Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH:11](I)([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:11]([CH3:13])[CH3:12])[CH:7]=1
Reactant: CC(C)I
Reactant: COc1ccc(Br)cc1O
Product: COc1ccc(Br)cc1OC(C)C
Yield: 86 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference Example 7-(a) except for using 10.1 g (49.8 mmol) of 5-bromo-2-methoxyphenol, and using 15 ml of isopropyl iodide in place of 1-bromo-2-chloroethane, whereby 10.4 g of the title compound was obtained as a pale yellowish solid. (Yield: 86%)
Reaction SMILES: O[C:2]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23]([N:25]5[CH2:30][CH2:29][O:28][CH:27]([CH2:31][OH:32])[CH2:26]5)=[N:22][C:21]4=[O:33])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:36]([F:39])([F:38])[F:37])[CH:6]=1)([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[OH:32][CH2:31][C@@H:27]1[O:28][CH2:29][CH2:30][N:25]([C:23]2[S:24][C:20](=[CH:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:10]([CH2:9][C:8]3[CH:34]=[CH:35][C:5]([C:2]([CH3:4])=[CH2:3])=[CH:6][C:7]=3[C:36]([F:37])([F:39])[F:38])[N:11]=[CH:12]4)[C:21](=[O:33])[N:22]=2)[CH2:26]1
Reactant: CC(C)(O)c1ccc(Cn2ncc3cc(C=C4SC(N5CCOC(CO)C5)=NC4=O)ccc32)c(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)c1ccc(Cn2ncc3cc(C=C4SC(N5CCO[C@@H](CO)C5)=NC4=O)ccc32)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.4 %

Procedure:
A solution of 5-{1-[4-(1-Hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-2-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one (400 mg, 0.71 mmol) in dichloromethane (2 mL) was treated with TFA (2 mL). The reaction mixture was stirred at room temperature for 1.5 hour and partitioned between water and dichloromethane. The dichloromethane layer was washed with aqueous saturated sodium carbonate, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (90% ethyl acetate in Heptane) to yield the title compound as a solid (94 mg, 24% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:25][N:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH2:3]1.[OH-].[Na+].Cl>C(O)C>[OH:1][CH:2]1[CH2:25][N:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)[N:9]=[C:4]2[CH2:3]1
Reactant: CCOC(=O)CCCCCCN1CC(O)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CC(O)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Enantiomer 2 of ethyl 7-(7-hydroxy-2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 3) (5.6 mg, 0.011 mmol) was dissolved in ethanol (0.5 ml) and 2M NaOH (0.023 ml, 0.046 mmol) was added. The solution was stirred at room temperature overnight under an atmosphere of nitrogen. 2M NaOH (0.023 ml, 0.046 mmol) was added to the mixture and the reaction was left to stir for a further hour at room temperature under an atmosphere of nitrogen. To the reaction mixture was added 2M HCl until the pH was below pH5. The volatile solvent was removed by distillation. To the residue was added water (10 ml) and the mixture was extracted with ethyl acetate (3×10 ml). The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as an oil which was dried in a vacuum oven at 40° C. overnight;
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O-].[Na+].CO.CI>CS(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Oc1cccnc1Br
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: CS(C)=O
Product: COc1cccnc1Br
Temperature: 90 °C
Reaction time: 17 h

Procedure:
31.11 g (corresponding to 178.88 mmol) of 2-bromo-3-hydroxypyridine was dissolved in 95.8 mL of dimethylsulfoxide, and 89.9 mL (corresponding to 89.9 mmol) of a 1 mol/L sodium methoxide-methanol solution was added thereto. Then, the reaction solution was heated to 90° C. to distill off methanol. After the reaction solution was cooled down to 5° C. or lower, 29.2 g (corresponding to 205.62 mmol) of methyl iodide was added, and then stirred at room temperature for 17 hours. After the completion of the reaction, the reaction solution was poured into ice-water and extracted twice with chloroform. The combined chloroform layer was washed with a 1 mol/L sodium hydroxide solution, washed twice with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, 20.74 g (corresponding to 110.31 mmol) of 2-bromo-3-methoxypyridine was obtained (FIG. 3, Step 1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1>>[C:19]1([CH3:23])[CH:20]=[CH:21][CH:22]=[C:17]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:11][CH:10]3[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=2)[CH:18]=1
Reactant: C#Cc1ccc(C2CC2C(=O)OC)cc1
Reactant: Cc1cccc(I)c1
Product: COC(=O)C1CC1c1ccc(C#Cc2cccc(C)c2)cc1

Procedure:
The title compound was prepared from methyl 2-(4-ethynylphenyl)cyclopropanecarboxylate (80 mg, 0.40 mmol) and 1-iodo-3-methylbenzene (60 μL, 0.47 mmol) according to the general procedure IF to give 42 mg (36%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:9): Rf=0.43 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 7.43 (d, J=8.3 Hz, 2H), 7.37-7.30 (m, 2H), 7.23 (t, J=7.6 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.06 (d, J=8.2 Hz, 2H), 3.72 (s, 3H), 2.61-2.45 (m, 1H), 2.35 (s, 3H), 1.92 (ddd, J=8.5, 5.3, 4.3 Hz, 1H), 1.63 (dt, J=9.9, 5.0 Hz, 1H), 1.33 (ddd, J=8.4, 6.5, 4.7 Hz, 1H); 13C NMR (CDCl3) δ 173.6, 140.3, 138.0, 132.2, 131.7, 129.1, 128.6, 128.2, 126.2, 123.1, 121.5, 89.7, 88.8, 52.0, 26.2, 24.2, 21.2, 17.2; ESI-MS m/z 313.1 (M+Na+).
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].Cl.[CH:29](Cl)(Cl)[Cl:30]>C(O)(=O)C>[ClH:30].[CH3:1][N:2]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[CH2:3][CH2:4][CH2:5][N:6]1[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[O:10][CH2:29]1
Reactant: COc1ccc(CCN(C)CCCNC(=O)c2ccccc2O)cc1OC
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(CCN(C)CCCN2COc3ccccc3C2=O)cc1OC

Procedure:
A solution of 2 g (5.37 mmol) of N-{3-[(methyl)(3,4-dimethoxyphenethyl)amino]propyl}salicylamide in 18 ml of chloroform and 1 ml of acetic acid is treated for 2 min with a stream of gaseous hydrochloric acid. 340 milligrams of trioxymethylene are then added to the above mixture, which is heated for 20 min to 70°-75° C. After return to room temperature, a stream of nitrogen is passed through for 30 min and the mixture is then filtered on a sinter and evaporated to dryness. The residue is taken up in toluene and re-evaporated to dryness in a rotary evaporator under vacuum. The solid residue (3.10 g) is ground in isopropyl ether and filtered. The cream powder obtained (m=2.1 g) is recrystallized in a 75:25 i-PrOH/EtOH mixture to give 1.53 g (yld=68%) of compound A of formula: ##STR6##
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[Cl:12])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[Cl:12][C:6]1[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1cccc(Cl)c1Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of 2-bromo-1-(2,3-dichlorophenyl)ethanone (4.25 g, 15.9 mmol) and potassium thiocyanate (1.54 g, 15.9 mmol) in ethanol (40 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 3.10 g (79.5%) of the desired product as a solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:60]=[C:61]([NH2:74])[C:62]4[C:66]([CH:67]=3)=[N:65][N:64](C3CCCCO3)[CH:63]=4)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:67]=[C:66]4[C:62]([CH:63]=[N:64][NH:65]4)=[C:61]([NH:74][C:14]([C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[N:13]=4)=[O:16])[CH:60]=3)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1
Reactant: O=C(O)c1cccc(CN2CCOCC2)n1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.3 %

Procedure:
A solution of 6-(4-morpholinylmethyl)-2-pyridinecarboxylic acid (33 mg, 0.15 mmol) in DMF (0.8 ml) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (72 mg, 0.19 mmol) and DIPEA (0.052 ml). After 5 minutes the resulting solution was added to 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (33 mg, 0.10 mmol). The mixture was stirred at room temperature for 15 mins then left to stand for 2 h. The reaction was treated with saturated sodium bicarbonate solution (10 ml) and extracted with dichloromethane (3×10 ml). The extracts were passed through a hydrophobic frit, combined and the solvent was evaporated under nitrogen flow. The residue was dissolved in methanol (1 ml) and hydrochloric acid (2M, 0.080 ml) was added. After about 1 hour the solvent was evaporated under a stream of nitrogen to give a crude product which was purified by Mass Directed Automated Preparative HPLC (Method B). Fractions containing pure product were evaporated under a nitrogen stream to give the title compound (11 mg) as a pale solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:7](COCC[Si](C)(C)C)[C:6]=2[C:5](=[O:31])[N:4]([CH2:32][CH2:33][CH2:34][O:35]C2CCCCO2)[C:3]1=[O:42].Cl>C(O)C>[OH:35][CH2:34][CH2:33][CH2:32][N:4]1[C:5](=[O:31])[C:6]2[NH:7][C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:22])[F:20])[CH:13]=3)=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:42]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Product: Cn1c(=O)n(CCCO)c(=O)c2[nH]c(Oc3cccc(OC(F)(F)F)c3)nc21
Yield: 83.3 %

Procedure:
To a solution of 3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (0.9 g, 1.5 mmol) in ethanol (10 mL) was added HCl (2 mL), then it was refluxed overnight. The solvent was concentrated to give a crude product which was collected, washed with ethanol and dried in vacuo to give 1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.5 g, 80% yield) as a white solid. 1H-NMR (DMSO-d6) δ 13.52 (br, 1H), 7.55-7.59 (t, 1H), 7.47 (s, 1H), 7.36-7.38 (d, 1H), 7.28-7.30 (d, 1H), 4.45 (br, 1H), 3.89-3.93 (t, 2H), 3.39-3.43 (t, 2H), 3.42 (s, 3H), 1.66-1.69 (m, 2H). LCMS retention time 1.308 min, LCMS MH+ 401.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[S:6][C:7]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)=[C:8]([Cl:10])[N:9]=1>CO>[Cl:10][C:8]1[N:9]=[C:5]([O:2][CH3:1])[S:6][C:7]=1[CH:11]1[O:15][CH2:14][CH2:13][O:12]1
Reactant: Clc1nc(Cl)c(C2OCCO2)s1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)c(C2OCCO2)s1
Yield: 57.1 %

Procedure:
Sodium methoxide (0.63 g, 11.66 mmol) is added to a solution of 2,4-dichloro-5-([1,3]dioxolan-2-yl)-thiazole (2.00 g, 8.85 mmol) in methanol (20 ml). The reaction is heated at reflux for 3.5 h, cooled, and concentrated. The residue is partitioned between aqueous saturated brine solution and ethyl acetate, separated, and the aqueous layer extracted with ethyl acetate. The ethyl acetate is dried over Na2SO4, filtered, and concentrated. The crude product is purified by flash chromatography on silica gel eluting with 12.5% ethyl acetate/hexanes to yield (1.12 g, 93%) of 4-chloro-5-([1,3]dioxolan-2-yl)-2-methoxy-thiazole: mass spectrum (ion spray): m/z=221.9 (M+1); 1H NMR (CDCl3): δ=6.05 (1H, s), 4.15-3.97 (7H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[O:3]1.C(O)C.N>CO.[Ni]>[NH2:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:14])([CH3:1])[CH:11]=[CH:10]2
Reactant: CC1(C)C=Cc2cc(C#N)ccc2O1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCO
Product: CC1(C)C=Cc2cc(CN)ccc2O1
Temperature: 60 °C
Yield: 97.9 %

Procedure:
Add 2,2-dimethyl-2H-chromene-6-carbonitrile (1.5 g, 8.1 mmol) and ethanol wet Raney® activated nickel (0.4 g) to a Parr pressure vessel. Immediately add 7N ammonia in methanol (170 mL) and seal the vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (3400 KPa), seal the vessel, agitate the reaction and heat to 60° C. for 20 h. Turn off the heat and allow the reaction mixture to cool to ambient temperature. Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the Raney® nickel. Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (9:1) to obtain the title compound (1.5 g, 97%). MS (ES+) m/z: 175 (M+H—NH3)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6]Br)[CH3:2].[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][N:13]1[C:9](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]1=[O:14])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)CCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1C(=O)c2ccccc2C1=O
Yield: 43.7 %

Procedure:
This compound was prepared according to the procedure used to prepare 1,3-dihydro-1,3-dioxo-2H-isoindoleoctanoic acid ethyl ester. Thus, a mixture of 100.0 g (0.55 mole) of 3-bromopropionic acid ethyl ester (99%, Aldrich) and 108.7 g (0.58 mole) of potassium phthalimide (98%, Aldrich) in 300 mL of dimethylformamide gave 59.4 g (44%) of crude title compound as an oily residue. A 3.0 g sample of this oil was purified by high-pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrepPak® 500 silica; ethyl acetate-hexanes, 1:10). Fractions containing title compound were combined and the solvents evaporated under reduced pressure to give 2.3 g (77% recovery) of a pale-yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:16]3[CH2:17][O:18][C:19]([CH3:23])([CH3:22])[O:20][CH2:21][CH:15]23)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-:24].[K+].Cl>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C@@H:15]2[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17][C@H:16]2[OH:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N2C3COC(C)(C)OCC32)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H]2COC(C)(C)OC[C@H]2O)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-acetylaminobenzenesulfonyl)-4,4-dimethyl-1a,2,6,6a-tetrahydro-1H,4H-[1,3]-dioxepino[5,6-b]azirine (0.33 g), potassium hydroxide (0.14 g) and water (2.6 ml) was boiled with reflux for 60 minutes. The mixture was cooled to room temperature, acidified with diluted hydrochloric acid to pH 6.5 and evaporated to dryness at reduced pressure. The chromatography of the evaporation residue on a silica gel column by elution with a mixture of ethyl acetate/methanol (9.8:0.2) yielded trans-6-(4-acetylaminobenzene-sulfonamido)-2.2-dimethyl-1,3-dioxepane-5-ol, m.p. 203°-205° C./methylene chloride- methanol (9:1), and trans-6-sulfanylamido-2,2-dimethyl-1,3-dioxepane-5-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH2:36][CH:32]1[C:29]1[CH:28]=[CH:27][N:26]=[CH:31][CH:30]=1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: c1cc(C2CCCN2)ccn1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2c2ccncc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(pyridin-4-yl)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.87 minutes; C26H23Cl2N5O2 (508.41); mass spectrum: (M−H)−=507/509/511 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.C([O:24][CH:25]=[C:26]([C:32](OCC)=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])C.C[O-].[Na+]>C(O)C>[CH2:30]([O:29][C:27]([C:26]1[CH:32]=[N:1][C:2]2[N:3]([N:4]=[CH:5][C:6]=2[C:7]2[CH:8]=[CH:9][C:10]([C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([CH3:15])[CH3:14])=[CH:11][CH:12]=2)[C:25]=1[OH:24])=[O:28])[CH3:31]
Reactant: CC(C)(c1ccccc1)c1ccc(-c2c[nH]nc2N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(-c3ccc(C(C)(C)c4ccccc4)cc3)cnn2c1O
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a suspention of 3-amino-4-[4-(2-phenylpropan-2-yl) phenyl]pyrazole (920 mg) in ethanol (10 ml) was added diethyl ethoxymethylenemalonate (1.34 ml), and the mixture was heated and refluxed for 3 days. To the mixture was added sodium methoxide (540 mg) under ice-cooling, and the mixture was stirred for 1 day. Ethanol was distilled away under reduced pressure, and thereto was added water (50 ml) under ice-cooling. The mixture was adjusted to acid with 10% hydrochloric acid, and the precipitate was separated by filtraltion, washed with water to give the title compound (1.26 g, 94.6%).
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH3:11][O:12][C:13](Cl)=[O:14].Cl>O>[CH3:11][O:12][C:13]([NH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
A mixture of (S)-2-amino-3-methyl-butyric acid (10 g, 85 mmol), NaOH (10.3 g, 255 mmol) in water (100 mL) was treated with methylchloridocarbonate (8 g, 85 mmol) at 0° C. The reaction mixture was stirred for 24 h at room temperature and then 5 N aqueous HCl was added to the reaction mixture to adjust pH to 4. The mixture was filtered through a pad of Celite to give the product (10 g, 67% yield) as a white solid. 1H NMR (CH3OD, 400 MHz) δ (ppm) 4.05 (d, 1H), 3.65 (s, 3H), 2.14 (m, 1H), 0.95 (m, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=1)=[O:14])=[C:8]([C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH:7]=[CH:6]2.Cl.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.CO>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:17][CH:16]=1)=[O:14])=[C:8]([C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2c(F)cc(F)cc2F)ccc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.1 %

Procedure:
Dissolve [6-methoxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (670 mg, 1.3 mmol) in dichloromethane (10 mL). Cool to 0° C., add 2M HCl (1.3 mL, 2.6 mmol) and stir at room temperature for 15 minutes. Concentrate in vacuo. Redissolve the salt in dichloromethane (10 mL) and cool to 0° C. Add boron tribromide (1.1 g, 3.9 mmol) dropwise and bring to room temperature. Stir reaction for 1.5 hours and pour reaction mixture onto ice, saturated sodium bicarbonate (10 mL) and methanol (10 mL). Extract with dichloromethane, combine extracts and wash with water and saturated sodium bicarbonate. Dry with sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography using a 1-3% gradient of methanol in dichloromethane to yield 454 mg (70%) of the title compound: mass spectrum (ion spray) m/z=506.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[N:6][O:7][CH2:8][CH2:9][N:10]([CH3:30])[CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[C:18]2C)[C@H:14]([OH:28])[C@@H:13]1[OH:29])[CH3:5])[CH3:2].[CH3:31][NH:32]C[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2NC)[C@H](O)[C@@H]1O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[N:6][O:7][CH2:8][CH2:9][N:10]([CH3:30])[CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[C:18]2[NH:32][CH3:31])[C@H:14]([OH:28])[C@@H:13]1[OH:29])[CH3:5])[CH3:2]
Reactant: CCOC(C)=NOCCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CNC[C@H]1O[C@@H](n2c(NC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(C)=NOCCN(C)C[C@H]1O[C@@H](n2c(NC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 6b was prepared by the same procedure as reported for 6a using 4c (500 mg, 1.61 mmol), ethyl N-(2-bromoethoxy)ethanamidate48 (407 mg, 1.93 mmol), DIEA (104 mg, 0.14 mL, 0.80 mmol), and DMF (5 mL). After column chromatography (elution with 7:1:0.3 chloroform:methanol:NH4OH), a yellow glassy sticky solid was obtained: yield 209 mg (30%), MS: m/z 439 (M+H)+; 1HNMR (DMSO-d6) δ 7.89 (s, 1H, H-2), 6.85 (q, 1H, 8CH3—NH), 6.47 (bs, 2H, 6-NH2), 5.69 (d, 1H, H-1′, J1′,2′=5.0 Hz), 5.27 (d, 1H, 2′-OH, J2′-2′OH=5.5 Hz), 5.06 (d, 1H, 3′-OH, J3′-3′OH=5.0 Hz), 4.88 (ddd, 1H, H-2′, J1′,2′=5.0 Hz, J2′,3′=5.8 Hz, J2′-2′OH=5.5 Hz), 4.17 (ddd, 1H, H-3′, J2′,3′=5.8 Hz, J3′,4′=4.7 Hz, J3′-3′OH=5.0 Hz), 3.86-3.95 (m, 3H, H-4′, NO—CH2), 3.92 (q, 2H, CH2CH3), 2.88 (d, 3H, 8NH—CH3, J=4.6 Hz), 2.71-2.77 (m, 1H, 5′-CH2), 2.56-2.67 (m, 3H, 5′-CH2, N(CH3)—CH2), 2.24 (s, 3H, N—CH3), 1.83 (s, 3H, C—CH3), 1.19 (t, 3H, OCH2CH3).