Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:11][C:9]2=[O:10])=[CH:4][CH:3]=1.[CH2:20]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].N1C=CC=CC=1.Cl.CC[O:47]CC>ClCCl>[CH2:20]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([O:47][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[C@H:8]2[CH2:13][C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:11][C:9]2=[O:10])=[O:34])=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCOCC
Reactant: CCCCCC[C@@H]1C[C@H](c2ccc(O)cc2)C(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccccc2[C@H]2C[C@@H](CCCCCC)OC2=O)cc1
Reaction time: 6 h
Yield: 70 %

Procedure:
In 4 ml of dichloromethane were dissolved 50 mg of (2R,4R)-2-(4-hydroxyphenyl)-4-decanolide obtained in Example 3 and 49 mg of 4-octyloxybenzoyl chloride. To this solution was added 1 ml of pyridine. The resulting mixture was stirred for 6 hours under heating to reflux. The reaction mixture was allowed to cool, and then 50 ml of ether and diluted hydrochloric acid were added thereto. The resulting organic layer was separated, washed with water, and then dried with anhydrous sodium sulfate. The solvent was removed by evaporation and the resulting crude produce was purified by silica gel column chromatography, thereby obtaining 65 mg of crystals of the desired compound (yield 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:8]([OH:9])[CH:7]=[C:5]([OH:6])[CH:4]=1.Cl[CH2:12]C#N.Cl.[C:16]([O-])(=[O:18])C>[Cl-].[Zn+2].[Cl-]>[OH:9][C:8]1[CH:10]=[C:3]2[C:4]([C:16](=[O:18])[CH2:1][O:2]2)=[C:5]([O:6][CH3:12])[CH:7]=1
Reactant: COc1cc(O)cc(O)c1
Reactant: CC(=O)[O-]
Reactant: N#CCCl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1cc(O)cc2c1C(=O)CO2

Procedure:
A process of synthesizing 5-methoxy psoralene comprising methylating phloroglucinol with methanol to obtain the monomethyl ether of phloroglucinol; cyclizing the phloroglucinol monomethyl ether by first reacting with chloracetonitrile in the presence of gaseous HCl and zinc chloride then heating with postassium acetate to obtain 6-hydroxy-4-methoxy-3-coumaranone; reducing the 6-hydroxy-4-methoxy-3-courmaranone by direct reduction in the presence of a hydrazine hydrate catalyst to obtain 6-hydroxy-4-methoxy coumaran; cylizing the 6-hydroxy-4-methoxy-coumaran by reacting with acrylonitrile in the presence of HCl and zinc chloride to obtain 3,4,4',5'-tetra-hydro-5-methoxy psoralene and dehydrogenerating the 3,4,4',5' tetrahydro-5-methoxy psoralen to obtain 5-methoxy psoralene.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C@:20]2([CH3:26])[CH2:24][O:23]C(=O)[NH:21]2)[CH:14]=[CH:13]3)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(O)C.[OH-].[Li+].O>>[NH2:21][C@@:20]([C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([O:9][C:8]3[CH:27]=[CH:28][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[CH:11]=2)[CH:16]=1)([CH3:26])[CH2:24][OH:23]
Reactant: CC(C)Oc1ccc(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
(R)-4-[6-(4-isopropoxy-phenoxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (1.092 g, 0.002894 mol) was dissolved in ethanol (60 mL, 1 mol), followed by 4 M lithium hydroxide in water (30 mL, 0.1 mol). The reaction mixture was then heated at 80° C. for 5 hours. LCMS indicates no SM remains with mostly DP RT=1.26 min, M+1=352. All solvent was removed under reduced pressure. The solid was triturated with DCM, and the solvent was then washed with water. Organic was dried over MgSO4, filtered and concentrated to dryness. Residue was then placed on the high vac for 5 hours. 1H NMR and LCMS were consistent with structure. ESI-MS: 360 (M−16)+ 1H NMR (400 MHz, CHLOROFORM-d) δ=7.88-7.67 (m, 3H), 7.50-7.21 (m, 5H), 7.00 (m, 2H), 6.45-6.13 (m, 1H), 4.82-4.67 (m, 1H), 4.43 (s, 2H), 2.17 (s, 3H), 1.46-1.28 (d, J=9.0 Hz, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[CH3:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][NH2:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:34][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([CH3:29])[CH:31]=1)=[O:27]
Reactant: O=C(Br)CBr
Reactant: COc1cccc(CC2NCCc3cc(OC)c(OC)cc32)c1
Reactant: Cc1cccc(CN)c1
Product: COc1cccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2cccc(C)c2)c1

Procedure:
prepared by reaction of 1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with 3-methyl-benzylamine
Reaction SMILES: C([C:3](CC)([C:13]([O-:15])=[O:14])[C:4](CC)([C:8]([O-:10])=O)[C:5]([O-:7])=O)C.Cl.[C:19]([NH2:22])(=[NH:21])[CH3:20].[CH3:23][O-].[Na+]>CO>[OH:7][C:5]1[C:4]([CH2:3][C:13]([O:15][CH3:23])=[O:14])=[C:8]([OH:10])[N:22]=[C:19]([CH3:20])[N:21]=1
Reactant: CC(=N)N
Reactant: CCC(CC)(C(=O)[O-])C(CC)(C(=O)[O-])C(=O)[O-]
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(O)nc(C)nc1O
Temperature: 90 °C
Yield: 68.8 %

Procedure:
A mixture of triethyl-1,1,2-ethanetricarboxylate (20ml, 87mM) and acetamidine hydrochloride (8.22g, 87mM) was added to a solution of sodium methoxide (9.4g, 174mM) in dry methanol (100ml). The mixture was heated at 90° C. for 15 hours. The solvent was evaporated and the residue dissolved in water (150ml). The pH of the solution was adjusted to pH6 using concentrated hydrochloric acid. The resultant precipitate was collected by filtration, washed with water and then acetone, to give 4,6-dihydroxy-2-methylpyrimidine-5-acetic acid, methyl ester as a white solid (11.85g, 68.8%), m.p. >270° C.; microanalysis, found: C,48.5; H, 5.1; N, 14.1%; C7HSN204 requires C, 48.3; H,5.1; N, 13.8%; NMR: NaOD; 2.45(3H, s, pyrimidine-CH3), 3.57(2H,s,CH2), 3.87(3H,s,OCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1I.[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH3:19])=[N:16][CH:17]=1)#[CH:11].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[C:11]#[C:10][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH3:19])=[N:16][CH:17]=1
Reactant: C#Cc1ccc(NC)nc1
Reactant: Cc1nccc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNc1ccc(C#Cc2c(Cl)ccnc2C)cn1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 20 mg (0.08 mmol) 4-chloro-3-iodo-2-methyl-pyridine and 11 mg (0.09 mmol) (5-Ethynyl-pyridin-2-yl)-methyl-amine using 1.5 mg (0.01 mmol) CuI, 5.5 mg (0.01 mmol) PdCl2(PPh3)2 and 0.11 mL (0.8 mmol) triethylamine in 1 mL dry DMF. After completion of the reaction the product is purified by RP-HPLC using a ACN/H2O gradient (95:5 to 70:30). Yield: 20 mg (98%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1cccc(Cl)c1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc(OC)c2)cc1
Yield: 96.8 %

Procedure:
3-Chloroanisole (76 mg, 0.54 mmol) reacted with 4-methoxyphenylboronic acid (117 mg, 0.77 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in toluene at 80° C. to give the title compound (112 mg, 97%) as a colorless oil: 1H-NMR (300 MHz CDCl3): δ 7.57 (d, 2H, J=8.7 Hz), 7.37 (t, 1H, J=7.8 and 8.1 Hz), 7.17 (m, 2H), 7.01 (d, 2H, J=8.7 Hz), 6.88-6.97 (m, 1H), 3.89 (s, 3H), 3.88 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 159.86, 159.17, 142.28, 135.51, 129.66, 128.13, 119.21, 114.09, 112.44, 111.93. GC/MS (EI): m/z 214 (M+), 199, 171, 128. Anal. Calcd for C14H4O2: C, 78.48; H, 6.59. Found C, 78.46: H, 6.62.
Reaction SMILES: [Cl-:1].[CH:2]([N:4]([CH2:9][CH2:10][CH2:11][N+:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:6][CH2:7][OH:8])=O.C=O>C(O)=O>[ClH:1].[Cl-:1].[OH:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][CH2:10][CH2:11][N+:12]([CH3:15])([CH3:14])[CH3:13])[CH3:2]
Reactant: C[N+](C)(C)CCCN(C=O)CCCO
Agent: C=O
Agent: [Cl-]
Solvent: O=CO
Product: CN(CCCO)CCC[N+](C)(C)C
Product: Cl

Procedure:
A mixture of 2 g. of 3-[N'-formyl-N'-(3-hydroxypropyl)amino]-N,N,N-trimethyl-1-propanaminium chloride 4 g. of 99% formic acid and 2 ml. of formalin is stirred and heated at 100° for seventeen hours. To the cooled mixture is added 11 ml. of concentrated hydrochloric acid and the reaction mixture is concentrated under reduced pressure. The product is taken up in 35 ml. of 1 N hydrochloric acid and the solution is filtered and concentrated to dryness under reduced pressure yielding 3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminium chloride hydrochloride.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]4)=[CH:16][CH:15]=3)=[C:12]([C:29]3[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C>ClC(Cl)C>[OH:35][C:32]1[CH:33]=[CH:34][C:29]([C:12]2[O:11][N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]3)=[CH:16][CH:15]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(-c2noc(-c3ccc(OC)cc3)c2-c2ccc(OCCC3CCCCN3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCS
Product: Oc1ccc(-c2noc(-c3ccc(O)cc3)c2-c2ccc(OCCC3CCCCN3)cc2)cc1

Procedure:
Dimethylation was performed using Method 2 described for Step C in Scheme I. To a solution of the isoxazole obtained from step 6 (1.0 equiv.) in dichloroethane was added aluminum chloride (5.0 equiv.) and ethane thiol (5.0 equiv.). The resultant mixture was stirred for 40 min at room temperature and quenched with THF, 20% HCl and water. A precipitate was formed and this was collected by filtration. After drying the product the material was taken up in methanol, treated with activated charcoal, filtered through sodium sulfate and concentrated in vacuo. Purification with flash chromatography followed by addition of HCl aq. and lyophilization, then afforded the product 4-[5-(4-hydroxyphenyl)-4-[4-(2-piperidylethoxy)phenyl]isoxazol-3-yl]phenol as hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[C:13]1([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:14]=1.C(=O)([O-])O.[Na+].Cl>CO.C(#N)C>[Cl:22][S:19]([C:15]1[CH:14]=[C:13]([S:23]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[C:7]3[OH:12])(=[O:25])=[O:24])[CH:18]=[CH:17][CH:16]=1)(=[O:20])=[O:21]
Reactant: Nc1cccc2c(O)cccc12
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: O=S(=O)(Cl)c1cccc(S(=O)(=O)Nc2cccc3c(O)cccc23)c1
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a stirred mixture of 2.1 g of 5-amino-1-naphthol (1/2 H2SO4 salt), 4.2 g of benzene-1,3-disulfonyl chloride, 10 ml of acetonitrile and 30 ml of methanol was added portionwise 3.4 g of sodium hydrogen carbonate at a temperature of 0° to 5° C. The mixture was stirred for 1 hour at 0° to 5° C. and poured into 300 ml of a 3% hydrochloric acid aqueous solution. The precipitated crude product was collected by filtration and recrystallized from benzene-ethyl acetate (1:1 by volume) to produce 2.9 g of the title compound.
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH2:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:16]([Br:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)(C)C>[Br-:24].[CH2:1]([N:9]1[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]1[CH2:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCn1ccnc1CC
Solvent: CC(C)O
Product: CCCCCCCCN1C=CN(CCCCCCCC)C1CC
Product: [Br-]

Procedure:
0.6 mole of 1-n-octyl-2-ethylimidazole is dissolved in 250 ml of i-propanol and 0.66 mole of n-octyl bromide are boiled with reflux for 5 hours. The alcohol then is separated and the remaining residue is washed with ether.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:3]=1.[CH3:33][N:34]([CH3:46])[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)=[O:36].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH3:33][N:34]([CH3:46])[C:35](=[O:36])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[O:18])[CH:12]=4)[CH:9]=3)[N:4]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:3]=2)[CH:38]=1
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(-c3cccc(C(=O)N4CCOCC4)c3)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CN(C)C(=O)c1cccc(-c2nn(COCC[Si](C)(C)C)c3ncc(-c4cccc(C(=O)N5CCOCC5)c4)cc23)c1
Temperature: 90 °C

Procedure:
A mixture of (3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)(morpholino)methanone (50 mg, 0.089 mmol), 3-(dimethylcarbamoyl)phenylboronic acid (34 mg, 0.177 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (3.6 mg, 0.0045 mmol) and sodium carbonate (2M aqueous solution, 0.134 mL, 0.267 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 90° C. for 30 min. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography purification of the crude product afford N,N-dimethyl-3-(5-(3-(morpholine-4-carbonyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide as a clear oil. MS: m/z 586.2 [M+H+].
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Br[CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.O>CN(C)C=O>[CH2:7]([O:6][P:4]([CH:9]([CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCOC1CCCCO1)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
856 mg of a sodium hydride dispersion (60% in oil) was washed three times with dry pentane under a nitrogen stream to separate the oil. After drying, the powder obtained was suspended in 7.2 ml of dry dimethylformamide under a nitrogen stream, and the suspension was cooled to 0° C. Then, 4.26 ml of ethyl diethylphosphonoacetate was dropwise added thereto over a period of one hour. The mixture was stirred at room temperature for 30 minutes and cooled to 0° C., and 5.4 g of 2-bromo-1-(2-tetrahydropyranyloxy)ethane was added thereto. The mixture was stirred at 65° C. overnight, and the reaction mixture was poured into 40 ml of water and extracted three times with 20 ml of ethyl acetate. The ethyl acetate layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (60 g of Kieselgel 60) by using a mixture of hexane/ethyl acetate (5/1 followed by 1/1). The product-containing fraction was again purified by silica gel column chromatography (110 g of Kieselgel 60) by using a mixture of hexane/acetone (4/1) to obtain 2.55 g of ethyl 2-diethylphosphono-4-(2-tetrahydropyranyloxy)butanoate as a colorless oily substance.
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[CH3:19][C:20]([NH2:29])([CH3:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH3:28][C:20]([NH:29][C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:19])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: CC(C)(N)Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2c(NC(C)(C)Cc3ccccc3)c(=O)c2=O)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) in ethanol (3 mL) was added 1,1-dimethyl-2-phenyl-ethylamine (0.182 g, 1.22 mmol). The mixture was stirred at 70° C. overnight then filtered hot through a pad of silica gel. The filtrate was concentrated and the resulting residue was recrystallized from ethyl acetate/hexanes to give 0.170 g (83%) of the title product as a tan solid: m.p. 150-151° C.; 1H NMR (DMSO-d6) δ8.28(s,1H), 8.00(m, 2H), 7.28(m,2H), 7.26(m,1H), 7.13(m,2H), 7.09(m,2H), 3.82(s,3H), 3.10(s,2H), 1.42(s,6H); IR (KBr) 3420, 2950, 1775, 1715, 1650, 1570, 1410, 1252, 1200, 1045, 850, 740, 700, 602, 530 cm−1; MS (m/z) 335 [M+].
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])(F)[F:5].C([Li])CCC.[CH:16]12[CH2:22][CH:19]([CH:20]=[CH:21]1)[CH2:18][CH:17]2[CH:23]=[O:24].[O:25]1CCCC1>>[CH:16]12[CH2:22][CH:19]([CH:20]=[CH:21]1)[CH2:18][CH:17]2[CH:23]([OH:24])[C:4]([F:7])([F:5])[C:3]([OH:25])([OH:8])[C:2]([F:10])([F:9])[F:1]
Reactant: C1CCOC1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: O=CC1CC2C=CC1C2
Agent: [Li]CCCC
Product: OC(C1CC2C=CC1C2)C(F)(F)C(O)(O)C(F)(F)F
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
70 g hexafluoroisopropyl alcohol was dissolved in 350 mL dry tetrahydrofuran (THF), followed by dropwise addition of 350 mL 2.5M n-butyllithium for 30 minutes at −70° C. in a nitrogen atmosphere. After stirring for 10 minutes at −70° C., the temperature was elevated in a 0° C.-ice bath. After stirring for additional 1 hour, 53 g of 5-norbornene-2-carboxaldehyde was dropwise added into the solution and stirred at 0° C. for 2 hours. After neutralization with 450 mL a 1 M aqueous solution of hydrochloric acid, the organic phase was separated. The organic layer was diluted with 500 mL of ethylacetate and washed with 500 mL of a saturated aqueous solution of NaCl. The aqueous phase was extracted with 500 mL of ethylacetate. After drying the isolated organic phase with anhydrous MgSO4, the ethylacetate was distilled under reduced pressure. The remaining product was subjected to column chromatography by using a 1:3 mixture of ethylacetate and hexane by volume as a solvent. Recrystallization at a low temperature following solvent removal resulted 1-bicyclo[2.2.1]hept-5-ene-2-yl-2,2,4,4,4-pentafluoro-butan-1,3,3-triol with a yield of 51%.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]=[CH2:54])[C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH:38]=[CH2:39])[C:19]([O-:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH:13]=[CH2:14].[OH-].[Na+].Cl>C(O)C.O>[CH2:41]([O:40][C:23]1[CH:22]=[C:18]([CH:17]=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH:13]=[CH2:14])[C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH:38]=[CH2:39])[C:19]([OH:21])=[O:20])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]=[CH2:54]
Reactant: C=CC=CCCCCCCCCCCOc1cc(C(=O)[O-])cc(OCCCCCCCCCCC=CC=C)c1OCCCCCCCCCCC=CC=C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CC=CCCCCCCCCCCOc1cc(C(=O)O)cc(OCCCCCCCCCCC=CC=C)c1OCCCCCCCCCCC=CC=C
Temperature: 80 °C

Procedure:
In the next step as shown in FIG. 18, the yellow oil prepared above, 3,4,5-tris((11,13-tetradecadienyl)oxy)benzoate, was dissolved in a solution of ethanol (400 mL), H2O (80 mL), and NaOH (3.21 g, 80.2 mmol) in a round-bottom flask equipped with a reflux condenser and a magnetic stir bar. The mixture was then stirred and refluxed at 80° C. for 12 hours. After this period, the solution was cooled to 0° C. using an ice bath and acidified to pH 5.0 with hydrochloric acid (42 mL, 3M) to afford a pale brown precipitate. The precipitate was then filtered, washed with hexane (2×100 mL), and dried overnight under vacuum to collect a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][N:20]3[C:25]=2[C:24]([NH:26][C:27]2[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)[N:31]=[CH:30]4)=[N:23][CH:22]=[N:21]3)[CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[F:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:32]1[C:33]2[C:29](=[CH:28][C:27]([NH:26][C:24]3[C:25]4=[C:17]([CH2:16][N:13]5[CH2:12][CH2:11][CH:10]([NH:9][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:7])[CH2:15][CH2:14]5)[CH:18]=[CH:19][N:20]4[N:21]=[CH:22][N:23]=3)=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 127.9 %

Procedure:
Acetoxyacetyl chloride (46 mg, 2 equiv) was added dropwise to a solution of [5-(4-amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (47 mg, 0.1 mmole) (80 mg, 0.17 mmole) and triethylamine (71 μL, 3 equiv.) in dry DCM (3 mL) at 0° C. under nitrogen. After stirring at 0° C. for 3 hr and at RT for 1 hr, it was diluted with DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 2% MeOH) afforded acetic acid (1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidin-4-ylcarbamoyl)-methyl ester as a solid (73 mg, 75%). A solution of this ester in THF (0.4 mL) was treated with aq. NaOH (IN, 0.38 mL, 3 equiv.). After 2 hr at RT it was diluted with DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate employing gradient elution with DCM containing 0 to 3% MeOH) afforded the title compound as a solid (47 mg, 70%). MS: 529 (M+H)+; HPLC Ret Time: 1.37 min (YMC Xterra ODS S7 3.0×50 mm column, 2 min gradient, 5 ml/min).