Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([Cl:22])=[CH:20][C:19]([Br:23])=[CH:18][C:15]=1[C:16]#[N:17].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:21]([Cl:22])=[CH:20][C:19]([Br:23])=[CH:18][C:15]=1[C:16]#[N:17])=[N+:2]=[N-:3]
Reactant: N#Cc1cc(Br)cc(Cl)c1N
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(Br)cc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (3.75 g, 22.6 mmol) and 2-amino-5-bromo-3-chlorobenzonitrile (5.24 g, 22.6 mmol) in DCM (75 mL) was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (9.5 mL, 68 mmol) was added, followed by titanium (IV) chloride solution (1 N in DCM, 13.6 mL, 13.6 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 hours and then allowed to reach room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was suspended in toluene and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the title compound which was used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[O:9])[CH:5]=[CH:4][C:3]=1[N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[N:18]=[N:17]1.[OH-].[Na+].O>C(O)C>[I:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[O:9])[CH:5]=[CH:4][C:3]=1[N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[N:18]=[N:17]1
Reactant: CCOC(=O)c1cn(-c2ccc(C(=O)NCC(F)(F)F)cc2I)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NCC(F)(F)F)c1ccc(-n2cc(C(=O)O)nn2)c(I)c1
Yield: 81.3 %

Procedure:
A solution of ethyl 1-(2-iodo-4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxylate (3.39 g, 7.24 mmol) obtained in Example 379c) in ethanol (100 ml), 8M aqueous sodium hydroxide solution (7 ml) and water (15 ml) was stirred at room temperature for 18 hr. Ethanol was evaporated under reduced pressure, and the obtained residual aqueous solution was acidified (pH<3) with 6M hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration and washed with water and dried to give the title compound as a pale-yellow powder (2.59 g, 81%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[I:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[CH3:51])[NH2:47]>CN(C=O)C>[I:43][C:44]1[CH:45]=[C:46]([NH:47][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[O:8])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: O=C(O)c1ccsc1
Reactant: Cc1ccc(N)cc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccsc2)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thiophene-3-carboxylic acid (2.75 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF (25 ml) were stirred at room temperature for 15 mins. HOBT (2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DRPEA (11.2 ml, 64.35 mmol) were added and the reaction stirred at room temperature for 16 hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane/ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)thiophene-3-amide. LCMS: retention time 3.69 min, MH+ 344. NMR: δH [2H6]-DMSO 10.06,(1H, b), 8.34,(1H, m), 8.29,(1H, d), 7.70,(1H, dd), 7.66,(1H, dd), 7.62,(1H, dd), 7.30,(1H, d), 2.34,(3H, s).
Reaction SMILES: [CH3:1][C@H:2]1[C:12]([CH:13]=[CH2:14])=[CH:11][C:9](=[O:10])[C@H:8]2[C@H:3]1[CH2:4][CH2:5][C@H:6]1[C:19]([CH3:21])([CH3:20])[C:17](=[O:18])[C@@H:16]([OH:22])[CH2:15][C@@:7]12[CH3:23].C[C@H]1C(C=C)=CC(=O)[C@H]2[C@H]1CC[C@H]1C(C)(C)[C@@H](O)[C@@H](O)[C@@H](O)[C@@]12C.C[C@H]1C(C=C)=CC(=O)[C@H]2[C@H]1CC[C@H]1C(C)(C)[C@@H](O)C[C@@H](O)[C@@]12C>>[CH3:1][C@H:2]1[C:12]([CH:13]=[CH2:14])=[CH:11][C:9](=[O:10])[C@H:8]2[C@H:3]1[CH2:4][CH2:5][C@H:6]1[C:19]([CH3:21])([CH3:20])[C@@H:17]([OH:18])[C:16](=[O:22])[CH2:15][C@@:7]12[CH3:23]
Reactant: C=CC1=CC(=O)[C@H]2[C@@H](CC[C@H]3C(C)(C)C(=O)[C@@H](O)C[C@]23C)[C@H]1C
Agent: C=CC1=CC(=O)[C@H]2[C@@H](CC[C@H]3C(C)(C)[C@@H](O)C[C@@H](O)[C@]23C)[C@H]1C
Agent: C=CC1=CC(=O)[C@H]2[C@@H](CC[C@H]3C(C)(C)[C@@H](O)[C@@H](O)[C@@H](O)[C@]23C)[C@H]1C
Product: C=CC1=CC(=O)[C@H]2[C@@H](CC[C@H]3C(C)(C)[C@@H](O)C(=O)C[C@]23C)[C@H]1C
Yield: 40 %

Procedure:
According to fractionating by the above three-step high performance liquid chromatography (HPLC), about 20 mg of phytocassane A, about 10 mg of phytocassane B, about 3 mg of phytocassane C and about 8 mg of phytocassane D were obtained as a single phytocassane fraction.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=2)[CH2:48][CH2:47]1.Cl>CN(C)C=O.O>[C:57]([C:56]1[CH:55]=[CH:54][C:53]([CH2:52][N:49]2[CH2:48][CH2:47][CH:46]([NH:45][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)=[O:11])[CH2:51][CH2:50]2)=[CH:60][CH:59]=1)#[N:58]
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NC2CCN(Cc3ccc(C#N)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a stirred mixture of 4-(methoxycarbonyl)benzoic acid (1 g, 5.55 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added triethylamine (2.6 ml, 18.32 mmol), HATU (2.32 g, 6.11 mmol), and 4-((4-aminopiperidin-1-yl)methyl)benzonitrile as its HCl salt (1.6 g, 5.55 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration, purified by column chromatography to yield 0.91 g (44%) of methyl 4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoate as a white solid. LCMS (m/z): 379 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([O:12]/[N:13]=[C:14](/[C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)\[C:15]([OH:17])=[O:16])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]CO.C1CCC1>CS(C)=O>[C:1]([O:5][C:6]([C:8]1([O:12]/[N:13]=[C:14](/[C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)\[C:15]([O:17][CH3:23])=[O:16])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)O)c2ccco2)CCC1
Agent: C1CCC1
Solvent: CS(C)=O
Product: COC(=O)/C(=N\OC1(C(=O)OC(C)(C)C)CCC1)c1ccco1
Yield: 98 %

Procedure:
This compound was prepared from Z-2-(1-tertbutyloxycarbonylcyclobutyloxyimino)-2-(fur-2-yl)acetic acid as described in Preparation 7(a). λmax (EtOH) 281.5 nm (ε17,000), νmax (Nujol) 1745 (--CO2R), 1723 cm-1 (α,β-unsaturated --CO2R), τ(DMSO d6) 8.59 (--C(Me)3), 7.3-8.4 (cyclobutane), 2.1, 3.15, 3.35 (furyl), 6.09 (--CO2CH3). Yield 98%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:24][CH2:25][C@@H:26]1[CH2:30][C@@H:29]([OH:31])[CH2:28][N:27]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:24][CH2:25][C@@H:26]2[CH2:30][C@@H:29]([OH:31])[CH2:28][N:27]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:4]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCCl
Reactant: Oc1ccc(Br)cc1CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(Br)cc1CCc1ccccc1
Yield: 33.6 %

Procedure:
500 mg of 4-bromo-2-(2-phenylethyl)phenol were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 220 mg of potassium t-butoxide and 440 mg of (2S,4R)-2-(2-chloroethyl)-1-ethoxycarbonyl-4-hydroxypyrrolidine and extracted in the same manner as described in step (a) of Example 1. The resulting oily substance was purified by silica gel column chromatography, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 280 mg (yield 34%) of the title compound as an oily substance.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH3:31][C:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][NH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:36]4[C:32]([CH3:31])=[N:33][NH:34][CH:35]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(-c3c[nH]nc3C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Yield: 15 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (100 mg, 0.191 mmol) in 1,4-dioxane (2 mL) was added 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (59.6 mg, 0.286 mmol), bis(triphenylphosphine)palladium(II) chloride (13.40 mg, 0.019 mmol) and potassium carbonate (79 mg, 0.573 mmol). Water (1 mL) was added and the mixture heated at 100° C. in a microwave for 15 min (×2). The solvent was removed in vacuo and the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase re-extracted with ethyl acetate (2×20 mL). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-80% ethyl acetate in cyclohexane and then further purified using MDAP (acidic conditions), to give the title compound (15 mg). LCMS (A) m/z: 525 [M+1]+, Rt 1.23 min (acidic).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][C:24]([F:26])([F:27])[F:25])(=[O:15])=[O:16])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2OC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Sulfur trioxide pyridine complex (720 mg, 4.5 mmol) was added to a solution of 3-[5-methyl-3-(2-trifluoromethoxyphenylsulfonyloxy)phenoxy]propanol (610 mg, 1.5 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.6 mL, 4.7 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in anhydrous dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (CH2Cl2) to give the title compound as a colorless oil (480 mg, 79%). 1H-NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.73 (t, J=8.2 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.62 (s, 1H), 6.54 (s, 1H), 6.47 (s, 1H), 4.20 (t, J=6.1 Hz, 2H), 2.87 (t, J=6.1, 2H), 2.26 (s, 3H).
Reaction SMILES: [CH:1]12[N:8](C(OC(C)(C)C)=O)[CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:16]([O:18][CH2:19][CH:20]1[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:2]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:5]12[NH:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:16]([O:18][CH2:19][CH:20]1[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:4]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)OCC1c3ccccc3-c3ccccc31)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CC2CCC(C1)N2
Reaction time: 1 h

Procedure:
A solution of 3-(9H-fluoren-9-yl)methyl 8-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate in DCM (2 mL) from the step 1 was treated dropwise with TFA (2.2 g, 1.5 mL, 19.5 mmol) at room temperature and the reaction mixture was stirred for 1 h. The solvents were removed under reduced pressure and the crude material was dissolved in 1 N HCl (2 mL) and washed with ether. The solution was basified with saturated bicarbonate solution and the aqueous layer was extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated to obtain a solution of (9H-fluoren-9-yl)methyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate in DCM (2 mL), which was used directly for the next step. LC/MS m/z 335.5 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].N#N.[O-:11][CH2:12]C.[Na+].C(OCC)=O.Cl>C(O)C.O>[O:11]=[CH:12][CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:7]#[N:8]
Reactant: N#CCc1cccs1
Reactant: CC[O-]
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: CCOC=O
Solvent: O
Solvent: CCO
Product: N#CC(C=O)c1cccs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Thiophen-2-yl-acetonitrile [20893-30-5] (6.7 mL, 62.6 mmol) was added to a N2 blanketed, 0° C., stirred solution of 21 wt % sodium ethoxide (25.7 mL, 68.9 mmol) in ethanol (100 mL). After 5 minutes, ethyl formate [109-94-4] (12.6 mL, 156.7 mmol) was added and the resultant solution was stirred for 20 minutes. The ice bath was then removed and replaced with a heating mantle. The reaction was heated to reflux for 2 h, cooled, and evaporated to provide a yellow solid. Crude product was dissolved in water, the solution chilled to 0° C. and acidified with aqueous hydrochloric acid to precipitate an off white powder. Product was isolated by filtration, washed with water, and dried to afford 7.4 g. LRMS (ESI) m/z 152.0 [(M+H)]+, calc'd for C7H6NOS: 151.19
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:18])[S:12][CH2:13][C:14](=O)[CH2:15][Cl:16].Cl>CO>[Cl:16][CH2:15][C:14]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[C:11](=[S:18])[S:12][CH:13]=1
Reactant: O=C(CCl)CSC(=S)Nc1ccc(F)c(F)c1F
Agent: Cl
Solvent: CO
Product: Fc1ccc(-n2c(CCl)csc2=S)c(F)c1F
Yield: 69 %

Procedure:
3-Chloro-2-oxopropyl N-(2,3,4-trifluorophenyl)dithiocarbamate (4.0 g) prepared in the same manner as in Reference Example 6 was added to 30% HCl in methanol (15 ml) and the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure and to the residue was added cooled water and the solution was extracted with chloroform. The extract was washed with a NaCl solution, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from cyclohexane to give the title compound (2.6 g) as pale yellow crystals, m.p. 127°-130° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.Cl.[CH:13]12[NH:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][O:15][CH2:14]2.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:20]2[CH:13]3[CH2:19][CH2:18][CH:17]2[CH2:16][O:15][CH2:14]3)[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(N2C3CCC2COC3)c2nc[nH]c2n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
A mixture of 2,6-dichloro-9H-purine (527 Mg, 2.79 mmol), 3-Oxa-8-aza-bicyclo[3.2.1]octane hydrochloride (500 mg, 3.34 mmol) and DIPEA (1.2 mL, 6.98 mmol) in IMS (15 mL) were heated at 80° C. for 3 h then stirred at r.t. for 18 h. The resulting precipitate was collected by filtration and washed with further IMS. The resulting solid was dried in vacuo affording the title compound (663 mg, 90%). 1H NMR (CDCl3, 400 MHz): δ 8.14 (1 H, s), 5.60 (1 H, brd s), 4.80 (1 H, brd s), 3.66 (4 H, brd s), 2.00 (4 H, s)
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH2:15][CH2:16][NH:17][C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[C:7]=2[N:25]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH2:15][CH2:16][NH:17][C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[C:7]=2[N:25]=1
Reactant: COc1ccc2c(n1)c(CCNC(=O)c1ccco1)c1n2CCCC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(NCCc1c2n(c3ccc(O)nc13)CCCC2)c1ccco1

Procedure:
Under argon and in an anhydrous medium, 0.884 mmol of the compound obtained in Example 16 is dissolved in 16 ml of dichloromethane, and then 4.42 mmol of aluminium chloride are added. The reaction mixture is stirred at reflux for 18 hours. The reaction mixture is hydrolysed, and then neutralised with a sodium hydrogen carbonate solution. After extraction with dichloromethane, the organic phases are dried over magnesium sulphate and evaporated in vacuo. The resulting residue is washed with hexane and diethyl ether to yield the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Cl[CH2:13][C:14]([OH:16])=[O:15].[OH-].[Na+]>O>[C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:13][C:14]([OH:16])=[O:15])(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1cc(Br)ccc1OCC(=O)O
Temperature: 25 °C

Procedure:
A solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (9.53 mmol) in water (70 mL) was treated with chloroacetic acid (11.64 mmol) and a solution of NaOH (21.25 mmol) in water (20 mL). The resulting yellow suspension was flushed with N2 and stirred at reflux overnight. Analysis by LCMS indicated the consumption of starting material and desired product formation. The reaction was cooled to room temperature and then acidified to pH˜3 with 1N aq HCl. The mixture was then cooled to 0° C. resulting in precipitate formation. A grey sticky solid was filtered and used without further purification. MS(ES)+ m/e 273/275 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20](OCC)=[O:21]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti]>[C:1]1([CH2:7][CH2:8][N:9]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:20]=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC=O
Reactant: CC1(C)CC(NCCc2ccccc2)CC(C)(C)N1
Agent: [Ti]
Solvent: CCCCO
Product: CC1(C)CC(N(C=O)CCc2ccccc2)CC(C)(C)N1

Procedure:
114 g of 4-(N-phenylethylamino)-2,2,6,6-tetramethylpiperidine and 41.3 g of tetrabutyl orthotitanate in 220 ml of ethyl formate were refluxed for 14.5 hours. After the volatile constituents had been distilled off at 140° C./1 mmHg, the solidified residue was recrystallized from petroleum ether. 4-(N-phenylethyl-N-formylamino)-2,2,6,6-tetramethylpiperidine of melting point 86° C. was isolated.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].Br[C:38]1[N:39]=[C:40]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([C:54]([N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[O:55])=[CH:50][CH:49]=2)[C:41]2[N:42]([CH:44]=[CH:45][N:46]=2)[CH:43]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:38]3[N:39]=[C:40]([NH:47][C:48]4[CH:49]=[CH:50][C:51]([C:54]([N:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)=[O:55])=[CH:52][CH:53]=4)[C:41]4[N:42]([CH:44]=[CH:45][N:46]=4)[CH:43]=3)[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22])[N:9]=[CH:8]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: O=C(c1ccc(Nc2nc(Br)cn3ccnc23)cc1)N1CCOCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cn3ccnc3c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Yield: 92.8 %

Procedure:
A solution of acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzyl ester (491.3 mg, 1 mmol), [4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-morpholin-4-yl-methanone (200 mg, 0.5 mmol), K2CO3 (137 mg, 1 mmol), Pd2(dba)3 (45.4 mg, 0.05 mmol) and X-Phos (94.5 mg, 0.2 mmol) in 30 mL dioxane and 10 mL water was stirred at 90° C. overnight. The crude reaction mixture was filtered. The filtrate was evaporated and the resulting residue was purified through a silica-gel column (ethyl acetate:petroleum ether=1:2) to give compound the desired product as a yellow oil (320 mg, 93% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:12]2[N:13](C#CC)[CH:14]=[CH:15][C:16](=[O:17])[C:11]=2[C:10]2[CH:21]=[C:22]([CH3:24])[O:23][C:9]=2[C:8](=[O:25])[CH:7]=1)=[O:5])C>Cl>[O:25]=[C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:12]2[NH:13][CH:14]=[CH:15][C:16](=[O:17])[C:11]=2[C:10]2[CH:21]=[C:22]([CH3:24])[O:23][C:9]1=2
Reactant: CC#Cn1ccc(=O)c2c3cc(C)oc3c(=O)cc(C(=O)OCC)c21
Agent: Cl
Product: Cc1cc2c(o1)c(=O)cc(C(=O)O)c1[nH]ccc(=O)c12
Temperature: 25 °C

Procedure:
A mixture of 7,10-dihydro-4,10-dioxo-2-methyl-7-propynyl-4H-furo[3', 2': 3,4]cyclohepta[1,2-b]pyridine-6-carboxylic acid ethyl ester (2.0 g, described in Example 24) and 19% hydrochloric acid (60 ml) is refluxed for 45 minutes and cooled to room temperature. The precipitate of the title compound is collected, washed with acetone and crystallized from pyridine to obtain crystals of the pyridine salt of the title compound, mp 292°-295° C.