Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:44]CC)([O:41]CC)([O:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C:22]3[N:23]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])[C:24](=[O:33])[C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:32])[N:12]=2)[CH:5]=1)=[O:2].C[Si](Br)(C)C>CC#N>[P:1]([OH:41])([OH:44])([O:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C:22]3[N:23]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])[C:24](=[O:33])[C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:32])[N:12]=2)[CH:5]=1)=[O:2]
Reactant: CCOP(=O)(OCC)Oc1cc(F)cc(-c2nn(Cc3cc4cccc(C)c4c(=O)n3-c3ccccc3C)c3ncnc(N)c23)c1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: Cc1ccccc1-n1c(Cn2nc(-c3cc(F)cc(OP(=O)(O)O)c3)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
3-(4-Amino-1-((8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenyl diethyl phosphate 4302 (170 mg, 0.26 mmol) was dissolved in anhydrous CH3CN (5 mL) and cooled to 0° C. under an argon atmosphere. TMSBr (0.34 mL, 2.64 mmol) was slowly added via a syringe and the resulting mixture was stirred from 0° C. to RT for 16 h. LC-MS showed small amount of starting material left, additional amount of TMSBr (0.1 mL) was added and stirred at RT for 5 h. LC-MS showed the complete conversion. The mixture was concentrated in vacuo, and the residue was dissolved in Et2O (10 mL) and H2O (0.5 mL) and stirred for 30 min. The mixture was concentrated in vacuo to affords the desired product, 3-(4-amino-1-((8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenyl dihydrogen phosphate 4903 (140 mg, 91% yield).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]=[CH:3][C:2]=1[C:11]([O:13]C)=O.[Cl-].[Mg+2].[Cl-].[CH3:18][NH:19][CH3:20].Cl>C1COCC1.O>[CH3:18][N:19]([CH3:20])[C:11]([C:2]1[N:1]=[CH:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1)=[O:13]
Reactant: CNC
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)N(C)C)nc1
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a 2° C. slurry of dimethyl 2,5-pyridinedicarboxylate (50 g, 0.256 mol) in THF (700 mL) was added magnesium chloride (26.8 g, 0.282 mol). After stirring for 15 min, dimethylamine (2 M in THF, 256 mL, 0.512 mol) was added dropwise over 40 min. The mixture was stirred for 30 min at 2° C. and then at room temperature for 1 h. To the mixture was added water (100 mL) and 1 N HCl (300 mL). The mixture was extracted with ethyl acetate (4×400 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide 53 g (100%) of methyl 6-[(dimethylamino)carbonyl]-3-pyridine carboxylate a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][CH2:11][NH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:21]([O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>O.O1CCOCC1>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:21]([O:23][CH2:24][CH:25]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a stirred solution of N-(3-aminopropyl)-N-methylcarbamic acid tert-butyl ester (2.00 g, 10.6 mmol) and sodium carbonate (2.81 g, 26.6 mmol) in water (7 mL) at 0° C. was added a solution of 9-fluorenylmethyl chloroformate (2.75 g, 10.6 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature for 2 h and then poured into water (10 mL). This mixture was extracted with diethyl ether (2×50 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a clear oil. The oil was purified by silica gel flash chromatography (0-70% EtOAc in hexanes) to give the title compound (4.24 g, 77% yield) as a clear oil (product contained a minor impurity, but was used without further purification).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol), pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Acetyl chloride (0.18 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 18 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.052 g, 24%). 1H NMR (Acetone d6, 400 MHz) δ 8.23 (d, J=9 Hz, 2 H), 8.02 (d, J=9 Hz, 2 H), 7.54 (d, J=9 Hz, 1 H), 7.01 (d, J=9 Hz, 1 H), 5.74 (d, J=9 Hz, 1 H), 5.68-5.62 (m, 1H), (dd, J=9 and 5 Hz, 1H), 2.37 (s, 3 H), 2.04 (s, 3H), 1.47 (d, J=6 Hz, 3 H).
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=[N:2]1.[NH2:9][C:10]1[N:15]=[CH:14][C:13]2[C:16]([CH3:24])([CH3:23])[C:17](=[O:22])[N:18]([CH:19]3[CH2:21][CH2:20]3)[C:12]=2[CH:11]=1>>[CH:19]1([N:18]2[C:12]3[CH:11]=[C:10]([NH:9][C:6]([C:5]4[O:1][N:2]=[CH:3][CH:4]=4)=[O:8])[N:15]=[CH:14][C:13]=3[C:16]([CH3:23])([CH3:24])[C:17]2=[O:22])[CH2:21][CH2:20]1
Reactant: O=C(O)c1ccno1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Product: CC1(C)C(=O)N(C2CC2)c2cc(NC(=O)c3ccno3)ncc21

Procedure:
Prepared in analogy to example 26 from isoxazole-5-carboxylic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as light yellow solid.
Reaction SMILES: [NH2:1][O:2][CH2:3][C:4]([CH3:10])([CH3:9])[C:5]([NH:7][CH3:8])=[O:6].[F:11][C:12]1[C:13]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])=[C:14]([CH:22]=[C:23]([CH:26]=O)[C:24]=1[F:25])[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16]>>[F:11][C:12]1[C:13]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])=[C:14]([CH:22]=[C:23]([CH:26]=[N:1][O:2][CH2:3][C:4]([CH3:10])([C:5](=[O:6])[NH:7][CH3:8])[CH3:9])[C:24]=1[F:25])[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16]
Reactant: CNC(=O)C(C)(C)CON
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Product: CNC(=O)C(C)(C)CON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F

Procedure:
The title compound was synthesized as a mixture of E/Z geometric isomers, using the procedure described in Step C of Example 19, from 3-aminooxy-2,2,N-trimethyl-propionamide obtained in Step B and 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy-benzamide obtained in Step F of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:35]CN(CC)CC.C=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]5)=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3c(-c4cnc(N5CCNCC5)c(C(F)(F)F)c4)cnc3s2)cc1OC
Reactant: CCN(CC)CC
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-c2nn3c(-c4cnc(N5CCN(C)CC5)c(C(F)(F)F)c4)cnc3s2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a mixture of 2-(3,4-Dimethoxy-phenyl)-5-(6-piperazin-1-yl-5-trifluoromethyl-pyridin-3-yl)-imidazo[2,1-b][1,3,4]thiadiazole (105 mg, 0.199 mmol, 1 eq), Et3N (0.056 mL, 0.399 mmol, 2 eq), formaldehyde (0.180 mL, 2.39 mmol, 12 eq) and acetic acid (0.02 mL, 0.239 mmol, 1.2 eq) in MeOH (4 mL) was added Sodium cyanoborohydride (0.175 g, 2.79 mmol, 14 eq). The reaction mixture was stirred at rt for 2 h. Solvents were evaporated to dryness and the residue was dissolved in sat NaHCO3/EtOAc. Layers were separated and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried, filtered and evaporated. The residue was purified on silica gel (isolute flash Si II, 10 g, 96:4 DCM/7N NH3 in MeOH) to give the desired product (50 mg, 50%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=3.47 min, [M+H]+ m/z 505.3; 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 8.49 (d, J=1.9 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J=1.7 Hz, 1H), 7.36 (dd, J=8.3, 2.0 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.41 (m, 4H), 2.57 (m, 4H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]([CH3:33])=[C:24]([CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:25]=2)=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]([CH3:33])=[C:24]([CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[N:25]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2ccc(-c3nc(CCN4CCCC4)c(C)o3)cc2)c(OC)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 2,4-Dimethoxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 393.2 (M+1)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:8]2[S:9][C:10]([C:12]([O:14]C)=[O:13])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.O.[OH-].[Li+].O>CO>[F:16][C:2]([F:1])([F:17])[C:3]1[C:8]2[S:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc2cccc(C(F)(F)F)c2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2cccc(C(F)(F)F)c2s1
Temperature: 75 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 800 mg of methyl 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 154 mg of lithium hydroxide monohydrate, 4 ml of water and 12 ml of methanol was stirred at 75° C. for 2 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added water, and then washed with tert-butyl methyl ether 3 times. To the aqueous layer was added concentrated hydrochloric acid, and then extracted with tert-butyl methyl ether 3 times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 632 mg of 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (the present compound 4).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5]O[CH2:3][CH2:2]1.C[C:8]1[CH:9]=[N+:10]([O-])[CH:11]=CC=1[N+]([O-])=O>>[NH:1]1[C:6]2[C:5](=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1c[n+]([O-])ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Product: c1cc2[nH]ccc2cn1

Procedure:
A process according to claim 15, wherein the adduct used is obtained by reacting 6 mols of morpholine with 3 mols of methyl or ethyl orthoformate per mol of 3-methyl-4-nitro-pyridine-1-oxide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:33]=[CH:32][C:18]3[N:19]([CH3:31])[C:20]([NH:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)=[N:21][C:17]=3[CH:16]=2)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[ClH:34].C(=O)([O-])[O-].[NH4+:39].[NH4+]>C(O)C>[ClH:34].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:33]=[CH:32][C:18]3[N:19]([CH3:31])[C:20]([NH:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]([NH2:39])=[NH:28])=[CH:25][CH:24]=4)=[N:21][C:17]=3[CH:16]=2)(=[O:12])=[O:13])[CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(Nc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(Nc2ccc(C(=N)N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 1e from 4-[(5-(quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-amino]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:18][C@H:19]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)[CH3:20])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:2]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:18][C@H:19]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)[CH3:20])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](NC(=O)c1ccc2c(ccn2Cc2ccc(Br)cc2)c1)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)c1ccc2c(ccn2Cc2ccc(-c3ccccc3)cc2)c1)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 100 %

Procedure:
A high-pressure vial was filled with the (S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide (50 mg, 0.1 mmol, 1 equiv), the phenylboronic acid (19 mg, 0.15 mmol, 1.5 equiv), K2CO3 (29 mg, 0.2 mmol, 2 equiv), Pd(PPh3)4 (12 mg, 0.01 mmol, 0.1 equiv), dioxane (1.5 mL) and water (0.3 mL). The mixture was degassed for 5 min under argon atmosphere and the vial was sealed. The reaction mixture was heated at 100° C. for 30 min under microwaves. The solution was then concentrated in vacuo, filtered and purified by preparative HPLC to afford a beige powder (50 mg, 0.1 mmol, 100%). ESI-MS (m/z): 476 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C([O-])(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH:21]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Nc1cccnc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cncc(Nc2nnc(Cc3ccncc3)c3ccccc23)c1
Temperature: 90 °C

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.565 g (6 mmol) 3-aminopyridine is heated for 3 h at 90° C. The residue is then distributed between acetate and 20% aqueous potassium carbonate solution. The organic phase dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol mixtures (49:1 to 4:1). Title compound is obtained after crystallization of the product-containing fractions from acetonitrile and drying under HV (6 h, 80° C.); m.p. 137-139° C.; ESI-MS: (M+H)+=314.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pt]=O>[C:1]1([CH2:7][CH2:8][CH:9]2[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccnc(/C=C/c2ccccc2)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[(E)-2-phenylvinyl]isonicotinate in acetic acid was added platinum oxide, followed by stirring at room temperature for 8 hours under a hydrogen atmosphere of 3 atm. The reaction mixture was filtered through Celite, and the filtrate was then concentrated under reduced pressure. To the residue were added an aqueous Na2CO3 solution, and the EtOAc was extracted. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to obtain methyl 2-(2-phenylethyl)piperidine-4-carboxylate as a colorless oil.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([CH3:32])=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[O:9][C:8]([CH2:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=1)([CH3:15])[CH2:7][CH2:6]2.CC(C)=[O:35]>O>[OH:35][C:8]([CH3:15])([CH2:7][CH2:6][C:5]1[C:10](=[O:9])[C:11]([CH3:14])=[C:12]([CH3:13])[C:3](=[O:2])[C:4]=1[CH3:32])[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:30][CH:31]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: CC(C)=O
Agent: Cl
Solvent: O
Product: CC1=C(C)C(=O)C(CCC(C)(O)COc2ccc(CC3SC(=O)NC3=O)cc2)=C(C)C1=O
Reaction time: 8 h

Procedure:
15 ml of an aqueous solution of ferric chloride acidified with hydrochloric acid [a mixture of about 65% by weight of ferric chloride (FeCl3.6H2O) and about 35% by weight of concentrated hydrochloric acid] were added dropwise, whilst ice-cooling and stirring, to a solution of 6.3 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine dissolved in 50 ml of acetone, and the resulting mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was diluted with 500 ml of water and then extracted with ethyl acetate. The extracts were combined, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by distillation under reduced pressure. The resulting residue was then purified by column chromatography through silica gel, using a 5:1 by volume mixture of benzene and ethyl acetate as the eluent, to afford 4.2 g of the title compound as a yellow powder softening at 55°-65° C.
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].O1CCOCC1.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[OH-].[Na+].O>[CH2:21]([O:28][C:29]([N:3]([CH2:1][CH3:2])[C@@H:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCN[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(C(=O)OCc1ccccc1)[C@H](Cc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
2.9 g (0.015 mole) of N-ethyl-D-phenylalanine (Example 3, Step A) are dissolved in 22.5 ml of 2N sodium hydroxide, 10 ml of dioxane are added, the mixture is cooled to 5° to 10° C., then 2.5 ml (about 0.017 mole) of benzyloxycarbonyl chloride are added and the reaction mixture is stirred for 3 hours at cooling. Subsequently it is diluted with 40 ml of water and extracted with 30 ml of a mixture of diethyl ether-petroleum ether-1:1, when a three-phase system is formed. The two lower phases are again extracted with 30 ml of diethyl ether, then the combined diethyl ether layers are washed with 20 ml of water. The aqueous layers are combined and acidified with N sulfuric acid to pH 2. The separated product is extracted three times with 30 ml of ethyl acetate. The ethyl acetate layers are combined, washed twice with 20 ml of water, dried over anhydrous sodium sulfate and evaporated on a water bath having a temperature of max. 40° C. at 15 to 20 millibars. Yield 2.7 g (55%) of an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH:19](Cl)[CH3:20]>CC(=O)CC>[Cl:18][CH2:19][CH2:20][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 70 %

Procedure:
2-Amino-3-nitrophenol (10.0 g, 64.9 mmol, commercially available from Aldrich) was dissolved in 200 mL 2-butanone, potassium carbonate (18.0 g, 0.13 mol) and dichloroethane (15 mL) were added. The suspension was refluxed for 20 hours. The reaction was allowed to cool to room temperature and filtered through a plug of Celite and the retained solid residue was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The crude material was redissolved in 200 mL of ethyl acetate, washed with water, 1N sodium hydroxide solution water, saturated sodium chloride solution dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure to give 9.8 g of 2-(2-Chloroethoxy)-6-nitroaniline (70% yield), which was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.80 (d, 1H), 6.95 (d, 1H), 6.61 (dd, 1H), 6.42 (b, 2H), 4.30 (t, 2H), 3.90 (t, 2H). MS (EI): 217 (MH+).
Reaction SMILES: CS[C:3]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1)=[N:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:25][C:26]1[CH:43]=[CH:42][C:29]([CH2:30][N:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH2:32][CH2:33][CH2:34][NH2:35])=[CH:28][CH:27]=1>N1C=CC=CC=1>[Br:25][C:26]1[CH:43]=[CH:42][C:29]([CH2:30][N:31]([CH2:32][CH2:33][CH2:34][NH:35][C:3]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[N:4][C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:28][CH:27]=1
Reactant: CSC(=NC(=O)c1ccccc1)N1CCN(c2ccccn2)CC1
Reactant: NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Solvent: c1ccncc1
Product: O=C(N=C(NCCCN(Cc1ccc(Br)cc1)c1ccccn1)N1CCN(c2ccccn2)CC1)c1ccccc1
Yield: 56.5 %

Procedure:
To a mixture of N-[methylsulfanyl-(4-(pyridin-2-yl)piperazin-1-yl)methylene]-benzamide (2.9 g, 8.52 mmol) in pyridine (50 ml) was added N1-(4-bromobenzyl)-N1-(pyridin-2-yl)-propane-1,3-diamine (3 g, 9.37 mmol) and the reaction mixture was heated at reflux for 18 h. The volatiles were evaporated in vacuo and the residue dissolved in dichloromethane (100 ml) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (600 ml) using first a mixture of ethyl acetate/triethylamine 95:5 (1 l) followed by a mixture of 20 ethyl acetate/methanol/triethylamine 90:5:5 as eluents affording 2.95 g of N-[[3-[N-(4-bromo-benzyl)-N-(pyridin-2-yl)amino]propylamino]-(4-pyridin-2-yl-piperazin-1-yl) methylene]benzamide as a foam.