piperidin-4-yl}-phenyl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (202 mg, 0.49 mmol) and 4-(5-Oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclohexanecarboxylic acid (104 mg, 0.49 mmol) as an off white solid (13 mg, 4%). LCMS calcd for C31H30F3N5O5 (m/e) 609, obsd 610 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18][CH2:19][CH3:20])[N:9]([CH3:21])[C:6]2=[N:7][CH:8]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:30])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH2:19][CH3:20])=[O:30])[N:9]([CH3:21])[C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: CCSc1ccccc1-c1nc2cc(C#N)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1ccccc1-c1nc2cc(C#N)cnc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a mixture of 6-cyano-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (0.40 g) and chloroform (5 ml), 70% of 3-chloroperbenzoic acid (0.35 g) was added under ice-cooling, and stirred at room temperature for 2 hours. To the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 0.40 g of 6-cyano-2-(2-ethylsulfinylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 49).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:29])[NH:13][C:14]2[C:15]([CH3:28])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=2[O:26][CH3:27])[CH3:10])[CH:6]=[CH:7][CH:8]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][C:43]([C:46]3([C:49]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[O:50])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)O1>>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:29])[NH:13][C:14]2[C:15]([CH3:28])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([C:40]3[CH:41]=[CH:42][C:43]([C:46]4([C:49]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[O:50])[CH2:48][CH2:47]4)=[CH:44][CH:45]=3)=[CH:21][C:20]=2[O:26][CH3:27])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(Br)ccc1-c1onc(C)c1NC(=O)O[C@H](C)c1cccc(C(F)(F)F)c1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Product: COc1cc(-c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)ccc1-c1onc(C)c1NC(=O)O[C@H](C)c1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-2-methoxy-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].Br[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH2:43][C:44]2C=CC=CC=2)=[O:41])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.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:26]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34][CH:33]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:30])[CH2:8][C@@H:9]1[CH3:29])(=[O:28])[CH3:27]
Reactant: O=C(CCc1ccc(Br)cc1)OCc1ccccc1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Yield: 35 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (100 mg, 0.240 mmol), phenylmethyl 3-(4-bromophenyl)propanoate (92 mg, 0.288 mmol), potassium carbonate (100 mg, 0.721 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.88 mg, 0.012 mmol) in ethanol (2.5 mL) and toluene (2.500 mL) was degassed for 15 min under house vacuum and quenched several times with nitrogen, and then was heated at 100° C. for 1 h before being cooled to room temperature and partitioned between AcOEt (35 mL) and water (20 mL). The layers were separated and the aqueous phase was extracted with AcOEt (15 mL). The combined organic phases were washed with brine (15 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 40 to 70% AcOEt in Hexanes) gave a residue which was further purified by MDAP (modifier: formic acid) to give ethyl 3-{4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}propanoate (39.7 mg, 0.085 mmol, 35%) as a white solid.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:20][C:21]([CH2:24][CH2:25][CH2:26][CH3:27])=[CH:22][CH:23]=1>>[CH2:24]([C:21]1[S:20][C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)=[CH:23][CH:22]=1)[CH2:25][CH2:26][CH3:27]
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: CCCCc1ccc(Br)s1
Product: CCCCc1ccc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)s1

Procedure:
rac-3,4-Dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 2.3 g (10 mmol) was reacted with 2.4 g (11 mmol) of 2-bromo-5-butylthiophene under the conditions described in Example 15. Chromatography of the crude product over 100 g of silica gel and crystallization from petroleum ether yielded colorless crystals with m.p. 80°-82°.