Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([CH3:11])[N:7]=[C:6]([CH3:12])[C:5]=2[C:4](=[O:13])[N:3]1[CH3:14].C1C(=O)N([Br:22])C(=O)C1.OS(O)(=O)=O.[OH-].[Na+]>O>[Br:22][C:9]1[C:10]2[N:2]([CH3:1])[N:3]([CH3:14])[C:4](=[O:13])[C:5]=2[C:6]([CH3:12])=[N:7][C:8]=1[CH3:11]
Reactant: Cc1cc2c(c(C)n1)c(=O)n(C)n2C
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(C)c2c(=O)n(C)n(C)c2c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1,2,4,6-tetramethyl-1H,2H,3H-pyrazolo[4,3-c]pyridin-3-one (0.33 g, 1.7 mmol), NBS (0.34 g, 1.9 mmol) and conc. H2SO4 (8 ml) is stirred at RT for 18 h. The mixture is poured onto ice-water. The water phase is made basic with an aqueous solution of sodium hydroxide (1 mol/l) and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. 7-bromo-1,2,4,6-tetramethyl-1H,2H,3H-pyrazolo[4,3-c]pyridin-3-one is used without further purification. Yield: 0.37 g (80%). HPLC-MS: M+H=270/272; tR=0.77 min (METHOD—1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[H-].[Na+].CS(C)=O.Cl[CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([O-])=[O:24]>O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH2:21][CH3:20])[C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: CC(C)(CCCl)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(C)(C)C(=O)n1cnc2c1c(=O)[nH]c(=O)n2C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
This example illustrates a synthesis of 1-(8,9-Oxidohexyl)-3-methyl-7-ethylpivaloylxanthine (inventive compound no. 1410). A mixture of 3-methylxanthine (Aldrich, 1.00 g, 6.0 mmol), sodium hydride (145 mg, 6.0 mmol) and dimethyl sulfoxide (20 mL) was stirred until homogeneous (0.5 hours). Chloromethylpivalate (865 mL, 904 mg, 6.0 mmol) was added and the reaction stirred for 18 hours. The reaction mixture was poured into water (70 mL) and then extracted with 25% ethanol/dichloromethane (4×60 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum to a volume of 40 mL. This solution was cooled in icewater, whereupon a thick white precipitate formed. The solid was filtered off under suction and dried under vacuum to yield 1.43 g (90% yield) 3-methyl-7-(methylpivaloyl)xanthine (inventive compound no. 1404).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][C:13]=1[Cl:14].[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1>O1CCOCC1>[Cl:18][C:19]1[CH:24]=[C:23]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)[N:22]=[CH:21][N:20]=1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
Potassium carbonate (2M solution, 200 ml, 400.0 mmol) was added in one portion to a stirred solution of 3,4-dichlorophenyl boronic acid (38.5 g, 201.4 mmol) and 4,6-dichloropyrimidine (50.0 g, 335.6 mmol) in dioxane (600 ml). The mixture was degassed with nitrogen for 5 minutes, after which time palladium tetrakis triphenylphosphine (7.78 g, 6.71 mmol) was added in one portion, the mixture was then heated to 90° C. and stirred at this temperature for 16 hours under a nitrogen atmosphere. After this time the reaction mixture was cooled to room temperature and concentrated. The resulting residue was dissolved in DCM (500 ml), washed sequentially with water (200 ml) then brine (200 ml) before being dried (MgSO4), filtered and concentrated to give the title compound (47.8 g, 91% yield) as a white solid which was used without further purification. Tr=2.32 min m/z (ES+) (M+H+) 258, 260.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[N:11]3[CH:18]=2)=[C:4]([F:19])[CH:3]=1.[C:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)(=[O:27])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([NH:24][S:25]([C:28]1[C:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[N:11]4[CH:18]=3)=[C:4]([F:19])[CH:3]=2)=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: COc1cccc2nc(-c3ccc(Br)cc3F)cn12
Product: COc1cccc2nc(-c3ccc(-c4ccccc4S(=O)(=O)NC(C)(C)C)cc3F)cn12

Procedure:
The title compound was prepared using methods analogous to those described in Example 88 using 2-(4-bromo-2-fluorophenyl)-5-methoxyimidazo[1,2-a]pyridine and 2-(tert-butylamino)sulfonylphenylboronic acid. MS (ESI): mass calcd. for C24H24FN3O3S, 453.15; m/z found, 454.4 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.58 (m, 1H), 8.19 (dd, J=8.0, 1.4, 1H), 8.10 (d, J=3.9, 1H), 7.81 (dd, J=6.7, 0.9, 1H), 7.60-7.55 (m, 1H), 7.54-7.48 (m, 1H), 7.43 (dd, J=12.1, 1.7, 1H), 7.38-7.32 (m, 2H), 6.73 (dd, J=7.6, 6.7, 1H), 6.50 (d, J=7.6, 1H), 4.07 (s, 3H), 3.68 (s, 1H), 1.02 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CC(=O)CC.O>[CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:14][CH:15]=2)[N:4]=1)[CH3:2]
Reactant: CCc1cc(CC)n(-c2ccc(O)cc2)n1
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCc1cc(CC)n(-c2ccc(OCCCN3CCCC3)cc2)n1
Temperature: 80 °C
Yield: 9.3 %

Procedure:
To a solution of 4-(3,5-diethylpyrazol-1-yl)phenol (50 mg, 0.23 mmol) in 2-butanone (2 mL) was added potassium carbonate (35 mg, 0.25 mmol) and 1-(3-chloropropyl)pyrrolidine (37 mg, 0.25 mmol). The vial was capped and the reaction was heated overnight at 80° C. After the reaction was diluted with water and extracted with methylene chloride, the organic layer was dried (MgSO4) and concentrated. The residue was purified by semi-prep LC-MS to give 7.0 mg of the desired product. LC-MS (C20H29N3O calculated 327) m/z 328 (M+H); 1H NMR (300 MHz, CDCl3) 7.29 (d, J=9.0 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.02 (s, 1H), 4.05 (t, J=6.3 Hz, 2H), 2.73-2.54 (m, 10H), 2.06 (quint, J=6.3 Hz, 2H), 1.83 (s, 4H), 1.28 (t, J=7.5 Hz, 3H), 1.19 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(O)(=O)C.BrBr>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(Br)cc2)=NN1
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(-c2ccc(Br)cc2)n[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 86.3 g of 6-(p-bromophenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as described in Example 5 of U.S. Pat. No. 3,689,652) in 500 ml. of glacial acetic acid is heated to 80° C. with continuous stirring. A solution of 60 g. (19.2 ml) of bromine in 80 ml. of acetic acid is added dropwise at 75°-80° C. over a period of 1 hour. The mixture is heated with stirring on a steam bath for 1/2 hour more and then poured into 3 liters of cracked ice and water. The white solid is collected by filtration and air dried, yielding 6-(p-bromophenyl)-3(2H)-pyridazinone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.Cl>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(N[C@H](CC(=O)O)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)[C@@H](CC(=O)O)Nc1ccnc(-c2c[nH]c3ncc(F)cc23)n1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoic acid, 128a (0.019 g, 0.037 mmol) in acetonitrile (0.6 mL) was added HCl (0.15 mL of 4 M in dioxane, 0.60 mmol). The solution was heated to 60° C. for 18 hours. Then, additional HCl (0.36 mL of 4 M in dioxane) was added and heating was continued for 4 hours. The mixture was cooled and concentrated in vacuo. Trituration with Et2O followed by purification by preparatory HPLC provided 17.5 mg of the desired product as a TFA salt. The NMR indicated a 4 to 1 ratio of atropisomers: 1H NMR (400 MHz, MeOD, major atropsomer) δ 8.70 (dd, J=8.9, 2.3 Hz, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 7.99 (d, J=7.3 Hz, 1H), 6.60 (d, J=7.2 Hz, 1H), 5.05 (d, J=10.7 Hz, 1H), 2.93 (dd, J=15.9, 1.8 Hz, 1H), 2.53 (dd, J=15.9, 11.2 Hz, 1H), 1.08 (d, J=0.8 Hz, 9H); LCMS Gradient 10-90%, 0.1% trifluoroacetic acid, 5 minutes, C18/ACN, RT=2.17 minutes (M+H) 358.02.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1F.[CH2:18]([SH:20])[CH3:19].[Na]>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[S:20][CH2:18][CH3:19]
Reactant: CCS
Reactant: O=c1[nH]c2cc(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CCSc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]

Procedure:
A solution of 7-Chloro-1,4-dihydro-6-fluoro-5-nitroquinoxaline-2,3-dione (0.100 g, 0.385 mmol) and ethanethiol, sodium salt (0.130 g, 1.55 mmol) in DMSO (1.0 mL) was stirred at room temperature for 24 h. The resulting solution was diluted with water (5 mL) and acidified with concd HCl (4-5 drops) to pH 5. The precipitated solid was collected by filtration under vacuum, washed with water (10 mL), and dried under vacuum to obtain 0.098 g (84%) pure (HPLC) title compound as a yellow powder; mp darkens at 323° C.; 1H NMR (DMSO-d6) δ 1.04 (t, 3H, J=7.2 Hz), 2.82 (q, 2H, J=7.5 Hz), 7.34 (s, 1H), 12.20 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](OC)=O)=[N:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].BrC[C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:26]([O:28][CH3:29])=[O:27])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CBr
Reactant: COC(=O)Nc1ccn(-c2ccc(OC)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CNc1ccn(-c2ccc(OC)cc2)n1
Temperature: 85 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-amino-1H-pyrazole-5-[(2′-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl)carboxyamide (1.0 g, 1.92 mmol) in 10 mL of DMF was added sodium bicarbonate (0.24 g, 2.88 mmol) and methyl bromoacetate (0.22 mL, 2.30 mmol) The resulting mixture was stirred at 85° C. for 16 h. The reaction was not complete so additional portions of sodium bicarbonate (0.48 g, 5.76 mmol) and methyl bromoacetate (0.22 mL, 2.30 mmol) were added and the reaction was stirred at 95° C. for 6 h longer. The reaction was cooled to ambient temperature and was diluted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 5 mL of trifluoroacetic acid and was stirred at reflux for 20 min and then was cooled to ambient temperature and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 450 mg (44%) of the title compound as a white powder. LRMS (ES+): 536.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+]([O-])=O)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+].[H-]>ClCCl.CN(C=O)C>[N+:1]([C:4]1[CH:12]=[C:11]([O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)c1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of 2,4-dinitrobenzoic acid [Aldrich] (1.06 g, 5 mmol) in dichloromethane (20 ml) was treated with oxalyl chloride (2 ml) and 1 drop DMF. Vigorous evolution of gas occurred which ceased after 1 hour. The solution was evaporated to the yellow acid chloride. A solution of phenol (1.5 g, 15.5 mmol) in DMF (20 ml) was introduced into a second flask charged with sodium hydride (480 mg, 60% oil dispersion, 12 mmol). When all the hydride had dissolved this solution was treated with the acid chloride, portionwise over five minutes. The solution was then heated to 60° C. for 12 h, cooled, the solvents removed by evaporation in vacuo, and the residue treated with a solution of 40% sodium hydroxide (50 ml) and ethanol (50 ml). The mixture was stirred at RT for 12 hours then acidified to pH 2 with (2M aq HCl) and extracted into ethyl acetate (3×100 ml). The combined organic phase was washed with saturated brine (50 ml), dried (MgSO4), filtered, and evaporated to a yellow solid. This was purified by flash chromatography (ethyl acetate-hexane) to give 2-nitro-4-phenoxy-benzoic acid (894 mg, 69%);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:17])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].Br[CH2:21][CH:22]=[CH2:23]>CN(C)C=O.C(OCC)C>[CH2:23]([O:17][C:9]1([CH2:8][N:5]2[C:6]([CH3:7])=[C:2]([Br:1])[CH:3]=[N:4]2)[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]1)[CH:22]=[CH2:21]
Reactant: Cc1c(Br)cnn1CC1(O)CCCC(C)(C)C1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOC1(Cn2ncc(Br)c2C)CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 157B (2.73 g) in N,N-dimethylformamide (20 mL) was added NaH (1.45 g) and the reaction mixture was stirred for 30 minutes at room temperature. 3-Bromoprop-1-ene (1.53 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether (75 mL), washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 1.5% to 15% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[C:13][CH:14]([CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[OH:15].[H-].[Na+].Br[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26]>CN(C)C=O>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[C:13][CH:14]([O:15][CH2:24][C:25]([OH:27])=[O:26])[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1nc2ncnn2c(N)c1C#CC(O)C1CCCC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2ncnn2c(N)c1C#CC(OCC(=O)O)C1CCCC1
Reaction time: 2 h
Yield: 21 %

Procedure:
To a stirring solution of Example 35B (20 mg, 0.074 mmol) in 0.5 mL of anhydrous N,N-dimethylformamide was added NaH (60%, 4.0 mg, 0.096 mmol). The resulting mixture was stirred for 20 min before tert-butyl bromoacetate (11 μL, 0.0.74 mmol) was added, and stirring continued for 2 h. The reaction mixture was then partitioned between ethyl acetate (10 mL) and brine (10 mL), the organic layer was dried over MgSO4, filtered, evaporated to dryness in vacuuo. The residue was treated with 1.0 mL of 4N HCl in 1,4-dioxane for 3 h. Organic solvent was then removed on a rotavap, and the residue was purified using reverse phase HPLC (C-18 column, eluting with a 5-100% CH3CN gradient in 10 mM ammonium acetate(aq.)) to give the title Compound (5 mg, 21% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.15 (brs, 2H), 4.79-4.60 (m, 2H), 4.34 (d, J=7.1 Hz, 1H), 2.54 (s, 3H), 2.25-2.15 (m, 1H), 1.81-1.38 (m, 8H). MS (ESI) m/z 330 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:14])=[CH:11]/[CH:12]=[O:13].C(N(CC)CC)C.[P:24]([O-:29])([O:27][CH3:28])[O:25][CH3:26]>C(#N)C>[OH:13][CH:12]([P:24](=[O:29])([O:27][CH3:28])[O:25][CH3:26])/[CH:11]=[C:10](\[CH3:14])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:15])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1]
Reactant: COP([O-])OC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C(O)/C=C(\C)CC/C=C(\C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of farnesal (245 mg, 1.11 mmol) in acetonitrile (1.1 ml) under argon at room temperature (r.t), was added triethylamine (0.31 ml, 2.22 mmol) and dimethyl phosphite (0.153 ml, 1.67 mmol) and the resulting mixture stirred at r.t. for 24 hr. The reaction mixture was concentrated in vacuo, the resulting residue was chromatographed over silica gel eluted with ethyl acetate to afford the title compound as a colorless oil: NMR (CDCl3) δ 1.60 (6H, s), 1.68 (3H, s), 1.71 (3H, d, J=3.1 Hz), 1.80-2.30 (9H, m), 3.80 (6H, m), 4.69 (1H, dt, J=9 and 5.4 Hz), 5.00-5.20 (2H, m), 5.34 (1H, m).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:1]([NH:11][C@H:12]([C:16]([O:18][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
A suspension of 3.40 g (13.5 mmol) of Cbz-valine and 1.56 g (13.5 mmol) of N-hydroxysuccinimide in 200 ml of dichloromethane was treated with 2.86 g (14.9 mmol) of N-ethyl-N'-(dimethylaminopropyl) carbodiimide hydrochloride and stirred at ambient temperature for 4 h. The resulting solution was washed sequentially with 10% citric acid, aqueous NaHCO3, and water; dried over Na2SO4, and concentrated in vacuo to provide 4.00 g (85%) of the desired compound.
Reaction SMILES: [C:1]([C:9]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:10]=1[C:11]([N:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH3:14])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl>CO.O1CCOCC1>[CH3:25][O:24][C:21]1[CH:20]=[C:10]2[C:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:15]([C:16]([O:18][CH3:19])=[O:17])[N:13]([CH3:14])[C:11]2=[O:12])=[CH:23][CH:22]=1
Reactant: COC(=O)CN(C)C(=O)c1cc(OC)ccc1C(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2ccccc2)c2ccc(OC)cc2c(=O)n1C
Temperature: 25 °C

Procedure:
The amide 4 from the previous step was dissolved in methanol (10 ml) and treated with 25% NaOMe in methanol (1 ml). The resulting yellow mixture was then heated at 65 C for 1 h. After cooling to room temperature the reaction mixture was acidified with 1M HCl in dioxane. The resulting mixture was filtered to remove NaCl. The filtrate was concentrated and the residue purified by automated flash chromatography.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][O:29][CH2:30][CH2:31][NH:32][CH2:33][CH:34]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([Cl:51])[CH:45]=1)[CH2:35][CH2:36][O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1.C(N(CC)CC)C.[CH:59]([O:62][C:63]1[CH:64]=[C:65]([CH2:69][C:70](O)=[O:71])[CH:66]=[CH:67][CH:68]=1)([CH3:61])[CH3:60]>C(Cl)Cl>[CH:59]([O:62][C:63]1[CH:64]=[C:65]([CH2:69][C:70]([N:32]([CH2:33][CH:34]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([Cl:51])[CH:45]=2)[CH2:35][CH2:36][O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[CH2:31][CH2:30][O:29][CH3:28])=[O:71])[CH:66]=[CH:67][CH:68]=1)([CH3:61])[CH3:60]
Reactant: COCCNCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
2.6 g of BOP are added to a solution cooled at 0° C. of 1.9 g of the product prepared in step 2, 1.2 g of triethylamine and 0.96 g of 3-isopropoxyphenylacetic acid in 50 ml of CH2Cl2. The reaction mixture is stirred for one hour and is then concentrated under vacuum. The residue is taken up in ethyl acetate, washed with water, dried over Na2SO4 and concentrated under vacuum. 2.2 g of the expected product is obtained, which is directly used in the next step.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=4)=[CH:11][N:10]3[CH:23]=2)=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:22][CH2:21][C:17]2[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]4[N:10]([CH:23]=[C:7]([C:4]5[CH:3]=[CH:2][C:1]([CH3:24])=[CH:6][CH:5]=5)[N:8]=4)[CH:11]=3)[CH:20]=[CH:19][CH:18]=2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(-c2cn3cc(-c4cccc(CO)c4)ccc3n2)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cn3cc(-c4cccc(COc5ccc(Cl)cc5)c4)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
200 mg of [3-(2-p-tolylimidazo[1,2-a]pyridin-6-yl)phenyl]methanol (Example 3) are dissolved in 20 ml of dry tetrahydrofuran, 123 mg of p-chlorophenol, 193 mg of tributylphosphine and 210 mg of 1,1′-azodicarbonyldipiperidine are added thereto and the mixture is left to stir at ambient temperature for 16 h. The solvent is evaporated off under reduced pressure. The residue is taken up with 10 ml of ethyl acetate, the precipitate is removed, the filtrate is concentrated and the residue is purified by chromatography. The solid obtained is taken up with petroleum ether and the precipitate is recovered by filtration and dried under reduced pressure. 52 mg of compound are obtained. Mp=182-184° C. 1H NMR (DMSO-d6, δ in ppm): 2.32 (s, 3H); 5.17 (s, 2H); 7.06 (d, J=7 Hz, 2H); 7.23 (d, J=7.2 Hz, 2H); 7.32 (d, J=7.3 Hz, 2H); from 7.40 to 7.80 (m, 6H); 7.84 (m, J=7.8 Hz, 2H); 8.32 (s, 1H); 8.86 (m, 1H). M+H=425.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl>C1COCC1>[CH3:17][Si:18]([CH3:21])([CH3:20])[O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)Cl
Reactant: Nc1ccc(CO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 945.1 %

Procedure:
To a stirred solution of 4-amino benzyl alcohol (16.0 g, 13.0 mmol, 1.0 eq) in THF (400 mL), was added triethylamine (18.9 mL, 13.6 mmol, 1.05 eq) followed by trimethylchlorosilane (17.2 mL, 13.6 mmol, 1.05 eq). The reaction mixture was stirred under a nitrogen atmosphere overnight at room temperature. THF was evaporated under vacuum and the mixture partitioned with ethyl acetate (300 mL) and water (300 mL). The organic phase was isolated and the aqueous layer re-extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (2×150 mL), dried (MgSO4), filtered and concentrated in vacuo. The product was obtained as a yellow oil (24.0 g, 95% yield) and used in stage 4 without further purification.