Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1Br)[C:6]([O:8][CH3:9])=[O:7].[F-].[K+].[CH2:18]([O:20][C:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22])[CH3:19]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([O:20][C:18]([C:12]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[O:14][CH3:15])=[CH2:19])[CH3:22]
Reactant: COC(=O)c1cc(OC)c(Br)c(OC)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(OC)cc(C(=O)OC)cc1OC
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Methyl 3,5-dimethoxy-4-bromobenzoate (500 mg) was dissolved in toluene in a nitrogen atmosphere, and 1-ethoxyvinyltributyltin (742 μL) and tetrakis(triphenylphosphine)palladium (211 mg) were added to it, and stirred overnight at 110° C. The reaction liquid was cooled to room temperature, then aqueous potassium fluoride solution was added to it, and stirred at room temperature. The reaction liquid was filtered through Celite, the Celite was washed with ethyl acetate, and the filtrate was washed with saturated saline water. The organic layer was dried with sodium sulfate, the sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 85/15) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.[CH2:8]([N:10]([CH2:15][CH2:16][CH2:17]Cl)[C:11](=[O:14])[CH2:12][CH3:13])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:17][CH2:16][CH2:15][N:10]([CH2:8][CH3:9])[C:11](=[O:14])[CH2:12][CH3:13])=[N:5][N:4]=[N:3]1
Reactant: CCC(=O)N(CC)CCCCl
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)N(CC)CCCSc1nnnn1C
Yield: 23 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (2.4 g) and N-ethyl-N-propionyl-3-chloropropylamine (3.6 g) are dissolved in acetone (50 ml). To the mixture are added potassium carbonate (2.8 g) and potassium iodide (0.1 g), and the mixture is refluxed for 4 hours. After acetone is distilled off, the residue is added to water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over sodium sulfate. After chloroform is distilled off, the residue is purified by column chromatography (neutral alumina, made by Merck) and eluted with n-hexane to give 1-methyl-5-[3-(N-ethyl-N-propionylamino)propylthio]-1,2,3,4-tetrazole (1.2 g) as pale yellow liquid, nD21.5 =1.5220.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C@H:28]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[CH2:38][CH2:39][C:40]([OH:43])([CH3:42])[CH3:41])[C@H:30]([CH3:44])[N:29]1[C:45](=[O:55])[CH2:46][C:47]1[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:54])(C(C)(C)C)(C)C>O1CCCC1.CC(O)C>[Cl:54][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]([Cl:53])[C:47]=1[CH2:46][C:45]([N:29]1[C@@H:28]([CH2:27][OH:26])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[CH2:38][CH2:39][C:40]([OH:43])([CH3:41])[CH3:42])[C@@H:30]1[CH3:44])=[O:55]
Reactant: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO)N1C(=O)Cc1c(Cl)cccc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
Add tetra-n-butylammonium fluoride (651.71 mL, 651.71 mmol, 1M in THF) to a solution of 1-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone (400 g, 566.71 mmol) in tetrahydrofuran (4 L) at 5° C. in an appropriate vessel. Heat the mixture to 20° C. and stir. After 3 hours, remove 3 L of tetrahydrofuran by concentrating under reduced pressure and dilute the residues with ethyl acetate (2.5 L). Wash the organics with saturated aqueous ammonium chloride (2 L), water (2 L) and brine (2×2 L). Dry the ethyl acetate solution over anhydrous sodium sulfate and concentrate under reduced pressure to give an oil. Dissolve this oil in 2-propanol (2.5 L) and concentrate under reduced pressure to give an oil. Purify by chiral SFC using AS-H column (50×250 mm, 5 micron particle size) eluting with 80% supercritical carbon dioxide and 20% of a 0.2% solution of diethylmethylamine in isopropyl alcohol at 280 g/min to give the title compound (182.8 g, 389.62 mmol). MS (m/z): 450.2 (M+1 (35C1)), 452.2 (M+1 (37Cl)). Optical rotation: [α]20D −39.4° (c=0.95, MeOH).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH3:15]O>OS(O)(=O)=O>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][OH:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CO)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 36 h

Procedure:
4-Hydroxymethyl-3-nitro-benzoic acid (step (a), 2.0 g, 10.2 mmol) was dissolved in 100 mL of MeOH, treated with 10 drops of concentrated H2SO4 and stirred at 70° C. After 36 h, the solution was concentrated in vacuo and redissolved in EtOAc. The EtOAc solution was washed with 1N NaOH and brine, dried over MgSO4, and concentrated to afford the title compound as a light-yellow solid upon drying under vacuum. MS m/z: 210.1 (M−1).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1>CN1CCCC1=O.O>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:22][CH:23]=1)[CH3:29]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CCOc1ccc(CCBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.001 mol) was dissolved in N-methyl 2-pyrolidone (3.0 mL), powdered potassium hydroxide (0.448 g, 0.008 mol) was added and heated at 120° C. for 2 h. 1-(2-Bromo-ethyl)-4-ethoxy-benzene (0.228 g, 0.001 mol) was added at the same temperature and stir for 3 h. at RT (TLC showed incomplete reaction). Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as light yellow oil (0.035 g, 10% yield). 5-[2-(4-Ethoxy-phenyl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.035 g, 0.0001 mol) was dissolved in THF (0.5 mL), A solution of oxalic acid dihydrate (0.013 g, 0.0001 mol) in THF (0.5 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.015 g, 34% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][S:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]3[CH:30]=[CH:29][C:26]4[S:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=4[N:32]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1CSc2ccc(CNC3CCN(CCn4c(=O)cnc5ccc(F)cc54)CC3)nc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To 10 mL of a chloroform solution containing 183 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 114 mg of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde, 36 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 228 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=100:1] to give 135 mg of 7-fluoro-1-(2-(4-((3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1.[OH-].[Na+].[F:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([C:30]([O:32]C)=[O:31])[CH:26]=[C:25]2B1OC(C)(C)C(C)(C)O1>C1COCC1.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].C(Cl)Cl.CO.O>[F:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([C:30]([OH:32])=[O:31])[CH:26]=[C:25]2[CH2:8][C:9]1[CH:14]=[N:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1
Reactant: COc1ccc(CCl)cn1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c2cccc(F)c2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cc2cc(C(=O)O)nc3c(F)cccc23)cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a mixture of the above compound (S1) (130 mg, 0.393 mmol) and Pd(dppf)Cl2-CH2Cl2 adduct (32.1 mg, 0.039 mmol) and Cs2CO3 (384 mg, 1.178 mmol) in a microwave tube was add a solution of 5-(chloromethyl)-2-methoxypyridine (124 mg, 0.785 mmol) in THF (3 mL) followed by water (0.3 mL). The mixture was heated at 100° C. for 1 h. LC-MS indicated the product (S2) existed as a mixture of both desired ester (ES-MS [M+1]+: 327.2) and hydrolyzed acid (ES-MS [M+1]+: 313.2). The mixture was transferred to a 100 mL round-bottom flask followed by adding MeOH (11 mL) and NaOH (1 N in H2O, 4.5 mL). The reaction was stirred at room temperature for 1 h to allow the complete conversion of the remaining ester to the acid. The solvents were removed to provide crude 8-fluoro-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxylic acid (S3). ES-MS [M+1]+: 313.2.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C>[Cl:19][C:18]1[C:13]2[CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=3)[NH:20][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Reaction time: 1 h

Procedure:
To a suspension of 30.0 g (100 mmol) 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester (WO 97/02266) in 450 ml dry THF at 10° C. under N2-atmosphere, 500 ml diisobutyl-aluminium hydride (1 M in THF) were added dropwise. The resulting clear solution is stirred for 1 h and then diluted with 2.1 l of dry THF. Then 98 ml of ethyl acetate are added, followed after 15 min by 45 ml of water and after 1 h by 22.5 ml of 4 N sodium hydroxide. After 1 h stirring, 200 g of Na2SO4 are added and stirring is continued for another hour. The mixture is filtered through Celite (Fluka, Buchs, Switzerland), the residue washed with THF and discarded. Concentration of the filtrate to a volume of ≈0.1 l, addition of 0.3 l of dichloromethane and filtration yields the title compound; Analysis for C13H10ClN3O: calc. C 60.13%, H, 3.88%, N, 16.18%, Cl 13.65%; found C, 60.23%, H 4.03%, N 16.51%, Cl 13.28%.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([N:10]2[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1.CCCCCC.C(OCC)(=O)C>O.C(O)C>[Cl:3][C:4]1[C:5]([N:10]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([C:20]([F:23])([F:21])[F:22])=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Potassium hydroxide (0.5 g, 85%, 2.28 mmol) in water (1 mL) was added to ethyl 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (i.e. the product of Step D) (0.66 g, 2.07 mmol) in ethanol (3 mL). After about 30 minutes, the solvent was removed under reduced pressure, and the mixture was dissolved in water (40 mL). The solution was washed with ethyl acetate (20 mL). The aqueous layer was acidified with concentrated hydrochloric acid and was extracted with ethyl acetate (3×20 mL). The combined extracts were dried and evaporated to give the product, as a solid (0.53 g, 93% yield), m.p. 178-179° C. (after crystallization from hexane-ethyl acetate).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=O)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:14][OH:15]>C(O)C.N1C=CC=CC=1>[O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[N:14][OH:15])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCOc2ccccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1CCCOc2ccccc21
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A solution of 10.0 g (62 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one (J. Chem. Soc., Perkin Trans. 1 (1991), 2763) and 4.63 g (68 mmol) of hydroxylamine hydrochloride in 45 ml of ethanol and 45 ml of pyridine was heated under reflux for 5 h. After distilling off the solvents on a rotary evaporator, the residue was treated with water, adjusted to pH 2 with dil hydrochloric acid and stirred for 3 h. After filtering off the precipitated product with suction and drying it, 10.2 g of 3,4-dihydro-1-benzoxepin-5(2H)-one oxime were obtained, m.p. 96-98° C. b) A solution of 2.0 g (11.3 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one oxime in 15 ml of 1,2-dimethoxyethane (DME) was added dropwise at 0° C. under argon to a mixture of 4.5 g (23.7 mmol) of titanium tetrachloride and 1.79 g (47.4 mmol) of sodium borohydride in 50 ml of DME over the course of 20 min. After stirring at RT for 2 days, 100 ml of water were added dropwise and the mixture was rendered alkaline using conc. ammonia solution. After filtering off the precipitate with suction, the filtrate was extracted three times with EA. After washing with sodium chloride solution, drying over magnesium sulfate and concentrating, 2.1 g of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine were obtained. c) 0.86 g (6.7 mmol) of ethanesulfonyl chloride was added dropwise with ice cooling to a solution of 1.0 g (6.1 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine and 2.5 g (24 mmol) of triethylamine in 20 ml of THF. The mixture was allowed to come to room temperature and was stirred overnight, and the solvent was distilled off in vacuo. After stirring the residue with water, the deposited product was filtered off with suction. 1.1 g of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-berzoxepine were obtained, m.p. 109-111° C. d) A solution of 1.0 g (3.9 mmol) of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF were added dropwise under nitrogen to a suspension of 0.16 g (5.4 mmol) of 80 percent sodium hydride in 10 ml of THF. After stirring at RT for 3 h, 1.6 g (11 mmol) of methyl iodide were added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. The organic phase was concentrated in vacuo after drying over sodium sulfate. 1.0 g of 5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 122-124° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[N:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:19][N:18]=4)[CH:12]=3)[C:6]=2[CH:32]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:33][N:34]1[CH:38]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[N:8][N:7]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]5[N:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)=[CH:21][N:22]=5)[CH:12]=4)[C:6]=3[CH:32]=2)[CH:36]=[N:35]1
Reactant: Brc1ccc2nnn(Cc3cccc(-c4ncc(OCCN5CCOCC5)cn4)c3)c2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2ccc3nnn(Cc4cccc(-c5ncc(OCCN6CCOCC6)cn5)c4)c3c2)cn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
200 mg (0.352 mmol) of 6-bromo-1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-1H-benzotriazole, 80.6 mg (0.387 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 150 mg (0.704 mmol) of tripotassium phosphate trihydrate are suspended in 6 ml of ethylene glycol dimethyl ether, degassed evacuated and flushed with nitrogen a number of times. 24.7 mg (0.035 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, and the mixture is again evacuated and flushed with nitrogen. The reaction mixture is stirred at 80° C. for 24 h. Water is added to the reaction mixture, which is then rendered basic using 32% NaOH and extracted with DCM. The organic phase is dried over sodium sulfate, evaporated under reduced pressure in a rotary evaporator and purified by column chromatography on silica gel; yield: 41 mg, HPLC: Rt=2.08 min (method C), LC-MS: [M+H]+=497;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)[N:21]=3)[CH2:16][CH:15]2[C:40](=[O:49])[N:41]([CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=C)[CH3:42])=[O:13])[CH2:8][CH:7]1[CH:9]=C)=[O:5])[CH3:2].N#N>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:47][CH2:46][CH2:45][CH2:44][CH2:43][N:41]([CH3:42])[C:40](=[O:49])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)[N:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-c3cccc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: N#N
Solvent: ClCCCl
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3nc(-c4cccc(F)c4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Temperature: 25 °C
Yield: 69.4 %

Procedure:
The diene 157 (0.70 g, 1.041 mmol) was dissolved in dry DCE (0.7 L). The solution was put under inert atmosphere (N2) and catalyst (Hoveyda Grubbs 2nd generation, 70 mg, 0.113 mmol) was added to the solution. The reaction mixture was refluxed for 16 h, cooled to room temperature and evaporated on silica by rotary evaporation. The product was purified by flash chromatography (heptane:ethyl acetate 1:1) which gave the title compound (0.466 g, 70%), LRMS (M+H) 645.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[C:26]([F:29])([F:28])[F:27].Cl.N1C=CC=CC=1.C(OCCO)C>>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[CH:21][C:20]=1[C:26]([F:27])([F:28])[F:29]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)c(C(F)(F)F)c3)c2cc1OC
Temperature: 139 °C
Yield: 65.2 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.215 g of 4-chloro-3-trifluoromethylaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 1.5 hours; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of IM NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.266 g (65.5%) of the desired product as cream crystals. MP 265-267° C.;: mass spectrum (electrospray, m/e,): 408.2(M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:63]1(=[O:69])[O:68][C:66](=[O:67])[CH2:65][CH2:64]1.O>N1C=CC=CC=1>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([O:40][C:63]([CH2:64][CH2:65][C:66]([OH:68])=[O:67])=[O:69])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](OC(=O)CCC(=O)O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reaction time: 3 h

Procedure:
After 3 hours at room temperature, a solution of 500 mg (0.59 mmole) of taxol, 900 mg (7.6 mmole) of succinic anhydride in 12 mL of pyridine is evaporated to dryness in vacuo. The residue is treated with 20 mL of water, stirred for 20 min. and filtered. The precipitate is dissolved in acetone, water slowly added, and the fine crystals collected. This yields 490 mg (86%) of title compound which showed: mp 178°-80° C., [a] -42.1° (c=1.1 EtOH); Anal. (C H NO H 0) C,H,N.