Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C2C=C(C([N:22]3C[CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=O)OC=2C2C=CC(F)=CC=2)C=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42](O)=[O:43])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42]([N:22]3[CH2:23][C:24](=[O:28])[NH:25][CH2:26]3)=[O:43])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)cc3)o2)CCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)c(-c3ccc(F)c(Cl)c3)o2)CN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 6 starting with the compound from Example 21A and the compound from Example 35A. 1.1 equivalents of the compound from Example 35A are used. 203 mg (60% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].Cl[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:8]=1.O>CN(C)C=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:9]2[N:8]=[C:7]([O:2][CH3:1])[CH:12]=[C:11]([CH3:13])[N:10]=2)=[CH:16][CH:17]=1
Reactant: CO
Reactant: Cc1cc(Cl)nc(Nc2ccc(Cl)cc2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)nc(Nc2ccc(Cl)cc2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A 28% methanol solution of sodium methylate (1.5 g) was added to a solution of 1.5 g of 4-chloro-2-(4-chloroanilino)-6-methylpyrimidine in 50 ml of dimethylformamide and the mixture was stirred for 2 hours at 70° C. After completion of the reaction, the reaction mixture was poured into water, extracted with 150 ml of toluene, washed with water, dried over Glauber's salt, and the toluene layer was concentrated by evaporation. The residue was purified by silica gel column chromatography to obtain 1.3 g (yield: 88%) of 2-(4-chloroanilino)-4-methoxy-6-methylpyrimidine having a melting point of 101°-103° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=O)=[CH:24][CH:23]=1.[OH-].[Na+]>>[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([CH2:26][NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:31][CH:30]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(NCc3ccc(Cl)cc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4-chloro-N-(4-hydroxyphenyl)benzamide from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H26ClNO6 [M+H]+: 484.
Reaction SMILES: C(OC[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][N:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[CH2:22][C:23]#[CH:24])[CH:16]=2)[N:11]=[CH:10]1)(=O)C(C)(C)C.[NH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[O:19]=[C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][N:21]([C:25]3[CH:26]=[CH:27][C:28]([C:29]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:30])=[CH:32][CH:33]=3)[CH2:22][C:23]#[CH:24])[CH:16]=2)[N:11]=[CH:10][NH:9]1
Reactant: NCc1cccnc1
Reactant: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)O)cc1
Product: C#CCN(Cc1ccc2nc[nH]c(=O)c2c1)c1ccc(C(=O)NCc2cccnc2)cc1
Yield: 61 %

Procedure:
Using the procedure described in Example 10, p-[N-(3,4-dihydro-3-pivaloyloxymethyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzoic acid was reacted with 3-aminomethylpyridine to give p-[N-(3,4-dihydro-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide (containing 4.5 equivalents of water, 61%), m.p. 137°-139° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:18]([O:17][C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCNCC1
Yield: 90.7 %

Procedure:
A solution of 1-benzyl-4-tertbutyloxycarbonylaminopiperidine 5 (7.95 g; 27.4 mmol) in 120 ml of MeOH is poured into a hydrogenation reactor. 10% Pd/c-based catalyst is added (1.46 g; 1.38 mmol) and the mixture is subjected to a hydrogen pressure of 3.5 bars (50 psi) for 24 hours in a Parr type shaker. After filtration on celite and washing with methanol, the medium is concentrated in order to produce 4.98 g (Yield=91%) of product in the form of white crystals.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>N1C=CC=CC=1>[Si:21]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
To a stirred solution of 2′-deoxycytidine 47 (1.00 g; 4.40 mmol) in dry pyridine (37 mL), TBDMSCl (814 mg; 5.39 mmol) was added. The mixture was stirred at room temperature for 20 h. After evaporation, the residue was purified by flash column chromatography using CH3OH—CH2Cl2 (1:10) as the eluent to afford 48 as white solid (1.26 g; 84% yield): 1H NMR (400 MHz, CH3OD) δ 8.03 (d, J=7.5 Hz, 1H, 6-H), 6.23 (t, J=6.3 Hz, 1H, 1′-H), 5.86 (d, J=7.5 Hz, 1H, 5-H), 4.35 (m, 1H, 3′-H), 3.91-3.98 (m, 2H, 4′-H and one of 5′-H), 3.85 (dd. J=2.5, 11.3 Hz, 1H, one of 5′-H), 2.36-2.43 (ddd, J=4.1, 6.1, 13.5 Hz, 1H, one of 2′-H), 2.05-2.13 (m, 1H, one of 2′-H), 0.94 (s, 9H, C(CH3)3), 0.14 (s, 3H, one of SiCH3), 0.13 (s, 3H, one of SiCH3); 13C NMR (100 MHz, CD3OD) δ 167.1, 157.6, 142.1, 95.6, 88.7, 87.4, 71.7, 64.1, 42.7, 26.5, 19.3, −5.2, −5.3; HRMS (FAB+) calcd for C15H28O4N3Si (M+H+): 342.1849. found: 342.1844.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:33][C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([OH:29])=[O:28])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:11]=1.CN(C=O)C>C1COCC1>[Br:8][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=[O:28])[CH:23]=2)[O:33][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
NBS (125 mg, 0.702 mmol) was added to a stirred suspension of 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (215 mg, 0.645 mmol) in THF (5 mL)/DMF (1 mL). The solids dissolved and the reaction was stirred at room temperature for 30 min, then quenched with 10% Na2S2O3, and acidified with 1 N HCl. The solvent was evaporated and the material was diluted with water, filtered and dried to afford a mixture of starting material and product. The material was resubjected to the reaction conditions (80 mg of NBS in 3 mL THF/0.5 mL DMF). After 3 h, the reaction was quenched by the addition of 10% Na2S2O3, and the solution was acidified with 0.1 N HCl. The volatiles were removed and the resulting off-white precipitate was collected by filtration, rinsed with water and Et2O, and air-dried to afford the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (140 mg, 53% yield) as an off-white powder consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (1H, d, J=2.26 Hz), 8.27-8.33 (2H, m), 8.19-8.26 (2H, m), 8.05-8.12 (1H, m), 8.03 (1H, d, J=7.78 Hz), 7.68 (1H, t, J=7.78 Hz), 7.45-7.55 (2H, m). LC-MS retention time: 1.20 min; m/z (MH+): 412, 414. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[NH2:11])=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[S:24](Cl)(Cl)=[O:25]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[N:9]=[C:10]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[NH:11][S:24]2=[O:25])=[CH:6][CH:7]=1
Reactant: NC(=NNc1ccc(Br)cc1)c1c(F)cccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=S1NC(c2c(F)cccc2Cl)=NN1c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the procedure described in step-4 of Intermediate-1 using N′-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbo hydrazonamide (step-3 of Intermediate-1, 0.100 g, 0.292 mmol), CHCl3 (10 mL), pyridine (2.0 mL) and thionyl chloride (1.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 0.5% MeOH:DCM to afford 0.050 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.45 (t, J=6.9 Hz, 3H), 7.51-7.68 (m, 4H), 12.05 (br s, 1H); MS (m/z): 388.02 my.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[CH3:12][C:13]([CH3:21])(O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CS(O)(=O)=O>>[OH:11][C:4]1[C:5]([O:9][CH3:10])=[CH:6][C:7]([C:13]([CH3:21])([CH3:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(OC)c1O
Reactant: CCCCCCC(C)(C)O
Agent: CS(=O)(=O)O
Product: CCCCCCC(C)(C)c1cc(OC)c(O)c(OC)c1

Procedure:
The process of claim 1, said process comprising reacting 2,6-dimethoxyphenol with 1,1-dimethyl-1-heptanol in the presence of methanesulfonic acid to provide 1-hydroxy-2,6-dimethoxy-4-(1,1-dimethylheptyl)benzene; reacting said 1-hydroxy-2,6-dimethoxy-4-(1,1-dimethylheptyl)benzene with a halogenated disubstituted phosphite to provide a 2,6-dimethoxy-4-(1,1-dimethylheptyl)phenyl disubstituted phosphate; reacting said 2,6-dimethoxy-4-(1,1-dimethylheptyl)phenyl disubstituted phosphate with an alkali metal to afford 1-(1,1-dimethylheptyl)-3,5-dimethoxybenzene; reacting said 1-(1,1-dimethylheptyl)-3,5-dimethoxybenzene with boron tribromide to provide 5-(1,1-dimethylheptyl)-resorcinol, and recovering said 5-(1,1-dimethylheptyl)-resorcinol therefrom.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:16][C:17]1[CH:22]=[C:21]([C:23]2[O:24][C:25]3[N:26]=[C:27]([S:36][CH3:37])[N:28]=[C:29]([O:32][CH2:33][CH2:34][CH3:35])[C:30]=3[N:31]=2)[CH:20]=[C:19]([CH3:38])[C:18]=1[OH:39].O>CN(C)C=O>[CH3:16][C:17]1[CH:22]=[C:21]([C:23]2[O:24][C:25]3[N:26]=[C:27]([S:36][CH3:37])[N:28]=[C:29]([O:32][CH2:33][CH2:34][CH3:35])[C:30]=3[N:31]=2)[CH:20]=[C:19]([CH3:38])[C:18]=1[O:39][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCOc1nc(SC)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1nc(SC)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12

Procedure:
3.20 g of potassium carbonate and then 0.93 ml of tert-butyl bromoacetate were added to a solution of 2.00 g of 2,6-dimethyl-4-(5-methylsulfanyl-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl)phenol in 20 ml of N,N-dimethylformamide. The mixture was reacted at 60° C. for 1 h and then allowed to cool and poured into water. The precipitate obtained was filtered off with suction and dried under reduced pressure. This gave 2.45 g of the title compound.
Reaction SMILES: O1CCOC[CH2:2]1.Cl.[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([F:19])[CH:11]=1)#[N:9]>CO>[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH3:2])=[O:15])=[C:12]([F:19])[CH:11]=1)#[N:9]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A 4 M hydrochloric acid dioxane solution (70.0 mL, 280 mmol) was added to a methanol (70.0 mL) solution of 4-cyano-2-fluorobenzoic acid (10.0 g, 60.6 mmol), and the mixture was stirred for one hour at 70° C. The reaction mixture was cooled to room temperature, and then the solvent was distilled off under reduced pressure. Thus, a crude product of the title compound was obtained.
Reaction SMILES: C([O:5][C:6](=[O:54])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:53])[C@H:13]([CH2:41][CH2:42][CH2:43][CH2:44][NH:45]C(OC(C)(C)C)=O)[NH:14][CH:15]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23](C(OCC2C=CC=CC=2)=O)[CH2:22][CH2:21]1)(C)(C)C.Br.C(O)(=O)C.C(OCC)C>C(O)(=O)C>[CH2:39]([O:38][C:36]([CH:15]([NH:14][C@H:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:54])=[O:5])=[O:53])[CH2:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:37])[CH3:40]
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)C(CCCCC1CCNCC1)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h
Yield: 113 %

Procedure:
In 1 ml of acetic acid is dissovled 0.43 g of N-[Nα -[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-Nε -tert-butoxycarbonyl-L-lysyl]-L-proline tert-butyl ester, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 1 hour. 50 ml of ethyl ether is added to the reaction solution, followed by shaking, and the supernatant layer is removed by decantation. The precipitate is collected and dried under reduced pressure to give 0.3 g of N-[Nα -[1-ethoxycarbonyl-5-(4-piperidyl)pentyl]-L-lysyl]-L-proline.trihydrobromide as a colorless powder.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[O:12][C:11]2[CH:13]=[C:14]([CH:17]([OH:25])[CH2:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[CH:15]=[CH:16][C:10]=2[O:9]1.[OH-].[Li+].Cl>O.C1COCC1>[OH:25][CH:17]([C:14]1[CH:15]=[CH:16][C:10]2[O:9][CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])[O:12][C:11]=2[CH:13]=1)[CH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CCCCC1Oc2ccc(C(O)CCc3cccs3)cc2O1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCC1Oc2ccc(C(O)CCc3cccs3)cc2O1
Temperature: 23 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A mixture of (±)-methyl-5-[[6-(1-hydroxy-3-(2-thienyl)propyl-1,3-benzodioxolyl]pentanoate (Compound F, 35 mg, 0.093 mmol) and lithium hydroxide (0.37 mL of a 0.5N solution in H2O, 0.186 mmol) in THF (0.74 mL) was stirred at 23° C. for 16 hours. The mixture was acidified with 1N HCl and extracted with EtOAc. The organic portion was dried (MgSO4) filtered and concentrated in vacuo. Flash column chromatography (silica gel, 100% EtOAc) afforded 33.3 mg (99%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 12.0 (brs, 1H), 7.14 (d, J=5.1 Hz, 1H), 7.00 (s, 1H), 6.93 (dd, J=3.3, 5.1 Hz, 1H), 6.83 (d, J=3.3 Hz, 1H), 6.59 (s, 1H), 5.91 (s, 2H), 4.87-4.92 (m, 1H), 2.97 (t, J=5.4 Hz, 2H), 2.43-2.47 (m, 2H), 2.32 (t, J=6.9 Hz, 2H), 1.86-2.18 (m, 2H), 1.44-1.64 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.Cl>C(Cl)Cl>[CH3:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH2:10][C:11]([N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)=[O:13])[CH3:15]
Reactant: C1COCCN1
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CC(=O)N1CCOCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
3-(tert-Butoxycarbonylamino)-3-methylbutanoic acid (2.7 g, 12.4 mmol), HBTU (CAN 94790-37-1, 6.1 g, 16.1 mmol) and triethylamine (CAN 121-44-8, 2.5 g, 24.8 mmol) was added to a solution of morpholine (CAN 110-91-8, 2.2 g, 24.8 mmol) in methylene chloride (50 mL). The mixture was stirred overnight at room temperature. Aqueous hydrochloride (1 N, 50 mL) was added, and the mixture extracted with methylene chloride. The organic extracts were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (silica gel, 50 g, eluting with 30% ethyl acetate in petroleum ether) to give the product (2.1 g, 59%); MS (EI): m/e 287.1 [M+H]+.
Reaction SMILES: [I-].[Na+].[C:3](=[O:6])(O)[O-].[Na+].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([C:24]2[O:25][CH:26]=[C:27](CCl)[N:28]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CS(C)=O.[Cl-].[Na+].O>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([C:24]2[O:25][CH:26]=[C:27]([CH:3]=[O:6])[N:28]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2nc(CCl)co2)cc1OCc1ccccc1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-c2nc(C=O)co2)cc1OCc1ccccc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
A 6.81 g quantity of sodium iodide and 5.09 g of sodium bicarbonate were added to a suspension of 10 g of 2-(3-benzyloxy-4-methoxyphenyl)-4-chloromethyloxazole obtained in Reference Example 5 in 60 ml of dimethylsulfoxide. The mixture was heated at 120° C. with stirring for 30 minutes. After the reaction mixture was allowed to cool, saturated brine was added and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 2.98 g of yellow oily 2-(3-benzyloxy-4-methoxyphenyl)oxazole-4-carbaldehyde.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[F:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][NH2:17])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: NN
Reactant: COc1nc2cc(F)ccc2nc1Cl
Solvent: O
Solvent: CCO
Product: COc1nc2cc(F)ccc2nc1NN
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution consisting of 47 g. (0.22 mole) of 2-chloro-6-fluoro-3-methoxyquinoxaline dissolved in 1000 ml. of ethanol, there were added 27.6 g. (0.55 mole) of hydrazine hydrate (26.8 ml.). The resulting mixture was stirred at room temperature overnight (i.e., at ca. 20° C. for approximately 16 hours). An additional amount of hydrazine hydrate (9.0 ml.) was then added and the final reaction mixture was allowed to stir at room temperature for a period of four hours. At this point, the precipitate was filtered and washed with ethanol to ultimately afford 43.3 g. (94%) of pure 6-fluoro-2-hydrazino-3-methoxyquinoxaline, m.p. 170°-174° C. (decomp.).
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([CH3:7])[O:5][C:4](=[O:8])[C@@H:3]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:7][C@@H:6]1[O:5][C:4](=[O:8])[C@H:3]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:2]1[O:1][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33]
Reactant: C[C@@H]1OC(=O)[C@H](CCc2ccccc2)[C@H]1O
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](O[C@H]1[C@H](C)OC(=O)[C@@H]1CCc1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of (3R,4R,5S)-4-hydroxy-5-methyl-3-phenethyldihydrofuran-2(3H)-one (800 mg, 3.63 mmol) in CH2Cl2 (20 mL) were added 2,6-dimethylpyridine (592 μl, 5.08 mmol) and triisopropylsilyl trifluoromethanesulfonate (1171 μl, 4.36 mmol) at 0° C., and the mixture was warmed to room temperature while stirring overnight. The reaction mixture was poured onto 50 mL saturated sodium bicarbonate solution and mixed thoroughly. The phases were separated, and the aqueous extracted with CH2Cl2 (2×25 mL). The combined CH2Cl2 extracts were dried and concentrated to a colorless oil which was purified by flash chromatography (SiO2, 0→50% EtOAc/hexanes) to give (3R,4R,5S)-5-methyl-3-phenethyl-4-((triisopropylsilyl)oxy)dihydro-furan-2(3H)-one (809 mg, 53%): 1H NMR (400 MHz, CDCl3) δ 7.33-7.25 (m, 2H), 7.25-7.17 (m, 3H), 3.98 (dd, J=5.9, 4.8 Hz, 1H), 4.34-4.24 (m, 1H), 2.99-2.88 (m, 1H), 2.88-2.76 (m, 1H), 2.61-2.51 (m, 1H), 2.04-1.94 (m, 2H), 1.43 (d, J=6.5 Hz, 3H), 1.09-0.99 (m, 21H); 13C NMR (101 MHz, CDCl3) δ 176.64, 140.98, 128.57, 128.51, 126.16, 82.10, 79.45, 49.17, 32.96, 31.14, 19.10, 18.00, 17.71; ESIMS m/z 378 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:19])[N:3]=1)=[C:11]([F:16])[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=3.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:16][C:11]1[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=[C:7]2[C:12]=1[N:13]=[C:14]([CH3:15])[C:5]1[N:6]2[C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH3:20])=[N:3][C:4]=1[CH3:19]
Reactant: COc1cc(F)c2nc(C)c3c(C)nc(Br)n3c2c1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(F)c2nc(C)c3c(C)nc(-c4ccccc4C)n3c2c1
Yield: 29.8 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 6A (65 mg, 0.2 mmol), 2-methylphenylboronic acid (40 mg, 0.3 mmol), K2CO3 (82 mg, 0.6 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) provided the coupling product as an off-white powder (20 mg, 30% yield). EIMS 336.1 [M+H]+.