Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:2]1.Cl.C([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O.C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:34][CH2:33][CH2:32][C:31]([OH:30])=[O:35])=[O:23])=[CH:20][CH:19]=2)[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:2]1
Reactant: O=C(O)c1ccc(NC(c2csc3ccccc23)C2CCCCC2)cc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)CCNC(=O)c1ccc(NC(c2csc3ccccc23)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a mixture of 4-{[1-benzothiophen-3-yl(cyclohexyl)methyl]amino}benzoic acid (250 mg) synthesized above, β-alanine ethyl ester hydrochloride (126 mg), 1-hydroxybenzotriazole.monohydrate (126 mg), triethylamine (114 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (157 mg), and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give a pale-yellow 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 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (201 mg, 67%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(#N)C>[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[OH:16])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(N)c1
Solvent: CC#N
Product: CC(=O)Nc1cc(C(C)(C)CC(C)(C)C)ccc1O
Yield: 70 %

Procedure:
2-Amino-4-tert-octylphenol was refluxed by heating in a mixture of acetonitrile and acetic anhydride to synthesize Intermediate B having the melting point of 176° to 177° C. in a yield of 70%. 26.3 g of 2-acetamido-4-tert-octylphenol thus obtained was dissolved in 200 ml of chloroform, the solution was cooled to 0° to 5° C. to which was added 8.1 g of sulfur monochloride (S2Cl2) and the mixture was stirred for 2 hours. Water was added to the reaction solution, and the chloroform layer was thoroughly washed with water and then concentrated. The residue was dissolved in 50 ml of dimethylformamide without purification and isolation, to the solution were added 16.6 g of anhydrous potassium carbonate and 23 g of butyl bromide and the mixture was heated at 100° C. for 3 hours. After the reaction, 300 ml of ethyl acetate and 200 ml of water were added to the reaction mixture and extracted. The ethyl acetate layer was concentrated and the residue was crystallized from acetonitrile to obtain 15.8 g of Intermediate D having the melting point of 150° to 153° C. 15.8 g of Intermediate D thus obtained was dissolved in a mixture of 100 ml of ethanol and 10 ml of 6N hydrochloric acid and the mixture was stirred at 40° to 50° C. for 1 hour whereby the acetyl group of Intermediate D was quantitatively hydrolized. The reaction solution was poured into ice water and the precipitate thus formed was collected by filtration and dried to obtain 14 g of Intermediate E. 14 g of Intermediate E thus obtained was dissolved in 100 ml of pyridine, to the solution was added 5.7 g of methanesulfonyl chloride in a nitrogen atmosphere and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, the oily product thus precipitated was separated by decantation and dissolved in 200 ml of ethyl acetate. The solution was thoroughly washed with an aqueous acidic solution of acetic acid. The ethyl acetate was concentrated and the residue was crystallized from a mixture of hexane and ethyl acetate to obtain 9.3 g of Intermediate F having a melting point of 102° to 103° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([NH:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])=[O:22])=[CH:15]2>C(OCC)(=O)C>[N:5]1([CH2:4][CH2:3][CH2:2][NH:1][C:25]([CH:24]([NH:23][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=3)=[O:22])[CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: NCCCN1CCOCC1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccccc1)C(=O)NCCCN1CCOCC1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h

Procedure:
4-(3-Aminopropyl)morpholine (0.34 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.30 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) substituting the following workup: the reaction was diluted with ethyl acetate, the resulting solution washed three times with 2N NaOH and once with brine, dried over Na2SO4, and concentrated. The residue was stirred under ether for 1 hour, the solid filtered and dried: Yield 125 mg, 87%; HPLC (60/40) 2.85 minutes (98%); PBMS 469/471 (MH+, 100/90%);
Reaction SMILES: [S:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([OH:10])=[C:4]2[CH:3]=[CH:2]1.[OH-].[K+].[O:13]=[CH:14][C:15]([OH:17])=[O:16].Cl.C(N(CCCC)CCCC)CCC>O.COC(C)(C)C>[OH:13][CH:14]([C:6]1[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[C:9]([OH:10])=[CH:8][CH:7]=1)[C:15]([OH:17])=[O:16]
Reactant: Oc1cccc2sccc12
Reactant: O=CC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: O=C(O)C(O)c1ccc(O)c2ccsc12
Reaction time: 3 h
Yield: 111.5 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-benzothiophen-4-ol (1.0 g, 6.32 mmol, 1.00 equiv, 95%), potassium hydroxide (821 mg, 1.46 mmol, 2.20 equiv, 10%). This was followed by the addition of 2-oxoacetic acid (592 mg, 4.00 mmol, 1.20 equiv) at 0-5° C. with 30 min. If necessary, more 2-oxoacetic acid is added such that the pH of the solution at the end of the addition was 11.5. After stirring for 3 h at 0-5 degree C. 20 mL of tert-butyl methyl ether were added to the reaction mixture followed by HCl(25%) solution in water such that the pH was 7. The biphasic mixture was filtered through Speedex, then HCl (25%) solution in water were added to the aqueous phase such that the pH was 2.0. After addition of tert-butyl methyl ether (3*20 mL), the organic phase was separated at 25° C., and 50 mL acetonitrile was added to organic phase. To the resulting clear solution was added portions wise at 20-30° C., a solution of tributylamine (1.23 g, 1.00 equiv) in 20 mL of tert-butyl methyl ether under seeding with crystals of the product. The resulting suspension was stirred over night at 20-30 degree C., and then filtered off. The filter cake was dried oven at 60° C. The result afford (1.0 g, 63%) of 2-hydroxy-2-(4-hydroxy-1-benzothiophen-7-yl)acetic acid as gray solid.
Reaction SMILES: [C:1]1([CH2:11][O:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.NN>CCO>[C:1]1([CH2:11][O:12][NH2:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1cccc2ccccc12
Agent: NN
Solvent: CCO
Product: NOCc1cccc2ccccc12
Reaction time: 8 h
Yield: 69.5 %

Procedure:
N-(1-naphthyl)methoxy phthalimide (1.21 g) was suspended in 95% EtOH and hydrazine (0.20 mL) was added. The reaction mixture was stirred overnight and then filtered. The filtrate was concentrated under reduced pressure and then taken up in a small amount of dichloromethane. The small amount of remaining phthalhydrazide was then removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (480 mg) as a colorless oil. MS(CI) m/e 174 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O.Cl>[OH:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The product from (c) (1.7 g) and excess of pyridine hydrochloride were heated together for 8 hours at 180° C. The mixture was cooled, diluted with water and 2-molar hydrochloric acid, and extracted with ether. The extracts were dried and evaporated to yield an oil identified as the required hydroxy compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([Br:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:10]([Br:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CNc1cc(F)c(Br)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(Br)cc1[N+](=O)[O-]
Yield: 90.3 %

Procedure:
1.33 (3H, t, J=7.4 Hz), 4.04 (2H, d, J=4.9 Hz), 4.30 (2H, q, J=7.4 Hz), 6.46 (1H, d, J=10.9 Hz), 8.44 (1H, d, J=7.3 Hz), 8.49 (1H, bs). 2) By using 3.36 g (10.5 mmol) of N-(4-bromo-5-fluoro-2-nitrophenyl)glycine ethyl ester, 2.86 g of imidazole and 20 ml of DMF, 3.50 g (90%) of N-[4-bromo-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][C:19](=O)[N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[N:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCOCC1>[CH3:1][N:2]1[CH2:21][CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[N:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1
Reactant: CN1CCC(=O)N2c3cccnc3Cc3ccccc3C2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CN1CCCN2c3cccnc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.7 %

Procedure:
1.46 g (0.05mol) 2-methyl-5-oxo-1,2,3,4,5,15b-hexahydro-11H-benzo[c][1,4]diazepino[1,2-a]pyrido[2,3-f]azepine is added to a suspension of 1.5 g LiAlH4 in 15 ml dry dioxan under nitrogen, and the whole is stirred for 10 minutes at room temperature, after which the reaction mixture is worked up in the way described in example X.2., giving 1.21 g (89%) 2-methyl-1,2,3,4,5,15b-hexahydro-11H-benzo[c][1,4]diazepino[1,2-a]pyrido[2,3-f]azepine as a clear colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:15](=[O:16])[N:14](CC2C=CC(OC)=CC=2OC)[C@@H:13]1[CH2:28][N:29]1[N:33]=[C:32]2[CH2:34][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][C:31]2=[N:30]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:28][N:29]1[N:30]=[C:31]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][C:32]2=[N:33]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nc3c(n2)CN(C(=O)OC(C)(C)C)C3)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1Cc2nn(C[C@H]3NC(=O)[C@H]3NC(=O)OCc3ccccc3)nc2C1
Temperature: 90 °C
Yield: 51.8 %

Procedure:
Slurried tert-butyl 2-(((2R,3S)-3-(((benzyloxy)carbonyl)amino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-2-yl)methyl)-4,6-dihydropyrrolo[3,4-d][1,2,3]triazole-5(2H)-carboxylate (85.5 mg, 0.144 mmol), potassium peroxydisulfate (51.8 mg, 0.186 mmol) and potassium phosphate, dibasic (57 mg, 0.33 mmol) in ACN/water (2 mL, 2:1) for 5 min, then heated to 90° C. for 1.5 h. More potassium peroxydisulfate (13.9 mg, 0.050 mmol) was added and it was heated for an additional hour. More potassium peroxydisulfate (12.1 mg, 0.043 mmol) was added and it was heated an additional hour, whereupon the slurry was partially concentrated in vacuo then partitioned between saturated NaHCO3 (aq) and EtOAc. After separating the layers, the aqueous was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 0-100%) to afford contaminated product (33 mg), which was repurified by reverse phase HPLC (XSELECT CSH, C18, 5μ, 30×100 mm, ACN/H2O with 0.1% formic acid buffer, 60 mL/min). The title compound (12.1 mg, 19%) was obtained as a white solid. Rt=0.78 min, m/z=433.2 (M+1) Method 2m_acidic. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.17 (d, J=9.7 Hz, 1H), 7.42-7.26 (m, 5H), 5.05 (s, 2H), 5.04-4.99 (m, 1H), 4.58 (d, J=6.6 Hz, 2H), 4.40 (d, J=4.7 Hz, 4H), 4.22 (q, J=6.5 Hz, 1H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[CH3:13].[Br:16][C:17]1[C:22]([NH2:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=1>N1C=CC=CC=1>[Br:16][C:17]1[C:22]([NH:23][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:12]([F:15])([F:14])[CH3:13])[CH:4]=2)(=[O:10])=[O:9])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: Nc1cc(Cl)cnc1Br
Reactant: CC(F)(F)c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: c1ccncc1
Product: CC(F)(F)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl

Procedure:
Prepared from 377 mg (1.37 mmol) of 4-chloro-3-(1,1-difluoro-ethyl)-benzenesulfonyl chloride and 270 mg (1.30 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in 2 mL pyridine using procedure x. Yield: 460 mg of a white solid. LC-MSD, m/z for C13H9BrCl2F2N2O2S [M+H]+=444.8, 446.8, 448.8.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(/C=C/C4C=CC=CC=4)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[C:34]1(/[CH:40]=[CH:41]/[C:42]2[C:50]3[O:49][CH:48]([CH2:51][N:52]=[N+]=[N-])[CH2:47][C:46]=3[CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:34]1(/[CH:40]=[CH:41]/[C:42]2[C:50]3[O:49][CH:48]([CH2:51][NH2:52])[CH2:47][C:46]=3[CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(/C=C/c3ccccc3)c2O1
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(/C=C/c4ccccc4)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: NCC1Cc2cccc(/C=C/c3ccccc3)c2O1
Yield: 34 %

Procedure:
Treatment of (±)-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (6.53 g, 16.06 mmol) with sodium azide (4.17 g, 64.25 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-(7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide. Treatment of (±)-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide (2.2 g, 7.9 mmol) with triphenylphosphine (2.08 g, 7.9 mmol) generally according to the procedure described for Example 21 afforded 0.675 g (34%) of (±)-1-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 209-211° C.; Anal. calcd. for C17H17NOHCl: C, 70.95; H, 6.3; N, 4.87. Found: C, 69.63; H, 6.46; N, 4.72.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:24][NH:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:25]([CH3:24])[CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNCCCN1CCCCC1
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Product: CN(CCCN1CCCCC1)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N-methyl-3-(piperidin-1-yl)propyl amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (d, J=9.60 Hz, 1 H) 1.66 (d, J=13.89 Hz, 3 H) 1.82 (br. s., 2 H) 2.01 (br. s., 2 H) 2.83-3.13 (m, 7 H) 3.32-3.58 (m, 4 H) 7.79 (d, J=8.34 Hz, 2 H) 8.13 (br. s., 3 H) 8.58 (br. s., 3 H) 9.05-9.50 (m, 1 H) 12.43-14.49 (m, 1 H). ESI-MS m/z [M+H]+ 445.2.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[CH:10]=[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.O=[Pt]=O>[CH:22]1([C:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[CH:12]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOc1ccc(-c2cc(-c3ccccc3)nc(-c3ccccc3)c2)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOc1ccc(-c2cc(C3CCCCC3)nc(C3CCCCC3)c2)cc1
Reaction time: 4.5 h

Procedure:
The 2,6 diphenyl-4-(p-ethoxyphenyl) pyridine is then dissolved in glacial acetic acid (20ml) to which 0.2g of Adam's catalyst is added. The compound is then hydrogenated at 3 atm with shaking for 4-5 hours. The catalyst and solvent were removed from the reaction mixture leaving 2,6-dicyclohexyl-4-(p-ethoxyphenyl) pyridine m.p. 106°C.
Reaction SMILES: CN(C)[CH:3]=[O:4].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([OH:23])=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1C>O=O>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:3](=[O:4])[C:18]=1[CH3:19]
Reactant: CN(C)C=O
Reactant: COc1cc(C)c(CCCCCCCCCCO)c(O)c1OC
Agent: O=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O

Procedure:
To a dimethylformamide solution (50 ml) of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methylphenol (2.53 g) is added bis(salicylidene)ethylenediiminocobalt(II) (salcomine) (0.1 g) and the mixture is stirred in oxygen streams at atmospheric temperature and pressure for 72 hours. The solvent is then distilled off and the product is extracted with ether. The ethereal layer is washed with water and dried over anhydrous sodium sulfate, and the solvent is distilled off. The above procedure yields 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (2.32 g) as orange-yellow needles melting at 52° C.
Reaction SMILES: C(Cl)(=O)C.[CH2:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])=[CH:11][CH:12]=2)[CH2:7][NH:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=C[C:42]([C:45](=[O:50])NCCC)=[CH:41][CH:40]=1)=O)C2>>[C:45]([N:6]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])[CH:9]=2)[CH2:5]1)(=[O:50])[CH2:42][CH2:41][CH3:40]
Reactant: O=C(Nc1ccc2c(c1)CNC2)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: CCCC(=O)N1Cc2ccc(NC(=O)N3Cc4ccccc4C3)cc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting butyryl chloride for acetyl chloride and N-(isoindolin-5-yl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 7.59-7.61 (bs, 1H), 7.43-7.48 (m, 1H), 7.30-7.41 (m, 4H), 7.22 (t, J=7.7 Hz, 1H), 4.77 (d, J=13.9 Hz, 2H), 4.77 (s, 4H), 4.55-4.60 (m, 2H), 2.33 (td, J=7.3, 3.7 Hz, 2H), 1.54-1.63 (m, 2H), 0.93 (td, J=7.3, 1.4 Hz, 3H); MS (ESI(+)) m/e 350 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[CH:25]=[CH:26][CH:27]=1)(O)[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[CH:25]=[CH:26][CH:27]=1)=[CH2:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1-c1cccc(C(C)(O)c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(c1cccc(-c2ccccc2OC)c1)c1cccc(C(C)(C)C)c1OCc1ccccc1

Procedure:
A solution of crude 27 (5 mmol) in toluene (120 mL) was treated with p-toluene sulfonic acid (0.2 g) and refluxed under a Dean-Stark trap for 2 hr. After cooling the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (80 mL) and water (2×80 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The crude product was purified by chromatography on silica (80 g) with hexane (4 L). Pure 28 (1.3 g, 58% over 2 steps) was isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[CH:6]/[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)/C=C/C(C)(C)c1cccc(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(C)(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
27.2 g (109.5 mmol) of ethyl-E-4-(3-methoxyphenyl)-4-methylpent-2-enoate is mixed in 293 ml of ethyl acetate with 2.72 g of palladium on carbon (10%) and stirred for 18 hours at room temperature under a hydrogen atmosphere. The catalyst is removed by filtration through a glass fiber filter, and the residue that remains after the concentration by evaporation (27.2 g=99.2%) is incorporated in crude form into the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1)=O.Cl.C(Cl)(=O)C1C=CC=NC=1>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:18][C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:10][N:9]=1
Reactant: O=C(NNC(=O)c1sccc1Cl)c1cccnc1
Agent: Cl
Agent: O=C(Cl)c1cccnc1
Product: Clc1ccsc1-c1nnc(-c2cccnc2)o1

Procedure:
Nicotinic acid N′-(3-chloro-thiophene-2-carbonyl)-hydrazide: The title compound was prepared from 3-chloro-thiophene-2-carbonyl hydrazide (70 mg, 0.40 mmol) and nicotinoyl chloride hydrochloride (348 mg, 1.96 mmol) similar to Example 84b, and yielded 76 mg (68%) of white solid. 1H NMR (DMSO-d6): 10.82 (s, 1H), 10.33 (s, 1H), 9.07 (s, 1H), 8.79 (d, J=3.84 Hz, 1H), 8.26 (d, J=6.87 Hz, 1H), 7.93 (d, J=5.22 Hz, 1H), 7.58 (dd, J=7.55, 4.53 Hz, 1H), 7.23 (d, J=4.95 Hz, 1H).
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CSc1ncnc2cnccc12
Product: Brc1cccc(Nc2ncnc3cnccc23)c1
Temperature: 10 °C
Yield: 52.7 %

Procedure:
A mixture of 4-methylthiopyrido[3,4-d]pyrimidine (75 mg, 0.42 mmol) (see previous experimental), and 3-bromoaniline (1 mL) is heated to 10° C. under N2 for 2 h. The reaction mixture is then chromatographed on silica using MPLC and eluting with a gradient system (CHCl3 to 5% MeOH in CHCl3). The fractions are concentrated under reduced pressure, and the resulting solid is recrystallized from Et2O to yield 4-(3-bromoanilino)pyrido[3,4-d]pyrimidine (66 mg, 52.7%) as a light brown solid. 1H NMR (DMSO) δ 10.15 (1H, s), 9.21 (1H, s), 8.80 (1H, s), 8.76 (1H, d, J=5.8 Hz), 8.44 (1H, d, J=5.6 Hz), 8.25 (1H, s), 7.93 (1H, d, J=7.7 Hz), 7.45-7.37 (2H, m).