Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:25])[CH2:24][NH:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:39][S:40]([CH2:43][C:44](O)=[O:45])(=[O:42])=[O:41].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:26]([F:27])([F:29])[F:28])[O:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:25])[CH2:22][N:23]([C:44](=[O:45])[CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:24]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: FC1(c2ccc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)CC(=O)N1CC(F)(c2ccc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.1 %

Procedure:
To a stirred solution of 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)phenyl)-3-fluoroazetidine hydrochloride (Example 1, Intermediate 3) (0.25 g, 0.535 mmol) in THF (5 mL) was added DIPEA (0.933 mL, 5.35 mmol) at room temperature and stirred for 10 minutes at room temperature. Methane sulfonyl acetic acid (0.147 g, 1.07 mmol), T3P (50% solution in ethyl acetate, 1.6 mL, 2.675 mmol) were added at room temperature. Resulting reaction mixture was stirred for 16 hours at room temperature under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (5×25 mL). Combined organic layer was washed with saturated solution of NaHCO3 (2×100 mL), dried over sodium sulphate and concentrated in vacuo to get pale yellow oil (0.32 g, crude). Crude was purified by column chromatography using 100-200 mesh silica gel. Desired product gets eluted in 0.6% MeOH in DCM to afford white semisolid (0.160 g), which was triturated with DCM: n-pentane (1:10; 2×5 mL) to afford product as off white solid. Yield: 0.145 g (49.15%). 1H NMR (400 MHz, DMSO-d6) δ: 3.11 (s, 3H), 3.20 (d, J=17.16 Hz, 1H), 3.65 (d, J=17.12 Hz, 1H), 4.24 (s, 2H), 4.34 (d, J=21.6 Hz, 2H), 4.70 (d, J=21.52 Hz, 2H), 7.27 (d, J=7.96 Hz, 2H), 7.47 (d, J=9.36 Hz, 2H), 7.73 (d, J=3.92 Hz, 3H). LC-MS (m/z): =550.1 (M−H). HPLC purity: 98.75%.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=5)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O[N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[N:38]1.C(N=C=NCCCN(C)C)C.O>ClCCl>[N:37]1([O:32][C:31](=[O:33])[C:30]2[CH:29]=[CH:28][C:27]([N:24]3[CH2:23][CH2:22][N:21]([C:18]4[CH:17]=[CH:16][C:15]([N:12]5[CH2:13][CH2:14][CH:9]([C:3]6[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=6)[CH2:10][CH2:11]5)=[CH:20][CH:19]=4)[CH2:26][CH2:25]3)=[CH:35][CH:34]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[N:38]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(N2CCN(c3ccc(N4CCC(c5ccccc5)CC4)cc3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(On1nnc2ccccc21)c1ccc(N2CCN(c3ccc(N4CCC(c5ccccc5)CC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 60.9 %

Procedure:
To a suspension of 4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic acid dihydrochloride salt (0.62 g) and 1-hydroxybenzotriazole (0.2 g) in dichloromethane (12 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.22 g) and stirred for 22 hours at ambient temperature. The reaction mixture was added to a mixture of water and dichloromethane. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic acid benzotriazol-1-yl ester (0.41 g).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH-].[K+].[CH2:14]([SH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: SCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(SCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 80.7 %

Procedure:
86 g of 2-nitro-5-chloroaniline is dissolved in 400 ml of ethanol and the solution heated to 70° C internal temperature. An addition is made dropwise of a solution of 30.5 g of potassium hydroxide and 68 g of benzylmercaptan in 300 ml of ethanol. The reaction proceeds exothermically. Stirring is maintained overnight at the same internal temperature. The cooled mixture is stirred into ice water; the precipitate is filtered off under suction and recrystallised from ethanol to obtain 104.7 g (= 80% of theory) of 2-nitro-5-benzylthio-aniline, M.P. 113°-115° C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[NH:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[N:22]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1.[H][H]>[Pd].[C]>[F:32][C:29]([F:30])([F:31])[C:25]1[CH:24]=[C:23]([C:21]2[N:22]=[C:18]([CH:15]3[CH2:14][CH2:13][CH:12]([CH2:11][NH2:10])[CH2:17][CH2:16]3)[NH:19][CH:20]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: [H][H]
Reactant: O=C(NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1)OCc1ccccc1
Agent: [Pd]
Product: NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1

Procedure:
An ethanolic solution of {4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-carbamic acid benzyl ester (4.15 g, 0.0091 mol) and 10% Pd/Carbon (400 mg) was shaken overnight under 55 psi of hydrogen in a Paar apparatus. The mixture was filtered through celite and concentrated under reduced pressure to give a foam, which was triturated with EtOAc/Hexanes/MeOH to produce C-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazole-2-yl]-cyclohexyl}-methylamine as a filterable solid. 1H NMR (DMSO-d6): δ 0.93–1.05 (m, 2H), 1.30–1.4 (m, 2H), 1.42–1.55 (m, 2H), 1.85 (d, J=12.8 Hz, 2H), 1.99 (d, J=11.6 Hz, 2H), 2.4–2.5 (m, 1H), 2.56–2.66 (m, 1H), 7.43–7.48 (m, 1H), 7.50–7.55 (m, 1H), 7.63 (s, 1H), 7.99 (d, J=7.9 Hz, 1H), 8.02 (s, 1H). MS 324 (M+H)+
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[C:7]([N:11]1C(=O)C(O)=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:12]1(=[O:25])=[O:24])([CH3:10])([CH3:9])[CH3:8].CN(C=O)C>C(Cl)Cl>[C:7]([N:11]1[C:2](=[O:3])[C:1]([Cl:6])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:12]1(=[O:25])=[O:24])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)N1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Temperature: 50 °C
Yield: 480.1 %

Procedure:
Oxalyl chloride (3.39 g, 2.71 mmol) was added dropwise to a solution of 2-tert-butyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (5 g, 17.77 mol) and DMF (15 mL) in DCM (220 mL) at 0° C. The reaction mixture was then heated at 50° C. for 4 h, concentrated and the residue was diluted with EtOAc and washed with water, then brine and evaporated. The residue was purified by silica gel column chromatography, using a 98:2 mixture of petroleum ether and EtOAc as eluant. The product containing fractions were evaporated, the residue was triturated in petroleum ether and the solvent was decanted to give the title compound (3.9 g, 74%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.97-7.92 (m, 2H), 7.61-7.51 (m, 3H), 1.75 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 156.5, 142.8, 132.3, 129.3, 128.8, 123.4, 63.0, 27.7.
Reaction SMILES: C([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)C>[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O>[CH:5]1[C:4]2[NH:3][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCn1c2ccccc2c2ccccc21
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Product: c1ccc2c(c1)[nH]c1ccccc12

Procedure:
Copper (II) triflate (ex. Aldrich, 0.38 g) was then dissolved in the above N-ethyl carbazole/NC solution (9.62 g).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]1[CH:17]([OH:25])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1.[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl.O>CCCCCC.CN(C)C=O>[O:3]=[C:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[CH:5]1[CH:17]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1C(O)c1ccc(F)cc1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOC(c1ccc(F)cc1)C1C(=O)NCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 0.13 g (0.0054 mole) of NaH (0.22 g of a 61% dispersion in oil, washed with hexane) in 10 ml of dimethylformamide (DMF) was added 1.6 g of 35 in 20 ml of dry DMF, and the mixture stirred at 0° C. for 30 minutes. A solution of 0.67 g (0.0055 mole) of (2-methoxyethoxy)-methyl chloride in 5 ml of dry DMF was added and the mixture allowed to warm to room temperature, stirred for 1 hour, and poured into 50 ml of water. The product was extracted into ethyl acetate and the extract washed with brine and dried over MgSO4. After filtration, the solvent was removed at reduced pressure and the residue triturated with hexane and filtered to give the title compound.
Reaction SMILES: [BH4-].[Na+].C(O)C.[O:6]=[C:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])/[CH:8]=[CH:9]/[CH:10]1[CH2:12][C:11]1([C:17]([O:19][CH3:20])=[O:18])[C:13]([O:15][CH3:16])=[O:14].C(O)(=O)C>O>[OH:6][CH:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])/[CH:8]=[CH:9]/[CH:10]1[CH2:12][C:11]1([C:13]([O:15][CH3:16])=[O:14])[C:17]([O:19][CH3:20])=[O:18]
Reactant: CCCCCC(=O)/C=C/C1CC1(C(=O)OC)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCCCCC(O)/C=C/C1CC1(C(=O)OC)C(=O)OC
Temperature: 25 °C

Procedure:
A solution of 5.5 g of sodium borohydride in 50 ml. of 95% ethanol is added to a solution of the compound of formula VI, dimethyl trans-2-(3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate (35 g), described in Example 2. After 15 min. at room temperature the mixture is cooled in ice and rendered neutral by the addition of acetic acid. Water is added and the mixture extracted with ethyl-acetate. The extract was dried (Na2SO4) and the evaporated. The residue is purified by chromatography on silica gel to afford the title compound, nmr (CDCl3) δ 0.90 (t, 3H), 2.33 (1H), 3.73 (s, 3H) 4.05 (m, 1H).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([Cl:19])[CH:14]=2)[C:9]1=[O:22])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([Cl:19])[CH:14]=2)[C:9]1=[O:22]
Reactant: CC=CCC1C(=O)c2cc(OC)c(Cl)cc2C1(C)C
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1Cl)C(C)(C)C(CC=O)C2=O
Reaction time: 0.83 h
Yield: 90 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 50 minutes while stirring through a solution, cooled to -70°, of 11.9 g of (RS)-2-(2-buten-1-yl)-5-chloro-6-methoxy-3,3-dimethyl-1-indanone in 160 ml of anhydrous dichloromethane and 40 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4.7 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 120 ml of dichoromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. The oil obtained was crystallized from hexane/ethyl acetate. 10.3 g (90%) of (RS)-2-(2-oxoethyl)-5-chloro-6-methoxy-3,3-dimethyl-1-indanone were obtained as a light yellow solid with m.p. 102°-103°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:12][C:6]2[CH:7]=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1.[OH:19][C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>C(O)(C)C>[OH:17][CH:16]([CH2:18][N:23]1[CH2:24][CH2:25][C:20]([OH:19])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:21][CH2:22]1)[CH2:15][O:14][C:13]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]=2[CH:12]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: COc1cc2oc(=O)ccc2cc1OCC1CO1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2oc(=O)ccc2cc1OCC(O)CN1CCC(O)(c2ccccc2)CC1
Yield: 69 %

Procedure:
Method C (3 d at 40° C.); starting materials: 7-methoxy-6-(oxiranylmethoxy)-2H-1-benzopyran-2-one and 4-hydroxy-4-phenylpiperidine; yield 69%; fusion point 155°-157° C. (from isopropanol). Hydrochloride: method G; yield 88%; fusion point 202°-203° C. (from isopropanol).
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][CH:7]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:8]([C:10]1[CH:25]=[CH:24][C:13]2[N:14]=[C:15](Cl)[N:16]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:12]=2[CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:36])[CH3:35]>C1COCC1>[C:1]([Si:5]([CH3:33])([CH3:32])[O:6][CH:7]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:8]([C:10]1[CH:25]=[CH:24][C:13]2[N:14]=[C:15]([NH:36][CH2:34][CH3:35])[N:16]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:12]=2[CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(Cl)nc2ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c3ccccc3)cc21
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nc2ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c3ccccc3)cc2n1S(=O)(=O)C(C)C
Yield: 84 %

Procedure:
Prepare essentially as described in the previous preparation (Preparation 97) starting from 2-(tert-butyldimethyl-silyloxy)-1-[2-chloro-3-(propane-2-sulfonyl)-3H-benzimidazol-5-yl]-2-phenyl-ethanone (760 mg, 1.50 mmol), ethyl amine (0.25 mL, 4.50 mmol, 3 equiv) in 2 mL of THF. Yield: 84%. MS(ES+): m(z=516.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][N:19]=[N+]=[N-])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: NCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Yield: 71 %

Procedure:
Treatment of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.75 g, 1.67 mmol) with sodium azide (0.43 g, 6.67 mmol) generally according to the procedure described for Intermediate 98 afforded 0.48 g (90%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with triphenylphosphine (0.393 g, 1.49 mmol) generally according to the procedure described for Example 21 afforded 0.348 g (71%) of (±)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 206-208° C.; Anal. calcd. for C15H13Cl2NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 54.38; H, 4.36; N, 4.12.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][C:16]([NH:28][C:29](=[O:33])[NH:30][CH2:31][CH3:32])=[CH:17][C:18]=3[C:19]3[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=3)=[CH:10][N:11]=2)[C:6](=[O:34])[C:5]([C:35]([O:37][CH2:38][CH2:39][CH2:40][O:41][P:42]([O:52]CC2C=CC=CC=2)([O:44]CC2C=CC=CC=2)=[O:43])=[O:36])=[CH:4]1)[CH3:2].C[Si](Br)(C)C.O>ClCCl.CO>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][C:16]([NH:28][C:29](=[O:33])[NH:30][CH2:31][CH3:32])=[CH:17][C:18]=3[C:19]3[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=3)=[CH:10][N:11]=2)[C:6](=[O:34])[C:5]([C:35]([O:37][CH2:38][CH2:39][CH2:40][O:41][P:42]([OH:44])([OH:52])=[O:43])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCCCOP(=O)(OCc2ccccc2)OCc2ccccc2)cn3CC)cn1
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCCCOP(=O)(O)O)cn3CC)cn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
3-{[Bis(benzyloxy)phosphoryl]oxy}propyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Example 21, 700 mg, 0.82 mM) was dissolved in dry dichloromethane (40 mL), and the reaction mixture was cooled to 0° C. Trimethylsilyl bromide (251 mg, 1.64 mmol) was added and the mixture was stirred for 16 h at room temperature. A solid formed on the walls of round bottom flask. The solvent was decanted and the solid was washed with ethyl acetate (30 mL) to give crude compound. The crude compound was dissolved in methanol (20 mL) and water (30 mL) was added to precipitate the product which was filtered and dried to afford 230 mg (35%) of 3-(phosphonooxy)propyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]([Si:14]([CH3:38])([CH3:37])[O:15][CH2:16][C@@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH3:18])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:63][CH:64]([N:66]1[CH:70]=[CH:69][C:68]([NH2:71])=[N:67]1)[CH3:65]>CN(C=O)C>[CH3:12][C:11]([Si:14]([CH3:38])([CH3:37])[O:15][CH2:16][C@@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=1)[C:23]([NH:71][C:68]1[CH:69]=[CH:70][N:66]([CH:64]([CH3:65])[CH3:63])[N:67]=1)=[O:25])[CH3:18])([CH3:13])[CH3:10]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: CC(C)n1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.6 %

Procedure:
DIPEA (3.11 mL, 18.03 mmol) was added to a solution of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (3.00 g, 7.21 mmol), HATU (3.12 g, 8.21 mmol) and 1-(1-methylethyl)-1H-pyrazol-3-amine (1.13 g, 9.01 mmol) in DMF (10 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The DMF was removed in vacuo. The solvent was evaporated and the residue was dissolved in 5% w/v citric acid (50 mL) and ethyl acetate (30 mL) and diethyl ether (30 mL) and the organic layer was further washed with saturated aqueous sodium bicarbonate solution (30 mL) and brine (30 mL). The organic layer was separated, then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:4 to 1:3 ethyl acetate:hexanes, afforded the title compound as a colourless oil (2.40 g, 65%). 1H NMR δ (CDCl3): 0.01 (s, 3H), 0.03 (s, 3H), 0.86 (s, 9H), 1.24 (d, 3H), 1.49 (s, 3H), 1.51 (s, 3H), 3.64 (dd, 1H), 3.78 (dd, 1H), 4.39 (m, 1H), 4.46 (m, 1H), 5.09 (s, 2H), 6.70 (s, 1H), 6.78 (s, 1H), 7.02 (s, 1H), 7.08 (s, 1H), 7.35 (m, 6H), 8.32 (br. s, 1H); m/z 524 (M+H)+, 522 (M−H)−.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][C:15]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])(O)[O:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:6]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[C:15]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[O:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC1(c2cc(F)ccc2F)CC(c2ccccc2)N(Cc2ccccc2)O1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(F)c(C2=CC(c3ccccc3)N(Cc3ccccc3)O2)c1
Reaction time: 0.5 h

Procedure:
A mixture of (2E)-1-(2,5-difluorophenyl)-3-phenylprop-2-en-1-one (1-1) (500 mg, 2.05 mmol, 1 equiv) and N-benzylhydroxylamine hydrochloride (327 mg, 2.05 mmol, 1.00 equiv) was heated at reflux in ethanol (10 mL) for 4 h. Additional N-benzylhydroxylamine hydrochloride (327 mg, 2.05 mmol, 1.00 equiv) was added and the mixture was heated at reflux for 16 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, 100% hexanes initially, grading to 100% EtOAc) to give 2-benzyl-5-(2,5-difluorophenyl)-3-phenylisoxazolidin-5-ol (1-2); LRMS m/z (M+H) 368.3 found, 368.1 required. Methanesulfonyl chloride (0.093 uL, 1.20 mmol, 1.11 equiv) was added to a solution of (1-2) (400 mg, 1.09 mmol, 1 equiv) and triethylamine (0.455 mL, 3.27 mmol, 3.00 equiv) in dichloromethane (30 mL) at 0° C. and the resultant mixture was warmed to 23° C. and stirred for 30 min. The reaction mixture was partitioned between saturated sodium bicarbonate solution (50 mL) and dichloromethane (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, 100% hexanes initially, grading to 100% EtOAc) to give 2-benzyl-5-(2,5-difluorophenyl)-3-phenyl-2,3-dihydroisoxazole (1-3) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.46-7.21 (m, 11H), 7.02 (m, 2H), 5.76 (t, 1H, J=3.0 Hz), 5.12 (d, 11H, J=2.8 Hz), 4.41 (d, 1H, J=12.8 Hz), 4.10 (d, 1H, J=12.8 Hz). LRMS m/z (M+H) 350.3 found, 350.1 required.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.[F-].[K+].[OH2:17]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:6]2[CH2:7][O:17][C:4](=[O:3])[CH:5]=2)=[CH:6][CH:5]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1C=C(c2ccc(OC(F)(F)F)cc2)CO1
Temperature: 25 °C
Yield: 86 %

Procedure:
A mixture containing 4-bromo-5(H)furanone (0.274 g, 1.681 mmol), 4-trifluoromethoxyphenylboronic acid (0.417 g, 2.025 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.060 g, 8.548×10−2 mmol), tetrabutylammonium iodide (0.032 g, 8.663×10−2 mmol) and potassium fluoride (0.401 g, 6.902 mmol) in toluene (10 mL) and water (10 mL) were gently refluxed for 24 h under nitrogen before the reaction mixture was allowed to cool to room temperature. Brine (50 mL) was added and the product extracted with dichloromethane (3×20 mL). The organic fractions were combined, washed with brine (3×20 mL), dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a dark brown solid. The resulting solid was chromatographed (silica gel: eluent 100% dichloromethane) to give 4-(4′-trifluoromethoxyphenyl)furan-2(5H)-one 5 (0.354 g, 86%) as a pale yellow powder, m.p. 122-123° C. (ref. PDS-1-115). UV-Vis λmax (MeOH) 211(22865), 269(28180) nm; 1H NMR (CDCl3) δ 7.56 (dt, 2H, J=2.6 Hz, J=9.4 Hz, H2′, H6′), 7.32 (d, 2H, J=7.9 Hz, H3′, H5′), 6.38 (t, 1H, J=1.9 Hz, H3), 5.21 (d, 2H, J=1.9 Hz, H5); 13C NMR (CDCl3) δ 173.3 (C2), 162.2 (C4′), 151.4 (C4), 128.20 (C1′), 128.17 (C3), 121.4 (C2′, C6′), 120.3 (q, J=257.0 Hz, C4′-OCF3), 113.9 (C3′, C5′), 70.8 (C5); 19F NMR (CDCl3, 282 MHz) δ −58.19 (s, 3F, C4′-OCF3); IR (KBr) 3109, 3073, 3011, 2936, 1790, 1747, 1624, 1588, 1513, 1443, 1422, 1252, 1159, 1046, 1018, 989, 921, 893, 847, 804, 742, 705, 611, 556, 471 cm−1.