Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[OH:4].[I-].[Na+].[N-:18]=[N+:19]=[N-:20].[Na+].CS(C)=O>O>[N:18]([CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[OH:4])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)Nc1ccc([C@H](O)CBr)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)Nc1ccc([C@@H](O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 37 %

Procedure:
A mixture of N-{4-[(1S)-2-bromo-1-hydroxyethyl]phenyl}methanesulfonamide (which was obtained in Example 112) (1.73 g, 5.9 mmol), sodium iodide (0.88 g, 5.9 mmol), sodium azide (1.53 g, 23.6 mmol), and methyl sulfoxide (15 mL) was stirred at ambient temperature for 7 days, poured into water and extracted with ethyl acetate. The organic extracts were washed with water, and dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/chloroform/isopropylalcohol,5/4.5/0.5) gave an off-white solid (0.56 g, 70% yield); MS (ES) m/z: 256 (M)+; 1H NMR (400 MHz, DMSO-d6) δ 2.94 (s, 3H), 3.30 (m, 2H), 4.74 (m, 1H), 5.75 (d, 1H), 7.17 (d, 2H), 7.32 (d, 2H), 9.67(s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[CH2:29]([N:31]([CH2:32][CH3:33])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:30]
Reactant: CCNCC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for O21H25FN6O2, 412.2
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[N:16]3[C:12](=[N:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)[S:11][CH:10]2[CH2:21][C:22]([OH:24])=[O:23])=[CH:5][CH:4]=1.CS(O)(=O)=O.C(OCC)(=O)C.C(O)(=O)C.C([O-])(=O)C.C(O)(=O)C>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:16]3[C:12](=[N:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)[S:11][C:10]=2[CH2:21][C:22]([OH:24])=[O:23])=[CH:5][CH:4]=1
Reactant: O=C(O)CC1Sc2nc3ccccc3n2C1(O)c1ccc(Cl)cc1
Agent: Br
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1sc2nc3ccccc3n2c1-c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A mixture of 100 g of 3-(p-Chlorophenyl)-2,3,-dihydro-3-hydroxythiazolo[3,2-a]benzimidazol-2-acetic acid, hydrobromide and 200 ml of methanesulfonic acid was stirred overnight in a 500 ml round bottom flask. Thin layer chromatography on silica plates (solvent ethyl acetate/acetic acid) indicated rapid formation of an intermediate. After 20 hours at room temperature thin layer chromatography (silica plates, ethyl) acetate/acetic acid) showed the presence of a single component. The mixture was poured into water and the resulting crystals removed by filtration. The crystalline product was suspended in 5 volumes of hot water for 1/2 hour, filtered and the procedure repeated. After a final aqueous wash the material was dried in vacuo to yield the title compound (75 g, 91%) m.p. 242°-3° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc(Cc3c(C)c(OC)c(OC)c(OC)c3OC)cc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(3-methoxyphenyl)benzoate (1.23 g, 2.6394 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (20 ml) and 1,4-dioxane (40 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (200 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (1.03 g, 2.2787 mmol, 85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]([O:11]C)=O)[CH:2]=1.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=2)=[O:11])[CH:2]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: COC(=O)COc1cccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: O=C(COc1cccnc1)NCc1ccc(C(=O)O)cc1
Reaction time: 24 h
Yield: 89.3 %

Procedure:
32 g (0.19 mole) of methyl 2-(pyridin-3-yloxy)-acetate, 27 g (0.18 mole) of 4-aminomethylbezoic acid and 59 g (0.39 mole) of DBU were added to ethanol (350 ml), and reaction was then carried out at room temperature for 24 hours. After the reaction mixture had been concentrated, partition was carried out between toluene and water. Concentrated hydrochloric acid was added to the resultant aqueous layer to accomplish neutralization, and a deposited solid was collected by filtration, washed with water and methanol, and then dried to obtain 46 g (yield: 89%) of 4-[N-(pyridin-3-yl)oxyacetylaminomethyl]benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:37][CH3:38])=[C:10](\[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=C/C(Cl)=O)=[CH:28][CH:27]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16](C1CCCCO1)[N:15]=[CH:14]2.N.C([N:42]([CH2:45][CH3:46])CC)C.Cl.[O:48]1CCOCC1>CCO.O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:37][CH3:38])=[C:10](\[C:26]1[CH:27]=[CH:28][C:29](/[CH:32]=[CH:46]/[C:45]([NH2:42])=[O:48])=[CH:30][CH:31]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2
Reactant: CCN(CC)CC
Reactant: CC/C(=C(/c1ccc(/C=C/C(=O)Cl)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(F)cc1Cl
Reactant: C1COCCO1
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CC/C(=C(/c1ccc(/C=C/C(N)=O)cc1)c1ccc2[nH]ncc2c1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acryloyl chloride (0.15 g, 0.27 mmol) in dioxane (2.7 mL) at 0° C., ammonia (2.6 mL, 0.5M solution in dioxane) and triethylamine (0.136 g, 1.35 mmol) were added sequentially. The resulting mixture was warmed to room temperature and stirred for 6 h. The mixture was concentrated down to give a residue that was redissolved in EtOH (5.4 mL). HCl (0.5 mL, 2N HCl in diethyl ether) was added, and the reaction was heated at 70° C. for 4 h. Then, the mixture was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to give the crude product. This crude material was purified on a RP-C18 column using 40-100% acetonitrile in water in the presence of 0.1% TFA to afford the title compound. NMR (400 MHz, DMSO-d6): δ 13.12 (s, 1H), 8.11 (s, 1H), 7.69 (s, 1H), 7.56 (d, 1H), 7.43 (s, 1H), 7.38-7.30 (m, 2H), 7.26-7.11 (m, 5H), 7.03 (s, 1H), 6.98 (d, 2H), 6.44 (d, 1H), 2.36 (q, 2H), 0.89 (t, 3H). LCMS: 446 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[Br:11][CH2:12][C:13]([OH:15])=[O:14]>CN(C=O)C>[Br-:11].[C:6]([C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[N+:3]([CH2:12][C:13]([OH:15])=[O:14])[CH:4]=1)(=[O:7])[NH2:8]
Reactant: O=C(O)CBr
Reactant: Cc1ccc(C(N)=O)cn1
Solvent: CN(C)C=O
Product: Cc1ccc(C(N)=O)c[n+]1CC(=O)O
Product: [Br-]
Yield: 16.8 %

Procedure:
A solution of 6-methyl nicotinamide (400 mg, 2.94 mmol, 1.0 eq) and bromoacetic acid (408 mg, 2.94 mmol, 1.0 eq) in DMF (10 mL) was stirred at room temperature for 6 days. The reaction mixture was monitored by LCMS. Solvent was then evaporated and the crude product was purified by preparative HPLC to afford 136 mg of the expected compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:37][CH:38]([NH2:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(OCC)(=O)C>[CH3:37][CH:38]([NH:45][C:16](=[O:18])[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:20][CH3:21])[CH:11]=1)[CH3:19])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: COc1cc(C(C)C(=O)O)ccc1OCc1ccccc1
Reactant: CCCCCCC(C)N
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCCCCCC(C)NC(=O)C(C)c1ccc(OCc2ccccc2)c(OC)c1
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-benzyloxy-3-methoxyphenyl)propionic acid (5.0 g, 17.5 mmoles) and 4-methylmorpholine (2.0 mL, 17.5 mmoles) in ethyl acetate (170 mL) at 0° C. was treated with isobutyl chloroformate (2.26 mL, 17.5 mmoles). The resulting white slurry was stirred for 20 minutes. A solution of racemic 2-octylamine (2.7 g, 21 mmoles) in ethyl acetate (10 mL total solution) was added to the suspension which was then stirred for 3 hours. The mixture was extracted with 1M hydrochloric acid (3×50 mL), with a saturated sodium bicarbonate solution (3×50 mL), with brine (1×50 mL) and dried over magnesium sulfate. The ethyl acetate was rotary evaporated affording N-2-octyl-2-(4-benzyloxy-3-methoxyphenyl)proprionamide as a white solid which was crystallized from ether/methylene chloride to give 4.55 g. This racemic mixture of diastereomers was separated by silica gel chromatography.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:23]1([CH2:29][O:30][CH2:31][CH2:32][CH2:33][Br:34])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[Br-:34].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:33][CH2:32][CH2:31][O:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: BrCCCOCc1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 54.9 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0677 g, 0.231 mmol) and 3-bromopropyl phenylmethyl ether (0.070 mL, 0.396 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0663 g, 55.2%). EI-MS m/z 442 (M+) Rt (2.23 min).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].Cl[CH:6]([CH3:12])[CH2:7][CH2:8][C:9](Cl)=[O:10].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)(Cl)Cl>[C:13]1([C:9]([CH2:8][CH2:7][CH2:6][CH2:12][Cl:1])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [Cl-]
Reactant: CC(Cl)CCC(=O)Cl
Reactant: c1ccccc1
Agent: [Al+3]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCCCCl)c1ccccc1
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
Aluminum chloride (16 g, 0.12 mol) is suspended in carbon tetrachloride (80 ml). To the suspension is added dropwise 4-chlorovaleric acid chloride (18.6 g, 0.12 mol) with ice-cooling. The mixture is stirred for 15 minutes and benzene (7.8 g, 0.1 mol) is added dropwise to the mixture at below 5° C. Stirring is continued at the same temperature for 1 hour. The mixture is poured into ice-hydrochloric acid and extracted with chloroform. The chloroform layer is washed with water, saturated aqueous sodium bicarbonate, water and then saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Chloroform is distilled off and the resulting crude crystals are recrystallized from hexane to obtain 4-chlorobutyl phenyl ketone (8.3 g) as colorless flakes, m.p. 49°-50° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH:10]=[CH:11][C:12]1[O:13][C:14]([CH2:17][CH3:18])=[CH:15][CH:16]=1)C(O)=O)=O)[CH3:2].C([O-])(=[O:21])C.[Na+].[C:24]([O:27][C:28](=O)[CH3:29])(=[O:26])C>>[C:1]([O:3][C:4]1[C:16]2[CH:15]=[C:14]([CH2:17][CH3:18])[O:13][C:12]=2[CH:11]=[C:10]([C:24]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]=1)(=[O:21])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C(C=Cc1ccc(CC)o1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cc(OC(C)=O)c2cc(CC)oc2c1
Yield: 28 %

Procedure:
A mixture of (ethoxycarbonyl)-4-(5-ethyl-2-furyl)but-3-enoic acid (45.4 g, 0.18 mol) and sodium acetate (59.0, 0.72 mol) in acetic anhydride (450 mL) was heated to reflux for 5 hours. TLC (petroleum ether/EtOAc 4:1) indicated complete consumption of the starting material. The reaction mixture was concentrated and the residue was poured into 15% aq. Na2CO3 (500 mL), and extracted with EtOAc (500 mL×3). The combined organic layers was washed with brine (200 mL), dried over Na2SO4, and concentrated. The product was purified via silica gel column chromatography using petroleum ether/EtOAc (70:1) to afford the desired compound (13.0 g, 28%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]2=[CH:15][CH:16]=[C:17]([C:23]([O:25][CH3:26])=[O:24])[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:13]2[N:12]=[C:11]1[CH3:27])[C:4]1C=CC=CC=1.[H][H].C(I)C>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([N:10]1[C:14]2=[CH:15][CH:16]=[C:17]([C:23]([O:25][CH3:26])=[O:24])[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:13]2[N:12]=[C:11]1[CH3:27])[CH3:4]
Reactant: COC(=O)c1ccc2c(nc(C)n2Cc2ccccc2)c1C(=O)OC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(C)nc2c(C(=O)OC)c(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
Sodium hydride (1.38 g, 46.0 mmol, 80% oil dispersion) is added in portions to a solution of dimethyl 1-benzyl-2-methyl-4,5-benzimidazoledicarboxylate (10.9 g, 43.8 mmol) in dry dimethylformamide at 0° C. After evolution of hydrogen ceases, ethyl iodide (3.68 mL, 46.1 mmol) is added. The reaction mixture is stirred at room temperature overnight, treated with ethyl acetate, and filtered. The filtrate is concentrated in vacuo; the resultant residue is recrystallized from 50% ethyl acetate:hexanes to yield the title product as a light yellow powder (3.84 g, 31.7%), mp 126.6°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[C:21]3[CH2:20][CH2:19][CH2:18][C:17]4(OCC(C)(C)C[O:22]4)[C:16]=3[CH:15]=[N:14][CH:13]=1)[C:5]2([CH3:30])[CH3:29].Cl.O1CCOCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7](=[O:11])[N:6]([C:12]3[C:21]4[CH2:20][CH2:19][CH2:18][C:17](=[O:22])[C:16]=4[CH:15]=[N:14][CH:13]=3)[C:5]2([CH3:30])[CH3:29])=[CH:9][CH:10]=1
Reactant: CC1(C)COC2(CCCc3c(N4C(=O)c5ccc(Cl)cc5C4(C)C)cncc32)OC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a solution of 5-chloro-2-(5,5-dimethyl-6′,7′-dihydro-5′H-spiro[1,3-dioxane-2,8′-isoquinolin]-4′-yl)-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (0.66 g, 1.55 mmol) in MeOH (2 mL) was added 4 N HCl in dioxane (1.5 mL, 6 mmol) and the reaction mixture was stirred at room temperature for 2 hours. After evaporation of the solvent, the residue was diluted with DCM (20 mL) and washed with satd. aq. NaHCO3 (10 mL) solution. The organic layer was dried over anhy. Na2SO4, filtered and evaporated to dryness. The residue obtained was purified by silica gel flash chromatography eluting with a 0 to 50% hexane-ethyl acetate gradient to give the title compound (421 mg, 80%) as a light yellow solid. MS: 341.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[OH:9].O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([O:9][C:3]2[CH:4]=[C:5]([I:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cc(I)ccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(I)ccc2Cl)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 79.7 %

Procedure:
2-Chloro-5-iodophenol (2.50 g, 9.83 mmol), tert-butyl 4-hydroxy-1-piperidinecarboxylate (2.97 g, 14.7 mmol) and triphenylphosphine (5.15 g, 19.6 mmol), were suspended in THF (50 mL) and cooled to 0° C. Diethyl azodicarboxylate (3.08 mL, 19.6 mmol) was then added dropwise, the reaction was stirred under a N2 atmosphere for 18 h. The reaction was then partitioned between H2O and EtOAc. The organic layer was separated, washed with saturated brine, dried over MgSO4, concentrated in vacuo and subjected to FCC, eluting with 0-50% EtOAc/cyclohexane, to afford the title compound (3.43 g, 80%). (Method 3): Rt 4.98 min, m/z 337.9 [M−BOC+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([S:8]([N:11]([CH3:29])[N:12]=[CH:13][C:14]2[N:18]3[CH:19]=[C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)(=[O:10])=[O:9])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:36].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([S:8]([N:11]([CH3:29])[N:12]=[CH:13][C:14]2[N:18]3[CH:19]=[C:20]([C:23]4[CH:24]=[N+:25]([O-:36])[CH:26]=[CH:27][CH:28]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(F)cc1S(=O)(=O)N(C)N=Cc1cnc2ccc(-c3cccnc3)cn12
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(F)cc1S(=O)(=O)N(C)N=Cc1cnc2ccc(-c3ccc[n+]([O-])c3)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To an ice-cooled solution of 5-fluoro-N, 2-dimethyl-N′-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide (step 1, 18 mg, 0.043 mmol) in CH2Cl2 was added 3-chloroperoxybenzoic acid (14.46 mg, 0.065 mmol). The reaction mixture was stirred for 3 h at RT. The reaction mixture was then poured on to water. Organic layer was separated, washed with saturated solution of NaHCO3 and dried over Na2SO4. Crude compound was purified by column chromatography (silica gel, 5% EtOAc in petroleum ether) to obtain the title compound. Yield: 64%; 1H NMR (DMSO-d6; 300 MHz,): δ 9.45 (s, 1H), 8.57 (s, 1H), 8.32-8.31 (m, 2H), 8.03 (s, 1H), 7.83-7.79 (m, 2H), 7.67-7.64 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.56 (m, 1H), 7.43-7.36 (m, 3H), 3.40 (s, 3H), 2.54 (s, 3H); MS: m/z 440 (M+1)+.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[N:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)[N:6]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH2:5][CH2:4]1)[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([CH:3]1[C:12]2[C:7](=[N:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)[N:6]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN1CCC(CC)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC1CCN(CCCCCCC(=O)O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-ethyl 7-(8-ethyl-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (15 mg, 0.032 mmol) in THF (4.5 ml) and water (1.5 ml) was added LiOH (4.57 mg, 0.191 mmol). The reaction mixture was heated to reflux for 3.5 hours and stirred at RT overnight. The pH of the reaction mixture was adjusted to pH<5 by addition of 2M HCl. The volatile solvent was removed in vacuo and the crude residue was dissolved in water (10 ml) and extracted with EtOAc (3×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound;
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][C:29](O)=[O:30])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][C:29]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:12]=3)[CH2:17]2)=[O:30])[CH:22]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)CCc1cccnc1)C2
Reaction time: 8 h
Yield: 52 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 120 mg of 3-(3-pyridyl)propionic acid, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred overnight. The resulting reaction mixture is purified by silica gel chromatography. 154 mg of the title compound are obtained as colorless foam.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:12][N:13]1[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH2:20])[CH2:14]1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:27]>ClCCl>[ClH:8].[Cl:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:12][N:13]1[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH:20][C:26](=[O:27])[O:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)[CH2:14]1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 144.3 %

Procedure:
A mixture of triethylamine (0.101 ml) and Intermediate 11 (2.0 g) in dichloromethane (20 ml) was added dropwise to a solution of 4-nitrophenyl chloroformate (1.62 g) in dichloromethane (10 ml) with stirring at 0° C. under nitrogen. The solution was stirred for 3 h at 0° C., allowed to warm to 20° C., and stand for 18 h. The volatile components were evaporated in vacuo, and the residue was purified by Biotage flash chromatography on silica gel (90 g cartridge), eluting initially with 10% methanol in dichloromethane and subsequently with 20% methanol in dichloromethane, to give the title compound as a light brown solid (2.5 g).