Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:12])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=[CH:20][C:21](=[O:23])[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CS(O)(=O)=O.O>C(#N)C>[C:1]1([C:7]2[NH:8][C:9](=[O:12])[O:10][C:11]=2[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][C:21](=[O:23])[CH3:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: O=c1[nH]c(-c2ccccc2)co1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC#N
Product: CC(=O)CC(c1ccccc1)c1oc(=O)[nH]c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of 4-phenyl-2-oxo-4-oxazoline (1.61 g) and benzalacetone (1.46 g) in acetonitrile (20 ml) was added dropwise methanesulfonic acid (0.96 g). After stirring the obtained mixture at room temperature for 30 min, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried (MgSO4), and the solvent was evaporated. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:1). The solvent was evaporated. Crystallization from isopropyl ether gave 4-(4-phenyl-2-oxo-4-oxazolin-5-yl)-4-phenyl-2-butanone (2.65 g; yield 86.3%). Recrystallization from ethanol gave colorless crystals.
Reaction SMILES: [C:1]1([N:7]2[C:12](=S)[C:11]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][NH:9][C:8]2=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24]O.Cl>[OH-].[K+].CO.O>[C:1]1([N:7]2[C:12](=[O:24])[C:11]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][NH:9][C:8]2=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]nc(Cc2c(F)cccc2F)c(=S)n1-c1ccccc1
Reactant: OO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]nc(Cc2c(F)cccc2F)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
4-Phenyl-6-(2,6-difluorobenzyl)-5-thioxo-2H-(1,2,4)triazin-3-one (1.00 g, 3.02 mmol) was dissolved in a solution of KOH (643 mg) in MeOH (12 mL) and water (6 mL). A solution of H2O2 (1.2 mL, 30% in water) in water (5 mL) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was acidified with conc. HCl (1.1 mL) and a white solid precipitated. Filtered and washed with water to give a white solid (816 mg, 85.8%): MS (CI) m/z 380.2 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].CC1C=CC(S(O[CH2:31][CH2:32][F:33])(=O)=O)=CC=1.CCOC(C)=O>CN(C)C1C=CN=CC=1.C1COCC1>[F:33][CH2:32][CH2:31][N:17]1[CH2:18][CH2:19][N:14]([C:6]2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1cc(N2CCNCC2)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(N2CCN(CCF)CC2)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
Mix (3-nitro-5-(trifluoromethyl)phenyl)piperazine (200 mg, 0.73 mmol), 2-fluoroethyl 4-methylbenzenesulfonate (320 mg, 1.46 mmol) and 4-dimethylaminopyridine (50 mg, 0.37 mmol) in THF (15 mL), stir at 90° C. overnight. TLC (EtOAc:PE=1:1) shows the reaction is complete. Concentrate under reduced pressure to give a residue, purify the residue by flash chromatography (silica gel, PE:EtOAc=1:1) to yield a white solid as the target compound (120 mg, 51%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH3:18][CH:19]([CH3:21])[CH2:20][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCC(C)C
Reaction time: 0.33 h

Procedure:
In 250 ml three necked flask, equipped with reflux condenser, mechanical stirrer, 30.4 g (200 mmol) of vanillin, 28 g (200 mmol) of dry K2CO3 and 150 ml of abs. dimethylformamide are placed in the flow of argon. The mixture is stirred for 20 min in argon condition, then 34.3 g (250 mmol) of isobutyl bromide is added. The mixture is refluxed with stirring in argon condition for 20 h at 90÷100° C., and concentrated in vacuum at 50÷80° C. to dryness. Then 200 ml of water is added to the residue, the mixture is extracted with (4×100 ml) of dichloromethane. The combined organic fraction is washed with 7% NaOH solution, dried over magnesium sulfate, filtered off, concentrated in vacuum at 50÷80° C. The residue (15 g of brown oil)-crude 4-(2-methylpropyloxy)-3-methoxybenzaldehyde is used on the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:9]=[CH:8][N:7](COC(=O)C(C)(C)C)[C:6]2=[O:29]>N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:29]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCc1ccncc1
Agent: N
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccncc1
Yield: 92.5 %

Procedure:
A solution of 6-methoxy-3-((pivaloyloxy)methyl)-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (500 mg, 1.26 mmol) in saturated methanolic ammonia (10 ml) was stirred for 20 hours at ambient temperature. The volatiles were removed by evaporation, the solid residue was triturated with ether, collected by filtration and dried under vacuum to give 6-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (330 mg, 92%).
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][CH2:11][CH:12]([OH:25])[CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>CN(C=O)C>[N+:7]([C:5]1[N:6]=[C:2]2[N:3]([CH:4]=1)[CH2:10][CH2:11][CH:12]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[O:25]2)([O-:9])=[O:8]
Reactant: CC(C)[Si](OCC(O)CCn1cc([N+](=O)[O-])nc1Br)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](OCC1CCn2cc([N+](=O)[O-])nc2O1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A stirred solution of alcohol 132 (2.45 g, 5.61 mmol) in anhydrous DMF (25 mL) under N2 at 0° C. was treated with 60% NaH (388 mg, 9.70 mmol), then quickly degassed and resealed under N2. After stirring at room temperature for 2 h, the reaction was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (20 mL), diluted with ice-water (150 mL) and extracted with EtOAc (8×80 mL). The extracts were washed with brine (100 mL) and then evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-25% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 25% EtOAc/petroleum ether gave 2-nitro-7-{[(triisopropylsilyl)oxy]methyl}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (133) (1.77 g, 89%) as a pale yellow solid: mp (CH2Cl2/pentane) 121-123° C.; 1H NMR (CDCl3) δ7.42 (s, 1H), 4.45 (m, 1H), 4.17 (ddd, J=12.3, 5.8, 3.7 Hz, 1H), 4.06 (ddd, J=12.3, 10.3, 5.4 Hz, 1H), 4.03 (dd, J=10.7, 4.1 Hz, 1H), 3.95 (dd, J=10.7, 5.8 Hz, 1H), 2.37 (dddd, J=14.5, 5.5, 3.6, 2.8 Hz, 1H), 2.27 (dtd, J=14.5, 10.1, 5.8 Hz, 1H), 1.17-1.03 (m, 21H). Anal. (C16H29N3O4Si) C, H, N.
Reaction SMILES: [F:1][CH:2]([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][CH:6]=1)[CH3:4].Br>C(O)(=O)C>[F:1][CH:2]([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4]
Reactant: COc1ccc(C(C)C(F)F)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC(c1ccc(O)cc1)C(F)F
Temperature: 25 °C

Procedure:
24.8 g (0.13 mol) of 1-(2,2-difluoro-1-methylethyl)-4-methoxybenzene were stirred in 350 ml of glacial acetic acid and heated under reflux. 67 g of 48% aqueous hydrobromic acid were subsequently added dropwise and the mixture was stirred under reflux for a further 5 h. After cooling to room temperature, the solvent was distilled off under reduced pressure and the residue was taken up in ethyl acetate, washed with aqueous sodium hydrogen carbonate dried and concentrated to give the title product as a colourless oil which was reacted further without any purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2cc(F)ccc2N)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under argon, a mixture of 9.0 g (37.9 mmol) of 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 10.25 g (45.5 mmol) of 4-bromobenzotrifluoride, 1.39 g (1.89 mmol) of 1,1′-bis(diphenyl-phosphino)ferrocenepalladium(II) chloride and 20.11 g (189 mmol) of sodium carbonate in 200 mL of DMSO and 70 mL of water is stirred at 90° C. overnight. After the reaction has ended, the mixture is cooled to room temperature, water is added and the mixture is extracted with ethyl acetate. The organic phase is once more washed with water, dried with sodium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography (mobile phase: cyclohexane/ethyl acetate gradient). This gives 5.28 g (53% of theory) of 5-fluoro-4′-(trifluoromethyl)biphenyl-2-amine having a content of 97% according to LC-MS and a logP (acidic) of 3.52.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH:9]=[O:10])=[C:6]([N:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:5]2[N:28]=[CH:29][CH:30]=[C:4]2[N:3]=1.P([O-])(O)(O)=[O:32].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[C:14]([O:13][C:12]([N:11]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH3:27])=[CH:23][CH:24]=1)[C:6]1[N:5]2[N:28]=[CH:29][CH:30]=[C:4]2[N:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([OH:32])=[O:10])=[O:18])([CH3:16])([CH3:15])[CH3:17]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC=O)c(Cl)nc3ccnn23)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC(=O)O)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.7 %

Procedure:
To a mixed solution of water (0.5 mL) and tert-butanol (5 mL) containing tert-butyl [5-chloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (431 mg, 1.0 mmol), sodium dihydrogen phosphate (1.56 g, 10 mmol), 2-methyl-2-butene (1.1 mL, 10 mmol) and sodium chlorite (181 mg, 2.0 mmol) were added, and this mixture was stirred at room temperature for 4 hr. After the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound (468 mg).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH:14]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH2:15][O:16][Si](C(C)(C)C)(C)C)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl>C(O)C.O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH:14]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=2)[CH2:15][OH:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(CO[Si](C)(C)C(C)(C)C)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(C(CO)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 1 h

Procedure:
A 25 ml round bottom flask is charged 2-tert-butyl-4-chloro-5-(2-tert-butyldimethylsilyloxy-1-(4-tert-butylphenyl)-1-ethyl)oxy-3(2H)-pyridazinone (0.5 g, 1.01 mmol) and to it is added 5 ml of 1% concd. HCl in ethanol. The solution is stirred for one hour after which it is poured in water and extracted with ethyl acetate. The ethyl acetate is removed using the rotary evaporator and subjected to flash chromatography using silica gel and ethyl acetate/hexanes mixture as the eluting medium.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][N:11]3[C:15](=[O:16])[CH2:14][S:13][C:12]3=[O:17])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:18](=O)[CH2:19][CH2:20][CH3:21].N1CCCCC1>C(O)C>[CH:18](=[C:14]1[S:13][C:12](=[O:17])[N:11]([CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:15]1=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: O=C1CSC(=O)N1Cc1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(Cc2cccc3nccn23)C1=O

Procedure:
To a solution of 223 mg (0.9 mmol) of 3-(imidazo[1,2-a]pyridin-5-yl)methylthiazolidine-2,4-dione and 0.09 ml (1.0 mmol) of n-butyraldehyde in 5 ml of ethanol, 0.001 ml (0.1 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/4) to yield 222 mg (82.2%, light yellow oily substance) of the desired product.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[BrH:8].[Br:9][CH2:10][CH2:11][NH2:12]>C(O)C>[BrH:9].[BrH:8].[N:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:10][CH2:11][NH2:12])=[CH:3][CH:4]=1
Reactant: NCCBr
Reactant: Sc1ccncc1
Agent: Br
Solvent: CCO
Product: NCCSc1ccncc1
Yield: 82 %

Procedure:
A solution of 32.72 g of 4-mercaptopyridine and 61.0 g of 2-bromoethanamine hydrobromide in 200 ml of absolute ethanol was heated to reflux under an argon atmosphere for 2 hours. After cooling the precipitated product was collected and washed with ethanol to give 76.31 g of crude 2-(4-pyridylthio)ethanamine dihydrobromide, mp 250°-254° C. Recrystallization from ethanol (1500 ml) and water (150 ml) with a charcoal treatment afforded 63.09 g (68%) of 2-(4-pyridylthio)ethanamine dihydrobromide, mp 265°-268° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C([O:19][CH2:20][CH3:21])(=O)C>C(N(CC)CC)C>[C:20]1(=[O:19])[N:2]([CH:3]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:5](=[O:6])[C:4]2=[CH:3][CH:9]=[CH:10][CH:11]=[C:21]12
Reactant: COC(=O)CC(N)c1ccc(C)cc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CC(c1ccc(C)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 14 g of methyl β-amino-β-(4-methylphenyl)propionate hydrochloride, were added 200 ml of ethyl acetate and 10.2 ml of triethylamine. The mixture was stirred at room temperature for 30 minutes, then washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure. To the residue, was added 8.5 g of phthalic anhydride. The mixture was stirred at 150° to 155° C. for one hour and recrystallized from an ether-n-hexane mixture to yield 15 g of methyl β-phthalimido-β-(4-methylphenyl)propionate; m.p. 97°-99° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][S:14]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[C:31]3[C:26](=[C:27]([C:38]([NH2:40])=[O:39])[CH:28]=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15].NN>CCO>[NH2:3][CH2:12][CH2:13][S:14]([N:17]1[CH2:18][CH2:19][CH:20]([C:23]2[C:31]3[C:26](=[C:27]([C:38]([NH2:40])=[O:39])[CH:28]=[C:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:30]=3)[NH:25][CH:24]=2)[CH2:21][CH2:22]1)(=[O:15])=[O:16]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCN4C(=O)c5ccccc5C4=O)CC3)c[nH]c12
Agent: NN
Solvent: CCO
Product: NCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a solution of 3-(1-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]sulfonyl}-4-piperidinyl)-5-phenyl-1H-indole-7-carboxamide (70 mg, 0.13 mmol) in EtOH (2 mL) at room temperature, hydrazine (0.3 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the resulting residue purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (26.9 mg, 50%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:32])[C@@H:6]([CH3:31])[NH:7][C:8](=[O:30])[C@H:9]([CH2:26][C:27](=[O:29])[OH:28])[NH:10][C:11](=[O:25])[C@@H:12]([CH3:24])[NH:13]C(OCC1C=CC=CC=1)=O)([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[CH:1]([O:4][C:5](=[O:32])[C@@H:6]([CH3:31])[NH:7][C:8](=[O:30])[C@H:9]([CH2:26][C:27](=[O:28])[OH:29])[NH:10][C:11](=[O:25])[C@@H:12]([CH3:24])[NH2:13])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)OC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N
Yield: 91.1 %

Procedure:
N-Benzyloxycarbonyl-D-alanyl-α-L-aspartyl-D-alanine isopropyl ester (2.5 g) was dissolved in 100 ml of 80% aqueous acetic acid, and the solution was subjected to catalytic reduction in a hydrogen gas stream at room temperature for four hours using palladium/carbon as catalyst. After filtering off the catalyst, the filtrate was concentrated to dryness under reduced pressure, affording 1.6 g of white powder. M.p.: 219°-221° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=2[O:3][CH2:2]1.C1(=O)O[CH2:14][CH2:13][O:12]1.C([O-])([O-])=O.[K+].[K+].C(=O)=O>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:14][CH2:13][OH:12])[C:4]=2[O:3][CH2:2]1
Reactant: Oc1cccc2c1OCO2
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1cccc2c1OCO2
Temperature: 150 °C
Yield: 65 %

Procedure:
A mixture of 1,3-benzodioxol-4-ol* (0.74 g, 5:36 mmol), ethylene carbonate (0.47 g, 5.3 mmol) and K2CO3 (0.67 g, 4.8 mmol) in DMF (30 mL) was heated at 150° C. After the evolution of carbon dioxide had ceased (1 h), the reaction mixture was filtered and concentrated. The crude product was purified by chromatography on silica gel using petroleum ether/EtOAc (70:30) as eluent to give 0.64 g (65%) of the title product as an oil which spontaneously crystallized to a white solid: mp 56-57° C. Anal. (C9H10O4) C, H.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: OB(O)c1ccc(F)cc1F
Product: Fc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c(F)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 323(MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=C([N+]([O-])=O)[C:5]=1[C:6]#[N:7])([O-:3])=[O:2].Cl.CNC.[OH-].[K+].[CH3:21][N:22]([CH3:25])[CH:23]=O>>[CH3:21][N:22]([CH3:25])[C:23]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: CNC
Agent: Cl
Agent: [K+]
Product: CN(C)c1cccc([N+](=O)[O-])c1C#N

Procedure:
2-Dimethylamino-6-nitrobenzonitrile is prepared from molar equivalents of 2,6-dinitrobenzonitrile and dimethylamine hydrochloride in dimethylformamide in the presence of aqueous KOH.
Reaction SMILES: C[O:2][C:3]([CH:5]1[S:17][C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:3][CH:5]1[S:17][C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)C1CCn2c(nc3ccccc32)S1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCn2c(nc3ccccc32)S1
Yield: 54.5 %

Procedure:
To a solution of 2.48 g (10 m mole) of 3,4-dihydro-2-methoxycarbonyl-2H-(1,3)-thiazino-[3,2-a]benzimidazole in dry tetrahydrofuran (50 ml) was added dropwise 0.5 g of lithium aluminum hydride devided in small pieces, with stirring under ice cooling condition. After thirty minutes, the resultant complex was decomposed by the addition of hydrated tetrahydro furan and subjected to filtration. Subsequent to drying the filtrate over anhydrous magnesium sulfate, tetrahydrofuran was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 1.2 g (yield: 54.5%) of the intended product, m.p. 112°-113° C.;
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]>C(OCC)(=O)C.[C].[Pd]>[NH2:1][C@H:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O

Procedure:
23.6 Grams (73.2 mmols) of Z-Asn-OtBu in 200 ml of ethyl acetate are hydrogenated in the presence of 2 g of palladium carbon (10% Pd) until, after 1 hour, hydrogen is no longer absorbed. The catalyst is filtered off and the filtrate concentrated, whereupon the product, melting at 96°-98° C., crystallizes out. Optical rotation [α]D20 =+2° (c=2.1 in methanol). In the thin-layer chromatogram on silica gel the Rf52 =0.30; Rf45 =0.50.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].[CH3:16][N:17]=[C:18]=[O:19]>C(Cl)Cl>[CH3:16][NH:17][C:18]([N:13]1[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH2:15][CH2:14]1)=[O:19]
Reactant: CN=C=O
Reactant: O=C(CN1CCCC1=O)N1CCNCC1
Solvent: ClCCl
Product: CNC(=O)N1CCN(C(=O)CN2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
700 mg (3.31 mmol) of (2-oxopyrrolidin-1-yl)acetylpiperazine was dissolved in 10.5 ml of CH2Cl2, and 0.215 ml (3.64 mmol) of methyl isocyanate was added to the mixture under ice-cooling, and the mixture was warmed to room temperature and stirred for 1 hr. After evaporating CH2Cl2, the precipitated crystals were washed with Et2O and collected by filtration. By recrystallizing from EtOH-Et2O, 856 mg of the objective compound (yield: 96.3%) was obtained as colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[CH2:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12])[C:5]([N+:21]([O-])=O)=[CH:4][N:3]=1>CC(O)=O.Cl.O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:21][C:11](=[O:12])[C:10]([F:17])([F:16])[CH2:9][N:8]([CH:18]([CH3:20])[CH3:19])[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)N1CC(F)(F)C(=O)Nc2cnc(Cl)nc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
Ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(isopropyl)amino)-2,2-difluoropropanoate (1.90 g, 5.39 mmol) was dissolved in HOAc (10 mL) and HCl (conc, 3.1 mL). Iron (0.610 g, 10.9 mmol) was added and the rm was stirred at rt for 3 h and at 60° C. overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated in vacuo. The residue was purified using flash column chromatography on silica gel (40 g SiO2, hexanes:ethyl acetate 2:1-1:1) to afford the title compounds as a light yellow solid (0.809 g, 54%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (d, J=6.82 Hz, 6H) 3.42 (s, 3H) 3.89 (t, J=12.38 Hz, 2H) 4.97-5.10 (m, 1H) 8.06 (s, 1H).