Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.[O:32]1[CH2:36][CH2:35][C:34](=O)[CH2:33]1>>[CH3:31][N:7]1[C:6]([CH2:5][CH:3]2[CH2:2][N:1]([C@H:34]3[CH2:35][CH2:36][O:32][CH2:33]3)[CH2:4]2)=[N:14][C:13]2[C:8]1=[N:9][C:10]([N:21]1[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]1[CH3:30])=[N:11][C:12]=2[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: O=C1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN([C@H]4CCOC4)C3)n(C)c2n1

Procedure:
Following General Procedure L, 4-(8-(azetidin-3-ylmethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and dihydrofuran-3(2 H)-one were reacted to give the racemic mixture. The enantiomers were separated by SFC to give 572. LCMS m/z: 245.2 (2M+H+)
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][C@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([C:28]([OH:30])=[O:29])[CH2:17]2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH3:33][Si](C=[N+]=[N-])(C)C.C(OCC)C>ClCCl>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][C@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[C@H:18]([C:28]([O:30][CH3:33])=[O:29])[CH2:17]2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cccc(OCc3ccccc3)n2)C[C@H]1C(=O)O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](Oc2cccc(OCc3ccccc3)n2)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A 500 mL round bottom flask under nitrogen was charged with the product of Step 2 (7.17 g, 17.30 mmol), methanol (50 ml), and dichloromethane (50 ml). Attached an addition funnel containing trimethylsilyldiazomethane in diethyl ether (2.0M) (25.9 ml, 51.9 mmol). Cooled reaction flask in an ice bath. Added contents of addition funnel dropwise. Bubbles. HPLC/MS looks good after 0.5 hours. Quenched by dropwise addition of 2.5% potassium bisulfate. Evaporated to remove methanol. Added water. Extracted three times with ethyl acetate, dried with anhydrous magnesium sulfate, filtered and rotary evaporated filtrate. Subjected to flash column chromatography eluting with 80 hexane/20 ethyl acetate. Evaporation of fractions containing product gave the title compound as a colorless oil. (6.50 g, 15.17 mmol, 88% yield). LCMS (ES+) m/z 429.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][C:7]=1[CH3:8].C(O)CCC.[C:21]([NH:24][NH2:25])(=O)[CH3:22].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl.CCCCCC>[Cl:15][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]3[N:3]([C:21]([CH3:22])=[N:24][N:25]=3)[N:4]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(-c2cccc(Cl)c2)nnc1Cl
Reactant: CC(=O)NN
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCCCO
Solvent: CCCCCC
Product: Cc1cc(-c2cccc(Cl)c2)nn2c(C)nnc12

Procedure:
A mixture of 7.17 g. of 3-chloro-6-(m-chlorophenyl)-4-methylpyridazine, 100 ml. of n-butanol and 6.96 g. of acetylhydrazine is refluxed overnight. The mixture is coated and filtered to give solid. The solid is dissolved in methylene chloride and the solution passed through a short column of hydrous magnesium silicate. The eluent is refluxed while hexane is gradually added until crystals separated. Cooling and filtering gives 3.30 g. of crystals, m.p. 193.5°-195.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]([NH:13][NH2:14])=[O:12].Cl.[C:16](=N)(OCC)[CH3:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[O:12][C:16]([CH3:17])=[N:14][N:13]=1
Reactant: Cc1cccc(C)c1NCC(=O)NN
Reactant: CCOC(C)=N
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nnc(CNc2c(C)cccc2C)o1
Yield: 34.1 %

Procedure:
A solution of 19.3 g (0.1 mol) alpha-(2,6-dimethylphenylamino)acethydrazide and 14 g (0.11 mol) ethyl actimidate hydrochloride (Aldrich Chemical Co.) in 150 ml pyridine was heated under reflux for 9 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give an oil. The oil was placed on 400 g silica gel in a chromatography column and eluted the following solvent systems: (1) petroleum ether, (2) petroleum ether/ethyl ether, (3) ethyl ether, and (4) ethyl ether/methanol. The crude product (11.5 g) was eluted from the column with the ethyl ether/methanol solvent system. Crystallization of the crude product from dichloromethane/ethyl ether gave 7.4 g of crystalline product, m.p. 134°-135° C. The product is tabulated in Table I as Compound No. 1-A.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=[O:26])[CH2:21][CH2:20]2)=[C:7]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:8]2=[N:9][C:10]=1[CH2:11][CH3:12])=[N+:2]=[N-:3].Cl.C([N:36](CC)C(C)C)(C)C.C[Si](N=C=O)(C)C>O1CCOCC1.ClCCl.O>[N:1]([CH2:4][C:5]1[C:6]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([NH2:36])=[O:26])[CH2:23][CH2:24]2)=[C:7]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:8]2=[N:9][C:10]=1[CH2:11][CH3:12])=[N+:2]=[N-:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1CN=[N+]=[N-]
Agent: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCN(C(N)=O)CC2)c1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
A solution of 1,1-dimethylethyl 4-{[5-(azidomethyl)-1,6-diethyl-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}-1-piperidinecarboxylate (8.9 g, 20.8 mmol, e.g. which can be as prepared in Intermediate 15) in 1,4-dioxane (50 ml) was treated with 4M HCl in 1,4-dioxane (125 ml). After 2 hours the solvent was evaporated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was collected and washed with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were back-extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and the solvent was evaporated to give an oil (LCMS showed MH+=329; TRET=1.75 min). The oil was dissolved in dichloromethane (100 ml), and the solution was treated with N,N-diisopropylethylamine (6.1 ml, 35.0 mmol) followed by trimethylsilyl isocyanate (3.6 ml, 26.6 mmol, commercially available e.g. trimethylsilyl isocyanate 85% from Aldrich). The reaction mixture was stirred at room temperature overnight. Additional N,N-diisopropylethylamine (6.1 ml, 35.0 mmol) and trimethylsilyl isocyanate (3.6 ml, 26.6 mmol) was added. After stirring for a further 7 hours, additional trimethylsilyl isocyanate (3.6 ml) was added and stirring was continued over the weekend (e.g. this can be about 62 hours). Water (100 ml) was added and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration, washed with water followed by diethyl ether, and then dried to give the title compound (2.21 g). LCMS m/z 372 [MH+]; TRET=2.08 min.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:25]2[N:29]=[CH:28][CH:27]=[N:26]2)=[C:20]([CH:24]=1)[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:25]2[N:29]=[CH:28][CH:27]=[N:26]2)=[C:20]([CH:24]=1)[C:21]([NH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:22]
Reactant: O=C(O)c1cc(Cl)ccc1-n1nccn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1NC(=O)c1cc(Cl)ccc1-n1nccn1

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 120 mg, 0.60 mmol), 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 38a; CAS number 1293284-54-4; 134 mg, 0.60 mmol), TBTU (231 mg, 0.72 mmol) and DIPEA (0.116 g, 0.9 mmol) in DMF (3 ml) was stirred at room temperature for 2 hours. The reaction was diluted with water (30 ml) and extracted with ethyl acetate (3×30 ml). The combined organics were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-30% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: [C:1](=[O:32])([O:10][CH2:11]/[C:12](/[C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)=[C:13](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[CH2:14][OH:15])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:35].CC(=CC)C.P(=O)(O)(O)O.[O-]Cl=O.[Na+]>ClCCl.C1COCC1.CC(O)(C)C.O>[Br:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][C:1]([O:10][CH2:11]/[C:12](/[C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=1)=[C:13](/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)\[C:14]([OH:35])=[O:15])=[O:32]
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCCCBr)=C(/CO)c2ccccc2)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC=C(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCCCBr)=C(/C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 12 g of 6-bromohexyl (2Z)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl carbonate in 125 mL of dichloromethane was added 12.1 g of Dess-Martin reagent; the resulting mixture was stirred at 25° C. for 2 h. Then 1 mL of water was added and the mixture was stirred at RT for 30 min. The mixture was filtered through a pad of silica gel and evaporated. The crude thus obtained was dissolved in a solvent mixture of THF and t-BuOH (100 mL/100 mL). To this solution was added 16 mL of 2-methyl-2-butene followed by the addition of 40 mL of phosphoric acid (1.2M soln) and 40 mL of NaClO2 (1M soln). The resulting mixture was stirred at RT for 30 min. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over Na2SO4, filtered, and then evaporated. The crude was purified by flash chromatography to afford titled compound as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[O:4].C([O:17][C@@H:18]1[C@@H:23]([O:24]C(=O)C)[C@@H:22]([O:28]C(=O)C)[C@@H:21]([CH2:32][O:33]C(=O)C)[O:20][C@@H:19]1Br)(=O)C>C(OCC)(=O)C>[O:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[C@@H:19]1[O:20][C@H:21]([CH2:32][OH:33])[C@H:22]([OH:28])[C@H:23]([OH:24])[C@H:18]1[OH:17]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: COC(=O)CCCCCCCCO
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
8-Methoxycarbonyl-1-octanol (21.4 g, 0.115 mole) and dried mercuric cyanide (30.3 g, 0.119 mole) were dissolved in a 1:1 mixture of dry distilled benzene-nitromethane (850 ml). The solution was stirred and 200 ml of solvent was distilled. Mixed solvent (200 ml) was added and calcium sulfate (40 g) was added followed by 2,3,4,6-tetra-O-acetyl-α-D-galactosyl bromide (38.7 g, 0.094 mole). The mixture was stirred at room temperature for 36 h and then heated at 70° for 2 h. After cooling, the solution was filtered and the filtrate evaporated in vacuo to give a yellow syrup. This syrup was dissolved in distilled ethyl acetate (500 ml) and the solution was washed with an aqueous solution (10% w/w, 500 ml) of sodium iodide. The organic phase was then washed successively with a saturated solution of sodium thiosulphate (200 ml) and H2O (2×250 ml). The organic phase was dried over sodium sulphate and then evaporated in vacuo after filtration. This syrup (~50 g) after drying under high vacuum overnight was dissolved in dry distilled methanol (200 ml) and to this solution, 200 ml of methanolic sodium methoxide (150 mg of sodium) was added. After stirring at room temperature for 24 h, acid resin (prewashed a few times in methanol) was added and stirred until the pH was neutral. After filtration, the solution was evaporated and the waxy residue dissolved at room temperature in 100 ml of H2O. This solution was extracted with ether (2×40 ml) and then placed in the fridge. Upon standing, crystallization occurred. The white crystals were filtered and dried. Weight 13.5 g (41%), mp 104°-105°, [α]D25 -13.4° (c 1, 95% ethanol).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24](Cl)[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:30]([CH:24]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[C:16]([Cl:23])=[CH:17][C:18]([Cl:22])=[CH:19][C:20]=4[Cl:21])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[C:25]([F:27])([F:28])[F:26])=[N+:31]=[N-:32]
Reactant: FC(F)(F)C(Cl)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 9-chloro-6-(1-chloro-2,2,2-trifluoroethyl)-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (290 mg, 0.576 mmol) and sodium azide (74.9 mg, 1.15 mmol) in dimethylsulfoxide (2.8 mL) was stirred at 100° C. for 2 h. After the mixture was diluted with ethyl acetate, the resultant mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous solid (286 mg, 0.560 mmol, 97%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[O:32]([CH3:34])[Na]>CO.CCOC(C)=O>[C:26]([C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[C:17]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([O:32][CH3:34])=[N:3][C:4]([C:28]([F:31])([F:30])[F:29])=[CH:5][CH:6]=1)#[CH:27]
Reactant: CO[Na]
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OC)cc(F)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (50 mg, 0.105 mmol) in CH3OH (1 mL) was added dropwise 30% NaOCH3 in CH3OH (3 eq) at 0° C. The mixture was stirred for 12 hours at room temperature. The reaction was diluted with EtOAc and washed two times with 1N HCl and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (10 mg, 20%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[PH:22](=O)OCC)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl[Si](C)(C)C.[PH2](=O)[O-].Cl>CCOC(C)=O.C1COCC1>[CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:7]=[C:6]([CH:13]([CH3:14])[CH3:15])[C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[PH2:22])([CH3:2])[CH3:3]
Reactant: CCO[PH](=O)c1ccccc1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: O=[PH2][O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P)c(C(C)C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 156.6 %

Procedure:
A solution of ethyl 2′,4′,6′-triisopropylbiphenyl-2-ylphosphinate (17.5 g, 47.0 mmol, 1.0 equiv) in 100 mL of anhydrous, degassed THF was cooled to 0° C. under an atmosphere of nitrogen. The lithium aluminum hydride/chlorotrimethylsilane solution was transferred by cannula into the solution of phosphinate over 20 min. The reaction was allowed to proceed overnight with slow warming to 22° C. Prior to quench the mixture was cooled in an ice bath. The reaction was quenched by slow addition of EtOAc (23 mL, 235 mmol, 5 equiv), followed by aqueous hydrochloric acid (2 M, 250 mL, 500 mmol, 10.6 equiv). This mixture was allowed to stir for 1 h under an atmosphere of N2. This mixture was diluted with EtOAc (250 mL), the layers were separated and the organic layer was washed once with a saturated solution of NaCl (100 mL). The organic solution was concentrated in vacuo to give a white solid (23.0 g) which was 66% potent (w/w by HPLC), for a 99% yield. This material was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][C:8]2[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:10][C:9]=2[F:29])=[C:5]([OH:32])[CH:4]=1)[CH3:2].O.NN.Cl>CO>[NH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]1[CH:27]=[CH:28][C:8]([O:7][C:6]2[CH:30]=[CH:31][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[OH:32])=[C:9]([F:29])[CH:10]=1
Reactant: CCc1ccc(Oc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc2F)c(O)c1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CCc1ccc(Oc2ccc(OCCCN)cc2F)c(O)c1
Temperature: 0 °C
Yield: 41.7 %

Procedure:
To a solution of 2-{3-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1,3-dione (0.096 mmol; 42 mg) in methanol (2 mL), under argon, was added hydrazine monohydrate (0.21 mmol; 10 μL). The reaction was heated to reflux for 1 h 30. After cooling to 0° C., the mixture was hydrolysed with HCl 1N and filtered. The filtrate was basified with NaOH 0.1 N (pH=11) and extracted with chloroform (3*5 ml). Combined organic phases were dried over Na2SO4, concentrated in vacuo. The title compound (13 mg; 0.04 mmol; 44%) was obtained as yellow oil, after purification by preparative TLC (dichloromethane/methanol/NH4OH: 90/10/1).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH:10]([NH:12][C:13](=[O:35])[C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH2:22][C:23]2[N:24]=[C:25]3[C:30](=[N:31][CH:32]=2)[N:29]=[C:28]([NH2:33])[N:27]=[C:26]3[NH2:34])[CH3:21])=[CH:16][CH:15]=1)[CH3:11])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.O.CO>CN(C=O)C>[NH2:33][C:28]1[N:27]=[C:26]([NH2:34])[C:25]2[C:30](=[N:31][CH:32]=[C:23]([CH2:22][N:20]([CH3:21])[C:17]3[CH:16]=[CH:15][C:14]([C:13]([NH:12][CH:10]([CH3:11])[CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:35])=[CH:19][CH:18]=3)[N:24]=2)[N:29]=1
Reactant: CCOP(=O)(CC(C)NC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(CP(=O)(O)O)NC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1
Temperature: 70 °C
Yield: 38 %

Procedure:
To a solution of crude (2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonic acid diethyl ester post silica column chromatography (32.2 mg, 66.2 μmol) in dry DMF (0.50 mL) was added TMSBr (68.0 μL, 529.6 μmol) at ambient temperature. The solution was then heated at 70° C. for 1.0 hour, when LCMS analysis demonstrated the reaction to be complete. The reaction mixture was allowed to cool to room temperature, and water (60 μL) and methanol (60 μL) were added. The crude reaction mixture was purified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 11.2 mg (38%) of the desired compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.50 (m, 2H), 1.61 (m, 2H), 3.22 (s, 3H), 3.25-3.40 (m, 2H), 4.84 (s, 2H), 6.80 (d, 2H, J=9 Hz), 7.69 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.69 (s, 1H). 31P (121.4 MHz, DMSO-d6) δ 26.3. MS (m/z) 447.3 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH:13]=[CH:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1.N1CCCCC1>CO>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1C=CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1/C=C\CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-enyl]piperidine-1-carboxylate (0.0265 g, 0.0660 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.00964 g, 0.0660 mmol) and piperidine (0.0800 mL, 0.810 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((Z)-4-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-enyl)piperidine-1-carboxylate (0.0293 g, 84%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([OH:24])[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]([F:34])([F:33])C([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([O:24][CH:29]([F:34])[F:33])[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(OC(F)F)cc21
Yield: 32.2 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-6-hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg), sodium chlorodifluoroacetate (253 mg), K2CO3 (172 mg), DMF (3 mL), and water (0.60 mL) was refluxed overnight. The reaction mixture was poured into water, and the mixture was extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10%-40% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-6-(difluoromethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (110 mg) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].[Cl-].O[NH3+:13]>C(O)(=O)C.C(OCC)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:13])=[CH:4][C:3]=1[CH3:10]
Reactant: [NH3+]O
Reactant: Cc1cc(C=O)ccc1O
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cc(C#N)ccc1O
Yield: 66 %

Procedure:
A mixture of 4-hydroxy-3-methylbenzaldehyde (530 mg, 3.91 mmol) and hydroxyl ammonium chloride (406 mg, 5.81 mmol) in acetic acid (5 mL) was heated under reflux for 90 minutes. The cooled reaction mixture was then diluted with diethyl ether (30 mL) and washed with water (30 mL). The combined organic solution was washed with brine, dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 97.5:2.5, to afford the title compound as a pale yellow oil in 66% yield, 345 mg.