Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.CCN(CC)CC.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1>[C:39]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:23]=3)[N:9]=2)[CH2:3]1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a solution of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (27.5 mg, 0.065 mmol) and Et3N (0.014 mL, 0.097 mmol) in THF (2 mL) was added benzoyl chloride (10.93 mg, 0.078 mmol). The reaction mixture was stirred at rt for 10 min, quenched with satd. NaHCO3, extracted twice with CH2Cl2, separated, and concentrated. The residue was purified by ISCO (100% ethyl acetate, 12 g column) to obtain 24 mg of (R)-6-(3-benzamidopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a white solid. LCMS: (M+H)+=529.38. 1H NMR (400 MHz, CDCl3) δ ppm 11.22 (1H, s), 7.66 (2H, d, J=8.56 Hz), 7.59-7.64 (2H, m), 7.53 (1H, d, J=9.06 Hz), 7.42-7.49 (1H, m), 7.37 (1H, d, J=7.81 Hz), 7.31 (1H, d, J=8.56 Hz), 6.55 (1H, d, J=6.80 Hz), 6.11-6.18 (1H, m), 5.60 (2H, s), 4.17-4.28 (1H, m), 3.86-3.94 (1H, m), 3.53-3.83 (11H, m), 1.96-2.06 (1H, m), 1.88-1.95 (1H, m), 1.74-1.85 (1H, m), 1.67-1.73 (1H, m).
Reaction SMILES: O.[N:2](=[CH:4][C:5](=[O:17])[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[OH:3].[CH2:18](O)[CH2:19][OH:20].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[CH2:19]1[O:20][C:5]([CH:4]=[N:2][OH:3])([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[O:17][CH2:18]1
Reactant: O=C(C=NO)CC(=O)OCc1ccccc1
Reactant: OCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Solvent: O
Product: O=C(CC1(C=NO)OCCO1)OCc1ccccc1
Yield: 35 %

Procedure:
In a two liter flask fitted with a Dean Stark water separator and a condenser were placed 186.5 g. (0.85 mole) of benzyl oximino-acetoacetate (17), 62 g. (1 mole) of ethylene glycol, 800 ml. of benzene (reagent grade) and 2 g. of toluenesulfonic acid. The reaction mixture was boiled at reflux until 15 ml. of water was removed (3 hours). The benzene solution was washed once with saturated sodium bicarbonate solution and once with brine. After drying over anhydrous sodium sulfate, the benzene solution was evaporated, leaving 212 g. (94%) of 17 as a light yellow oil. Its NMR spectrum was consistent with the assigned structure. Generally the compound was used as used in subsequent reaction but one of the isomers can be crystallized in 35% yield from toluene-petroleum ether, m.p. 52° C. ##STR144##
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[C:28](=[O:29])[C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[C:25](=[O:34])[C:24]=1[CH3:35])(=[O:11])[CH3:10]>CCOCC.O>[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[C:28]([OH:29])=[C:27]([O:30][CH3:31])[C:26]([O:32][CH3:33])=[C:25]([OH:34])[C:24]=1[CH3:35])(=[O:11])[CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCOC(C)=O)=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1c(O)c(C)c(CCCCCCCCCCOC(C)=O)c(O)c1OC

Procedure:
2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methyl-1,4-benzoquinone (3.38 g) was dissolved in dichloromethane (50 ml). Pyridine (1 ml) was added, and acetyl chloride (0.8 ml) was added with stirring under ice-cooling. After stirring for 1 hour at the same temperature, the mixture was washed with 0.1N hydrochloric acid (50 ml) followed by water (50 ml). The dichloromethane layer was concentrated under reduced pressure to obtain 6-(10-acetoxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone as a red oil. This oil was dissolved in ether (50 ml), and a solution of sodium hydrosulfite (4 g) in water (50 ml) was added. Stirring was continued at room temperature until the red color of the ether layer disappeared. The ether layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired compound (3.8 g) as a pale yellow oil.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH2:8][N:7]2[N:11]=[C:12]([N+:14]([O-])=O)[CH:13]=[C:6]2[CH2:5]1)([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:14][C:12]1[CH:13]=[C:6]2[CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:9](=[O:10])[CH2:8][N:7]2[N:11]=1
Reactant: CC(C)N1Cc2cc([N+](=O)[O-])nn2CC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)N1Cc2cc(N)nn2CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 151d (220 mg, 1.0 mmol) in ethanol (20 mL) was added Pd/C (10%, 22 mg). The reaction mixture was charged with hydrogen gas (via balloon) and stirred at room temperature for 1 h. The reaction mixture was filtered through a plug of CELITE® and the filtrate was concentrated under reduced pressure to afford 151e as a yellow solid (180 mg, 92%), which was used without further purification. MS-ESI: [M+H]+ 195.3
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].Cl>C(O)C.C(O)(=O)C>[CH2:15]([NH:22][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCN1CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CCN1CCC(NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
Then, ethyl 3-(4-oxopiperidino)propionate (1.29 g, 6.47 mol) and benzylamine (0.85 ml, 7.78 mmol) were dissolved in ethanol (40 ml). A solution of sodium cyanoborohydride (256 mg, 4.22 mmol) dissolved in ethanol (20 ml) was added at room temperature and acetic acid (1 ml) was further added to adjust its pH to 6-7. The mixture was stirred at room temperature for 18 hours and added with concentrated hydrochloric acid (3 ml) to adjust the pH to 1-2. The resulting precipitate was collected by filtration and a saturated aqueous sodium hydrogencarbonate solution (150 ml) was added to adjust the mixture to pH 8-9. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 1.39 g of ethyl 3-(4-benzylaminopiperidino)propionate as a colorless oil (74%). This oil (1.11 g, 3.82 mmol) was dissolved in ethanol (120 ml) and 10% palladium-carbon (320 mg) was added. The mixture was refluxed under heating for 5 hours under a hydrogen atmosphere. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure to give 617 mg of ethyl 3-(4-aminopiperidino)propionate as a colorless oil (81%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:10]([OH:11])[C:5]2=[C:4]([Br:16])[C:3]=1N.N([O-])=O.[Na+].[ClH:22]>>[Br:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:10]([OH:11])[C:5]2=[C:4]([Br:16])[C:3]=1[Cl:22]
Reactant: Cl
Reactant: Nc1c(Br)nc2nc(C(F)(F)F)n(O)c2c1Br
Agent: O=N[O-]
Agent: [Na+]
Product: On1c(C(F)(F)F)nc2nc(Br)c(Cl)c(Br)c21

Procedure:
5,7-Dibromo-6-amino-1-hydroxy-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (1.2 grams) in 7 milliliters of concentrated HCl was cooled to o°-10°C. Thereafter, sodium nitrite (0.35 gram) was added as a solid. The addition was carried out portionwise to maintain the temperature below 10°C. Five minutes after completion of the addition of the sodium nitrite, cuprous chloride (0.45 grams) was added portionwise and the resulting reaction mixture stirred for thirty minutes and filtered to separate the desired 5,7-dibromo-6-chloro-1-hydroxy-2-(trifluoromethyl)-1-H-imidazo(4,5-b)pyridine product, m.p. 215°C.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].O.C[N:19]1CCO[CH2:21][CH2:20]1.C(Cl)(=O)OCC.C(N)C>C1COCC1>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([NH:19][CH2:20][CH3:21])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CN1CCOCC1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
25 g of Boc-D-Leu-OH.H2O was dissolved in 200 ml of THF. The solution was cooled to -20° C. 11 ml of N-methylmorpholine and 9.56 ml of ethyl chlorocarbonate were added to the solution. After 5 min, 12.9 g of a 70% aqueous ethylamine solution was added thereto and the mixture was stirred at about -5° C. for 2 h. After concentration, the residue was dissolved in ethyl acetate and washed with an aqueous NaHCO3 solution and water successively. After concentration to dryness, 24.5 g of Boc-D-Leu-NHC2H5 was obtained.
Reaction SMILES: Br[C:2]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:14])[CH:3]=1.[O:15]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.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>[F:14][C:4]1[CH:3]=[C:2]([C:17]2[CH:18]=[CH:19][O:15][CH:16]=2)[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: OB(O)c1ccoc1
Reactant: COCOc1cc(C=O)c(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1cc(C=O)c(F)cc1-c1ccoc1
Temperature: 100 °C
Yield: 39.3 %

Procedure:
4-Bromo-2-fluoro-5-methoxymethoxy-benzaldehyde (160 mg, 0.61 mmol) and 3-furanboronic acid (100 mg, 0.90 mmol) and Pd(PPh3)4 (60 mg, 0.052 mmol) and Cs2CO3 (400 mg, 1.23 mmol) were mixed in N,N-dimethylformamide (10 mL) and degassed and then heated at 100° C. for 1 hour. The mixture is allowed to cool to room temperature and an aqueous work up is performed. The residue is purified to afford the desired product (60 mg, 39%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]1([C@H:17]([CH2:19][OH:20])[NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:18][C@H:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:19][OH:20])=[O:6]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: N[C@@H](CO)c1ccccc1
Solvent: ClCCl
Product: O=C(N[C@@H](CO)c1ccccc1)c1cccc(Br)c1
Reaction time: 3 h

Procedure:
To a vigorously stirred solution of 3-bromobenzoyl chloride (13 g, 58 mmol) in dichloromethane (500 ml) was rapidly added a solution of (R)-(-)-2-phenyl-glycinol (10.5 g, 76 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for 3 h and insolubles removed by filtration. Concentration of the filtrate gave 2-(3-bromobenzamido)-2(R)-phenylethan-1-ol as colorless solids (18.5 g, quant).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[O:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[O:17][C:18]([CH3:25])([CH3:24])[C:19]([OH:21])=[O:20])[CH2:10][CH2:9]2)=[O:7])=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(Oc1cccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
1.90 g (4.00 mmol) of ethyl [3-{4-(4-bromobenzoyl)piperazinyl}phenoxy]α,α-dimethylacetate was dissolved in a solvent mixture containing 20 ml of dioxane and 20 ml of methanol, to which 20 ml of aqueous 1N NaOH solution was added and stirred for 2 hours at room temperature. After completion of the reaction, diluted hydrochloric acid was added to the reaction mixture to convert the system to acidic, followed by extraction with chloroform, washing with water and drying over anhydrous sodium sulfate. Subsequently, chloroform was distilled off under reduced pressure. The oily residue obtained was crystallized from a solvent mixture of petroleum ether, ether and ethyl acetate to obtain 1.45 g (81.0%) of the target compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:33])[CH:25]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:35]1C=C(S(Cl)(=O)=O)C=C[CH:40]=1>>[CH2:35]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:22])=[CH:25][C:26]=1[F:33])[CH3:40]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CCO2
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCO3)cc1F

Procedure:
4-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=489.1 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 3-chloro-benzenesulfonyl chloride and yielded 4-{[4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([F:21])[C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([F:21])[C:14]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(Br)ccc1F
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COc1cc(F)c(-c2ccc(F)c(C(=O)O)n2)c(F)c1
Yield: 9 %

Procedure:
Method 1 was followed using 6-bromo-3-fluoropicolinic acid (1.0 equiv.) and 2,6-difluoro-4-methoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 6-(2,6-difluoro-4-methoxyphenyl)-3-fluoropicolinic acid in 9% yield. LC/MS=284.0 (M+H), Rt=0.74 min.
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:36]=[CH:35][C:22]2[N:23]([CH2:33][CH3:34])[C:24](=[O:32])[C:25]([CH3:31])([CH3:30])[C:26](=[O:29])[N:27]([CH3:28])[C:21]=2[CH:20]=1.[OH-].[Na+]>CO>[NH2:6][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:36]=[CH:35][C:22]2[N:23]([CH2:33][CH3:34])[C:24](=[O:32])[C:25]([CH3:30])([CH3:31])[C:26](=[O:29])[N:27]([CH3:28])[C:21]=2[CH:20]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCN3C(=O)c4ccccc4C3=O)ccc21
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCN)ccc21
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 87.7 %

Procedure:
Hydrazine hydrate(0.5 ml) was added to a methanol solution (60 ml) of 7-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione(1.93 g). The mixture was stirred for 5.5 hours while heated under reflux. After cooled to room temperature, a 1N-sodium hydroxide aqueous solution was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and condensed under reduced pressure to give the title compound(1.2 g) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]1[CH:44]=[CH:45][C:46]([CH3:53])=[C:47]([S:49](Cl)(=[O:51])=[O:50])[CH:48]=1>C(#N)C>[CH3:53][C:46]1[CH:45]=[CH:44][C:43]([F:42])=[CH:48][C:47]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(F)cc1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 39.8 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0287 g, 0.0622 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-fluoro-2-methylbenzenesulfonyl chloride (0.0286 mL, 0.195 mmol) to obtain 4-(2-methyl-5-fluorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0157 g, yield 40%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([C:10]2[N:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12][CH:11]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(-n2ccc([N+](=O)[O-])n2)nc1
Temperature: 100 °C
Yield: 74.3 %

Procedure:
A mixture of 3-Nitro-1H-pyrazole (0.265 gm, 2.34 mmol), tert-butyl 6-chloropyridine-3-carboxylate (0.500 gm, 2.34 mmol) was dissolved in anhydrous DMF (10 mL). Cesium carbonate (1.90 gm, 5.86 mmol) was added and reaction mixture was heated at 100° C. for 6 h. The reaction mixture was cooled to room temperature and poured into ice water, a white precipitate formed was filtered and dried under vacuum to give tert-butyl 6-(3-nitropyrazol-1-yl)pyridine-3-carboxylate (0.505 gm).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=O)[C:19]([F:22])([F:21])[F:20])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([F:22])([F:20])[F:21])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccc2cc(OCc3ccccc3)ccc21)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)Cn1ccc2cc(OCc3ccccc3)ccc21
Temperature: 0 °C
Yield: 82.4 %

Procedure:
A solution of Example 78A (1.98 g, 6.20 mmol) in THF (20 mL) at 0° C. was treated dropwise with 1M BH3 THF in THF (11.2 mL, 11.2 mmol), heated at reflux for 16 hours, cooled to 0° C., treated 6M HCl (approximately 1 mL), diluted with ethyl acetate (60 mL), washed with 10% NaHCO3 (30 mL) and brine (30 mL), dried (MgSO4), filtered, and concentrated to provide 1.56 g of the desired compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:6][O:7][C:8](=[O:19])[C:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>CN(CCN(C)C)C.C1COCC1.CCOCC.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>[CH3:6][O:7][C:8](=[O:19])[C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: c1ccoc1
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1ccc(-c2ccco2)cc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
To a cooled (0° C.) solution of furan (5.7 mL, 78 mmol) in TMEDA/THF (81.4 mL, 14/86) is added n-buLi (15 mL, 2.5 M in hexanes). The cold bath is removed and the resulting solution stirred for 45 minutes, then a solution of ZnCl2 in THF added (40 mL, 0.5M). To this solution is added (Ph3P)4Pd (1.0 g, 0.86 mmol) and 2-(4-Bromo-phenyl)-2-methyl-propionic acid methyl ester (4.5 g, 17.5 mmol) (reference example 31 a). The resulting solution is warmed to 60° C. and stirred for 3 hours. The reaction mixture is then cooled, diluted with ether, washed with hydrochloric acid (2M), then brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 5% ether in hexanes) to give 3.84 g of the title compound as a solid. 1H NMR (CDCl3) d 1.60 (s, 6H), 3.67 (s, 3H), 6.45 (m, 1H), 6.63 (d, J=3 Hz, 1H), 7.35 (m, 2H), 7.46 (m, 1H), 7.65 (m, 2H). MS (EI) m/z 245 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Br:30])[CH:29]=1)[CH2:25]Br>>[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Br:30])[CH:29]=1)[CH2:25][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCc1cc(Br)cc(Br)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Br)cc(Br)c2)c1
Yield: 70.6 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dibromobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (380 mg, yield: 70.6%).
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:26])[C@@H:18]([CH:19]=[C:20]([CH3:22])[CH3:21])[C@H:17]1[C:23](Cl)=[O:24].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:15][C:16]1([CH3:26])[C@@H:18]([CH:19]=[C:20]([CH3:21])[CH3:22])[C@H:17]1[C:23]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:24]
Reactant: CC(C)=C[C@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: OCc1cnc(Oc2ccccc2)s1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)=C[C@H]1[C@@H](C(=O)OCc2cnc(Oc3ccccc3)s2)C1(C)C
Temperature: 20 °C
Reaction time: 17 h

Procedure:
2.07 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of (1R,3S) 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylic acid chloride prepared from 1.68 g of the corresponding acid in 20 ml of benzene and 0.81 ml of pyridine were added dropwise thereto. The mixture was stirred at 20° C. for 17 hours and was poured into dilute aqueous hydrochloric acid. The decanted aqueous phase was extracted with ether and the combined organic phases were washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 1.6 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane -1-carboxylate.