Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=O)=[CH:9][CH:8]=[CH:7]2.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:24](=[O:31])[NH:23][CH2:22]2)=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.C(OCC)C.CC(O)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]3([CH2:26][CH2:27][N:28]([CH2:12][C:10]4[C:11]5[C:6](=[CH:5][CH:4]=[CH:3][C:2]=5[CH3:1])[CH:7]=[CH:8][CH:9]=4)[CH2:29][CH2:30]3)[C:24](=[O:31])[NH:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: Cc1cccc2cccc(C=O)c12
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cccc2cccc(CN3CCC4(CC3)C(=O)NCN4c3ccc(F)cc3)c12
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A 1-L 3-neck flask equipped with an overhead stirrer and a thermocouple was charged with 8-methyl-naphthalene-1-carbaldehyde (13.75 g, 0.08 mol) and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (21.5 g, 0.085 mol) under N2 in CH2Cl2 (500 mL). After stirring for 20 min, HOAc (1 mL) was added followed by careful addition of solid NaBH(OAc)3 (33.4 g, 0.157 mol). The mixture was stirred for 16 h at room temperature (suspension becomes a solution). The reaction was then warmed at 50° C. for 2 h, cooled down to room temperature and then treated with 0.5 N NaOH (50 mL), stirred for 10 min and then diluted with CH2Cl2 (100 mL). The organic layer was isolated and dried over MgSO4. The solvent was evaporated to yield a residue, which was suspended in diethyl ether, stirred for 20 min, filtered and dried in a 60° C. vacuum oven to yield 1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-one as a white solid;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[C:14](C)[CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:27]N(C)C=O.[CH2:32](I)[CH3:33]>O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([O:20][CH2:32][CH3:33])=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: CCI
Reactant: Cc1cc(CNC(=O)OC(C)(C)C)c(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1c([N+](=O)[O-])ccc(C)c1CNC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of the compound (350 mg) obtained in Example 520b, cesium carbonate (404 mg), dimethylformamide (15 ml) and ethyl iodide (0.4 ml) was stirred at 60° C. for 2 h. To the reaction mixture, ethyl acetate and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=2:8) to give the titled compound quantitatively.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=O)[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.[CH3:11][CH:12]([CH3:15])[CH2:13][NH2:14].[S-:16][C:17]#[N:18].[K+].II>C(#N)C>[CH2:13]([N:14]1[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]=2[S:16][C:17]1=[NH:18])[CH:12]([CH3:15])[CH3:11]
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: CC(C)CN
Reactant: N#C[S-]
Agent: II
Agent: [K+]
Solvent: CC#N
Product: CC(C)Cn1c2c(sc1=N)C(C)(C)OC2(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 23 %

Procedure:
To a solution of 2,2,5,5-tetramethyldihydrofuran-3(2H)-one (2.0 g, 14.1 mmol, Aldrich) in acetonitrile (10 mL) were added molecular sieves (2.0 g) and 2-methylpropan-1-amine (1.0 mL, 12.8 mmol, Aldrich). The reaction mixture was stirred at 60° C. for 48 hr and then filtered through celite. To the filtrate were added potassium thiocyanate (1.65 g, 17.0 mmol, Aldrich). The reaction mixture was stirred at 60° C. until the solids were dissolved and then iodine (6.5 g, 25.6 mmol, EMD chemicals) was added. The reaction mixture was stirred 60° C. for 48 hr, cooled, concentrated and dissolved in ethyl acetate (15 mL). The solution was washed with sodium metabisulfite 20% (35 mL) by mixing the layers for 30 min. The organic layer was washed twice with HCl 1N (35 mL). The aqueous layers (sodium metabisulfite and HCl) were combined and the pH was adjusted to pH˜9 by adding NH4OH and then extracted with ethyl acetate (4×40 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to obtain the crude product (0.75 g) of the title compound. MS (ESI+) m/z 255 (M+H)+
Reaction SMILES: C([O:8][C@@H:9]([C@@H:11]1[N:16]2[C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]([NH2:27])[C:18]=3[N:28]=[C:15]2[CH2:14][O:13][CH2:12]1)[CH3:10])C1C=CC=CC=1.Cl>CO.[Pd].C(O)C>[NH2:27][C:19]1[C:18]2[N:28]=[C:15]3[CH2:14][O:13][CH2:12][C@H:11]([C@H:9]([OH:8])[CH3:10])[N:16]3[C:17]=2[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: C[C@@H](O)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 24 h
Yield: 90.6 %

Procedure:
(11R)-11-[(1R)-1-(Benzyloxy)ethyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (512 mg, 1.37 mmol) was dissolved in 30 mL of methanol and the solution was placed in a pressure bottle. Palladium on carbon (10%, 200 mg) and 2.5 mL of 3 M HCl in ethanol were then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 24 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in H2O and the solution was made basic by the addition of concentrated aqueous NH4OH solution. The aqueous solution was extracted with 10% MeOH/CHCl3 several times and the combined organic layers were concentrated under reduced pressure. Chromatography (SiO2, 25-50% CMA/CHCl3) gave an off-white powder. Crystallization from ethyl acetate and methanol gave 353 mg of the title compound as white needles, mp 215.3-218.6° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH3:24])=[O:22])=[C:9]([CH3:25])[N:8]=[C:7]1[S:26]CC1C=CC(OC)=CC=1)=[O:5])[CH3:2].F[C:37](F)(F)[C:38]([OH:40])=O.[CH2:43](S)C>ClCCl>[CH:9]([O:40][CH:38]([CH3:37])[CH3:43])([CH3:25])[CH3:10].[CH2:1]([NH:3][C:4]([N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH3:24])=[O:22])=[C:9]([CH3:25])[NH:8][C:7]1=[S:26])=[O:5])[CH3:2]
Reactant: CCS
Reactant: CCNC(=O)N1C(SCc2ccc(OC)cc2)=NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: CCNC(=O)N1C(=S)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 165 %

Procedure:
1-[(Ethylamino)carbonyl]-1,6-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-4-methyl-6-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, methyl ester (0.94 g, 1.89 mmole) in 10 ml of dry dichloromethane under argon at room temperature was treated with trifluoroacetic acid (0.5 ml, 0.74 g, 6.5 mmole) and ethanethiol (0.35 ml, 0.29 g, 4.67 mmole) and the mixture was allowed to stir overnight. Volatiles were removed in vacuo and the residue upon trituration with isopropyl ether, gave 0.59 g of the title compound, melting point 244°-246° C.
Reaction SMILES: [OH-].[Na+].[C:3]1([CH2:9][O:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH2:20]([N:22]([CH2:25]C)[CH2:23]C)C.Cl.C([N:30]=C=NCCCN(C)C)C>O1CCCC1.C(Cl)Cl>[CH3:20][N:22]([CH2:25][C:6]1[CH:7]=[CH:8][C:3]([C:9]2[O:10][C:11](=[O:12])[C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[N:30]=2)=[CH:4][CH:5]=1)[CH3:23]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(OCc1ccccc1)C1CCCCC1
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)Cc1ccc(C2=NC3(CCCCC3)C(=O)O2)cc1
Reaction time: 1 h
Yield: 68 %

Procedure:
0.7 ml of 2N aqueous sodium hydroxide solution was added to a solution of 100 mg (0.25 mmol) of 1-[[[4-(dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester in 1 ml of tetrahydrofuran, and the mixture was heated under reflux overnight. After the mixture was neutralized by concentrated hydrochloric acid, the reaction solution was distilled off under reduced pressure. 3 ml of methylene chloride, 126 mg (1.25 mmol) of triethylamine and 96 mg (0.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to the residue, and the mixture was stirred for 1 hour. The reaction solution was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 52 mg (68%) of the title compound.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[C:9]([O:49][CH3:50])=[C:10]([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([CH3:48])=[C:25]([CH:47]=2)[O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)[CH:28]=2)=[O:20])[CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1.C(N(CC)CC)C.O>ClCCl>[C:14]([C:12]1[CH:13]=[C:8]([NH:7][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[C:9]([O:49][CH3:50])=[C:10]([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([CH3:48])=[C:25]([CH:47]=2)[O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:38][CH2:39]3)[CH:28]=2)=[O:20])[CH:11]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: O=C(Cl)C1CC1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NC(=O)c1ccc(C)c(Oc2ccnc(CC3CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1c(NC(=O)c2ccc(C)c(Oc3ccnc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)cc(C(C)(C)C)cc1NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At ambient temperature 36 μl cyclopropanecarboxylic acid chloride are added to a solution of 160 mg tert-butyl 4-{4-[5-(3-amino-5-tert-butyl-2-methoxy-phenylcarbamoyl)-2-methyl-phenoxy]-pyridin-2-ylmethyl}-piperidine-1-carboxylate and 70 μl triethylamine in 2 ml dichloromethane. The solution is stirred overnight at ambient temperature and then mixed with water. The mixture is extracted with dichloromethane, and the combined extracts are washed with water and saturated aqueous saline solution, dried (MgSO4) and evaporated down. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate (50:500:100) as eluant.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1.[CH3:17][S:18]SC.O>CCCCCC.CCOCC>[Br:16][C:14]1[CH:13]=[CH:12][C:9]2[S:10][CH:11]=[C:7]([S:18][CH3:17])[C:8]=2[CH:15]=1
Reactant: CSSC
Reactant: Brc1ccc2scc(Br)c2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CSc1csc2ccc(Br)cc12
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of n-butyl-lithium in hexane (35 ml of 1.55M solution) was added dropwise to a stirred solution of 3,5-dibromobenzo[b]thiophene (14.6 g) in dry ether (600 ml) at -70° C. under dry nitrogen. The mixture was stirred at -70° C. for 30 minutes and then a solution of dimethyl disulphide (4.90 g) in 10 ml of dry ether was added with stirring over 5 minutes. The resulting mixture was stirred at -70° C. for 4 hours and then allowed to warm up to room temperature. Water (50 ml) was added and the organic layer was separated, washed with water and dried (Na2SO4). Evaporation of the ether gave an oil which was chromatographed on silica gel. Elution with petrol (b.p. 40°-60°) gave a small amount of impurity followed by pure product. The product-containing fractions were evaporated and the residue was distilled to give 5-bromo-3-methylthiobenzo[b]thiophene (10.36 g), b.p. 140°-144° @ 0.6 mm, m.p. 56°-57°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](C)[C:11](Cl)=[CH:10][C:9]=1[NH:16][C:17](=[O:42])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[C:31]([CH2:33][O:34]C3CCCCO3)[N:30]=[C:29]([CH3:41])[CH:28]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[CH2:51]([Cl:53])Cl>>[Cl:53][C:51]1[C:12]([CH3:11])=[CH:13][C:8]2[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[C:29]([CH3:41])[N:30]=[C:31]([CH2:33][OH:34])[CH:32]=4)[CH:22]=3)[CH2:18][C:17](=[O:42])[NH:16][C:9]=2[CH:10]=1
Reactant: ClCCl
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)cc(CO)n1

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-methyl-2-(3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M297) (0.45 g, 0.74 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (200 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17](I)[CH:18]=1)[CH3:11].[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][C:29]#[CH:30])([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CCN(CC)CC.[Cu]I.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:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][C:29]#[C:30][C:17]1[CH:16]=[N:15][C:14]([NH2:20])=[C:13]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[CH:18]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Oc1cc(C#CCNC(=O)OC(C)(C)C)cnc1N)c1c(Cl)ccc(F)c1Cl
Yield: 29.2 %

Procedure:
To a solution of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (7.1 g, 16.6 mmol) and prop-2-ynyl-carbamic acid tert-butyl ester (3.1 g, 20.0 mmol) in THF (60 mL) and Et3N (60 mL) was added CuI (63 mg, 0.3 mmol) and Pd(PPh3)4 (384 mg, 0.3 mmol). The mixture was stirred under nitrogen and monitored by TLC until the reaction was complete. The mixture was extracted with EtOAc and washed by water. The crude product was purified on a silica gel column eluting with 20-40% EtOAc in hexanes to provide (3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester (2.2 g, 29% yield).
Reaction SMILES: C(=O)([O-])[O-].[CH:5]1[C:10](N=C=S)=[CH:9][C:8]2[C:14]([O:16][C:17]3([C:27]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=4[O:25][C:19]4[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:18]3=4)[C:7]=2[CH:6]=1)=[O:15].C1(=O)OC(=O)CC1>O.CS(C)=O>[CH:5]1[CH:10]=[CH:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]([C:17]2[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[O:25][C:26]3[C:27]=2[CH:28]=[CH:29][C:30]([CH:31]=3)=[O:32])[CH:6]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)O1
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Each of the HA-DETA, HA-DAHP, and HA-DAP obtained in Example 4-2 and Example 4-3-1 was dissolved in distilled water (Milli Q water), so as to prepare a solution of a concentration of 20.0 mg/ml. Thereafter, a 0.2 M carbonate buffer (pH 9.0) was added to the prepared solution, resulting in a concentration of 10.0 mg/ml. Thereafter, fluorescein isothiocyanate that was 0.07 mole times to an HA unit was dissolved in DMSO that was 1/10 the volume of a modified HA solution. The DMSO solution was then added to the above solution, and the obtained mixture was then stirred in the dark at room temperature for 1 hour. Thereafter, succinic anhydride that was 40 mole times to the HA unit was dissolved in DMSO that was 1/10 the volume of the HA-AM solution. The DMSO solution was then added to the above solution, and the obtained mixture was then stirred in the dark at room temperature for 30 minutes. Thereafter, each sample was dialyzed against large excess amount of 0.5 M NaCl aqueous solution for purification, and the external dialysis solution was then exchanged with distilled water (Milli Q water), followed by further dialysis and purification (Spectrapore 4; molecular weight cut off (MWCO): 12 k-14 kDa). The obtained aqueous solution was freeze-dried, so as to obtain a fluorescein-labeled modified HA.
Reaction SMILES: C(=O)=O.CC(C)=O.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:19]([N:26](C1CCCCC1)[C@H](C=O)C)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[C:22]([O:21][C:19]([NH:26][CH:15]([CH:14]=[CH2:13])[CH2:16][CH:17]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:18]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: [Li]CCCC
Reactant: CCCCCC
Reactant: C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1CCCCC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C=O
Agent: [Br-]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C=CC(CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of methyltriphenyl phosphonium bromide (10.97 g, 30.70 mmol) in anhydrous tetrahydrofuran (200 ml) at -78° C. (dry ice/acetone bath) under an argon atmosphere, was added n-butyl lithium (19.8 ml of a 1.55M hexane solution) dropwise over the course of 5 min. After 10 min, the -78° C. bath was replaced with a 0° C. bath for 0.5 h, at which time the resulting orange solution was cooled again to -78° C. The solution was then added dropwise by cannula to a stirred -78° C. solution of Boc-cyclohexylalaninal (27.91 mmol) in anhydrous tetrahydrofuran (30 ml) over the course of 0.5 h. The mixture was then allowed to warm to room temperature during a 3 h period after which water (150 ml) was added. Extraction with hexane (4×100 ml) provided a combined organic phase which was washed with brine (100 ml), dried (Na2SO4), and concentrated. Chromatography with ether/hexane (1/9) provided the desired compound. Mass spectrum: (M+H)+ =254.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)O)[CH:5]=[CH:4][N:3]=[CH:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(COC)OC>[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1/[CH:9]=[CH:8]/[CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OC(CCCn1ccnc1)c1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCOC
Solvent: O
Product: C(=C/c1ccc2ccccc2c1)\CCn1ccnc1
Yield: 26.7 %

Procedure:
A mixture of 4-(1H-imidazol-1-yl)-1-(2-naphthyl)-1-butanol (0.450 g) and p-toluenesulfonic acid hydrate (0.589 g) in dimethoxyethane (20 ml) was refluxed for 16 hours. To the mixture was added water, then the whole was concentrated and extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel (ethyl acetate-MeOH=20:1) followed by crystallization from ethyl acetate-hexane to give the titled compound (0.112 g) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][N:20]=[N+]=[N-])[O:16][C:15]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10](C)=[N:9]1.N[CH2:25][C@@H]1OC(=O)N(C2C=CC(N3C=C(C)N=N3)=C(F)C=2)C1.CO>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][N:11]([CH3:25])[CH:10]=[N:9]1
Reactant: Cc1ncn(-c2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)n1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CN)OC3=O)cc2F)nn1
Solvent: ClCCl
Solvent: CO
Product: CN1C=NN(c2ccc(N3CC(CN)OC3=O)cc2F)C1

Procedure:
3-[3-Fluoro-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-5-(azidomethyl)oxazolidin-2-one (Intermediate 24) (1.8 g, 5.67 mmol) was hydrogenated as described for Intermediate 16. Chromatography on silica gel with 3-7% methanol in dichloromethane gave the title compound (1.28 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[NH:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[NH:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CCOC(=O)c1[nH]c(Br)nc1C
Product: CCOC(=O)c1[nH]c(-n2ccc(OCc3ccccc3)cc2=O)nc1C
Yield: 26 %

Procedure:
Following the procedure as described in Example 12, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-phenylpyridin-2-ol to react with ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate in place of ethyl 2-bromo-4-methylthiazole-5-carboxylate at 130° C. for 64 hours, the title compound was obtained as a colorless solid in 26% yield: mp 135-136° C.; 1H NMR (300 MHz, CDCl3) δ 12.01 (s, 1H), 8.60-8.50 (m, 1H), 7.44-7.36 (m, 5H), 6.21 (dd, J=8.0, 2.6 Hz, 1H), 6.04 (d, J=2.6 Hz, 1H), 5.06 (s, 2H), 4.44-4.29 (m, 2H), 2.59-2.51 (m, 3H), 1.44-1.34 (m, 3H); MS (ES+) m/z 354.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH3:30])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH3:30])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 115 %

Procedure:
(2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (10.8 g, 25.3 mmol) was dissolved in THF (50 mL) and MeOH (50 mL) and to this solution was added LiOH (2.425 g, 101 mmol) in Water (50.0 mL). The reaction mixture was stirred at rt for 16 h. The solvent was removed under vacuum and the resulting aqueous residue was diluted with water, and EtOAc. The mixture was neutralized with 1 N HCl and adjusted the pH˜2.5 and the mixture was extracted with EtOAc. The organic layer was collected, washed with brine, dried over Na2SO4, and concentrated to give crude (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (12 g) as yellow viscous oil. MS: MS m/z 413.2 (M++1).