Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl.[O-]S([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:16]/[S@:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cu+2]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1ccc(Br)cc1
Temperature: 37 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To 4-bromobenzaldehyde, 18-a, (50 g, 0.27 mol) in dichloromethane (500 mL) were added (S)-2-methylpropane-2-sulfinamide (43 g, 0.36 mol), PPTS (6.7 g, 0.027 mmol) and anhydrous CuSO4 (131 g, 0.82 mol) and the resulting mixture was stirred at 37° C. overnight. The mixture was then filtrated and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1) to provide the product, 19-a, (70 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:23][CH:22]=1
Reactant: Ic1ccc(Oc2ncccn2)cc1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(Oc2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 62.3 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (54.4 mg) was reacted with 2-(4-iodophenoxy)pyrimidine (59.2 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyrimidin-2-yloxy)phenyl]pent-4-enoic acid methyl ester (53.0 mg). Thin layer chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate=10/1) was used for purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].[F-].C[N+](C)(C)C>COCCOC>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:33]([F:35])([F:34])[F:32]
Reactant: COc1ccc2c(OCCn3nc(-c4ccc(C=O)c(Cl)c4)ccc3=O)ccnc2c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: COCCOC
Product: COc1ccc2c(OCCn3nc(-c4ccc(C(O)C(F)(F)F)c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 0 °C

Procedure:
To a stirring solution of 2-chloro-4-(1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzaldehyde (370 mg, 849 μmol) and (trifluoromethyl)trimethylsilane (121 μL, 849 μmol) in DME (10 mL) at −50° C. under nitrogen was added solid tetramethylammonium fluoride (79 mg, 849 μmol). The reaction was then removed from cooling bath and slowly warmed to 0°C. The reaction was then partitioned between DCM (100 mL) and 5% NaHCO3 (50 mL). The organic was dried over MgSO4, concentrated under reduced pressure, then purified on silica (40 g) eluting with 2 to 3% of MeOH/DCM. Product was isolated as an off white solid. MS (ESI pos. ion) m/z: 506 (MH+); calc'd for C24H19ClF3N3O4: 505.
Reaction SMILES: [CH2:1]1C[O:4][CH2:3][CH2:2]1.Cl[C:7]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:8]=1[C:9]([NH:11][CH:12]1[CH:19]2[CH2:20][CH:15]3[CH2:16][C:17]([OH:22])([CH2:21][CH:13]1[CH2:14]3)[CH2:18]2)=[O:10]>CCOC(C)=O>[Cl:27][C:25]1[CH:24]=[CH:23][C:8]([C:9]([NH:11][CH:12]2[CH:13]3[CH2:14][CH:15]4[CH2:16][C:17]([OH:22])([CH2:18][CH:19]2[CH2:20]4)[CH2:21]3)=[O:10])=[C:7]([O:4][CH2:3][CH2:2][CH3:1])[N:26]=1
Reactant: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1ccc(Cl)nc1Cl
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCOc1nc(Cl)ccc1C(=O)NC1C2CC3CC1CC(O)(C3)C2
Temperature: 150 °C
Yield: 93.5 %

Procedure:
Bis-sodium hexamethyldisilylamide 1.0M in THF (1 ml, 1 mmol) was added to 2,6-dichloro-N-(5-hydroxyadamantan-2-yl)nicotinamide (341 mg, 1 mmol) and heated at 150° C. for 2 hours. The reaction mixture was diluted with EtOAc (60 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 6-chloro-N-(5-hydroxyadamantan-2-yl)-2-propoxynicotinamide (341 mgs, 93%) as a white solid.
Reaction SMILES: N(C(OC)=O)=NC([O-])=O.[C:10]([OH:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:19]1[CH:24]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:20]=1.C(O)CC>C1COCC1>[C:10]([O:18][CH2:20][CH2:19][CH3:24])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)N=NC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCCO
Product: CCCOC(=O)c1ccccc1
Reaction time: 26 h
Yield: 55 %

Procedure:
The methyl azodicarboxylate resin (4.0 g of 0.28 meq/g, ~1.1 meq) was suspended in THF (150 ml). A solution of benzoic acid (0.134 g, 1.1 mmol) in the THF (10 ml) was added. Ph3P (0.288 g, 1.1 mmol) and n-propanol (0.180 g, 0.22 ml, 3 mmol) in THF (7 ml) were added slowly at 25° C. and the mixture stirred for 26 hours. The resin was filtered and washed with CH2Cl2 (4×150 ml), and Et2O (2×100 ml). The yellow oil obtained on concentration of filtrate and washings was purified by flash chromatography (0.5% EtOAC in hexane) to yield to 55% of n-propyl benzoate. (Using dimethyl azodicarboxylate instead of the resin, a 56% yield was obtained). FT IR (neat) on the ester 1721, 1315 (m), 1276, 1111, 711cm-1 ; 1H NMR (80 MHz CDCl3) δ 0.98 (t, 3H, -CH2CH3), 1.75 (m, 2H, -CH2CH2CH3), 4.25 (t, 2H, --OCH2), 7.43 (t, 3H,) 8.30 (m, 2H) (Ph); EI--MS: 164.0836 (M+, 164.0838 calcd. for C10H12O2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19]([OH:21])=O.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:26]2[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]2)=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)=[O:21]
Reactant: O=C(O)Cc1c(Cl)cc(-n2cnc3cccnc32)cc1Cl
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)Cc3c(Cl)cc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 7 but using (2,6-dichloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 56.1) and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (WO 03/099771). Title compound: ES-MS: 576.8/578.9 [M+H]+; tR=3.72 min (System 1); Rf=0.17 (CH2Cl2/(2N NH3 in MeOH), 95:5).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[CH:16]([C:18]1[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CNS(C)(=O)=O)c1ccc(-c2cccc(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.2 g (8.1 mmol) of 3-formylbenzeneboronic acid and 1.1 g (8.1 mmol) of potassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) of tetrakis-(triphenyl-phosphine)palladium(0). The mixture was heated to 100° C. for 16 hours whereupon 5 mL of water was added and heating continued for 1 hour. The mixture was then cooled to ambient temperature and 10 mL of water was added. The organic portion was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (40% ethyl acetate/hexane) afforded 0.7 g (41%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[C:12]3[N:21]=[C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[S:19][C:13]=3[C:14](=[O:18])[NH:15][CH2:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)(O)[O-].[Na+].[I-:33].[K+].II>C(#N)C.O.CC(=O)OCC.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3([O:8][C:7](=[O:9])[C:6]=2[CH:10]=1)[CH:17]([I:33])[CH2:16][NH:15][C:14](=[O:18])[C:13]1[S:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:21][C:12]3=1
Reactant: [I-]
Reactant: O=C(O)c1cc(Cl)ccc1C1=CCNC(=O)c2sc(N3CCOCC3)nc21
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1OC2(c3ccc(Cl)cc31)c1nc(N3CCOCC3)sc1C(=O)NCC2I
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
5-chloro-2-[2-(morpholin-4-yl)-4-oxo-5,6-dihydro-4H-[1,3]thiazolo[5,4-c]azepin-8-yl]benzoic acid (0.0500 g, 0.123 mmol) was dissolved in acetonitrile (0.50 mL) and saturated aqueous sodium bicarbonate solution (2.5 mL), then added a solution of potassium iodide (0.102 g, 0.616 mmol) and iodine (0.0406 g, 0.160 mmol) in water (1.0 mL) dropwise and the solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with EA and 15% aqueous sodium thiosulfate solution and the mixture was stirred for 20 minutes. The layers were separated and the aqueous layer was extracted twice more with EA. The combined organic layer was then washed with water and brine then dried over anhydrous sodium sulfate and concentrated. The residue was purified using column chromatography on silica gel (12 gr Analogix column, gradient DCM to 60% EA in DCM over 15 minutes) to give the product (0.0540 g, 82%). LCMS: (AA) ES+ 532, 534. 1H NMR (400 MHz, d6-DMSO) δ: 8.44 (t, J=4.8 Hz, 1H), 8.07-7.90 (m, 1H), 7.92-7.72 (m, 2H), 5.12-4.91 (m, 1H), 3.93-3.81 (m, 1H), 3.77-3.65 (m, 1H), 3.61-3.48 (m, 4H), 3.23-3.08 (m, 4H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][CH2:29][C:30]2=[O:33])=[CH:25][CH:24]=1.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)P(N(C)C)(N(C)C)=O.[NH4+].[Cl-].[Na+].[Cl-]>O1CCCC1>[CH2:34]([CH:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[C:30]1=[O:33])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc2c(c1)C(=O)C(Cc1ccccc1)CC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 26.3 %

Procedure:
To a -78° C. solution of lithium diisopropyl amide (from 43.8 ml (0.312 mol) of diisopropyl amine in 280 ml tetrahydrofuran and 119 ml (0.298 mol) of 2.5M n-butyllithium) was slowly added a solution of 50 g (0.285 mol) of 7-methoxy-3,4-dihydro-1(2H)-naphthalenone in 100 ml tetrahydrofuran. The resultant reaction mixture was stirred 10 minutes at -78° C. The cooling bath was charged to a 0° C. ice bath, followed immediately by the rapid addition of 38 ml (0.32 mol) of benzyl bromide. Hexamethylphosphoramide (106 ml, 0.60 mol) was then added and the resultant solution stirred at 25° C. for 2 hours. The reaction was added to saturated NH4Cl and saturated NaCl, dried over MgSO4, and evaporated to an oil, which was purified via column chromatography on 1 Kg of silica gel eluted with 10% ether-hexane to give 20 g (26%) of the title compound as an oil.
Reaction SMILES: [Br-].[CH:2]12[C:14](=[N+:15]3CCCC3)[CH:11]([CH2:12][CH2:13]1)[CH2:10][C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:3]2.O.Cl.NO.O.O.O.C([O-])(=[O:29])C.[Na+]>CCO>[CH:2]12[C:14](=[N:15][OH:29])[CH:11]([CH2:12][CH2:13]1)[CH2:10][C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:3]2
Reactant: CC(=O)[O-]
Reactant: c1ccc2c(c1)CC1CCC(C2)C1=[N+]1CCCC1
Agent: Cl
Agent: NO
Agent: [Br-]
Solvent: O
Solvent: CCO
Product: ON=C1C2CCC1Cc1ccccc1C2
Temperature: 25 °C
Yield: 90 %

Procedure:
1-Tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-ylidene-pyrrolidinium bromide (48.14 g, 0.15 mol) was suspended in EtOH (200 mL) and H2O (100 mL) and stirred. Hydroxylamine hydrochloride (31.27 g, 0.45 mol) was added, resulting in the starting material dissolving. Sodium acetate trihydrate (61.2 g, 0.45 mol) was added to the solution. After a few minutes a thick white precipitate formed. The mixture was heated to reflux until a clear solution was obtained and then allowed to cool to room temperature. The product oxime crystallized from solution and was filtered off, washing with water. The resulting pure oxime was dried to give 27.18 g (90%) of a pure white crystalline solid. 1H NMR (d6-DMSO, 360 MHz) δ 10.17 (1 H, s, N—OH), 7.19-7.12 (4 H, m, aromatic), 3.51 (1 H, bt, bridgehead CH), 3.01-2.87 (2 H, m, benzylic), 2.80 (1 H, bt, bridgehead CH), 2.77 (2 H, t, J=14 Hz, benzylic), 1.68-1.63 (2 H, m), 1.10-1.05 (2 H, m). m/z 202 (M+H+).
Reaction SMILES: OS(O)(=O)=O.C(O)(C(F)(F)F)=[O:7].[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[C:26]([C:27]3[CH:28]=[CH:29][C:30]4[N:31]([C:33]([C:36]#[N:37])=[CH:34][N:35]=4)[CH:32]=3)=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:17]=[CH:18][C:19]=1[F:20].[OH-].[Na+]>>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[C:26]([C:27]3[CH:28]=[CH:29][C:30]4[N:31]([C:33]([C:36]([NH2:37])=[O:7])=[CH:34][N:35]=4)[CH:32]=3)=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1cnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)cn12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1cnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)cn12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Conc. H2SO4 was added dropwise to stirring TFA at room temperature for 5 min. 6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile (870 mg) was added all at once to the homogenous solution after fuming subsided from acid mixture. Additional TFA and conc. H2SO4 were added successively to the heterogeneous reaction mixture. After 6 h, the reaction mixture was added to ice/water and stirred. The homogeneous solution was basified with aq. NaOH (50%). The resultant heterogeneous slurry was filtered and dried. Subsequently, the white solid was purified by flash chromatography (Combiflash® companion System® with RediSep® silica gel column 24 g, 70% EtOAc/hexanes-3% MeOH/EtOH) to obtain 6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (720 mg). 1H NMR (300 MHz, DMSO-d6): δ 9.48 (s, 1H), 8.72 (dd, J=4.8, 1.6 Hz, 1H), 8.33 (s, 1H), 7.97 (dd, J=7.8, 1.7 Hz, 2H), 7.64 (d, J=6.8 Hz, 1H), 7.61-7.57 (m, 1H), 7.55 (dd, J=7.9, 4.9 Hz, 1H), 7.52-7.48 (br s, 2H), 7.26 (dd, J=7.7, 1.5 Hz, 1H), 7.10 (dd, J=9.4, 1.9 Hz, 1H). 19F NMR (282 MHz, DMSO-d6): δ −117.01 (q, J=7.5, 7.1 Hz). LCMS: rt 4.65 min (A), purity 99%, MS (m/e) 367 MH+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1.O1C2C=CC=CC=2C=CN1>O1CCOCC1.C(OCC)(=O)C.C(O)(=O)C>[Cl:20][C:19]1[C:14]([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc2c(c1)NCCO2
Reactant: Clc1cccnc1Cl
Agent: C1=Cc2ccccc2ON1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Clc1cccnc1N1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
To a solution of 3,4-dihydro-2H-1,4-benzoxazine (198 mg, 1-47 mmol) in dry dioxane (3 mL) was added 60% sodium hydride/mineral oil (90 mg, 2.25 mmol) and let stir at ambient temperature for 15 min. Then 2,3-dichloropyridine (264 mg, 1.78 mmol) was added and the mixture was warm to 80 C. Over 24 hours periodically added small portions (˜10 mg) of NaH and another 90 mg of 2,3-dichloropyridine until all of the benzoxazine was gone. Cooled and diluted with ethyl acetate, neutralized with acetic acid and then washed with NaHCO3 solution, followed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. This residue was purified by chromatography on silica gel eluting with a 10-15% acetone/hexane gradient to give the title compound as a viscous oil which slowly solidified (168 mg, 46% yield). 1H-NMR (500 MHz, CDCl3): δ 8.35 (1H, d, J=4.6 Hz), 7.74 (1H, d, J=8.1 Hz), 7.05 (1H, dd, J=4.7, 8.0 Hz), 6.90 (1H, d, J=7.4 Hz), 6.83 (1H, t, J=7.3 Hz), 6.75 (1H, t, J=7.3 Hz), 6.55 (1H, d, J=7.8 Hz), 4.39 (2H, t, J=4.3), 3.84 (2H, t, J=4.Hz). m/e (m+1): 247.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([C:23]([O:25]C)=[O:24])[C:19]([F:22])([F:21])[F:20])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH:18]([C:19]([F:22])([F:21])[F:20])[C:23]([OH:25])=[O:24])=[O:16])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(OC(=O)N1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C(OC(=O)N1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a stirring solution of 1,1,1-trifluoro-3-methoxy-3-oxopropan-2-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate (6h) (18 mg, 0.036 mmol) in a 1:1 mixture of 1,4-dioxane:water (1 mL) was added NaOH (360 μL, 0.36 mmol, 1.0 N in water). After stirring the reaction mixture overnight at room temperature, the reaction was quenched by the addition of aqueous 1N HCl (5 mL) and extracted with dichloromethane (3×, 25 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by SiO2 preparative TLC (50% EtOAc/hexanes, 1% HCO2H) to give the title compound as a colorless oil (9.1 mg, 52%): 1H NMR (600 MHz (CDCl3) δ 7.42 (d, J=7.32 Hz, 4H), 7.30 (d, J=8.16 Hz, 4H), 5.35 (s, 1H), 4.53 (bs, 1H), 3.78-3.53 (m, 4H), 2.81-2.54 (m, 4H); HRMS m/z calc'd for [M+H]+ C21H19Cl2F3N2O4: 491.0747. found 491.0735.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:25][C:26]([OH:28])=O)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:40][OH:41].N#N>C(Cl)Cl.O.C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:25][C:26]([NH:40][OH:41])=[O:28])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: COc1ccc(CN(CC(=O)O)S(=O)(=O)c2ccc(OCCCCl)cc2)cc1
Reactant: NO
Agent: N#N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(CC(=O)NO)S(=O)(=O)c2ccc(OCCCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 48.81 g (0.114 mol) of {[4-(3-chloro-propoxy)-benzenesulfonyl]-(4-methoxybenzyl)-amino}-acetic acid in 500 ml of CH2Cl2, 19.56 ml (0.228 mol) of oxalyl chloride and 0.88 ml (0.011 mol) of DMF are added dropwise at 0–5° C. under N2 atmosphere. The mixture is stirred for 1 h at 0–5° C. and 1 h at r.t. To a solution of 226 ml (3.42 mol) of) 50% hydroxylamine in H2O (Aldrich) in 1200 ml of THF, a solution of the freshly prepared above acid chloride in CH2Cl2 is added over 45 min. at −10 to −5° C. through a teflon tube using N2 gas pressure. The reaction mixture is stirred for 30 min at −5 to 0° C. and filtered through paper filter to remove insoluble precipitates. The filtrate is diluted with H2O and extracted with CH2Cl2. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The product is collected by filtration and washed with ether to give 43.03 g of 2-{[4-(3-chloro-propoxy)-benzenesulfonyl]-(4-methoxy-benzyl)-amino}-N-hydroxy-acetamide; NMR (CDCl3): 2.2–2.35 (m, 2H), 3.69 (s, 2H), 3.76 (t, 2H, J=6 Hz), 3.79 (s, 3H), 4.21 (t, 2H, J=6 Hz), 4.26 (s, 2H), 6.77 (br s, 1H), 6.85 (d, 2H, J=9.04 Hz), 7.03 (d, 2H, J=9.04 Hz), 7.15 (d, 2H, J=9.04 Hz), 7.78 (d, 2H, J=8.56 Hz), 8.82 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[OH:13].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1.O>CN(C=O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:13][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1
Reactant: O=c1cc(CO)occ1OCCCCCBr
Reactant: Oc1ccnc2ccc(C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(CO)occ1OCCCCCOc1ccnc2ccc(C(F)(F)F)cc12
Reaction time: 0.17 h
Yield: 21 %

Procedure:
6-Trifluoromethyl-quinolin-4-ol (0.23 g, 1.08 mmol) was dissolved in DMF (3 mL). Cs2CO3 (0.35 g, 1.08 mmol) was added at RT and the mixture was stirred for 10 min. A solution of 5-(5-bromo-pentyloxy)-2-hydroxymethyl-pyran-4-one 10 (0.30 g, 1.03 mmol) in DMF (2 mL) was added via syringe. This mixture was stirred at 50° C. for 1 h. Water (10 mL) was added and the mixture extracted with EtOAc (2×50 mL), washed with water (3×50 mL), brine (3×50 mL) dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent (CH2Cl2:MeOH)=90:10. 5-(5-(6-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 11 was obtained (93 mg, 21% yield) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[CH2:21][OH:22])[N:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:61][C@H:62]1[CH2:67][CH2:66][C@H:65]([OH:68])[CH2:64][CH2:63]1>CN(C=O)C.O.C(OCC)(=O)C>[OH:68][C@H:65]1[CH2:66][CH2:67][C@H:62]([NH:61][C:13]([C:12]2[C:7]([NH:6][CH2:5][C:4]3[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:2]([Cl:1])[CH:3]=3)=[N:8][C:9]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:21][OH:22])=[N:10][CH:11]=2)=[O:15])[CH2:63][CH2:64]1
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C(=O)O)cc1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1Cl
Reaction time: 0.33 h

Procedure:
In DMF (20 mL) was dissolved (s)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)tetrahydropyrrole-1-yl)-5-pyrimidine carboxylic acid (3.9 g, 10 mmol). The solution was cooled in an ice bath. HATU (5.67 g, 15 mmol) and DIPEA (1.93 g, 15 mmol) were added. After 20 min, trans-4-aminocyclohexanol (1.39 g, 12 mmol) was added in batches. The reaction was conducted overnight. LC-MS was used to monitor the reaction. Ethyl acetate (50 mL) and water (50 mL) were added. The separate aqueous phase was washed with ethyl acetate twice. The organic phase was combined, dried, concentrated and purified by silica gel column chromatography (VDCM:VMeOH=15:1) to give the product (1.5 g, 31% yield).