Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH:16]1([S:19](Cl)(=[O:21])=[O:20])[CH2:18][CH2:17]1.[F:23][C:24]([F:36])([F:35])[CH:25]([CH3:34])[O:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>>[CH:16]1([S:19]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:33]([C:30]4[CH:31]=[CH:32][C:27]([O:26][CH:25]([CH3:34])[C:24]([F:23])([F:35])[F:36])=[CH:28][CH:29]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)(=[O:21])=[O:20])[CH2:18][CH2:17]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CC(Oc1ccc(N2CCC3(CCN(S(=O)(=O)C4CC4)CC3)C2=O)cc1)C(F)(F)F

Procedure:
White solid. MS (ESI): 447.15 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), cyclopropanesulfonyl chloride, 4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[O:9]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH3:27])=[CH:21][CH:20]=1)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].IC.O>O1CCCC1>[O:9]([CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([C:28]([O:30][CH3:31])=[O:29])([CH3:1])[CH3:27])=[CH:23][CH:24]=1)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(C)Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of lithium diisopropylamide (0.1 mol/l solution in tetrahydrofuran, 15 ml) was added a solution of 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonylpropyl)benzene (0.62 g) in tetrahydrofuran (2 ml) at -78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of iodomethane (0.20 g) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene (0.49 g) as an oily liquid. To a solution of 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene (0.49 g) in tetrahydrofuran (1.5 ml) was added tetra-n-butylammonium fluoride (1 mol/l solution in tetrahydrofuran, 1.34 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride and diethyl ether (7:1) as eluent to give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) as an oily liquid. To a solution of 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) in methylene chloride (3 ml) were added carbon tetrabromide (0.48 g) and triphenylphosphine (0.38 g), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl bromide (0.323 g) as an oily liquid.
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:8]/[C:9](/[CH3:14])=[CH:10]\[C:11]([O-:13])=[O:12].[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([O-:17])=[O:16]>C(O)(C)C>[CH3:5][C:3]1[NH:8][C:9]([CH3:14])=[C:10]([C:11]([OH:13])=[O:12])[CH:21]([C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[C:2]=1[C:1]([OH:7])=[O:6]
Reactant: C/C(N)=C/C(=O)[O-]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)[O-]
Solvent: CC(C)O
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)O)=C(C)N1
Yield: 73.3 %

Procedure:
In 30 ml of isopropyl alcohol were dissolved 1.1 g of 2-nitratopropyl acetoacetate, 1.1 g of 3-nitratopropyl 3-aminocrotonate and 0.79 g of 3-nitrobenzaldehyde. The solution was treated in the manner described in Example 1 to obtain a residue, which was then subjected to column chromatography on silica gel (eluted with n-hexane-ethyl acetate=5:1) and recrystallized from ether to obtain 1.22 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nitratopropyl) ester-5-(3-nitratopropyl) ester.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH:6]3[NH:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[C:16]([O:18]CCCC)=[O:17])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)CCC>[CH2:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH:6]3[NH:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[C:16]([OH:18])=[O:17])[CH2:3][CH2:2]1
Reactant: CCCCOC(=O)c1cccc(CNC2CC3CC2C2CCCC32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(O)c1cccc(CNC2CC3CC2C2CCCC32)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
600 mg of butyl 3-[(octahydro-4,7-methanoinden-5-ylamino)methyl]benzoate were dissolved in 1 ml of n-butanol, and 2.1 ml of a 1 N aqueous NaOH solution were added. The mixture was stirred at RT for 18 hours and then at 60° C. for 4 hours. The volatile components were then removed under reduced pressure and residual n-butanol was then distilled off twice, azeotropically, under reduced pressure, using in each case 5 ml of water. The residue was taken up in 5 ml of a 10% strength aqueous HCl solution, the volatile components were removed under reduced pressure, and the water was distilled off azeotropically twice, under reduced pressure, using in each case 5 ml of toluene. Since the product still contained considerable amounts of starting material, it was once more dissolved, in 6 ml of methanol, and admixed with 1 ml of a 2 N aqueous NaOH solution. The mixture was stirred at RT for 3 hours, and a further 5 ml of a 2 N aqueous NaOH solution were then added and the mixture was boiled under reflux for 4 hours. The volatile components were removed under reduced pressure, the residue was taken up in 20 ml of water, and the mixture was adjusted to pH=7 using dilute aqueous HCl solution. The mixture was stirred at RT for 1 hour and the product was filtered off with suction and dried under reduced pressure. This gave 260 mg of a crystalline solid, mp 258-261° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:24])[N:17]([CH2:21][CH2:22]Cl)[CH2:18][CH2:19]Cl)([CH3:14])([CH3:13])[CH3:12]>CS(C)=O.CCOC(C)=O>[C:11]([O:15][C:16]([N:17]1[CH2:21][CH2:22][C:8]([C:9]#[N:10])([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)=[O:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: N#CCc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 4-iodophenylacetonitrile (6.88 g, 28.3 mmol, 1 eq.) and bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (7.2 g, 30 mmol, 1.05 eq.) in DMSO (100 mL) under argon (Ar) was added NaNH2 (2.46 g, 60 mmol, 2 eq.) in portions over 15 min. The reaction was stirred at room temperature for 0.5 h, then poured onto ice (200 g), diluted with EtOAc (250 mL) and stirred for 1 h. The organic layer was separated and the aqueous layer was washed repeatedly with EtOAc until colorless. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to afford an orange oil which was purified by flash column chromatography by eluting with 7-12% EtOAc/hexanes to yield 4-cyano-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a pale orange oil/solid (8.28 g, 18.96 mmol, 67%). 1H NMR (300 MHz, CDCl3): δ 7.82 (dd, 2H), 7.26 (dd, 2H), 4.38 (br. s, 2H), 4.28 (br. t, 2H), 2.15 (m, 2H), 2.0 (td, 2H), 1.59 (s, 9H). (Ref.: D. Gnecco et al, Org. Prep. Proceed. Int., (1996) 28 (4), 478-480.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[C:6]=1[CH3:22])=[O:4].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)[C:6]=1[CH2:22][Br:23])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(C#N)cc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(C#N)cc2)c1CBr
Yield: 90.8 %

Procedure:
A mixture of 5-bromo-1-(4-cyano-benzyl)-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.05 g, 5.68 mmol), N-bromosuccinimide (1.11 g, 6.25 mmol), and benzoyl peroxide (0.14 g, 0.568 mmol) in CCl4 (60 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-45% EtOAc/hexanes) to give 2.27 g of the title compound as a white solid. 1H NMR (CDCl3, 200 MHz): δ=8.42 (s, 1H), 7.65 (d, 2H, J=8.2 Hz), 7.20-7.40 (m, 2H), 5.69 (br s, 2H), 4.87 (br s, 2H), 3.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10]C(=O)C.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([NH2:10])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(F)c(F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(F)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A solution of N-(2-chloro-4,5-difluorophenyl)acetamide (4.69 g, 22.8 mmol) in acetic acid (4.5 mL) and concentrated sulfuric acid (15 ml) was cooled to 0° C. To the solution was added a mixture of fuming nitric acid (2 mL) and acetic acid (0.5 mL). After stirring for 1.5 h at 0° C., the mixture was poured into ice. A precipitate formed, and it was collected by filtration. The filtrate was extracted with ether, and the organic phase was dried over magnesium sulfate, filtered, and concentrated to sticky yellow syrup. The solid and the syrup were combined, and to the resulting residue was added concentrated hydrochloric acid (30 mL). This mixture was heated to 120° C. for 1.25 h. It was then cooled to rt and subsequently poured onto ice. The aqueous solution was extracted with ethyl acetate. The organics were washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (80% hexanes: 20% ethyl acetate) to provide the desired 6-chloro-3,4-difluoro-2-nitroaniline (3.30 g, 15.8 mmol, 69% yield). 1H NMR (400 MHz, CDCl3): 7.43 (dd, 1H), 5.86 (br s, 2H); GCMS for C6H3ClF2N2O2: 208 (M+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[N:17]#[C:18][NH2:19].CC(C)([O-])C.[K+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([S:36][CH3:37])[CH:31]=1)=[O:29]>C(#N)C.C(O)(C)(C)C.C(OCC)(=O)C>[NH2:17][C:18]1[N:19]=[C:2]([NH:1][C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)=[CH:8][CH:9]=2)[S:3][C:27]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([S:36][CH3:37])[CH:31]=1)=[O:29]
Reactant: CN1CCN(c2ccc(N=C=S)cc2)CC1
Reactant: N#CN
Reactant: CSc1cccc(C(=O)CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CSc1cccc(C(=O)c2sc(Nc3ccc(N4CCN(C)CC4)cc3)nc2N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a mixture of 1-(4-isothiocyanatophenyl)-4-methylpiperazine (of Example 1; 0.466 g, 2.0 mmol) and cyanamide (0.088 g, 2.1 mmol) in acetonitrile (3 mL) and t-butanol (5 ml), a solution of potassium tert-butoxide (2.0 mL, 1.0 M in tert-BuOH) was added. After 30 minutes at room temperature, 2-bromo-1-(3-methylsulfanyl-phenyl)ethanone (which can be prepared by the procedure of Rogers, N. H. et. al. EP 87953; 0.49 g, 2.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then refluxed for 15 minutes. The cooled mixture was diluted with ethyl acetate and washed in turn with saturated aqueous sodium carbonate and brine. The dried (sodium sulfate) solution was evaporated and the residue chromatographed on silica gel. Elution of the desired product with 9:1 dichloromethane/methanol and crystallization from ethyl acetate/hexane provided 0.439 g (50% yield) of [4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-methylsulfanyl-phenyl)methanone. Mass spectrum (ES) MH+=440.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[C]=O.[C:29]([O:32][CH2:33]C)(=[O:31])C>CO>[CH3:33][O:32][C:29]([C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1)=[O:31]
Reactant: Nc1ncc(Br)nc1-c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(C)=O
Agent: [C]=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N)c(-c2ccc(OC(F)(F)F)cc2)n1
Yield: 73 %

Procedure:
To a solution of 10.20 g (0.029 mol) 5-bromo-3-(4-trifluoromethoxy-phenyl)-pyrazin-2-ylamine in 100 ml methanol and 40 ml ethyl acetate was added 0.500 g (0.0006 mol) PdCl2 dppf CH2Cl2 ([1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct, Cas Registry No. [95464-05-4]) and 8.113 ml (5.9 g, 0.058 mol) triethylamine and the mixture was stirred at 110° C. under 70 bar carbon monoxide pressure for 4 h. The solvents were evaporated and the residue was purified by chromatography on silica gel with a gradient of 100% heptane to 100% ethyl acetate to yield 6.800 g (73% yield) of the title compound as off white crystalline solid. MS (ISP) (M+H+)=314.0.
Reaction SMILES: [F:1][C:2]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([C:18]([N:20]2CC(=C)C2)=[O:19])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[F:12].C[N+]1([O-])CC[O:29][CH2:28]C1.[CH3:33][C:34]([CH3:36])=[O:35].O>[Os](=O)(=O)(=O)=O>[F:1][C:2]1[C:3]([NH:4][C:5]2[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=2[F:12])=[C:13]([C:18]([N:20]2[CH2:36][C:34]([CH2:28][OH:29])([OH:35])[CH2:33]2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(CO)C1
Reaction time: 4 h
Yield: 28 %

Procedure:
2,3-Difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-methylideneazetidin-1-yl)carbonyl]aniline (56 mg, 0.126 mmol) and 4-methylmorpholine N-oxide (44 mg, 0.376 mmol) were dissolved in acetone/water (4:1; 10 mL) and osmium tetroxide (4 wt. % in water; 0.7 mL) was added. The solution was stirred at ambient for 4 h, then was quenched with saturated sodium bisulfite (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 80% ethyl acetate in hexanes) and then reverse phase HPLC gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol (17 mg, 0.036 mmol, 28% yield): 1H NMR (400 MHz, CDCl3): 8.43 (br s, 1H), 7.40 (dd, 1H), 7.35-7.31 (m, 1H), 7.16-7.10 (m, 1H), 6.81 (ddd, 1H), 6.61 (ddd, 1H), 4.25-4.00 (m, 4H), 3.78 (s, 2H); MS (EI) for C17H14F3IN2O3: 479 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH2:18]([S:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[CH3:19].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CN1C(=O)CCC1.C(OCC)(=O)C>[CH2:18]([S:20][CH2:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=3[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=2)[CH:26]=[CH:27][CH:28]=1)[CH3:19]
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: CCSCc1cccc(N)c1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: CCSCc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (750 mg; 2.92 mmol), 3-[(ethylsulfanyl)methyl]aniline (376 mg; 2.24 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct (139 mg; 0.17 mmol; ABCR GmbH & CO. KG) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (80 mg; 0.17 mmol; Aldrich Chemical Company Inc.) and potassium phosphate (2.39 g; 11.24 mmol) in toluene (15 ml) and NMP (3 mL) was stirred at 130° C. for 3 hours. After cooling, the batch was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 2:1) to give the pure product (536 mg; 1.38 mmol).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[C@@H:7]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[CH2:2]1.FC(F)(F)C(O)=O.[C:37]([OH:46])(=[O:45])[C@@H:38]([C@H:40]([C:42]([OH:44])=[O:43])[OH:41])[OH:39]>ClCCl>[C:42]([C@@H:40]([C@H:38]([C:37]([OH:46])=[O:45])[OH:39])[OH:41])([OH:44])=[O:43].[O:1]1[CH2:5][CH2:4][C@@H:3]([N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:27])([F:28])[F:29])[C@H:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N(Cc2ccccc2C(F)(F)F)[C@@H]2CCOC2)C1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccccc1CN([C@@H]1CCOC1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1,1-dimethylethyl (3R)-3-((3R)-tetrahydrofuran-3-yl{[2-(trifluoromethyl)phenyl]-methyl}amino)pyrrolidine-1-carboxylate (0.12 g, 0.29 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL). After stirring at room temperature for 3 h the solvent was removed in vacuo and the crude product taken up in methanol. This solution was absorbed onto a cationic ion exchange resin (Isolute™ SCX-2) and the basic components recovered from the column by elution with 2N ammonia in methanol. The eluate was evaporated, taken up again in methanol and L-tartaric acid (1 equivalent) added. The solvent was removed in vacuo and the resultant gum triturated with diethyl ether to yield the title compound as a pink microcrystalline solid. 1H NMR (300 MHz, CD3OD) δH: 7.82 (d, 1H), 7.57 (d, 1H), 7.53 (t, 1H), 7.32 (t, 1H), 4.31 (s, 2H), 3.92-3.82 (m, 3H), 3.70-3.47 (m, 5H), 3.37-3.22 (m, 2H), 3.17-3.03 (m, 1H), 2.94 (dd, 1H), 2.12-1.96 (m, 2H), 1.85-1.67 (m, 2H); MS: [M+H]=315.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Br:19][C:20]1[CH:26]=[CH:25][C:23](N)=[C:22]([F:27])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[C:22]([F:27])[CH:21]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Br)cc4F)c3c2s1
Yield: 30 %

Procedure:
Prepared from VII and 4-bromo-2-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 30%; brown solid; mp>260° C.; IR (KBr) νmax/cm−1 3325, 3053, 2230, 1649, 1614, 1582, 1556, 1499, 1462, 1380, 1351, 1250, 1154, 1132, 1052, 969, 904, 875, 817; 19F NMR (282 MHz, DMSO-d6) δ −119.9; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (d, 1H, J=9.0 Hz), 8.26 (d, 1H, J=9.0 Hz), 7.78 (m, 1H), 7.55-7.52 (m, 1H), 7.38-7.25 (m, 2H); HRMS calcd for C16H8N5SBrF (M+H+): 399.9668, found 399.9662.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[O:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=3)[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:17].[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[O:29][C:30]([C:33]([F:36])([F:34])[F:35])=[N:31][N:32]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:9][CH:8]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: Cl
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(-c5nnc(C(F)(F)F)o5)cc34)cc2)c1

Procedure:
The title compound was prepared according to Procedure A from 4-(3-fluoro-benzyloxy)aniline and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.74(1H, bs), 9.51(1H, s), 8.91(1H, s), 8.66(1H, dd), 8.12(1H, d), 7.65(2H, d), 7.48(1H, m), 7.32(2H, m), 7.19(1H, m), 7.17(2H, d), 5.20(2H, s); m/z (M+1+) 482.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH2:22][CH2:23][OH:24]>>[C:1]([O:20][CH2:3][CH2:2][CH2:1][O:19][C:23](=[O:24])[CH2:22][CH2:21][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
(Diester of GLA and Oleic Acid with 1,3-Propane Diol).
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].C(N(CC)CC)C.[CH:14](/[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](OS(C(F)(F)F)(=O)=O)[CH:29]=2)[NH:24][N:23]=1)=[CH:15]\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=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>[CH3:3][O:2][P:1]([C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[C:22]2/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:6])[O:4][CH3:5]
Reactant: COP([O-])OC
Reactant: O=S(=O)(Oc1ccc2[nH]nc(/C=C/c3ccccc3)c2c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COP(=O)(OC)c1ccc2[nH]nc(/C=C/c3ccccc3)c2c1
Temperature: 85 °C
Yield: 6.4 %

Procedure:
40.7 μl (1.09 eq; 0.444 mmol) of dimethyl phosphite, 61.9 μl (1.09 eq; 0.444 mmol) of triethylamine and 18.8 mg (0.04 eq; 0.016 mmol) of tetrakis(triphenylphosphine)palladium(0) are stirred under an argon atmosphere for 15 minutes. 150 mg (1 eq; 0.407 mmol) of trifluoromethanesulfonic acid 3-((E)-styryl)-1H-indazol-5-yl ester in solution in 5 ml of dimethylformamide are added. The medium is heated at 85° C. overnight. 41 μl of dimethylphosphite, 62 μl of triethylamine and 20 mg of tetrakis(triphenylphosphine)palladium(0) are added to the medium, which is heated for a further two hours. 100 μl of dimethylphosphite, 100 μl of triethylamine and 30 mg of tetrakis(triphenylphosphine)palladium(0) are then added to the medium, which is heated overnight at 105° C. After filtration of the catalyst through filter paper, the solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by LC/MS to obtain 8.6 mg of [3-((E)-styryl)-1H-indazol-5-yl]phosphonic acid dimethyl ester, along with 27.2 mg of [3-((E)-styryl)-1H-indazol-5-yl]phosphonic acid monomethyl ester (Example 13).