Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].[CH3:20][CH:21]([CH2:23][C@H:24]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:25](ON1C(=O)CCC1=O)=[O:26])[CH3:22]>O.O1CCOCC1.CN(C=O)C>[NH:35]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[C@H:24]([C:25]([NH:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:26])[CH2:23][CH:21]([CH3:22])[CH3:20]
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reaction time: 8 h
Yield: 78.9 %

Procedure:
H-Ser(Bzl)-OH (11.7 g.) was dissolved in water (50 ml.) and sodium bicarbonate (10.1 g.) and dioxane (10 ml.) added thereto. BOC-Leu-OSU (16.4 g.) in dioxane (15 ml.) and DMF (5 ml.) were then added. After overnight stirring, the pH of the reaction mixture was adjusted to pH 7, and the mixture concentrated in vacuo to remove organic solvent. The aqueous layer was shaken with ethyl acetate (100 ml.) and the organic layer was washed twice with 1 N HCl and water. The organic layer was dried with anhydrous magnesium sulfate, concentrated in vacuo and the residue was twice recrystallized from ethyl acetate - n-hexane to obtain BOC-Leu-Ser(Bzl)-OH (16.1 g., Yield: 78.8%, m.p.: 82° - 86° C.).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:14]2[CH2:17][CH2:16][CH2:15]2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[OH-:18].[Na+]>CS(C)=O>[C:1]([C:3]1[C:4]([CH:14]2[CH2:17][CH2:16][CH2:15]2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])(=[O:18])[NH2:2]
Reactant: COC(=O)c1cc(C#N)c(C2CCC2)cc1C
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C2CCC2)c(C(N)=O)cc1C(=O)O
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a 1-L round bottom flask was added methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (compound 6.4, 12.00 g, 52.3 mmol) and dissolved in DMSO (100 mL). With stirring, aqueous sodium hydroxide (1 M, 260 mL, 260 mmol) was added carefully and the mixture was purged with nitrogen. The mixture was stirred at 95° C. for 13 hours and then cooled to room temperature. The solution was washed with diethyl ether (100 mL) and the basic aqueous was acidified to pH˜2 by slow addition of aqueous HCl (1M) followed by aqueous H3PO4 (1M). The precipitated solids were filtered, and washed with water (2×100 mL), then dried to constant mass to yield the title compound as a white powder (11.68 g, 96%). m/z (ES−) 232 (M−H)−. 1H NMR (400 MHz, DMSO-d6): δ 12.75 (br s, 1H), 7.75 (s, 1H), 7.74 (br s, 1H), 7.34 (br s, 1H), 7.28 (s, 1H), 3.90 (app p, J=9.0 Hz, 1H), 2.56 (s, 3H), 2.32-2.20 (m, 2H), 2.16-2.02 (m, 2H), 2.00-1.87 (m, 1H), 1.82-1.71 (m, 1H).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:17]=1)=[O:15])=[O:11].[C:36](=O)([O:44]C1C=CC([N+]([O-])=O)=CC=1)[O:37][CH:38]([O:40][C:41](=[O:43])[CH3:42])[CH3:39].O>CN(C)C=O>[C:41]([O:40][CH:38]([O:37][C:36]([N:6]1[CH2:7][CH2:8][C:9]2[S:1][C:2]([C:10]([NH:12][CH2:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:17]=3)=[O:15])=[O:11])=[CH:3][C:4]=2[CH2:5]1)=[O:44])[CH3:39])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)COc1ccc(C(=O)CNC(=O)c2cc3c(s2)CCNC3)cc1OCC(=O)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(C(=O)CNC(=O)c2cc3c(s2)CCN(C(=O)OC(C)OC(C)=O)C3)cc1OCC(=O)OCC
Temperature: 25 °C
Yield: 16.3 %

Procedure:
To a suspension of 126 mg of diethyl [[4-[[[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]amino]acetyl]-o-phenylen]dioxy]diacetate synthesized according to the method described in WO 9421599 in 3 ml of N,N-dimethylformamide was added 105 mg of 1-acetoxyethyl 4-nitrophenyl carbonate under stirring at room temperature, and the mixture was stirred at 40° C. for 20 hours. The reaction was poured into 3 ml of water, and extracted with 5 ml of ethyl acetate. The separated organic layer was dried over magnesium sulfate, and the solvent was removed by distillation. The residue thus obtained was purified by chromatography on an LH-20 column (chloroform:methanol=1:1) and a silica gel column (chloroform:acetone=8:1) to give the title compound (25.8 mg, 16%) as a free base.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]2[C:28]3[N:19]([CH2:20][C@@H:21]4[C@H:26]([C:27]=3[CH:29]=1)[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH2:18][CH2:17][CH2:16]2>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[C:28]3[N:19]([CH2:20][C@@H:21]4[C@H:26]([C:27]=3[CH:29]=1)[CH2:25][NH:24][CH2:23][CH2:22]4)[CH2:18][CH2:17][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN3CCCc4cc(Br)cc(c43)[C@@H]2C1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2CN4CCC3)c(Cl)c1

Procedure:
Using 2,4-dichlorophenylboronic acid and following the procedures described in EXAMPLE 20, (±)-cis tert-butyl 2-bromo-5,6,8,8a,9,10,12,12a-octahydro-4H,11H-quino[1,8-bc]-2,6-naphthyridine-11-carboxylate from EXAMPLE 127, Part F was converted into the title compound of EXAMPLE 128. 1H NMR (CDCl3) δ: 7.44 (d, 1H, J=1.6 Hz), 7.27-7.18 (m, 2H), 6.94 (B, 1H), 6.81 (s, 1H), 3.96 (dd, 1H, J=11.5, 3.1 Hz), 3.51-3.43 (m, 1H), 3.30-3.20 (m, 2H), 3.13 (d, 2H, J=7.3 Hz), 2.98-2.85 (m, 2H), 2.84-2.73 (m, 2H), 2.08-1.88 (m, 4H), 1.71-1.60 (m, 1H), 0.90-0.80 (m, 1H). LRMS (ES)+: 373.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[N:7]=[C:6]2[CH3:16].[N+:17]([O-])([OH:19])=[O:18].OS(O)(=O)=O>>[CH3:1][O:2][C:3]1[C:4]([N+:17]([O-:19])=[O:18])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[N:7]=[C:6]2[CH3:16]
Reactant: COc1cc2[nH]c(=O)nc(C)c2cc1OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1cc2[nH]c(=O)nc(C)c2c([N+](=O)[O-])c1OC
Temperature: 0 °C

Procedure:
One equivalent of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone is added during 3/4 hr. to a mixture (5:1) of 6 equivalents of concentrated nitric acid (70%) and concentrated H2SO4 at 0°±3° C. After one hour at the same temperature the solution is poured onto crushed ice (1000 ml). The crude product is collected by filtration, digested with boiling alcohol and the suspension is filtered. Crystallization from ethyl alcohol affords 6,7-dimethoxy-5-nitro-4-methyl-2(1H)quinazolinone.
Reaction SMILES: C(O[C:9]([N:11](C)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31](=[O:33])[NH2:32])[CH:26]=2)[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)=O)C1C=CC=CC=1>[Pd]>[C:31]([C:27]1[CH:26]=[C:25]([NH:24][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][NH:11][CH3:9])=[CH:19][CH:18]=2)[C:21]([OH:23])=[O:22])[CH:30]=[CH:29][CH:28]=1)(=[O:33])[NH2:32]
Reactant: CN(CCc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Product: CNCCc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1
Yield: 98.7 %

Procedure:
A solution of 28E (265 mg, 0.39 mmol) and Pd/C (10%, 40 mg) was stirred under H2 (1 atm) for 15 h. The reaction was filtered through Celite and concentrated to yield 28F (126 mg, 99%) as a yellow oil. MS (ESI) m/z 328.29 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:40]([OH:42])[CH3:41]>>[CH2:40]([O:42][C:2]1[C:7]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:41]
Reactant: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3cccnc3F)nc3c2CCC3)n[nH]1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1ncccc1NC(=O)[C@@H]1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a suspension of (S)—N-(2-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (25 mg, 0.053 mmol) in ethanol (1 mL) was added Cs2CO3 (26 mg, 0.080 mmol) and the reaction mixture was allowed to stir at 80° C. for 12 h. The reaction mixture was concentrated, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue that was purified by reverse phase HPLC to afford 8 mg of (S)—N-(2-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide as the TFA salt. 1HNMR (400 MHz, CD3OD) δ (ppm): 1.00-1.17 (m, 6H), 1.27 (t, 3H), 2.08-2.30 (m, 4H), 2.36-2.42 (m, 2H), 2.70-2.90 (m, 3H), 2.92-3.03 (m, 2H), 3.60-3.70 (m, 1H), 3.78-3.88 (m, 1H), 4.37 (q, 2H), 4.85-4.95 (m, 1H), 6.24 (s, 1H), 6.82-6.92 (m, 1H), 7.78-7.93 (m, 1H), 8.10-8.18 (m, 1H). The other enantiomer is prepared using the (R) chiral starting material.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1)#[CH:35].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[C:16]([C:35]#[C:34][C:36]3[CH:37]=[CH:38][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][CH:41]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3ncccc3C(F)(F)F)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3ncccc3C(F)(F)F)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.46 mmol) and 1-Ethynyl-4-methanesulfonyl-benzene (249.2 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 197 mg (67%). HPLC-MS: m/z: 642.4 (M+H)+; Rt: 2.73 min
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[C:11]([S:12][CH3:13])=[CH:10][C:9]([CH3:14])=[CH:8][C:7]=1Br)=[O:4].C([Li])CCC.[C:23](=[O:25])=[O:24]>C(OCC)C.CCCCCC>[CH3:14][C:9]1[CH:10]=[C:11]([S:12][CH3:13])[C:6]([NH:5][C:3](=[O:4])[C:2]([F:17])([F:16])[F:1])=[C:7]([CH:8]=1)[C:23]([OH:25])=[O:24]
Reactant: CSc1cc(C)cc(Br)c1NC(=O)C(F)(F)F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CSc1cc(C)cc(C(=O)O)c1NC(=O)C(F)(F)F
Reaction time: 2 h
Yield: 74.4 %

Procedure:
Under an atmosphere of argon, 46.6 g (142 mmol) of N-(trifluoroacetyl)-2-bromo-4-methyl-6-(methylthio)aniline in 750 ml of dry diethyl ether were cooled to a temperature of −65° C. At this temperature, 119 ml of a 2.5M solution (297.5 mmol) of n-butyllithium in hexane were added dropwise. The mixture was subsequently stirred at this temperature for 2 h. The contents were then carefully poured onto a mixture of 62.5 g (1.42 mol) of carbon dioxide (as dry ice ground in a mortar) and 150 ml of dry ether. The mixture was thawed to RT and extracted three times with water. The combined aqueous phases were acidified to pH<2 with dilute hydrochloric acid and cooled to a temperature of 0° C.-5° C. The mixture was filtered, giving 31.0 g of 5-methyl-3-(methylthio)-2-(trifluoroacetylamino)benzoic acid as residue.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br.Br[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Br.[OH-].[K+]>O>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Cc1cccc(N)c1Cl
Reactant: BrCCNCCBr
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(N2CCNCC2)c1Cl
Reaction time: 9 h
Yield: 56.1 %

Procedure:
To a mixture of 6.08 g of 2-chloro-3-methylaniline, 9 g of di(2-bromoethyl)amine hydrobromide and 4 ml of water was added a solution of 0.8 g of potassium hydorxide and 2.5 ml of water 3 times of 1 hour interval at 100° C., then the reaction mixture was stirred at the same temperature for 9 hours. To the resultant reaction mixture was added potassium hydroxide to make the mixture alkaline, and the mixture was extracted with diethyl ether, washed with water, dried with anhydrous magnesium sulfate. The solvent was removed by evaporation and the residue thus obtained was purified by means of a silica gel column chromatography (eluent: 5%-methanol/chloroform), and obtained 3.41 g of 4-(2-chloro-3-methylphenyl)piperazine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])/[CH:33]=[CH:34]/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:24]2)=[CH:19][CH:18]=1>N1C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[C:35]1(/[CH:34]=[CH:33]/[C:32]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:23]2[CH2:22][CH2:21][C:20]3[C:25](=[CH:26][C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:18][CH:19]=3)[CH2:24]2)=[O:41])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(/C=C/c1ccccc1)NCCCCN1CCc2ccc(O)cc2C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccccc1)NCCCCN1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.3 %

Procedure:
Trifluoromethanesulfonic anhydride (0.26 ml, 1.52 mmol) was added dropwise with stirring to an ice cooled solution of (E)-7-hydroxy-2-(4-(3-phenylpropenoyl)aminobutyl)-1,2,3,4-tetrahydroisoquinoline (0.41 g, 1.17 mmol) in anhydrous pyridine (5 ml). After stirring at room temperature for 18 h the reaction mixture was poured into 10% aqueous copper (II) sulfate (100 ml). The mixture was extracted with ethyl acetate (2×75 ml). Combined extracts were washed with 10% aqueous copper (II) sulfate (2×50 ml), water (50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica using 10-100% ethyl acetate-hexane gradient elution to afford the title compound (0.205 g, 43%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH:25]([CH3:27])[CH3:26])[C:17]([NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18].[CH:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=12)=O>ClCCCl.C(O)(=O)C>[CH:20]1([NH:19][C:17](=[O:18])[C@H:16]([NH:15][CH2:28][C:30]2[CH:35]=[CH:34][N:33]=[C:32]3[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=23)[CH:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC(C)[C@@H](N)C(=O)NC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A mixture of sodium triacetoxyborohydride (104 mg, 0.493 mmol) and (R)-2-amino-N-cyclopentyl-3-methylbutanamide (68.1 mg, 0.370 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (75 mg, 0.246 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (105 mg, 90%). [M+H] calc'd for C25H36N4O5, 473; found, 473.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[N:23][OH:24])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1.Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>[Ag]=O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[N:23][O:24][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:32])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1
Reactant: COC(=O)c1c(C=NO)cccc1Oc1nc(OC)cc(OC)n1
Reactant: CCOC(=O)C(C)Br
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)ON=Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Yield: 27 %

Procedure:
2 0 g of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-hydroxyiminomethylbenzoate, 3 ml of ethyl 2-bromopropionate and 0.9 g of silver oxide (I) were place in a 50 ml eggplant type flask, and were allowed to stand for one night at room temperature. 10 ml of acetone and 10 g of silica gel were added to the resultant reaction liquor, and the acetone was distilled off under reduced pressure. The resultant product was purified by column chromatography to obtain 0.7 g of the aimed compound (refractive index=1.5261) at a yield of 27%.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].N[C:30]([O:32][CH2:33][CH3:34])=O.CC(C)([O-])C.[Li+].C(C1OC1)Br>CC(N(C)C)=O>[CH2:34]([CH2:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1])[CH:33]1[O:32][CH2:30]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOC(N)=O
Agent: BrCC1CO1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CCC1CO1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A schematic diagram of the reactions used for covalent binding of cholesterol to the urethane hard segments by the reaction of bromobutylated Tecothane® with 2-hydroxy-3-β-cholesteryloxypropanethiol is presented in FIGS. 1 and 2. Glycidyl cholesterol (FIG. 1) was synthesized by dissolving cholesterol in DMAc under a flow of dry argon and adding 1 M lithium tert-butoxide in hexanes. After cooling to 5° C., freshly distilled epibromohydrin was added and the mixture was stirred at 3-5° C. for 2 hours and allowed to slowly come to room temperature (21-23° C.) where it was incubated for an additional hour. The reaction mixture was diluted with 0.5% aqueous KHCO3 and extracted with three administrations of n-heptane. The combined organic layers were dried over Na2SO4. After filtration from the desiccant, the solvent was removed in vacuo and the residue was purified by flash-chromatography on silica gel employing elution with hexane, hexane/toluene (1:1 mixture), and toluene. The fractions containing pure glycidyl cholesterol were pooled and dried in vacuo until crystallization occurred. Purity was confirmed with 1H NMR (data not shown).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([NH2:54])[S:52][CH:53]=1)[CH3:45].C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([NH:54][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[S:52][CH:53]=1)[CH3:45]
Reactant: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (prepared in Example 22A, 263.0 mg, 1.0 mmol) in N,N-dimethylformamide (10 mL) was treated with O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (379 mg, 1.0 mmol), (2-amino-thiazol-4-yl)-acetic acid ethyl ester (279 mg, 1.5 mmol) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol). The reaction mixture was stirred at 25° C. for 5 h. The reaction mixture was then poured into a 2 N aqueous hydrochloric acid solution (25 mL) and extracted with ethyl acetate (3×25 mL). The organic layers were combined and washed with water (1×75 mL), a saturated aqueous sodium bicarbonate solution (1×75 mL), a saturated aqueous sodium chloride solution (3×75 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (70.0 mg, 39.4%) as a pale yellow oil: FAB-HRMS m/e calcd for C21H25N3O5S (M+H)+ 432.1593, found 432.1595.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[C:12]([O:16][CH2:17][O:18][CH3:19])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)#[CH:21]>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:21]#[C:20][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:12]([O:16][CH2:17][O:18][CH3:19])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1cnc(OCc2ccccc2)cc1I
Reactant: C#Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Product: COCOc1cnc(OCc2ccccc2)cc1C#Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 85.8 %

Procedure:
2-(benzyloxy)-4-iodo-5-(methoxymethoxy)pyridine (3.0 g, 8.08 mmol), copper (I) iodide (92 mg, 0.485 mmol), PdCl2(PPh3)2 (284 mg, 0.404 mmol), 1-ethynyl-4-fluorobenzene (1.07 g, 8.89 mmol) were combined in dioxane (40 mL) and TEA (40 mL), degassed and stirred at 80° C. for 1.5 hrs. The mixture was diluted with EtOAc and washed with sat NaCl and H2O. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 2-(benzyloxy)-4-((4-fluorophenyl)ethynyl)-5-(methoxymethoxy)pyridine (2.52 g, 6.93 mmol, 86% yield) consistent by LCMS. LC-MS retention time: 2.71 min; m/z (MH+): 364. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u 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 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.