Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OC)(OC)(=O)=O.[CH3:8][S:9][C:10]1[C:11]2[C:12]3[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=O)[C:13]=3[CH:20]=[CH:21][CH:22]=2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:8][S:9][C:10]1[C:11]2[C:12]3[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([SH:24])[C:13]=3[CH:20]=[CH:21][CH:22]=2
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: COS(=O)(=O)OC
Solvent: c1ccncc1
Product: CSc1ccc2c3c(cccc13)C(S)=N2

Procedure:
Chlorosulfonation of benz(cd)indol-2-(1H-one yields the 6-sulfonylchloride derivative, which upon treatment with zinc dust in acetic acid-hydrochloric acid solution, yields 6-mercaptobenz(cd)indol-2-(1H)-one. Treatment with dimethyl sulfate in alkaline solution leads to 6-methylthiobenz(cd)indol-2-(1H)-one, which on heating with P2S5 in pyridine yields 6-methylthiobenz(CD)indol-2-thiol. The reaction of the latter compound with molar equivalents of 3-(4-pyridinyl)propanamine and mercuric acetate in ethanol, under the conditions of Example 55, leads to the title compound.
Reaction SMILES: N#N.[CH2:3]([P:7]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].[N-:16]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18].[C:31](=O)(OC)OC>CO>[F:30][C:27]([F:28])([F:29])[S:24]([N-:16][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19])(=[O:25])=[O:26].[CH3:31][P+:7]([CH2:3][CH2:4][CH2:5][CH3:6])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)OC
Reactant: CCCCP(CCCC)CCCC
Agent: N#N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: CCCC[P+](C)(CCCC)CCCC
Temperature: 0 °C

Procedure:
In an reactor wherein air was replaced by N2, 300.0 g (1.5 mol) of tributyl phosphine and 1000 mL of methanol were added and cooled to about 0° C. by a ice-bath. 427.6 g (1.5 mol) of trifluoromethanesulfonimide was then added dropwise under strong stirring, and 202.0 g (2.2 mol) of dimethyl carbonate was also added afterwards. After one hour of reaction and mixing, the reaction mixture was transferred to an autoclave, wherein air was removed prior to heating. After 6 hours of reaction at temperature of 180° C. and pressure of from 1.6 MPa to 1.7 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 705.7 g of methyl tributyl phosphonium bis(trifluoromethanesulfonyl)amide was obtained after washing and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C(Cl)Cl.[F:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=2)=[C:12](CO)[CH:11]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(OCC)C>[Br:5][CH2:1][C:12]1[CH:11]=[C:10]([F:9])[C:15]([F:16])=[CH:14][C:13]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CO)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CBr)cn1
Temperature: 25 °C

Procedure:
Neat CBr4 (4.6 g, 13.7 mmol) was added to a 0° C., DCM solution (66 mL) of ethyl 3-(5-(4,5-difluoro-2-(hydroxymethyl)phenyl)picolinamido)propanoate (4.2 g, 11.4 mmol) and PPh3 (3.6 g, 13.7 mmol), the cold bath was removed, and the resulting mixture was allowed to warm to room temperature. After 2 h the resulting mixture was diluted with diethyl ether, filtered through a pad of CELITE, concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[CH2:22][NH+:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:24])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH3:26])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.[I-].[C:28]([Mg]Br)#[C:29][CH3:30].O1CCCC1>C(OCC)C>[CH3:1][O:2][C:3]1[C:23]2[CH:22]([C:28]#[C:29][CH3:30])[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:24])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH3:26])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4
Reactant: CC#C[Mg]Br
Reactant: COc1ccc2c(c1OC)C[NH+]1CCc3cc4c(cc3C1=C2C)OCO4
Agent: [I-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC#CC1c2c(ccc(OC)c2OC)C(C)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a suspension of 9,10-dimethoxy-13-methyl-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (200 mg, 0.4 mmol) in anhydrous diethyl ether (5 mL) at 0° C. was added a solution of 1-propynylmagnesium bromide in tetrahydrofuran (0.5 M, 17 mL, 8.5 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 9,10-dimethoxy-13-methyl-8-prop-1-ynyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (100 mg, 61%). LC/MS m/e calcd for C24H23NO4 (M+H)+: 390.46, observed: 390.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (d, J=1.52 Hz, 3 H) 2.22 (s, 3 H) 2.59-2.69 (m, 1 H) 2.89-2.99 (m, 1 H) 3.16-3.27 (m, 2 H) 3.81 (d, J=7.58 Hz, 6 H) 5.38 (d, J=1.77 Hz, 1 H) 6.04 (d, J=2.78 Hz, 2 H) 6.84 (s, 1 H) 6.96 (m, 2 H) 7.06 (s, 1 H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:18]#[C:19][CH3:20].O>ClCCl>[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:6][CH:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:18]#[C:19][CH3:20]
Reactant: COC(=O)[C@H](N)CO
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)NC(CO)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a 0° solution of D-serine methyl ester hydrochloride (0.62 g, 4 mmol) in 5 mL of dichloromethane was added triethylamine (1.67 mL,12 mmol) followed by a dichloromethane (6 mL) solution of 4-(2-butynyloxy)-benzenesufonyl chloride (0.98 g, 4 mmol). The reaction was stirred at room temperature overnight and then the mixture was poured into water. The organic layer was washed with 2N citric acid, water and brine, dried over sodium sulfate, filtered and concentrated to give 1.16 g of methyl 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-hydroxypropanoate. Yield˜89.2%. mp 72-74° C. Electrospray Mass Spec 328.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)=[O:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.C(N(CC)CC)C.[C:42]([O:45]C(=O)C)(=[O:44])[CH3:43]>ClCCl>[C:42]([OH:45])(=[O:44])[CH3:43].[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:42](=[O:44])[CH3:43])=[CH:27][CH:28]=3)=[O:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(O)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(OC(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-amino-5-chloro-2-methoxy-N-((1-(6-(4-hydroxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide (10.0 g) in dichloromethane (60 ml) were added triethylamine (12.5 ml) and acetic anhydride (2.5 ml), and the resulting mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with chloroform. The organic layer was washed with brine and dried. The solvent was evaporated under reduced pressure and the obtained crystals were recrystallized from a mixed solvent of ethanolethyl acetate to give 8.50 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(4-acetoxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide acetate, m.p. 140°-141° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([OH:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(Cl)([Cl:18])=O>>[CH:8]1([C:7]([Cl:18])=[O:15])[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1.[CH:8]1([C:7]([OH:15])=[O:14])[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1
Reactant: O=C(O)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(Cl)C1CC=CCC1
Product: O=C(O)C1CC=CCC1
Reaction time: 12 h

Procedure:
The 4-hydroxy group of 4-hydroxybenzoic acid is protected by reacting 4-hydroxybenzoic acid, 5 g (0.036 mol), obtained commercially, with benzyl chloride, 5.1 g (0.04 mol) in ethanol:water (1:1) containing 5 g K2CO3 (0.04 mol) at a temperature of 30 degrees C. for 12 hours. The 4-PgO benzoic acid is converted to the acid chloride using thionyl chloride by a procedure similar to that employed for producing 3-cyclohexene carboxylic acid chloride from 3-cyclohexene carboxylic acid in Example I.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[NH:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3]1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:6]1[C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3][C:2]1([CH3:10])[CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: CC1(C)NC(=O)C(C)(C)N1
Product: CC1(C)NC(C)(C)N(Cc2ccccc2)C1=O

Procedure:
If, instead of 7,14-diaza-15-oxo-dispiro[5.1.5.2]pentadecane, 2,2,5,5-tetramethyl-4-oxo-imidazolidine is used, and this alkylated with benzyl chloride as described in Example 1, then 3-benzyl-2,2,5,5-tetramethyl-4-oxo-imidazolidine (VII), M.P. 210°C, is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(=O)(=O)(O)O.[CH3:18]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:18])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(O)c(Cl)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred solution of 2-(3-chloro-4-hydroxyphenyl)acetic acid (3 g, 16.078 mmol) in methanol (35 mL) were added sulfuric acid (0.3 mL). The reaction mixture was refluxed for 15 h and cooled to room temperature. The solvent was evaporated. The residue dissolved in ethyl acetate and extracted with NaHCO3. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. Methyl 2-(3-chloro-4-hydroxyphenyl)acetate (3.557 g) was obtained as 99% yield.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH2:13]([O:15][C:16]1[C:17](=O)[C:18](=[O:23])[C:19]=1[O:20]CC)[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]1[C:19](=[O:20])[C:18](=[O:23])[C:17]=1[NH:8][C:7]1[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=1)[CH3:14]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCO
Product: CCOc1c(Nc2ccc(OC(F)(F)F)cc2)c(=O)c1=O
Yield: 53 %

Procedure:
4-Trifluoromethoxyaniline (5.00 g, 28.2 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absolute ethanol (50 mL). The mixture was heated at reflux overnight, then vacuum filtered hot. The filtrate was reduced in volume and the resulting precipitate was filtered to afford 4.50 g (53%) of white solid: mp 145°-146° C.; 1H NMR (DMSO-d6): δ 10.87 (s, 1H), 7.45 (d, 2H), 7.36 (d, 2H), 4.75 (q, 2H), 1.41 (t, 3H).
Reaction SMILES: N[C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[ClH:18].O1CCOCC1.N([O-])=O.[Na+]>C(OCC)(=O)C.[Cu]Cl.ClCCl>[Cl:18][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1N
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)O)c(Cl)c(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine methyl 2-amino-3,4,5-trimethoxybenzoate (4.8 g, 20 mmol) and dichloromethane (20 mL). Cool in an ice bath. Add a solution of hydrochloric acid in dioxane (10 mL, 4 M, 40 mmol). Add polyethylene glycol 200 (20 mL) followed by sodium nitrite (2.76 g, 40 mmol). After 10 minutes add copper(I) chloride (3.96 g, 40 mmol). Warm to ambient temperature. After 18 hours, dilute the reaction mixture with ethyl acetate and extract with a 1 M aqueous solution of sodium hydroxide an then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. the title compound. Chromatograph the residue on silica gel eluting sequentially with hexane and then 5% ethyl acetate/hexane to give methyl 2-chloro-3,4,5-trimethoxybenzoate: Rf=0.7 (silica gel, 20% ethyl acetate/toluene).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:5][C:4]=1[F:20])=[CH2:2].FC(F)(F)C(O)=O.[CH2:28]([N:35]([CH2:39][Si](C)(C)C)[CH2:36]OC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[F:20][C:4]1[CH:5]=[C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:7]=[CH:8][C:3]=1[CH:1]1[CH2:2][CH2:36][N:35]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:39]1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=Cc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(Cc4ccccc4)C3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (S)-(-)-N-[[3-[4-vinyl-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 41, Step 1, 3.50 g) and trifluoroacetic acid (0.23 mL) in dry methylene chloride under N2 is treated with a solution of N-benzyl-N-(methoxymethyl) trimethylsilylmethylamine (6.10 g) in dry methylene chloride (50 mL) dropwise over 4.5 hours, and the resulting solution was stirred at ambient temperature for 17 hours. The reaction mixture is then washed with saturated aqueous sodium bicarbonate (30 mL), water (30 mL) and saline (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue which is chromatographed on silica gel (230-400 mesh, 350 g), eluting with a gradient of methanol/methylene chloride (1/99-10/90). Pooling and concentration of those fractions with an Rf =0.19 by TLC (methanol/chloroform, 10/90) and trituration with methanol/diethyl ether gives the title compound, NMR (CDCl3, 400 MHz) 7.35, 7.25, 7.13, 6.08, 4.78, 4.03, 3.76, 3.69, 3.62, 2.97, 2.78, 2.56, 2.33, 2.02, 1.85 δ.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C)c(C)c2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C)c(C)c2)c1O
Yield: 68.2 %

Procedure:
1-[5-(3,4-Dimethylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.2423 mmol, HPLC purity 84.3%, 70.2 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.2423 mmol, 51.2 mg) were stirred with dimethylformamide (3 mL) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (72.3 mg, yield 68%).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.[CH3:20]N(C=O)C>>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][C:5]2[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=2)=[O:18])=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCCCCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 3.7 g) was treated under argon with repeated washes of hexane. The oil-free residue was suspended in dry DMF (100 ml) and 4-hydroxyphenylacetic acid (13.0 g) was added portionwise to the stirred cooled (4° C.) mixture. After 30 minutes, benzyl bormide (9.2 ml) was added dropwise and, after a further 1 hour at 4° C., stirring was continued overnight at ambient temperature. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was re-extracted with further ethyl acetate and the combined organic extracts washed with water and brine, then dried (MgSO4) and evaporated. The crystaline residue gave benzyl 4-hydroxyphenylacetate, 17.8 g, as off-white crystals: m.p. 70°-72° C. NMR (CDCl3) δ7.32(5H,m), 7.14(2H,d), 6.76(2H,d), 5.12(2H,s), 3.59(2H,s); m/e 242 (M·)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[N:3]=1.[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)(=[O:19])[CH3:18].FC1C=CC(C2C=C3C(=CC=2)N=CN=C3O)=CC=1>>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]3[CH:25]=[CH:26][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[CH:22][CH:23]=3)[CH:8]=2)[N:3]=1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: CC(C)Oc1nc(N)nc2ccc(Br)cc12
Agent: Oc1ncnc2ccc(-c3ccc(F)cc3)cc12
Product: CC(=O)Nc1ccc(-c2ccc3nc(N)nc(OC(C)C)c3c2)cc1
Yield: 84 %

Procedure:
This compound, synthesized from 2-amino-6-bromo-4-isopropoxy-quinazoline and 4-acetamido-phenylboronic acid in 84% yield as a white solid using the procedure described for the synthesis of 6-(4-fluorophenyl)-4-hydroxy-quinazoline, was characterized by its mass spectrum as follows: MS (m/z): 298 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:13]1[C:21]2[CH:20]=[C:19]([CH3:22])[N:18]=[CH:17][C:16]=2[NH:15][C:14]1=[O:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[I-].[CH3:32][N:33]1[C:41]2[C:36](=[C:37]([CH3:42])[CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:43][N+](C)(C)C)=[CH:34]1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:13]1[C:21]2[CH:20]=[C:19]([CH3:22])[N:18]=[CH:17][C:16]=2[N:15]([CH2:43][C:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][C:37]=3[CH3:42])[N:33]([CH3:32])[CH:34]=2)[C:14]1=[O:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(C)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cnc(C)cc21
Temperature: 60 °C
Yield: 66.3 %

Procedure:
To a solution of (R)-3-(6-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]pyridin-1-yl)-3-phenyl-propionic acid ethyl ester (80 mg, 0.25 mmol) in DMF (3 mL) were added K2CO3 (41 mg, 0.30 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (102 mg, 0.30 mmol). The reaction mixture was heated to 60° C. for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 80 mg (67%) of the title compound. LCMS, M++1, m/z: 484.10.
Reaction SMILES: FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.C([C:25]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:41][C:42](=[O:51])[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[O:40])=[CH:34][C:33]=2[F:52])[CH:28]=[CH:27][N:26]=1)(=O)N.O.[N:54]1C=CC=CC=1.[ClH:60]>CN(C=O)C>[ClH:60].[NH2:54][C:25]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:41][C:42](=[O:51])[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[O:40])=[CH:34][C:33]=2[F:52])[CH:28]=[CH:27][N:26]=1
Reactant: c1ccncc1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Agent: Cl
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 61.7 %

Procedure:
Bis-(trifluoroacetoxy)-iodobenzene (Aldrich, 3.09 g, 7.20 mmol, 1.4 eq) was added to a solution of 1-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea (2.19 g, 5.14 mmol, 1.0 eq), water (0.241 mL, 13.4 mmol, 2.6 eq) and pyridine (1.62 mL, 20 mmol, 3.9 eq) in DMF (20 mL) at room temperature and the reaction mixture was stirred for 5 h. The reaction mixture was quenched with 1 N HCl and the aqueous solution extracted with Et2O, discarding the organic layer. The aqueous layer was neutralized with 1 N NaOH and extracted with EtOAc. The combined organic layers were washed with 10% aq LiCl, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0-5% MeOH in CHCl3) and the appropriate fractions were concentrated in vacuo. The residue was dissolved in THF (50 mL) cooled to 0° C. and treated with anhydrous HCl (4N, 10 mL, 40 mmol, 7.8 eq). The reaction mixture was allowed to warm to room temperature and stirred for 2 h resulting in a heterogeneous solution. The solution was filtered and the solid washed with Et2O and dried in vacuo to afford the title compound (1.38 g, 63%) as a solid. 1H NMR (DMSO-d6) δ 11.09 (s, 1H), 10.65 (s, 1H), 7.97-8.00 (m, 1H), 7.83-7.90 (m, 3H), 7.35-7.48 (m, 4H), 7.15-7.21 (m, 2H), 6.70-6.72 (m, 1H), 6.16-6.17 (m, 1H), 3.77 (s, 2H); MS (ESI+) m/z 399 (M+H)+. HRMS (ESI+) calcd.: 399.1269. found: 399.1258. Elem analysis for C20H16N4O3F2 1.0 HCl . . . 0.22H2O
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-])=O.[Cl-].[NH4+]>[Fe].CCO.O>[C:13]1([N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=3[CH:6]=[N:7]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cccc2c1cnn2-c1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c1cnn2-c1ccccc1
Yield: 58 %

Procedure:
A solution of 4-nitro-1-phenyl-1H-indazole (0.140 g, 0.585 mmol), ammonium chloride (0.016 g, 0.293 mmol) in 4:1 v/v EtOH/water (5 mL) was treated with iron (0.327 g, 5.85 mmol) and refluxed for 2 hours. The mixture was concentrated and the residue taken in EtOAc/water, filtered through glass fiber filter paper and concentrated again to provide 1-phenyl-1H-indazol-4-amine (0.071 g, 58% yield) as a beige solid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1O)(=[O:3])[CH3:2].[CH2:16]([NH2:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[C:35](Cl)(=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>>[CH2:16]([N:34]([CH:6]1[O:8][C@H:9]([CH2:14][OH:15])[C@@H:10]([OH:13])[C@H:11]([OH:12])[C@H:5]1[NH:4][C:1](=[O:3])[CH3:2])[C:35](=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O

Procedure:
The preparation is analogous to Example 20 from N-acetylglucosamine, stearylamine and tetradecanoic acid chloride.