Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].SC1C=C(CO)C=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(F)ccc1S
Agent: OCc1cccc(S)c1
Product: OCc1cc(F)ccc1S

Procedure:
The required (5-Fluoro-2-mercapto-phenyl)-methanol is prepared from 5-Fluoro-2-mercapto-benzoic acid following the procedure for the preparation of (3-Mercapto-phenyl)-methanol described in Chemistry Express, Vol 7, No. 11, pp. 865-868).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[N:18]=[C:17](Cl)[C:16]2[C:11](=[CH:12][C:13]([C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>C(O)C>[NH2:8][C:9]1[N:18]=[C:17]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:16]2[C:11](=[CH:12][C:13]([C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:15]=2)[N:10]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc2c(Cl)nc(N)nc2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1
Temperature: 110 °C
Yield: 63.1 %

Procedure:
1-Methyl-piperazine (210 uL, 1.9 mmol) was added to a mixture of methyl 2-amino-4-chloroquinazoline-7-carboxylate (300 mg, 1 mmol) in ethanol (3 mL) and triethylamine (350 μL, 2.5 mmol). The mixture was heated in an oil bath at 110° C. for 1 h. The reaction mixture was concentrated to remove the ethanol and was partitioned between water and EtOAc. The organic phase was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered, and concentrated to give the crude product, (190 mg, 50%) as an off white amorphous solid. 1H NMR (300 MHz, DMSO) δ 2.23 (s, 3H), 3.56 (m, 4H), 3.86 (s, 3H), 3.90 (m, 4H), 6.53 (b, 2H), 7.50 (d, 1H), 7.80 (m, 2H); Analytic LCMS (M+H)+: m/z=302.1.
Reaction SMILES: [CH2:1]1[NH:6][C:5]2[NH:7][C:8]([NH2:12])=[N:9][C:10](=[O:11])[C:4]=2[N:3]([CH:13]=[O:14])[C@H:2]1[CH2:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C@H:26]([C:32]([O-:34])=[O:33])[CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:24])=[CH:19][CH:18]=1.O.O.O.O.O.[Ca+2].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[Ca+2].Cl>O.C(O)(C)C.C(O)(=O)C>[CH2:1]1[NH:6][C:5]2[NH:7][C:8]([NH2:12])=[N:9][C:10](=[O:11])[C:4]=2[N:3]([CH:13]=[O:14])[C@H:2]1[CH2:15][NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([NH:25][C@H:26]([C:32]([OH:34])=[O:33])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])=[CH:21][CH:22]=1
Reactant: Nc1nc(=O)c2c([nH]1)NC[C@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc1)N2C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Nc1nc(=O)c2c([nH]1)NC[C@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)N2C=O
Temperature: 40 °C

Procedure:
100 kg of calcium levofolinate pentahydrate (166 mol) are suspended in 500 litres (L) of purified water. The suspension is heated at 40° C. and is then decalcificated by addition of 25 kg of sodium carbonate (236 mol); acetic acid is added to maintain the pH of the system at a value of about 8.0. The formed calcium carbonate is eliminated by centrifugation and the obtained sodium levofolinate solution is clarified by fine filtration. The filtered solution is diluted with water to a volume of 850 L and 51 L of isopropanol are added thereto, thus forming a first solution. The first solution is then progressively added, during 1 hour under stirring, to a hydroalcoholic batch formed by 350 L of water and 35 L of isopropanol previously heated at 45° C. During this addition, the pH is monitored and kept in the range between 3.5 and 4.0 by progressive addition of 50 L of a 25% b.w. solution of HCl; the temperature is in its turn slowly decreased to 35° C. At the end of the addition phase (i.e., the operation of adding the first solution to the hydroalcoholic batch), the obtained solution is kept at 35° C. under stirring, while controlling the pH with further additions of the same HCl solution used before, until a stable value of 4.0 is reached; a total of 50 liters of HCl solution is added in the two phases. Levofolinic acid crystallizes out of the obtained solution during the addition phase and the subsequent stirring period. The crystallized levofolinic acid is then isolated by centrifugation, washed with water and dried under reduced pressure. 80 kg of product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[O:14][CH2:13][CH2:12][O:11]1.[Li]CCCC.[I:20]I>C1COCC1>[F:1][C:2]1[C:7]([I:20])=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[O:11][CH2:12][CH2:13][O:14]1
Reactant: II
Reactant: COc1ccc(C2OCCO2)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2OCCO2)c(F)c1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 2-(2-fluoro-4-methoxy-phenyl)-[1,3] dioxolane (4.27 g, 21.54 mmol) in anhydrous THF (30 mL) was added, at −78° C. under argon, n-BuLi (1.6 M in hexane, 13.5, 21.54 mmol). The resulting orange solution was stirred at −78° C. for 2 hours then iodine (6.015 g, 23.70 mmol) in THF (30 mL) was added. At the end of the addition the reaction mixture was warmed to room temperature and stirred for 1 hr. The solution was extracted with ethyl acetate. The organic phase was washed successively with 10% aqueous sodium thiosulfate (2×50 mL), water, brine and dried (MgSO4), filtered and evaporated to give 5.794 g of crude 2-(2-fluoro-3-iodo-4-methoxy-phenyl)-[1,3] dioxolane. use as this in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(O)(=O)C>O1CCCC1.CN(C)C=O.O>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(CSc2ccc(O)cc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 50.47 g of p-hydroxythiophenol in 250 ml of tetrahydrofuran was added to a suspension of 38.40 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 380 ml of dimethylformamide, whilst ice-cooling, and under an atmosphere of nitrogen, and the resulting mixture was stirred for 0.5 hour. At the end of this time, a solution of 54.2 ml of p-methoxybenzyl chloride in 120 ml of tetrahydrofuran was added dropwise to the resulting mixture, which was then stirred for 1 hour. The reaction mixture was then neutralized by adding acetic acid, whilst ice-cooling, after which it was poured into water. The mixture was then extracted with ethyl acetate, and the extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The resulting solution was then dried, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:3 by volume mixture of cyclohexane and tetrahydrofuran as the eluent. The eluted product was recrystallized from a mixture of tetrahydrofuran and hexane, to afford 88.99 g of the title compound.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12]3)C=CC=CC=1.[H][H]>C(O)C.[Pd]>[N:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:14]2[C:15]3[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)=[CH:24][CH:23]=1
Reactant: c1ccc(COc2ccc3c(ccn3Cc3ccncc3)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc2c(ccn2Cc2ccncc2)c1

Procedure:
To a suspension of 10% Pd/C (1.5 g) in 50 ml ethanol in a 500 ml Parr hydrogenation bottle, was added a suspension of 5-phenylmethoxy-1-(4-pyridinylmethyl)-1H-indole in 200 ml ethanol. The mixture was shaken at 50° C. under 50 psi hydrogen for one hour, then cooled, filtered, and the filtrate evaporated to a solid, 10 g, dec. 178° C. A sample of this material was eluted on a silica gel column with 2% methanol/dichloromethane via HPLC. The desired fractions were combined and evaporated to yield 2.3 g of 1-(4-pyridinylmethyl)-1H-indol-5-ol, as a solid, m.p. 185°-186° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].[C:7]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])(OCC)=O>O>[C:13]1(=[O:22])[N:12]([C@@H:7]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:1]([OH:2])=[O:4])[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (+)-L-ε-hydroxynorleucine [prepared according to the procedure of Bodanszky et al., J. Med Chem., 1978, 21, 1030-1035] (1.030 g., 7.0 mmol.) and sodium carbonate (745 mg., 7.0 mmol.) in water (12 ml.) was treated with N-carbethoxyphthalimide (1.495 g., 7.0 mmol.) and the mixture was stirred at room temperature for 2 hours. The solution was filtered, cooled to 0° C., and acidified with 6N hydrochloric acid to afford a white precipitate. The solid was collected by filtration and dried in vacuo at 80° C. for one hour to give 1.297 g. of the title compound; m.p. 162°-163° C.; [α]D =-35.7° (c=1.3, methanol).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[NH:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5].[C:14](Cl)(=[O:16])[CH3:15].C(N(CC)CC)C>>[CH3:1][CH2:2][O:3][C:4]([CH:6]1[N:10]([C:14](=[O:16])[CH3:15])[CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5]
Reactant: CCOC(=O)C1NC(C(=O)O)CS1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1SCC(C(=O)O)N1C(C)=O

Procedure:
Thiazolidine-2,4-dicarboxylic acid 2-ethyl ester (1.0 g, 4.89 mmol) was subjected to acylation with acetyl chloride (0.52 ml, 7.31 mmol) in the presence of triethylamine (1.02 ml, 7.33 mmol) to give N-acetylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (with the ratio of two kinds of stereoisomers of about 37:63 as confirmed by NMR) as an amorphous solid (1.19 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][NH:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([CH3:4])([CH3:3])[CH3:2].I[CH:41]([CH3:43])[CH3:42].C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH:41]([CH3:43])[CH3:42])=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][NH:32][C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)I
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Yield: 64.9 %

Procedure:
A solution of 3-[4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (300 mg, 0.557 mmol, Example 406) in ethanol (20 mL) was treated with 2-iodopropane (473 mg, 2.78 mmol) and K2CO3 (231 mg, 1.67 mmol) and was heated at reflux overnight. The reaction mixture was cooled and concentrated. The residue was diluted with H2O and ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated to yield an oil. Purification using silica gel chromatography (3:1 hexane:ethyl acetate) yielded 3-(2-(isopropoxycarbonylamino-methyl)-4-{2-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid tert-butyl ester as a yellow oil (210 mg). 1H NMR (300 MHz CDCl3) δ 1.28 (d, 6H), 1.40 (d, 6H), 1.45 (s, 9H), 2.38 (s, 3H), 2.53 (t, 2H), 2.91 (t, 2H), 2.99 (t, 2H), 4.25 (t, 2H), 4.39 (d, 2H), 4.66 (m, 1H), 5.00 (br m, 2H), 6.80 (dd, 1H), 6.87 (d, 1H), 6.95 (d, 2H), 7.13 (d, 1H), 7.95 (d, 2H) MS [ES] 581 (M+H).
Reaction SMILES: [CH2:1]([N:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH:2]=[CH2:3].[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>C1COCC1>[CH2:1]([NH:4][CH:5]([C:6]1[CH:7]=[CH:8][C:9]([Br:12])=[CH:10][CH:11]=1)[CH2:15][CH:14]=[CH2:13])[CH:2]=[CH2:3]
Reactant: C=CC[Mg]Br
Reactant: C=CCN=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Product: C=CCNC(CC=C)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Allyl-(4-bromo-benzylidene)-amine (1.13 g, 5.0 mmol) is dissolved in THF (15 mL) and the mixture is cooled to 0° C. with an ice bath. Allyl magnesium bromide (6.0 mL, 1.0 M in ethyl ether, 6.0 mmol) is added. The resulting mixture is stirred at 0° C. for 1 hour and warmed to room temperature followed by reaction quenching. EtOAc and water were added and the EtOAc layer is washed with brine and dried. After removal of EtOAc, the product (1.0 g, 75%) is obtained. MS (ESI): 266, 268 (M+1)+1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([N:9]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)[CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(N(CCCO)CCCCc2ccc([N+](=O)[O-])cc2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCc1cccc(N(CCCO)CCCCc2ccc(N)cc2)c1
Yield: 100.3 %

Procedure:
Part E. 3-[[3-cyanophenyl][4-(4-nitrophenyl)butyl]amino]-1-propanol (1.4 gm, 3.96 mmol) was dissolved in 25 mL of methanol, followed by the addition of 0.14 gm of 20% Pd(OH)2 /C and placed under a balloon of hydrogen for 2.5 hours. The resulting solution was filtered through a pad of celite and the volatiles removed under vacuum to give the title compound as a clear semi-solid 1.30 gm, (100%) MS m/e 328.3 (M+H)+ 1 H NMR (CD3OD) 1.60 (br s, 4H), 1.78 (m, 2H), 2.54 (br s, 2H), 3.32 (s, 2H), 3.42 (t, 2H), 3.62 (t, 2H), 3.99 (s, 2H), 6.71-6.62 (m, 5 H), 6.93 (d, 2H), 7.20 (t, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[N:4][C:3]=1[C:23]#[N:24].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:23]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:2]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)#[N:24]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)cc1
Temperature: 95 °C
Yield: 44.6 %

Procedure:
To a mixture of tert-butyl (3R,4R)-4-(6-chloro-5-cyanopyrazin-2-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (100 mg, 0.28 mmol) in Dioxane (2 mL) was added p-toluidine (37 mg, 0.35 mmol), Pd(OAc)2 (13 mg, 0.056 mmol), BINAP (35 mg, 0.056 mmol) and K2CO3 (116 mg, 0.84 mmol). After heating at 95° C. for 4 h, the mixture was filtered, the filtrate was concentrated and purified by preparative HPLC to give tert-butyl (3R,4R)-4-(5-cyano-6-(p-tolylamino)pyrazin-2-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (53 mg).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([O:26][CH3:27])[C:11]2[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH2:13][C:12]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:1]([C:8]1[N:9]=[C:10]([O:26][CH3:27])[C:11]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:12]=2[N:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1nc(Cc2ccccc2)nc2c1CCNCC2
Yield: 100 %

Procedure:
2,7-Dibenzyl-4-methoxy-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine of Preparation 38, Step C, (75 mg, 0.2 mmol) was dissolved in 10 ml of methanol and ammonium formate (66 mg, 1.04 mmol) and 10% palladium on carbon (20 mg) was added. The reaction was refluxed under nitrogen for 2 h. The reaction mixture was filtered through Arbocel and concentrated in vacuo. The residue was purified by column chromatography on Biotage 40S cartridge, eluting with DCM:MeOH:0.880NH3 (95:5:0.5 to 90:10:1), to afford the title compound as a colourless oil in 100% yield, 56 mg.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[C:11](Br)[C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>CN(C=O)C.CCOCC.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([O:14][CH3:15])=[CH:7][C:8]([CH:9]=[O:10])=[C:11]([CH:12]=1)[CH:25]=[CH:24][C:23]([O:27][CH3:28])=[O:26])(=[O:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: COc1cc(C=O)c(Br)cc1OC(C)=O
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)C=Cc1cc(OC(C)=O)c(OC)cc1C=O
Temperature: 135 °C

Procedure:
To a degassed solution of 4-acetoxy-6-bromo-3-methoxybenzaldehyde (15.4 g), and bis(triphenylphosphine)palladium (11) (1.2 g) in DMF (150 ml) is added triethylamine (31.9 ml) and methyl acrylate (19.6 g). The mixture is heated 135° C. for about 1.5 hours, cooled to room temperature and diluted with ether and water. The organic layer is washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by HPLC, eluting with 33% ethyl acetate in hexanes, then methylene chloride, to give the desired product.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH3:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](=O)[CH2:19]Br)=[CH:16][CH:15]=1.C(OCC)(=O)C>C(N(CC)C1C=CC=CC=1)C.C1(C)C(C)=CC=CC=1>[CH3:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]2[NH:8][C:7]3[C:9]([CH:19]=2)=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=3)=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cc3cc(OC(F)(F)F)ccc3[nH]2)cc1
Temperature: 165 °C

Procedure:
To a stirred solution of 5.3 g (30 mmol) of 4-trifluoromethoxyaniline in 8 ml of N,N-diethylaniline was added dropwise at 165° C. a solution of 4.3 g of 4-methylphenacyl bromide in 7.5 ml of xylene. It was heated at 165° C. for 3 h. The mixture was cooled followed by addition of 50 ml of ethyl acetate. It was washed with 2N hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via repeated column chromatography on silica gel using a hexane dichloromethane gradient (100:0 to 50:50). The title compound thus obtained was recrystallized from hexane.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1B(O)O>>[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1
Reactant: BrCc1ccc(-c2ccccc2)nc1
Reactant: Cc1ccncc1B(O)O
Product: Cc1ccncc1Cc1ccc(-c2ccccc2)nc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 61a (100 mg, 0.40 mmol) and 4-methylpyridine-3-boronic acid (83 mg, 0.61 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using ethyl acetate as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Light yellow solid. Yield: 54 mg, 52%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.22-2.29 (m, 3H), 4.02 (s, 2H), 7.11 (d, J=5.0 Hz, 1H), 7.37-7.51 (m, 4H), 7.64 (dd, J=8.2, 0.6 Hz, 1H), 7.95-8.01 (m, 2H), 8.38-8.46 (m, 2H), 8.52-8.57 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=19.3, 33.8, 120.5, 125.7, 126.9, 129.0, 129.1, 133.2, 133.8, 136.8, 139.2, 146.1, 148.7, 149.9, 150.7, 155.9; (ESI): m/z=260.85 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([C:13]#[N:14])[N:10]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:8]=1)[CH3:2].C([O-])=O.[NH4+].C(O)C>O.[OH-].[Pd+2].[OH-].[Pd]>[NH2:14][CH2:13][C:11]1[N:10]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:8]=[C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])[CH:12]=1
Reactant: CCN(CC)CCOc1cc(C#N)nc(-c2ccccn2)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: O=C[O-]
Solvent: O
Solvent: CCO
Product: CCN(CC)CCOc1cc(CN)nc(-c2ccccn2)c1
Temperature: 27 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(2-Diethylamino-ethoxy)-[2,2′]bipyridinyl-6-carbonitrile (1.4 g, 5.22 mmol), Palladium hydroxide-Pd 20%-50% in water (2.25 g, excess), ammonium formate (1.65 g, excess) and ethanol (66 mL) was stirred at 27° C. for 2 hours. The reaction was then filtered thorough celite, washed with methanol (200 mL) and dichloromethane (200 mL) and the organic phase evaporated to dryness affording [2-(6-aminomethyl-[2,2′]bipyridinyl-4-yloxy)-ethyl]diethylamine as an orange oil (1.03 g, 30%, in a ratio 1 to 1 product vs. byproduct).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:5]=1[CH2:6][NH:7][C:8]1[C:9]2[N:10]([C:14]([Cl:18])=[C:15]([CH3:17])[N:16]=2)[CH:11]=[CH:12][CH:13]=1)([O-])=O.Cl>CO.O1CCOCC1.[Pt]>[ClH:18].[NH2:1][C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:5]=1[CH2:6][NH:7][C:8]1[C:9]2[N:10]([C:14]([Cl:18])=[C:15]([CH3:17])[N:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc([N+](=O)[O-])c1CNc1cccn2c(Cl)c(C)nc12
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cccc(N)c1CNc1cccn2c(Cl)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 164.1 %

Procedure:
A solution of 8-(2-nitro-6-methylbenzylamino)-3-chloro-2-methylimidazo[1,2-a]pyridine (2.0 g, 6 mmol) in methanol (175 ml) and dioxane (175 ml) is treated with platinum-on-carbon catalyst (5% strength) and hydrogenated at RT under atmospheric pressure for 2 h. After 2 h, 2N hydrochloric acid (5 ml) is added and the mixture is hydrogenated under the same conditions again for 1 h. The catalyst is then filtered off, the filtrate is adjusted to pH 8.5 using 2N sodium hydroxide solution and the solvent is distilled off on a rotary evaporator. The residue is dissolved in boiling ethyl acetate (400 ml). After cooling to RT, diisopropyl ether (250 ml) is added and, to complete crystallization, the mixture is stirred at 4° C. for 30 min. The precipitate is then filtered off with suction, washed with diisopropyl ether and dried in vacuo. The title compound (1.66 g, 92%) is isolated as a beige solid. M.p. 243-246° C.