Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(CCC[C@H:7]([C@@H:9]1[C@:27]2(C)[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2(C)[C:16](C[C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])C.C1C(NCCN)=C2C(C3C=CN=CC=3C(=O)C2=C(NCCN)C=1)=[O:40]>>[CH3:8][CH2:7][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:27]\[CH2:26]/[CH:25]=[CH:24]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:22][CH2:21][CH2:20][C:18]([OH:19])=[O:40]
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: NCCNc1ccc(NCCN)c2c1C(=O)c1ccncc1C2=O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O

Procedure:
Therefore, the invention provides a liposome formulation of compound BBR 2778 consisting of liposomes comprising phosphatidylcholine, cholesterol and BBR 2778, in a cholesterol/phospholipide 1:2 to 1:7 weight ratio and in a BBR 2778/phospholipide 1:4 to 1:25 weight ratio. Phosphatidylcholine preferably includes residues of fatty acids selected from palmitic, oleic, linoleic, gamma-linoleic, linolenic and stearic acids, and the liposome is formed by a mixture of hydrogenated and non-hydrogenated phosphatidylcholines, having the fatty acids composition indicated, in a 1:2 to 2:1 ratio, more preferably said mixture consists of hydrogenated phosphatidylcholine having melting point of 120° C. and crystallization point of 90° C., and non-hydrogenated phosphatidylcholine having a thermogram as reported in FIG. 5. The hydrogenated and non-hydrogenated phosphatidylcholines, having the above-indicated composition, are commercially available respectively under the name PHOSPHOLIPON® 90 H and PHOSPHOLIPON® 90.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Cl>>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([CH2:37][C:36]5[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH3:32])[CH:35]=5)[C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(CCl)c1
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Product: COc1cccc(CN2Cc3ccc(N4CCN(CCC(c5ccccc5)c5ccccc5)CC4)cc3C2=O)c1
Yield: 60.6 %

Procedure:
In the same manner as in Example 51, the title compound (35 mg) was prepared from the compound (50 mg) obtained in Example 50 and 3-methoxybenzyl chloride (17 mg).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@H:18]2[CH2:22][C@@H:21]([OH:23])[CH2:20][NH:19]2)=[O:17])=[CH:11][CH:10]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>ClCCl.ClC(Cl)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:19]2[CH2:20][C@H:21]([OH:23])[CH2:22][C@@H:18]2[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:4]3[CH2:5][CH2:6][O:7][CH2:8][C:3]3=[O:2])=[CH:14][CH:13]=2)=[O:17])=[O:40])=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1C(=O)Nc1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
7.1 16 g (12.86 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ) are added to a suspension of 15 g (64.86 mmol) of cis-N′-BOC-4-hydroxy-D-proline and 12.47 g (64.86 mmol of 1-(4-amino-phenyl)-1H-pyridin-2-one in 250 ml of toluene, and the mixture is stirred at room temperature for 18 hours. The precipitated product is subsequently filtered off, washed successively with 50 ml of toluene and 50 ml of diethyl ether and dried in a desiccator, giving 24.5 g (93.2%) of tert-butyl (2R,4R)-4-hydroxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as a grey-white powder. ESI 406. 7.2 300 ml of 4N hydrochloric acid in dioxane are added to a solution of 15 g (37 mmol) of tert-butyl (2R,4R)-4-hydroxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate in 200 ml of dioxane, and the mixture is stirred at room temperature for 12 hours. The precipitate is subsequently filtered off, washed with 50 ml of dioxane and 50 ml of diethyl ether and dried in a desiccator, giving 12.64 g (100%) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-2-carboxamide hydrochloride as a white powder. ESI 306. 7.3 12.64 g (36.98 mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-2-carboxamide hydrochloride are suspended in 1200 ml of dichloromethane, and 5.4 ml of triethylamine are added with cooling in an ice bath. The solution of 5.96 g (38.83 mmol) of 4-chloro-phenyl isocyanate in 100 ml of dichloroethane is subsequently added dropwise to the mixture at 2° C. over the course of 1.5 hours, and the reaction solution is then left to stir for a further 30 minutes with ice cooling. The dichloromethane solution, is then washed successively with 100 ml of 1N hydrochloric acid and 100 ml of water and dried over sodium sulfate. After the drying agent has been filtered off and the methylene chloride solution has been evaporated to ⅓ of the original volume in a rotary evaporator, the precipitated product is filtered off, washed with 50 ml of petroleum ether and dried in a desiccator, giving 14.6 g (86%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxamide (“A8”) as a white powder, ESI 459; m.p. 216°.
Reaction SMILES: [Br:1][C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH:17]=1)=[C:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[Br:1][C:2](=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(Oc2cccc(C(Br)=C3CCNCC3)c2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
To a solution of tert-butyl 4-(bromo(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylene)piperidine-1-carboxylate (0.42 g, 0.82 mmol) in CH2Cl2 (10 mL) was added TFA (3 mL). The pale yellow solution went to a darker yellow solution. The reaction was stirred at room temperature for 5 h. The reaction was concentrated to give the title compound as a solid (235 mg, 54% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH:22]=2)=[C:6]2[C:10]([Cl:11])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:8][C:7]=12.Cl>C(Cl)Cl>[ClH:11].[Cl:11][C:10]1[C:6]2[C:7](=[C:2]([NH2:1])[N:3]=[CH:4][C:5]=2[C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)[CH:22]=2)[O:8][C:9]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5ccccc5)c(Cl)c34)cn2)CC1
Agent: Cl
Solvent: ClCCl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2c(Cl)c(-c3ccccc3)oc12
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of tert-butyl 4-[4-(7-amino-3-chloro-2-phenylfuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate in DCM (1.0 mL) was treated with HCl (1 M in Et2O, 2.0 mL, 2.0 mmol) and stirred at RT. The reaction was concentrated in vacuo to provide 43 mg (76%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 6.94-6.98 (m, 2H), 6.80 (s, 1H), 6.53 (s, 1H), 6.32-6.36 (m, 4H), 3.40 (tt, J=9.98, 4.93 Hz, 1H), 2.34 (dt, J=13.26, 3.35 Hz, 2H), 1.94-2.00 (m, 2H), 1.05-1.15 (m, 4H); MS (ESI): 394.14 [M+H]+; HPLC tR=0.97 min (TOF: polar—3 min).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@@H:12]([CH2:22][CH:23]=[CH2:24])[C:11]1=[O:25])=[O:4].B1C2CCCC1CCC2.[OH-:41].[Na+].OO>C1COCC1.CCO>[CH:16]1([CH:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:31])[CH3:29])[S:6][C:5]=3[C:3]([OH:2])=[O:4])[C:11](=[O:25])[C@H:12]([CH2:22][CH2:23][CH2:24][OH:41])[CH2:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: [OH-]
Reactant: C=CC[C@@H]1CCC(C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@H](CCCO)CCC2C2CCCCC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of 3-((S)-3-allyl-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (less polar diastereomer from previous step) (60 mg, 0.14 mmol, 1.0 equiv) in anhydrous THF (2.0 ml) was added 9-BBN (0.5 M in THF, 0.68 ml, 0.34 mmol, 2.5 equiv) at 0° C. and the resulting solution was stirred at room temperature for 2 hours. The solution was then cooled at 0° C. and to the solution was added EtOH, 1.0 M aq. NaOH solution and aqueous H2O2 solution. The reaction mixture was heated to reflux for 90 minutes and then cooled at room temperature. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by prep-HPLC (0.1% NH4OH) to give 20 mg of the desired product (yield 33%). MS: 446 [M+H+]. 1H-NMR (400 MHZ, CD3OD): 6.81 (s, 1H), 4.00 (br, 1H), 3.53 (t, 2H), 2.27 (br, 1H), 1.97 (m, 3H), 1.82˜1.64 (m, 7H), 1.58 (m, 2H), 1.37 (m, 2H), 1.31 (s, 9H), 1.14 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:17]([O-:19])=[O:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Fluoro-4-methylbenzoic acid (1 g, 6.49 mmol) in H2SO4 (19 ml, 356 mmol) was cooled to 0° C. in an ice salt water bath and treated dropwise with mixture of H2SO4 (0.763 ml, 14.31 mmol) and nitric acid (0.65 ml, 14.54 mmol) over 10 min. The reaction mixture was stirred at 0° C. for 3 hrs and poured into ice/water (200 ml) and stirred for a further hour. The resulting suspension was collected by filtration, dried in vacuo and collected in EtOH, azeotroping to dryness to afford the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]1[CH:12]=[C:11]([OH:13])[C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:9][N:8]=1>CN(C)C=O>[N:1]([CH2:6][C:7]1[CH:12]=[C:11]([OH:13])[C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:9][N:8]=1)=[N+:2]=[N-:3]
Reactant: CCCOc1cnc(CCl)cc1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1cnc(CN=[N+]=[N-])cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium azide (2.82 g, 43.3 mmole) in 30 mL of N,N-dimethylformamide is added 2-chloromethyl-5-propoxy-pyridin-4-ol (8.74 g, 43.3 mmole). This is stirred for overnight at ambient temperature then quenched into ice water. The solid formed is filtered, washed with cold water and dried to give an off white solid, 5.74 g, (63%); MS (ES+): m/z 209.3 (M+H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CN(C)C=O.CS(O[CH:15]1[CH2:20][CH2:19][CH:18]([O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]([F:30])[CH2:16]1)(=O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CCCCCC>[C:24]1([CH2:23][CH2:22][O:21][CH:18]2[CH2:19][CH2:20][CH:15]([N:1]=[N+:2]=[N-:3])[CH2:16][CH:17]2[F:30])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1CCC(OCCc2ccccc2)C(F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1CCC(OCCc2ccccc2)C(F)C1
Temperature: 50 °C
Yield: 71.3 %

Procedure:
Sodium azide (0.500 g, 7.69 mmol) was added to a N,N-dimethylformamide (10 mL) solution of 3-Fluoro-4-(2-phenylethoxy)cyclohexyl methanesulfonate (0.597 g, 1.89 mmol) under nitrogen. The resulting mixture was heated at 50° C. for 24 h, then cooled and poured into saturated sodium bicarbonate. The aqueous mixture was extracted with ethyl acetate (3×) and the combined organic extracts were washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Flash column chromatography (hexane:ethyl acetate, e 90:10) gave 4-Azido-2-fluorocyclohexyl 2-phenylethyl ether as a colorless oil (0.355 g, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[I:9]([O-])(=O)=O.[K+].[I-].[K+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: Nc1ccc(Cl)cn1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Nc1ncc(Cl)cc1I
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 169.6 %

Procedure:
A stirred solution of 5-chloro-pyridin-2-ylamine (51.4 g, 0.40 mol) in 2M sulfuric acid (700 mL) was treated portionwise with potassium iodate (43.7 g, 0.2 mol) and the mixture heated to 100° C. A solution of potassium iodide (36.5 g, 0.55 mol) in water (100 mL) was added dropwise over ca. 1 hour. The mixture was allowed to stir for a further 30 minutes then cooled to ambient temperature. The pH of the aqueous phase was adjusted to 8-9 and the mixture extracted with ethyl acetate (×3). The combined organic layer was washed with aqueous sodium thiosulfate solution, water and brine, dried (Na2SO4), filtered and evaporated to afford the title compound as a tan solid (86.3 g, 84%). LCMS (Method B): RT=3.76 min, M+H+=255/257. 1H NMR (400 MHz, CDCl3): 7.98 (d, J=2.3 Hz, 1H), 7.84 (d, J=2.3 Hz, 1H), 5.03 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[N:13][CH:14]=[CH:15][CH:16]=2)=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:11]2[C:12]([NH:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccnc1NCC1CCN(c2ccncc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Clc1ccc(NCc2cccnc2NCC2CCN(c3ccncc3)CC2)cc1
Temperature: 65 °C
Yield: 62.3 %

Procedure:
A solution of N-(4-chlorophenyl)-2-[1-(4-pyridyl)-piperidin-4-ylmethyl]aminopyridine-3-carboxamide (25 mg, 0.059 mmol) in THF (1 mL) was treated with lithium aluminum hydride (1.0 M in THF, 0.21 mL, 0.21 mmol). The mixture was heated at 65° C. for 4 days, cooled, diluted with methanol (5 mL), and loaded onto an SCX ion exchange resin. The resin was eluted with methanol followed by 2 N NH3 in methanol and fractions containing the desired material were concentrated. The residue was triturated with EtOAc, yielding 15 mg (62%) of the title compound.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O>[Si:13]([O:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=C1CC(O)c2ccc(F)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A solution of 3-hydroxy-6-fluoro-1-indanone (4.09 g, 24.6 mmoles) in dimethylformamide (10 mL) was added to a solution of tert-butyldimethylsilyl chloride (4.60 g, 30.5 mmoles, Aldrich) and imidazole (4.22 g, 62.0 mmoles, Aldrich) in dimethylformamide (20 mL). The solution was stirred at ambient temperature for 18 hours and evaporated in vacuo. The residue was dissolved in dichloromethane (200 mL) and washed with water (6×75 mL) and brine (100 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane:ethyl acetate (95:5). The fractions containing the major spot were combined and evaporated in vacuo, and the residue was dried in a vacuum at ambient temperature for 18 hours to give 4.14 g (60%) of 3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanone as a white solid, mp 56-58° C.;
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH:13][CH:14]=[NH:15])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:12])[CH:11]=2)[N:6]=1.[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17]>O1CCCC1>[CH3:1][C:2]1[N:3]2[C:4]([C:16](=[O:17])[NH:15][CH:14]=[N:13]2)=[C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:12])[CH:11]=2)[N:6]=1
Reactant: Cc1nc(-c2cnn(C)c2)cn1NC=N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1nc(-c2cnn(C)c2)c2c(=O)[nH]cnn12
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
N-[2-Methyl-4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]imidoformamide (58.3 g, 285 mmol) was combined with 1,1′-carbonyldiimidazole (98%, 59.0 g, 357 mmol) in tetrahydrofuran (1140 mL) at 63° C., and the suspension was stirred for 2.5 hours at 65° C. The mixture was cooled and concentrated in vacuo; the resulting solid was slurried with methanol (400 mL), warmed to reflux for 20 minutes and cooled to 7° C. The solid was collected to provide C1 as a pale yellow solid. Yield: 45.9 g, 199 mmol, 70%. LCMS m/z 231.1 (M+1). 1H NMR (500 MHz, DMSO-d6) δ 2.48 (s, 3H), 3.88 (s, 3H), 7.79 (s, 1H), 8.08 (s, 1H), 8.37 (s, 1H), 11.59 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[NH:55])[C:10]1[S:14][C:13]([S:15][CH3:16])=[C:12]([S:17]([C:20]2[CH:21]=[C:22]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([NH:33]C(OCC[Si](C)(C)C)=O)=[CH:28][C:27]=3[NH:43][C:44](=[O:54])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([OH:53])=[O:52])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:33][C:29]1[CH:30]=[C:31]([CH3:32])[C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([C:12]3[CH:11]=[C:10]([C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[NH:55])[S:14][C:13]=3[S:15][CH3:16])(=[O:18])=[O:19])[CH:21]=2)=[C:27]([NH:43][C:44](=[O:54])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([OH:53])=[O:52])[CH:28]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)OCC[Si](C)(C)C)cc2NC(=O)NCCCCCC(=O)O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2NC(=O)NCCCCCC(=O)O)c1
Temperature: 40 °C
Yield: 57.3 %

Procedure:
A solution of 6-{3-[3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-hexanoic acid ((Example 259: step b) 0.422 g, 0.506 mmol) in dry THF (20 mL) was treated with tetrabutylammonium fluoride (1 M in hexanes, 3.39 mL, 3.39 mmol) and stirred at 40° C. 4 h. Solvents were evaporated in vacuo. The residue was taken up in CH2Cl2 and washed with water (4×50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (4% MeOH in CH2Cl2) afforded the product 6-(3-{4-amino-3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-hexanoic acid (0.200 g, 57%) as an off-white solid. The material was combined with 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (0.252 g, 0.870 mmol) and acetic acid (0.5 mL) in MeOH (10 mL) and was stirred at 40° C. 2 h. The solvent was removed in vacuo. Silica gel chromatography (4% MeOH in CH2Cl2 then 10% MeOH in CH2Cl2) afforded the title compound (0.215 g, 80%) as a white solid. 1H-NMR (CD3OD): δ 8.22 (s, 1H), 8.06 (m, 1H), 7.89 (m, 1H), 7.72 (m, 1H), 7.69 (m, 1H), 7.53 (m, 1H), 7.32 (m, 1H), 3.01 (m, 2H), 2.66 (s, 3H), 2.27 (t, 2H, 7.4 Hz), 1.97 (s, 3H), 1.57 (m, 2H), 1.54 (s, 18H), 1.51 (s, 9H), 1.37 (m 2H), 1.27 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+].O.O>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24][S:1][C:2]3[NH:11][C:10](=[O:12])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:22][CH:21]=2)=[O:19])=[CH:28][CH:29]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: O=c1[nH]c(S)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)c1ccc(CSc2nc3ccccc3c(=O)[nH]2)cc1
Yield: 80.3 %

Procedure:
A solution of 2-mercapto-4(3H)-quinazolinone (1.78 g), 4-(4-chlorobenzoyl)benzyl bromide (3.07 g) and 1N-sodium hydroxide/water (10.5 ml) in ethanol (20 ml) was stirred at room temperature for 30 minutes. To the reaction mixture was added water and the resulting precipitate was collected by filtration, washed with water, methanol and ethyl acetate, dried, and recrystallized from ethyl acetate to provide the title compound as colorless solid (3.24 g).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20]([O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Br)[CH3:21]>CN(C=O)C.C(OCC)C>[CH2:20]([O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH3:21]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 125.4 %

Procedure:
To a suspension in dry DMF of 4-phenylphenol (4.99 g,.29.4 mmol) and cesium carbonate (14.35 g, 44.0 mmol) was added ethyl-4-bromobutyrate (8.85 g, 45.3 mmol) in a single portion and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl ether and extracted with pH 7 buffer. The organic phase was washed twice with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 4-(4-phenylphenoxy)butanoic acid ethyl ester (10.48 g) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH3:13])([CH3:12])[C@@H:5]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[NH2:6].C(N(CC)CC)C.S=[C:22]1[CH2:26][S:25][C:24](=[O:27])[NH:23]1>C(O)C>[CH3:2][O:3][C:4]([CH3:13])([CH3:12])[C@@H:5]([C:7]([N:9]([CH3:10])[CH3:11])=[O:8])[NH:6][C:22]1[CH2:26][S:25][C:24](=[O:27])[N:23]=1
Reactant: COC(C)(C)[C@H](N)C(=O)N(C)C
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(C)(C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude product containing 3-methoxy-N,N-dimethyl-L-valinamide hydrochloride obtained in B) (697 mg) and triethylamine (810 mg) in ethanol (10 mL) was added 4-thioxothiazolidin-2-one (533 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (560 mg).