Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:19]1[CH2:23][O:22]C(C)(C)[O:20]1)[CH2:3][NH:4][C:5](=[O:18])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[C:7]=1[OH:17].O>CO>[OH:1][CH:2]([CH:19]([OH:20])[CH2:23][OH:22])[CH2:3][NH:4][C:5](=[O:18])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([C:13]([F:15])([F:16])[F:14])[C:7]=1[OH:17]
Reactant: CC1(C)OCC(C(O)CNC(=O)c2cc(F)cc(C(F)(F)F)c2O)O1
Solvent: O
Solvent: CO
Product: O=C(NCC(O)C(O)CO)c1cc(F)cc(C(F)(F)F)c1O

Procedure:
6.86 g (15 mmol) of 5-fluoro-2-hydroxy-3-(trifluoromethyl)-benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in 30 ml of methanol, 30 ml of water and 300 mg of cation exchanger Amberlyst 15 are added and refluxed for 2 hours. The ion exchanger is then filtered off, 250 mg of palladium-carbon (10%) is added to the filtrate and hydrogenated for 1 hour at normal pressure. The catalyst is then filtered off, the filtrate is evaporated to dryness in a vacuum and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane/methanol. 3.08 mg (9.41 mmol)=62.7% of the theoretical yield of the compound is obtained as an amorphous solid.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8](=[N:10][OH:11])[CH3:9].[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[C:19]([C:21](=[O:23])[CH3:22])[C:18](F)=[C:17]([F:25])[C:16]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33]>C1COCC1>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[C:19]([C:21](=[O:23])[CH3:22])[C:18]([O:11][N:10]=[C:8]([CH3:9])[CH3:7])=[C:17]([F:25])[C:16]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33]
Reactant: CC(C)=NO
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)=O)c(ON=C(C)C)c(F)c1Nc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
t-BuOK (0.47 mL, 1.0 M in THF) was added to propan-2-one oxime (35 mg, 0.47 mmol). After stirring for 30 minutes, THF (0.5 mL) was added, and the reaction mixture was cooled to −78° C. A solution of 5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (6) (50.0 mg, 0.147 mmol) in THF (1 mL) was added. The reaction mixture was slowly warmed to 0° C. and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl, diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give 5-acetyl-2-(2-chlorophenylamino)-3-fluoro-4-isopropylideneaminooxybenzoic acid methyl ester. The recovered oxime was suspended in a 1:1 mixture of 5% aqueous HCl and MeOH (30 mL) and heated to reflux. After 1 hour, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated. Purification by flash column chromatography using the Biotage system (40% methylene chloride in hexanes) provided 17 mg (35% for two steps) of the desired product (7).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[C:31]1([CH:37]([NH2:45])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([CH:37]([NH:45][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(Cc1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(Cc1ccccc1)c1ccccc1

Procedure:
A procedure similar to that described in Example 3(b) was repeated, except that S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1,2-diphenylethylamine were employed as starting materials, in relative proportions similar to those used in that Example, to give the title compound in a quantitative yield.
Reaction SMILES: [H][H].C([O:10][NH:11][C:12](=[O:33])[CH:13]([CH3:32])[C:14]1([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:27])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[OH:10][NH:11][C:12](=[O:33])[CH:13]([CH3:32])[C:14]1([CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:27]
Reactant: CC(C)CC1(C(C)C(=O)NOCc2ccccc2)CCN(CCc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC1(C(C)C(=O)NO)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
An atmosphere of hydrogen is placed over a mixture of N-benzyloxy-α-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (80.0 mg, 0.189 mmol), MeOH (4.5 mL) and Pearlman's catalyst (15 mg). The mixture is stirred at room temperature for 4 hours. The mixture is filtered, the solids rinsed with MeOH (4×5 mL), and the filtrate concentrated to give 55.9 mg of an oil. Crystallization from hexane provided 46.9 mg (75%) of the title compound as a white solid (mp 107°-108° C.).
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[C:11]1([N:17]2[C:21]([C:22](=[O:24])[CH3:23])=[CH:20][CH:19]=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[O:24]=[C:22]([C:21]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[CH:19][CH:20]=1)[CH2:23][C:1]([O:5][CH2:6][CH3:7])=[O:8]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccnn1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)c1ccnn1-c1ccccc1

Procedure:
To a mixture of diethyl carbonate (20.0 mL) and 60% NaH (0.34 g) was added 1-(1-phenyl-1H-pyrazol-5-yl)ethanone (1.30 g) at room temperature, and the mixture was heated under reflux for 2 hr. To the reaction mixture was added water, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (1.10 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:13]3=[N:14][S:15](=[O:18])(=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(C2=CC=CN3CCS(=O)(=O)N=C23)ccc1-c1ccccc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C2CCCN3CCS(=O)(=O)N=C23)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
Platinum(IV) oxide (60 mg) was added to a solution of 9-(2-methylbiphenyl-4-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (265 mg) in THF (dry) (75 mL), MeOH (75 mL) and the mixture was stirred at room temperature under hydrogen for 12 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was crystallized from MeCN-THF/IPE to give the title compound (200 mg) as a colorless crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=12)[CH3:2].C(O)(=O)C.Cl>O>[CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][C:30]([F:31])([F:33])[F:32])=[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC)C2=O)c(F)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOc1c2c(c(OCC(F)(F)F)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1F)C2=O
Yield: 65.2 %

Procedure:
Ethyl (4-{4-(ethyloxy)-1,3-dioxo-9-[(2,2,2-trifluoroethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}-3-fluorophenyl)acetate (0.119 g, 0.23 mmol) was heated to 100° C. in a 1:1 mixture of acetic acid:2N aqueous hydrochloric acid (10 ml) for 2 hours. On addition of water, the resulting cream solid was collected by filtration and washed with water. This was purified by MDAP to give the title compound as a white solid (0.073 g, 0.15 mmol). LC/MS: Rt=3.38, [MH]+ 492.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][C:16]=2[C:27]([F:30])([F:28])[F:29])=[N:22]1)=[O:12])[CH3:9]
Reactant: Cc1cc(Oc2ccc(Cl)cc2C(F)(F)F)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2ccc(Cl)cc2C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.2 %

Procedure:
Triethylamine (0.17 g, 1.65 mmol) and ethyl isocyanate (0.31 g, 2.2 mmol) were added to a solution of 3-(4-chloro-2-trifluoromethylphenyloxy)-5-methylpyrazole (0.55 g, 2.0 mmol) in ethyl acetate (5 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a colorless viscous substance of N-ethyl-3-(4-chloro-2-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.53 g, yield: 75.9%). 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (t, J=7.3 Hz, 3H), 2.59 (d, J=0.7 Hz, 3H), 3.37 (q, J=7.3 Hz, 2H), 5.73 (q, J=0.7 Hz, 1H), 6.91 (br s, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.49 (dd, J=2.5 and 8.8 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:13][NH2:14].[BH4-].[Na+].O>CO>[CH3:13][NH:14][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: CN
Reactant: Cn1ccc2cc(C=O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1ccc2c(ccn2C)c1
Reaction time: 3 h
Yield: 99.6 %

Procedure:
N-Methylindole-5-carbaldehyde (800 mg, 5.1 mmol) was dissolved in anhydrous methanol (15 mL). Methylamine (7.15 mL of 2M solution in methanol, 15.3 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (15 mL). Sodium borohydride (194 mg, 5.1 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated to an orange oil. Sodium hydroxide (5 mL, 1N) was added and the product was extracted with ethyl acetate (3×20 mL), dried over MgSO4 and concentrated to afford the title compound as an orange oil (885 mg, 100%). 1H NMR (200 MHz, CDCl3) δ 7.57 (s, 1H), 7.35-7.11 (m, 3H), 6.51 (d, J=2.9 Hz, 1H), 3.85 (s, 2H), 3.79 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=O)[CH:19]=[CH:20][CH:21]=1.[Cl:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1.ClCCCl>CCOCC>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([C:29]2[S:28][C:27]([Cl:26])=[CH:31][CH:30]=2)=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Clc1cccs1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOCC
Solvent: ClCCCl
Product: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 500-mL round-bottomed flask was added silica gel 60 (21 g, 350 mmol) and the flask was heated with a heat gun under high vacuum for 30 min. The system was cooled to room temperature and phosphorus pentoxide (8.75 mL, 148 mmol) was added. The mixture was stirred at 110° C. (oil bath) under high vacuum for 120 min. The mixture was allowed to cool to room temperature. 3-chlorophenylacetic acid (15.6 g, 91 mmol), 2-chlorothiophene (33.8 mL, 366 mmol) and DCE (50 mL) were added. The reaction mixture was stirred at reflux for 4 hours. LCMS analysis showed the reaction was complete. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with ether (300 mL) and filtered. The organic solution was concentrated under reduced pressure. The residue was triturated with hexane to afford the title compound as an off-white solid. The hexane mother liquid was concentrated and purified by flash chromatography (SiO2, 0 to 30% EtOAc/Hex, a gradient elution) provided another batch of the title compounde as a light yellow solid. Mass Spectrum (ESI) m/z=271 (M+1).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)(=[O:17])=[O:16])=[O:13])[N:5]=1.[H][H]>[Pd].C(O)(=O)C>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[S:15]([NH:14][C:12]([NH:11][C:6]1[N:5]=[C:4]([O:3][CH3:2])[CH:9]=[C:8]([CH3:10])[N:7]=1)=[O:13])(=[O:17])=[O:16]
Reactant: [H][H]
Reactant: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1
Agent: [Pd]
Agent: [Na]
Solvent: CC(=O)O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2N)n1

Procedure:
A suspension containing 2 g of the sodium salt of N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-2-nitrobenzenesulfonamide, 25 ml of glacial acetic acid and 0.2 g of 10% palladium on carbon was shaken in a Paar apparatus at 40 p.s.i.g. hydrogen at ambient temperature. After twenty-four hours, no further pressure drop was observed. The reaction mixture was filtered and the filtrate stripped to yield a small amount of the desired product. The solids which contained most of the product and catalyst, were stirred with 20 ml of 5% aqueous sodium hydroxide, filtered and the filtrate combined with the residue from the acetic acid filtrate. After refiltering the resultant alkaline solution, it was acidified to pH 3 with dilute hydrochloric acid to precipitate the desired compound. After filtration and drying, the compound, when heated to 160°, underwent a transformation in physical appearance and subsequently melted at 210°-215°. The infrared absorption pressure for the compound showed absorption peaks at 3300 and 3400 cm-1, consistent for an amino substituent, and absorption bands at 1700, 1690, 1600 and 1550 cm-1 which are consistent for the amino-carbonyl sulfonamide function. The product thus obtained was sufficiently pure for the purposes of this invention.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4C(F)(F)F)cc23)CC1
Yield: 90.3 %

Procedure:
Beginning with 13 mg (0.056 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 13.0 mg (0.062 mMol) 2-trifluoromethylbenzoyl chloride, 20.3 mg (89%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[OH:12])[O:8][C:7]([CH3:14])=[C:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:5]2O.O.[NH2:25][NH2:26]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[C:7]([CH3:14])[NH:26][N:25]=2)[C:9]([OH:8])=[C:10]([CH3:13])[C:11]=1[OH:12]
Reactant: NN
Reactant: COc1ccc(C2=C(C)Oc3c(cc(Cl)c(O)c3C)C2O)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c(-c3cc(Cl)c(O)c(C)c3O)n[nH]c2C)cc1

Procedure:
6-Chloro-3-(4-methoxy-phenyl)-2,8-dimethyl-4H-chromene-4,7-diol (1 eq) was taken up in a 1:1 solution of EtOH:Hydrazine hydrate and heated under microwave conditions (120° C., 300 sec). The solution was concentrated in vacuo, residue quenched with cold water, extracted with ethyl acetate and purified by flash chromatography (neat DCM). The yellow oil was then triturated with ether:hexane to give 4-chloro-6-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-benzene-1,3-diol as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23].N1C=CN=C1>CN(C=O)C>[CH3:23][C:22]([Si:26]([CH3:29])([CH3:28])[O:17][CH2:16][C:13]1[CH:12]=[C:11]([C:18]([O:20][CH3:21])=[O:19])[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:15][CH:14]=1)([CH3:25])[CH3:24]
Reactant: COC(=O)c1cc(CO)ccc1-c1cc(OC)ccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A 50 mL round bottom flask was charged with 66.13E (1.19 g, 4.1 mmol), tert-butyldimethylchlorosilane (commercially available from Aldrich) (0.68 g, 4.5 mmol), DMF (4 mL), and imidazole (0.70 g, 10 mmol). The mixture was stirred overnight at 25° C. and then diluted with hexanes. The organic phase was washed with 1 N HCl, water, and brine, dried (MgSO4), and concentrated to afford 83.18A (1.6 g, 96% yield) as a colorless oil. The product thus obtained was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:8]([C:11]1[CH:12]=[C:13]([C:16]([NH:18][N:19]([CH2:35][C@@H:36]([OH:40])[C:37]([OH:39])=[O:38])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[F:34])=[CH:23][CH:22]=2)=[O:17])[NH:14][N:15]=1)(=[O:10])[CH3:9].C1COCC1>>[C:8]([C:11]1[CH:12]=[C:13]([C:16]([NH:18][N:19]([CH2:35][C@@H:36]([O:40][C:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4])[C:37]([OH:39])=[O:38])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[F:34])=[CH:23][CH:22]=2)=[O:17])[NH:14][N:15]=1)(=[O:10])[CH3:9]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](OC(=O)CC(C)C)C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Isovaleryl chloride (51.4 μL, 421.2 μmol) and (R)-3-[N′-(5-acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (20.0 mg, 42.1 μmol) were combined in THF (205 μL, 2.5 mmol), and stirred overnight at room temperature. The solvent was evaporated and the residue was purified (reverse phase HPLC column) to yield the title compound (11.8 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C27H28ClFN4O6, 559.17. found 559.1.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][CH:29]([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][CH:29]([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC(C)CC(=O)O
Agent: Cl
Product: CC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (48 mg, 72%), MS (ISP) m/z=415.5 [(M+H)+], mp 187° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) and 3-methyl-butyric acid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].C([O:13][C:14](=O)[CH:15]([CH3:19])[C:16](=O)[CH3:17])C>CCO.CC(O)=O>[OH:13][C:14]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:16]([CH3:17])[C:15]=1[CH3:19]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: N#Cc1ccnc(NN)c1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nn(-c2cc(C#N)ccn2)c(O)c1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carbonitrile (134 mg, 1 mmol, PREPARATION 2) and 2-methyl-3-oxo-butyric acid ethyl ester (158 mg, 1.1 mmol) in EtOH (5 mL) and AcOH (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (CH2Cl2) to afford the title compound (100 mg, 47%) as an orange solid. [M+H] Calc'd for C11H10N4O, 215; Found, 215.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[NH:12][CH:13]=[N:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:23]1[O:39][C:38]([CH2:46][O:47][S:48]([CH3:51])(=[O:50])=[O:49])([CH2:40][O:41][S:42]([CH3:45])(=[O:44])=[O:43])[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:24]1[O:25][C:26](=[O:28])[CH3:27])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C(#N)C>[C:26]([O:25][C@@H:24]1[C@H:29]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]([CH2:46][O:47][S:48]([CH3:51])(=[O:50])=[O:49])([CH2:40][O:41][S:42]([CH3:45])(=[O:43])=[O:44])[O:39][C@H:23]1[N:18]1[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:11]2[C:15](=[N:14][CH:13]=[N:12]2)[N:16]=[CH:17]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC1OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)O[C@H]1[C@H](n2cnc3ncnc-3c2NC(=O)c2ccccc2)OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
6-N-Benzoyladenine (11.02 g.; 46.1 mmol) was dried in vacuo overnight. 1,2-Di-O-acetyl-3-O-benzyl-4-C-methanesulfonyloxymethyl-5-O-methanesulfonyl-D-ribofuranose (19.6 g.; 38.4 mmol) (3) was coevaporated in anh. acetonitrile (3×50 mL) and dried in vacuo overnight. 3 was redissolved in anh. 1,2-dichloroethane (stored over molecular sieves) (175 mL), 6-N-Benzoyladenine was added followed by N,O-bistrimethylsilylacetamide (25.1 mL; 101.3 mmol). The mixture was refluxed for 1 h and cooled to rt. TMS-triflate (13.9 mL; 76.8 mmol) was added and the mixture was refluxed for 5h, stirred overnight at rt, refluxed for further 24 h (red-brown solution) and cooled to rt. The solution was poured into an ice-cold saturated aqueous solution of NaHCO3 (200 mL) and stirred for 0.5 h. The precipitate was filtered off, the phases were separated and the organic phase was washed with a saturated aqueous solution. of NaHCO3 (3×150 mL), dried (Na2SO4) and evaporated. Purification by silica gel column chromatography (1-1.5% MeOH in CH2Cl2) gave 4D as a slightly yellow solid in 68% yield (18.0 g.). NMR was consistent with the data reported in an earlier patent.