Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH:12]([O:16][CH3:17])[C:13](=O)[CH3:14].C(O)C.[OH-].[Na+]>O>[CH3:10][O:11][CH:12]([O:16][CH3:17])[C:13]1[CH:14]=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1ncccc1C=O
Reactant: COC(OC)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(OC)c1ccc2cccnc2n1
Temperature: 7.5 °C

Procedure:
The procedure described in J. Org. Chem., 2004, 69 (6), pp 1959-1966 was used. Into a 20 l 4-necked round-bottom flask was placed 2-aminopyridine-3-carbaldehyde (1000 g, 8.19 mol), 1,1-dimethoxypropan-2-one (1257 g, 10.64 mol), ethanol (10 l), and water (2 l). This was followed by the addition of a solution of sodium hydroxide (409.8 g, 10.24 mol) in water (1000 ml) drop wise with stirring at 0-15° C. The solution was stirred for 3 h at 0-20° C. and then concentrated under vacuum. The resulting solution was extracted with 3×1200 ml of ethyl acetate and the organic layers were combined. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was washed with 3×300 ml of hexane and the solid was collected by filtration. This resulted in the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.11 (dd, 1H), 8.53 (d, 1H), 8.50 (dd, 1H), 7.73 (d, 1H), 7.67 (dd, 1H), 5.44 (s, 1H), 3.41 (s, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=12.[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>CN(C=O)C.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].[Cu]I>[CH3:18][O:17][C:7]1[C:6]2[N:5]([N:4]=[CH:3][C:2]=2[C:20]#[C:19][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:8]=1
Reactant: C#Cc1cccnc1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(I)c12
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cccnc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (20.0 mg, 0.056 mmol), 3-ethynylpyridine (17.5 mg, 0.169 mmol), tetrakis(triphenylphosphine)palladium (0) (6.5 mg, 5.7 mmol), and copper (I) iodide (6.5 mg, 0.034 mmol) were suspended in DMF (1 ml). Triethylamine (0.016 ml, 0.113 mmol) was added, the mixture was sparged with argon for 10 minutes then allowed to stir at ambient temperature. After 1 h, the reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate, filtered and concentrated to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-(pyridin-3-ylethynyl)pyrazolo[1,5-a]pyridine. 1H NMR (600 MHz, DMSO-d6) δ 8.68 (s, 1H); 8.65 (d, 1H); 8.51 (dd, 1H); 8.30 (s, 1H); 8.17 (s, 1H); 8.03 (s, 1H); 7.85-7.88 (m, 1H); 7.40-7.43 (m, 1H); 7.02 (s, 1H); 4.02 (s, 3H); 3.85 (s, 3H). LRMS (ESI) calculated for C19H16N5O [M+H]+, 330.1; found 330.0.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26]Br>C(#N)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[N:15]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N1CCCC1
Yield: 88.1 %

Procedure:
1-N-Boc-1,2-cis-cyclohexyldiamine 5 (CAS 184954-75-4) (1.65 g, 7.7 mmol) was dissolved in 100 mL acetonitrile. Potassium carbonate (5.3 g, 39 mmol) and 1,4-dibromobutane (2.8 g, 13 mmol) were added and the reaction mixture was refluxed overnight. The solvent was evaporated off. The residue was taken up in water and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0->140:10:1) yielded cis-(2-pyrrolidin-1-yl-cyclohexyl)-carbamic acid tert-butyl ester as a yellow liquid (1.82 g, 88%), MS: m/e=269.4 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[NH:5][CH:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)[CH3:2].[H-].[Na+].[CH3:23]I>CN(C=O)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[N:5]([CH3:23])[CH:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)NC1CCC=C(C#Cc2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)C1CCC=C(C#Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
22 mg (0.082 mmol) (3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester are dissolved in 2 ml DMF and 1 THF. 8 mg (0.165 mmol) of a 60% dispersion of NaH in oil is added and the mixture stirred under argon for 90 minutes at room temperature. The reaction mixture is cooled to 0°, and 16 microliters MeI in 0.5 ml THF are added dropwise. After stirring one hour at room temperature, the reaction mixture is cooled to 0° again, ice is added and the crude product extracted with ethyl acetate, washed with water and saline, dried with sodium sulfate and column chromatographed using a 4:1 mixture of petroleum ether and ethyl acetate. Yield: 43%.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[C:7](=[O:13])[CH2:6]2>O>[C:1]([C:7]1([OH:13])[CH:8]2[CH2:11][CH2:12][N:5]([CH2:10][CH2:9]2)[CH2:6]1)#[N:2]
Reactant: [C-]#N
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CC1(O)CN2CCC1CC2
Reaction time: 3 h

Procedure:
A solution of potassium cyanide (10.15 g, 0.156 mol) in water (31.25 ml) was added dropwise to a solution of 1-azabicyclo[2.2.2]octan-3-one hydrochloride (25.0 g, 0.155 mol) in water (31.25 ml) at 0°-5°. Following the addition, the reaction mixture was stirred for 3 h and then filtered. The solid was washed with ice-cold water (2×15 ml) and was then dried over phosphorus pentoxide overnight, m.p. 155°-156°. Recrystallisation of a 1 g sample from dioxane gave pure 3-cyano-3-hydroxy-1-azabicyclo[2.2.2]octane, m.p. 172°-173°.
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]([C:10]1[N:14]2[CH2:15][CH2:16][N:17]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:18]3([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:13]2=[CH:12][CH:11]=1)#[N:9]>ClCCl>[ClH:1].[C:8]([C:10]1[N:14]2[CH2:15][CH2:16][N:17]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:18]3([CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)[C:13]2=[CH:12][CH:11]=1)#[N:9]
Reactant: CCOC(=O)N1CCn2c(C#N)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)N1CCn2c(C#N)ccc2C12CCNCC2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
4 N HCl in dioxane (8.7 mL, 34.7 mmol) was added to a solution of 1-tert-butyl 2′-ethyl 6′-cyano-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1,2′-dicarboxylate (0.27 mmol) in dichloromethane (5 mL) and the mixture was stirred at 40° C. for 1 hour. The reaction mixture was evaporated to dryness to give ethyl 6′-cyano-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-2′-carboxylate hydrochloride. ESI-MS m/z calc. 288.2, found 289.3 (M+1)+; Retention time: 0.75 minutes (3 minute run).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:10][C:11]([F:19])([F:18])[CH2:12][O:13][CH2:14][C:15](N)=[NH:16].C(OCC)(=O)C>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH2:12][C:11]([F:19])([F:18])[F:10])[N:16]=1
Reactant: N=C(N)COCC(F)(F)F
Reactant: N#Cc1nccnc1N
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nc(COCC(F)(F)F)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 7.2 g (0.060 mole) of 3-amino-2-pyrazinecarbonitrile and 14.2 g (0.091 mole) of 2-(2,2,2-trifluoroethoxy)acetamidine in 230 ml of absolute ethanol. Refluxing time: 7 hours. Yld: 6.5 g (42%), m.p. 145°-147° C. (ethyl acetate).
Reaction SMILES: C1(N2C3C(=CC=CC=3)C(CCCN3CCC(C4C=C(NC(=O)C(C)C)C=CC=4)CC3)=C2C2C=CC=CC=2)C=CC=CC=1.[CH3:43][CH:44]([CH3:71])[C:45]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH:54]2[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][CH2:62][C:63](=O)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:56][CH2:55]2)[CH:49]=1)=[O:46].[NH:72]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][N:75]=1)[NH2:73]>>[CH3:43][CH:44]([CH3:71])[C:45]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH:54]2[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][CH2:62]/[C:63](/[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[N:73]\[NH:72][C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][N:75]=3)[CH2:56][CH2:55]2)[CH:49]=1)=[O:46]
Reactant: NNc1ccccn1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Agent: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC/C(=N\Nc3ccccn3)c3ccccc3)CC2)c1
Yield: 23.2 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide (8.70 mg, 0.0223 mmol) and 2-hydrazinopyridine (2.92 mg, 0.0268 mmol) provided 2-methyl-N-(3-{1-[(4E)-4-phenyl-4-(2-pyridinylhydrazono)butyl]-4-piperidinyl}phenyl)propanamide (2.5 mg, 24%). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 1H, J=8.6 Hz), 7.85 (d, 1H, J=7.3 Hz), 7.64–7.27 (m, 9H), 7.09 (d, 1H, J=8.0 Hz), 6.97 (d, 1H, J=8.4 Hz), 6.73 (q, 1H, J=6.6 Hz), 3.52–3.48 (m, 2H), 3.20–3.10 (m, 2H), 2.85–1.75 (m, 13H), 1.26 (d, 6H, J=6.8 Hz); ESMS m/e: 484.4 (M+H)+.
Reaction SMILES: Br[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[C:15](B(O)O)=[CH:14][CH:13]=[N:12]1.C([O-])(O)=O.[Na+]>COCCOC.O.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>[F:10][C:9]1[C:2]([C:13]2[NH:12][N:11]=[CH:15][CH:14]=2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1cccc(F)c1Br
Reactant: OB(O)c1ccn[nH]1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cccc(F)c1-c1ccn[nH]1
Temperature: 23 °C
Yield: 20.7 %

Procedure:
2-Bromo-3-fluorobenzonitrile (1.0 g, 5.0 mmol) and (1H-pyrazol-5-yl)boronic acid (647 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 mL) then treated with NaHCO3 (1260 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 (288 mg, 0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. Cooled to 23° C. filtered and solid rinsed with EtOAc and the layers separated. The organic layers were combined, dried and concentrated under reduced pressure. Chromatography (0-30% ethyl acatate/hexanes) afforded 3-fluoro-2-(1H-pyrazol-5-yl)benzonitrile (178 mg, 19%).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]([F:23])([F:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:7][O:6]1)=[O:4].[OH-].[Na+:25]>C(O)C.O>[Na+:25].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:5]2([C:3]([O-:4])=[O:2])[CH2:7][O:6]2)([F:22])[F:23])=[CH:16][CH:17]=1
Reactant: COC(=O)C1(C(F)(F)CCCCCOc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])C1(C(F)(F)CCCCCOc2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A solution of 348 mg (1 mmol) of 2-[6-(4-chlorophenoxy)-1,1-difluorohexyl]-2-oxiranecarboxylic acid methyl ester of Example 7 in 10 ml of 95% ethanol is treated with a solution of 40 mg (1 mmol) of sodium hydroxide in 5 ml of water. The solution is stirred at room temperature for 3 hours and is then rotoevaporated. The obtained solid is triturated two times with ethyl ether and the solvent is removed to give 289 mg (77.1%) of the title compound: m.p. 140°-153° C.; IR (KBr) 1645, 1618 cm-1 ; NMR (d6 -DMSO) δ 1.46 (4H, m), 1.73 (2H, p, J=7 Hz), 2.42 (2H, m), 2.70 (1H, d, J=7 Hz), 2.76 (1H, d, J=7 Hz), 3.98 (2H, t, J=7 Hz), 7.00 (2H, d, J=10 Hz) and 7.36 (2H, d, J=10 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=[N:12][OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][F:23].Cl>CS(C)=O.O>[F:23][CH2:22][O:13][N:12]=[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])[C:3]([O:2][CH3:1])=[O:14]
Reactant: FCBr
Reactant: COC(=O)C(=NO)c1ccccc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(=NOCF)c1ccccc1C
Reaction time: 20 h

Procedure:
A mixture of 57 g of 2-tolylglyoxylic acid methyl ester oxime and 80 g of powdered potassium carbonate is mixed into 550 ml of dimethyl sulfoxide for 30 minutes at room temperature and then a solution of 40 g of bromofluoromethane in 30 ml of dimethyl sulfoxide is added dropwise at room temperature. The reaction mixture is stirred for a further 20 hours and then poured into 1200 ml of water, neutralised with 230 ml of hydrochloric acid and extracted four times with 250 ml of ethyl acetate each time. The combined organic phases are washed with 200 ml of saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in vacuo. Purification by flash chromatography (silica gel, ethyl acetate/hexane 1:9) yields 2-tolylglyoxylic acid methyl ester O-fluoromethyloxime in the form of a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][C@H:49]([OH:52])[CH2:50][OH:51])[CH2:44][CH2:43]2)=[CH:38][C:37]=1[O:53][CH3:54]>COCC(O)C>[CH3:54][O:53][C:37]1[CH:38]=[C:39]([CH:42]2[CH2:43][CH2:44][N:45]([CH2:48][C@H:49]([OH:52])[CH2:50][OH:51])[CH2:46][CH2:47]2)[CH:40]=[CH:41][C:36]=1[NH:35][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: COc1cc(C2CCN(C[C@H](O)CO)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc(C2CCN(C[C@H](O)CO)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 100 °C
Yield: 26.6 %

Procedure:
Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (320.00 mg, 0.857 mmol), N,N-Diisopropylethylamine (0.779 mL, 4.47 mmol), and (S)-3-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-propane-1,2-diol (600.65 mg, 2.142 mmol) were dissolved in 1-methoxy-2-propanol (2.3 mL) and the reaction mixture was heated at 100° C. for 8 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous NaHCO3, and the organic layer was separated and dried over MgSO4, then filtered. The solvent was evaporated under reduced pressure and the product was isolated by column chromatography (ISCO, Silicagel, methanol/dichloromethane 0-10%). The product needed to be further purified by preparative reverse phase HPLC (Gilson, 0.1% TFA water/acetonitrile gradient) followed by neutralization of the resulting TFA salt to afford (S)-3-(4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-propane-1,2-diol as a light orange solid (115 mg, 27%). MP: 66-80° C.; 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.99 (dd, J=8.0, 1.6 Hz, 1H), 7.44 (m, 2H), 7.13 (m, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.02 (d, J=4.7 Hz, 1H), 6.83 (d, J=4.7 Hz, 1H), 6.72 (s, 1H), 6.71 (d, J=8.0 Hz, 1H), 3.90 (s, 3H), 3.86 (m, 1H), 3.85 (s, 3H), 3.77 (m, 1H), 3.55 (m, 1H), 3.22 (d, J=10.6 Hz, 1H), 3.08 (d, J=10.6 Hz, 1H), 2.77 (br s, 2H), 2.69 (m, 1H), 2.48 (m, 3H), 2.20 (m, 1H), 1.85 (m, 4H); LC/MS (ESI+): 504.19 (M+H).
Reaction SMILES: [C:1]1([C:7]([NH2:10])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[N+:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([O-:22])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N+:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8])=[O:33])([O-:22])=[O:21]
Reactant: O=C(O)c1cccc(-c2ccncc2[N+](=O)[O-])c1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1cccc(-c2ccncc2[N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution containing 2-phenylpropan-2-amine (5.5 g, 40.4 mmol), diisopropylethylamine (18.8 mL, 108 mmol), 3-(3-nitropyridin-4-yl)benzoic acid (8.8 g, 27.0 mmol) and DMF (180 mL) was added HATU (15.4 g, 40.4 mmol) in one portion. The solution was maintained at room temperature for 1 h then concentrated. Purification on silica gel (50-100% ethyl acetate/hexanes, 60 min. gradient) afforded 3-(3-nitropyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide as a dark yellow, fluffy solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.21 (s, 1H), 8.93 (d, J=5.02 Hz, 1H), 8.51 (s, 1H), 7.97 (dt, J=7.03, 1.76 Hz, 1H), 7.92 (s, 1H), 7.73 (d, J=5.02 Hz, 1H), 7.52-7.61 (m, 2H), 7.34-7.41 (m, 2H), 7.27 (t, J=7.65 Hz, 2H), 7.16 (t, J=7.28 Hz, 1H), 1.64-1.72 (m, 6H). LCMS: retention time: 2.060 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 u, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol/90% H2O/10 mM TFA and solvent B was 10% H2O/90% methanol/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 362 (MH+).
Reaction SMILES: N1CCCCC1.[NH:7](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:8]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10].[CH3:39][C@@H:40]1[O:45][C@@H:44]([O:46][C@@H:47]2[C:52]3=[C:53]([OH:70])[C:54]4[C:66](=[O:67])[C:65]5[C:60](=[CH:61][CH:62]=[CH:63][C:64]=5[O:68][CH3:69])[C:58](=[O:59])[C:55]=4[C:56]([OH:57])=[C:51]3[CH2:50][C@@:49]([OH:75])([C:71]([CH2:73][OH:74])=[O:72])[CH2:48]2)[CH2:43][C@H:42]([NH2:76])[C@@H:41]1[OH:77]>CN(C)C=O>[NH2:7][C@H:8]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10].[CH3:39][C@@H:40]1[O:45][C@@H:44]([O:46][C@@H:47]2[C:52]3=[C:53]([OH:70])[C:54]4[C:66](=[O:67])[C:65]5[C:60](=[CH:61][CH:62]=[CH:63][C:64]=5[O:68][CH3:69])[C:58](=[O:59])[C:55]=4[C:56]([OH:57])=[C:51]3[CH2:50][C@@:49]([OH:75])([C:71]([CH2:73][OH:74])=[O:72])[CH2:48]2)[CH2:43][C@H:42]([NH2:76])[C@@H:41]1[OH:77]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCC[C@H]1C(=O)O
Agent: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A solution of piperidine in dimethylformamide 50% (1.92 mL) was added to Fmoc-Val-Pro-doxorubicin (F) (29.7 mg, 0.03 mmol) and the reaction mixture was stirred at room temperature for 1 minute (the reaction colour changes form red to purple). Then, the reaction mixture was evaporated to dryness under reduced pressure and the residue thus obtained was purified by reverse phase chromatography with water/acetonitrile (70:1) to give the deprotected compound G (50% yield)
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH3:20])=[C:17]2[C:12]([C:13](=[O:31])[C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[C:15]([CH:21]([CH3:23])[CH3:22])[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>O1CCCC1.C(O)C.Cl.[Pd].[C]>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:14]2[C:13](=[O:31])[C:12]3[C:17](=[C:18]([O:19][CH3:20])[C:9]([OH:8])=[CH:10][CH:11]=3)[O:16][C:15]=2[CH:21]([CH3:23])[CH3:22])=[CH:29][CH:28]=1
Reactant: COc1c(OCc2ccccc2)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: COc1c(O)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 7-benzyloxy-3-(4-chlorophenyl)-2-isopropyl-8-methoxy-chromen-4-one (2.68 g, 6.16 mmol) and Pd/carbon (20%, 268 mg) in tetrahydrofuran (30 ml), absolute ethanol (30 ml) and 5M HCl solution (15 ml) is stirred under a balloon of H2 at room temperature for 3 h. The reaction mixture is filtered through a pad of Celite filter aid, which is itself washed with tetrahydrofuran. The solvent is removed under reduced pressure to afford the desired product, which is used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[C:22]([CH2:34][CH:35]=[C:36]([CH3:39])[CH2:37]O)=[C:23]([O:32][CH3:33])[C:24]([CH3:31])=[C:25]2[C:29]=1[C:28](=[O:30])[O:27][CH2:26]2.C(Br)(Br)(Br)[Br:41]>ClCCl>[Br:41][CH2:37][C:36]([CH3:39])=[CH:35][CH2:34][C:22]1[C:21]([OH:20])=[C:29]2[C:25]([CH2:26][O:27][C:28]2=[O:30])=[C:24]([CH3:31])[C:23]=1[O:32][CH3:33]
Reactant: BrC(Br)(Br)Br
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CO)C(=O)OC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1CC=C(C)CBr)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
Polymer-supported triphenylphosphine (3 mmol/g, 0.5 g) was soaked in dichloromethane (10 mL) for 1 hour 7-Hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one (100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) were added sequentially and the mixture was shaken for 1 hour at room temperature. More carbon tetrabromide (143 mg, 0.43 mmol) was added and the mixture was shaken further for 1 hour The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (0% to 60% ethyl acetate/hexanes) to afford 6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one as an oil (52 mg, 42%); 1H NMR (300 MHz, CDCl3) δ 1.95 (s, 3H), 2.16 (s, 3H), 3.44 (d, J=7.2, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s, 2H), 5.68 (t, J=7.2 Hz, 1H), 7.71 (brs, 1H) ppm.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]=2)=[CH:5][N:4]=1)#[CH:2].I[C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1>C(N(CC)CC)C>[F:9][C:8]1[C:3]([C:1]#[C:2][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]3)=[CH:32][CH:33]=2)=[N:4][CH:5]=[C:6]([C:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]=2)[CH:7]=1
Reactant: C#Cc1ncc(C2=CCC(C)CC2)cc1F
Reactant: CC1CCN(CCOc2ccc(I)cc2)CC1
Solvent: CCN(CC)CC
Product: CC1CC=C(c2cnc(C#Cc3ccc(OCCN4CCC(C)CC4)cc3)c(F)c2)CC1

Procedure:
The product was prepared analogously to Example 48.1c from 130 mg (0.60 mmol) of 2-ethynyl-3-fluoro-5-(4-methylcyclohex-1-enyl)pyridine and 207 mg (0.60 mmol) of 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidine (Example 19.1 a) (24 at RT, triethylamine as base). Yield: 15 mg (6% of theoretical); C28H33FN2O (M=432.573); calc.: molpeak (M+H)+:433; found: molpeak (M+H)+:433; HPLC-MS: 5.60 minutes (method H).