Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br-].[Na+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl>O1CCCC1.CCCCCC.O>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:26][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Reactant: ClCc1cccc(Cl)c1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(Cl)c1
Temperature: -40 °C
Yield: 92 %

Procedure:
31.5 g of N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide is dissolved in 600 mL of dry tetrahydrofuran and the resulting solution is cooled to -40° C. Two equivalents of n-butyllithium in hexane are added while the temperature is maintained at -40° C. The solution turned deep purple-red. 1.6 g of sodium bromide is added and the mixture is stirred. A solution of 26.5 g (0.174 mole) m-chlorobenzylchloride in 125 mL of tetrahydrofuran is added while the temperature is maintained at -40° C. The reaction mixture is stirred until the reaction is complete as determined by thin layer chromatography. Water is added to the reaction until the color is dissipated. The reaction mixture is extracted with ethyl acetate, washed with water, and concentrated to a residue. A yield of 92% for the product is shown by chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].[NH4+].[Cl-]>CCO.C1COCC1.O.[Fe]>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)no1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(N)cc2)no1
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a solution of the compound of step 1 (1.0 g; 3.8 mmol) and NH4Cl (0.61 g; 11.4 mmol) in EtOH (30 ml), THF (20 ml) and water (5.0 ml), was added iron powder (0.5 g, 8.9 mmol) under vigorous stirring. The resulting reaction mixture was heated at 80° C. under stirring for 3 hours. The reaction mixture was cooled to 25° C. and filtered through celite and washed with EtOH. The filtrate was concentrated and basified with NaHCO3. The oil separated was extracted with dichloromethane (3×20 ml). The dichloromethane layer was washed with water (2×10 ml) and dried over anhydrous Na2SO4. The solvent was evaporated, and the residue was purified by flash chromatography with EtOAc: light petroleum (1:1) to give the title compound of step 2 (0.67 g; 75%). Mass (ES−), 231 (M−1); 1H NMR (DMSO-d6) δ: 1.31 (t, 3H), 4.36 (q, 2H), 5.64 (s, 2H), 6.61 (d, 2H), 7.60 (d, 2H), 7.66 (s, 1H).
Reaction SMILES: C(N[C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:20][CH3:21])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19])=[C:8]([NH2:22])[N:7]=1)CCC.FC(F)(F)C(O)=O.COC1N=C2C(N=1)=C(N)NC([O:42][C@@H:43]([CH3:46])[CH2:44][CH3:45])=N2.BrCCCCCl>C(OCC)(=O)C.C1CCCCC1>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[C:11]([O:20][CH3:21])=[N:10][C:9]2[C:13]1=[N:14][C:6]([O:42][C@@H:43]([CH3:46])[CH2:44][CH3:45])=[N:7][C:8]=2[NH2:22]
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: CC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Agent: ClCCCCBr
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 18 from 8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane with purification on an aminopropyl (NH2) cartridge using a 0-100% ethyl acetate-cyclohexane gradient.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][C:22]4=[O:31])[CH2:17][CH2:16]3)=[O:14])[C:9](=[O:32])[N:8]([CH3:33])[CH2:7][C:6]=2C=1.CO.CCOCC.S(Cl)([Cl:45])(=O)=O.Cl[CH2:48][Cl:49]>>[Cl:45][C:3]1[C:2]([OH:1])=[C:48]([Cl:49])[C:6]2[CH2:7][N:8]([CH3:33])[C:9](=[O:32])[CH:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][C:22]4=[O:31])[CH2:17][CH2:16]3)=[O:14])[CH2:11][C:5]=2[CH:4]=1
Reactant: ClCCl
Reactant: O=S(=O)(Cl)Cl
Reactant: CN1Cc2cc(O)ccc2CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Solvent: CO
Solvent: CCOCC
Product: CN1Cc2c(cc(Cl)c(O)c2Cl)CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reaction time: 12 h
Yield: 58 %

Procedure:
To a stirred solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid (8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide (27 mg, 0.058 mmol) in dichloromethane (10 mL) was added methanol (2 mL), ether (3 mL) followed by sulfuryl chloride (70 μL) at room temperature. The reaction mixture was stirred for additional 12 h and then concentrated. The crude product was purified by Prep HPLC to give 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid (7,9-dichloro-8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide in 58% yield. MS (ESI) 532 (M+H); Rf=1.40.
Reaction SMILES: Cl.O[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:29]3[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=3)[S:8][C:7]=2[CH:36]=1.C(N([CH2:42][CH3:43])CC)C.[CH2:44]([S:48](Cl)(=[O:50])=[O:49])[CH2:45][CH2:46][CH3:47]>O1CCCC1.CN(C1C=CN=CC=1)C>[CH2:44]([S:48]([C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:29]3[CH:34]=[CH:33][C:32]([S:48]([CH2:44][CH2:45][CH2:42][CH3:43])(=[O:50])=[O:49])=[CH:31][CH:30]=3)[S:8][C:7]=2[CH:36]=1)(=[O:50])=[O:49])[CH2:45][CH2:46][CH3:47]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: O=C(c1ccc(OCCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)c1ccc(-c2sc3cc(S(=O)(=O)CCCC)ccc3c2C(=O)c2ccc(OCCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.5 g (4.77 mmol) of [6-hydroxy-2-[4-hydroxyphenyl]benzo-[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]-phenyl]methanone hydrochloride was dissolved in 100 ml of tetrahydrofuran, 3.9 g (39 mmol) of triethylamine and 10 mg of DMAP were added. The reaction mixture was stirred for 15 minutes at room temperature and under a nitrogen blanket. 4 g (25.5 mmol) of n-butylsulfonyl chloride in 15 ml of tetrahydrofuran was slowly added. The reaction was allowed to proceed for eighteen hours at room temperature and under nitrogen. The reaction was quenched with the addition of 25 ml methanol and volume reduced in vacuo. The crude product was chromatographed on a silica gel column, eluted with chloroform-methanol (19:1 v/v). The desired fractions were determined by thin layer chromatography, combined, and evaporated to a tan oil.
Reaction SMILES: [Cl:1][C:2]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12][C:11]2[C:3]=1[N:4]=[C:5]1[C:10]=2[C:9]([F:19])=[CH:8][CH:7]=[CH:6]1.[C:20]1(C)C=CC=CC=1.O(C)S(C(F)(F)F)(=O)=O>C(OCC)C>[ClH:1].[Cl:1][C:2]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH+:12]([CH3:20])[C:11]2[C:3]=1[N:4]=[C:5]1[C:10]=2[C:9]([F:19])=[CH:8][CH:7]=[CH:6]1
Reactant: Cc1ccccc1
Reactant: Fc1cccc2nc3c(Cl)c4ccccc4[nH]c-3c12
Agent: COS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Product: C[NH+]1C2=c3c(F)cccc3=NC2=C(Cl)c2ccccc21
Product: Cl
Reaction time: 24 h
Yield: 98 %

Procedure:
To a solution of 11-chloro-6-fluoroquindoline from Example 89 (0.110 g, 3.89 mmol) and toluene (5 ml, freshly distilled) stirring under nitrogen was added methyl triflate (0.110 mL, 0.972 mmol). The mixture stirred for 24 h at room temperature and was diluted with diethyl ether (15 mL) and filtered. The orange filter cake was placed under high vacuum for 24 h. The orange residue was suspended in chloroform (400 mL), 5% KOH (150 mL) was added, and the resulting violet organic solution was separated. The violet organic solution was dried (Na2SO4) and filtered. The violet filtrate was acidified with ethereal 1M HCl to a bright yellow endpoint and adsorbed onto basic alumina. The adsorbent was chromatographed over basic alumina (eluting with chloroform-ethyl acetate gradient from 1:0 to 4:1 until the eluent was free of impurities by TLC then eluting with 2% methanol in chloroform). The violet fractions were collected and concentrated to a small volume (20 mL). The violet solution was acidified with ethereal 1 M HCl to a bright yellow endpoint. The mixture was cooled below room temperature and filtered. The filter cake rinsed with diethyl ether (5 mL) and dried under high vacuum at 45° C. for several days to yield 0.109 g (98%) of the title compound as a bright orange solid. The title compound is poorly soluble in all common NMR solvents; 1H NMR (DMSO-d6 /CD3OD 1:1 v/v) δ 8.64 (d, J=9.2, 1H), 8.63 (dd, J=8.0, J=1.2, 1H), 8.18 (ddd, J=9.2, J=6.6, J=1.2, 1H), 8.00 (ddd, J=8.4, J=6.2, J=1.2, 1H), 7.87 (td, J=8.4, J=5.2, 1H), 7.59 (dd, J=8.4, J=0.4, 1H), 7.22 (ddd, J=13.6, J=8.0, J=0.8, 1H), 4.98 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[CH2:14][CH2:15][CH2:16][OH:17].[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:14][CH2:15][CH2:16][OH:17])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCCCOc1ccc2cc(Br)ccc2c1
Yield: 40 %

Procedure:
mixture of 6-bromo-2-naphthol (10.0 g), 3-bromopropanol (9.4 g) and potassium hydroxide (3.0 g) in 50 ml of ethanol was refluxed for 16 h. The mixture was washed with diethyl ether and water. The combined organic layers were dried, filtered, and concentrated. The crude product was crystallized from ethanol to give 6-bromo-2-(3-hydroxypropyloxy)-naphthalene in 40% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:9]=[C:10](I)[C:3]=12.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:30]=1[NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([NH:44][C:45]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:54])=[C:29]([O:28][CH3:27])[CH:34]=3)[C:3]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cn2nc(I)c3c(N)ncnc32)CC1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1
Temperature: 85 °C
Yield: 29.8 %

Procedure:
A mixture of tert-butyl 4-[(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl]-4-hydroxy-1-piperidinecarboxylate (0.27 g, 0.00057 mol), benzyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.26 g, 0.00068 mol), tetrakis(triphenylphosphine)palladium (0.039 g, 0.000034 mol) and sodium carbonate (0.15 g, 0.0014 mol) in ethylene glycol dimethyl ether (7 mL) and water (3 mL) was heated at 85° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and ethylene glycol dimethyl ether was removed under the reduced pressure. The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with water and brine, and dried over magnesium sulfate. The organic layer was filtered through silica gel twice to remove the catalyst, and the solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl 4-{[4-amino-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.1 g, 0.00017 mol).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C([Li])CCC.[O:15]1[C:19]2([CH2:23][CH2:22][CH:21]([C:24]3[C:29]([F:30])=[CH:28][C:27](C(N4C=CN=C4)=O)=[C:26]([F:38])[CH:25]=3)[CH2:20]2)[O:18][CH2:17][CH2:16]1.Cl>CCCCCC.O1CCCC1.N1C=CC=CC=1C1C=CC=CN=1.O>[F:38][C:26]1[CH:25]=[C:24]([CH:21]2[CH2:22][CH2:23][C:19]3([O:15][CH2:16][CH2:17][O:18]3)[CH2:20]2)[C:29]([F:30])=[CH:28][C:27]=1[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(c1cc(F)c(C2CCC3(C2)OCCO3)cc1F)n1ccnc1
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)c1cc(F)c(C2CCC3(C2)OCCO3)cc1F
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
A solution of 16.4 g (0.2 mol) of monoethyl malonate, 0.1 g of 2,2'-bipyridyl and 175 ml of dry tetrahydrofuran was cooled to -35° under a dry nitrogen atmosphere and treated dropwise with 80 ml (0.2 mol) of a 2.5 M solution of n-butyl lithium in hexane. After the addition was complete, the reaction mixture was allowed to warm to -5° where it was treated dropwise with 80 ml (0.2 mol) of 2.5 M n-butyl lithium in hexane, titrating the final addition to a pale pink color which persisted for 5 minutes. The mixture was cooled to -78° and treated with a solution of 16.7 g (50 mmol) of 1-[[4-(1,4-dioxaspiro[4.4]non-7-yl)-2,5-difluorophenyl]carbonyl]-1H-imidazole in 100 ml of dry tetrahydrofuran. The suspension was stirred at -78° for 45 minutes, then allowed to warm to -35° and poured into a mixture of ice, water, and concentrated hydrochloric acid (17.0 ml-0.2 mole). The organic layer was separated, washed with water, 5% sodium bicarbonate, dilute hydrochloric acid, and water. After drying over magnesium sulfate, the solvent was removed in vacuo to give 13.8 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([OH:16])[CH3:15])[CH2:11][O:10]C1(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](I)[CH3:22].O.C1(C)C=CC(S(O)(=O)=[O:32])=CC=1>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][C@@H:12]([CH2:13][C@@H:14]([O:16][CH2:21][CH3:22])[CH3:15])[C:11]([OH:10])=[O:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCI
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@H](O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCO[C@@H](C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a cooled solution of (S)-4-((S)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester (prepared as in Example 94, 860 mg, 3.32 mmol) in dry tetrahydrofuran (15 mL) was added sodium hydride at 0° C. (60% in mineral oil, 292 mg). The suspension was warmed to room temperature and ethyl iodide (1.2 mL) was added. The mixture was stirred at room temperature for 20 h and extracted with diethyl ether and saturated sodium chloride solution. The organic layer was washed with saturated sodium chloride solution and dried over sodium sulfate. After the evaporation of solvents, an oily material was obtained (966 mg). This oily material was dissolved in a mixture of tetrahydrofuran (1 mL) and methanol (10 mL). To this solution was added p-toluene sulfonic acid monohydrate (32 mg). The mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was extracted with ethyl acetate and sodium bicarbonate solution. After the evaporation of solvents, the resulting oily compound (800 mg) was dissolved in a mixture of acetonitrile (17 mL) and phosphate buffer (12 mL, pH=7). Then 1-oxyl-2,2,6,6-tetramethylpiperidine (41 mg) and sodium chlorite solution (731 mg in 4.0 mL of water) were added. The solution was warmed to 35° C. and catalytic amount of diluted bleach (1 mL of 5.25% sodium hypochlorite solution diluted to 20 mL in water, 1.6 mL of the diluted solution was used) was added in 5 portions. The mixture was stirred for 2 h. Then second portion of sodium chlorite (750 mg in 4.0 mL of water) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. and adjusted to pH=9 with dilute sodium hydroxide solution. Sodium sulfite solution (2.7 vg in 30 mL of water) was added and the mixture was stirred for 20 min. The resulting solution was extracted with methyl t-butyl ether. Organic layer was discarded and the aqueous layer was acidified with 1N aqueous hydrochloric acid to a pH value of about 2.0. The mixture was extracted with methyl t-butyl ether three times and dried over sodium sulfate. The solvents were evaporated to afford (2S,4S)-2-t-butoxycarbonylamino-4-ethoxy-pentanoic acid (401 mg) as a thick oil: LR-ES-MS m/z calculated for C12H23NO5 [M] 261, observed 260 [M−H]; 1H NMR (300 MHz, CDCl3) δ ppm 1.18-1.29 (m, 6H), 1.446 (s, 9H), 1.88-2.00 (m, 2H), 3.36-3.51 (m, 1H), 3.66-3.89 (m, 2H), 4.24-4.37 (m, 1H), 5.89 (d, J=4.5 Hz, 1H), 10.23 (br. s., 1H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[F:6][C:7]([F:17])=[CH:8][CH2:9][CH2:10][S:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1.CN(C)C=O.O>C(Cl)(Cl)Cl>[Cl:4][C:14]1[S:13][C:12]([S:11][CH2:10][CH2:9][CH:8]=[C:7]([F:6])[F:17])=[N:16][CH:15]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: FC(F)=CCCSc1nccs1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(F)=CCCSc1ncc(Cl)s1
Temperature: 45 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
A solution of sulfuryl chloride (0.66 g) and chloroform (2.0 ml) was added dropwise over a period of 1.5 hour to a stirred mixture of 2-(4,4-difluorobut-3-enylthio)thiazole (1.01 g), and dimethylformamide (10 ml) maintained at 45° C. under a nitrogen atmosphere and the resultant mixture stirred for a further 2.5 hour. A further aliquot of sulfuryl chloride (0.07 g) dissolved in chloroform (1.0 ml) was then added over 15 minutes and the mixture stirred at 45° C. for 16 hours. A third portion of sulfuryl chloride (0.07 g) in chloroform (1.0 ml) was added over 30 minutes with the mixture being stirred for a further 2 hours, following which a final portion of the sulfuryl chloride (0.07 g) in chloroform (1.0 ml) was added and the mixture stirred for a final period of 30 minutes. After cooling the reaction mixture to the ambient temperature water (20 ml) was added and the mixture extracted with hexane (25 ml). The pH of the aqueous portion was adjusted to pH7 with 10% sodium hydroxide solution and extracted with hexane (25 ml). The combined hexane extracts were washed with water (2×20 ml) and then dried over anhydrous magnesium sulfate. Removal of the solvent by evaporation under reduced pressure yielded of 5-chloro-2-(4,4-difluorobut-3-enylthio)thiazole (1.13 g, 88%), identical to the product of Example 3.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22]CCCC(OC)=O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:50][O:51][C:52](=[O:65])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]CCO>N1C=CC=CC=1>[CH3:50][O:51][C:52](=[O:65])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:22][CH2:21][O:20][C:1]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCCCCCCCCCO
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)CCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 40 %

Procedure:
The synthesis procedure of 15a was followed. Trityl chloride (1412 mg, 5.1 mmol), 14c (583 mg, 2.5 mmol), and pyridine (10 mL) were used and the reaction was prolonged to 3 days. The filtration step was omitted, instead the crude material was purified by flash column chromatography (10% EtOAc in hexanes) yielding 477 mg (40%) of a pale yellow oil 15c. 1H-NMR (400 MHz, CDCl3, δH ppm): 7.44 (6H, m, p-Ar), 7.28 (6H, m, m-Ar), 7.21 (3H, m, o-Ar), 3.66 (3H, s, CO2CH3), 3.03 (2H, t, 3JH—H=6.6 Hz, H)—CH2), 2.29 (2H, t, 3JH—H=7.5 Hz, CH2CO2), 1.55-1.65 (4H, m, 2CH2), 1.10-1.39 (14H, m, 7CH2). HRMS (EI): m/z calcd 472.2977 (C32H40O3), found 472.2968 [M]+.
Reaction SMILES: CO[C:3]1[C:8]([O:9]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11](=[O:23])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)=[O:14]>I.CC(O)=O.O>[OH:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[O:14][C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[CH:12][C:11]2=[O:23]
Reactant: COc1ccc(C(=O)CC(=O)c2cccc(OC)c2OC)cc1
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(-c2ccc(O)cc2)oc2c(O)cccc12
Temperature: 110 °C
Yield: 51.9 %

Procedure:
1-(2,3-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (3.1 g, 9.86 mmol) was dissolved in mixture of HI (10 mL) and AcOH (10 mL) and heated at 110° C. for 4 days. The reaction mixture was cooled to rt, diluted with water and solids were filtered. The solid product was washed with water, dried and purified by column chromatography, using 30% EtOAc in dichloromethane to give 1.3 g (52%) of 8-hydroxy-2-(4-hydroxy-phenyl)-4H-chromen-4-one. MS (ES) m/z: 255.08 (M+1), and 154.15.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.[CH3:13]O>>[CH3:13][O:10][C:9](=[O:11])/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[CH:2][CH:1]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: CO
Product: COC(=O)/C=C/c1ccc(O)cc1

Procedure:
Similarly, the monolalkylated derivative of m- or p-coumaric acid can be produced by esterifying coumaric acid in MeOH to produce coumaric acid methyl ester, which is then reacted with an alkylating agent to produce a mono-alkylated intermediate. This intermediate is subsequently hydrolyzed under basic conditions to produce the corresponding alkylated derivative of m- or p-coumaric acid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[F:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=1[CH3:16].[Mg].[Cl-].[NH4+:19]>O1CCCC1.N1C=CC=CC=1>[F:8][C:9]1[CH:14]=[C:13]([CH:9]2[CH:14]=[CH:13][N:19]([C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH:11]=[CH:10]2)[CH:12]=[CH:11][C:10]=1[CH3:16]
Reactant: [NH4+]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(Cl)cc1F
Agent: [Cl-]
Agent: [Mg]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(C2C=CN(C(=O)C(C)(C)C)C=C2)cc1F
Temperature: -40 °C
Reaction time: 3 h

Procedure:
To a solution of 45 ml pyridine in 800 ml tetrahydrofuran (THF) was added dropwise 50 ml trimethylacetyl chloride. The mixture was stirred 3 hrs. at room temperature, 4.0 g cuprous iodide was added, and the mixture stirred for 1 hr. longer. The mixture was then cooled to -40° C. and a Grignard reagent prepared from 45 ml 2-fluoro-4-chlorotoluene and 10 g magnesium in 300 ml THF was added dropwise The reaction mixture was stirred overnight at room temperature, ammonium chloride solution added, and the product was extracted and isolated to give 90 g of an oil used directly in the next reaction.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:19]2=[S:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: S=C=Nc1ccccc1
Product: O=C1CN(c2ccccc2)C(=S)N1c1ccccc1
Temperature: 150 °C
Yield: 37.3 %

Procedure:
A mixture of N-phenyl glycine (7.5 gram, 0.05 mole) and phenylisothiocyanate (8 grams, 0.06 mole) was heated at 150° C. for 3 hours with stirring. The reaction mixture solidified, was ground up, and crystallized from toluene, twice, to produce 5 grams (37% yield) of the above-identified product having a melting point of about 214° C.