Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O.[Pd].CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccccc1B(O)O
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Product: Cc1ccccc1-c1ccc(O)c(C(=O)O)c1
Yield: 95.1 %

Procedure:
Using 0.1 mol % Pd. The general procedure described in Example 3 was used with 5-chloro-2-hydroxy-benzoic acid (173 mg, 1.00 mmol), 2-methylphenylboronic acid (163 mg, 1.20 mmol), K2CO3 (345 mg, 2.50 mmol), water (2.0 mL), Pd/L solution (0.200 mL of a Pd(OAc)2 (1.1 mg, 0.005 mmol, 0.5 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (5.0 mg, 0.010 mmol, 1 mol %) solution in 1.0 mL water), 12 h, 100° C. The product was isolated as a white solid (217 mg, 96%). Mp=151° C. (lit. 150-152° C.). 1H NMR (400 MHz, CDCl3) δ: 11.91 (br-s, 1H), 10.28 (br-s, 1H), 7.83 (d, 1H, J=2.0 Hz), 7.42 (dd, 1H, J=2.4 Hz, J=8.6 Hz), 7.20-7.13 (m, 4H), 6.98 (d, 1H, J=8.4 Hz), 2.20 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 175.4, 161.3, 140.4, 138.2, 135.6, 133.7, 131.4, 130.7, 129.9, 127.4, 126.2, 117.9, 111.2, 20.7 IR (neat, cm−1): 3062, 1664, 1614, 1583, 1478, 1440, 1229, 1190, 728.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[OH:31])([O:4]P(OP(O)(O)=O)(O)=O)(=[O:3])[OH:2].C1N=C(N)C2N=CN([C@@H]3O[C@@H]4COP(O)(O[C@H]4[C@H]3O)=O)C=2N=1>>[CH:27]1[N:26]=[C:24]([NH2:25])[C:23]2[N:22]=[CH:21][N:20]([C@@H:18]3[O:19][C@H:15]([CH2:14][O:13][P:1]([OH:4])([OH:3])=[O:2])[C@@H:16]([OH:31])[C@H:17]3[OH:30])[C:29]=2[N:28]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Temperature: -20 °C
Reaction time: 36 h

Procedure:
This step involves incubation of the sample with ATP and calmodulin to generate cAMP. The assay may be initiated at any time within 48 hours of specimen collection, usually at a central laboratory. The assay is carried out in a sterile solution which encourages bacterial viability (e.g. Stainer-Scholte medium, Stainer, D. W. and Scholte, M. J., A simple chemically defined medium for the production of phase I Bordetella pertussis. J. Gen. Microbiol. 63:211-220, 1971) supplemented with 200 nM to 5 mM (e.g. about 1 mM) adenosine triphosphate, 0,05 μM to 5 μM (e.g. about 0.1 μM) calmodulin, and radiolabeled cAMP in 1 nM to 200 nM concentration as appropriate for optimal sensitivity. Alternatively, any medium which permits the preservation and short term survival of Bordetella may be substituted. The assay solution is maintained frozen at about -20° C. until the day of use. The assay solution is thawed. The cap is removed from the transport tube and a measured amount of 0.5 to 2 ml (e.g. about 1 ml) of assay medium is added on top of the transport medium. The swab is not removed. The tube is capped and incubated at 35°-37° C. upright with rotation for 24 to 48 hours.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:7][C@H:6]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:5]1.F[C:18]1[C:23]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C=O)C.CCOC(C)=O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:8]([C@H:6]1[CH2:7][C@H:4]([O:3][C:18]2[C:23]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:5]1)=[O:9]
Reactant: O=C(Nc1ccccn1)[C@H]1C[C@H](O)C1
Reactant: Fc1ncccc1C1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccn1)[C@H]1C[C@H](Oc2ncccc2C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.073 g, 1.8 mmol, 60% dispersion in mineral oil) was added to a stirred solution of trans-3-hydroxy-N-(pyridin-2-yl)cyclobutanecarboxamide (0.18 g, 0.92 mmol) in DMF (3.5 mL) under an argon atmosphere. The mixture was stirred at RT for 1 h. 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.17 g, 0.92 mmol) was added, and the reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was diluted with EtOAc and washed with saturated ammonium chloride. The organic layer was separated, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified via silica gel chromatography to give trans-N-(pyridin-2-yl)-3-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutanecarboxamide as a white solid. [M+1]=354.0. IC50 (uM): 3.066.
Reaction SMILES: [Br-:1].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1)(=[O:24])[CH3:23]>C1COCC1>[Br:1][CH2:23][C:22]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1)=[O:24]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(C#N)cn1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)CBr)nc1
Yield: 80.5 %

Procedure:
Add pyridinium tribromide (9.2 g, 28.7 mmol) to a solution of 6-acetyl-nicotinonitrile (4.2 g, 28.7 mmol) in THF (200 mL) at room temperature. Filter off the solids and wash with minimal THF. Recrystallize the solid from EtOAc/hexane to obtain the desired intermediate as a light orange solid (5.2 g, 80%) that was used without further purification. MS (ES−) m/z: 223 (M−H)−.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[CH:19][CH:18]=3)[N:13]=2)[N:6]=1)([CH3:3])[CH3:2].[OH2:25].[OH2:26].C[N+]1([O-])CCOCC1>CC(C)=O.C(Cl)Cl.O=[Os](=O)(=O)=O>[CH:1]([NH:4][C:5]1[N:6]=[C:7]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([OH:26])[CH2:24][OH:25])=[CH:21][CH:22]=3)[N:13]=2)[CH:8]=[C:9]([CH3:11])[N:10]=1)([CH3:2])[CH3:3]
Reactant: C=Cc1ccc(-c2noc(-c3cc(C)nc(NC(C)C)n3)n2)cc1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cc(-c2nc(-c3ccc(C(O)CO)cc3)no2)nc(NC(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of isopropyl-{4-methyl-6-[3-(4-vinyl-phenyl)-[1,2,4]oxadiazol-5-yl]-pyrimidin-2-yl}-amine (Intermediate 8: 2.78 g, 8.67 mmol) in acetone (45 mL) are added water (4 mL) and a 2.5% aq. solution of OsO4 (136 μL), followed by N-methyl-morpholine-N-oxide monohydrate (1.4 g, 10.4 mmol). The reaction mixture is stirred at rt for 18 h. Another 68 μL of 2.5% aq. solution of OsO4 is added and stirring is continued for another 3 h. The mixture is then diluted with DCM (150 mL), and washed with water (3×50 mL), dried over MgSO4, filtered and evaporated to give 0.97 g of racemic 1-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethane-1,2-diol as a brown solid; LC-MS: tR=0.84 min; [M+H]+=356.04. 1H NMR (CDCl3) δ 1.30 (d, J=6.5 Hz, 6H), 2.16 (s br, 1H), 2.49 (s, 3H), 2.74 (s br, 1H), 3.72 (dd, J=11.0, 8.0 Hz, 1H), 3.86 (dd, J=11.0, 3.3 Hz, 0H), 4.31 (m, 1H), 4.94 (dd, J=7.8, 3.3 Hz, 1H), 5.28 (s br, 1H), 7.30 (s, 1H), 7.55 (d, J=8.3 Hz, 2H), 8.20 (d, J=8.3 Hz, 2H).
Reaction SMILES: CO.C(=O)=O.C(Cl)(=O)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[C@@H:29]([CH3:40])[CH2:28]3)=[N:19][N:18]=2)=[CH:13][CH:12]=1>CC(C)=O.O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([N:27]3[CH2:32][CH2:31][NH:30][C@@H:29]([CH3:40])[CH2:28]3)=[N:19][N:18]=2)=[CH:15][CH:16]=1
Reactant: C[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Agent: O=C=O
Solvent: CO
Solvent: CC(=O)Cl
Solvent: CC(C)=O
Product: C[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1
Reaction time: 0.25 h

Procedure:
Cool methanol (2.82 L) to 0° C. via a 1:1 acetone/water bath with dry ice, and add acetyl chloride (142 mL, 2.0 mol) dropwise over a period of 30 min, maintaining the temperature below 15° C. during the addition. Stir the mixture for 15 min. Add (S)-tert-butyl 4-(4-(4-fluorophenyl)phthalazin-1-yl)-2-methylpiperazine-1-carboxylate (282 g, 667 mmol) in one portion. Stir the mixture for 12 h at 25° C. Concentrate, and dissolve the residue in water (3.0 L). Add solid NaHCO3 until the pH is 7. Extract the product with CH2Cl2 (2×2.0 L), combine the organic layers, and concentrate to give the title compound as a brown crushable foam in quantitative yield (236 g, >100%). ES/MS m/z 323.0 (M+1).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C([N:14]1[CH2:20][CH:19]2[O:21][CH:16]([C:17]3[CH:25]=[C:24]4[O:26][CH2:27][O:28][C:23]4=[CH:22][C:18]=32)[CH2:15]1)C1C=CC=CC=1>CO.CC(O)=O.[Pd]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[O:21]1[CH:19]2[C:18]3[CH:22]=[C:23]4[O:28][CH2:27][O:26][C:24]4=[CH:25][C:17]=3[CH:16]1[CH2:15][NH:14][CH2:20]2
Reactant: c1ccc(CN2CC3OC(C2)c2cc4c(cc23)OCO4)cc1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Solvent: CO
Product: c1c2c(cc3c1C1CNCC3O1)OCO2
Yield: 46.1 %

Procedure:
A solution of the product prepared in Example 37 (6.6 g, 0.017M) in methanol (200 ml) and AcOH (20 ml) was hydrogenated (10% Pd-C, 0.66 g) in a Parr apparatus at an initial pressure of 40 psi overnight. The resulting solution was filtered through Celite, evaporated, and crystallized from methanol/ether to give the titled compound (2.33 g, 46% yield). The product was recrystallized from methanol/CCl4 and dried in vacuo to give pure product, mp 193°-195° C. (dec). NMR (DMSO-d6) δ 2.70-3.50 (m, 4H, --CH2 --N--CH2), 5.15 [s, 2H, (2×) ArCHO), 5.95 (s, 2H, --OCH2O), 6.95 (s, 2H, aromatic H), 7.25 (m, OH); MS: 205 (M+).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[C:5]([Cl:17])=[N:4][N:3]=1.C(N(CC)CC)C.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C1COCC1.C(O)C>[Cl:17][C:5]1[C:6]2[C:11]3[CH:12]=[N:13][N:14]([CH2:15][CH3:16])[C:10]=3[N:9]=[CH:8][C:7]=2[C:2]([N:29]2[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]2)=[N:3][N:4]=1
Reactant: CCn1ncc2c3c(Cl)nnc(Cl)c3cnc21
Reactant: OC1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1ncc2c3c(Cl)nnc(N4CCC(O)CC4)c3cnc21
Temperature: 60 °C
Yield: 80 %

Procedure:
To a suspension of 6,9-dichloro-3-ethyl-3H-pyrazolo[4′,3′:5,6]pyrido[3,4-d]pyridazine (3.2 g, 12.0 mmol) in THF/ethanol (40 mL, 1:1) in a 100 mL pressure tube was added triethylamine (5 eq) and 4-hydroxy-piperidine (1.1 eq) sequentially. The reaction mixture was heated in an oil bath at 60° C. for 2 h. The progress of the reaction was monitored by HPLC. The reaction mixture was transferred to a 200 mL round-bottomed flask, and the solvent was removed via evaporation under reduced pressure. The light brown residue was resuspended in saturated sodium bicarbonate (100 mL), and the precipitated solid was collected by filtration. This orange solid was washed thoroughly with water and dried in a vacuum oven at 40° C. over night to afford the title compound (3.2 g, 80% yield). This material was >93% pure and was used directly without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH:16]=[C:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:6]=1[C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:3])[CH3:2].B(F)(F)F.O>ClCCl>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]2[O:15][C:17]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][C:7]=2[C:6]=1[C:22]([CH3:23])([CH3:24])[CH3:25])(=[O:3])[CH3:2]
Reactant: CCC(=Cc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: O
Product: CCC1(CC)Cc2c(cc(C(C)(C)C)c(OC(C)=O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
4-Acetoxy-3,5-di-tert-butyl-2-(2-ethyl-1-butenyl)phenol (0.85 g, 2.5 mmol) was dissolved in dichloromethane (10 ml) and BF3 etherate (0.4 ml) was added dropwise to the solution under a nitrogen atmosphere. After stirring at room temperature for 3 h, water was added to the reaction mixture and extracted with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butyl-2,2-diethyl-2,3-dihydrobenzofuran [0.45 g (yield, 53%)] as a pale yellow oil. Mass 346(M+), 304, 57
Reaction SMILES: Br[C:2]1[CH2:6][CH:5]([C:7]([NH2:9])=[O:8])[O:4][N:3]=1.[Br:10][C:11]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:10][C:11]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:12]=1[O:13][CH:14]1[CH2:15][CH2:16][N:17]([C:2]2[CH2:6][CH:5]([C:7]([NH2:9])=[O:8])[O:4][N:3]=2)[CH2:18][CH2:19]1
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Reactant: NC(=O)C1CC(Br)=NO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=O)C1CC(N2CCC(Oc3cc(F)ccc3Br)CC2)=NO1
Reaction time: 1 h

Procedure:
A mixture of 3-bromo-4,5-dihydroisoxazole-5-carboxamide (1.5 g, 7.77 mmol), 4-(2-bromo-5-fluorophenoxy)piperidine (2.56 g, 9.33 mmol) and N,N-diisopropylethylamine (3.5 mL, 20.04 mmol) in ethanol (15 mL) was heated at reflux temperature overnight. Solvent was then removed in vacuo. The residue was suspended in water and stirred for 1 h. The solid was collected, washed with water and Et2O. Drying under vacuum gave the title compound as a light brown powder.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH2:22])[C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:13][CH:14]=1.[C:23](Cl)(=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]([CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:40]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[N:22][C:11]=2[CH:10]=1
Reactant: CN(C)CCCNc1ccc(Cl)cc1N
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc(Cl)ccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
Triethylamine (1.75 ml) was added to a solution containing 4-chloro-N1-[3-(dimethylamino)propyl]-1,2-benzenediamine (2.60 g) in chloroform (25 ml), and then a solution containing stearoyl chloride (3.46 g) in chloroform (5 ml) was added thereto while being cooled with ice. After being stirred for 3 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (9.00 ml) was added to a solution containing the residue (5.94 g) in ethanol (50 ml). After being stirred for 2 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (5.61 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1-20:1), thereby yielding the entitled compound (4.90 g) as pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([OH:18])[CH:12]=2)[CH2:9][CH2:8][O:7][CH:6]([CH3:10])[CH2:5]1)[CH3:2]>C(O)C.[Pd]>[CH2:4]([O:18][C:13]1[CH:12]=[C:11]([C:4]2([O:3][CH2:1][CH3:2])[CH2:9][CH2:8][O:7][CH:6]([CH3:10])[CH2:5]2)[CH:16]=[C:15]([F:17])[CH:14]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC1(c2cc(O)cc(F)c2)CCOC(C)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC1(c2cc(F)cc(OCc3ccccc3)c2)CCOC(C)C1

Procedure:
The (2SR,4SR)-4-ethoxy-4-(5-fluoro-3-hydroxyphenyl)-2-methyltetrahydropyran, used as a starting material, was obtained by hydrogenolysis of a solution of (2SR,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-ethoxy-2-methyltetrahydropyran (2.6 g, described in Note i. below Table X in Example 45) in ethanol (25 ml) in the presence of 10% palladium-on-charcoal catalyst (0.26 g ). The mixture was filtered and the filtrate was evaporated. There was thus obtained the required starting material (1.69 g, 89%), as an oil.
Reaction SMILES: [Li+].[OH-].[N:3]1([C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([CH:20]=2)[C:16]([O:18]C)=[O:17])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl>O.O1CCCC1>[N:3]1([C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([CH:20]=2)[C:16]([OH:18])=[O:17])=[O:10])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of LiOH (420 mg, 10 mmol) in water (8 ml) was added to a stirred solution of methyl 5-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 56; 450 mg, 1.27 mmol) in tetrahydrofuran (2 ml) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was acidified with HCl (6 mol/l), extracted with ethyl acetate (3×40 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate, and evaporated in vacuo to give crude title compound as a white solid. 400 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1.CC([O-])=O.[Na+].CCOC(C)=O>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]([C:11]([C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13](=[O:15])[CH3:14])[CH:17]=[CH:18][C:19]=1[O:25][CH3:26]
Reactant: COc1ccc(Br)cc1OC
Reactant: COc1cc(C=CC(C)=O)cc(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(C(=CC(C)=O)c2ccc(OC)c(OC)c2)c1
Temperature: 60 °C
Yield: 14.4 %

Procedure:
A suspension of Pd(OAc)2 (67 mg, 0.30 mmol) in DMF (1 ml) was added to a stirred suspension of 4-(3,5-dimethoxyphenyl)-but-3-en-2-one (2.05 g, 9.96 mmol), 4-bromo-1,2-dimethoxybenzene (2.15 ml, 14.94 mmol), NaOAc (1.39 g, 16.94 mmol), and tetrabutylammonium bromide (3.53 g, 10.96 mmol) in DMF (19 ml). The suspension was heated at ˜60° C. overnight. The mixture was then poured into EtOAc (50 ml) and H2O (150 ml), followed by extraction with EtOAc (2×50 ml), washing with H2O (2×50 ml), brine (50 ml) and drying over MgSO4. The crude was purified flash column chromatography (10% EtOAc in hexane gradient to 25% EtOAc in hexane) to give 4-(3,4-dimethoxy-phenyl)-4-(3,5-dimethoxy-phenyl)-but-3-en-2-one as a gummy oil (0.49 g, 15%): 1HNMR (CDCl3) δ 6.93-6.92 (m, 1H, Ar), 6.82-6.77 (m, 2H, Ar), 6.53-6.51 (m, 2H, Ar and double bond proton), 6.38 (d, J=2 Hz, 2H, Ar), 3.87 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.79 (s, 6H, 2OCH3), 1.91 (s, 3H, CH3); 13C NMR (CDCl3) δ 160.9, 153.8, 150.7, 148.9, 141.1, 132.9, 126.5, 122.4, 113.2, 110.8, 100.9, 56.1, 55.8, 55.6, 55.4, 30.0; Anal. Calcd. For C20H22O5: C, 70.16; H, 6.48. Found: C, 70.26; H, 6.37; N, <0.05.
Reaction SMILES: [N+](C1C=CC=C2C=1C(=O)C1C(C2=O)CC=CC1)([O-])=O.[N+:20]([C:23]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:24]=1[C:25](=[O:40])[CH:26]1[CH:31]([C:32]2=[O:37])[CH2:30][C:29]([CH3:38])=[C:28]([CH3:39])[CH2:27]1)([O-])=O>>[NH2:20][C:23]1[C:24]2[C:25](=[O:40])[C:26]3[C:31](=[CH:30][C:29]([CH3:38])=[C:28]([CH3:39])[CH:27]=3)[C:32](=[O:37])[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: CC1=C(C)CC2C(=O)c3c(cccc3[N+](=O)[O-])C(=O)C2C1
Agent: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Product: Cc1cc2c(cc1C)C(=O)c1c(N)cccc1C2=O
Yield: 99 %

Procedure:
The process of Example 1 is repeated, replacing 64.3 parts of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone by 71.3 parts of 5-nitro-2,3-dimethyl-1,4,4a,9a-tetrahydroanthraquinone (obtained from 1-nitronaphthoquinone and 2,3-dimethyl-1,4-butadiene by Diels-Alder reaction), to give 61.9 parts of 1-amino-6,7-dimethylanthraquinone in 99% purity, corresponding to a yield of 99% of theory.
Reaction SMILES: [CH:1]1([N:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(O)C.[Pd]>[CH:1]1([N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1c2ccccc2ccn1C1CCCCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C1c2ccccc2CCN1C1CCCCC1
Reaction time: 3.5 h
Yield: 83.3 %

Procedure:
The compound (200 mg) obtained in step (c) just above was dissolved in a mixed solution (10.7 ml) of ethanol: concentrated hydrochloric acid=15:1. 10% Pd-C (60 mg) was added to the solution, followed by hydrogenation for 3.5 hr. Pd-C was removed by filtration through Celite. The filtrate was concentrated under the reduced pressure. Water was then added the residue. The mixture was extracted with ethyl acetate. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation to give 2-cyclohexyl-3,4-dihydro-2H-isoquinolin-1-one (168 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:18][O:19][C:20]([C:22]1[S:26][C:25]2[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:24]=2[CH:23]=1)=[O:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:18][O:19][C:20]([C:22]1[S:26][C:25]2[C:27]([NH:31][C:6]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:8])=[CH:28][CH:29]=[CH:30][C:24]=2[CH:23]=1)=[O:21]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: COC(=O)c1cc2cccc(N)c2s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cccc(NC(=O)c3ccc(Cl)nc3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution of 6-chloronicotinic acid (1.5 eq) and triethylamine (2.0 eq) in CH2Cl2 (5 mL) was added BopCl (2.0 eq). After 15 min, 7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (87 mg) in CH2Cl2 and 4-dimethylaminopyridine (DMAP) (1.0 eq) were added to the reaction solution above. The reaction was stirred at room temperature 12 h. The reaction was then diluted with EtOAc, and washed with NaHCO3 solution and brine. The organics were dried over MgSO4, filtered and concentrated to give a crude material which was purified by flash chromatography on silica gel (20%-50% EtOAc/hexane) to provide 100 mg (68%) of the desired 7-[(6-chloro-pyridine-3-carbonyl)-amino]-benzo[b]thiophene-2-carboxylic acid methyl ester as a light yellow solid.