Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].F[P-](F)(F)(F)(F)F.[CH:14]([N+:17]([CH:25]([CH3:27])[CH3:26])=[CH:18]N1CCCCC1)([CH3:16])[CH3:15].[C:28]([O:32][C:33]([N:35]1[C:39](=[O:40])[CH2:38][CH2:37][C@H:36]1[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1.C(OC(C)C)(=O)C>[C:28]([O:32][C:33]([N:35]1[C@H:36]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[CH:46][CH:47]=2)[CH2:37]/[C:38](=[CH:18]\[N:17]([CH:14]([CH3:15])[CH3:16])[CH:25]([CH3:26])[CH3:27])/[C:39]1=[O:40])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)[N+](=CN1CCCCC1)C(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)C
Product: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1 M solution of potassium tert-butoxide in THF (11.7 ml) is added to diisopropyl(piperidin-1-ylmethylidene)ammonium hexafluorophosphate (5 g, prepared according to Example 12). The resulting mixture is then stirred for 1 h at 50° C. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (8-a, R1=Boc) (1 g) is then added to the reaction and the resulting mixture is stirred for 1 h at room temperature. The mixture is diluted with isopropyl acetate and filtered through silica. The residue is concentrated in vacuo then purified by column chromatography (ethyl acetate) to give (R)-5-biphenyl-4-ylmethyl-3-[1-diisopropylamino-meth-(E)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=iPr, R7=iPr). Rf 0.55 (ethyl acetate). 1H NMR (DMSO-d6), 7.65-7.62 (2H), 7.61-7.58 (2H), 7.47-7.42 (2H), 7.37-7.31 (1H), 7.29-7.25 (2H), 7.01 (1H), 4.28-4.20 (1H), 3.84-3.70 (2H), 3.07-3.01 (1H), 2.82-2.73 (1H), 2.71-2.63 (1H) 2.49-2.44 (1H), 1.49 (9H), 1.13-1.08 (12H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]([CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37])[CH:31]=[CH:32][C:33]=1[F:34].[BH4-].[Li+].ClCCl>O1CCCC1.O>[F:27][C:28]1[CH:29]=[C:30]([CH2:35][C:36]([NH:39][CH2:21][CH:20]([C:11]2[C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=[C:9]([OH:8])[CH:10]=2)[OH:26])([CH3:37])[CH3:38])[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: CC(C)(N)Cc1ccc(F)c(F)c1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(Cc1ccc(F)c(F)c1)NCC(O)c1cc(O)cc2c1OCC(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
357 mg (1 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 185 mg (1 mmol) of 2-(3,4-difluorophenyl)-1,1-dimethylethylamine are stirred for 30 minutes in 5 mL tetrahydrofuran at ambient temperature. It is cooled to 0° C. and, under an argon atmosphere, 1.5 mL of a 2 molar solution of lithium borohydride in tetrahydrofuran is added dropwise. The mixture is stirred for 30 minutes at ambient temperature, combined with 10 mL dichloromethane, and 3 mL water, stirred for a further hour and then filtered through an EXTRELUT® column. The eluate containing the ethanol amine is freed from solvent. The residue is dissolved in methanol and hydrogenated with palladium on charcoal (10%) as catalyst at 2.5 bar and ambient temperature. Then the catalyst is separated off and the crude product is purified by chromatography. White solid. Yield: 31 mg (6%, trifluoroethyl acetate); mass spectroscopy: [M+H]+=393.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH:7]=[CH:8][CH2:9][CH:10]=1)[C:4]([OH:6])=[O:5]>C1C2C(CCCC2)CCC1.CCCCCC>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC1=CCC=CC1C(=O)O
Agent: *O[SiH2]*
Solvent: C1CCC2CCCCC2C1
Solvent: CCCCCC
Product: Cc1ccccc1C(=O)O
Yield: 954.8 %

Procedure:
To a suspension of 2-methyl-1,4-dihydrobenzoic acid (0.085 g, 0.05 mmol; 81% pure, from Aldrich Chemical Company) in decalin (5 mL) under a nitrogen atmosphere was added the polysiloxane matrix material containing a homogeneous dispersion of metal particles (0.100 g). The solution was heated to reflux for 19 h. On cooling the reaction mixture was diluted with hexane (25 mL) and extracted with aqueous sodium hydroxide (5%) solution (2×5 mL). The basic aqueous solution was acidified and extracted with chloroform (3×4 mL). The combined organic layer was dried over anhydrous sodium sulfate. Removal of solvent on rotary evaporator gave 2-methylbenzoic acid (0.065 g. 96%). IR(KBr) 3600-2000 (br), 2923, 1694, 1300, 920, 731 cm-1. 1H NMR (300 MHz, CDCl3) δ8..03 (ddd, J=8.5, 3.0, 1.5 Hz, 1 H), 7.42 (td, J=8.5, 1.5 Hz, 1H, 7.26 (td, J=8.5, 1.5 Hz, 1H), 7.22 (dd, J=8.5, 1.5 Hz, 1H), 2.64 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:19][CH:18]=1)=O.Cl.[NH2:34][OH:35].C([O-])(=O)C.[Na+].CO>O>[OH:35][N:34]=[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:19][CH:18]=1)[CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CCCC2OC(=O)NC2=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCC(=NO)c1ccc(CCCC2OC(=O)NC2=O)cc1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A mixture of 5-[3-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]propyl]-2,4-oxazolidinedione (0.28 g), hydroxylamine hydrochloride (0.09 g), sodium acetate (0.11 g) and 80% methanol (20 ml) was stirred under refluxing conditions for 2 hours. The reaction mixture was poured over water; the resulting crystal was collected by filtration to yield 5-[3-[4-[1-hydroxyimino-3-(5-methyl-2-phenyl-4-oxazolyl)propyl]phenyl]propyl]-2,4-oxazolidinedione (0.26 g, 90%), which was then recrystallized from dichloromethane-methanol to yield colorless prisms having a melting point of 185°-186° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:19][C:20](Cl)=[O:21])=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([OH:25])[CH3:24].N1C=CC=CC=1>C1C=CC=CC=1>[CH2:23]([O:25][C:20](=[O:21])[CH2:19][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:9]=1)[CH3:24]
Reactant: CCO
Reactant: Cc1ccc(-n2cc(-c3ccccc3)c(CC(=O)Cl)n2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1nn(-c2ccc(C)cc2)cc1-c1ccccc1
Reaction time: 16 h

Procedure:
2.2 g. of [4-phenyl-1-(4-tolyl)-3-pyrazolyl]-acetyl chloride crude product are reacted with 5 ml. of absolute benzene and 5 ml. of absolute ethanol. 0.2 ml. of pyridine are added dropwise to this mixture, which is allowed to stand at room temperature for 16 hours, and then diluted with 20 ml. of benzene. The reaction mixture then is washed in turn with water, diluted hydrochloric acid and water; dried and concentrated in vacuum. The residue is recrystallized from acetone/hexane. 1.7 g. of [4-phenyl-1-(4-tolyl)-3-pyrazolyl]-acetic acid ethyl ester with a melting point of 76°-79° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)N.N(OC(C)(C)C)=O.[I:21]I.OS([O-])=O.[Na+]>C(Cl)(Cl)Cl>[I:21][C:5]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: II
Agent: CC(C)(C)ON=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(I)cc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
3-methoxy-5-(trifluoromethyl)aniline (100 mg, 0.52 mmol) was dissolved in CHCl3 (5.2 mL) and t-butyl nitrite (124 μL, 1.05 mmol) was added dropwise by syringe. Iodine (266 mg, 1.05 mmol) was added and then the reaction was slowly heated to 50° C. and was maintained at this temperature for an hour and thirty minutes. The reaction was then cooled to room temperature and poured into aq. NaHSO3 (50 mL). The mixture was extracted with EtOAc (50 mL) and the organic extracts were washed with aq. NaHSO3 (3×50 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 1% to 15% EtOAc/hexanes afforded 1-iodo-3-methoxy-5-(trifluoromethyl)benzene. Rf=0.75 (25% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.53 (s, 1H), 7.41 (s, 1H), 7.09 (s, 1H), 3.82 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:16](O)=O>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH3:16])=[CH:4][C:3]=1[CH3:9]
Reactant: O=CO
Reactant: Cc1cc(N)ccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNc1ccc(Br)c(C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A solution of 4-bromo-3-methylaniline (3.72 g, 20 mmol) in formic acid (15 mL) was heated at 100° C. for 8 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and aq NaHCO3 (50 mL). The layers were separated and the organic layers was dried (Na2SO4) and concentrated. The residue was dissolved in THF (80 mL) and cooled to 0° C. Lithium aluminum hydride (1.52 g, 40 mmol) was added portionwise over 10 min. The mixture was stirred at rt for 8 h and an additional equivalent (750 mg) of LAH was added. After 16 h, the mixture was quenched with EtOAc and MeOH and the solids were filtered. The material was purified by SiO2 flash column chromatography to yield the title compound (2.56 g, 64%) as a colorless oil. 1H-NMR (CDCl3): δ 7.29 (d, 1H, J=8.6 Hz), 6.33 (dd, 1H, J=2.8 Hz), 7.29 (d, 1H, J=2.8, 8.6 Hz), 3.66 (s, 2H), 2.81 (d, 1H, J=5.4 Hz), 2.33 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:14])=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[CH2:40])=[CH:37][CH:36]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:7]1[CH:6]=[C:5]2[C:10]([C:2](/[CH:40]=[CH:39]/[C:38]3[CH:41]=[CH:42][C:35]([F:34])=[CH:36][CH:37]=3)=[N:3][N:4]2[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: C=Cc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc2c(Br)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc2c(/C=C/c3ccc(F)cc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Temperature: 80 °C
Reaction time: 6.5 h
Yield: 46.8 %

Procedure:
To a solution of 600 mg of 3-bromo-6-fluoro-5-nitro-1-trityl-1H-indazole in 6 mL of N,N-dimethylformamide were successively added 292 mg of 4-fluorostyrene, 71 mg of 2-(di-tert-butylphosphino)biphenyl, 27 mg of palladium acetate (II) and 0.85 mL of triethylamine, and stirred at 80° C. for 6.5 hours. The solvent was evaporated, and the resulting residue was dissolved in 25 mL of ethyl acetate. The organic layer was successively washed with water (twice) and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained crude crystal was recrystallized from ethyl acetate-diisopropylether, to afford 304 mg of the title compound as bright yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3](S(C)(=O)=O)=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)=[N:6][CH:7]=1.[OH:21][C:22]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[C:3]([O:21][C:22]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][CH:23]=2)=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: Oc1csc(C(F)(F)F)c1
Reactant: Cc1cnc(-n2cc(C(F)(F)F)cn2)nc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(-n2cc(C(F)(F)F)cn2)nc1Oc1csc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 48.8 %

Procedure:
A mixture of 0.8 g (2.6 mmol) of 5-methyl-4-methylsulfonyl-2-(4-trifluoromethyl-1H-1-pyrazolyl)pyrimidine, 0.44 g (2.6 mmol) of 3-hydroxy-5-trifluoromethylthiophene and 0.72 g (5.2 mmol) of K2CO3 in 10 ml of DMF is stirred at 60° C. for 6 h and then at RT for 48 h. It is subsequently poured into 20 ml of water and extracted with four times 15 ml of CH2Cl2. The combined organic phase is dried over Na2SO4, filtered and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (3:7) as eluent gives 0.5 g of 5-methyl-2-(4-trifluoromethyl-1H-1-pyrazolyl)-4-(5-trifluoromethyl-3-thienyloxy)pyrimidine as colorless crystals.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]2[N:22]=[C:23]([NH:26][C:27](=[O:29])[CH3:28])[S:24][CH:25]=2)=[CH:15][CH:14]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:36]>ClCCl>[ClH:36].[NH:1]([C:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]2[N:22]=[C:23]([NH:26][C:27](=[O:29])[CH3:28])[S:24][CH:25]=2)=[CH:17][CH:18]=1)=[O:11])[NH2:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(OC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(OC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a suspension of 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl tert-butyl hydrazine-1,2-dicarboxylate (445.2 mg, 1.06 mmol) in anhydrous dichloromethane (5.3 ml) was added 4M hydrogen chloride dioxane solution (5.3 ml, 21.3 mmol). After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. This operation was performed 3 times to remove hydrogen chloride gas azeotropically. The residue was suspended in ethyl acetate, and the solid was collected by filtration, washed twice with ethyl acetate, and dried under reduced pressure to give the title compound (380.5 mg, quantitative) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:5].[OH:20][CH2:21][CH2:22][O:23][C:24]1[C:31]([CH3:32])=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[CH3:33]>C(O)C.[Cu](Cl)Cl>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:17][CH:16]=[C:15]([O:18][CH3:19])[CH:14]=3)[N:1]=[C:28]2[C:27]2[CH:30]=[C:31]([CH3:32])[C:24]([O:23][CH2:22][CH2:21][OH:20])=[C:25]([CH3:33])[CH:26]=2)=[CH:12][CH:11]=1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: COc1ccc(N)c(C(=O)Nc2ccc(Br)cc2)c1
Agent: Cl[Cu]Cl
Solvent: CCO
Product: COc1ccc2nc(-c3cc(C)c(OCCO)c(C)c3)n(-c3ccc(Br)cc3)c(=O)c2c1

Procedure:
To a solution of 2-amino-N-(4-bromo-phenyl)-5-methoxy-benzamide (0.240 g, 0.740 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.145 g, 0.740 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.298 g, 2.22 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with ethyl acetate (100 mL) and water (100 mL). After separation the organic phase was further backwashed with water (100 mL), brine (100 mL), dried over sodium sulfate, and concentrated. The crude was purified by column chromatography (SiO2, hexane/ethyl acetate=1:1) to give the title compound as white solid. Yield: 120 mg (33%). MP 160-162° C. 1H-NMR (400 Hz, CDCl3): δ 7.74 (d, 1H), 7.69 (s, 1H), 7.46 (d, 2H), 7.40 (m, 1H), 7.03 (d, 2H), 6.96 (s, 2H), 3.94 (s, 3H), 3.91 (m, 2H), 3.82 (t, 2H), 2.17 (s, 6H), 2.05 (t, 1H). MS (ES+) m/z: 497.41 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C.O>ClCCl>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCCNCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 1-methyl-[1,4]diazepane (2.19 mL) in dry dichloromethane (30 mL) was treated with a solution of 4-nitrobenzoyl chloride (3.6 g) in dry dichloromethane (30 mL) dropwise over 10 minutes. After stirring at room temperature for a further 10 minutes the reaction mixture was treated with triethylamine (2.8 mL) and then stirred for a further 3 hours. The reaction mixture was then treated with water (10 mL), the organic phase separated and further washed twice with a 2 M aqueous solution of sodium hydroxide (20 mL), then four times with water (15 mL). The organic phase was then dried over magnesium sulfate and evaporated to give the title compound (4.4 g) as brown oil, Rf 0.64 (dichloromethane:methanol, 4:1). MS: 264 [MH]+.
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][O:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[OH:12]>C1(C)C=CC=CC=1>[C:13]1([CH:2]2[O:12][C:6]3[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=3[O:4][CH2:3]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(O)c(OCC(O)c2ccccc2)c1
Solvent: Cc1ccccc1
Product: Oc1ccc2c(c1)OCC(c1ccccc1)O2

Procedure:
A solution of 2-(2-hydroxy-2-phenylethoxy)benzene-1,4-diol (1.2 g) in toluene (75 ml) was heated with Amberlyst 15 catalyst (0.5 g) under reflux for 7 hrs. After filtering the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (toluene/ethyl acetate/acetic acid, 8:1:1). The yield of 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol is 0.5 g. 1H NMR (DMSO-d6) δ: 4.02 (dd, J 8.5, 11.4 Hz, 1H), 4.35 (dd, J 2.3, 11.4 Hz, 1H), 5.11 (dd, J 8.5, 2.3 Hz, 1H), 6.29 (dd, J 2.8, 8.5 Hz, 1H), 6.32 (d, J 2.8 Hz, 1H), 6.75 (d, J 8.5 Hz, 1H), 7.36-7.47 (m, 5H), 8.99 (s, 1H).
Reaction SMILES: [C:1]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])(=[O:4])[CH2:2][CH3:3].[CH:18](=[O:20])[CH3:19]>>[CH3:3][C@@H:2]([C@H:18]([OH:20])[CH3:19])[C:1]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][O:7][C:6]1=[O:17])=[O:4]
Reactant: CC=O
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@@H](C)O

Procedure:
Prepared from (4S)-N-propionyl-4-benzyl-2-oxazolidinone and acetaldehyde according to the procedure described in Example 1, paragraph A. 1H-NMR (360 MHz, CDCl3): δ 7.2–7.4 (m,5H); 4.71 (m,1H); 4.12–4.25 (m,2H); 3.76 (dq,1H); 3.26 (dd,1H); 2.79 (dd,1H); 1.30 (d,3H), 1.21 (d,3H).
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C:3]1[C:8]([CH2:9][C:10]([O:12]C)=[O:11])=[C:7]([N:14]([CH3:16])[CH3:15])[N:6]=[C:5]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[N:4]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:37][N:2]([CH3:1])[C:3]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[C:7]([N:14]([CH3:15])[CH3:16])[N:6]=[C:5]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:36])[C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=3)=[CH:22][CH:23]=2)[N:4]=1
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc(N(C)C)c1CC(=O)O

Procedure:
A solution of methyl [4,6-bis(dimethylamino)-2-(4-{[4-(trifluoromethyl)benzoyl]amino}-benzyl)pyrimidin-5-yl]acetate (4.34 g, 8.42 mmol) in 20% tetrahydrofuran in methanol (100 mL) was treated with 1N sodium hydroxide solution (25 mL). The resulting mixture was heated at refluxing temperature for 5 hours and then the volatiles were removed by rotary evaporation under vacuum. The remaining aqueous solution was washed with diethyl ether and then neutralized with 1N hydrochloric acid at 0° C. The separated precipitate was collected by suction and rinsed with cold water. Recrystallization from methanol then gave [4,6-bis(dimethylamino)-2-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)pyrimidin-5-yl]acetic acid (3.86 g, 81%) as colorless needles.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:24]=[CH:23][C:22]([CH2:25][N:26]6[CH2:31][CH2:30][NH:29][CH:28]([CH3:32])[CH2:27]6)=[CH:21][CH:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CO.C(N(CC)CC)C.[C:52](OC(=O)C)(=[O:54])[CH3:53]>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:20]=[CH:21][C:22]([CH2:25][N:26]6[CH2:31][CH2:30][N:29]([C:52](=[O:54])[CH3:53])[CH:28]([CH3:32])[CH2:27]6)=[CH:23][CH:24]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(CN5CCNC(C)C5)cc4)cnc32)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CC1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-(1H-indol-5-yl)-5-(4-((3-methylpiperazin-1-yl)methyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (50 mg) was suspended in 1 mL dichloromethane and 1 mL of methanol and treated with triethylamine (100 mL) and acetic anhydride (20 μL) and stirred for one hour. The mixture was concentrated in vacuo, taken up in EtOAc and washed with water and brine and dried over MgSO4. The residue was suspended in methanol and treated with 5 N NaOH and heated at 50° C. for one hour. The mixture was diluted with dichloromethane and washed with water and brine, dried over MgSO4 and purified by MPLC silica gel chromatography (0-20% MeOH in DCM) to yield an analytical sample (464 M+H).
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:15])[NH:11][S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:16][CH3:17])[CH:5]=1)([CH3:3])[CH3:2].[C:18](OCCl)(=O)C(C)(C)C.C(N(C(C)C)CC)(C)C.[BrH:36].C(O)(=O)C>C(#N)C>[Br:36][CH2:18][N:11]1[C:10](=[O:15])[C:9]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]([O:16][CH3:17])=[CH:7][C:8]=2[S:12]1(=[O:14])=[O:13]
Reactant: Br
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Yield: 60.3 %

Procedure:
A mixture 4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (0.51 g, 2 mmol), acetonitrile (5.0 ml), chloromethyl pivalate (0.32 ml, 2.2 mmol) and diisopropylethylamine (0.42 ml, 2.4 mmol) was heated to reflux until the starting material was consumed and then 33% HBr/acetic acid (2.4 g, 10 mmol) was added and the mixture was refluxed for 15 minutes. The reaction mixture was coooled, quenched with ice-water and filtered to afford 0.42 g (65%) of 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, m.p. 158°-160.5° C., after recrystallization from ethyl acetate/hexane (3/2).