Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@:5]12[CH2:10][C@@H:9]1[C@@H:8]([N:11]1[CH:19]=[N:18][C:17]3[C:12]1=[N:13][C:14]([Cl:36])=[N:15][C:16]=3[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]#[CH:35])[CH:23]=1)[C@H:7]([OH:37])[C@@H:6]2[OH:38])=[O:4].CNC([C@@]12C[C@@H]1[C@@H](N1C=NC3C1=NC(Cl)=NC=3NCC1C=CC=C(C#CCCCC3[N:72]=[N:73][N:74]([C:76]4[CH:81]=[CH:80][C:79]([F:82])=[C:78]([N+:83]([O-:85])=[O:84])[CH:77]=4)C=3)C=1)[C@H](O)[C@@H]2O)=O>>[CH3:1][NH:2][C:3]([C@@:5]12[CH2:10][C@@H:9]1[C@@H:8]([N:11]1[CH:19]=[N:18][C:17]3[C:12]1=[N:13][C:14]([Cl:36])=[N:15][C:16]=3[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]3[N:72]=[N:73][N:74]([C:76]4[CH:81]=[CH:80][C:79]([F:82])=[C:78]([N+:83]([O-:85])=[O:84])[CH:77]=4)[CH:35]=3)[CH:23]=1)[C@H:7]([OH:37])[C@@H:6]2[OH:38])=[O:4]
Reactant: C#CCCCCC#Cc1cccc(CNc2nc(Cl)nc3c2ncn3[C@H]2[C@H](O)[C@H](O)[C@]3(C(=O)NC)C[C@H]23)c1
Reactant: CNC(=O)[C@@]12C[C@@H]1[C@@H](n1cnc3c(NCc4cccc(C#CCCCc5cn(-c6ccc(F)c([N+](=O)[O-])c6)nn5)c4)nc(Cl)nc31)[C@H](O)[C@@H]2O
Product: CNC(=O)[C@@]12C[C@@H]1[C@@H](n1cnc3c(NCc4cccc(C#CCCCCc5cn(-c6ccc(F)c([N+](=O)[O-])c6)nn5)c4)nc(Cl)nc31)[C@H](O)[C@@H]2O
Yield: 94 %

Procedure:
Compound 204 (94%) was synthesized from compound 201 following the same procedure as for compound 203. 1H NMR (CD3OD, 400 MHz) δ 8.65-8.58 (m, 1H), 8.45 (s, 1H), 8.23-8.19 (m, 1H), 8.03 (s, 1H), 7.65 (t, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.33-7.25 (m, 2H), 5.07 (d, J=6.8 Hz, 1H), 4.80 (s, 1H), 4.72 (br s, 2H), 4.00 (d, J=6.8 Hz, 1H), 2.87 (s, 3H), 2.51 (t, J=6.8 Hz, 2H), 2.07-2.04 (m, 1H), 1.97-1.91 (m, 2H), 1.82 (t, J=5.2 Hz, 2H), 1.74-1.69 (m, 2H), 1.39-1.35 (m, 1H). HRMS calculated for C34H33ClFN10O5 (M+H)+: 715.2308. Found 715.2302.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:3]=1.[C:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[N:41]=2)[CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27].CCCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[N:41]=[C:42]([C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[CH:5]=[C:4]([CH2:18][O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[N:3]=3)[CH:43]=[CH:44][CH:45]=2)[CH:35]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: FC(F)(F)c1ccc(-c2cc(Br)nc(COC3CCCCO3)c2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)n1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(COC4CCCCO4)n3)n2)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A stirred mixture of 2-bromo-6-(tetrahydro-pyran-2-yloxymethyl)-4-(4-trifluoromethyl-phenyl)-pyridine (Example A.65) (0.400 g, 0.894 mmol), N-tert-butyl-3-(6-tributylstannanyl-pyridin-2-yl)-benzenesulfonamide (Example F.6) (0.518 g, 0.894 mmol), tetrakis(triphenyl-phosphine)palladium (0.052 g, 5 mol %) in toluene (5 mL) was heated under reflux conditions for 18 h. After cooling to rt, the reaction mixture was directly subjected to silica gel column chromatography with n-heptane/ethyl acetate to give the N-tert-butyl-3-[6′-(tetrahydro-pyran-2-yloxymethyl)-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (550 mg, 98%) as a light yellow oil. MS (ISP) 626.0 [(M+H)+].
Reaction SMILES: [C:1]1([N:7]=[C:8]2[CH2:17][CH2:16][N:15]3[CH:10]([CH2:11][CH2:12][CH:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CCOC(C)=O.CC(C)=O>CO>[NH:7]([CH:8]1[CH2:17][CH2:16][N:15]2[CH:10]([CH2:11][CH2:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)[CH2:9]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(N=C2CCN3CC(c4ccccc4)CCC3C2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: c1ccc(NC2CCN3CC(c4ccccc4)CCC3C2)cc1

Procedure:
The crude anil (IV) (7.2 g.) was dissolved in MeOH (100 ml.), cooled in an ice bath and then NaBH4 (3.6 g.) added portionwise. The mixture was refluxed for 1 hr. and cooled. The solvent was removed and the residue treated with EtOAc/H2O. The EtOAc extracts were combined, dried over MgSO4 and solvent removed in vacuo. Yield, 6.7 g. The TLC showed two spots (most likely two isomers). The mixture was run through a HPLC using EtOAc/acetone (5:1). The mixture was not easily separated and the main portion (4 g.) was still a mixture. The mixture was carried through the rest of the synthesis. Also obtained was the fast component pure (0.7 g.) and the slow component pure (0.4 g.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)O)=[O:9])=[CH:4][CH:3]=1.[CH2:19]([CH2:21][NH2:22])[OH:20].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CCOCC>[ClH:1].[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]([NH:22][CH2:21][CH2:19][OH:20])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])=[CH:13][CH:14]=1
Reactant: NCCO
Reactant: O=C(c1ccc(Cl)cc1)C(O)c1ccc(Cl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOCC
Product: Cl
Product: O=C(c1ccc(Cl)cc1)C(NCCO)c1ccc(Cl)cc1

Procedure:
A mixture of 4,4'-dichlorobenzoin (3.52 g, 0.0125 mole), ethanolamine (0.83 g, 0.0235 mole), and phosphorus pentoxide (0.10 g) was heated on a steam bath for 6 minutes with thorough mixing. After cooling, the reaction mixture was dissolved in ether and the ether solution decanted from the phosphorus pentoxide. The solution was treated with ethereal hydrogen chloride and the solid salt collected by filtration and washed with isopropyl ether. The solid was purified by trituration with acetonitrile. The white solid was collected, washed with isopropyl ether, and dried in a vacuum oven at 50° C. for two hours. The yield was 3.24 g (72%), m.p. 190°-193° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)=[N:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:14]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2].[Cl-].[NH4+]>O1CCOCC1.O.[Zn]>[NH2:30][C:26]1[CH:25]=[C:24]([C:11]2[C:10]([C:8]3[CH:7]=[CH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=3)=[CH:14][N:13]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[N:12]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCNc1nccc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc([N+](=O)[O-])c2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1COCCO1
Solvent: O
Product: CCNc1nccc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(N)c2)n1
Reaction time: 5 h
Yield: 93.3 %

Procedure:
391 mg (0.91 mmol) of N-ethyl-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine were dissolved in a mixture of 20 ml of dioxane and 4 ml of water. 239 mg (3.64 mmol) of metallic zinc and 485 mg (9.1 mmol) of ammonium chloride were then added to the resulting solution. The reaction was carried out at 100° C. under stirring for 5 hours. The suspension was then filtered through a celite pad and the filtrate evaporated in vacuo. The residue was partitioned between dichloromethane and aqueous sodium hydrogenocarbonate and the organic layer dried over sodium sulphate and concentrated to give a crude purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3; from 9/1 to 7/3), affording 340 mg (93%) of the title compound.
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].Cl[Si](C)(C)C.[CH3:21][CH2:22]O>>[CH2:10]([C:9]1[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:2]([O:1][CH2:21][CH3:22])=[O:3])=[CH:15][CH:14]=1)[CH:11]([CH3:12])[CH3:13]
Reactant: CCO
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: C[Si](C)(C)Cl
Product: CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of ibuprofen 1A (9.89 g, 48 mmol) in anhydrous EtOH (35 mL) was added chlorotrimethylsilane (18.27 mL, 144 mmol) at room temperature, and the mixture was stirred at the same temperature for 2 h. After the removal of the excess EtOH and chlorotrirethylsilane under reduced pressure, the oily residue was treated with ice-cold saturated NaHCO3 (150 mL), and the resulting mixture was extracted with hexanes (450 mL). The hexanes solution was washed with brine (3×50 mL), and dried over anhydrous Na2SO2. Evaporation of the solvent afforded ethyl 2-(4′-isobutylphenyl)propionate 2A (11.24 g, in 100% yield) as a colorless oil.
Reaction SMILES: [H][H].C(OC(C)C)(C)C.[F:10][C:11]1[CH:34]=[C:33]([F:35])[C:14]2[NH:15][C:16]([C:18]3[C:30]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23](=[N:31]O)[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[N:17][C:13]=2[CH:12]=1>C(O)C.O1CCCC1.[Ni]>[F:10][C:11]1[CH:34]=[C:33]([F:35])[C:14]2[NH:15][C:16]([C:18]3[C:30]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]([NH2:31])[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[N:17][C:13]=2[CH:12]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(F)cc(F)c2[nH]1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4cc(F)cc(F)c4[nH]3)cccc21
Yield: 74.3 %

Procedure:
The procedure used in Example 6 is followed. In a 211 ml autoclave, dissolve 1.85 g of 4-(5,7-difluoro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 70 ml of ethanol and 70 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to an initial hydrogen pressure of 1 bar and heat the autoclave at 60° for 6 hours. After cooling, the volume of hydrogen absorbed is 342 ml. After filtration of the catalyst, the filtrate is concentrated under reduced pressure and then taken up in a mixture of dichloromethane with a small amount of methanol and dried over magnesium sulphate, and the crude solid obtained is made into a paste with diisopropyl ether. In this way, we obtain 1.32 g of 4-(5,7-difluoro-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a grey powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[O:18].Cl.Cl.[CH2:23]([O:25][C:26]([C:28]1[C:29]([CH3:47])=[C:30]([C:34]([NH:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:35][C:36]=1[CH3:37])[C:31](O)=[O:32])=[O:27])[CH3:24]>C(OCC)C>[CH2:23]([O:25][C:26]([C:28]1[C:29]([CH3:47])=[C:30]2[C:34](=[CH:35][C:36]=1[CH3:37])[N:38]([CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:17](=[O:18])[N:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([F:8])([F:19])[F:20])[C:31]2=[O:32])=[O:27])[CH3:24]
Reactant: CCOC(=O)c1c(C)cc(NCCN2CCCCC2)c(C(=O)O)c1C
Reactant: O=C=Nc1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)cc2c(c1C)c(=O)n(-c1ccccc1C(F)(F)F)c(=O)n2CCN1CCCCC1
Yield: 72 %

Procedure:
Triethylamine (0.58 g) and o-(trifluoromethyl)phenyl isocyanate (0.53 g) were added to a solution of the benzoic acid described above (1.2 g) in diethyl ether (20 ml), and the mixture was refluxed for 4 hours. After evaporating the solvent, the residue was dissolved in ethanol (20 ml) containing 10% hydrogen chloride. The solution was refluxed for one hour and then concentrated. The concentrate was diluted with water and extracted with CHCl3, and the CHCl3 extracts were combined, washed successively with 10% aqueous Na2CO3 solution and brine, and dried over anhydrous Na2SO4. The solvent was evaporated, and the residue was recrystallized from diethyl ether-n-hexane to give 6-ethoxycarbonyl-5,7-dimethyl-1-(2-piperidinoethyl)-3-[2-(trifluoromethyl)phenyl]-2,4(1H,3H)-quinazolinedione (1.1 g, 72%) melting at 144°-145° C. MS: m/e, 517(M+), 498, 472, 433, 406. NMR: δ (ppm. CDCl3), 1.40 (3H, t), 1.50 (6H, b), 2.45 (3H, s), 2.52 (6H, t), 2.70 (3H, s), 4.30 (2H, t), 4.45 (2H, q), 7.10-7.80 (5H, m).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClCCl.CS(C)=O.[OH:14][CH2:15][CH:16]1[CH2:20][N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[O:27])[CH2:17]1>C(N(CC)CC)C>[O:27]=[C:18]1[N:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:20][CH:16]([CH:15]=[O:14])[CH2:17]1
Reactant: O=C1CC(CO)CN1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CC1CC(=O)N(c2ccccc2)C1
Reaction time: 0.33 h

Procedure:
Oxalyl chloride was added to a dichloromethane solution of DMSO at −78° C. and stirred for 20 minutes. Successively, this was mixed with a dichloromethane solution of 4-(hydroxymethyl)-1-phenylpyrrolidin-2-one and then with triethylamine 15 minutes thereafter, and stirred for 30 minutes. Thereafter, work-up and purification were carried out to obtain 5-oxo-1-phenylpyrrolidine-3-carboaldehyde. EN: 188.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][CH2:11][CH2:12][NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH2:24][CH3:25])CC)C.ClCC(Cl)=[O:29].[H-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:10]1[CH2:25][CH2:24][N:13]([C:14]([CH3:15])([CH3:17])[CH3:16])[C:12](=[O:29])[CH2:11]1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)NCCNC(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)N1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
To a solution of (2-tert-butylaminoethyl)carbamic acid benzyl ester (1.44 g, 5.75 mmol) and triethylamine (2.4 mL, 17.26 mmol) in DCM (50 mL), at room temperature, was added dropwise chloroacetyl chloride (0.55 mL, 6.9 mmol) and the reaction mixture was stirred for 6 h at room temperature. The aqueous phase was extracted with EtOAc (10 mL) The reaction mixture was partitioned between DCM and a staturated aqueous solution of NaHCO3. The organic layer was separated, dried over sodium sulphate and concentrated in vacuo. The brown residue was dissolved in dry THF (50 mL) and sodium hydride 60% in mineral oil (0.345 g, 8.63 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water and partitioned between EtOAc and water. The organic layer was washed with brine, separated, dried over sodium sulphate and concentrated in vacuo. The residue was dissolved in MeOH, loaded onto an Isolute® SCX-2 cartridge, and eluted using MeOH to give 4-tert-Butyl-3-oxopiperazine-1-carboxylic acid benzyl ester as yellow oil (1.57 g, 94%). LCMS (Method A): RT=3.96 min, [M+H]+ 291.2
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][NH:17][CH2:18]2.[F:23][C:24]1[S:28][C:27]([NH:29][S:30](N2C=CN=C2)(=[O:32])=[O:31])=[N:26][CH:25]=1.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[Br:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][N:17]([S:30]([NH:29][C:27]1[S:28][C:24]([F:23])=[CH:25][N:26]=1)(=[O:32])=[O:31])[CH2:18]2
Reactant: FC(F)(F)c1ccc(-c2cccc3c2CCNC3)c(Br)c1
Reactant: O=S(=O)(Nc1ncc(F)s1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Yield: 27.5 %

Procedure:
A solution of 5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate D, 0.400 g, 1.019 mmol), N-(5-fluorothiazol-2-yl)-1H-imidazole-1-sulfonamide (Intermediate N, 1.012 g, 4.07 mmol), and triethylamine (2.84 ml, 20.37 mmol) in 3 mL THF was heated to 80° C. for 30 minutes. LC/MS showed product so the reaction mixture was diluted with EtOAc and washed with 1 N citric acid. The organics were dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.150 g, 0.280 mmol). 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.06 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.51-7.57 (m, 1H), 7.24-7.35 (m, 2H), 7.08 (s, 1H), 7.05 (d, J=5.7 Hz, 1H), 4.37 (s, 2H), 3.30-3.39 (m, 2H), 2.47-2.60 (m, 2H)
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.[CH3:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[C:16](=[O:21])[CH:15]=[CH:14][C:13]2=[O:22].C1C=CC=CC=1>[Pd].CO>[CH2:4]([CH:5]1[C:14]2[C:13](=[O:22])[C:12]3[C:17](=[CH:18][C:19]([CH3:20])=[C:10]([CH3:9])[CH:11]=3)[C:16](=[O:21])[C:15]=2[CH2:8][CH2:7][CH2:6]1)[CH2:3][CH2:2][CH3:1]
Reactant: Cc1cc2c(cc1C)C(=O)C=CC2=O
Reactant: C=CC1CC=CCC1
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: CCCCC1CCCC2=C1C(=O)c1cc(C)c(C)cc1C2=O
Reaction time: 4 h
Yield: 36 %

Procedure:
A 3.0 g. sample of the butadiene dimer-6,7-di-methylnaphthoquinone adduct was dissolved in 100 ml. benzene. After the addition of 0.30 g 10% Pd/C catalyst, the mixture was hydrogenated at 35 psi for four hours. After removal of catalyst by filtration, five drops DBN were added and the mixture was stirred overnight while exposed to air. The benzene was then blown off with air and the residue chromatographed on acidic alumina with a 9:1 benzene-ethyl acetate solution. The crude product (1.1 g.; 36% yield) was recrystallized from methanol to give an analytical sample with m.p. 88°-90° C.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:33][CH:34]2[CH2:43][CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[O:44][CH3:45])[CH2:35]2)(=O)=O)=CC=1>CN(C)C=O>[CH3:45][O:44][C:40]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:41]=1[CH2:42][CH2:43][CH:34]([CH2:33][N:12]1[C:11](=[O:14])[CH:10]=[CH:9][C:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:13]1)[CH2:35]2
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)n[nH]1
Reactant: COc1cccc2c1CCC(COS(=O)(=O)c1ccc(C)cc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
A suspension of 6-diphenylmethyl-3(2H)-pyridazinone (0.58 g) and sodium hydride (60%, 110 mg) in dry N,N-dimethylformamide (7 ml) was stirred at 0° C. for 30 minutes. A solution of (5-methoxy-1,2,3,4-tetrahydro-2-naphthyl)methyl p-toluenesulfonate (0.77 g) in dry N,N-dimethylformamide (5 ml) was added dropwise to the suspension at room temperature. The mixture was stirred for 6 hours and poured into ice-1N hydrochloric acid and extracted with ethyl acetate. The extract was separated, washed with water (twice) and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate =5:1~3:1) to give 2-[(1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.61 g) as a pale yellow oil.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=1>ClCCl>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])=[CH:11][CH:12]=1)#[CH:17]
Reactant: O=C1CCCC(=O)O1
Reactant: C#Cc1ccc(N)cc1
Solvent: ClCCl
Product: C#Cc1ccc(NC(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
Glutaric anhydride (540 mg, 4.70 mmol) was dissolved in anhydrous dichloromethane (7 mL) and followed with the addition of p-aminophenyl-acetylene (500 mg, 4.27 mmol). The mixture was allowed to stir at room temperature for 6 hours before the solvent was evaporated under reduced pressure to provide 900 mg of a yellow white product 24 (96%); mp 135-140° C.; 1H NMR (DMSO-d6, 300 MHz) δ 1.77 (p, J=8.21 Hz, 2H), 2.25 (t, J=9.30 Hz, 2H), 2.34 (t, J=6.56 Hz, 2H), 4.05 (s, 1H), 7.38 (d, J=8.52 Hz, 2H), 7.59 (d, J=7.91 Hz, 2H) 9.90 (s, 1H); HRMS m/e calculated for (M+H)+: C13H13NO3 231.0895; found 231.0895.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH:14]=O.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1/[CH:14]=[C:24]1\[C:25](=[O:29])[NH:26][C:27]2[C:23]\1=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=2
Reactant: COC(=O)C(C)(C)COc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)C(C)(C)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 66.6 %

Procedure:
3-(4-chloro-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester (6.7 g, 25 mmol) and 6-Chloro-1,3-dihydro-indol-2-one (4.35 g, 25 mmol) were mixed in 20 mL of anhydrous methanol. Then pyrrolidine (2 mL, 25 mmol) was added dropwise at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration and dried to give title compound as yellow solid (Yield: 7 g, 67%).
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:31][CH:32]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1.CO>[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:31][CH:32]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2coc(-c3ccccc3)n2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2coc(-c3ccccc3)n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
Lithium hydroxide monohydrate (49.9 mg) was added to a solution of methyl E-4-phenyl-4-[4-(2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (280 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-bexane to obtain E-4-phenyl-4-[4-(2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid (237 mg, yield 87%) as colorless crystals. m.p. 144-145° C.