Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[I-].[Cl:3][C:4]1[N:9]=[CH:8][C:7]2[C:10]([C:32]([CH3:34])=[CH2:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=1.[F:35][C:36]([Si](C)(C)C)([F:38])F>C1COCC1>[Cl:3][C:4]1[N:9]=[CH:8][C:7]2[C:10]([C:32]3([CH3:34])[CH2:33][C:36]3([F:38])[F:35])=[N:11][N:12]([C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:6]=2[CH:5]=1
Reactant: C=C(C)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)CC1(F)F
Temperature: 65 °C
Yield: 107 %

Procedure:
Reference: Angew. Chemie Int. Ed., 2011, 50(31), 7153. To a 2 dram pressure vial charged with a magnetic stir bar was added anhydrous NaI (3.4 mg, 0.023 mmol), THF (1 ml), and 6-chloro-3-(prop-1-en-2-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (50 mg, 0.115 mmol) under nitrogen. To this was added (trifluoromethyl)trimethylsilane (0.042 ml, 0.287 mmol). The reaction vessel was sealed and heated to 65° C. in an oil bath for a period of 2.5 hours. LCMS and TLC indicated product and remaining starting material. Additional sodium iodide (3.4 mg, 0.023 mmol) and (trifluoromethyl)-trimethylsilane (0.042 ml, 0.287 mmol) were added and the reaction was heated overnight at 65° C. The reaction mixture was concentrated and taken up in ether (15 ml). The organic layer was washed with water (15 ml), saturated sodium thiosulfate solution (15 ml), saturated sodium bicarbonate solution (15 ml), and water (15 ml), in that order. The ethereal layer dried over anhydrous magnesium sulfate, concentrated, and purified (12 g silica gel, eluting with 0-10% tOAc/hexanes) to give 6-chloro-3-(2,2-difluoro-1-methylcyclopropyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (60 mg, 0.123 mmol) as a beige foam. MS ESI calc'd. for C29H22ClF2N3[M+1]+ 486, found 486.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]([O:26][C:27]([O:29][CH3:30])=[O:28])[CH2:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[N:21][C:22]([O:24][CH3:25])=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:31]>C(O)C>[C:1]1([O:11][CH2:12][CH:13]([O:26][C:27]([O:29][CH3:30])=[O:28])[CH2:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2([Cl:31])[NH:21][C:22]([O:24][CH3:25])=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)N=c1ccccn1CC(COc1cccc2ccccc12)OC(=O)OC
Reactant: Cl
Solvent: CCO
Product: COC(=O)NC1(Cl)C=CC=CN1CC(COc1cccc2ccccc12)OC(=O)OC

Procedure:
18 Grams of 3-(1-naphthoxy)-1-(2-methoxycarbonylimino-1,2-dihydro-1-pyridyl)-2-methoxycarbonyloxypropane were dissolved in about 50 ml of absolute ethanol. Concentrated hydrochloric acid was added dropwise until the pH was 1.0. The mixture was heated until a homogeneous solution was obtained and additional hydrochloric acid was added to bring the pH to 1.0. The solvent was evaporated under vacuum and the residual oil was dissolved in 25 milliliters of hot isopropyl alcohol. The product which crystallized on cooling was collected on a filter, washed with isopropyl alcohol, and dried to yield 3-(1-naphthoxy)-1-(2-chloro-2-methoxycarbonylamino-1,2-dihydro-1-pyridyl)-2-methoxycarbonyloxypropane. M.P. 133°-135° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].Cl.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][CH:13]=1.[Cl-].[OH-].[Na+]>C1C=CC=CC=1>[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:1]2([CH2:18][C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][C:2]2=[O:10])=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C1Cc2ccccc2C1(Cc1ccncc1)Cc1ccncc1

Procedure:
To stirred mixture of 2-indanone (2.64 g, 0.02 mol), 4-picolyl chloride hydrochloride (7.22 g, 0.044 mol ), and benzyltriethylanmonium chloride (0.45 g, 0,002 mol) in 100 ml of benzene was added 1N sodium hydroxide (84 ml, 0.084 mol ) dropwise over a period of 30 min. The mixture was stirred for an additional 2.5 h. at room temperature, then heated to 60° and maintained at this temperature for 1 h. Thin layer chromatographic analysis indicated that the reaction was complete. The reaction mixture was cooled, the organic layer was separated, and diluted with an additional 80 ml of benzene. The benzene solution was extracted with 100 ml of 1N HCl. The acidic layer was basified with 10% sodium hydroxide, wherein the crude product separated as a gum. The crude material was crystallized frcn cyclohexane, and further purifed by recrystallization from cyclohexane to give 1,1-bis(4-pyridinylmethyl)-1,3-dihydro-2H-indene-2-one as a white solid, 0.300 g, m.p. 95°-96°. NMR (200 MHz, CDCl3) δ 2.66 (s, 2H); 3.07-3.34 (d, 4H); 6.73 (d, 4H); 6.82-7.47 (m, 4H). IR (nujol) 1714 cm-1. Analysis. Calcd. for C21H18N2O: C, 80.23; H, 5.77; N, 8.91. Found: C, 80.47; H, 5.76; N, 8.89.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=1>>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:2]2[N:7]3[CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[C:5]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[N:4][CH:3]=2)[CH:30]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Product: c1cncc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)c1

Procedure:
Compound 15a (150.0 mg, 0.34 mmol) was subjected to Suzuki coupling conditions with 3-pyridineboronic acid pinacol ester using the methods described in Example 1, Step G to obtain compound 46a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C25H22N6O2: 439.1 (M+H). Found 439.1.
Reaction SMILES: [C:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1nccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: ON=C(c1ccccc1)c1nccs1
Temperature: 25 °C

Procedure:
To Phenyl-thiazol-2-yl-methanone (0.5 g) in ethanol (6 mL) was added hydroxylamine hydrochloride (3 eq) and sodiumcarbonate (3 eq). The reaction mixture was stirred at reflux overnight and then allowed to cool down to room temperature. The precipitate was then isolated by filtration and washed with water to yield the title compound as a light grey solid. MS (m/e): 207.1 (5), 206.1 (10), 205.1 (100% M+H+)
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][CH:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][CH:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(CC2CCc3ccc(OC)cc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(CC2CCc3ccc(O)cc32)cc1
Temperature: 25 °C

Procedure:
A solution of BBr3 (1.0M DCM, 0.32 mL) was added dropwise to a DCM (2 mL) solution containing the intermediate from Step C (71 mg, 0.24 mmol). The solution was stirred at room temperature until no starting material remained by HPLC analysis. The reaction was quenched with MeOH (1 mL) and AcOH (1 mL). The solution was then concentrated and the residue partitioned between aqueous 1N HCl and ethyl acetate. The organic phase was washed with water and brine and dried over MgSO4. The filtered solution was concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. LCMS1 3.51 min (M-31)=251
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:11][C:4]1[CH:3]=[C:2]([CH:12]=[CH2:13])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc([N+](=O)[O-])c(F)c1
Reaction time: 5 h
Yield: 343 %

Procedure:
4-Bromo-2-fluoro-1-nitro-benzene (691 mg, 3.14 mmol), tributyl-vinyl-stannane (1.2 g, 3.77 mmol), triphenylphospine (49 mg, 0.19 mmol) and tetrakistriphenylphosphinpalladium(0) (73 mg, 0.06 mmol) were dissolved in toluene (25 ml) and stirred for 5 hours at reflux. The reaction mixture was concentrated in vacuo. The residue was partitioned between water (25 ml) and diethyl ether (50 ml). The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo to yield an oil (1.8 g). The residue was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0-5%). Fractions containing the product were combined and the solvent evaporated to give an oil (360 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C([O-])(=O)C.[NH4+:23]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:23])=[O:13]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: NC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 8 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 16 mmol of. ammonium acetate. LC/MS [7.27 min; 358 (M+1)].
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:49][CH:50]1[C@H:54]2[C@H:55](OC3CCCCO3)[N:56](C(OC(C)(C)C)=O)[C:57]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:58]=3[C:59](=[O:60])[N:53]2[CH2:52][CH2:51]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[C@H:22]2[C@H:23](OC3CCCCO3)[N:24](C(OC(C)(C)C)=O)[C:25]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:26]=3[C:27](=[O:28])[N:21]2[CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:16]([O:17][CH:18]1[C@@H:22]2[CH:23]=[N:24][C:25]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:26]=3[C:27](=[O:28])[N:21]2[CH2:20][CH2:19]1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:49][CH:50]1[C@@H:54]2[CH:55]=[N:56][C:57]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:58]=3[C:59](=[O:60])[N:53]2[CH2:52][CH2:51]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 83.3 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8g (170 mg, 0.18 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9g (93 mg, 0.15 mmol, 88%) as a solid: [α]20D=+547° (c=0.13, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.31-1.53 (m, 10H, 14-H, 14′-H, 15-H, 15′-H, 16-H), 1.83-1.94 (m, 4H, 13-H, 13′-H), 2.00-2.12 (m, 4H, 2-H, 2′-H), 2.27-2.38 (m, 4H, 1-H, 1′-H), 3.54-3.64 (m, 2H, 3-H, 3′-H), 3.69-3.78 (m, 2H, 11a-H, 11a′-H), 3.79-3.87 (m, 2H, 3-H, 3′-H), 3.92 (s, 6H, 7-OMe, 7′-OMe), 4.01-4.19 (m, 4H, 12-H, 12′-H), 6.81 (s, 2H, 9-H, 9′-H), 7.52 (s, 2H, 6-H, 6′-H), 7.67 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.9, 29.0, 29.3, 29.4, 29.6, 46.6, 53.7, 56.0, 69.1, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.2, 164.6; IR (neat): 3325, 2933, 1600, 1507, 1448, 1388, 1261, 1217, 1092, 1024 cm−1; MS (FAB) m/z (relative intensity) 617 (M+., 100), 635 (10), 785 (6).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.[C:10](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>CC(=O)CC>[OH:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(O)cs1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(O)cs1

Procedure:
50.0 g (0.347 mol) of 4-hydroxy-2-thiophenecarboxylic acid and 58.3 g (0.694 mol) of sodium carbonate are heated to the boiling point in 990 ml of absolute 2-butanone under nitrogen, and 43.7 g (0.347 mol) of dimethyl sulfate are added dropwise in the course of 20 minutes. The mixture is heated under reflux for a further 2.5 hours. It is then evaporated in vacuo and the residue is partitioned between saturated sodium carbonate solution and ether. The aqueous phase is extracted five more times with 80 ml of ether each time. The combined organic phases are dried over sodium sulfate/active charcoal, filtered and evaporated.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(N(CC)CC)C.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>CC(C)=O.ClCCl>[C:1]([O:5][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:4])[CH2:2][OH:3]
Reactant: O=C(O)CO
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CO)OCc1ccccc1
Temperature: 60 °C
Yield: 51.4 %

Procedure:
Glycolic acid (200 mg, 2.6 mmol) and triethylamine (401 μL, 2.86 mmol) were dissolved in 2.6 mL of acetone. After a couple minutes of stirring, benzyl bromide (279 μL, 2.34 mmol) was added to the solution. The reaction was refluxed at 60° C. for 12 h. The solution was filtered to remove precipitated triethylammonium bromide and was concentrated en vacuo. Purification was done by silica chromatography with dichloromethane (DCM) to remove the non-polar impurities and then 2% ethyl acetate (EtOAc) in DCM to elute the desired product as a colorless oil (200 mg, 51% yield). 1H-NMR (400 MHz, CDCl3) δ 7.362 (5H, s) δ 5.198 (2H, s) δ 4.201 (2H, s) δ 3.366 (1H, s) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][CH:12]=[O:13])=[C:4]([F:14])[CH:3]=1.[H-].[Na+].Cl[CH2:18][C:19]1[CH:29]=[CH:28][C:22]2[N:23]=[C:24]([S:26][CH3:27])[S:25][C:21]=2[CH:20]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([N:11]([CH2:18][C:19]2[CH:29]=[CH:28][C:22]3[N:23]=[C:24]([S:26][CH3:27])[S:25][C:21]=3[CH:20]=2)[CH:12]=[O:13])=[C:4]([F:14])[CH:3]=1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: O=CNc1c(F)cc(Br)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(CN(C=O)c3c(F)cc(Br)cc3[N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
To a stirred solution of N-(4-bromo-2-fluoro-6-nitrophenyl)formamide (2.79 g, 10.61 mmol) from the previous step in anhydrous DMF (40 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 485 mg, 12.13 mmol). The mixture was stirred at 0° C. for 15 min, then allowed to warm to rt. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (3.04 g, 13.24 mmol) from Step 3 of Example 3 in DMF (10 mL), and the mixture was stirred at rt for 15 h. The mixture was partitioned between water and DCM and the organic layer was separated and washed sequentially with water and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford N-(4-bromo-2-fluoro-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide (4.8 g, 98%) as an oil, which was not purified further. LCMS (ESI) m/z 456 and 458 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][C@@H:25]2[CH3:34])=[C:20]([CH:35]=[CH:36][CH3:37])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C2C=C(C3(C)NC(=O)NC3=O)C=CC=2CC1.[O:55]1[C:64]2[C:59](=[N:60][CH:61]=[C:62]([C:65]3([CH3:72])[NH:69][C:68](=[O:70])[NH:67][C:66]3=[O:71])[CH:63]=2)[O:58][CH2:57][CH2:56]1>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:67]3[C:66](=[O:71])[C:65]([C:62]4[CH:63]=[C:64]5[O:55][CH2:56][CH2:57][O:58][C:59]5=[N:60][CH:61]=4)([CH3:72])[NH:69][C:68]3=[O:70])[CH2:26][C@@H:25]2[CH3:34])=[C:20]([CH:35]=[CH:36][CH3:37])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)C[C@@H]1C
Reactant: CC1(c2cnc3c(c2)OCCO3)NC(=O)NC1=O
Agent: CC1(c2ccc3c(c2)OCC3)NC(=O)NC1=O
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3cnc4c(c3)OCCO4)C2=O)C[C@@H]1C

Procedure:
(S)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}-3-methylpiperazin-1-yl)-2-bromoethanone, 5-(2,3-dihydrobenzofuran-6-yl)-5-methylimidazolidine-2,4-dione and 5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.[OH-].[Na+]>O1CCOCC1>[C:10]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[CH2:3][CH2:2][O:1][S:35]([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36])(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N1CCCCC1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCC(=O)N1CCCCC1CCOS(=O)(=O)c1ccc(C)cc1

Procedure:
1,4-Dioxane solution of 1-[2-(2-hydroxyethyl)piperidino]octadecan- 1-one and p-toluenesulfonyl chloride is added to sodium hydroxide solution and the mixture is reacted at room temperature to obtain 1-octadecanoyl-2-[2-(tosyloxy)ethyl]piperidine.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]3[CH2:31][C:32]([OH:34])=[O:33])=O)C3C(=CC=CC=3)C=2C=CC=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)=[O:44]>CN(C=O)C>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][NH:18][CH:19]([CH2:31][C:32]([O:34][CH2:42][C:43]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)=[O:44])=[O:33])[CH2:20]1)=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C(CC(=O)O)C1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCNC(CC(=O)OCC(=O)c2ccc(F)cc2)C1

Procedure:
(RS)-2-Carboxymethylpiperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(9H-fluoren-9-ylmethyl) ester from description 109 (2.0 g) was dissolved in DMF (25 ml) and stirred at room temperature under argon for 3 days in the presence of potassium carbonate (0.697 g) and 2-bromo-4′-fluoroacetophenone (0.930 g). The reaction solution was then partitioned between ethyl acetate and water. the organic solution was washed with brine, dried (MgSO4) and evaporated. The crude product was chromatographed over silica gel, eluting with 25 to 100% ethyl acetate in hexane, followed by 10% ethanol in ethyl acetate. The title compound was obtained as a pale yellow solid (0.887 g), mass spectrum (API+) 381 [MH+], C19H25FN2O5 requires 380.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>O1CCCC1>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CN(C)c1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(=O)Cl)cc1

Procedure:
To a 1000 mL round bottomed flask was added 4-dimethylamino-benzoic acid (50.0 g, 1.0 eq) and THF (600 mL). A solution of thionyl chloride (44.16 mL, 2.0 eq) in tetrahydrofuran was added and the resulting mixture heated to reflux for 4 hours. The excess thionyl chloride and solvent were removed under reduced pressure to yield 4-dimethylamino-benzoyl chloride as a solid, which was used without further purification in the preparation of compound 560.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.[CH3:17][O:18][CH2:19][CH2:20][CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:21][CH2:20][CH2:19][O:18][CH3:17])[CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Reactant: COCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COCCCN1CCC(C(=O)OC)=Cc2cc(Br)ccc21
Reaction time: 24 h
Yield: 93.1 %

Procedure:
To a solution of methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.80 g) and 3-methoxypropionaldehyde (1.25 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (1.81 g) at room temperature, and the mixture was stirred for 24 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the resulting residue was separated and purified with column chromatography (ethyl acetate hexane=1:3→1:2) to give methyl 7-bromo-1-(3-methoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (935 mg) as yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([I:16])=[CH:9][N:8]=1)C.O.O.Cl[Sn]Cl>C(O)C>[I:16][C:10]1[CH:9]=[N:8][C:7]2[NH:6][CH2:5][C:4](=[O:3])[NH:13][C:12]=2[CH:11]=1
Reactant: CCOC(=O)CNc1ncc(I)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: O=C1CNc2ncc(I)cc2N1

Procedure:
(5-Iodo-3-nitro-pyridin-2-ylamino)-acetic acid ethyl ester (17 g) was dissolved in ethanol. SnCl2.2H2O was added and the reaction mixture was heated to 80° C. for two (2) hours. The resulting precipitate was filtered and washed with ethanol to give the title compound as a rust colored solid (59-77% yield). M.p. 81° C., LCMS: m/z=275.91 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.94 (s, 2H), 6.94 (bs, 1H), 7.12 (d, J=1.8 Hz, 1H), 7.74 (s, J=1.8 Hz, 1H), 10.40 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([O:12][C:13](=[O:18])[C:14](=O)[CH2:15]Br)[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[N:8]=[C:6]2[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]2[CH:15]=1)=[O:18])[CH3:11]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc(Cl)nc(Cl)n1
Product: CCOC(=O)c1cn2c(Cl)nc(Cl)cc2n1

Procedure:
2,6-Dichloro-pyrimidin-4-ylamine and 3-bromo-2-oxo-propionic acid ethyl ester were reacted to provide 5,7-dichloro-imidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester. The title compound was prepared from 5,7-dichloro-imidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester and 5-methyl-1H-pyrazol-3-ylamine according to the procedure described in Scheme 7. 1H NMR (400 MHz, DMSO) 10.81 (s, 1H) 9.10 (s, 1H) 7.10 (s, 1H) 6.48 (s, 1H) 4.37 (q, J=7.2 Hz 2H) 2.28 (s, 3H) 1.33 (t, J=7.2 Hz, 3H). [M+H] calc'd for C13H14ClN6O2, 321; found, 321.