Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:12]#[CH:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:27])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)[CH3:15].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH2:14]([O:16][C:17](=[O:27])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([C:13]#[C:12][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[CH:9][C:8]=2[CH3:11])=[CH:22][CH:21]=1)[CH3:15]
Reactant: CCOC(=O)C=Cc1ccc(I)cc1
Reactant: C#Cc1cc(C(C)(C)C)ccc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C=Cc1ccc(C#Cc2cc(C(C)(C)C)ccc2C)cc1

Procedure:
Following General Procedure B and using 4-tert-butyl-2-ethynyl-1-methyl-benzene (Intermediate 110, 0.08 g, 0.47 mmol), ethyl-4-iodocinnamate (0.12 g, 0.4 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 2-4% ethyl acetate in hexane as the eluent, the title compound was obtained (0.09 g, 55%).
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[OH-].[Li+]>CO.O>[F:14][CH:2]([F:1])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(F)F)[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(F)F)[nH]c1=O

Procedure:
7.4 g (36.4 mmol) of methyl 6-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate were dissolved in 100 ml of methanol, and a solution of 1.3 g (54.6 mmol) of lithium hydroxide in 50 ml of water was added. After two hours of heating under reflux, the mixture was concentrated to a volume of about 50 ml and the solution was washed with dichloromethane. The aqueous phase was then acidified with 2N hydrochloric acid and extracted with ethyl acetate. Drying and concentration of the extract gave 5.6 g (82% of theory) of a brownish powder.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:16]C(OC(C3CC3)C)=O)[C@H:4]2[S:3]1.CCOCC>C(O)=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH2:16])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)OC(C)C3CC3)c3ccccc3)[C@H]2S1
Solvent: CCOCC
Solvent: O=CO
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2S1
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
A solution of 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl-2-phenylglycyl]amino-3-cephem-4-carboxylic acid (2.0 g) in formic acid (10 ml) was stirred for 2.5 hours at room temperature. After the reaction was completed, ether (30 ml) was added to the reaction mixture, and the supernatent was removed three times by decantation. Colorless powder was collected by filtration and washed with ether. Thus obtained powder was suspended in a mixture of acetonitrile (15 ml) and water (1 ml), and the suspension was stirred for 1.5 hours under ice-cooling. The precipitate was collected by filtration and dried to give 2-methyl-7-(2-phenylglycyl)amino-3-cephem-4-carboxylic acid (1.13 g), mp 168.5° to 171° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[CH2:20][OH:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[Na+]>ClCCCl.CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[CH:20]=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)n1c(CO)cc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cc2ccccc2n1S(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of 0.93 g of {1-[(4-bromophenyl)sulfonyl]-1H-indol-2-yl}methanol and 1.1 mL of triethylamine in 10 mL of 1,2-dichloroethane, a solution of 1.21 g of sulfur trioxide-pyridine complex in 5 mL of DMSO was added under ice cooling, and the resulting mixture was stirred under ice cooling for 1 hour. The solution was poured into a mixed solution of 25 ml of ice water and 25 mL of saturated aqueous sodium chloride solution, the resulting mixture was extracted with 100 mL of ethyl acetate, the extract was washed with 5% aqueous potassium hydrogen sulfate solution, water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane to obtain 0.91 g of 1-[(4-bromophenyl)sulfonyl]-1H-indole-2-carbaldehyde as a beige solid. FAB+: 364, 366
Reaction SMILES: [F:1][C:2]1[C:3]([F:28])=[C:4]2[O:9][CH2:8][C:7]3([CH2:13][CH2:12][O:11][CH2:10]3)[N:6]3[CH:14]=[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16](=[O:22])[C:17]([C:18]=1[N+:19]([O-])=O)=[C:5]23>CC(O)=O.[Fe]>[NH2:19][C:18]1[C:17]2[C:16](=[O:22])[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:14][N:6]3[C:7]4([CH2:13][CH2:12][O:11][CH2:10]4)[CH2:8][O:9][C:4]([C:5]=23)=[C:3]([F:28])[C:2]=1[F:1]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OCC21CCOC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OCC21CCOC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 52.9 %

Procedure:
A mixture of ethyl 9′,10′-difluoro-8′-nitro-7′-oxospiro[oxolane-3,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (3.15 g, 7.95 mmol) and iron (2.66 mg, 47.7 mmol) in AcOH (40 mL) was stirred at 90° C. for 5 h. After the reaction mixture was concentrated in vacuo, DMF was added and the mixture was filtrated through Celite. The filtrate was poured into water and the resulting precipitate was collected by filtration and dried to yield ethyl 8′-amino-9′,10′-difluoro-7′-oxospiro[oxolane-3,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (1.54 g, 53%) as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ1.25 (3H, t, J=7.3 Hz), 2.29-2.38 (2H, m), 3.72 (1H, d, J=11.0 Hz), 3.90-3.96 (1H, m), 4.06-4.11 (1H, m), 4.15 (1H, d, J=11.0 Hz), 4.19 (2H, q, J=7.3 Hz), 4.32 (1H, d, J=11.0 Hz), 4.41 (1H, d, J=11.0 Hz), 7.42 (2H, brs), 8.34 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:14]3[C:19]=1[C:18]([NH2:20])=[N:17][CH:16]=[N:15]3)=[CH:6]2.[C:38](Cl)(=[O:40])[CH3:39]>ClCCCl.N1C=CC=CC=1>[NH2:20][C:18]1[C:19]2=[C:11]([C:7]3[CH:8]=[CH:9][C:10]4[C:5]([CH:6]=3)=[N:4][N:3]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:2]=4[NH:1][C:38](=[O:40])[CH3:39])[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:14]2[N:15]=[CH:16][N:17]=1
Reactant: CS(=O)(=O)N1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(=O)Nc1c2ccc(-c3cc(C4CCN(S(C)(=O)=O)CC4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.6 %

Procedure:
To a suspension of 5-(3-Amino-2-benzyl-2H-indazol-6-yl)-7-(1-methanesulfonyl-piperidin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (150 mg, 0.29 mmol) in DCE (2.9 mL) and pyridine (0.29 mL) was added acetyl chloride (20 μl, 0.38 mmol, 1.3 mmol), and the reaction mixture was stirred at rt under N2 for 18 h. The mixture was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The MeOH was removed and the residue was crystallized from DCM-hexane to provide the title compound (14 mg, 9%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.91 (s, 1H), 7.58 (d, 1H), 7.51 (s, 1H), 7.35 to 7.22 (m, 5H), 7.14 (dd, 1H), 6.65 (s, 1H), 5.49 (s, 2H), 3.68 to 3.64 (m, 2H), 3.26 (dt, 1H), 2.92 to 2.86 (m, 5H), 2.16 to 2.07 (m, 5H), 1.77 to 1.73 (m, 2H); ES-MS m/z 559.4 [M+H]+, RT (min) 2.39.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)=O)=[O:5].[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26].S(=O)(=O)(O)O.O>C(O)(=O)C>[C-:12]1([C:10]2[CH2:9][CH2:8][CH2:7][C:6]=2[C:4](=[O:5])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[F:1])[CH:16]=[CH:15][CH:14]=[CH:13]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: O=C(CCCCC(=O)[c-]1cccc1)c1ccccc1F
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: c1cc[cH-]c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(C1=C([c-]2cccc2)CCC1)c1ccccc1F

Procedure:
5-(2-Fluorobenzoyl)-pentanoylferrocene (16g, 0.04 mole) and 5% v/v concentrated sulphuric acid in glacial acetic acid (300 ml) were stirred for 15 minutes at room temperature and were then poured into water. The aqueous layer was extracted with chloroform. The combined extracts were washed with water, dried (magnesium sulphate) and evaporated under vacuum. The resulting oil was purified by preparative thin layer chromatography using silica gel, with toluene as eluent, to yield pure b 1-ferrocenyl-2-[2-fluorobenzoyl)cyclopent-1-ene as red crystals; 1.2g (8%) mp 90°-92°.
Reaction SMILES: O1CCOCC1.CO.[CH3:9][O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=3)=[N:18][C:17]=2[CH:32]=1)=[O:12].[Cl-].[Ca+2].[Cl-]>O.[Zn]>[NH2:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)/[CH:22]=[CH:21]/[C:19]1[S:20][C:16]2[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:32][C:17]=2[N:18]=1
Reactant: COC(=O)c1ccc2sc(/C=C/c3cccc([N+](=O)[O-])c3)nc2c1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2sc(/C=C/c3cccc(N)c3)nc2c1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solvent mixture of 50 ml of dioxane and 30 ml of methanol, 2.0 g of 5-methoxycarbonyl-2-(trans-3-nitrostyryl)benzothiazole was added and, under vigorous stirring, a solution of 0.37 g of calcium chloride in 55 ml of water and 9.8 g of zinc powder were added, followed by refluxing for 2 hours. After cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the solid residue formed was washed with toluene to give 1.4 g (yield 77%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1CC[N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:39])[CH2:30]OCC4C=CC=CC=4)[C@@H:25]([OH:40])[C@H:24]3[OH:41])=[C:16]([NH:42][CH2:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:15]=2)[CH2:10]1.Cl[C:58]1N=C2C(N=CN2[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.C(N)CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][NH:11][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[C@@H:23]2[CH2:27][C@H:26]([NH:28][C:29](=[O:39])[CH2:30][CH3:58])[C@@H:25]([OH:40])[C@H:24]2[OH:41])=[C:16]([NH:42][CH2:43][CH:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:15]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCN)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate (Example 1 step 2) by replacing 2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-acetamide with N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) and by replacing (3R)-3-aminopyrrolidine with ethylene diamine. (MH+ 545.4)
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:16][NH2:17]>O>[C:6]1([C:4]2[C:3]3[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:17][N:16]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccccc1F
Reactant: NN
Solvent: O
Product: c1ccc(-c2n[nH]c3ccccc23)cc1
Temperature: 170 °C
Yield: 67 %

Procedure:
To 2-fluorobenzophenone (1.0 g, 5.0 mmol) was added hydrazine (5 mL) and the reaction was heated to reflux for 3 hours. The reaction was then added to water (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried with sodium sulfate (Na2SO4) and concentrated to an oil. The subsequent hydrazine adduct was heated with pyridine (20 mL) to 170° C. for 4 days. Pyridine was then removed under vacuum and the resulting oil taken up in water (100 mL) and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate layers were dried (Na2SO4) and concentrated to give the final compound (650 mg, 67% yield). 1H NMR (CDCl3) δ 10.6 (br s, 1H), 8.04-7.99 (m, 2H), 7.56-7.50 (m, 2H), 7.47-7.33 (m, 2H), 7.29-7.19 (m, 3H); ES-MS (m/z) 195 [M+1]−.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:16])([CH3:15])[C:5](=[O:14])[NH:6]2.FC(F)(F)S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:16])([CH3:15])[C:5](=[O:14])[N:6]2[CH2:23][C:24]([F:27])([F:26])[F:25]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC1(C)C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)N(CC(F)(F)F)c2ccc([N+](=O)[O-])c(F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 1610.7 %

Procedure:
A suspension of 4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (0.10 g), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.16 g), potassium carbonate (0.12 g) and DMF (2 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]([C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[O:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]1)[OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:12][C@@H:11]([C:13]1[CH:33]=[CH:32][CH:31]=[C:15]([O:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[CH:14]=1)[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(COc2cccc([C@H](O)CCNC(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butyl 4-((3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate (0.70 g, 1.50 mmol) was added at 0° C. to a suspension of LiAlH4 (0.171 g, 4.5 mmol) in anhydrous THF (10 mL) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction as judged by TLC, the reaction mixture was quenched with EtOAc (10 mL) and 10% aqueous NaOH, filtered through Celite, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (CH2Cl2-10% MeOH:CH2Cl2, 0-5% gradient) gave (R)-tert-butyl (3-hydroxy-3-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)propyl)carbamate as a pale yellow semi-solid. Yield (0.50 g, 87%); 1H NMR (400 MHz, CDCl3): δ 7.22 (t, J=4.40 Hz, 1H), 6.92 (s, 2H), 6.76 (d, J=8.0 Hz, 1H), 4.31 (s, 1H), 3.85 (d, J=5.6 Hz, 2H), 3.69 (s, 1H), 3.27 (d, J=6.8 Hz, 2H), 2.58 (s, 2H), 2.46 (s, 2H), 2.04-1.91 (m, 4H), 1.84 (t, J=5.20 Hz, 4H), 1.70-1.67 (m, 1H), 1.45 (s, 9H); MS: m/z 379.28 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([C:12]1[CH:24]=[CH:23][C:15]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=1)=[O:11])(=[O:3])[CH3:2].B.[Na].O.Cl>C(O)C.C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:24]=[CH:23][C:15]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=1)[OH:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOCCC(=O)c1ccc(Cc2cccnc2)cc1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(=O)OCCOCCC(O)c1ccc(Cc2cccnc2)cc1
Yield: 82.7 %

Procedure:
In 27 ml of ethanol was dissolved 2.70 g of 3-[p-[3-(2-acetoxyethyl)oxypropionyl]benzyl]pyridine, and to the resulting solution was added 0.34 g of sodium boron hydride in portions with ice-cooling over 30 minutes, after which the resulting mixture was subjected to reaction at the same temperature for one hour. To the reaction mixture were added 30 ml of iced water and 20 ml of ethyl acetate, and then, the pH thereof was adjusted to 2.0 with 2N hydrochloric acid. The aqueous layer was separated, and 30 ml of ethyl acetate was added thereto, after which the pH thereof was adjusted to 7 with sodium hydrogencarbonate. The organic layer was separated, washed with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation to obtain 2.25 g (yield 82.7%) of colorless, oily 3-[p-[3-(2-acetoxyethyl)oxy-1-hydroxypropyl]benzyl]pyridine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][C:29]=1[F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=1[F:26]>>[F:13][C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][C:29]=1[F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)=[CH:20][C:19]=1[F:26]
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to those described for E1 starting from 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (4-(3,4-difluorophenoxy)-3-fluorophenyl)methanol.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:41]=[CH:40][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:27]=4)[CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][CH:68]2[CH2:70][O:69]2)=[CH:62][CH:61]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH:35]1([O:34][C:28]2[CH:27]=[C:26]([CH:23]3[CH2:22][CH2:21][N:20]([C:18]([N:15]4[CH2:14][CH2:13][CH:12]([NH:11][C:10]5[CH:40]=[CH:41][C:7]([CH2:6][CH2:5][NH:4][CH2:70][C@H:68]([OH:69])[CH2:67][O:66][C:63]6[CH:64]=[CH:65][C:60]([OH:59])=[CH:61][CH:62]=6)=[CH:8][CH:9]=5)[CH2:17][CH2:16]4)=[O:19])[CH2:25][CH2:24]3)[CH:31]=[CH:30][C:29]=2[O:32][CH3:33])[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COc1ccc(C2CCN(C(=O)N3CCC(Nc4ccc(CCN)cc4)CC3)CC2)cc1OC1CCCC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=CO
Solvent: CO
Product: COc1ccc(C2CCN(C(=O)N3CCC(Nc4ccc(CCNC[C@H](O)COc5ccc(O)cc5)cc4)CC3)CC2)cc1OC1CCCC1
Yield: 20.6 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}{4-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-piperidinyl}methanone formate (0.50 g, 0.88 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.350 g, 0.88 mmol) according to Procedure G to yield (eluant: 20:1 chloroform-methanol) the title compound (0.168 g, 0.181 mmol)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1)[P:13]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:37]>CO.O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:29]1[CH:30]=[CH:31][C:32]([C:35](=[NH:37])[NH2:36])=[CH:33][CH:34]=1)[P:13]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:21])[O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: N#Cc1ccc(C(NC(=O)OCc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: N=C(N)c1ccc(C(NC(=O)OCc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was synthesized according to (8) with slight modifications. The iminoester prepared from diphenyl [N-(benzyloxycarbonyl)amino](4-cyanophenyl)methane phosphonate (1.5 g, 3.0 mmol) was dissolved in a mixture of methanol (30 ml) and 0.5 M NH3 in 1,4-dioxane (15 ml), the solution stirred at room temperature overnight, solvent was removed and the oily residue dissolved in CHCl3 (30 ml). Diethyl ether (100 ml) was added, the precipitate collected by filtration, washed with diethyl ether (30 ml×5) and dried in vacuo [yield 1.2 g (73%)]. The crude product was judged sufficiently pure for biotinylation. For use in kinetic studies, further purification was carried out by HPLC (100 mg crude 1) yielding 36 mg 1. [tR 31.58 min, purity 99% (A:B 80:20 to 20:80 in 60 min); m/z (ESI) 516 (M+H)+, 1031 (2M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=[CH:6][C:5]=1[NH:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=[CH:6][C:5]=1[NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=1
Reactant: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2N)cc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 27.1 %

Procedure:
To a solution of 4-(((2-nitro-4-(quinolin-2-ylmethoxy)phenyl)amino)methyl)benzonitrile (2.8 g, 6.7 mmol) in EtOAc (100 mL) was added SnCl2.2H2O (9.4 g, 42 mmol) and the mixture heated to 70° C. for 3 h. The mixture was then cooled to RT and basified to pH=8 by addition of 2 M Na2CO3 and stirred at RT. After 12 hours, the mixture was extracted with EtOAc and concentrated to dryness. The residue was then purified by FCC to afford 0.69 g of the title compound. MS (ESI): mass calcd. for C24H20N4O, 380.45; m/z found 381.2 [M+H]+.