Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]([C:13](NCC2NCCCC2)=[O:14])=[C:3]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:2]=1.OC1C=CC(O)=CC=1C(O)=O.FC(F)(S([O:55][CH2:56][C:57]([F:60])([F:59])[F:58])(=O)=O)C(F)(F)C(F)(F)C(F)(F)F>>[F:27][C:25]([F:26])([F:28])[CH2:24][O:23][C:3]1[CH:2]=[CH:1][C:6]([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]([O:55][CH2:56][C:57]([F:60])([F:59])[F:58])=[O:14]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: O=C(O)c1cc(O)ccc1O
Product: O=C(OCC(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
Process for the synthesis of FLECAINIDE comprising the reaction between 2,5-dihydroxybenzoic acid with trifluoroethanol perfluorobutanesulphonate to give the intermediate trifluoroethanol 2,5-bis-trifluoroethoxybenzoate, the reaction of said intermediate with 2-aminomethylpiperidine to give FLECAINIDE.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:27])[CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:18]2)=[O:15])[C:11]([CH2:34][OH:35])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:10]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:37]>C1C=CC=CC=1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:27])[CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]([O:26][CH3:37])=[O:25])[CH2:21][CH2:22]2)=[O:15])[C:11]([CH2:34][OH:35])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:10]=1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1)C1CCN(CC(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)CN1CCC(N(C)C(=O)N2CC(c3cc(F)ccc3F)=CC2(CO)c2ccccc2)CC1
Reaction time: 2 h

Procedure:
To 30 mg (0.06 mmol) of amino acid 17-1 in 1:1 PhH/MeOH was added 120 μL (0.24 mmol) of TMS-diazomethane. After stirring for 2 h, the reaction was concentrated by rotary evaporation and the residue was purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 17-2 as a colorless film. Data for 17-2: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.45 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 3.7 (s, 3H), 3.2 (m, 2H), 3.05 (m, 2H), 2.9 (s, 3H), 2.3 (m, 2H), 2.0-1.8 (m, 3H), 1.7 (m, 1H) ppm. HRMS (ES) calc'd M+H for C27H31F2N3O4: 500.2356. Found: 500.2331.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])=[C:6]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].O>C(Cl)Cl>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])=[CH:7][C:6]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)ccc1=O
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2ccc(=O)n(C)c2)c1
Temperature: 30 °C
Reaction time: 12 h
Yield: 26.4 %

Procedure:
To a solution of 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-1-methylpyridin-2-one (30 mg, 0.09 mmol) in DCM (4 mL) was added TEA (27.3 mg, 0.27 mmol) and EtSO2Cl (35.39 mg, 0.27 mmol). The mixture was stirred at 30° C. for 12 h. Water (4 mL) was added and the mixture was extracted with DCM (4 mL×3). The organic layer was concentrated and the residue was purified by prep-HPLC to give the title compound (10 mg, 26%) as light yellow gum. 1H NMR (CDCl3, 400 MHz) δ7.68-7.66 (m, 2H), 7.28 (d, J=2.4 Hz, 1H), 7.13-7.10 (m, 1H), 7.09 (s, 1H), 7.00-6.92 (m, 2H), 6.84-6.86 (m, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.73 (d, J=9.2 Hz, 1H), 3.65 (s, 3H), 3.14 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H). LCMS (M+H)+ 421.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH:3]([C:11]([OH:13])=O)[CH2:2]1.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>C(O)C>[CH2:14]([NH:17][C:11]([CH:3]1[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2]1)=[O:13])[CH:15]=[CH2:16]
Reactant: O=C(O)C1COc2ccccc2C1
Reactant: C=CCN
Solvent: CCO
Product: C=CCNC(=O)C1COc2ccccc2C1

Procedure:
A solution of 5 g of 2A and 5.7 g of 2-propenamine in 50 ml of ethanol was refluxed for 6 days. Stripping of the solvent, followed by charcoal treatment of the product and recrystallization of the treated product from ether-hexane, gave 2, as white crystals, mp: 114.5°-115.5° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:18][CH2:19][CH3:20])=[C:10]([C:14](OC)=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:24]([NH:31]C=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:21]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:18][CH2:19][CH3:20])=[C:10]([C:14]([NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:15])[CH:11]=2)[CH2:6]1)[CH2:22][CH3:23]
Reactant: CCCN(CCC)C1Cc2cc(OCC)c(C(=O)OC)cc2C1
Reactant: O=CNCc1ccccc1
Product: CCCN(CCC)C1Cc2cc(OCC)c(C(=O)NCc3ccccc3)cc2C1

Procedure:
Using procedure 41, methyl 2-(dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxylate (77, 0.32 g, 1 mmol) was treated with N-benzylformamide (1.35 g, 10 mmol). Chromatographic purification yielded pure product 84 as a oil which was converted into the HCl salt and crystallized from EtOAc to give a white solid (m.p. 219-221° C.).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][O:4][CH2:3]1.Cl[C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:15][N:14]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH2:13]2)[O:9][N:8]=1>O1CCOCC1>[N:30]1([C:28]([N:14]2[CH2:15][CH:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)[CH2:17][CH:12]([C:10]3[O:9][N:8]=[C:7]([O:1][CH:2]4[CH2:5][O:4][CH2:3]4)[N:11]=3)[CH2:13]2)=[O:29])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: OC1COC1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: C1COCCO1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(OC3COC3)no2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 83.3 mg (1.12 mmol) of 3-hydroxyoxetane in 4.00 ml of 1,4-dioxane were added, at RT, 4 Å molecular sieve and 0.23 ml (0.45 mmol; 2 M solution in THF) of phosphazene P4 base. Subsequently, 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 2.0 ml of 1,4-dioxane were added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was filtered, diluted with dichloromethane and washed with 1 N aqueous hydrogen chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 18.6 mg (17% of theory)
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10]([C:12]1[C:13]([NH2:21])=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)=[O:11].N1C=CC=CC=1.Cl>ClCCl>[CH3:8][O:9][C:10]([C:12]1[C:13]([NH:21][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)=[O:11]
Reactant: COC(=O)c1ccc2c(c1N)CCC2
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1NC(=O)OC(C)C)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
Add isopropyl chloroformate (2.22 mL, 2.22 mmol, 1.0 M in toluene) dropwise to a solution of 4-Amino-indan-5-carboxylic acid methyl ester (425 mg, 2.22 mmol) and pyridine (0.44 mL, 5.5 mmol) in dichloromethane (4.4 mL) at 0° C. under an atmosphere of nitrogen and stir at room temperature for 24 h. Add 1M HCl and separate the layers. Extract the aqueous layer with dichloromethane. Dry the organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure, to afford the title compound (576 mg, 93%): 1H NMR (MeOD) δ 1.37 (d, J=6.5 Hz, 6H), 2.16 (quintuplet, J=7.7 Hz, 2H), 2.97 (t, J=7.3 Hz, 2H), 3.05 (t, J=7.3 Hz, 2H), 3.94 (s, 3H), 4.97 (m, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H). MS (ES+): 278 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[CH:16]1([CH:21]=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.N1CCCC1>CO>[CH:16]1([CH:21]=[C:11]2[CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]=3[C:2]2=[O:1])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=CC1CCCC1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (3.4 g, 16.7 mmol) in methanol (30 mL) was added cyclopentanecarboxaldehyde (3.3 g, 33.3 mmol) and pyrrolidine (2.78 mL, 33.3 mmol). The solution was stirred for twenty hours at ambient temperature. The reaction was recharged with 0.5 mL of cyclopentanecarboxaldehyde. The resulting precipitate was collected by vacuum filtration to provide methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a solid (2.8 g, 60% yield). LC/MS on 4.6×50 mm C-18 column, tR=6.71 minutes (10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 285 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24-1.39 (m, 2H), 1.52-1.74 (m, 4H), 1.76-1.89 (m, 2H), 2.77 (t, J=5.77 Hz, 2H), 2.79-2.90 (m, 1H), 2.97 (t, J=6.44 Hz, 2H), 3.85 (s, 3H), 6.71 (d, J=9.94 Hz, 1H), 7.88 (d, J=6.44 Hz, 1H), 7.91 (s, 1H), 7.98 (d, J=8.06 Hz, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C(OCC)C>[OH:13][CH2:12][C:11]1[CH:10]=[C:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-benzoylbenzoic acid (6.26 g, 27.7 mmol) was carefully added in several portions to borane-N,N-diethylaniline complex (7.38 mL, 41.5 mmol) in anhydrous THF (60 mL) at ambient temperature. After 15 minutes, the reaction mixture was heated at reflux for 5 hours and then cooled to ambient temperature. The reaction mixture was diluted with diethyl ether, quenched with 1N HCl and the separated aqueous phase was extracted with diethyl ether. The organic layers were combined, washed with 1N HCl, brine, dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 40% ethyl acetate/hexanes) to provide a mixture of the title compound and the diol, [3-(hydroxymethyl)phenyl](phenyl)methanol, as a colorless oil (3.59 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:16]=O.C([O-])(O)=O.[Na+].O>O1CCOCC1>[C:18]1([C:15]2[N:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)=[CH:7][C:2]3=[N:1][CH:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(-c2ccncc2)ccn1
Reactant: O=CC(Br)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of 2-amino-4,4′-bipyridine (0.482 g, 2.815 mmol, 1 equiv) in dioxane (14 mL) was added bromophenylacetaldehyde (0.897 g, 4.50 mmol, 1.6 equiv) and NaHCO3 (0.473 g, 5.63 mmol, 2 equiv). The suspension was stirred at rt for 30 min and then heated to 80° C. for 6 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layer was dried, concentrated and purified by flash column chromatography (5% MeOH in CH2Cl2 ) to give 3-phenyl-7-(4-pyridyl)imidazo[1,2-a]pyridine as a solid. 1H NMR (CDCl3) δ 8.72 (d, 2H, J=6.1), 8.45 (d, 1H, J=7.3), 8.00 (s, 1H), 7.80 (s, 1H), 7.61–7.55 (m, 6H), 7.48–7.44 (m, 1H), 7.14 (d, 1H, J=7.3); LRMS m/z (M+H) Calcd: 272.3, found: 272.2.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25](B(O)O)=[CH:26][C:21]=2[O:20][CH2:19]1>>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:2]3[C:10]4[N:9]5[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]5=[C:7]([CH3:16])[C:6]=4[CH:5]=[C:4]([F:17])[CH:3]=3)=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc5c(c4)OCO5)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (73 mg, 86%), MS (ISP) m/z=339.5 [(M+H)+], mp 206° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available benzo[d][1,3]dioxol-5-ylboronic acid (53.9 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: OCc1ccc(F)cc1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccc(F)cc1
Reaction time: 3 h

Procedure:
From 4-fluorobenzyl alcohol (5.0 g; 40 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 3 h at 90° C. The yield was 1.02 g (62%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2=[C:7]([OH:12])[CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[O:4][CH2:3]1.Cl[C:15]1[N:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.C(OCC)(=O)C>[N+:21]([C:18]1[CH:17]=[N:16][C:15]([O:12][C:7]2[C:6]3[C:2]([CH3:13])([CH3:1])[CH2:3][O:4][C:5]=3[C:10]([CH3:11])=[CH:9][CH:8]=2)=[N:20][CH:19]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: Cc1ccc(O)c2c1OCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cc1ccc(Oc2ncc([N+](=O)[O-])cn2)c2c1OCC2(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
3,3,7-Trimethyl-2,3-dihydro-1-benzofuran-4-ol (Intermediate 27, 178 mg, 1.0 mmol) and 2-chloro-5-nitropyrimidine (191.5 mg, 1.2 mmol) were dissolved in CH3CN (3.0 mL) and K2CO3 (345.5 mg, 2.5 mmol) was added. The resulting suspension was heated to 40° C. and stirred for 1 hour. The reaction mixture was then diluted with water (50 mL) and ethyl acetate (50 mL), The organic phase was collected, washed with brine (50 mL) and dried over Na2SO4. The residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 97:3 as eluents affording the title compound (243 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[NH:59][CH2:58][CH2:57][CH2:56]2>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:59]2[C:60]3[C:55](=[CH:54][C:53]([F:52])=[CH:62][CH:61]=3)[CH2:56][CH2:57][CH2:58]2)=[O:13])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: O=C(O)c1cncnc1Oc1cc(Cl)ccc1Cl
Reactant: Fc1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cncnc1Oc1cc(Cl)ccc1Cl)N1CCCc2cc(F)ccc21
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 3 %

Procedure:
To a solution of 57 mg (0.2 mmol) 4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid (Example 76, intermediate a) in 1.5 mL N,N-dimethylformamide were added 91 mg (0.24 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N;N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.102 mL (0.6 mmol) N,N-diisopropyl-ethylamine. The solution was stirred 15 minutes at 45° C. followed by addition of 36 mg (0.22 mmol) 6-fluoro-1,2,3,4-tetrahydroquinoline (commercially available, CAS RN 59611-52-8). The reaction was stirred at 45° C. overnight and purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 2.5 mg (3%) of the desired compound. MS (ESI): m/z=418.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][N+:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:20]=[N:21][NH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[Cl:18][C:19]1[CH:20]=[N:21][N:22]([CH2:6][CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][C:2]([OH:1])([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:11][CH2:10]2)[CH:23]=1
Reactant: OC1(c2ccccc2)CC[N+]2(CCCC2)CC1
Reactant: Clc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: OC1(c2ccccc2)CCN(CCCCn2cc(Cl)cn2)CC1
Yield: 77.3 %

Procedure:
A mixture of 15.0 g (48 mmol) of 8-hydroxy-8-phenyl-5-azoniaspiro[4,5]decane, 5.4 g (53 mmol) of 4-chloropyrazole and 13.2 g of potassium carbonate in 200 ml of dimethylformamide is heated at reflux for 20 hours. Evaporation to dryness is then carried out at reduced pressure, the residue is redissolved in chloroform and washing is carried out repeatedly with water. The organic phase is dried with anhydrous sodium sulfate and evaporation is carried out at reduced pressure, a crude product being obtained which is suspended in ethyl ether, which is filtered while cold and which is washed with ethyl ether. 12.4 g (37.1 mmol) of 4-chloro-1-[4-(4-hydroxy-4-phenyl-1-piperidyl)butyl)-1H-pyrazole are obtained.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][Si:18]([CH2:21][CH2:22]Br)([CH3:20])[CH3:19].O>ClCCl>[CH2:1]([N:8]1[CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(CCBr)CCBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C[Si]1(C)CCN(Cc2ccccc2)CC1
Yield: 58.4 %

Procedure:
Benzylamine (17.56 g, 0.16 mol) and K2CO3 (3.4 g, 24.6 mmol) are added to a solution of bis(2-bromoethyl)dimethylsilane 2(4.0 g, 16.4 mmol) in Dichloromethane (DCM). The mixture is then refluxed for 16 h. Water is added and the aqueous layer is extracted with DCM. It is then washed with 5% sodiumhydroxide (NaOH) solution, dried and concentrated. The product is purified by column chromatography on silica using hexane-ethylacetate mixtures to obtain the product as a colorless liquid 3 (2.1 g) in 59% yield.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][S:14][CH:15]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[S:14]1[CH:15]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][NH2:1])[N:12]=[N:13]1
Reactant: [N-]=[N+]=NCc1ccccc1-c1csnn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccccc1-c1csnn1

Procedure:
A solution of 4-(2-azidomethyl-phenyl)-[1,2,3]thiadiazole (1.0 g, 4.6 mmol), triphenylphosphine (1.4 g, 5.5 mmol) and water (0.12 ml, 6.9 mmol) in tetrahydrofuran (20 ml) was stirred at room temperature overnight. Solvent evaporation and flash chromatography (silica gel, chloroform-2-propanol, 95:5–92:8) gave 2-[1,2,3]thiadiazole-4-yl-benzylamine; 1H NMR (CDCl3, 300 MHz) δ 8.87 (s, 1H), 7.67 (d, 1H, J=8 Hz), 7.45 (m, 3H), 3.88 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23]>C(OCC)(=O)C>[F:21][C:17]1[CH:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])[CH:20]=[CH:19][CH:18]=1
Reactant: NCCO
Reactant: CC(C)n1cnc2c(Nc3cccc(F)c3)nc(Cl)nc21
Solvent: CCOC(C)=O
Product: CC(C)n1cnc2c(Nc3cccc(F)c3)nc(NCCO)nc21

Procedure:
0.2 g (0.63 mmol) of 2-chloro-9-isopropyl-6-(3-fluoro-phenyl-amino)-9H-purine (prepared according to Stage 91.1) is stirred in 1 ml of ethanolamine at 150° C. for 5 h, and the mixture is then allowed to cool and is diluted with ethyl acetate. The organic phase is washed with water and dried over sodium sulfate. On concentration of the solvent, 6-(3-fluoro-phenyl-amino)-2-(2-hydroxy-ethyl-amino)-9-isopropyl-9H-purine is obtained as a crystalline mass. This is filtered off and dried; m.p. 142° C.; FAB-MS: (M+H)+=330; Rf=0.6 (CH2Cl2:methanol 9:1).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=2[O-])=[CH:10][CH:9]=1.C(N(CC)CC)C>>[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:5]#[N:6])[N:14]=2)=[CH:10][CH:9]=1
Reactant: [O-][n+]1ccccc1Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(Cc2ccc(Cl)cc2)n1
Temperature: 25 °C
Yield: 14.8 %

Procedure:
Trimethylsilyl cyanide (12.42 g, 16.7 ml, 0.125 moles) was added dropwise to a solution of 2-p-chlorobenzyl-pyridine-N-oxide (11.0 g, 0.05 moles) and triethylamine (7.61 g, 10.5 ml, 0.075 moles) in acetronitrile (40 ml) at 20° C. After complete addition the mixture was heated under reflux for 48 hours, cooled to room temperature and partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was washed with water and saturated sodium chloride and dried over anhydrous magnesium sulphate. Removal of the solvent gave a brown oil which was purified by column chromatography (silica gel eluted with hexane:ethyl acetate 9:1) to give 2-p-chlorobenzyl-6-cyanopyridine (1.69 g, 15%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-])=O)=[C:16]([NH2:24])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([NH2:21])=[C:16]([NH2:24])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cc(N)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cc(N)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(3-Amino-5-methyl-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (15 g, 44.6 mmol) in methanol (2200 mL) was added 20% Pd(OH)2/C (1.6 g) and the suspension flushed well with nitrogen, followed by hydrogen. The resulting suspension was stirred overnight at room temperature under an atmosphere of hydrogen (ca. 1 atm). The resulting suspension was filtered under nitrogen through a pad of Celite and washed with methanol (400–500 mL). The resulting material was used immediately. LCMS (M+H)+ m/z 307.