Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[CH3:6][N:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C=O>C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:7][CH3:6])=[C:11]([CH:12]=1)[C:17](=[N:4][OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CNc1ccc(Cl)cc1C(=NO)c1ccccc1
Yield: 99.7 %

Procedure:
A mixture of 4.0 g (0.1 mole) of powdered sodium hydroxide, 13.9 g (0.2 mole) of hydroxylamine hydrochloride, and 27.4 g (0.1 mole) of N-methyl-N-(2-benzoyl-4-chlorophenyl)formamide in 200 ml of ethanol was refluxed for 3 days. About one-half of the ethanol was distilled off and the reaction mixture was poured into 500 ml of water and then extracted with three 100-ml portions of methylene chloride. The extracts were combined, washed with water, dried (MgSO4) and evaporated to dryness under reduced pressure to give 26 g (100%) of a light yellow glass: 1H nmr (DMSO-d6) partial: δ 2.74 ppm (d, J=5 Hz) and δ 2.94 ppm (d, J=5) for CH3 split by NH; δ 11.26 ppm (45% ) and 11.53 ppm (55%) for =NOH (on addition of D2O, the splitting of the methyl peaks is lost).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].O.[OH-].[Na+:34]>CCO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:34]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Reaction time: 4.5 h
Yield: 64.7 %

Procedure:
A 100 ml round bottom flask was loaded with fluvastatin methyl ester (5.0 g, 11.8 mmole), water (15 ml), EtOH (25 ml) and NaOH (0.49 g). The mixture became clear and was stirred for 4.5 h. The EtOH was evaporated, water (completing to 10 vol.) was added and extracted with ethyl acetate (2×20 ml). The aqueous phase was evaporated, then acetonitrile (70 ml) was added and the mixture was stirred at room temperature over night. The product was isolated by filtration under nitrogen flow, washed with acetonitrile (20 ml) and dried at 40° C. in a vacuum oven for 24 h to obtain 3.31 g (65%) of fluvastatin sodium crystal Form LXXIII.
Reaction SMILES: P(Cl)(Cl)(O[P:4]([O-:14])([O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O)=O.[ClH:17].[CH2:18]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH3:19].CCN(CC)CC>C(Cl)Cl>[Cl:17][P:4]([NH:23][C@H:22]([C:21]([O:20][CH2:18][CH3:19])=[O:25])[CH3:24])([O:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:14]
Reactant: O=P(Cl)(Cl)OP(=O)([O-])Oc1ccc(Cl)cc1
Reactant: Cl
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)NP(=O)(Cl)Oc1ccc(Cl)cc1

Procedure:
Following the procedure described for Step 1 of Example 1, treatment of a DCM (0.16 M) solution of para-chlorophenyl dichlorodiphosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colourless oil as a 1:1 mixture of diastereomers.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10](O)=[O:11].B(F)(F)F.CCOCC>ClCCl.O>[CH3:9][C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:1]([OH:2])[C:3]=1[OH:4])=[O:11]
Reactant: CC(=O)O
Reactant: Oc1ccccc1O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1cccc(O)c1O
Temperature: 25 °C
Yield: 10.4 %

Procedure:
To a solution of 1,2-dihydroxybenzene (28)(2.0 g, 18.2 mmol) in AcOH (1.3 g, 21.7 mmol) was added boron trifluoride diethyl ether (98% in Et2O, 2 mL). The mixture was reacted under microwave irradiation (300 W) for 1.5 min and then cooled to 25° C. The reaction mixture was dissolved in dichoromethane (10 mL) and H2O (about 20 mL). The organic lay was washed with 10% NaHCO3 and then with water, dried over MgSO4 and concentrated. The crude was purified by column chromatography (SiO2, CH2Cl2) to give 30. Yellow solid; yield: 10.4%; mp 76-77° C.; 1H-NMR (CDCl3,200 MHz): δ 2.58 (s, 3H), 5.79 (s, 1H), 6.79 (t, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 12.45 (s, 1H); 13C-NMR (CDCl3, 50 MHz): δ 26.73, 118.79, 119.52, 120.39, 121.44, 145.40, 149.50, 205.08; Anal. calcd for C8H8O3: C, 63.15; H, 5.30. Found: C, 63.10; H, 5.33.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21])=[N+:2]=[N-:3].[C:22]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][O:24][CH2:23]1>ClCCl.O>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:26](=[O:27])[CH2:25][O:24][CH2:23][C:22]([OH:29])=[O:28])=[N+:2]=[N-:3]
Reactant: O=C1COCC(=O)O1
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCN
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NCCOCCOCCOCCOCCOCCNC(=O)COCC(=O)O
Reaction time: 8 h

Procedure:
To a solution of 17-azido-3,6,9,12,15-pentaoxaheptadecanamine (15 g, 50 mmol) in dichloromethane (100 mL) was added diglycolic anhydride (Acros, 6.4 g, 55 mmol). The reaction mixture was stirred overnight. The reaction was monitored by ESI-MS analysis, and more reagents were added to drive the reaction to completion. The solution was concentrated to give a yellow residue which was dissolved in water (250 mL). The product was isolated from the aqueous phase by continuous extraction with dichloromethane over night. Drying and evaporation of the solvent gave a yield of 18 g (85%). The product was characterized by ESI-MS analysis (MH+ calculated: 423.20; found 423.4). The product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[N:14])[C:6]=2[CH:15]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[CH:19]2[CH2:23][CH2:24][CH:25]=[CH:26][CH:18]12.C(O)(=O)C>O>[C:13]([CH2:12][N:7]1[C:6]2[CH:15]=[C:2]([N:1]3[C:20](=[O:21])[C:19]4[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=4[C:17]3=[O:22])[C:3]([F:16])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])#[N:14]
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: N#CCN1C(=O)COc2cc(F)c(N)cc21
Solvent: O
Solvent: CC(=O)O
Product: N#CCN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 73.5 %

Procedure:
6-amino-4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (0.5 g), tetrahydrophthalic anhydride (0.38 g) and acetic acid (10 ml) were mixed with each other, then the mixture was refluxed under heating for 3 hours. After the liquor was allowed to cool, it was added to water (40 ml), and separating crystals were collected by filtration, and then the crystals were dissolved in dichloromethane (30 ml). The dichloromethane solution was washed with a saturated solution of sodium bicarbonate, and water, in that order, and then dehydrated with anhydrous sodium sulfate, and subsequently concentrated. Separated crystals were washed with a small amount of ether to give the desired 2-[4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-on 6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.59 g). mp. 227°-229° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:12][C:13]1[CH:14]=[C:15]([NH:22][C:23]([C:25]2([CH3:28])[CH2:27][O:26]2)=[O:24])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]>>[OH:26][C:25]([CH3:28])([CH2:27][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1)[C:23]([NH:22][C:15]1[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:13]([CH3:12])[CH:14]=1)=[O:24]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: COCCc1ccc(O)cc1
Product: COCCc1ccc(OCC(C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1

Procedure:
2-Hydroxy-3-[4-(2-methoxyethyl)phenoxy]-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 4-methoxyethylphenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1% methanol). 1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 2.71 (2H, t, J=6.8 Hz), 3.21 (3H, s), 3.45 (2H, t, J=6.8 Hz), 3.94 (1H, d, J=9.5 Hz), 4.17 (1H, d, J=9.5 Hz), 6.20 (1H, s), 6.82 (2H, d, J=7.8 Hz), 7.10 (2H, d, J=8.0 Hz), 7.89 (1H, d, J=9.0 Hz), 7.94 (1H, s), 8.03 (1H, d, J=8.8 Hz), 10.16 (1H, s).
Reaction SMILES: [F:1][CH:2]([F:36])[CH2:3][N:4]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30](F)=[CH:29][C:28]=1OC)C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.[F:37]C1C=CC=CC=1B(O)O>CCCCCCC.CCOC(C)=O>[F:1][CH:2]([F:36])[CH2:3][NH:4][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:37]
Reactant: OB(O)c1ccccc1F
Reactant: COc1cc(F)ccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1ccncc1NCC(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine (example 153, intermediate b) and 2-fluorophenylboronic acid (CAS RN 1193-03-9) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless solid (87%). MS (ESI): m/z=252.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)([CH:10]2[CH2:15][CH2:14][N:13](S(C3C=CC=CC=3)(=O)=O)[CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[BrH:39]>>[OH2:9].[BrH:39].[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:26][CH:27]=1
Reactant: O=S(=O)(c1ccccc1)N1CCC(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Agent: Br
Solvent: Oc1ccccc1
Product: Clc1ccc(C(=C2CCNCC2)c2ccc(Cl)cc2)cc1
Product: O
Temperature: 25 °C
Reaction time: 10 h
Yield: 43.6 %

Procedure:
A mixture of 69.33 g (0.146 mole) of α,α-bis(4-chlorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol and 26 g (0.277 mole) of phenol in 400 ml of 48% hydrobromic acid was refluxed for 6 hr and then was stirred at room temperature for 10 hr. The reaction solution was decanted from a gun which had formed in the bottom of the reaction flask. The gum was washed with several portions of water and then was crystallized from ether to give a solid. The solid was recrystallized from a mixture of methanoldiethyl ether to give 26.52 g (43.6%) of white crystalline solid, m.p. 106°-109° C.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C([N:28](CC)CC)C.ClC(OC)=O.N>O1CCCC1>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][CH2:18][CH2:19][C:20]([NH2:28])=[O:21])=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: O=C(O)CCCOc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)CCCOc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-[3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]butyric acid (0.24 g) was stirred in dry tetrahydrofuran (5 ml) at ambient temperature and triethylamine (0.20 ml) was added. The mixture was stirred at ambient temperature for 15 minutes then cooled in an ice bath and then methyl chloroformate (0.2 ml) was added. The mixture was stirred at ice bath temperature for 1 hour and then concentrated ammonia solution (SG 0.880, 5 ml) was added dropwise by pipette. The mixture was stirred at 0° C. for 5 minutes and then evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica using dichloromethane/IMS/triethylamine (8:1:1) as the mobile phase. Appropriate fractions were combined and evaporated to give 4-[3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]butyramide, m.p. 200-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10](Cl)[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].CO.CCCCCC.[C:28](OCC)(=[O:30])C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:30][CH3:28])[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncc(-c2cccc(Cl)c2)cc1Cl
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(-c2cccc(Cl)c2)cnc1C#N
Temperature: 25 °C
Yield: 96 %

Procedure:
To a 500 mL round bottom flask adapted for magnetic stirring and fitted with a reflux condenser and nitrogen inlet was charged with 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine, 1, (10 g, 40 mmol), sodium methoxide (13.8 mL, 60 mmol) and methanol (200 mL). With stirring, the reaction solution was heated to reflux for 20 hours. The reaction was determined to be complete due to the disappearance of 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction mixture was cooled to room temperature and combined with water (500 mL). A solid began to form. The mixture was cooled to 0° C. to 5° C. and stirred for 3 hours. The resulting solid was collected by filtration and washed with water, then hexane. The resulting cake was dried in vacuo at 40° C. to afford 9.4 g (96% yield) of the desired product as an off-white solid. 1H NMR (DMSO-d6) δ 8.68 (d, 1H), 8.05 (d, 1H), 8.01 (s, 1H) 7.86 (m, 1H), 7.59 (s, 1H), 7.57 (s, 1H) and 4.09 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CN(C=O)C.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:20]([F:27])=[CH:19][C:18]=1[OH:28].C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[C:20]([F:27])=[CH:19][C:18]=1[OH:28])=[O:5]
Reactant: O=C(Cl)c1ccncc1Cl
Reactant: Nc1cc(C(F)(F)F)c(F)cc1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)c(F)cc1O)c1ccncc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 0.69 g of 3-chloroisonicotinic acid, 5 ml of thionyl chloride and 30 mg of DMF was heated to reflux for 3.5 hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give 3-chloroisonicotinic acid chloride. A mixture of the resultant 3-chloroisonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.85 g of 2-amino-5-fluoro-4-trifluoromethylphenol, 0.88 g of triethylamine and 4 ml of DMF while ice-cooling. Thereafter, the reaction mixture was stirred at room temperature for one hour and at 50° C. for one hour. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate twice. The combined organic layers wee washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resultant solid was washed with diethyl ether to give 0.77 g of 3-chloro-N-[4-fluoro-2-hydroxy-5-(trifluoromethyl)phenyl]-isonicotinamide.
Reaction SMILES: [CH3:1][C:2]1[C:3](NC(=O)OC(C)(C)C)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.[C:29]([O-:32])([O-])=O.[K+].[K+].[C:35]1(C)C=CC=C[CH:36]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CCOC(C)=O>[CH3:1][C:2]1[CH:10]=[C:9]([CH:35]=[CH2:36])[C:8]2[N:7]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=3)(=[O:12])=[O:13])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:29]=[O:32]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC(=O)OC(C)(C)C)c(C)ccc32)cc1
Reactant: Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Solvent: CCOC(C)=O
Product: C=Cc1cc(C)c(C=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Temperature: 80 °C

Procedure:
To a suspension of 7-chloro-5-methyl-1-tosyl-1H-indole-4-carbaldehyde (Example 110-E) (73 mg, 0.210 mmol) and vinylboronic anhydride pyridine complex (152 mg, 0.630 mmol) and K2CO3 (290 mg, 2.09 mmol) in toluene (1.7 mL) water (0.7 mL) Pd(OAc)2 (4.71 mg, 0.021 mmol) and S-Phos (CAS#657408-07-6) (17.2 mg, 0.042 mmol) were added, and the reaction was stirred at 80° C. After 1 hour the reaction was diluted with EtOAc. The organics were washed with water, dried over MgSO4, filtered and concentrated. The mixture was loaded onto silica gel and purified by flash chromatography (0-40% EtOAc in heptanes) to the title compound. MS (ESI+) m/z 340.1 (M+H).
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C@@H:21]1[CH2:39][I:40])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.F.F.F.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[I:40][CH2:39][C@@H:21]1[C@@H:20]([CH2:19][OH:18])[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:22]1[O:34][CH2:35][CH2:36][O:37][CH3:38]
Reactant: COCCO[C@@H]1[C@H](CI)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCO[C@@H]1[C@H](CI)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Yield: 69.4 %

Procedure:
A solution of 5′-O-(tert-butyldiphenylsilyl)-3′-deoxy-3′-(iodomethyl)-2′-O-(2-methoxyethyl)-5-methyluridine (1.12 g, 1.65 mmol) and triethylamine trihydrofluoride (1.1 mL, 1.1 g, 6.7 mmol) in 20 mL of THF was stirred at rt for 24 h. The reaction mixture was diluted with 50 mL of ethyl acetate and washed with water and brine. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on a silica gel column. Gradient elution with 2:1, 1:2 and then 1:3 hexanes-EtOAc provided 504 mg of the title compound as a white foam.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH:3]([OH:32])[CH2:4][N:5](C(OCC1C=CC=CC=1)=O)[C@H:6]([C:11]([NH:13][C@H:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9].C(OC(N[C@@H](CC(C)C)C(O)CN(C(OCC1C=CC=CC=1)=O)[C@H](C(OCC[Si](C)(C)C)=O)CC(C)C)=O)(C)(C)C.[ClH:78].[H][H].O>CO.[Pd].C(Cl)(Cl)Cl>[ClH:78].[ClH:78].[NH2:1][C@@H:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH:3]([OH:32])[CH2:4][NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: [H][H]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](CC(C)C)N(CC(O)[C@@H](N)CC(C)C)C(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)CN(C(=O)OCc1ccccc1)[C@@H](CC(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NCC(O)[C@@H](N)CC(C)C)C(C)C
Reaction time: 3 h

Procedure:
A solution of 109 mg of (3S)-N-[N-(3-amino-2-hydroxy-5-methylhexyl)-N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-valine, methyl ester (Isomer B, prepared from N-[(3S)-3-[[(t-butyloxy)carbonyl]amino]-2-hydroxy-5-methylhexyl]-N-[(phenylmethoxy)carbonyl]-L-leucine, 2-(trimethylsilyl)ethyl ester, Isomer B using a procedure analogous to that described in Example 8 for preparing the corresponding Isomer A) in 3 ml of methanol was treated with 0.63 ml of 1N hydrochloric acid and 75 mg of 10% palladium on charcoal and subjected to a steady stream of hydrogen at 1 atmosphere pressure. After 3 hours, a silica gel TLC run in 9:1, chloroform:methanol, checked with UV and PMA, indicated complete disappearance of the starting compound. The reaction was worked up by filtering through a Celite pad, concentrating the filtrate in vacuo, and recrystallizing the residue from methanol/ether at room temperature, then storing in the freezer overnight to afford 73 mg of partially purified product, melting at 232°-234° C. Chromatography was performed on a 35 ml column of HP-20 resin, eluting with a gradient from 175 ml of 96:3:1 to 2:2:96, water: 1N hydrochloric acid:methanol. The fractions were checked by silica gel TLC run in 5:1:1:1, butanol:pyridine:acetic acid:water and sprayed with ninhydrin. Pooling of product containing fractions followed by lyophilization yielded 17 mg of the title compound as a hydrate with 1.0 mole of water, melting point 125°-140° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:24]=[CH:23][C:11]2[NH:12][C:13]([CH:15](Cl)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]1([C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C.O>CN(C=O)C>[CH2:1]([C:8]1[CH:24]=[CH:23][C:11]2[NH:12][C:13]([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:28]3[CH2:29][CH2:30][N:25]([C:31]4[N:32]=[CH:33][CH:34]=[CH:35][N:36]=4)[CH2:26][CH2:27]3)=[N:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: ClC(c1ccccc1)c1nc2cc(Cc3ccccc3)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc(Cc2ccc3[nH]c(C(c4ccccc4)N4CCN(c5ncccn5)CC4)nc3c2)cc1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
300 mg of 5-benzyl-2-(chloro(phenyl)methyl)-1H-benzo[d]imidazole and 300 mg 2-(piperazin-1-yl)pyrimidine were dissolved in 5 ml of DMF at room temperature. After a few seconds, 0.5 ml of triethylamine was added, and the reaction mixture was stirred at room temperature, while being monitored by TLC. Once the starting material was no longer detected (overnight), additional 0.2 ml of triethylamine was added, followed by 3 ml of water, and the reaction mixture was cooled to 0° C. The precipitated solid was collected by vacuum filtration, washed with cold water and dried for 2 hours at 50° C., to give 360 mg (80% yield) of the product (BPRM-VR-2′ b).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1
Reactant: Oc1ccc(F)cc1F
Reactant: Cc1nc(Cl)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(Oc2ccc(F)cc2F)ccc1C#N
Temperature: 80 °C

Procedure:
A mixture of 6-chloro-2-methylnicotinonitrile (Example 1, step 1; 500 mg, 3.27 mmol), 2,4-difluorophenol (0.47 mL, 4.91 mmol) and cesium carbonate (1.60 g, 4.91 mmol) in DMF (5 mL) was heated in an oil bath at 80° C. for 5 h. The reaction mixture was treated with water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with 1 N NaOH (15 mL) followed by brine, dried over MgSO4 and concentrated. Purification on an ISCO (40 g column, 5-50% EtOAc in hexanes) provided 6-(2,4-difluorophenoxy)-2-methylnicotinonitrile as a white crystalline solid. MS (ESI, pos.ion) m/z: M+1=247.0
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=[O:10])[C:4](=[N:8]O)[C:5](=O)[CH3:6].[H][H].[O-:14][C:15]#[N:16].[K+]>C(O)C.Cl.O>[O:14]=[C:15]1[NH:16][C:5]([CH3:6])=[C:4]([C:3]([N:2]([CH3:11])[CH3:1])=[O:10])[NH:8]1
Reactant: N#C[O-]
Reactant: [H][H]
Reactant: CC(=O)C(=NO)C(=O)N(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1[nH]c(=O)[nH]c1C(=O)N(C)C

Procedure:
A solution of 15.8 g (0.1 mol) of N,N-dimethyl-2-(hydroxyimino)-3-oxobutanamide in 400 ml of ethanol and 100 ml of 2N hydrochloric acid over 2 g of catalyst (5% palladium on charcoal) is hydrogenated in a Paar shaker until 1 molar equivalent of hydrogen is taken up (3-5 hours). The catalyst is removed by filtration. A solution of 16.2 g (0.2 mol) of potassium cyanate in 80 ml of water is added, the solution is refluxed for 1 hour and concentrated until the product crystallizes. Recrystallization from 50% aqueous ethanol gives the title compound, m.p. 244°-246° C. (dec).