Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].[O-]CC.[Na+].O>C(O)C>[N+:8]([CH2:11][C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([O-:10])=[O:9]
Reactant: O=C1CCOCC1
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CCOCC1
Yield: 33.7 %

Procedure:
A solution of tetrahydro-4H-pyran-4-one (45.0 g, 449 mmol) and nitromethane (36.5 mL, 674 mmol) in ethanol (27 mL) was treated with a solution of sodium ethoxide in ethanol (2.67 M, 8.40 mL, 22.5 mmol) using the method described in Part A of Example 9. The reaction mixture was transferred to a separatory funnel and water (450 mL) was added. The mixture was extracted with ethyl acetate (3×900 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to a light brown oil. Ethyl acetate/hexanes was added and pale brown crystals formed that were isolated by filtration and dried to provide 4-(nitromethyl)tetrahydro-2H-pyran-4-ol (24.4 g, 34%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CCOC(C)=O>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccc(I)cc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(I)cc1)OCC
Temperature: 160 °C
Reaction time: 4 h
Yield: 52.7 %

Procedure:
A mixture of 4-iodobenzyl bromide 14 (5.2 g, 17.51 mmol) and triethyl phosphite (3.3 g, 20 mmol) was stirred at 160° C. After 4 h, the mixture was cooled to room temperature. The residue was subjected to flash chromatography (EtOAc: Hex, 1:4), and gave 3.27 g of 15 (53%). 1H NMR (200 MHz, CDCl3): δ1.24 (t, J=7.04 Hz, 6H), 3.07 (d, J=21.72 Hz, 2H), 4.01 (m, 4H), 7.04 (m, 2H), 7.62 (m, 2H); 13C NMR (50 MHz, CDCl3): δ 16.24 (J=5.90 Hz), 33.21 (J=137.55 Hz), 62.04 (J=6.70 Hz), 92.15 (J=4.80 Hz), 131.31 (J=9.10 Hz), 131.57 (J=6.55 Hz), 137.43 (J=2.95 Hz).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3Cl)[O:7]1)(=O)C.[NH3:30]>>[NH2:30][C:24]1[N:23]=[C:22]([I:29])[N:21]=[C:20]2[C:25]=1[N:26]=[CH:27][N:19]2[C@H:8]1[C@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:6]([CH2:5][OH:4])[O:7]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N
Product: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 6 h
Yield: 80 %

Procedure:
To a flask containing 6.0 g (11.1 mmol) [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(6-chloro-2-iodopurin-9-yl)oxolan-2-yl]methyl acetate (6.4) was added 100 ml of liquid NH3 at −78° C. and the solution was allowed to stir for 6 hours. After which time it was allowed to come to room temperature overnight with concurrent evaporation of the NH3 to yield a brown oil. The product was crystallized from hot isopropanol to provide 6.5 (80%), m.p. 143–145° C., r.f.=0.6 in 20% MeOH/CHCl3. 1H NMR (300 MHz, DMSO-d6) 8.24 (s, 1H), 7.68 (s, 2H), 5.75 (d, J=6.16, 1H), 5.42 (d, J=5.40 Hz, 1H), 5.16 (d, J=4.62 Hz, 1H), 4.99 (t, J=5.39 Hz, 1H), 4.67 (d, J=4.81 Hz, 1H), 4.06 (d, J=3.37 Hz, 1H), 3.89 (m, 1H), 3.54 (m, 2H).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:37](=[O:38])[CH2:36][O:35][CH3:34])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.07 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, methoxyacetyl chloride (0.22 g, 2.03 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo'and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 100:2.5) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-methoxyacetamide (0.44 g, 66%) as a white solid: mp 196-198° C.; 1H NMR (DMSO-d6) δ d 11.14 (s, 1H), 8.49 (t, J=6.1 Hz, 1H), 7.86-7.79 (m, 2H), 7.68-7.65 (m, 1H), 5.19-5.12 (dd, J=5.3 and 12.5 Hz, 1H), 4.77 (d, J=6.1 Hz, 2H), 3.92 (s, 2H), 3.36 (s, 3H), 2.96-2.83 (m, 1H), 2.64-2.49 (m, 2H), 2.09-2.04 (m, 1H); 13C NMR (DMSO-d6) δ d 172.71, 169.78, 169.58, 167.52, 166.94, 139.09, 134.70, 133.00, 131.51, 127.08, 121.82, 71.46, 58.70, 48.86, 37.47, 30.91, 21.95; Anal. Calcd. For C17H17N3O6: C, 56.82; H, 4.77; N, 11.69. Found: C, 57.02; H, 4.87; N, 11.36.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.I[C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: N#Cc1ccc(I)cn1
Product: N#Cc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1

Procedure:
The title compound (E206) was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3) and 5-iodo-2-pyridinecarbonitrile (Biochemical Journal, 1973, 131(4), 625) according to the method outlined for E177a; MS (ES+) m/e 320 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][C@@H:83]1[CH3:88])=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:84][C@@H:83]1[CH3:88])=[O:81])[CH3:78]
Reactant: CCOC(=O)N1CCNC[C@@H]1C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C[C@@H]1C
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 28 μl DIPEA, 64 mg HATU and 29 mg (S)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 186 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[N:12]=2)[CH:6]=1)[CH3:2].[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:12]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CCOC(=O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 8c was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 364. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 9.15 (s, 1H) 8.72 (br s, 8.35 (m, 2H) 8.07 (d, 1H) 7.65 (m, 1H) 7.18 (m, 1H) 7.05 (m, 2H) 6.68 (d, 2H) 4.35 (q, 2H) 3.5 (m, 2H) 2.78 (m, 2H) 1.35 (t, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1B(O)O>>[CH:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:23]=1[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)/C=C/c1ccccc1CBr
Reactant: OB(O)c1ccc2ccccc2c1
Product: CCOC(=O)/C=C/c1ccccc1Cc1ccc2ccccc2c1

Procedure:
The benzyl bromide (500 mg) of example 1, step 2 was treated with 2-naphthylboronic acid according to the same procedure previously described to yield 360 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[NH:13]2
Reactant: CCO
Reactant: Fc1cccc(F)c1-c1cccc2[nH]ccc12
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To the suspension of 4-(2,6-difluoro-phenyl)-1H-indole (9.5 g, 41.4 mmol) in t-BuOH:ethanol:acetic acid (262 mL:155 mL:81 mL) was added pyridinium tribromide (40.28 g, 126 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added more acetic acid (200 mL). Zinc dust (14.2 g, 217 mmol) was added to the reaction mixture portionwise. After stirring for one hour, the unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), sat. NaHCO3 (2×), brine (3×), dried over Na2SO4, concentrated, triturated with ether to give 7.1 g (70%) of 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.O.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]([CH3:35])=[CH:31][C:32](Cl)=[O:33]>CO>[CH3:29][C:30]([CH3:35])=[CH:31][C:32]([N:19]1[CH2:18][CH2:17][N:16]([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH2:21][CH2:20]1)=[O:33]
Reactant: Oc1cccc(CC(c2ccccc2)N2CCNCC2)c1
Reactant: CC(C)=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)=CC(=O)N1CCN(C(Cc2cccc(O)c2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
In methanol (300 ml) is dissolved dl-N-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine (3.5 g) and thereto are added water (6 ml) and potassium carbonate (3.3 g). To the mixture is further added dropwise with stirring 3,3-dimethylacryloyl chloride (1.9 g) over a period of about 1 hour. The mixture is stirred at room temperature for 2 hours, and then the solvent is distilled off under reduced pressure. To the residue is added a 10% sodium carbonate aqueous solution and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate, and the solvent is distilled off to give the desired compound (3.6 g), which is recrystallized from methanol to give coloress crystals, melting point: 186°-187° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4.C(N(CC)CC)C.Br.[Br:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.Br>C1COCC1>[BrH:29].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:20]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: BrCc1cccnc1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(Cc1cccnc1)CC3

Procedure:
Similarly to the preparation of Example 4, the title compound was prepared from the reaction of (+)-3-methoxy-morphinan hydrochloride (1 g, 3.4 mmol) in THF (20 ml), triethylamine (1.43 ml, 10.3 mmol), and 3-(bromomethyl)pyridine hydrobromide (0.95 g, 3.75 mmol) gave a solid which was treated with 45% HBr to afford 1 g of a tan solid (68% yield); ms (ESI+): m/z 349 (M+1).
Reaction SMILES: FC(F)(F)C(O)=[O:4].CON=[C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:21]=[C:22]([C:31]([OH:33])=[O:32])[O:23][C:24]=3[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.O1CCOCC1.[ClH:40]>CC(C)=O>[ClH:40].[O:4]=[C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:21]=[C:22]([C:31]([OH:33])=[O:32])[O:23][C:24]=3[C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: O=C(O)C(F)(F)F
Reactant: CON=C1CCc2cc(-c3cc(C(=O)O)oc3-c3ccncc3)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: O=C(O)c1cc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)o1
Reaction time: 1.5 h

Procedure:
The product from Step 3 (5.46 g, 11.7 mmol) was suspended in 5M hydrochloric acid (50 ml), dioxane (50 ml) and acetone (10 ml). The suspension was heated to reflux for 30 minutes, whereupon the suspended solids dissolved. The heating was continued for a further 90 minutes before the mixture was cooled, diluted with acetone (100 ml) and evaporated in vacuo to a wet solid. The solid was dried by repeatedly (×3) suspending in toluene and evaporating to dryness.
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]2[CH2:8][CH2:9][CH:4]([CH2:5][CH2:6]2)[C:3]1=[O:10].C(OO)(=[O:13])C.O.O.O.C([O-])(=O)C.[Na+]>>[CH2:1]=[C:2]1[CH:7]2[CH2:6][CH2:5][CH:4]([CH2:9][CH2:8]2)[C:3](=[O:10])[O:13]1
Reactant: C=C1C(=O)C2CCC1CC2
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C=C1OC(=O)C2CCC1CC2
Yield: 93.9 %

Procedure:
Analogously to the procedure indicated in Example P1, 955 mg (7 mmol) of 3-methylene-bicyclo[2.2.2]octan-2-one is reacted with 1.64 g (8.4 mmol) of 32% peracetic acid in the presence of 286 mg (21 mmol) of sodium acetate trihydrate. 1 g of 4-methylene-3-oxa-bicyclo[3.2.2]nonan-2-one is isolated. After purification by column chromatography using 10% ethyl acetate in hexane, pure 4-methylene-3-oxabicyclo[3.2.2]nonan-2-one is obtained in the form of an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].CN1C(=O)CCC1.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[NH2:43][C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH:46]=[N:47][N:48]2[CH2:53][C:54]1[CH:55]=[C:56]([CH:61]=[CH:62][CH:63]=1)[C:57]([O:59][CH3:60])=[O:58]>CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([NH:43][C:44]4[CH:52]=[CH:51][CH:50]=[C:49]5[C:45]=4[CH:46]=[N:47][N:48]5[CH2:53][C:54]4[CH:55]=[C:56]([CH:61]=[CH:62][CH:63]=4)[C:57]([O:59][CH3:60])=[O:58])=[O:22])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Reactant: COC(=O)c1cccc(Cn2ncc3c(N)cccc32)c1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: COC(=O)c1cccc(Cn2ncc3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.09578 g, 0.2933 mmol) and NMP (1.5 mL) were warmed to provide a homogeneous solution and then cooled to ambient temperature. 2,4,6-Trichlorobenzoyl chloride (0.04277 mL, 0.2737 mmol) was added and the mixture stirred at ambient temperature for 0.5 hours. Methyl 3-((4-amino-1H-indazol-1-yl)methyl)benzoate (0.055 g, 0.1955 mmol) was added as a NMP solution (1.5 mL) and the mixture was heated to 80° C. and stirred for 4 hours. The mixture was dissolved in MeOH and concentrated. The residue was dissolved in saturated aqueous NaHCO3 and EtOAc and the organic layer was washed with brine and dried over Na2SO4. The crude material was purified by column chromatography (15% MeOH/CH2Cl2 adding 1% 7N NH3/MeOH) to provide methyl 3-((4-(7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoate as the free base. This material was dissolved in MeOH (3.0 mL) and CHCl3 (1.0 mL), and HCl (1.955 mL, 3.910 mmol, 2.0M Et2O) was added and the mixture was stirred for 2 hours and then concentrated. The resulting solid was washed with Et2O and then with hexanes, and dried under vacuum to afford 0.085 g (64%) of the title compound. MS (ES+APCI) m/z=568 (M+H-2HCl).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15]I.CCCCCCC>C(#N)C>[Cl:12][CH2:13][CH2:14][CH2:15][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: O=C1COc2ccccc2N1
Reactant: ClCCCI
Solvent: CC#N
Solvent: CCCCCCC
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2H-1,4 benzoxazine-3(4H)one (1.0 g, 6.70 mmol) and Cs2CO3-(3.28 g, 10.1 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.58 g, 7.38 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacou to give 1.65 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the pure title compound as a colorless oil. Yield 1.36 g, 89.2%. Rf=0.24 [Heptane:EtOAC(4:1)], 1H NMR (CDCl3): δ 2.16 (m, 2H), 3.62 (t, 2H), 4.10 (t, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.05 (m, 2H), 13C NMR (CDCl3): δ 30.16, 39.04, 42.45, 67.72, 114.80, 117.38, 123.07, 124.14, 128.49, 145.47, 164.58.
Reaction SMILES: I[C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[CH3:10][C:3]1[C:4]([CH2:5][OH:6])=[CH:7][CH:8]=[CH:9][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccccc1
Reactant: Cc1c(I)cccc1CO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: Cc1c(CO)cccc1-c1ccccc1

Procedure:
In a photoreactor was placed 3-iodo-2-methylbenzyl alcohol (5.0 g, 0.02 mole) and 800 ml of benzene. To this was added sodium thiosulfate (5.0 g, 0.04 mole) in 15 ml of water. The mixture was purged with argon for 30 minutes, then irradiated with a 200 watt medium pressure ultraviolet lamp for 36.5 hours. The reaction mixture was then transferred to a separatory funnel. The photoreactor was washed with approximately 20 ml each of water, chloroform, and acetone. These washes were added to the separatory funnel. The organic layer was washed with aqueous 0.5 M sodium thiosulfate, then with an aqueous solution saturated with sodium chloride. The organic layer was then dried and filtered. The filtrate was evaporated under reduced pressure to an oily residue. The residue was purified by column chromatography on silica gel, elution with 1:1 hexane:chloroform, to give 2-methyl[1,1'-biphenyl]-3-methanol (2.4 g). The nmr and ir spectra were consistent with that expected for the named compound.
Reaction SMILES: C[O:2][C:3](=[O:54])[C@@H:4]([NH:21][C:22]([C@@H:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:8][CH:7]=1.[CH:55]([C:58]1[O:59][C:60]([CH3:66])=[C:61]([C:63]([OH:65])=O)[N:62]=1)([CH3:57])[CH3:56]>C(Cl)Cl>[Cl:53][C:48]1[CH:47]=[C:46]([CH:51]=[CH:50][C:49]=1[Cl:52])[CH2:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([C@H:36]2[CH2:35][O:34][C:30]3=[CH:31][C:32]4[CH2:33][C@@H:24]([C:22]([NH:21][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([O:12][C:13]6[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=6[CH3:20])=[CH:8][CH:7]=5)[C:3]([OH:54])=[O:2])=[O:23])[N:25]([C:63]([C:61]5[N:62]=[C:58]([CH:55]([CH3:56])[CH3:57])[O:59][C:60]=5[CH3:66])=[O:65])[CH2:26][C:27]=4[CH:28]=[C:29]3[O:37]2)=[CH:39][CH:40]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1oc(C(C)C)nc1C(=O)O
Solvent: ClCCl
Product: Cc1nccc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3nc(C(C)C)oc3C)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (30 mg) was reacted with 2-isopropyl-5-methyl-oxazole-4-carboxylic acid (according to a procedure in Synthesis, Vol. 10, pp. 1569-71 (2005)) in DCM (3.0 mL) according to General Procedure A and directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (8.5 mg). LCMS (m/z) 906.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:34]([CH2:36][NH2:37])[OH:35]>C1COCC1>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:29](=[O:31])[NH:37][CH2:36][CH2:34][OH:35])=[CH:32][CH:33]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(C(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
1,1′-Carbonyldiimidazole (0.6 g, 3.71 mmol) was added into the solution of 26 (0.91 g, 3.09 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature overnight under argon atmosphere, then ethanolamine (0.28 mL, 4.64 mmol) was added. The stirring was continued for 24 h at room temperature and argon atmosphere. The solvent was evaporated and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, 18:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide). 0.74 g (71%) of a white solid 27 was isolated. 1H NMR (300 MHz, CDCl3) δ 1.40 (s, 9H), 1.48 (m, 2H), 1.60 (m, 2H), 2.62 (m, 2H), 3.10 (m, 2H), 3.79 (m, 2H), 4.55 (br s, 1H), 6.74 (m, 1H), 7.18 (d, 2H), 7.66 (d, 2H).