Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:18]([O:22][C@@H:23]([C:29]1[C:44]([CH3:45])=[CH:43][C:32]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][N:39]=[C:38](Cl)[CH:37]=3)[S:35][C:31]=2[C:30]=1[C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[C:18]([O:22][C@@H:23]([C:29]1[C:44]([CH3:45])=[CH:43][C:32]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][N:39]=[C:38]([C:8]4[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=4)[CH:37]=3)[S:35][C:31]=2[C:30]=1[C:46]1[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:19])([CH3:20])[CH3:21]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: COc1ncccc1B1OC(C)(C)C(C)(C)O1
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+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cccnc4OC)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (13 mg, 0.0878 mmol), (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (31 mg, 0585 mmol) and 2M potassium carbonate solution (88 μL, 0.178 mmol) in dioxane (0.5 mL) was sparged with nitrogen for 10 minutes. Pd(PPh3)4 (6.9 mg, 0.0059 mmol) was added and reaction mixture was heated in microwave at 100° C. for 1 h . Reaction mixture was diluted with ethyl acetate, washed with brine. The aqueous layer was back extracted with ethyl acetate and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 40% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C33H33ClN3O4S: 602.1 (M+H+); Found: 602.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[N:14][N:15]([CH2:16][C@H:17](O)[CH3:18])[C:9]=3[C:7]=2[N:8]=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:36]=[N+:37]=[N-:38].[Na+]>O1CCCC1>[N:36]([C@@H:17]([CH3:18])[CH2:16][N:15]1[C:9]2[C:7]3[N:8]=[C:4]([CH2:3][O:2][CH3:1])[O:5][C:6]=3[CH:12]=[CH:11][C:10]=2[CH:13]=[N:14]1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: COCc1nc2c(ccc3cnn(C[C@@H](C)O)c32)o1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCc1nc2c(ccc3cnn(C[C@H](C)N=[N+]=[N-])c32)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
A solution of the product from Step B (0.20 g, 0.77 mmol in tetrahydrofuran (10 mL) was cooled (ice bath), triethylamine (0.43 mL, 3.06 mmol) and methanesulfonic anhydride (0.24 g, 1.38 mmol) were added and the mixture was stirred at 0° C. for 20 minutes. Sodium azide (0.50 g, 7.66 mmol) was added to the reaction mixture, which was evaporated to a residue that was dissolved in dimethyl sulfoxide (10 mL) and heated at 90–100° C. for 2 hours. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (magnesium sulfate), filtered, and evaporated to give a residue which was purified by chromatography (silica gel, hexane/ethyl acetate) to give a yellow oil (80 mg, 37%): LC/MS m/z 287.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(Cl)(=O)C(Cl)=O.O[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[C:27]([O:33][CH3:34])[CH:26]=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[C:27]([O:33][CH3:34])[CH:26]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COc1cc(O)ccc1C=O
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)c(OC)c2)cc1
Reaction time: 2 h
Yield: 15.3 %

Procedure:
Prepared using General Procedure 2: To a stirred solution of 4-(heptyloxy)benzoic acid (1.41 g, 5.98 mmol) in DCM (10 mL) was added DMF (3 drops) and oxalyl chloride (0.589 mL, 6.87 mmol). After stirring for 2 h, the reaction mixture was added to a solution of 4-hydroxy-2-methoxybenzaldehyde (1 g, 6.57 mmol) and TEA (1.25 mL, 8.96 mmol) in DCM (10 mL) and stirred for 18 h. The reaction mixture was diluted with DCM (100 mL) and was washed with NaHCO3 (100 mL). The organic layer was pre-absorbed onto silica gel and purified by chromatography (EA/isohexanes) to afford 340 mg (15%) 4-formyl-3-methoxyphenyl 4-(heptyloxy)benzoate INT-25 as a white solid. LCMS-ESI (m/z) calculated for C22H26O5: 370; found 371 [M+H]+, tR=3.17 min (Method 10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[N+:12]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:7]([CH:8]=[O:9])[C:6]=1[OH:11])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(O)c(C=O)c1
Solvent: CC(=O)O
Product: COc1cc(C=O)c(O)c([N+](=O)[O-])c1
Temperature: 15 °C
Reaction time: 7 h
Yield: 40.5 %

Procedure:
First, 8.0 g (52.6 mmol) of 5-methoxysalicylaldehyde 5 was dissolved in 50 ml of acetic acid. Then, a mixed solution of 2.5 ml (59.7 mmol) of fuming nitric acid (99%, specific gravity 1.52) and 8 ml of acetic acid was added dropwise into the above mixture over a period of 1 hour while maintaining the temperature of the reaction mixture at approximately 15° C. with ice-cold water and strongly agitating the reaction mixture. Agitation was further continued for 7 hours. The precipitate formed was filtered, after which the precipitate was recrystallized from 500 ml of ethanol, thereby obtaining 4.2 g (21.3 mmol, yield 40.5%) of 3-nitro-5-methoxysalicylaldehyde 6 in the form of yellow needle crystals. This reaction can be expressed by the following chemical equation: ##STR7##
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH:16]([C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:32][CH3:33])=[C:26]([C:29](=O)[CH3:30])[CH:27]=2)[O:22][C:21]([CH3:35])([CH3:34])[CH:20]=1)([CH3:18])[CH3:17]>>[F:7]/[C:6](=[C:29](/[C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:32][CH3:33])[O:22][C:21]([CH3:35])([CH3:34])[CH:20]=[C:19]2[CH:16]([CH3:17])[CH3:18])\[CH3:30])/[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: COc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.44 mL, 2.18 mmol) and 1-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 54, 199 mg, 0.73 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[N:5]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH2:3]1.[Li+].[OH-].CC1(C)C2C(=CC=C(C#CC3C=CC(C(O)=O)=CC=3)C=2)NC(OC(C)C)C1>C1COCC1.CCO>[CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)[CH:10]=2)[N:5]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:4](=[O:32])[CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(=O)N3Cc2ccccc2)cc1
Agent: CC(C)OC1CC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc2N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(Cc2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
163 mg (0.39 mmol) of ethyl 4-[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-1-benzyl-6-quinolinyl)ethynyl]benzoate (Compound 37) in 2 ml of THF, 2 ml of EtOH, and 2 ml of 1N LiOH were reacted substantially in accordance with the procedure used for the preparation of 4-[(4,4-dimethyl-2-iso-propoxy-3,4-dihydro-6-quinolinyl)ethynyl]benzoic acid (Compound 11) to give the title compound as a white flaky solid.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][NH:5][C:6]1[N:11]=[C:10]([F:12])[C:9]([CH:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)O)=[CH:8][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:13][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[C:10]([F:12])[N:11]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(NCc3ccccc3Cl)nc2F)c2cccnc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Fc1nc(NCc2ccccc2Cl)ccc1Cc1c[nH]c2ncccc12

Procedure:
To [6-(2-chloro-benzylamino)-2-fluoro-pyridin-3-yl]-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (606, 180.0 mg, 0.33 mmol) in acetonitrile (15.0 mL) were added triethylsilane (1.00 mL, 6.26 mmol) and trifluoroacetic acid (0.50 mL, 6.50 mmol). The reaction was heated to reflux for 2 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-0335, 24.9 mg, 19.4%). MS (ESI) [M+H+]+=367.0.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[C:5]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:4][CH:3]=1.C(Cl)Cl.[S:22]1[C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2.Cl>N1C=CC=CC=1>[F:1][C:2]1[C:7]([NH:8][C:27]([C:26]2[S:22][C:23]3[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=3[CH:25]=2)=[O:28])=[C:6]([CH3:9])[C:5]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1N
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1NC(=O)c1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A 200-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with 6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.45 g, 13.7 mmol), methylene chloride (85 mL), and pyridine (3 mL) and cooled to 0° C. To the resulting solution, benzo[b]thiophene-2-carbonyl chloride (2.7 g, 13.7 mmol) was. The reaction was warmed to room temperature and stirred for 1 h. After this time, aqueous HCl (1M, 50 mL) was added to the reaction. The separated aqueous layer was extracted with dichloromethane (2×25 mL). The combined organics were washed with aqueous HCl (1M, 2×50 mL), water (1×50 mL) and brine (50 mL), dried over sodium sulfate; filtered and concentrated under reduced pressure. The resulting crude white solid (5.6 g, 99% yield) was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:8][CH3:9])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ccc(OCCCCCCCC)cc2)cc1
Yield: 170 %

Procedure:
56 g of 4,4′-dihydroxybiphenyl was dissolved in 500 g ethanol. To this solution was added 40 g of potassium hydroxide, and the mixture was reacted. Next, this solution was heated, and 128 g of 1-bromooctane was dropped at 70° C., and subsequently, the mixture was reacted at 70° C. for 7 hours. The reaction was performed under a nitrogen atmosphere. After the reaction, this solution was cooled, and the generated precipitate was filtrated to recover. Next, this precipitate was washed with 500 ml of methanol, then, washed with a mixed solvent of methanol 500 ml/ion exchanged water 300 ml, and further, washed with a mixed solvent of acetone 500 ml/ion exchanged water 300 ml. This precipitate was dried under reduced pressure, to obtain 105 g of 4,4′-dioctyloxybiphenyl represented by the following structural formula:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:22])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: COc1ccc(N)cc1OC
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
A mixture of 5,7-dichloro-thiazolo[5,4-d]pyrimidine (0.925 g, 4.49 mmol), 3,4-dimethoxy-phenylamine (0.89 g, 5.83 mmol) and DIEA (0.86 g, 6.73 mmol) in 12 mL of DMSO was stirred at room temperature for two hours. The mixture was poured into 50 mL of water and filtered; the solid obtained was washed with water (50 mL) to give a crude product. It was purified by silica gel chromatography (silica gel 200-300 mesh, ethyl acetate as eluent) to give (5-chloro-thiazolo[5,4-d]pyrimidin-7-yl)-(3,4-dimethoxy-phenyl)-amine (0.92 g, 63.8%) as a solid. LC-MS: 323.1 [M+H]+, tR=1.56 min.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:25]([Cu])#[N:26].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[C:25]([C:5]1[C:4]2[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:15][O:16][C:3]=2[C:2]([OH:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)#[N:26]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccc(OC)cc3)noc2c1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(-c3ccc(OC)cc3)noc2c1O
Temperature: 110 °C
Yield: 58.9 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-(4-methoxyphenyl)isoxazolo[4,5-c]pyridine-6-carboxylate (390 mg, 0.89 mmol) and CuCN (238 mg, 2.66 mmol) were added to 6 mL of N-methyl-2-pyrrolidone. The resulting suspension was heated in an oil bath (T=110° C.) for 1 h. The reaction mixture was cooled slightly and poured into a vigorously stirring mixture of ammonium hydroxide (100 mL, 30% aqueous solution) and EtOAc (100 mL). The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-100% EtOAc/hexanes) to afford 178 mg of the title compound. MS: (+) m/z 340.42 (M+1).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:10]>>[Cl:10][C:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=Cc1ccccc1
Reactant: Cl
Product: ON=C(Cl)c1ccccc1

Procedure:
60.5 g (0.5 mol) of benzaldoxime was suspended in 390 ml of 8N hydrochloric acid and chlorine gas was bubbled into the suspension while stirring and maintaining the reaction temperature at from 5° to 15°C. The oxime immediately showed a green color upon reaction with chlorine and, after allowing the reaction mixture to stand, pale yellow crystals of α-chlorobenzaldoxime precipitated. Filtration of the reaction mixture yielded 66 g of crystals having a melting point of 45°-47°C. Yield, about 84%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH2:22]C(O)=O)[CH:14]=1.Cl>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:20][CH:21]=1)[C:17](=[O:18])[O:10][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])=[CH:22]2
Reactant: COC(=O)CCCCC(=O)O
Reactant: O=C(O)Cc1cc(Br)ccc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CCCCc1cc2cc(Br)ccc2c(=O)o1
Temperature: 25 °C
Yield: 11.5 %

Procedure:
To a stirred mixture of adipic acid monomethyl ester (9.27 g, 57.9 mmol, 1.50 equiv.) in THF (50 mL) was added N,N′-carbonyldiimidazole (9.39 g, 57.9 mmol, 1.50 equiv.) and the mixture was stirred at room temperature. After stirring for 30 min, the reaction mixture was cooled to 0° C. followed by dropwise addition of 4-bromo-2-(carboxymethyl)benzoic acid (10.0 g, 38.6 mmol) in THF (25 mL). The reaction was stirred gradually from 0° C. to room temperature for 48 h. Upon completion of the reaction, 0.5 N HCl (25 mL) solution was added and extracted with EtOAc (2×25 mL). The organic layer was washed with aqueous sat. NaHCO3, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-15% EtOAc/hexanes to give 1.5 g of methyl 5-(6-bromo-1-oxo-1H-isochromen-3-yl)pentanoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][N:14]3[C:19](=[O:28])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)N[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]1(=[O:35])[O:34][C:32](=[O:33])[CH2:31][CH2:30]1.CN(C=[O:40])C>>[O:21]([CH2:20][C:19]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[C:10]1[O:40][N:12]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:29](=[O:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:7]=[CH:6][CH:5]=2)[N:9]=1)=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1cccc(-c2n[nH]c(C3CCCCN3C(=O)COc3ccccc3)n2)c1
Reactant: CN(C)C=O
Product: O=C(O)CCC(=O)Nc1cccc(-c2noc(C3CCCCN3C(=O)COc3ccccc3)n2)c1
Reaction time: 8 h

Procedure:
0.1 mmol of 1-{2-[5-(3-Amino-phenyl)-2H-[1,2,4]triazol-3-yl]-piperidin-1-yl}-2-phenoxy-ethanone were dissolved in 1 ml DMF and 1 eq of succinic anhydride added. The reaction was stirred overnight and the intermediate (N-(3-{5-[1-(2-Phenoxy-acetyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-phenyl)-succinamic acid) isolated via preparative HPLC. The isolated material was redissolved in DMF and 1 eq of HATU was added. The reaction mixture was heated to 120° C. using microwave heating. The product was isolated via preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:15]=1)[C:10]([O-:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:37](=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:16][CH:15]=1)[C:10]([O:12][CH3:37])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C(=O)[O-]
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C

Procedure:
Nitrogen is passed through a suspension of (S)-2-(t-butoxycarbonylamino)-3-[4-(trifluoromethylsulfonyloxy)-phenyl]-propionate (1.75 mmol), phenylboronic acid (3.5 mmol), anhydrous potassium carbonate (2.63 mmol) and toluene (17 mL) for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) is added, and the mixture is heated at 85°-90° for 3 hours. The reaction mixture is cooled to 25°, diluted with ethyl acetate (17 mL) and washed sequentially with saturated sodium bicarbonate (1×20 mL), water (1×20 mL), 10% citric acid (1×20 mL), water (1×20 mL) and saturated sodium chloride solution (1×20 mL). The organic phase is concentrated, and the residue is purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to yield methyl (S)-2-(t-butoxycarbonylamino)-3-(4-biphenylyl)-propionate which can also be called N-(S)-t-butoxycarbonyl-(4-biphenyl)-alanine methyl ester, m.p. 83°-85°; [α]20D +54.81° (c=1, CHCl3).
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=1.[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:15][C:11]3[C:10]([CH3:16])=[CH:9][C:8]([NH2:7])=[C:13]([CH3:14])[CH:12]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1cc(O)c(C)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(N)cc3C)ccnc2cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
Sodium hydride (60 wt %, 1.17 g) was added to dimethyl sulfoxide (25 ml), and the mixture was stirred at 60° C. for 30 min and was then cooled to room temperature. Next, 4-amino-2,5-dimethylphenol (4.00 g) was added thereto, and the mixture was stirred at room temperature for 10 min. 7-(Benzyloxy)-4-chloro-6-methoxyquinoline (4.36 g) was then added thereto. The mixture was stirred for 22 hr before water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension. The precipitated crystal was collected by suction filtration to give 3.04 g (yield 52%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([CH2:25]O)[CH:10]=2)=[CH:5][CH:4]=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([CH2:25][N:33]3[C:29](=[O:39])[C:30]4[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:32]3=[O:34])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cnc(CO)cc2OCc2ccc(OC)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2cnc(CN3C(=O)c4ccccc4C3=O)cc2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of (4,5-bis(4-methoxybenzyloxy)pyridin-2-yl)methanol (Intermediate 63, 1.5 g, 3.93 mmol), phthalimide (0.579 g, 3.93 mmol) and triphenylphosphine (1.028 g, 3.93 mmol) in THF (15 mL) at room temperature was added diisopropyl azodicarboxylate (2.091 mL, 10.62 mmol). The reaction was stirred at room temperature overnight then concentrated onto silica gel. Silica gel chromatography (0%-70% ethyl acetate) afforded the title compound as a light brown solid (1.1 g, 55%).