Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:26]=1>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:36][CH:37]=1)#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CCOC(=O)COc1ccc(CCNC)cc1
Product: CCOC(=O)COc1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1

Procedure:
Reaction of 1f with 2k produced 3al. MS found M+H=497. The oxalate salt of 3al was recrystallized from ethyl acetate.
Reaction SMILES: C(N[C:5]1[CH:6]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Br:17])=[CH:9][CH:10]=1)(=O)C.Br[C:24]1C=CC(C)=CC=1C(OCC)=O>>[Br:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][C:5]([CH3:24])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cc(C)ccc1Br
Reactant: CCOC(=O)c1cc(NC(C)=O)ccc1-c1ccccc1Br
Product: CCOC(=O)c1cc(C)ccc1-c1ccccc1Br

Procedure:
Prepared in a similar way to ethyl 4-(acetylamino)-2′-bromo-2-biphenylcarboxylate but using ethyl 2-bromo-5-methylbenzoate instead of ethyl 5-(acetylamino)-2-bromobenzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:12]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)CCl>C1COCC1.CN(C=O)C>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([O:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:20][CH:21]=3)[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc2nc(Nc3ccc(Oc4ccccc4)cc3)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.4 %

Procedure:
A solution of 2-amino-5-methylbenzoic acid (172 mg, 1.10 mmol) in THF (1 ml) was treated with 4-phenoxyphenyl isocyanate (241 mg, 1.10 mmol). The mixture was kept at room temperature for 24 h, during which time the solvent was allowed to evaporate to leave a pale brown solid. This was dissolved in DMF (5 ml) and added to a suspension of PS-EDC (0.8 mmol g−1, 2.8 g) in DMF (20 ml). The resulting mixture was agitated at room temperature for 18 h, after which the resin was filtered off and washed with DMF (2×5 ml). The filtrate and washings were combined and evaporated under reduced pressure. Flash column chromatography over silica (20% ethyl acetate in hexane as eluent) afforded the required compound as an off-white solid (153 mg, 40%); δH (400 MHz, DMSO-d6) 2.36 (3H, s, CH3), 6.96 (2H, d, J 8, Ph), 7.04 (1H, d, J 8, Ph), 7.09 (1H, t, J 8, Ph), 7.26 (1H, d, J 8, Ph), 7.34-7.38 (2H, m, Ph), 7.55-7.56 (1H, m, Ph), 7.76-7.78 (4H, m, Ph); m/z (ES+) 345 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[C:10]([CH:20]=[O:21])=[CH:9]2.C([O-])([O-])=O.[K+].[K+].S([CH2:43][N+:44]#[C-:45])(C1C=CC(C)=CC=1)(=O)=O>CO>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[C:10]([C:20]1[O:21][CH:45]=[N:44][CH:43]=1)=[CH:9]2
Reactant: N#CCCCn1c(C=O)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#CCCCn1c(-c2cnco2)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Yield: 94.7 %

Procedure:
A mixture of 4-[5-(2,6-dichlorobenzyloxy)-2-formyl-indol-1-yl]butyronitrile (0.2 g, 0.52 mmol), from Example 9(b), K2CO3 (0.14 g, 1.03 mmol) and tosylmethyl isocyanide (0.11 g, 0.57 mmol) in MeOH (15 mL) was stirred at room temperature for 5 min followed by reflux for 3 h to give a clear yellow solution. The solvent was removed under reduced pressure and the resulting solid was partitioned between chloroform and water. The aqueous layer was washed with chloroform twice and the combined organic layers were washed with water, brine and dried over Na2SO4. After filtration, the yellow filtrate was concentrated to yield the desired oxazol (0.21 g, 95%) as a yellow oil. MS(ES) m/e 426.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[NH:7][CH:6]=[CH:5]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[NH:7][CH2:6][CH2:5]2
Reactant: CN(C)CCOc1cc2[nH]ccc2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CCOc1cc2c(cc1Cl)CCN2
Reaction time: 1 h
Yield: 10.9 %

Procedure:
5-Chloro-6-(2-dimethylaminoethoxy)-1H-indole (D8, 0.2 g, 0.008 mol) in glacial acetic acid (5 ml) was treated with sodium cyanoborohydride (0.25 g, 0.004 mol ) at room temperature with stirring for 1 h. The mixture was diluted with water and basified with 10% aq NaOH. The product was extracted into CH2Cl2, and the combined extracts dried (Na2SO4) and concentrated in vacuo to give the title compound as a brown oil (0.21 g, 100%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Cl>>[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[CH2:24][N:8]1[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:9]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: ClCc1ccc(Cl)cc1Cl
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 88.3 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 2,4-dichlorobenzyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 88.3%.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:14][CH:15]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].CC1(C)N([O])C(C)(C)CCC1.[K+].[Br-].C([O-])(O)=O.[Na+].[O-]Cl.[Na+].S(=O)(O)[O-].[Na+]>ClCCl.C1OCCOCCOCCOCCOCCOC1.O.C1COCC1>[CH3:1][CH:2]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][CH2:18][CH:19]=[O:20])=[CH:14][CH:15]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)Cc1ccc(OCCCO)nc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(C)Cc1ccc(OCCC=O)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of the product of Step 3 (0.39 g, 1.39 mmol) in dichloromethane (7 mL), and THF (2.0 mL) at 0° C., 2,2,6,6-tetramethyl-1-piperidinyloxy-radical, (TEMPO) (0.005 g), KBr (16.7 mg), NaHCO3 (0.015 g), and 18-crown-6 (0.005 g) were added. To this reaction mixture, was added dropwise a solution of NaOCl (5%, 2.5 mL) and then stirred at 0° C. for 1 hour. After stirring for 1 hour at room temperature, sodium bisulphite solution (5%, 1 mL), dichloromethane (20 mL), and water (10 mL) were added. The organic phase was washed with water (2×20 mL), dried (Na2SO4), and concentrated to dryness under reduced pressure to give ethyl β-methyl-6-(3-oxopropoxy)-3-pyridinebutanoate as a light brown liquid (0.34 g). 1H-NMR and mass spectral data were consistent with the structure. This material was used without purification in the following step.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][NH:15][C:16]([C:18]1([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O)=[S:17].C(OCC)(=O)C>O1CCCC1.O>[C:1]([CH:3]=[C:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C:18]1([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[C:16](=[S:17])[NH:15][CH3:14])#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CNC(=S)C1(c2cccnc2)CCCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=S)C1(c2cccnc2)CCCCC1=CC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A solution of diethyl cyanomethylphosphonate (215 mg, 1.2 mmol) at room temperature in dry tetrahydrofuran (20 ml) was treated with a 60% oil dispersion of sodium hydride (40 mg, lmmol). After 15 mins at room temperature (±)-N-methyl-2 -oxo-1-(pyrid-3 -yl)cyclohexane carbothioamide (245 mg, lmmol) was added and the resulting solution stirred for 3 hours at room temperature. Ethyl acetate (50 ml) and then water (50 ml) were added to the reaction mixture. The layers were separated and the organics washed with water (50 ml). The organic extract was dried over magnesium sulphate and concentrated in vacuo to give a crude gum. Purification by flash chromatography, eluting with a 1:1 (v/v) mixture of ethyl acetate/hexane gave (±)-2 -cyanomethylene-N-methyl-1-(pyrid-3 -yl)cyclohexane carbothioamide as a colourless gum (190 mg, 0.7 mmol). Trituration with ether yielded a white solid (190 mg, 0.7 mmol), m.p. 182°-183° C.;
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13]C)=O)[C:5]=2[CH:4]=[CH:3]1.[ClH:15].[NH2:16][C:17]([NH2:19])=[NH:18].C[O-].[Na+]>CO>[ClH:15].[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([NH:18][C:17]([NH2:19])=[NH:16])=[O:13])[C:5]=2[CH:4]=[CH:3]1
Reactant: N=C(N)N
Reactant: COC(=O)c1cccc2c1ccn2C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1ccc2c(C(=O)NC(=N)N)cccc21
Yield: 66.1 %

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 0.85 g (4.49 mmol) of methyl 1-methyl-4-indolecarboxylate, 4.29 g (44.9 mmol) of guanidine hydrochloride and 50 ml of a methanol solution of 2.43 g (44.9 mmol) of sodium methoxide. Thus 0.75 g (66.1%) of 1-methyl-4-indoloylguanidine hydrochloride was obtained.
Reaction SMILES: [F:1][C:2]([F:14])([C:7]1[O:11][N:10]=[C:9]([CH2:12]O)[CH:8]=1)[C:3]([F:6])([F:5])[F:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C(OCC)C>[Br:35][CH2:12][C:9]1[CH:8]=[C:7]([C:2]([F:14])([F:1])[C:3]([F:6])([F:5])[F:4])[O:11][N:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(C(F)(F)C(F)(F)F)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: FC(F)(F)C(F)(F)c1cc(CBr)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
2.78 g of (5-pentafluoroethyl-isoxazol-3-yl)methanol was dissolved in 10 ml of diethyl ether, and 5.25 g of triphenylphosphine and 6.63 g of carbon tetrabromide were then added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was subjected to silica gel column chromatography to obtain 1.83 g of 3-(bromomethyl)-5-pentafluoroethylisoxazole.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].[CH2:32]([CH:34]1[O:36][CH2:35]1)Br.O>CN(C)C=O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:32][CH:34]1[CH2:35][O:36]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (130 mg) was dissolved in N,N-dimethylformamide (4 ml) to prepare a solution. Potassium carbonate (162 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (83 mg, yield 55%).
Reaction SMILES: [CH:1]([SiH:4]([CH:10]([CH3:12])[CH3:11])CC(C)(C)C)([CH3:3])[CH3:2].Br[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]>>[CH3:17][CH:16]([CH3:18])[CH2:15][CH2:14][SiH:4]([CH:10]([CH3:12])[CH3:11])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[SiH](CC(C)(C)C)C(C)C
Reactant: CC(C)CCBr
Product: CC(C)CC[SiH](C(C)C)C(C)C

Procedure:
The procedure of synthesizing Compound 51a was repeated, except that 1-bromo-3-methylbutane (12.6 mL, 100 mmol) was employed, whereby the Compound 53a was obtained as a colorless liquid (12.6 g, 73%).
Reaction SMILES: [C:1]([O:5][P:6]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([O:8][CH:9](C)[CH2:10][O:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=2)[C@@:16]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])([F:27])[C:15]1=[O:37])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].OCCOP(=O)(OC(C)(C)C)OC(C)(C)C>>[C:40]([O:39][P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][CH2:9][CH2:10][O:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([F:26])([F:24])[F:25])[CH:21]=2)[C@@:16]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])([F:27])[C:15]1=[O:37])=[O:13])=[O:7])([CH3:43])([CH3:42])[CH3:41]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCC(C)OP(=O)(OC(C)(C)C)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Agent: CC(C)(C)OP(=O)(OCCO)OC(C)(C)C
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCCOP(=O)(OC(C)(C)C)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Yield: 52 %

Procedure:
The title compound was prepared analogously to (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid 2-(di-tert-butoxy-phosphoryloxy)-propyl ester ((S)-VII, n=2) in 52% yield, using phosphoric acid di-tert-butyl ester 2-hydroxy-ethyl ester. 1H NMR (CDCl3, 500 MHz) δ 8.29 (s, 1H), 7.77 (d, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 7.27 (d, 1H), 6.75 (d, 1H), 4.67 (m, 2H), 4.31 (m, 2H), 3.53 (s, 3H), 1.47 (s, 18H); LC-MS, 640.15 (MH+, 96); 31P NMR (CDCl3, 500 MHz) δ−8.71; 19F NMR (CDCl3, 500 MHz) δ−63.3, 153.6.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:14][CH:13]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:4]2[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=2[OH:10])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:17]=1
Reactant: O=C(O)CCCCCC(O)c1ccc(F)cc1
Reactant: Cc1cc(C)c(O)cc1C
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(O)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1C
Reaction time: 6 h
Yield: 85488.3 %

Procedure:
To a solution of 2,4,5-trimethylphenol (2.0 mg) and 7-(4-fluorophenyl)-7-hydroxyheptanoic acid (3.5 g) in toluene (60 ml) was added boron trifluoride ethyl ether (0.56 ml) at 70° C. and the reaction was carried out at the same temperature for 6 hours. After cooling in air, the reaction mixture was extracted by addition of water and ethyl acetate. The organic layer was washed in turn with water and saturated saline and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate/hexane (1 : 5) and the objective compound was recrystallized from ethyl acetate/hexane to obtain 7-(4-fluorophenyl)-7-(2-hydroxy-3,5,6-trimethylphenyl)heptanoic acid (4.5 g) (Compound 1). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[P:10]([O:15]CC)(=[O:14])[O:11]CC)(=[O:8])[O:5]CC)C.C[Si](C)(C)Br>ClCCl>[O:22]([CH2:21][CH2:20][CH2:19][NH:18][CH:9]([P:10]([OH:15])(=[O:11])[OH:14])[P:4]([OH:5])(=[O:3])[OH:8])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOP(=O)(OCC)C(NCCCOc1ccccc1)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)C(NCCCOc1ccccc1)P(=O)(O)O
Reaction time: 72 h

Procedure:
3.0 g (0.0068 mol) of N-(3-phenoxypropyl)aminomethanediphosphonic acid tetraethyl ester are dissolved in 20 ml of dichloromethane, and 4.4 ml (0.0343 mol) of trimethylbromosilane are added. After 72 hours at room temperature, the solvent is removed under reduced pressure. The remaining oil is dissolved in warm 95% aqueous methanol. On cooling, N-(3-phenoxypropyl)aminomethanediphosphonic acid of m.p. 226°-228° (decomp.) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]([C:13]([F:16])([F:15])[F:14])=O.[CH3:18][NH:19][NH2:20]>C(O)(=O)C.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:19]([CH3:18])[N:20]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cc(F)ccc1F
Reactant: CNN
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(F)ccc2F)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
34.5 g of 1-(2,5-difluorophenyl)-3-(trifluoromethyl)-propane-1,3-dione was dissolved in 250 ml of acetic acid and 9.5 mL of methylhydrazine slowly added. The mixture was heated at 100° C. for 5 minutes then cooled and diluted with ether. The ether solution was washed with water and potassium carbonate solution, then dried with magnesium sulfate, filtered and concentrated. The residue was chromatographed to give 9.5 g of 3-(2,5-difluorophenyl)-1-methyl-5(trifluoro-methyl)-1H-pyrazole.
Reaction SMILES: [Br:1][CH:2](Br)[CH3:3].[Cl:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[OH:15]>C(=O)([O-])[O-].[K+].[K+].O>[Cl:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:15][CH2:3][CH2:2][Br:1]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCBr)c(Cl)c1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
Dibromoethane (14.9 ml, 0.1728 mol) and 2-chloro-4-nitrophenol (10 g, 0.0576 mol) were dissolved in dimethylfomamide (250 ml) and potassium carbonate (9.55 g) was added to the resulting solution, followed by stirring at 85° C. for 30 min. Thereafter, the reaction solution was diluted with water and subjected to three extractions with ethyl acetate. The organic extracts were combined, dried with magnesium and the solvent was evaporated; thereafter, the residue was purified by being subjected to column chromatography using a 1:1 solvent system of n-hexane and ethyl acetate as an eluent and the fractions containing the end product were collected and subjected to evaporation to yield the end compound 1-(2-chloro-4-nitrophenoxy)-2-bromoethane (14.0 g) as a yellow solid mass.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:37][NH:38][CH3:39].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[CH3:37][N:38]([CH3:39])[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: CNC
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 18.6 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (47 mg, 0.1 mmol) and dimethylamine (2.0M in THF, 0.5 mL, 0.5 mmol), were allowed to react in the presence of K2CO3 (55.2 mg, 0.4 mmol) and NaI (Cat. 1.51 mg). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (8.7 mg, 19%).
Reaction SMILES: [B:1]([C@@H:4]([NH:16][C:17]([C:19]1[C:27]2[CH2:26][CH2:25][NH:24][CH2:23][C:22]=2[S:21][CH:20]=1)=[O:18])[CH2:5][C:6]1[C:7](O)=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([OH:3])[OH:2].[CH2:28]=O>CO.[Pd]>[OH:2][B:1]1[C@@H:4]([NH:16][C:17]([C:19]2[C:27]3[CH2:26][CH2:25][N:24]([CH3:28])[CH2:23][C:22]=3[S:21][CH:20]=2)=[O:18])[CH2:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]=2[O:3]1
Reactant: C=O
Reactant: O=C(O)c1cccc(C[C@H](NC(=O)c2csc3c2CCNC3)B(O)O)c1O
Agent: [Pd]
Solvent: CO
Product: CN1CCc2c(C(=O)N[C@H]3Cc4cccc(C(=O)O)c4OB3O)csc2C1

Procedure:
To (R)-3-(2-borono-2-(4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamido)ethyl)-2-hydroxybenzoic acid (10.0 mg from Example 4) in MeOH (5 mL) was added formaldehyde (1.0 mL, 37% solution), followed by 10% Pd/C (20 mg). The reaction mixture was hydrogenated under H2 balloon for 3 hr. The reaction mixture was filtrated and the solvent was removed under vacuum. The final product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 387 (MH)+.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[CH2:4][O:5][C:6](=[O:17])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH3:9].[CH2:26]([O:28][C:29](=[O:48])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:27].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:26]([O:28][C:29](=[O:48])[CH2:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=2[CH2:4][O:5][C:6](=[O:17])[N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH3:9])[C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)[CH3:27]
Reactant: CCN(Cc1ccccc1)C(=O)OCc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2COC(=O)N(CC)Cc2ccccc2)c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Benzyl-ethyl-carbamic acid 2-bromo-5-trifluoromethyl-benzyl ester (0.354 g, 0.85 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.300 g, 0.94 mmol), and potassium carbonate (0.410 g, 2.98 mmol) were combined in a deoxygenated solution of DME (8 mL) and H2O (4 mL). Tetrakis(triphenylphosphine)palladium(0) (0.100 g, 0.09 mmol) was added, and the reaction was stirred at 75° C. for 2 hours. After work-up, the crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.