Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][NH2:11])[CH2:3][C@@H:4]([C:6](N)=[O:7])[NH2:5].FC(CCN)C[C@@H](C(N)=[O:18])N>Cl>[OH:1][CH:2]([CH2:9][CH2:10][NH2:11])[CH2:3][C@@H:4]([C:6]([OH:18])=[O:7])[NH2:5]
Reactant: NCCC(O)C[C@H](N)C(N)=O
Reactant: NCCC(F)C[C@H](N)C(N)=O
Agent: Cl
Product: NCCC(O)C[C@H](N)C(=O)O
Yield: 52 %

Procedure:
N,N'-Dicarbobenzyloxy-γ-hydroxy-L-lysine amide (2.0 g, 4.65 mmol) (described by Izumiya et al., Biochem, 4, 2501 (1965)) was placed in a Kel-F® reactor and anhydrous hydrogen fluoride (40 ml) was condensed at -78° C. Sulfur tetrafluoride (1.8 ml, 31 mmol) was condensed at -78° C. in a graduated tube attached to the reaction vessel. The cooling bath was removed and sulfur tetrafluoride was transferred into the reaction solution (cooled at -78° C.) by evaporation. The mixture was stirred at -78° C. for 5 hours and allowed to stand overnight. Hydrogen fluoride was removed by a stream of nitrogen and the residue dissolved in 30 ml of 2.5 N HCl. Insoluble material was filtered and the filtrate evaporated to dryness in vacuo to yield 1.01 g of crude 4-fluoro-L-lysine amide contaminated with unreacted 4-hydroxy-L-lysine amide. The crude amide (1.4 g) was hydrolyzed in 90 ml 2.5 N HCl by refluxing for 1.5 hours, the reaction solution was evaporated to dryness and separated by ion exchange chromatography (Dowex 50-X8 resin, 120 ml, H+ form, washed first with 500 ml water and eluted with 2.5 N HCl). The 4-hydroxy-L-lysine in strong acid formed the lactone which, being a strong base, was not eluted from the resin with 2.5 N HCl. 4-Fluoro-L-lysine.2HCl was obtained in 52% yield and >90% purity, [α]D25 +16.8° (3% in 2.5 N HCl. The monohydrochloride was obtained in 76% yield by dissolving the dihydrochloride in 15 volumes methanol and adding 50% molar excess pyridine. This material was recrystallized from isopropanol/water (2:1) to give a product with a rotation of [α]D25 +25° (2% in 2.5 N HCl) mp: 210° (discoloration), 215°-17° (d).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C(OC(C)C)(C)C>[CH:12]1([NH:15][C:10]([NH:9][C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:11])[CH2:14][CH2:13]1
Reactant: Cc1cc(C)cc(N=C=O)c1
Reactant: NC1CC1
Solvent: CC(C)OC(C)C
Product: Cc1cc(C)cc(NC(=O)NC2CC2)c1

Procedure:
14.7 g of 3,5-dimethylphenylisocyanate were slowly added by a dropper upon stirring at a temperature of 28° C. to a solution of 5.7 g of cyclopropylamine in 200 ml diisopropylether. The formed precipitate was removed by suction after an hour, was washed with a small amount of diisopropylene and finally dried. There were thus obtained 18.9 g of 1-cyclopropyl-3-(3,5-dimethylphenyl)-urea (92.5% of the theoretical value) having a melting point of 169° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[N:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:33][C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: Nc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(Nc3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 2 h

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (50 mg, 0.134 mmol), 4-pyridinamine (12.59 mg, 0.134 mmol), cesium carbonate (131 mg, 0.401 mmol), 1,4-dioxane (2 mL), palladium(II) acetate (1.501 mg, 6.69 μmmol) and BINAP (8.33 mg, 0.013 mmol), wherein the reaction time was 2 h. The final product was collected as 29 mg (50%). LCMS E-S (M+H)=432.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45-1.59 (d, J=6.8 Hz, 6 H), 2.14 (s, 3 H), 2.23 (s, 3 H), 4.36 (d, J=5.0 Hz, 2 H), 5.16 (m, 1 H), 5.91 (s, 1 H), 7.09 (s, 1 H), 7.99 (d, J=6.1 Hz, 2 H), 8.12 (s, 1 H) 8.49 (d, J=6.6 Hz, 2 H), 8.74 (t, J=5.1 Hz, 1 H), 10.58 (s, 1 H), 11.58 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@@H:16]([O:20]C(C)(C)C)[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1.C(N(CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@@H:16]([OH:20])[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)O[C@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Sc4ccccc43)CCN2C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O[C@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Sc4ccccc43)CCN2C1
Reaction time: 1 h
Yield: 72.5 %

Procedure:
8-chloro-11-[(6S,8S)-8-t-butoxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenz[b,f]-1,4-thiazepine (0.311 g, 0.704 mmol) was dissolved in trifluoroacetic acid (20 mL) and stirred for 1 hour. The trifluoroacetic acid was removed under reduced pressure and the residue dissolved in methylene chloride (20 mL). Triethylamine (0.142 g, 1.40 mmol) was then added via syringe and the reaction stirred for 1 hour, washed with water, dried (MgSO4) and evaporated to dryness to give 8-chloro-11-[(6S,8S)-8-hydroxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenz[b,f]-1,4-thiazepine as an off-white solid (0.197 g, 72%); mp 58°-60° C.; Rf (40% acetone/hexanes): 0.15; HRMS (FAB): MH+ of C20H20N3OSCl, calculated 386.1094, found 386.1085.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-].[C]>[N:15]1([CH2:14][CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: c1ccc(CN2CCOC(CN3CCCC3)C2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C1CCN(CC2CNCCO2)C1
Yield: 95 %

Procedure:
4-Benzyl-2-(pyrrolidin-1-ylmethyl)morpholine (450 mg, 1.73 mmol) prepared according to Process Step 1 was dissolved in ethanol (10 mL), and 20% palladium hydroxide-carbon (200 mg, 0.285 mmol) was suspended therein, followed by stirring under the hydrogen gas atmosphere for two days. Celite (registered trademark: 2.0 g) was suspended in the reaction mixture, the solid was separated by filtration, and the solvent was distilled off under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (chloroform:methanol=5:1) and thereby yielded 2-(pyrrolidin-1-ylmethyl)morpholine (280 mg, in a yield of 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>O1CCCC1>[CH2:17]([N:14]1[CH2:13][CH2:12][CH:11]([N:10]2[CH2:9][C:3]3[C:2](=[CH:7][CH:6]=[C:5]([OH:8])[CH:4]=3)[NH:1][C:24]2=[O:25])[CH2:16][CH2:15]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc(O)cc1CNC1CCN(Cc2ccccc2)CC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C1Nc2ccc(O)cc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A stirred solution of 4-amino-3-[(1-benzyl-piperidin-4-yl-amino)-methyl]-phenol (0.16 g, 0.51 mmol) in tetrahydrofuran (3 mL) at 0° C. was treated with carbonyl diimidazole (52 mg, 0.51 mmol). The reaction was stirred for 30 min at 0° C. and at reflux for 1 h. After cooling to room temperature, the solvent was evaporated and the residue purified by column to afford 100 mg (57%) of the desired product. LC/MS: tR=1.09 min, 338.28 (MH)+.
Reaction SMILES: [CH:1]1[CH:13]=N/C(=C\NNC(N)=S)/[C:3](=[O:4])[CH:2]=1>OS(O)(=O)=O.C(O)CCC>[C:3]([O:4][CH2:3][CH2:2][CH2:1][CH3:13])(=[O:4])[CH:2]=[CH2:1]
Reactant: NC(=S)NN/C=C1\N=CC=CC1=O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: C=CC(=O)OCCCC
Yield: 48.4 %

Procedure:
10.0 g of 30% 3-HP, 100 ml of n-butanol and 5 drops of conc. H2SO4 were mixed in a 250 ml flask. The mixture was refluxed with a Dean-Stark trap attached to remove the water. The refluxing was continued until no more water was collecting in the Dean-Stark trap. A distillation apparatus was attached and most of the n-butanol was distilled off. Next, the temperature was reduced and a vacuum applied (0.5 torr, 80° C.) to distill the remaining liquid. 1.58 g of butyl acrylate was obtained, along with some butanol. The yield of butyl acrylate was 37%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)=[O:12])[N:7]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH2:33][NH:32][CH:31]([C:37](OC)=[O:38])[CH2:30]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45]>Cl.CO>[OH:46][CH:43]([CH2:44][OH:45])[CH2:42][NH:41][C:37]([CH:31]1[CH2:30][C:29]2[C:34](=[CH:35][CH:36]=[C:27]([N:7]3[C:8]([NH:10][C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[CH:15]=4)=[O:12])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]3)[CH:28]=2)[CH2:33][NH:32]1)=[O:38]
Reactant: NCC(O)CO
Reactant: COC(=O)C1Cc2cc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Oc4cccnc4)c3)ccc2CN1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3cccnc3)c2)n(-c2ccc3c(c2)CC(C(=O)NCC(O)CO)NC3)n1
Reaction time: 8 h
Yield: 102.6 %

Procedure:
Using the same method as for Example 184, a solution of methyl 6-(3-t-butyl-5-(3-(3-(pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (0.017 g, 0.026 mmol, available in Example 179) in 3N HCl in MeOH (2 mL) was stirred at RT overnight. The solvent was evaporated and the residue was dissolved in MeOH (0.5 mL). 3-Amino-1,2-dihydroxypropane (0.200 g, 2.20 mmol) was added and the solution was kept at RT overnight. The mixture was directly loaded on to a reverse phase column and purified to yield 1-(1-(3-((2,3-dihydroxypropyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea (16 mg, 97% yield) as a yellow solid. 1H-NMR (MeOH-d4): δ 8.66 (s, 1H), 8.60 (d, 1H, J=−5.6 Hz), 8.23-8.20 (m, 1H), 8.05 (dd, 1H, J=8.8, 5.6 Hz), 7.57 (t, 1H, J=2.0 Hz), 7.52-7.40 (m, 4H), 7.23 (d, 1H, J=8.4 Hz), 6.89 (dd, 1H, J=7.6, 1.6 Hz), 6.54 (s, 1H), 4.56 (d, 1H, J=16.8 Hz), 4.51 (d, 1H, J=16.8 Hz), 4.29 (dd, 1H, J=12.0, 4.4 Hz), 3.78-3.72 (m, 1H), 3.54-3.45 (m, 5H), 1.36 (s, 9H), one proton is buried under the MeOH peak, urea, amide, amine and hydroxy protons not visible. MS expected 600.3 found 600.2
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[Cl:23][CH2:24][C:25]([N:12]([CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[CH:4]=1)[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNCCc1ccc(F)c(C#N)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CCc1ccc(F)c(C#N)c1)C(=O)CCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-Butyl (2-{[2-(3-cyano-4-fluorophenyl)ethyl]amino}ethyl)carbamate (0.9 g, 3.1 mmol) and TEA (0.4 g, 3.7 mmol) in 10 mL of anhydrous DCM was added chloroacetyl chloride (0.4 g, 3.7 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 1 h, and then the solvent was evaporated. The residue was partitioned between EtOAc and water. The organic layer was dried and evaporated. The residue was purified with prep-TLC to give tert-Butyl (2-{(chloroacetyl) [2-(3-cyano-4-fluorophenyl)ethyl]amino}ethyl)carbamate.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:8]=1[C:9](Cl)=[O:10]>CN(C)C=O.N1C=CC=CC=1>[CH3:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:8]=1[C:9]([NH:1][NH:2][C:3]([NH2:5])=[S:4])=[O:10]
Reactant: NNC(N)=S
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C(=O)NNC(N)=S)c(C)c1
Temperature: 80 °C

Procedure:
37.25 g of thiosemicarbazide was dissolved in 400 ml dimethylformamide and 32.05 g of pyridine, after which 74 g of 2,4,6-trimethylbenzoyl chloride was added at 0° C. in 20 minutes. The reaction mixture was heated at 80° C. for 2 hours and then concentrated to three-quarters in vacuo and the remaining mixture was poured into 1500 ml of cold water. The resulting white precipitate was filtered, washed in water and dried.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[N:8][N:7]4[C:2]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Product: COc1ccc(-c2nn3c(N4CCOCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 120 °C
Yield: 85 %

Procedure:
A mixture of 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (75 mg, 0.18 mmol) and morpholine (5 mL, 57 mmol) was heated at 120° C. for 4 hours, then cooled and concentrated. Flash chromatography (3:1 to 1:3 hexanes-ethyl acetate) afforded N-cyclopentyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (72 mg, 86%) as a yellow solid. 1H NMR (CDCl3): δ 8.14 (d, 1 H), 7.93 (broad, 1 H), 7.58 (d, 2 H), 7.33 (t, 1 H), 6.97 (d, 2 H), 6.35 (m, 2 H), 4.38 (m, 1 H), 3.99 (m, 4 H), 3.87 (s, 3 H), 3.50 (m, 4 H), 2.08 (m, 2 H), 1.79–1.54 (m, 6 H); MS m/z 471 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH2:4][CH2:5]Cl.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17].C(N(C(C)C)CC)(C)C.N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH2:4][CH2:5][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: COC(CCCl)c1ccc(C)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 21.2 %

Procedure:
A mixture of 3-methoxy-3-(p-tolyl)-1-chloropropane (24.9 mg, 0.126 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.126 mmol), diisopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane (2.0 mL) was stirred at 90° C. for 72 hrs. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (10.9 mg, 21.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.38 (m, 1H), 7.3–7.1 (m, 5H), 6.96 (d, 1H, J=7.4 Hz), 4.18 (apparent dd, 1H, J=5.6, 7.9 Hz), 3.24 (d, 1H, J=8.2 Hz), 3.2 (s, 3H) 3.11 (m, 2H, J=10.1 Hz), 2.49 (m, 4H), 2.35 (s, 3H), 2.3–2.1 (m, 3H), 1.92 (d, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 409.4 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6](=[O:25])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15](I)=[C:14]([Cl:24])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O>[CH:1]1([CH2:4][O:5][C:6](=[O:25])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)=[C:14]([Cl:24])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(I)c(OCC2CC2)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc(Cl)cc2)c(OCC2CC2)c1
Temperature: 100 °C
Yield: 84.1 %

Procedure:
To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.32 g, 0.67 mmol) in DME (anhydrous, 20 mL) under argon atmosphere were added 4-chlorophenylboronic acid (0.13 g, 0.83 mmol), CsF (0.24 g, 1.58 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.05 g, 0.07 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give 2-(2,4′-dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.26 g, 87%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.37 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 7.07 (s, 1H), 6.86 (s, 1H), 3.96-3.89 (m, 2H), 3.76 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.7 Hz, 1H), 2.04-1.95 (m, 1H), 1.71-1.48 (m, 2H), 1.21-1.00 (m, 2H), 0.94 (d, J=6.3 Hz, 6H), 0.55-0.48 (m, 4H), 0.27-0.15 (m, 4H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.5, 157.1, 140.8, 133.7, 133.5, 133.0, 131.8, 128.1, 127.8, 121.5, 111.1, 73.2, 69.6, 49.6, 42.6, 26.1, 22.6, 22.5, 10.0, 9.8, 3.3, 3.0.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[NH:24]1[CH2:34][CH2:33][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25]1.CN1CCCC1=O>O>[CH2:31]([O:30][C:28]([CH:27]1[CH2:33][CH2:34][N:24]([C:2]2[CH:11]=[C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=3)[N:3]=2)[CH2:25][CH2:26]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccc2nc(Cl)cc(NCc3ccc4c(c3)OCO4)c2c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCN(c2cc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Reaction time: 3 h

Procedure:
A reaction of a mixture comprising 130 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinoline, 500 μl of ethyl isonipecotate and 1 ml of N-methyl-2-pyrrolidone was conducted on an oil bath at 150° C. for 3 hours. The reaction mixture was cooled, followed by the addition of water. The resulting mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography with 20 to 50% ethyl acetate/hexane to give 150 mg of the title compound.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:19]([SH:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>ClCCl>[OH:18][C:7]1[C:8]2[C:9](=[O:17])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][C:11]=3[OH:16])[CH:2]([S:31][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCCS
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Solvent: ClCCl
Product: CCCCCCCCCCCCSC1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 85 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (75 mg) was dissolved in dichloromethane (5 ml) and 1-dodecanethiol (0.06 ml) was added. The solution was stirred at room temperature for 7 hours. Removal of the solvent gave a yellow solid which was then recrystallised from absolute ethanol to give 1,8-dihydroxy-10-dodecylthio-9-anthrone (89 mg, 85%) as pale yellow needles, melting point 76° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:40]1([S:50](Cl)(=[O:52])=[O:51])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[N:14]([S:50]([C:40]1[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=[CH:42][CH:41]=1)(=[O:52])=[O:51])[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc2ccccc12)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.015 g, 0.04 mmol) and Et3N (0.01 ml, 0.07 mmol) in anhydrous THF (0.35 ml) was added to a solution of 1-naphthalenesulfonyl chloride (0.04 mmol) in anhydrous THF (0.4 ml) at rt in a sealed reaction vessel. The resulting suspension was stirred at rt for 20 hr, then evaporated to dryness. The product was suspended in a mixture of H2O(0.4 ml) and saturated NaHCO3 solution (0.4 ml), then extracted with CH2Cl2 (3×0.75 ml). The combined extracts were evaporated to dryness to give the crude product. Purification by reverse-phase HPLC on a Primesphere C-18HC (50.0 mm×10.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN 1% TFA/H2O (85:10:5), increasing to H2O:CH3CN:1% TFA/H2O (5:90:5) at 8 min., detected on a Micromass Platform 2 mass spectrometer (DAD 190-600 nM) gave material which, after evaporation to dryness, was purified by reverse-phase HPLC on a Primesphere C-18HC (3.0 mm×2.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:TFA (99.9:0:0.1), increasing to H2O:CH3CN:TFA (0:99.9:0.1) at 4 min., detected with a UV detector (300 nM +/−90 nM and 254 nM +/−25 nM), gave an eluent that was evaporated to dryness to give the named product. MS m/e 583 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N+:9]([O-])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[C:25]([O:28]C(=O)C)(=[O:27])[CH3:26]>>[C:25]([O:28][CH:8]1[C:7]2[CH:19]=[N:20][CH:21]=[N:22][C:6]=2[C:5]2[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:9]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: [O-][N+]1=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2ncncc2C1
Product: CC(=O)OC1N=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2ncncc21

Procedure:
A mixture of 3 g (8 mmole) of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide and 50 ml of acetic anhydride was heated on the steam bath for 22 hrs. The reaction mixture was concentrated at reduced pressure to dryness and the residue was crystallized from a mixture of methylene chloride and ether to give a product of mp 211°-212° C. Recrystallization from a mixture of methylene chloride and ether gave the pure product as colorless prisms, mp 211°-212° C.