Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH:17]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([N:16]3[CH:17]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[CH:15]3)=[CH:26][CH:25]=2)[CH2:29][CH2:28]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: NC1CC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)NC3CC3)cc2)cn1
Yield: 12 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using cyclopropylamine instead of cyclopropylmethylamine, to the title compound (14 mg, 12%) which was obtained as an off-white solid. MS: m/e=384.9 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([N:6]2C(=O)C3C(=CC=CC=3)C2=O)=[N:2]1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccn(Cc2ccccc2)n1
Temperature: 50 °C
Reaction time: 15 h
Yield: 32 %

Procedure:
3.1 2-(1H-Pyrazole-3-yl)-isoindole-1,3-dione (11.7 mmol) is added to a suspension of NaH (2 eq.) in DMF at 0° C. Benzylbromide (1 eq.) is added and the reaction is stirred 15 h at 50° C. The solvent is removed in vacuo. Hydrazine hydroxide (10 ml) and ethanol (20 ml) are added and the reaction is stirred 17 hours at 120° C. The precipitate is filtered and the solvent is removed in vacuo. The residue is suspended in dichloromethane and filtrated. The solvent of the filtrate is removed in vacuo. The remaining residue is purified via column chromatography (Ethyl acetate/methanol). 1-Benzyl-1H-pyrazole-3-ylamine is isolated as a yellow powder in a yield of 32%; HPLC (Method B): 2.45 min; LC-MS (Method B): 1.203 min, 174.15 (M+H+);
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:19])=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)c2cc[nH]c12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c2[nH]ccc12

Procedure:
Under N2 atmosphere, 7-methyl-1H-indole-4-carboxylic acid (1 g, 5.71 mmol), sulfuric acid (300 μL, 5.63 mmol) and methanol (50 mL) were heated at reflux for 10 h. The MeOH was removed in vacuo and the residue dissolved in 30 mL DCM. The solution was washed with water and saturated NaHCO3, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (Biotage; 0% to 100% EtOAc:Hex; 25 g-HP-silica gel column) to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.59 (s, 3H), 4.00 (s, 3H), 7.08 (d, J=7.58 Hz, 1H), 7.20-7.26 (m, 1H), 7.38 (t, J=2.78 Hz, 1H), 7.88 (d, J=7.58 Hz, 1H), 8.32 (br. s., 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:10](=[N:11]O)[CH:9]2[CH2:13][CH2:14][N:6]1[CH2:7][CH2:8]2)[CH3:3]>[Ni].C(O)C>[CH3:3][N:2]([CH2:4][CH:5]1[CH:10]([NH2:11])[CH:9]2[CH2:13][CH2:14][N:6]1[CH2:7][CH2:8]2)[CH3:1]
Reactant: CN(C)CC1C(=NO)C2CCN1CC2
Agent: [Ni]
Solvent: CCO
Product: CN(C)CC1C(N)C2CCN1CC2
Reaction time: 18 h
Yield: 77.9 %

Procedure:
A solution of 2-(dimethylaminomethyl)-1-azabicyclo[2.2.2]octan-3-one oxime (3.55 g, 18 mmoles) in reagent grade ethanol (150 ml) was treated with Raney Nickel and hydrogenated in a Parr apparatus at room temperature and 55-58 psi for 18 hours. The product solution was filtered through Celite®, concentrated in vacuo, and subjected to bulb-to-bulb distillation (bp 100°-120° C. at 0.30 mm Hg) to provide 2.57 g (78%) of a colorless oil. The product was shown to be a mixture of cis:trans (1:3) isomers by nmr and glc analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)=[C:12]([CH:18]=2)[C:13]([O:15]CC)=[O:14])[CH:5]=[N:6][CH:7]=1.[OH-].[Li+].Cl>C(O)(C)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)=[C:12]([CH:18]=2)[C:13]([OH:15])=[O:14])[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cncc(C)c2)ccc1-c1cnccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1cncc(-c2ccc(-c3cnccn3)c(C(=O)O)c2)c1
Temperature: 60 °C

Procedure:
To a mixture of ethyl 5-(5-methylpyridin-3-yl)-2-pyrazin-2-ylbenzoate (3-3, 0.065 g, 0.204 mmol, 1.0 equiv) in isopropanol/water (3:1, 2 mL) was added 1M lithium hydroxide solution (0.244 mL, 0.244 mmol, 1.2 equiv) and the reaction was heated to 60° C. for 30 minutes in the microwave. The reaction mixture was cooled and the pH was adjusted to ˜7 by the addition of 1N HCl. The reaction mixture was concentrated and the solids azeotroped from toluene to afford the product (3-4) as a solid. ESI+ MS [M+H]+ C17H13N3O2: 292.1 found, 292.31 required.
Reaction SMILES: [CH2:1]([C:3]1[N:7](CCC)[N:6]=[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])=[CH:14][CH:13]=2)[C:4]=1[C:32]([O:34][CH3:35])=[O:33])[CH3:2].[C:36]1(OC)[CH:41]=CC=C[CH:37]=1.CCOC(C)=O>FC(F)(F)C(O)=O>[NH2:27][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:5]2[N:6]([CH2:37][CH2:36][CH3:41])[N:7]=[C:3]([CH2:1][CH3:2])[C:4]=2[C:32]([O:34][CH3:35])=[O:33])=[CH:13][CH:14]=1)(=[O:26])=[O:25]
Reactant: COc1ccccc1
Reactant: CCCn1nc(Cc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(C(=O)OC)c1CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCn1nc(CC)c(C(=O)OC)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of the compound obtained in example 43 (2.65 g, 5.3 mmol) in trifluoroacetic acid (58 mL) was added anisole (1 mL) and the mixture stirred under an argon atmosphere for 18 h. The solvent was concentrated and the residue purified by chromatography on silica-gel (hexane-EtOAc mixtures) to give a 1:1 mixture of regioisomers, from which the title compound was obtained as a white solid by recrystallization from EtOAc (1.34 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2[O:6][CH:7]([CH3:9])[CH3:8])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(OC(C)C)nc(C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-5-[2-chloro-5-fluoro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and sodium isopropylate in isopropanol there is obtained isopropyl 2-chloro-5-[5-fluoro-2-isopropoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate, 1H-NMR (CDCl3, 400 MHz): 7.83 ppm (d,1H), 7.40 ppm (d,1H), 5.36 ppm (m,1H), 5.27 ppm (m,1H), 1.39 ppm (d,3H), 1.38 ppm (d,3H), 1.29 ppm (d,3H), 1.28 ppm (d,3H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:14]([F:25])[CH:13]=1>C1(C)C(C)=CC=CC=1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:14]([F:25])[CH:13]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1cc(Cl)c(Nc2nc3ccccc3o2)cc1F
Temperature: 25 °C
Yield: 74 %

Procedure:
In xylene (4 ml), 2-chlorobenzoxazole (278 μl, 2.43 mmol) and ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (512 mg, 2.21 mmol) were heated under reflux for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate. The resulting solution was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (7:1, v/v) eluate fractions, ethyl (4-(2-benzoxazolyl)amino-5-chloro-2-fluorophenyl)acetate (570 mg, 74%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][CH2:10][NH:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:14]1[CH2:19][CH2:18][N:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][CH2:10][N:11]([C:20]([N:17]1[CH2:18][CH2:19][S:14][CH2:15][CH2:16]1)=[O:21])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)N1CCSCC1
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN(C)C(=O)N1CCSCC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 111.5 %

Procedure:
N-t-Butoxycarbonyl-N,N'-dimethylethylenediamine (200 mg) was added to a solution of thiomorpholinocarbonyl chloride (228 mg) and triethylamine (123 mg) in methylene chloride (10 ml) which was cooled at 0° C. The mixture was stirred at ambient temperature for 20 minutes and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 0.6N hydrochloric acid, water, saturated sodium bicarbonate solution, and saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure to give N-t-butoxycarbonyl-N'-thiomorpholinocarbonyl-N,N'-dimethylethylenediamine (376 mg) as an oil. Rf: 0.43 (chloroform:methanol, 10:1, V/V)
Reaction SMILES: [B]1OC2C(=CC=CC=2)O1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:43])[C:39]([F:42])([F:41])[F:40])=[C:34]([N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[CH:33]=1>C1COCC1>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([C@@H:38]([OH:43])[C:39]([F:42])([F:41])[F:40])=[C:34]([N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[CH:33]=1
Reactant: Cc1ccn(-c2cc(Br)ccc2C(=O)C(F)(F)F)n1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(Br)ccc2[C@@H](O)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Alternatively, the trifluoromethyl (or other prochiral) ketones of formula G or J (scheme 2) were asymmetrically reduced as follows (see for example: Corey, E. J. & Link, J. O. A General, Catalytic, and Enantioselective Synthesis of Alpha-amino Acids. J. Am. Chem. Soc. 114, 1906-1908 (1992)): Catechol borane (95 mL, 1 M in THF) and (S)-2-methyl-CBS oxazaborolidine (2.6 g, 9.6 mmol) were mixed in a jacketed glass reactor. The mixture was stirred at RT for 20 min, then the jacket was cooled to −78° C. At a reaction temperature of −65° C., 1-[4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanone (16 g, 48 mmol) in THF (150 mL) was added dropwise over 2 h. The reaction was then warmed to −36° C. and held at this temperature for 22 h. Then the reaction was quenched with 3 N NaOH (100 mL) while maintaining a reaction temperature of <−25° C. The reaction was then warmed to 0° C. and H2O2 (30%, 100 mL) was added over 30 min, then warmed to RT for 4 h. The reaction mixture was quenched with 1 N NaOH, extracted with ether, washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification on normal phase silica gel chromatography (EtOAc/heptane) provided the product as a viscous oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([N:10]1[C:15](=[O:16])[CH:14]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:12]=[N:11]1)([CH3:9])([CH3:8])[CH3:7].CN([CH:23]=[O:24])C>>[C:6]([N:10]1[C:15](=[O:16])[C:14]([CH:23]=[O:24])=[C:13]([N:17]([CH3:19])[CH3:18])[CH:12]=[N:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CN(C)c1cnn(C(C)(C)C)c(=O)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1cnn(C(C)(C)C)c(=O)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (6.5 g) was added dropwise to DMF (15 ml) with ice-cooling and the mixture was stirred at room temperature for 30 minutes. Then, 2-t-butyl-5-dimethylamino-3(2H)-pyridazinone (3.3 g)/DMF (40 ml) was added dropwise with ice-cooling and the mixture was stirred at 70° C. for 1 hour. This reaction mixture was poured gradually into ice-NaHCO3 /water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was washed with n-hexane and dried. Yellow powder, 3.7 g. 1H-NMR (CDCl3) δ: 1.63(9H,s), 3.10(6H,s), 7.71(1H,s), 10.27(1H,s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[C:9]=2/[CH:20]=[CH:21]/C(O)=O)=[CH:4][CH:3]=1.[Cl-].[Mg+2].[Cl-].[K+].[C:29]([O:35][CH3:36])(=[O:34])[CH2:30][C:31]([O-])=[O:32]>C1COCC1>[CH3:36][O:35][C:29](=[O:34])[CH2:30][C:31](=[O:32])/[CH:21]=[CH:20]/[C:9]1[N:10]([CH:17]([CH3:18])[CH3:19])[C:11]2[C:16]([C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: CC(C)n1c(/C=C/C(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Reactant: COC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 1 h

Procedure:
0.8 g (2.46 mmol) of (E)-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-acrylic acid in 4 ml of THF are introduced into a 50 ml three-necked round-bottomed flask equipped with a magnetic stirrer, thermometer, reflux condenser and nitrogen delivery line. 0.5 g (2.96 mmol) of 1,1-carbonyldiimidazole is then added in portions in the course of 5 min. and stirring is carried out at room temperature for 1 hour. 0.24 g (2.46 mmol) of magnesium chloride and 0.39 g (2.46 mmol) of monomethyl malonate potassium salt are then added and the suspension is stirred for 24 hours at 35° C. The reaction mixture is cooled and filtered and the residue is washed twice with 25 ml of THF. The filtrate is concentrated by evaporation, taken up in 30 ml of ethyl acetate, washed with 15 ml of 1N hydrochloric acid, three times with 20 ml of saturated sodium hydrogen carbonate solution and three times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. The residue is purified by means of flash chromatography (hexane/ethyl acetate=8:1). An orange resin is obtained which, according to NMR, is the product in a keto-enol equilibrium of approximately 3:1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1.[P:38]([O:45]CC)([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41]>CCOCC.ClCCCl>[CH2:40]([O:39][P:38]([CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)([O:42][CH2:43][CH3:44])=[O:45])[CH3:41]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)c1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Solvent: CCOCC
Product: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of methyl 4-methylbenzoate (2.01 g, 13.3 mmol) and 1,2-dichloroethane (100 mL) was added benzoyl peroxide (catalytic amount) and NBS (2.84 g, 16.0 mmol). The resulting mixture was heated to reflux while being stirred under nitrogen. After three hours, another catalytic amount of benzoyl peroxide was added and the mixture was refluxed for an additional three hours. The reaction mixture was allowed to cool to RT, followed by the addition of Et2O (20 mL) and filtration of a solid which precipitated out of solution. The filtrate was washed with water (2×) and brine (2×), dried over MgSO4, filtered and the solvent was removed under reduced pressure to give a light yellow clear oil. Triethyl phosphite (2.28 mL, 13.3 mmol) was added to the oil and the reaction was stirred under nitrogen at 160° C. for three hours. Excess triethyl phosphite was distilled off and the product was purified by column chromatography (EtOAc) to give a transparent light yellow oil (2.28 g, 7.97 mmol, 60%). Characterization data matches literature. E. N. Durantini, Synthetic Communications, 29:4201-4222 (1999).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[C:20]([C:22](=[O:41])[NH:23][C:24]4[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]=4[O:39][CH3:40])[CH:19]=[CH:18][C:17]=3[CH3:42])[CH:15]=2)=[O:10])[CH2:2]1.C=O.[C:45]([BH3-])#N.[Na+]>CO.C(Cl)Cl>[CH3:45][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[C:20]([C:22](=[O:41])[NH:23][C:24]4[CH:29]=[C:28]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[C:25]=4[O:39][CH3:40])[CH:19]=[CH:18][C:17]=3[CH3:42])[CH:15]=2)=[O:10])[CH2:2]1
Reactant: [BH3-]C#N
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)NCC4CCCNC4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)NCC4CCCN(C)C4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.6 %

Procedure:
To a 0° C. suspension of 106 mg (0.268 mmol) of 1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-[1,2,3]triazole-4-carboxylic acid (piperidin-3-ylmethyl)-amide in 2 mL of MeOH containing 1% HOAc was added 70 μL of aqueous formaldehyde. The suspension was stirred at 0° C. for five minutes then 18 mg (0.281 mmol) of sodium cyanoborohydride was added and the mixture was warmed to rt. After stirring for ˜1 the reaction mixture was diluted with 40 mL of CH2Cl2 and washed with 25 mL of water. The aqueous wash was extracted with CH2Cl2 (2×25 mL), the combined organic extracts were dried (Na2SO4), filtered and evaporated to afford a yellow solid. Chromatography provided 42 mg of product. mp: 209–211. ESI MS (m/z 612, 100, M+H).
Reaction SMILES: [H-].[Na+].CI.[Cl:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([N:17]3[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24](=O)OC(C)(C)C)[CH2:18]3)=[O:16])[S:14][C:7]=12>C1COCC1>[Cl:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([N:17]3[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][CH3:24])[CH2:18]3)=[O:16])[S:14][C:7]=12
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CNCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Temperature: 25 °C
Yield: 134.3 %

Procedure:
NaH (0.033 g, 0.82 mmole) and CH3I (0.064 ml, 1.02 mmole) were added to a solution of tert-butyl {1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl}methyl-carbamate 43 (0.271 g, 0.68 mmole) in THF at 0° C. The reaction mixture was stirred and warmed to room temperature overnight and partitioned between H2O (50 ml) and EtOAc (2×50 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 0–2% CH3OH in CH2Cl2 to give a yellow solid (0.283 g, 82%). 1H NMR (300 MHz, CDCl3) δ 8.62 (1H, d, J=5.1 Hz), 7.85 (1H, s), 7.34 (1H, d, J=5.1 Hz), 4.72 (1H, s), 3.99 (1H, m), 3.77 (2H, m), 3.50 (1H, m), 3.19 (2H, m), 2.88 (3H, d, J=12.06 Hz), 2.62 (1H, m), 2.14 (1H, m), 1.83 (1H, m); ESIMS (MH+): 310.10.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[C:30]1([B:36]([OH:38])[OH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(C)C=CC=CC=1>O>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[C:30]1([B:36]([O-:38])[O-:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1ccccc1
Agent: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Solvent: O
Solvent: Cc1ccccc1
Product: [O-]B([O-])c1ccccc1
Temperature: 2.5 °C

Procedure:
A suspension of lovastatin (350 g, 0.865 mmol), phenylboronic acid (110.8 g, 0.909 mmol) and toluene (1.75 L) was heated with agitation under a nitrogen atmosphere. A reflux temperature of 100-105° C. was maintained for 55 minutes as water was collected and separated from the reaction mixture. The solution was cooled and 1.39 L of toluene was removed by vacuum distillation at 40-50° C. The concentrated solution was treated with hexanes (3.15 L) between 40-50° C. The resulting suspension was cooled to 0-5° C. for 2 hours and the product was filtered and washed with 0-5° C. hexanes (350 mL). The product was dried at 35-40° C. under vacuum to provide 427.9 g (37%) of lovastatin phenylboronate at >99% purity by HPLC.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][N:26]=1)[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1.[Li+].[BH4-].N#N>CO>[CH3:31][C:30]1[C:25]([CH2:24][N:13]([CH2:12][C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH2:3][OH:2])[CH:14]2[C:23]3[N:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17][CH2:16][CH2:15]2)=[N:26][CH:27]=[C:28]([CH3:32])[CH:29]=1
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(C)cc1C)C1CCCc2cccnc21
Agent: N#N
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: Cc1cnc(CN(Cc2ccc(C#N)cc2CO)C2CCCc3cccnc32)c(C)c1

Procedure:
To a solution of 5-cyano-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8yl)-amino]-methyl}-benzoic acid methyl ester (6.29 g, 14.3 mmol) dissolved in MeOH (72 mL) was added LiBH4 (3.1 g, 0.14 mmol). The mixture was stirred for 18 hours under a positive pressure of N2. The mixture was concentrated in vacuo and redissolved in CH2Cl2 (75 mL). A saturated solution of NaHCO3 (75 mL) was added. Extract with CH2Cl2 (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford 4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzonitrile as an off white foam (5.82 g, 99%). 1H NMR (CDCl3) δ 1.62 (m, 1H), 2.02 (m, 1H), 2.13 (m, 1H), 2.18 (s, 3H), 2.26 (s, 3H), 2.68 (m, 1H), 2.81 (m, 1H), 3.82 (m, 4H), 4.23 (m, 3H), 7.06 (dd, 1H, J=7.0, 5.7 Hz), 7.36 (d, 2H, J=7.5 Hz), 7.44 (m, 2H), 7.65 (s, 1H), 8.17 (s, 1H), 8.37 (d, 1H, J=3.9 Hz).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=1[C:21]([OH:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]=[C:25]1[CH:30]([N:31]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:29][CH2:28][C:27](=[O:47])[NH:26]1>>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]2[C:13]=1[C:21](=[O:23])[N:31]([CH:30]1[CH2:29][CH2:28][C:27](=[O:47])[NH:26][C:25]1=[O:24])[C:15]2=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(NCCOCc2ccccc2)c1C(=O)O
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Product: O=C1CCC(N2C(=O)c3cccc(NCCOCc4ccccc4)c3C2=O)C(=O)N1
Yield: 57 %

Procedure:
3-(2-Benzyloxy-ethylamino)-phthalic acid (1.78 g, 5.65 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-Dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was recrystallized from a minimal amount of ethanol to give 1.32 g (57%) of product as a yellow solid: mp 158-160° C.; 1H NMR (DMSO-d6) d 11.11 (s, 1H), 7.57 (t, J=7.3 Hz, 1H), 7.37-7.24 (m, 5H), 7.14 (d, J=8.6 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.67 (t, J=5.7 Hz, 1H), 5.07 (dd, J=5.4 and 12.5 Hz, 1H), 4.54 (s, 2H), 3.66-3.62 (m, 2H), 3.55-3.49 (m, 2H), 2.97-2.82 (m, 1H), 2.63-2.45 (m, 2H), 2.06-2.02 (m, 1H); 13C NMR (DMSO-d6) d 172.81, 170.08, 168.96, 167.28, 146.40, 138.23, 136.16, 132.06, 128.22, 127.42, 117.47, 110.69, 109.30, 71.90, 68.09, 48.54, 41.68, 30.97, 22.13; Anal. Calcd. For C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.95; H, 5.03; N, 10.27.