Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[C:9]([CH:10]=O)[C:8]=2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[C:9]([CH:10]=[N:21][C:20]3[CH:22]=[CH:23][C:17]([I:16])=[CH:18][CH:19]=3)[C:8]=2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=Cc1cccc(-c2ccccc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Oc1c(C=Nc2ccc(I)cc2)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
An amount of 20.6 mmol of 3-phenyl salicylaldehyde (2) (4.08 g) was dissolved in 150 ml of toluene. After addition of 4-iodoaniline (5.42 g/24.8 mmol) and a few crystals of para-toluenesulfonic acid, the reaction mixture was stirred under reflux for three hours applying a Dean-Stark-trap. After cooling down to room temperature, sodium hydrogencarbonate solution (150 ml) was added. The organic phase was separated and filtered over sodium sulfate and silica. Removing the solvent and recrystallization from ethanol at −20° C. gave the title compound as a red solid. Yield: 7.25 g (88%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH2:19])[C:16]([O:20]C)=[CH:15][N:14]=2)=[N:6]1.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.C(O)=O>CN1CCCC1=O>[NH2:19][C:17]1[C:16]([OH:20])=[CH:15][N:14]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[N:6]=2)[N:18]=1
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1N
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O=CO
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)ncc1O
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
5.61 g of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxypyrimidin-4-amine 1-4-2 (16.5 mmol, 1.00 eq) were dissolved in 680 mL of dry 1-methylpyrrolidin-2-one. 1.14 g of potassium carbonate (8.27 mmol, 0.5 eq.), and 3.40 mL benzenethiol (33.1 mmol, 2.0 eq.) were added. The mixture was stirred for 0.5 h at 190° C. bath temperature. Then the reaction mixture was partitioned between aqueous half saturated ammonium chloride solution and ethyl DCM/isopropanol (4:1). The organic layer was dried with magnesium sulfate and concentrated in vacuo. The purification of the residue by flash chromatography provided 6.60 g (17.0 mmol, 100%) of the target compound without formic acid. Further purification of 170 mg by HPLC resulted in analytically pure target compound: 53 mg.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11]Br)=[CH:2]1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:2]1
Reactant: C1CNCCN1
Reactant: BrCCc1coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2c(CCN3CCNCC3)coc2c1

Procedure:
84 mmol of 2-(benzofuran-3-yl)-1-bromoethane, 67 mmol of piperazine and 56 mmol of potassium carbonate are added to 200 ml of acetonitrile. After refluxing for 4 hours, the reaction mixture is cooled and then concentrated. The residue is taken up in dichloromethane, is washed with water, dried, filtered and then concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethanol: 90/10) allows the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=3[Cl:24])=[O:13])[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.ClC1C(C(F)(F)F)=CC=CC=1C(O)=O.CCN=C=NCCCN(C)C.[CH:50]1[CH:51]=[CH:52][C:53]2[N:58]([OH:59])[N:57]=[N:56][C:54]=2[CH:55]=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[C:15]=3[Cl:24])=[O:13])[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:58]1([O:59][C:2]2[C:3]3[CH2:11][CH2:10][N:9]([C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=4[Cl:24])=[O:13])[CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:53]2[CH:52]=[CH:51][CH:50]=[CH:55][C:54]=2[N:56]=[N:57]1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(Cl)ncnc2C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(ncnc2On2nnc3ccccc32)C1
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of the product of Intermediate 3 step a (305 mg, 1.80 mmol) in DCM (9 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid (404 mg, 1.80 mmol) followed by EDCI (517 mg, 2.70 mmol), HOBt (170 mg, 1.26 mmol) and TEA (0.50 mL, 3.60 mmol). The mixture was stirred overnight and then loaded directly on a column. Chromatography on SiO2 eluting with EtOAc/Hex afforded the desired product (267 mg, 39%) and 4-(1H-benzotriazol-1-yloxy)-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (203 mg, 24%) as a side product. MS (ESI) mass calcd. C15H10Cl2F3N3O, 375.02. m/z found 376.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.89-8.74 (m, 1H), 7.84-7.76 (m, 1H), 7.55-7.45 (m, 2H), 5.13-4.94 (m, 1H), 4.54-4.35 (m, 1H), 4.23-4.06 (m, 1H), 3.64-3.52 (m, 1H), 3.10-2.78 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)[CH:3]=1.[C:25](Cl)(=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1.C(N(CC)CC)C>ClCCl>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[C:25]([NH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[C:4]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)[CH:3]=1)=[O:34]
Reactant: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OC(C)(C)C)c(-c3ccnn3C)c2)c1
Temperature: 22 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
Tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (265 mg, 797.2 μmol), m-anisoyl chloride (168.0 μl, 1.5 eq) and triethylamine (266.7 μl, 2.4 eq) were taken up in 20 mL of dichloromethane in a round bottomed flask and stirred at 22° C. for 18 hr. The reaction was then concentrated and purified by column chromatography (40-75% ethyl acetate in hexane) to afford the title compound as a pale yellow oil in 73.9% yield LCMS m/z (%)=467 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9H), 3.42 (q, J=5.56 Hz, 2H), 3.78 (s, 3H), 3.88 (s, 3H), 4.04 (t, J=4.80 Hz, 2H), 6.28 (d, 1H), 7.01 (d, J=9.09 Hz, 1H), 7.10 (dt, J=4.55, 2.53 Hz, 1H), 7.38-7.41 (m, 2H), 7.43-7.45 (m, J=3.03 Hz, 1H), 7.54 (d, J=2.02 Hz, 1H), 7.66-7.71 (m, 1H), 7.76 (s, 1H).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH2:13])=[N:3]1.[F:14][C:15]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:16]=1[CH2:17][C:18]1[O:22][N:21]=[C:20]([C:23](O)=[O:24])[CH:19]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH:13][C:23]([C:20]2[CH:19]=[C:18]([CH2:17][C:16]3[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:15]=3[F:14])[O:22][N:21]=2)=[O:24])=[N:3]1
Reactant: NCCc1n[nH]c2ccccc12
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1n[nH]c2ccccc12)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.1 %

Procedure:
A mixture of 2-(1H-indazol-3-yl)ethanamine hydrochloride (0.040 g; 0.202 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.053 g; 0.223 mmol) N,N-diisopropylethylamine (0.87 mL; 0.506 mmol) and HATU (0.84 g; 0.223 mmol) in DMF (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with sodium hydrogen sulphate, sodium carbonate and brine. The organic layer was dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 1 to 10% methanol in dichloromethane) and by preparative HPLC method 4 to yield 0.007 g (9%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=O)[CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:7](=O)[CH2:6]1)=[O:4].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.[ClH:25]>CO>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:7]2[CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:11]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([Cl:25])=[CH:19][CH:20]=3)[CH2:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: Cl
Reactant: COC(=O)C1CC(=O)C(C(=O)OC)CC1=O
Reactant: Nc1ccc(Cl)cc1
Solvent: CO
Product: COC(=O)C1=C(Nc2ccc(Cl)cc2)CC(C(=O)OC)=C(Nc2ccc(Cl)cc2)C1
Yield: 96 %

Procedure:
Dimethyl 1,4-cyclohexanedione-2,5-dicarboxylate (4.5 6 gm; 20 mmol) and methanol (100 ml) were heated to boiling; then 4-chloroaniline (5.36 gm; 42 mmol) was added followed by conc. hydrochloric acid (200 μl). The mixture was refluxed for 5 hours under a nitrogen atmosphere. On cooling, a cream solid precipitated out which was collected by filtration, washed with methanol and dried under vacuum to give 8.62 gm (96%) of dimethyl 2,5-bis{(4-chlorophenyl)amino}cyclohexa-1,4-diene-1,4-dicarboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[N+:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)[CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1cccc2cc[nH]c12
Product: O=[N+]([O-])c1cccc(-c2cccc3cc[nH]c23)c1

Procedure:
Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 3-nitrophenylboronic acid: ESMS m/e: 238.9 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[I-].[Na+].CO>C1COCC1.C(Cl)Cl>[CH3:9][C:3]1([CH2:2][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: C1CCNC1
Reactant: CC1(CCl)COC(=O)N1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(CN2CCCC2)COC(=O)N1
Temperature: 85 °C
Yield: 35.1 %

Procedure:
To a solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (1.41 g, 9.43 mmol) in THF (40 ml) was added pyrrolidine (5.0 ml, 61 mmol) and sodium iodide (1.03 g, 6.87 mmol). The solution was sealed, heated to 85° C. for 24 h, cooled to RT, filtered, and concentrated in vacuo. Flash chromatography (2%→12% MeOH in CH2Cl2) afforded the oxazolidinone (609.8 mg, 3.31 mmol, 35%) as a brown oil which solidified upon standing. The dihydrooxazole was isolated in roughly 75% purity (1.8 g crude yield) and was characterized only by MS. 1H NMR (CDCl3, 400 MHz) δ 1.35 (s, 3H), 1.7-1.8 (m, 4H), 2.5-2.7 (m, 6H), 4.02 (d, J=8.4 Hz, 1H), 4.24 (d, J=8.4 Hz, 1H), 5.3-5.4 (br s, 1H). ESI/APCI expected for C9H16N2O2: 184.12. Found: 185 (MH+). 1H NMR (CDCl3, 400 MHz) δ 1.35 (s, 3H), 1.7-1.8 (m, 4H), 2.5-2.7 (m, 6H), 4.02 (d, J=8.4 Hz, 1H), 4.24 (d, J=8.4 Hz, 1H), 5.3-5.4 (br s, 1H). ESI/APCI expected for C9H16N2O2: 184.12. Found: 185 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl.[CH:18](=O)/[CH:19]=[CH:20]/[CH3:21].N>>[CH3:18][C:19]1[CH:20]=[CH:21][C:14]2[C:13](=[CH:12][CH:11]=[C:10]([S:9][S:8][C:5]3[CH:4]=[C:3]4[C:2](=[CH:7][CH:6]=3)[N:1]=[C:3]([CH3:4])[CH:2]=[CH:7]4)[CH:15]=2)[N:16]=1
Reactant: Nc1ccc(SSc2ccc(N)cc2)cc1
Reactant: C/C=C/C=O
Agent: Cl
Agent: N
Product: Cc1ccc2cc(SSc3ccc4nc(C)ccc4c3)ccc2n1

Procedure:
To a stirred slurry of 4-aminophenyl disulfide (5.0 g, 0.02 mol) in refluxing 6M HCl (65 ml) was added crotonaldehyde (4.2 g, 0.06 mol) dropwise over 90 minutes. The resulting mixture was refluxed for an additional 2 hours, then cooled to ambient. Conc aqueous ammonia was added to adjust the pH to neutral and the mixture extracted with ethyl acetate. The combined extracts were washed with water, then saturated aqueous brine, dried (MgSO4), filtered and concentrated. The crude was purified on silica gel, eluting with 50 to 100% ethyl acetate/petrol. The product was an oil (2.57 g, 37%); MS ES+349.17.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2=[O:21])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCCCCC.C(OCC)(=O)C>[OH:21][CH2:11][CH:10]([C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[OH:12])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1
Reactant: Cc1ccc(C)c2c1OC(=O)C2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C)c(C(CO)c2ccc(C(C)C)cc2)c1O
Yield: 88 %

Procedure:
Using 3-(4-isopropylphenyl)-4,7-dimethyl-1-benzofuran-2(3H)-one synthesized in Reference Example 230, the title compound was synthesized in the same manner as in Reference Example 8. Yield 88%. Melting point: 88-89° C. (hexane-ethyl acetate).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:27]([O:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:35])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 90 °C
Yield: 54.6 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (80 mg, 0.30 mmol), potassium carbonate (84 mg, 0.61 mmol) and tert-butylbromoacetate (67 μL, 0.46 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 90° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 afforded 62 mg (62%) 3-(2-pyridyl)-5-(3-cyano-5-(2-tert-butoxy-2-oxoethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.91 (t, 1H), 7.50 (t, 1H), 7.28 (s, 1H), 5.30 (s, 2H), 1.52 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]#[N:14])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]#[N:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C#N)c2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: N#Cc1ccc(O)c2ccccc12

Procedure:
Ten grams of 1-methoxy-4-naphthonitrile was dissolved in 270 ml of benzene, 15.4 grams of aluminum chloride was added thereto, and the mixture was heated to reflux for eighteen hours with stirring. After the reaction was completed, the reaction mixture was partitioned between ethyl acetate and water, the ethyl acetate layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated to afford crude 1-hydroxy-4-naphthonitrile. This was dissolved in 250 ml of dimethyl formamide, 3.39 grams of sodium hydride (50%) was added thereto little by little with ice, cooling and stirring, then 10.21 grams of benzyl bromide was added, and the mixture was stirred for three hours at room temperature. The reaction mixture was subjected to a partition with benzene and water, the benzene layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated therefrom followed by recrystallization of the residue to give 1-benzyloxy-4-naphthonitrile, pale yellow needles, yield 11.85 grams. Nuclear magnetic resonance spectra (CDCl3) δ: 5.20 (2H, s, --CH2 -- Ph).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([OH:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[CH2:23]([O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:13]([OH:15])[CH3:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(O)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.1 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid (3.0 g, 13.69 mmol) in DMF (50 mL) was added K2CO3 (3.73 g, 27.39 mmol) and stirred at RT for 15 min. (Bromomethyl)benzene (2.81 g, 16.43 mmol) was added and stirred at RT for 6 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 20% EtOAc/hexane as eluent to afford benzyl 2-(tert-butoxycarbonylamino)-3-hydroxybutanoate 10 (2.8 g, 66%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.C([O:15][C:16]1[CH2:20][CH2:19][C:18](=O)[CH:17]=1)C.Cl>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:18]1[CH2:19][CH2:20][C:16](=[O:15])[CH:17]=1
Reactant: CCOC1=CC(=O)CC1
Reactant: Brc1ccccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1C=C(c2ccccn2)CC1
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a solution of 2-Bromopyridine (5.00 g, 31.6 mmol) in THF (30 ml) was added dropwise n-BuLi (2.55 M in Hexane, 12.5 mL. 31.9 mmol) at −78° C., and stirred for 10 min. To a reaction mixture was added dropwise 3-ethoxy-2-cyclopentenone (2.00 g, 15.9 mmol) in THF (10 mL) at −78° C., and stirred at 0° C. for 2 h. The reaction mixture was acidified with 2M HCl (10 mL), and aqueous layer was washed with EtOAc. The aqueous layer was basified with 1M NaOH aq., and then extracted with CH2Cl2. The organic layer was washed with brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=1/3) to yield 3-(2-pyridyl)-2-cyclopenten-1-one (1.57 g, 58%) as brown solid.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39]>O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[C:35]([O-:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([O-:40])=[O:39]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
A suitable reactor is charged with acetone (56 mL). The acetone solution is sequentially charged with carvedilol (15.0 grams) and water (8 mL). Upon addition of the water, the slurry dissolves completely with heating. To the solution is added 1 M of aqueous Maleic acid (1 Equiv. 36.9 mL.) The reaction mixture is stirred at between 17° C. and 35° C. The solid precipitate is formed over 10 hours to 24 hours. Later, the mixture is filtered and the cake is washed with a mixture of acetone and water (10 to 1) at 3 volume or 45.0 mL. The cake is dried under vacuum to a constant weight. The final weight is 14.08 grams.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13]C)=O)=[N:3]1.[CH3:15][NH2:16]>CO>[CH3:15][NH:16][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[N:3]=1)=[O:13]
Reactant: COC(=O)c1nn(C)c2ccccc12
Reactant: CN
Solvent: CO
Product: CNC(=O)c1nn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A suspension of methyl 1-methyl-1H-indazole-3-carboxylate (3.88 g, 20.4 mmole) in 40% aqueous CH3NH2 (100 mL) and MeOH (5 mL) was stirred at RT for 4 hr, during which time a homogeneous solution formed. The solution was concentrated to approximately ⅓ volume and the precipitated solid was collected by filtration, washed with H2O, and dried in vacuo to give the title compound (3.42 g. 89%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.24 (m, 1H), 7.47 (m, 2H), 7.34 (m, 1H), 6.95 (br s, 1H), 4.19 (s, 3H), 3.05 (d, J=12.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]([CH3:23])(=[N:13][C:14]([C:16]2[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=2)=[O:15])=[O:12])[CH:6]=1.[C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([C:36]2[N:40]([CH3:41])[N:39]=[C:38]([CH3:42])[CH:37]=2)=[O:35])[CH:30]=[CH:31][CH:32]=1)#[CH:26]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]([CH3:23])(=[N:13][C:14]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([C:26]#[C:25][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([C:36]4[N:40]([CH3:41])[N:39]=[C:38]([CH3:42])[CH:37]=4)=[O:35])[CH:28]=3)[CH:21]=2)=[O:15])=[O:12])[CH:6]=1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Reactant: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)c1
Product: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 460, methyl(3-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}phenyl)acetate (202 mg, 0.492 mmol) and N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (153 mg, 0.64 mmol), were converted to the title compound as a light yellow solid foam (275 mg, 98%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[C:23](=[C:35](SC)SC)[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.O.[NH2:48][NH2:49]>C(O)C>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:48][NH:49][C:35]([N:41]6[CH2:46][CH2:45][O:44][CH2:43][CH2:42]6)=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CSC(SC)=C1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Reactant: C1COCCN1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(N5CCOCC5)c3CC4)cc2)CCC1
Temperature: 80 °C
Yield: 28.8 %

Procedure:
To a solution of tert-butyl(1-(4-(6-(bis(methylthio)methylene)-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (100 mg, 0.18 mmol) in ethanol (873 μl) was added morpholine (76 μl, 0.87 mmol) and the mixture heated to 80° C. under a nitrogen atmosphere for 2 hours. Hydrazine monohydrate (12.7 μl, 0.26 mmol) was added and the mixture heated to 80° C. for 1 hour. Further hydrazine monohydrate (72 μl, 1.48 mmol) was added and the mixture heated to 80° C. for 18 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified via Biotage chromatography (silica, cyclohexane:ethyl acetate, gradient elution from 92:2 to 100:0) to give a white solid (30 mg, 30% yield). 1H-NMR (500 MHz, CDCl3) δ 7.67 (1H, s), 7.31 (2H, d), 7.23-7.28 (2H, m), 7.18-7.24 (3H, m), 7.07-7.14 (2H, m), 4.95-5.44 (1H, br m), 3.82 (4H, t), 3.24 (2H, t), 3.21 (4H, t), 2.91 (2H, t), 2.19-2.64 (4H, br m), 1.97-2.09 (1H, m), 1.73-1.84 (1H, m), 1.10-1.46 (9H, br m). LCMS (Method A) RT=6.18 min, M+H+=578.24.