Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]3)[CH:13]=[CH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26].CO>O1CCOCC1>[C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:17][C:18](=[O:21])[C:19](=[CH:24][N:25]([CH3:27])[CH3:26])[CH2:20]3)[CH:13]=[CH:12][N:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCN(c2ccnc(C(=O)Nc3ccccc3)c2)C1
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)C=C1CN(c2ccnc(C(=O)Nc3ccccc3)c2)CC1=O
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A suspension of 4-(3-oxopyrrolidin-1-yl)-pyridine-2-carboxylic acid phenylamide (130 mg, 0.46 mmol) and dimethylformamide dimethylacetal (0.12 mL, 0.90 mmol) in 1,4-dioxane (2 ml) was heated under nitrogen at 100° C. for 4.5 h. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (25 g) eluted with dichlromethane:methanol 19:1 and gave the title compound (95 mg, 0.28 mmol, yield 61%).
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH:6]=[CH:5]1>C1C=CC=CC=1.C(O)C>[CH3:1][NH:2][CH:6]1[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4](=[O:3])[CH2:5]1
Reactant: CN
Reactant: O=C1C=CCCc2ccccc21
Solvent: CCO
Solvent: c1ccccc1
Product: CNC1CCc2ccccc2C(=O)C1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
A solution of 22.7 g of monomethylamine in 160 ml of benzene was added to a solution of 40 g of 5-oxo-8,9-dihydro [5H] benzocycloheptene in 400 ml of ethanol and the mixture was stirred for 2 1/2 hours and was evaporated to dryness to obtain 47.5 g of 7-methylamino-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene which was used as is for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[O:9]2)=[C:4]([O:23]C)[C:3]=1[O:25][CH3:26].[Cl-].[Cl-].[Cl-].[Al+3]>C(#N)C>[OH:23][C:4]1[C:3]([O:25][CH3:26])=[C:2]([OH:1])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:22])[CH:7]=[C:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[O:9]2
Reactant: COc1ccc(-c2cc(=O)c3c(OC)c(OC)c(O)cc3o2)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC#N
Product: COc1ccc(-c2cc(=O)c3c(O)c(OC)c(O)cc3o2)cc1OC
Temperature: 25 °C
Yield: 74.5 %

Procedure:
After 7-hydroxy-3',4',5,6-tetramethoxy flavone (4.44 g, 12.4 mmol) was suspended in 88 mL of acetonitrile and aluminum trichloride (8.27 g, 5 equivalents) was added hereto at room temperature, the reaction mixture was refluxed for 1.5 hour and the solvent was removed by evaporation under reduced pressure. To the residue was added 10% aqueous solution of hydrochloric acid and chloroform, then the solution was refluxed until it became clear. After the solution was cooled to room temperature, the organic layer was washed with water and brine, then dried over anhydrous magnesium sulfate and the solvent of the organic layer was removed by reduced pressure. The residue was recrystallized in methanol to afford 3.18 g of the product (74%).
Reaction SMILES: C(O)C.C(Cl)(Cl)Cl.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:19][N:18]=2)=[CH:13][CH:12]=1)(=[O:10])[CH3:9].[BH4-].[Na+]>O>[OH:10][CH:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:19][N:18]=2)=[CH:15][CH:16]=1)[CH3:9]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a mixed solvent of 200 ml of ethanol and 100 ml of chloroform were added 35.5 g (0.1 mole) of 2-(4-acetylphenyl)-5-decyloxypyrimidine, and while maintaining the temperature at 30° to 35° C., 2.65 g (0.07 mole) of sodium borohydride were gradually added thereto. After stirring at the same temperature for 4 hours, the reaction mixture was poured into 500 ml of water and extracted with 400 ml of ethyl acetate. The organic phase was washed sufficiently, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 35.6 g (yield: 99.9 %) of 2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[CH2:12](O)[CH2:13][OH:14].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]2[O:14][CH2:13][CH2:12][O:8]2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: OCCO
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(C2OCCO2)c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A solution of m-nitrobenzaldehyde 69d (20 g, 0.13 mol), ethylene glycol (9.0 g, 0.15 mol) and p-TsOH (catalytic amount) in toluene (50 mL) was refluxed under a Dean-Stark trap for 12 hr. The solution was then cooled to room temperature, diluted with toluene (20 mL) and washed with NaOH solution (1 M, 20 mL), water, brine and then dried with MgSO4. Evaporation of the solvent under reduced pressure gave 2-(3-Nitro-phenyl)-[1,3]dioxolane (24 g, 95%): 1H NMR (CDCl3) δ 4.11 (d of mult, ethylenedioxy, 4H), 5.78 (s, 1H), 7.56 (t, J=8 Hz, 1H), 7.80 (d of mult, J=8 Hz), 8.22 (d of mult., 1H), 8.35 (m, 1H). 13C NMR (CDCl3) δ 148.3, 140.5, 132.8, 129.5, 124.1, 121.7, 102.3, 65.6.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[C:7]([OH:9])=O)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[C:7]([N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1)=[O:9])([O-:3])=[O:2]
Reactant: CCCCC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1ccc(C(=O)N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In tetrahydrofuran (800 ml), 3-nitro-4-valeramidobenzoic acid ([1]-(11)-1) (20.0 g) was dissolved. Dicyclohexylcarbodiimide (17.1 g) and 1-hydroxybenzotriazole (11.2 g) were added to the solution, and the mixture was stirred at room temperature for 15 minutes. Morpholine (7.27 g) was further added to the solution. The mixture was stirred for 16 hours. After the insolubles were removed from the reaction solution, the solution was concentrated and dried. The crude product was dissolved in chloroform, and the insolubles were removed, and the solution was purified by silica gel column chromatography (Kieselgel 60=400 g, chloroform/methanol=30/1) to obtain the compound ([1]-(12)-1) (22.95 g) as yellow needle crystals.
Reaction SMILES: [CH2:1]([C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([C:22]([OH:24])=O)=[CH:17][C:18]=3[CH2:19]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:27])=O>CN(C)C=O>[CH2:1]([C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([C:22]([Cl:27])=[O:24])=[CH:17][C:18]=3[CH2:19]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)O)ccc1-2
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)Cl)ccc1-2

Procedure:
To 0.70 g (2.17 mM) of 7-octyl-2-fluorenecarboxylic acid, 2.1 ml of thionyl chloride and a drop of N,N-dimethylformamide (DMF) were added, followed by heat-refluxing for 20 minutes under stirring. After the reaction, an excessive thionyl chloride was distilled-off under reduced pressure to obtain 7-octyl-2-fluorenecarbonyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([F:19])[CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2]>C1COCC1.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([F:19])[CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2]
Reactant: CCOC(=O)/C=C/c1c[nH]c2c(C#N)cc(F)cc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(C#N)cc(F)cc12
Temperature: 50 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
To a solution of ethyl (2E)-3-(7-cyano-5-fluoro-1H-indol-3-yl)-2-propenoate (D134) (4 g) in THF (100 mL) was added Pd/C (0.8 g, with 1% water). The reaction was stirred under H2 (50 psi) atmosphere at 50° C. for about 4 hrs, TLC showed the material was completely consumed. Then Pd/C was removed by filtration, the filtrate was concentrated and washed with PE to afford ethyl 3-(7-cyano-5-fluoro-1H-indol-3-yl)propanoate (D135) (2.57 g) as a white solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 2.67 (2H, t), 3.05 (2H, t), 4.14 (2H, q), 7.20 (1H, s), 7.25 (1H, dd), 7.52 (1H, dd), 8.64 (1H, br); MS (ES): C14H13FN2O2 requires 260; found 261.1 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](Cl)=[O:30].N1C=CC=CC=1>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:30])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: O=C(Cl)c1ccccn1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Agent: Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccccn1
Yield: 64.3 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (40 ml), picolinoyl chloride hydrochloride (1.41 g) and pyridine (1.28 ml) were added, and the mixture was refluxed for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (150 ml), successively washed with water and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, diethyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 1.75 g of the titled compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.[C:25](Cl)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH2:23][NH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=NOCc1cccc(CN)n1)c1ccccc1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCC(=O)NCc1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.5 %

Procedure:
To a solution of 1-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}methanamine (0.21 g, 0.649 mmol, 1 eq.) in 2 ml of DCM was added TEA (0.197 g, 1.94 mmol, 3 eq.) followed by hexanoyl chloride (0.131 g, 0.974 mmol, 1.5 eq.). The reaction was stirred 4 h at room temperature and the solvent was evaporated. The crude was purified by chromatography on silica gel to give N-({6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}methyl)hexanamide (0.182 g, 62% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[N:3]=1.Cl.[NH2:29][C:30]1[C:35]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:34][CH:33]=[C:32]([NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]2)[N:31]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:29][C:30]1[C:35]([C:36](=[O:41])[C:37]([F:39])([F:40])[F:38])=[CH:34][CH:33]=[C:32]([NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:2]3[N:7]4[N:8]=[C:9]([CH:11]5[CH2:16][CH2:15][N:14]([CH:17]([CH3:18])[CH3:19])[CH2:13][CH2:12]5)[N:10]=[C:6]4[CH:5]=[C:4]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[N:3]=3)[CH2:44]2)[N:31]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(Cl)n3n2)CC1
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(N4CCCC(Nc5ccc(C(=O)C(F)(F)F)c(N)n5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.2 mmol) of 5-chloro-7-(2,4-difluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine, 81.2 mg (0.24 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 22A) and 0.213 ml (1.23 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 56 mg (42% of theory) of the product as a solid.
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: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: C[C@@H]1OC(=O)[C@H](CCc2ccccc2)[C@H]1O
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: B(Br)(Br)Br.[CH2:5]([C:9]1([C:14]2[CH:19]=[C:18]([O:20]C)[CH:17]=[C:16]([O:22]C)[CH:15]=2)[S:13][CH2:12][CH2:11][S:10]1)[CH2:6][CH2:7][CH3:8]>C(Cl)Cl>[CH2:5]([C:9]1([C:14]2[CH:15]=[C:16]([OH:22])[CH:17]=[C:18]([OH:20])[CH:19]=2)[S:10][CH2:11][CH2:12][S:13]1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC1(c2cc(O)cc(O)c2)SCCS1
Temperature: 0 °C
Yield: 77.3 %

Procedure:
Boron tribromide (32.9 ml of 1M soln, 32.9 mmol) was added to a solution of Compound 9 (4.51 g, 3.23 mmol) in CH2Cl2 (546 ml) under argon at −78° C. The reaction temperature was then raised slowly to 0° C. over a period of 3 hrs. Stirring was continued at 0° C. for 12–14 hrs or until completion of reaction. Unreacted boron tribromide was destroyed by adding methanol, solvent removed and the residual oil diluted with diethyl ether. The organic phase was washed with saturated NaHCO3, water and brine, dried and concentrated. The residue was resolved over silica gel eluting with diethylether/hexanes (4:6) to yield 0.675 g (74.1%) of Compound 16 as a waxy solid. Rf=0.28 (hexane:ethyl acetate 8:2) 1H NMR δ 6.79 (d, J=2.5 Hz, 2H), 6.23 (t, J=2H, 1H), 5.30 (br s, 2H), 3.38–3.19 (m, 4H), 2.25 (t, J=9.75 Hz, 2H), 1.29–1.18 (m, 4H), 0.83 (t, J=7 Hz, 3H); 13C NMR δ 156.24, 148.45, 107.23, 101.50, 73.90, 45.50, 39.01, 29.96, 22.74, 13.86; MS: (ESI, Neg.) m/z 269 ([M−H]−).
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([C:10]([NH:12][C@H:13]([C:18](O)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:28][C@H:29]([C:34]([NH2:36])=[O:35])[CH2:30][CH2:31][CH2:32][CH3:33].Cl.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([C:10]([NH:12][C@H:13]([C:18]([NH:28][C@H:29]([C:34]([NH2:36])=[O:35])[CH2:30][CH2:31][CH2:32][CH3:33])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCC[C@H](N)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O
Yield: 60 %

Procedure:
Condensation of BocDPheOH (2.65 g.) and HLeuOBz hydrobromide salt (3.02 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocDPhe-LeuOBz in 54% yield. Debenzylation of BocDPhe-LeuOBz (2.25 g.) by hydrogenation with palladium catalyst gave BocDPhe-LeuOH in 87% yield. Condensation of BocDPhe-LeuOH (1.50 g.) and HNleNH2 hydrochloride salt (0.667 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocDPhe-Leu-NleNH2 in 60% yield. De-t-butoxycarbonylation of BocDPhe-Leu-NleNH2 (1.00 g.) using hydrogen chloride in acetic acid gave HDPhe-Leu-NleNH2 hydrochloride salt in 79% yield.
Reaction SMILES: C([O:4][C@H:5]([C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([C:28]2([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:30][CH2:29]2)[N:22]=3)=[C:15]([F:37])[CH:14]=1)=[O:11])[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[OH-].[Na+]>C1COCC1>[F:37][C:15]1[CH:14]=[C:13]([NH:12][C:10](=[O:11])[C@@H:5]([OH:4])[CH2:6][C:7]([OH:9])=[O:8])[CH:18]=[CH:17][C:16]=1[C:19]1[S:20][C:21]2[C:26]([N:27]=1)=[CH:25][CH:24]=[C:23]([C:28]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:29][CH2:30]1)[N:22]=2
Reactant: CC(=O)O[C@@H](CC(=O)O)C(=O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C[C@H](O)C(=O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(3S)-3-Acetoxy-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenylamino)-4-oxobutanoic acid (65 mg, 0.125 mmol) was dissolved in THF (1.3 mL) before 0.1 N sodium hydroxide (3.75 ml, 0.375 mmol) was added and stirred at ambient temperature for 24 h; the reaction had not gone to completion, so more NaOH was added and stirred for another 4 h. The reaction mixture was concentrated to remove the THF, acidified with 2 N HCl to crash out the product, filtered, washed with water, and dried in a vacuum oven to give the title compound. MS (ESI) m/z: Calculated: 477.1; Observed: 477.7 (M++H).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:29][CH:28]2[N:6]([C:7](=[O:82])[C:8](=[O:81])[C:9]3([OH:80])[O:76][CH:13]([CH:14]([O:74][CH3:75])[CH2:15][CH:16]([CH3:73])[CH2:17][C:18]([CH3:72])=[CH:19][CH2:20][C:21](=[O:71])[CH2:22][CH:23]([O:63][Si](C(C)(C)C)(C)C)[CH:24]([CH3:62])[CH:25]([C:31]([CH3:61])=[CH:32][CH:33]4[CH2:38][CH2:37][C:36]([O:51][Si](CC)(CC)CC)([CH2:39][CH2:40][CH:41]([C:43]5[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=5)[OH:42])[CH:35]([O:59][CH3:60])[CH2:34]4)[O:26][C:27]2=[O:30])[CH:12]([O:77][CH3:78])[CH2:11][CH:10]3[CH3:79])[CH2:5][CH2:4]1)[CH3:2]>C(#N)C>[CH2:1]([CH:3]1[CH2:29][CH:28]2[N:6]([C:7](=[O:82])[C:8](=[O:81])[C:9]3([OH:80])[O:76][CH:13]([CH:14]([O:74][CH3:75])[CH2:15][CH:16]([CH3:73])[CH2:17][C:18]([CH3:72])=[CH:19][CH2:20][C:21](=[O:71])[CH2:22][CH:23]([OH:63])[CH:24]([CH3:62])[CH:25]([C:31]([CH3:61])=[CH:32][CH:33]4[CH2:38][CH2:37][C:36]([OH:51])([CH2:39][CH2:40][CH:41]([C:43]5[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=5)[OH:42])[CH:35]([O:59][CH3:60])[CH2:34]4)[O:26][C:27]2=[O:30])[CH:12]([O:77][CH3:78])[CH2:11][CH:10]3[CH3:79])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCN2C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CCC(=O)CC(O[Si](C)(C)C(C)(C)C)C(C)C(C(C)=CC4CCC(CCC(O)c5cc(C)cc(C)c5)(O[Si](CC)(CC)CC)C(OC)C4)OC(=O)C2C1)C(OC)CC3C
Solvent: CC#N
Product: CCC1CCN2C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CCC(=O)CC(O)C(C)C(C(C)=CC4CCC(O)(CCC(O)c5cc(C)cc(C)c5)C(OC)C4)OC(=O)C2C1)C(OC)CC3C
Reaction time: 18 h

Procedure:
A solution of 220 mg (0.186 mmole) of 7-ethyl-1-hydroxy-12-[2'-(4"-triethylsilyloxy-4"-[3-(3,5-dimethylphenyl)-3-hydroxypropyl]-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in 10 mL of a 10% HF-acetonitrile solution was stirred at room temperature. After 18 h, the reaction was quenched with 5 mL of ethoxytrimethylsilane and the solution was concentrated. The oily residue was purified by HPLC (Waters RCM silica gel, 25×100 mm) using hexane-methyl t-butyl ether-acetonitrile (6:3:1) to afford 45 mg of the faster diastereomer as a white solid. MASS: 960 (M+Li)
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13](O)[CH:14]([OH:16])[CH3:15])=[CH:9][C:8]=1[O:18][CH3:19]>C1(C)C=CC=CC=1>[CH3:15][C:14]([CH2:13][C:10]1[CH:11]=[CH:12][C:7]([OH:6])=[C:8]([O:18][CH3:19])[CH:9]=1)=[O:16]
Reactant: COc1cc(C(O)C(C)O)ccc1O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: COc1cc(CC(C)=O)ccc1O

Procedure:
To a refluxing azeotropic mixture of 125 ml toluene and 100 ml 10% sulfuric acid is added an aqueous solution (~250 ml.) to 9.0 g 1-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol (from step C) at such a rate that the volume of the aqueous phase remained constant during the addition, returning the toluene and separating the aqueous phase of the distillate by a Dean-Stark head. The separation of the water is discontinued after ~250 ml is collected and the reaction mixture is refluxed for an additional hour.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[N:5]=[N:6][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:8][N:9]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH:12][CH:10]([C:7]1[N:6]=[N:5][C:4]([S:3][CH3:2])=[N:9][CH:8]=1)[CH3:11])=[O:18]
Reactant: CSc1ncc(C(C)N)nn1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1ncc(C(C)NC(=O)c2cccc(Br)c2)nn1
Reaction time: 18 h
Yield: 83.8 %

Procedure:
To a stirred solution of 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethanamine hydrochloride (Intermediate 4) (10 g, 49 mmol) in N,N-dimethylformamide (100 mL) was added 3-bromobenzoic acid (11 g, 54 mmol), O-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospahte (20 g, 52 mmol) and triethylamine (24 mL, 170 mmol). After stirring for 18 hours the solution was concentrated under reduced pressure to approximately 50 mL. The solution was diluted with ethyl acetate (200 mL) and washed with 0.1N HCl (2×100 mL) and saturated sodium bicarbonate solution (100 mL). The solution was dried with magnesium sulfate and filtered, and silica gel (25 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (0:100) to ethyl acetate:hexanes (40:60) using a RediSep silica gel cartridge (120 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 3-bromo-N-{1-[3-(methylthio)-1,2,4-triazin-6-yl]ethyl}benzamide (14.5 g) as a white solid. 1H NMR (CDCl3): δ8.47(s, 1H), 7.95 (dd, J=1.8, 1.7 Hz, 1H), 7.72 (ddd, J=7.9, 1.6, 1.1 Hz, 1H), 7.64 (ddd, J=7.9, 2.0, 1.1 Hz, 1H), 7.32 (dd, J=8.0, 7.7 Hz, 1H), 7.20 (d, J=7.2 Hz, 1H), 5.47 (dq, J=7.2, 7.0 Hz, 1H), 2.68 (s, 3H), 1.70 (d, J=7.0 Hz, 3H). MS m/z 353, 355 (M+1, M+3).