Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[S:7][C:8]([C:13]([O:15]CC)=[O:14])=[C:9]([OH:12])[C:10]=1[OH:11])([O:3]CC)=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:24]1OC2C(=CSC=2)O[CH2:25]1.BrCCBr.BrCC(Br)CCCCCCCCCCCCCC.BrCC(Br)CCCC.C(C1SC(C(OCC)=O)=C2OCCOC=12)(OCC)=O.[OH-].[Na+]>CN(C=O)C>[C:13]([C:8]1[S:7][C:6]([C:1]([OH:3])=[O:2])=[C:10]2[O:11][CH2:25][CH2:24][O:12][C:9]=12)([OH:15])=[O:14]
Reactant: c1scc2c1OCCO2
Reactant: CCOC(=O)c1sc(C(=O)OCC)c(O)c1O
Agent: CCCCC(Br)CBr
Agent: CCCCCCCCCCCCCCC(Br)CBr
Agent: CCOC(=O)c1sc(C(=O)OCC)c2c1OCCO2
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: O=C(O)c1sc(C(=O)O)c2c1OCCO2

Procedure:
The salt either 5 or 6 is dissolved in water and acidified with 1 Molar HCl added slowly dropwise with constant stirring until the solution becomes acidic. Immediately following, thick white precipitate falls out. After filtration, the precipitate is washed with water and air-dried to give 2,5-dicarbethoxy-3,4-dihydroxythiophene (7). The salt either (5, 2.5 grams) or 6 can be alkylated directly or the dihydrothiophene derivative (7) can be suspended in the appropriate 1,2-dihaloalkane or substituted 1,2-dihaloalkane and refluxed for 24 hours in the presence of anhydrous K2CO3 in anhydrous DMF. To prepare EDOT, either 1,2-dicholorethane (commercially available from Aldrich) or 1,2-dibromoethane (commercially from Aldrich) is used. To prepare the various substituted EDOT derivatives the appropriate 1,2-dibromoalkane is used, such as 1-dibromodecane, 1,2-dibromohexadecane (prepared from 1-hexadecene and bromine), 1,2-dibromohexane, other reported 1,2-dibromoalkane derivatives, and the like. The resulting 2,5-dicarbethoxy-3,4-ethylenedioxythiophene or 2,5-dicarbethoxy-3,4-alkylenedioxythiophene is refluxed in base, for example 10 percent aqueous sodium hydroxide solution for 1 to 2 hours, and the resulting insoluble material is collected by filtration. This material is acidified with 1 Normal HCl and recrystallized from methanol to produce either 2,5-dicarboxy-3,4-ethylenedioxythiophene or the corresponding 2,5-dicarboxy-3,4-alkylenedioxythiophene. The final step to reduce the carboxylic acid functional groups to hydrogen to produce the desired monomer is given in the references above.
Reaction SMILES: C(OC(N(C)[C@@H](C)C(N[C@@H](C(C)(C)C)C(N1[C@H](C(=O)N[C@H]2C3C(=CC=CC=3)CCC2)CC2C(=CC(C(O)=O)=CC=2)C1)=O)=O)=O)(C)(C)C.[C:48]([O:52][C:53]([N:55]([CH3:132])[C@@H:56]([CH3:131])[C:57]([NH:59][C@@H:60]([C:127]([CH3:130])([CH3:129])[CH3:128])[C:61]([N:63]1[C@H:72]([C:73]([NH:75][C@@H:76]([CH2:81][C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[C:77]([O:79]C)=[O:78])=[O:74])[CH2:71][C:70]2[C:65](=[CH:66][C:67]([C@H:88]3[CH2:92][C@@H:91]([C:93](=[O:105])[NH:94][C@H:95]4[C:104]5[C:99](=[CH:100][CH:101]=[CH:102][CH:103]=5)[CH2:98][CH2:97][CH2:96]4)[N:90]([C:106](=[O:126])[C@@H:107]([NH:112][C:113](=[O:125])[C@@H:114]([N:116]([C:118]([O:120][C:121]([CH3:124])([CH3:123])[CH3:122])=[O:119])[CH3:117])[CH3:115])[C:108]([CH3:111])([CH3:110])[CH3:109])[CH2:89]3)=[CH:68][CH:69]=2)[CH2:64]1)=[O:62])=[O:58])=[O:54])([CH3:51])([CH3:50])[CH3:49]>>[C:48]([O:52][C:53]([N:55]([CH3:132])[C@@H:56]([CH3:131])[C:57]([NH:59][C@@H:60]([C:127]([CH3:130])([CH3:129])[CH3:128])[C:61]([N:63]1[C@H:72]([C:73]([NH:75][C@@H:76]([CH2:81][C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[C:77]([OH:79])=[O:78])=[O:74])[CH2:71][C:70]2[C:65](=[CH:66][C:67]([C@H:88]3[CH2:92][C@@H:91]([C:93](=[O:105])[NH:94][C@H:95]4[C:104]5[C:99](=[CH:100][CH:101]=[CH:102][CH:103]=5)[CH2:98][CH2:97][CH2:96]4)[N:90]([C:106](=[O:126])[C@@H:107]([NH:112][C:113](=[O:125])[C@@H:114]([N:116]([C:118]([O:120][C:121]([CH3:124])([CH3:123])[CH3:122])=[O:119])[CH3:117])[CH3:115])[C:108]([CH3:109])([CH3:111])[CH3:110])[CH2:89]3)=[CH:68][CH:69]=2)[CH2:64]1)=[O:62])=[O:58])=[O:54])([CH3:49])([CH3:50])[CH3:51]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1Cc2ccc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)C3)cc2CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C
Agent: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)O)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Yield: 59.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound K of Example 1, (S)-methyl 2-((S)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-7-((3R,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)-3-phenylpropanoate (290 mg, 0.25 mmol) was converted to the title compound (172 mg, 60%). MS (ESI+) m/z 1163.9 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O.[C:12](=O)(O)[O-].[Na+].COS(OC)(=O)=O>C(OCC)(=O)C>[CH3:12][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
1,2,3,4-Tetrahydroquinoline (6.66 g, 50 mmol) was added to 40 ml of water, 40 ml of ethyl acetate, and 5.04 g (60 mmol) of sodium bicarbonate to which was added 5.68 ml (60 mmol) of dimethylsulfate dropwise. The reaction was stirred at room temperature for 21/2 hours, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, then the organic layers were combined and evaporated to give 4.56 g (62% yield) of the title compound. NMR (CDCl3) δ 1.93 (quintet, 2, CH2), 2.74 (tr, 2, CH2), 2.81 (s, 3, NMe), 3.17 (tr, 2, CH2), 6.55 (m, 2, Ar), 6.97 (m, 2, Ar).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][NH2:11])[CH:8]=[CH:9][C:2]1=2.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:15]=1[CH:16]=O>>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][N:11]3[CH:16]([C:15]4[C:14]([O:13][CH3:12])=[CH:21][CH:20]=[CH:19][C:18]=4[O:22][CH3:23])[CH2:19][CH2:18][CH2:15][C:14]3=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: NCc1ccc2sccc2c1
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2sccc2c1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available benzo[b]thiophen-5-ylmethanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.79 min.; [M+H]+: 382.09 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl.C(#N)C>[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([C:40]([O:27][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:26][CH:25]=2)=[O:41])=[CH:43][CH:44]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)cc2)cc1
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Prepared using General Procedure 3: To a stirred solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate (5.57 g, 15.0 mmol) and TEA (6.27 mL, 45.0 mmol) in DCM (15 mL) and acetonitrile (30 mL) was added 4-(heptyloxy)benzoyl chloride (3.78 mL, 15.75 mmol) dropwise. After stirring overnight, the mixture was quenched with saturated aqueous NaHCO3 (50 mL). The organic layer was dried over MgSO4, and concentrated. The product was purified by chromatography (EA/hexanes) to afford 8.19 g (93%) of (S)-4-(2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)-3-oxopropyl)phenyl 4-(heptyloxy)benzoate INT-4. LCMS-ESI (m/z) calculated for C35H43NO7: 589; no mass ion observed, tR=5.26 min (Method 3). 1H NMR (400 MHz, CDCl3) δ 8.17-8.08 (m, 2H), 7.41-7.28 (m, 5H), 7.19 (d, J=8.4 Hz, 2H), 7.15-7.07 (m, 2H), 7.01-6.91 (m, 2H), 5.35-5.23 (m, 1H), 5.17-5.04 (m, 2H), 4.54 (dd, J=13.9, 6.1 Hz, 1H), 4.04 (t, J=6.6 Hz, 2H), 3.10 (d, J=5.9 Hz, 2H), 1.91-1.76 (m, 2H), 1.47 (ddd, J=15.2, 8.9, 6.7 Hz, 2H), 1.43-1.36 (m, 10H), 1.36-1.30 (m, 5H), 0.90 (t, J=6.9 Hz, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([B:25]4[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:34][CH:9]1[CH2:10][CH2:11]2)=[O:7])(C)(C)C.Cl.[CH3:36][O:37][C:38]([NH:40][CH:41]([CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1)C(O)=O)=[O:39].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CCOC(C)=O>[CH3:36][O:37][C:38](=[O:39])[NH:40][CH:41]([CH:45]1[CH2:46][CH2:47][O:48][CH2:49][CH2:50]1)[C:6](=[O:7])[N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([B:25]4[O:29][C:28]([CH3:30])([CH3:31])[C:27]([CH3:32])([CH3:33])[O:26]4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:34][CH:9]1[CH2:10][CH2:11]2
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)O)C1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of 3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.25 g, 0.54 mmol) in CH2Cl2 (5 mL) and MeOH (0.5 mL) was added HCl (in dioxane, 4 M, 1.35 mL, 5.40 mmol). The solution was stirred at room temperature for 2 h and concentrated to dryness. The resulting solid was slurried in CH2Cl2 (5 mL) and DMF (1 mL). Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.15 g, 0.71 mmol), COMU (0.25 g, 0.59 mmol), and DIPEA (0.50 mL, 0.59 mmol) were added, and the resulting solution was stirred at room temperature for 1 h. The reaction was diluted with EtOAc and washed with saturated sodium bicarbonate and brine. The aqueous layers were back extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 10→100% EtOAc (10% MeOH) in Hexanes) to provide [2-Oxo-1-(tetrahydro-pyran-4-yl)-2-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]hept-2-yl)-ethyl]-carbamic acid methyl ester (0.24 g, 79%). LCMS-ESI+: calc'd for C30H41BN4O6: 564.31 (M+); Found: 565.40 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=2[CH:17]=1.[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1)(=[O:20])[CH3:19]>>[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=3[CH:17]=2)=[CH:24][CH:23]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: O=C1Nc2ccc(OCCCCCl)cc2CO1
Product: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: [F:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(=O)(O)[O-].[Na+].C(OCC)C>[F:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=[O:4]
Reactant: OCC(F)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: O=CC(F)c1ccccc1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 88.8 %

Procedure:
To a 500 mL RBF containing 2-fluoro-2-phenylethanol (440.00 mg, 3139 μmol) was added DCM (30 mL) and the mixture was allowed to stir at 23° C. for 5 min. At this time, sodium bicarbonate (343 mg, 4081 μmol) and Dess-MartinPeriodinane (1731 mg, 4081 μmol) were added in one portion and the reaction mixture was allowed to stir for 15 min before the reaction was quenched by the addition of sodium thiosulfate (2482 mg, 15697 μmol) in water (50 ml) and sodium bicarbonate (sat, 50 ml) and diethyl ether (100 ml). The quenched reaction was allowed to stir for 20 min and the organic layer was washed with sodium bicarbonate (sat., 3×75 ml) and brine. The organic layer was dried over magnesium sulphate, filtered and concentrated to give the title compound (385 mg) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]([CH3:15])[C:9](=[O:14])[CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1.[Na].C([C:21]([O:23][CH2:24][CH3:25])=[O:22])#N>CN(C)C=O>[Cl:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]([CH3:15])[C:9](=[O:14])[CH:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1
Reactant: CN1C(=O)CS(=O)(=O)c2cc(Cl)ccc21
Reactant: CCOC(=O)C#N
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)N(C)c2ccc(Cl)cc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a suspension of sodium hydride (5.13 g, 60% oil dispersion, washed with dry petroleum ether) in dimethylformamide (110 ml) was added 7-chloro-4-methyl-2H-1,4-benzothiazin-3(4H)one 1,1-dioxide (30 g) at 5° to 10° C. The mixture was allowed to warm to room temperature and stirred for 15 minutes for the preparation of the sodium salt. The reaction mixture was then cooled in an ice bath and a solution of ethyl cyanoformate (16.29 g) in dimethylformamide (15 ml) was added dropwise over 30 minutes. After being stirred for one hour, the mixture was quenched with acetic acid (14 ml), poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The oily residue was crystallized from ethanol to afford 31 g of 7-chloro-2-ethoxycarbonyl-4-methyl-2H-1,4-benzothiazin-3(4H)one 1,1-dioxide, mp 86° to 91° C. (melt).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[CH3:17])=[N:9][C:8]=2[CH:18]=1)([O-:3])=[O:2].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.N(CCCC#N)=NCCCC#N>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[CH2:17][Br:19])=[N:9][C:8]=2[CH:18]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccsc1-c1nc2cc([N+](=O)[O-])ccc2o1
Agent: N#CCCCN=NCCCC#N
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2oc(-c3sccc3CBr)nc2c1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A mixture of 5-nitro-2-(3-methyl-2-thienyl)benzoxazole (11.0 g, 0.042 mole) and N-bromosuccinimide (7.55 g, 0.042 mole) are refluxed for 36 hours in 400 ml of chloroform. Approximately every 12 hours azobisbutyronitrile (0.1 g) is added as a catalyst. The reaction mixture is cooled to room temperature and the precipitated succinimide removed by filtration. The chloroform solution is washed with 150 ml of 5% sodium hydroxide and dried over anhydrous magnesium sulfate. The chloroform is removed under vacuum yielding a solid. Crystallization from ethanol yields 8.6 g of product, melting point 146°-148° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10](=[O:19])[CH2:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=[O:15].S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10](=[O:19])[CH2:11][C:12]([CH3:17])([CH3:18])[CH2:13][C:14]([O:16][CH2:25][CH3:26])=[O:15]
Reactant: CCO
Reactant: Cc1ccc(C)c(CC(=O)CC(C)(C)CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC(C)(C)CC(=O)Cc1cc(C)ccc1C
Yield: 78 %

Procedure:
Utilizing the procedure of EXAMPLE XX 6-(2',5'-dimethylphenyl)-5-keto-3,3-dimethyl hexanoic acid was esterified with absolute ethanol in the presence of a catalytic amount of concentrated sulfuric acid to provide 15.52 g (78% yield) of ethyl 6-(2',5'-dimethylphenyl)-5-keto-3,3-dimethylhexanoate as a pale viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[CH:14]=[C:13]([N:15]=[C:16]([NH2:23])[N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[O:12][N:11]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=1.C(Cl)Cl.B(Br)(Br)Br.[OH-].[Na+]>O1CCCC1>[NH2:23][C:16]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[N:15][C:13]1[O:12][N:11]=[C:10]([CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)=[C:2]([F:1])[CH:7]=2)[CH3:9])[CH:14]=1
Reactant: COc1ccc(-c2ccc(C(C)c3cc(N=C(N)N4CCOCC4)on3)cc2F)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(c1ccc(-c2ccc(O)cc2)c(F)c1)c1cc(N=C(N)N2CCOCC2)on1
Reaction time: 1 h
Yield: 53.5 %

Procedure:
The compound (5.16 g) obtained in Example 63 was dissolved in tetrahydrofuran (100 ml) under a nitrogen atmosphere and then a methylene chloride solution (40 ml) of boron tribromide (1.6 ml) was added at -78° C., after which the temperature was elevated to room temperature over one hour and the stirring was further conducted at room temperature for 3 hours. The reaction mixture was neutralized with a 15% aqueous sodium hydroxide solution and then subjected to extraction with ethyl acetate and methanol. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (chloroform alone→chloroform/methanol=50/1→33/1) to obtain the desired compound (2.67 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=1)=[O:4].Cl[Sn]Cl>CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CO
Product: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Yield: 95.2 %

Procedure:
To a solution of 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester (10.00 g, 36.9 mmol) in methanol was added SnCl2 (27.98 g, 147.6 mmol) at room temperature. The reaction mixture was refluxed for 3 hours, then cooled. Solvent was removed in vacuo and the residue was dissolved in H2O, then basified by addition of Na2CO3 to pH=9. The mixture was extracted by CH2Cl2, and the organic phase was washed with water followed by brine, and dried over Na2SO4. The solvent was removed under vacuum to give 5-amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (8.48 g, 95%) as yellow oil. MS (M+H)=242.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[N:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:13]=[S:14].CC(O)C>O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][N:2]=[C:13]2[SH:14])=[CH:20][CH:19]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(-n2c(-c3ccccc3)cnc2S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 17.5 parts of 2-amino-1-phenylethanone hydrochloride, 16.5 parts of 1-isothiocyanato-4-methoxybenzene, 10 parts of sodium hydrogen carbon and 200 parts of 2-propanol is stirred first for 30 minutes at room temperature and further for 2 hours at reflux temperature. The reaction mixture is poured onto 500 parts of water. The product is filtered off and stirred and refluxed for 1 hour with 240 parts of hydrochloric acid solution 10%. After cooling, the product is filtered off, washed with water and 2-propanol, and dried, yielding 25.3 parts (90%) of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole-2-thiol; mp. 267.4° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH2:9]O)[CH:5]=[C:6]([F:8])[CH:7]=1.N1C(C)=CC=CC=1C.[Cl-].[Li+].S([Cl:27])(C)(=O)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:27][CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[O:11][CH3:12]
Reactant: COc1c(F)cc(F)cc1CO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: COc1c(F)cc(F)cc1CCl
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.7 %

Procedure:
To a mixture of 0.87 g (5.02 mmol) of (3,5-difluoro-2-methoxy-phenyl)-methanol, 0.82 ml (7.03 mmol) of 2,6-lutidine, and 0.425 g (10 mmol) of lithium chloride in 5 ml N,N-dimethylformamide were added dropwise at 0° C. 0.5 ml (6.5 mmol) of mesylchloride. The suspension was stirred during 18 hours at room temperature and then treated with 1 ml of saturated aqueous sodium hydrogencarbonate solution. The volatile components were distilled at 35° C./1 Torr and the residue was partitioned between ethyl acetate and water. The organic phase was separated and evaporated under reduced pressure and the crude product was purified by chromatography on silica gel with dichloromethane as the eluent. There were obtained 0.49 g (51% of theory) of 1-chloromethyl-3,5-difluoro-2-methoxy-benzene as a colorless liquid; MS: 192 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[C:23]([C:24]#[N:25])=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]>CO.Cl.[Pd]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[C:23]([CH2:24][NH2:25])=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nccnc3C#N)cc(C)c21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nccnc3CN)cc(C)c21
Yield: 94 %

Procedure:
To a solution of [6-(3-cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (200 mg, 0.566 mmol) in MeOH (10 mL) was added Pd/C (20 mg), HCl (conc., 2 drops). The resulting solution was degassed, and reacted under 1-atm H2 balloon for 6 hrs. The mixture was filtrated. The filtration was removed in vacuo to afford the title compound (190 mg, 94%) as a light yellow solid. MS found: (M+H)+=358.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]CC2C=CC=CC=2)[C:5]([F:16])=[CH:4][C:3]=1[N:17]1[C:25]2[C:20](=[C:21]([O:26]CC3C=CC=CC=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:16])=[CH:4][C:3]=1[N:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:26])[C:20]=2[CH:19]=[CH:18]1
Reactant: Fc1cc(-n2ccc3c(OCc4ccccc4)cccc32)c(F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1cc(F)c(-n2ccc3c(O)cccc32)cc1F
Yield: 74.7 %

Procedure:
1-{2,5-difluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indole (D22) (258 mg, 0.584 mmoL)) was dissolved in ethyl acetate (10 mL) and was hydrogenated at room temperature and atmospheric pressure in the presence of 10% palladium on charcoal (50% wet) (120 mg). After 22 hours the mixture was filtered and concentrated in vacuo. The crude product was purified by MDAP to give the title compound (E12), (114 mg).