Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12]Br.[NH3:15]>CO.[NH4+].[OH-]>[CH3:11][O:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:2])[NH:15][CH2:12]2
Reactant: COC(=O)c1ccc(OC)cc1CBr
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)CNC2=O

Procedure:
2-Bromomethyl-4-methoxy-benzoic acid methyl ester, 2% ammonia in MeOH (4 mL) and NH4OH (1.5 mL) were stirred for at 18 hours at room temperature. The reaction was partitioned between CH2Cl2 and water and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford a white solid (151 mg). 1H NMR (300 MHz, CDCl3): δ 7.80 (d, 2H), 7.02 (dd, 1H), 6.97 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[S:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2cccs2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)s2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)thiophen-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)thiophene and N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (40% EtOAc-hexanes) gave the product as a yellow solid (0.122 g, 46% yield). MS: m/z 532.4 [M+H]+.
Reaction SMILES: B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:2]1.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1.OOS([O-])=O.[K+]>O.C(Cl)Cl.C[OH2+].C[OH2+].C1CC=CCCC=C1.C1CC=CCCC=C1.[Ir].[Ir]>[Br:19][C:20]1[CH:25]=[C:24]([OH:2])[CH:23]=[C:22]([Cl:26])[CH:21]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Clc1cccc(Br)c1
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: C[OH2+]
Solvent: C1=CCCC=CCC1
Solvent: ClCCl
Solvent: O
Product: Oc1cc(Cl)cc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 134.9 %

Procedure:
A flask containing (1,5-cyclooctadiene)(methoxy)-iridium(I) dimer (84 mg, 0.13 mmol), 4,4′-di-tert butyl-2-2′-dipyridyl (69 mg, 0.26 mmol) and bis(pinacolato)diboron (1.29 g, 5.11 mmol) was purged with Ar, then hexanes (26 mL) and 1-bromo-3-chlorobenzene (1 mL, 8.51 mmol) were added sequentially. The solution was stirred at RT for 18 h. The reaction mixture was concentrated in vacuo, re-dissolved in acetone (26 mL), then oxone (5.23 g, 8.51 mmol) in water (26 mL) added [Caution: exotherm observed]. After 10 min, the reaction mixture was diluted with DCM. The layers separated, and the aqueous layer extracted with DCM. The combined organics were washed with brine, dried and concentrated in vacuo to give the title compound (1.43 g, 81%). LCMS (Method 3): Rt 3.74 min, m/z 205, 207 [M-H+].
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:25])[NH:4][C:5]([C:11]2[CH:16]=[C:15]([C:17](=[O:20])[CH2:18]Br)[CH:14]=[CH:13][C:12]=2[O:21][CH2:22][CH2:23][CH3:24])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[C:3](=[O:25])[NH:4][C:5]([C:11]2[CH:16]=[C:15]([C:17](=[O:20])[CH2:18][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[CH:14]=[CH:13][C:12]=2[O:21][CH2:22][CH2:23][CH3:24])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CCCOc1ccc(C(=O)CBr)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Reactant: CN1CCNCC1
Product: CCCOc1ccc(C(=O)CN2CCN(C)CC2)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1

Procedure:
The title compound was prepared by reacting the compound of example 71 with N-methyl piperazine, in the same manner as that of example 72. 1H NMR (CDCl3) δ: 9.23 (1H, d), 8.19 (1H, dd), 7.10 (1H, d), 4.28 (2H, t), 3.77 (2H, s), 3.53 (1H, m), 2.66 (4H, t), 2.52 (4H, t), 2.31 (3H, s), 2.02 (2H, m), 1.29 (6H, d), 1.15 (3H, t).
Reaction SMILES: Cl.O[NH2:3].CC([O-])=O.O.O.O.[Na+].[NH:12]1[C:17]2=[N:18][C:19]([CH:22]=O)=[CH:20][CH:21]=[C:16]2[CH2:15][CH2:14][CH2:13]1.[OH-].[Na+]>CO.O.FC(F)(F)C(O)=O.[Zn].C(Cl)Cl>[NH:12]1[C:17]2=[N:18][C:19]([CH2:22][NH2:3])=[CH:20][CH:21]=[C:16]2[CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc2c(n1)NCCC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NCc1ccc2c(n1)NCCC2
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Hydroxyamine hydrochloride (2 eq), sodium acetatetrihydrate (2 eq) and water (0.4M) were heated at 60° C. 1,2,3,4-tetrahydropyridino[2,3-b]pyridine-7-carbaldehyde was dissolved in methanol (2.5 mL) and added to the resulting solution. Additional methanol was added until the solution became clear, the reaction was stirred at 60° C. for 18 hrs. The mixture was cooled to room temperature, diluted with water (25 mL) and extracted with ether. The organic layer was extracted with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated by in vacuo. To a solution of the oxime in trifluoroacetic acid (5 mL) was added zinc dust (5.6 eq) in several portions, while keeping the temperature between 15-25° C. After stirring for 15 mins., the mixture was added to a solution of an aqueous 2N NaOH (39 mL) solution and methylene chloride (21 mL) at 0° C. and stirred for an additional 15 mins. The reaction was filtered and the organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated in vacuo to yield the product. EI-MS m/z 163(M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=O)=[C:8]([F:15])[CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:30][C:31]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34]>N1C=CC=CC=1.CN(C)C=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]2[NH:40][C:39]3[CH:38]=[CH:37][CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]=3[N:30]=2)=[C:8]([F:15])[CH:7]=1
Reactant: O=C(O)c1ccc(C2OCCO2)cc1F
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4OCCO4)cc3F)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
A solution of EXAMPLE 20D (1.5 g, 7.1 mmol) in pyridine (5 mL) and N,N-dimethylformamide (20 mL) was treated with 1,1′-carbonyldiimidazole (1.4 g, 8.5 mmol) at 40° C. for 30 minutes. 2,3-Diaminobenzamide dihydrochloride (synthesized as described in U.S. Pat. No. 6,737,421, column 11, EXAMPLE 2, step (e), 1.58 g, 7.1 mmol) was added and the mixture stirred at ambient temperature overnight. Solvents were removed and the residue suspended in 10 mL of acetic acid. The mixture was stirred at 80° C. overnight, cooled, and concentrated and the residue was purified by flash chromatography using ethyl acetate to give the title compound (500 mg, 22%). MS (DCI/NH3) m/z 329 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:13][C:14]([OH:16])=O)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(O)=[O:2].C([N:19](CC)CC)C.FC(F)(F)C(N)=O.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[CH2:4][C:1](=[O:2])[NH:19][C:14](=[O:16])[CH2:13]2)=[CH:7][CH:8]=1
Reactant: O=C(O)CN(CC(=O)O)c1ccc(F)cc1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC(=O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(c2ccc(F)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
To a solution of 5 g (16.8 mmoles) of tert.-butoxycarbonylmethyl-(4-fluoro-phenyl)-amino]-acetic acid methyl ester in 100 ml of MeOH, 33.7 ml of 1 mole aqueous KOH is added at 0° C. The reaction mixture is stirred for 4 hours and acidified with 1 mole aueous HCl. The mixture is extracted with CH2Cl2 several times and the combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 4.08 g of desired crude mono acid in 85% yield. The crude acid in 200 ml of CH2Cl2 is treated with 31 ml of TFA. After being stirred for 18 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure to give 4.92 g of desied [carboxymethyl-(4-fluoro-phenyl)-amino]-acetic acid in 100% yield as trifluoroacetic acid salt. To a solution of 4.92 g (14.4 mmoles) of [carboxymethyl-(4-fluoro-phenyl)-amino]-acetic acid in 300 ml of CH2Cl2, 9.63 ml (69.2 mmoles) of triethylamine, 4.67 g (34.6 mmoles) of 1H-hydroxybenztriazole and 2.45 g (21.7 mmoles) of trifluoroacetamide are successively added and then 6.64 g (34.6 mmoles) of 1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride is added at 0° C. The reaction mixture is allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture is quenched with cold H2O and extracted with CH2Cl2. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: n-Hexane:AcOEt=1:1) to give 1.15 g of desired 4-(4-fluoro-phenyl)-piperazine-2,6-dione in 38% yield.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].C(N(CC)CC)C.[C:36]1([CH2:42][C:43](Cl)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O.O1CCCC1>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:43](=[O:44])[CH2:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a mixture of 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (384 mg) prepared in Example 1 and triethylamine (0.35 ml) in water (10 ml) was dropped a solution of phenylacetyl chloride (0.171 g) in tetrahydrofuran (10 ml) under cooling in an ice bath and stirring, which was continued for 30 minutes at the same temperature. The mixture was evaporated to remove tetrahydrofuran and the remaining aqueous solution was washed with diethyl ether and acidified with 6N hydrochloric acid. The mixture was extracted with a mixture (80 ml) of ethanolchloroform (1:1) and the extract was dried over magnesium sulfate, evaporated and triturated with diethyl ether to give 1-(6-benzoylamino-9H-purin-9-yl)-3-(phenylacetylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (370 mg), mp. 135°-140° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[N:13][OH:14])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1.C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH2:31][C:30]([C:28]3[CH:27]=[C:26]([Cl:36])[CH:25]=[C:24]([Cl:23])[CH:29]=3)([C:32]([F:33])([F:35])[F:34])[O:14][N:13]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=Cc1ccc(Br)c2ncccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3ncccc23)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirred solution of 8-bromo-5-quinolinecarboxaldehyde oxime (i.e. the product from Step C) (1.7 g, 6.8 mmol) in N,N-dimethylformamide (13.0 mL) was added N-chlorosuccinimide (1.24 g, 9.3 mmol). The reaction mixture was stirred for 1 h at room temperature, and then a solution of 1,3-dichloro-5-[1-(trifluoromethyl)ethenyl]benzene (i.e. the product from Example 1, Step B) (1.96 g, 8.1 mmol) and triethylamine (2.86 mL, 20.4 mmol) in N,N-dimethylformamide (7.0 mL) was added. After stirring for additional 12 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate as eluent to afford the title compound as a white solid (2.0 g, 61% yield).
Reaction SMILES: C([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:10]([O:16][C:17](=O)[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.[C:39]([O-])([O-])=O.[Na+].[Na+].CO.O.C(OCC)(=O)C>C1(C)C=CC=CC=1.[Pd].C[Ti](C)(C1C=CC=C1)C1C=CC=C1>[F:29][C:28]([F:31])([F:30])[C:20]1[CH:19]=[C:18]([C@H:17]([O:16][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:15][CH2:14]3)[CH3:39])[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Ti](C)(C1C=CC=C1)C1C=CC=C1
Agent: [Pd]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H](O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 82 °C
Reaction time: 2.5 h

Procedure:
(1R*,2R*,5R*)-8-Benzyl-2-[3,5-bis(trifluoromethyl)benzoyloxy]-1-phenyl-8-azabicyclo[3.2.1]octane (Description 9; 821 mg, 1.54 mmol) was treated with a solution of dimethylbis(cyclopentadienyl)titanium in toluene (0.2M, 30 ml). The reaction mixture was stirred in the dark at 82° C. for 2.5 hours. The mixture was cooled to 40° C., than solid Na2CO3 (2 g) added followed by a mixture of methanol-water (9:1, 20 ml). The mixture was stirred for 1 hour at 40° C. and filtered through a pad of Celite™. The filtrate was dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-35% containing 0.5% triethylamine) to give a 10:1 mixture of (1R*,2R*,5S*,6R*)-2-{1-[3,5-bis(trifluoromethyl)phenyl]ethenyloxy}-1-phenyl-8-azabicyclo[3.2.1]octane and (1R*,2R*,5S*,6R*)-8-benzyl-2-[3,5-bis(trifluoromethyl)benzoyloxy]-1-phenyl-8-azabicyclo[3.2.1]octane. 2/5 of this crude mixture was treated with I-propanol (8 ml), ethyl acetate (8 ml) and 10% palladium on charcoal (340 mg) and stirred under hydrogen atmosphere (1 atm) at room temperature for 12 hours. The mixture was filtered through a pad of Celite™ and concentrated to give a 7:1 (S*:R*) mixture of the title compounds. The isomers were separated by preparative TLC (dichloromethane:methanol) and converted into hydrochloride salts.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:8][N:7]=1)=[O:5])[CH3:2].[O-][Cl:15].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Cl:15])=[C:9]([CH2:11][CH2:12][CH3:13])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCCc1cc(C(=O)OCC)n[nH]1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1[nH]nc(C(=O)OCC)c1Cl

Procedure:
Following protocol K, 5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester was treated with glacial acetic acid and NaOCl under similar reaction conditions, yieliding the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:17]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1)#[N:2].[C:29]([O:33][C:34](=[O:43])[NH:35][CH:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:43])[NH:35][CH:36]1[CH2:37][CH2:38][CH:39]([NH:42][C:12](=[O:14])[C:11]2[CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:17]=[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:28][CH:27]=3)[CH:10]=2)[CH2:40][CH2:41]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: N#Cc1ccc(COc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 89.4 %

Procedure:
Following the procedure of Example 5(c) 3-(4-cyano benzyloxy)-5-(4-cyano phenoxy)benzoic acid 0.55 g (1.48 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.316 g, 1.48 mmol) were used to afford 0.75 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.3 (2H, s), 6.74 (1H, d), 7.02 (1H, s), 7.1 (2H, s), 7.22 (1H, s), 7.44 (1H, s), 7.66 (2H, d), 7.88 (4H, m), 8.28 (1H, d).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][CH2:18][CH3:19])=O)C.O.[OH-].[Li+]>C(O)(=O)C(O)=O>[CH2:18]([NH:17][CH2:16][CH2:15][N:14]1[CH2:13][CH2:12][C:7]2[NH:8][CH:9]=[C:10]([CH3:11])[C:6]=2[C:4]1=[O:3])[CH3:19]
Reactant: CCNCCNCCc1[nH]cc(C)c1C(=O)OCC
Agent: O=C(O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCNCCN1CCc2[nH]cc(C)c2C1=O
Temperature: 135 °C
Yield: 30.2 %

Procedure:
A stirred mixture of 2-[2-(2-ethylamino-ethylamino)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (400 mg, 1.498 mmol), lithium hydroxide monohydrate (503 mg, 11.985 mmol) in 25 ml of oxalic acid was heated to reflux at 135° C. The mixture was concentrated under reduced pressure, added with water (10 ml) and extracted with dichloromethane (20 ml×3). The combined extracts Were dried over anhydrous magnesium sulfate, filtered and concentrated wider reduced pressure to give 5-(2-ethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-4-one (100 mg, 30.2%) as a brown oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([O:11][CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([NH:13][C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([O:11][CH3:12])[C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(N)cc1
Reactant: COC1CCc2c(Cl)ncnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC1CCc2c(Nc3ccc(C#N)cc3)ncnc21
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
0.92 g of 4-chloro-6,7-dihydro-7-methoxy-5H-cyclopenta[d]pyrimidine [prepared as described in step (e) above] and 0.59 g of p-aminobenzonitrile were dissolved in 5 ml of ethanol, and the solution was stirred at 130° C. for 10 minutes. At the end of this time, the mixture was cooled to room temperature, and the resulting solid reaction product was pulverized. 50 ml of a 1N aqueous solution of sodium hydroxide and 200 ml of ethyl acetate were added to the resulting powder, and the ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated off under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluted with ethyl acetate, to give 0.54 g of the title compound as colorless crystals melting at 167°-169° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:25]1([OH:28])[CH:26]=[CH:27][N:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=[CH:24]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: c1ccc2occc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cc3ccccc3o2)C=CN(Cc2ccccc2)C=C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of benzofuran (4 g, 33.9 mmol) in tetrahydrofuran (90 ml) at -10° C. was slowly added a solution of n-butyllithium (2.5M in hexanes, 13.6 ml, 34 mmol), keeping the temperature at -10° C. The reaction was stirred and allowed to warm to room temperature over 1 hr, after which a solution of 1-benzyl-4-piperidone (6.3 ml, 34 mmol) in tetrahydrofuran (30 ml) was added dropwise. Stirring was continued for 2 hr at room temperature. The solvent was evaporated and the residue partitioned between saturated aqueous sodium carbonate (75 ml) and ethyl acetate (3×100 ml). The combined organics were dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate, to give 4-(benzofuran-2-yl)-1-benzyl-4-hydroxypyridine (7.5 g, 75%); δH (CDCl3) 1.96-2.00 (2H, m, piperidinyl CH2), 2.21-2.29 (2H, m, piperidinyl CH2), 2.44 (1H, t, J 6.2 Hz, piperidinyl CH), 2.56 (2H, dt, J 11.1, 2.7 Hz, piperidinyl CH2), 2.64-2.68 (3H, m, piperidinyl CH2, OH), 2.73 (1H, t, J 6.2 Hz, piperidinyl CH), 3.55 (2H, s, PhCH2N), 6.58 (1H, s, 3'-H), 7.19-7.34 (7H, m, ArH), 7.44 (1H, d, J 7.3 Hz, ArH), and 7.52 (1H, d, J 6.6 Hz, ArH).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:11]=1.[C:26]([C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([CH3:30])[CH3:29])#[N:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:34]3[CH:35]=[CH:36][C:31]([C:28]([CH3:30])([CH3:29])[C:26]#[N:27])=[CH:32][CH:33]=3)[CH:17]=2)[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:11]=1
Reactant: CC(C)(C#N)c1ccc(B(O)O)cc1
Reactant: Brc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(-c2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)cc1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
3-(1H-Benzo[d]imidazol-2-yl)-5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (20 mg, 0.050 mmol), [4-(1cyano-1-methylethyl)phenyl]boronic acid (10 mg, 0.074053 mmol) and triphenylphosphine (2 mg, 0.007 mmol) were dissolved in a mixture of THF (6 mL) and 1M Na2CO3 (aq) (10 mg, 0.094 mmol). Palladium acetate (1 mg, 0.004 mmol) was added and the solution was heated overnight at reflux. After cooling to room temperature, and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (25 mL) and washed with water (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (25 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound (7 mg). 1H NMR (400 MHz, CDCl3): δ 8.79 (s, 1H), 7.80 (bs, 1H), 7.75 (m, 2H), 7.70 (m, 1H), 7.64 (m, 1H), 7.53-7.48 (m, 3H), 7.25-7.22 (m, 2H), 5.76 (d, 1H, J=8.4 Hz), 4.06 (m, 1H), 3.77 (m, 1H), 2.55 (m, 1H), 2.10 (m, 2H), 1.73 (m, 3H), 1.72 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:11]([O:13][C:14](=[O:21])[C:15](=O)[CH2:16][C:17](=O)[CH3:18])[CH3:12]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH3:18])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[N:10]=1)=[O:21])[CH3:12]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNc1ccc(F)c(Cl)c1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2ccc(F)c(Cl)c2)n1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
A solution of 3-chloro-4-fluorophenylhydrazine (2 g, 12.4 mmol) and ethyl-2,4-dioxovalerate (2.36 g, 14.9 mmol) in ethanol (40 ml) was refluxed for 16 hours, then cooled to room temperature and partitioned between EtOAc and water. The organic layer was washed with saturated bicarbonate, brine solution, dried over sodium sulfate, filtered, concentrated and purified by silica-gel column chromatography using 4% EtOAc in heaxanes to give the product (2.45 g, 71%) as a solid.