Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=2[C:38]([F:39])([F:40])[F:41])[N:8]=1)=[O:5]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(CBr)c1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2cc([N+](=O)[O-])ccc2C(F)(F)F)n1)c1c(F)cccc1F
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(3.9 g, 17.5 mmol) in THF (35 ml) at ambient temperature was added 1.0 M lithium bis(trimethylsilyl)amide in THF (17.5 ml, 17.50 mmol, Aldrich) dropwise. The solution was stirred for 20 min. To the solution was added a solution of 2-(bromomethyl)-4-nitro-1-(trifluoromethyl)benzene (7.3 g, 25.7 mmol) in THF (10 ml). The resulting dark brown solution was stirred at ambient temperature for 4.5 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (125 ml) and saturated aqueous sodium hydrogen carbonate (75 ml). The phases were separated and the organic phase washed with saturated aqueous sodium hydrogen carbonate (25 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave a brown oil (˜11 g). The residue was loaded in dichloromethane and purified on silica 100 g×2 using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (4.31 g); LCMS: (System 4) MH+=427, tRET=2.80 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[C:12]3[C:18]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:17][N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:13]3=[N:14][CH:15]=2)=[CH:5][CH:4]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:19]([C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:8][CH:7]=3)[N:11]=2)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:17]=1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(CO)cc3)nc12
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Temperature: 5 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a 100 ml three necked round bottom flask 1-(2-(4-(hydroxymethyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethylpropan-1-one (2.3 g, 0.0051 mole) was taken in CH2Cl2 (25 ml). The reaction mixture was cooled to 5° C. and PCC (4.84 g, 0.0225 mole) was added at the same temperature under nitrogen atmosphere. The reaction mixture was warmed up to RT and then stirred for 2 hr. After completion of the reaction, the reaction mixture was poured into saturated NaHCO3 solution (50 ml) under stifling at 10° C. and the aq. layer was extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product which was purified using column purification by eluting the compound with 15-20% ethyl acetate in hexanes to yield 1.7 g of 4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde.
Reaction SMILES: [S:1](=[O:30])(=[O:29])([O:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][C@@H:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[C:13]=3[CH:12]=[CH:11]2)[CH:7]=[CH:6]1)[NH2:2]>[Pd].CCOC(C)=O>[S:1](=[O:30])(=[O:29])([O:3][CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][C@@H:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[C:13]=3[CH:12]=[CH:11]2)[CH2:9]1)[NH2:2]
Reactant: NS(=O)(=O)OC[C@H]1C=C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)OC[C@H]1CC[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Yield: 62.2 %

Procedure:
A suspension of ((1R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopent-2-en-1-yl)methyl sulfamate (17.3 mg, 0.0406 mmol) and 10% palladium on carbon (8.60 mg) in EtOAc (0.500 mL) was put under an atmosphere of hydrogen. After 3 h the flask was purged with nitrogen and the suspension was filtered through Celite eluting with EtOAc to afford the title compound as a white solid (10.8 mg, 62%). 1H NMR (400 MHz, CDCl3, δ): 8.36 (s, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.29-7.15 (m, 3H), 7.00 (d, J=3.4 Hz, 1H), 6.33 (d, J=3.4 Hz, 1H), 5.91-5.87 (m, 1H), 5.41 (br s, 2H), 5.23-5.15 (m, 2H), 4.26 (dd, J=5.8, 9.8 Hz, 1H), 4.18 (dd, J=6.2, 9.8 Hz, 1H), 3.09-3.02 (m, 1H), 2.99-2.90 (m, 1H), 2.36-2.27 (m, 2H), 2.21-2.12 (m, 2H), 2.09-1.93 (m, 3H), 1.66-1.57 (m, 1H) ppm. LC/MS: Rt=1.24 min, ES+ 428 (FA standard).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:42])([CH2:9][CH2:10][CH2:11]/[C:12](=[N:19]\[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[CH:24][CH:23]=1)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([O:7]C)=[O:6].CO.Cl>O1CCCC1>[CH3:3][C:4]([CH3:42])([CH2:9][CH2:10][CH2:11]/[C:12](=[N:19]\[O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[CH:26][CH:27]=1)/[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(C)(C)CCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCC(C)(C)C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A 4N aqueous solution of potassium hydroxide (5 ml) was added to a solution of methyl E-2,2-dimethyl-6-[4(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (340 mg) in tetrahydrofuran (5 ml)-methanol (5 ml), which was heated to reflux for 2 hours and cooled to room temperature. Dilute hydrochloric acid was added to the reaction mixture to neutralize and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain E-2,2-dimethyl-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoic acid (275 mg, yield 83%) as colorless crystals. m.p. 111-112° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:19]([CH3:25])([CH3:24])[C:18](=[O:26])[CH2:17][C:16]([CH3:28])([CH3:27])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23][Br:29])=[CH:21][C:20]3[C:19]([CH3:24])([CH3:25])[C:18](=[O:26])[CH2:17][C:16]([CH3:28])([CH3:27])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(cc1/C=C/c1ccc(C(=O)O)c(C)c1)C(C)(C)CC(=O)C2(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(/C=C/c2cc3c(cc2CBr)C(C)(C)C(=O)CC3(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of 1.4 g (3.7 mmol) of methyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-methyl-6-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid and 0.86 g (4.8 mmol) of N-bromosuccinimide in 50 ml carbon tetrachloride was added 45 mg (0.19 mmol) of benzoyl peroxide and the reaction was heated to reflux temperature. After 1 h, added additional 45 mg of benzoyl peroxide and 25 ml carbon tetrachloride. After 3 h total added 0.2 g N-bromosuccinimide. After 6 h total, cooled to room temperature, washed with 10% aqueous sodium bisulfite and brine, dried over sodium sulfate and adsorbed onto silica gel. Purified by flash chromatography (hexane-8% ethyl acetate/hexane) to give 1.0 g (59%) of methyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-bromomethyl-6-oxo -5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([OH:25])=[O:24].[CH3:26][S:27]([O-:29])=[O:28].[Na+].Cl>CS(C)=O.C(OCC)(=O)C.O.[Cu]I>[CH3:22][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:8][C:9]2[C:4]([C:5]=1[C:23]([OH:25])=[O:24])=[CH:3][C:2]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:11][CH:10]=2
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(Br)cc2c1C(=O)O
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc2c1C(=O)O
Temperature: 120 °C
Reaction time: 22 h
Yield: 45.3 %

Procedure:
To a suspension of 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (10 g, 21.94 mmol) in dimethyl sulfoxide (146 mL) was added copper(I) iodide (8.36 g, 43.9 mmol) and sodium methanesulfinate (5.27 g, 43.9 mmol). The reaction mixture was alternately evacuated and purged with nitrogen three times and heated to 120° C. for 18 h. Additional copper(I) iodide (8.36 g, 43.9 mmol) and sodium methanesulfinate (5.27 g, 43.9 mmol) was added, and the mixture was stirred for an additional 22 h. The mixture was cooled to room temperature and diluted with ethyl acetate and water. The mixture was acidified to pH 2-3 with 2N HCl, filtered through Celite®, and rinsed with ethyl acetate. The organic layer was separated, washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (4.07 g, 30% yield) as an orange solid. MS (m/z) 410.0 (M+H+).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])C)=[O:2].C([Li])(C)(C)C.CCCCC.[C:25]([N:32]1[CH2:37]CC(=O)C[CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CC(C)([O-])C.[K+].Cl>O1CCCC1.C(OCC)C>[O:2]=[C:1]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:4]2([CH2:6][CH2:37][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:33][CH2:7]2)[O:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)OC(=O)Nc1ccccc12
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
N-Boc-aniline (16.12 g, 83.4 mmol) (A1) was dissolved in anhydrous tetrahydrofuran (120 mL) and cooled to −70° C. To this solution was added dropwise, under nitrogen, a 1.7 M solution of tert-butyllithium in pentane (110 mL, 187 mmol) at −70° C. After 30 min at −70° C., the solution was warmed to −20° C. and maintained at that temperature for 2 hours. The solution was again cooled to −70° C. and treated dropwise with a solution of N-Boc-4-piperidone (15.98 g, 80.2 mmol) (A2) in anhydrous tetrahydrofuran (50 mL). The solution was slowly warmed to room temperature, treated with potassium tert-butoxide (25 mg) and stirred at room temperature overnight under nitrogen. The solution was diluted with diethyl ether (300 mL), cooled in an ice water bath and adjusted to pH 7 with 1.0 N HCl (aq). The layers were separated and the aqueous layer extracted once with diethyl ether (100 mL). The pooled organic layers were washed with water and saturated brine, then dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford a crude product as a viscous pale yellow oil. The crude product was purified via silica gel flash chromatography (25-50% ethyl acetate in hexanes) to afford tert-butyl 2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate (A3) as a pale yellow solid. LC/MS m/z 319.0 [M+H]+, retention time 2.72 min (RP-C18, 10-99% CH3CN/0.05% TFA); 1H-NMR (400 MHz, CDCl3) δ 9.06 (br s, 1H), 7.28 (m, 1H), 7.12 (m, 2H), 6.91 (d, J=8.5 Hz, 1H), 4.12 (br d, J=9.9 Hz, 2H), 3.36 (br t, J=12.4 Hz, 2H), 2.13 (br d, J=13.1 Hz, 2H), 1.98 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:24]([OH:26])[CH3:25])[CH:10]=[CH:11][C:12]=1[O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:24](=[O:26])[CH3:25])[CH:10]=[CH:11][C:12]=1[O:13][Si:14]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:19])[CH3:20])[CH:21]([CH3:23])[CH3:22]
Reactant: COCCCOc1cc(C(C)O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COCCCOc1cc(C(C)=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Yield: 78.7 %

Procedure:
1-{3-(3-methoxypropoxy)-4-[(triisopropylsilyl)oxy]phenyl}ethanol (12.5 g, 32.7 mmol) was dissolved in toluene (1200 mL) and manganese dioxide (74.7 g, 860 mmol) was added. The mixture was brought to reflux for 7 hrs. The mixture was then filtered off and the solvent was evaporated to yield 9.8 g (quantitative yield) of the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1>FC(F)(F)C(O)=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 65 %

Procedure:
Into a 200 ml glass reactor equipped with a reflux condenser and a stirrer, 50 g (0.207 mol) of the mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone of Example 2, and 50 ml of trifluoroacetic acid were charged, and the mixture was refluxed for 72 hours with vigorous stirring. Then, the reaction mixture was separated by distillation to obtain 29.6 g of tetrafluorophthalic anhydride. The yield was 65%.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].S(Cl)(Cl)=O.[CH3:18]O>ClCCl>[CH3:18][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([NH:1][C:2]([NH2:4])=[NH:3])=[CH:6][CH:7]=1
Reactant: CO
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(NC(=N)N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred suspension of 4-guanidino benzoic acid (20.0 g, 93 mmol) in methanol (600 mL) was added thionyl chloride (12 mL) drop wise. The reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo to give a white powder. The crude material was dissolved in dichloromethane and evaporated to provide the title compound as a white powder (17.95 g, 100% yield): HPLC Retention Time; 1.27 min (Method A). M+1; 193.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:21][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:19]#[N:20])=[CH:11][C:12]=3[C:13]3(OCCC[O:14]3)[C:5]2=[N:4][CH2:3]1.[NH4+].[OH-]>CS(O)(=O)=O>[CH3:1][C:2]1([CH3:22])[CH2:21][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:19]#[N:20])=[CH:11][C:12]=3[C:13](=[O:14])[C:5]2=[N:4][CH2:3]1
Reactant: CC1(C)CN=C2N(C1)c1ccc(C#N)cc1C21OCCCO1
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC1(C)CN=C2C(=O)c3cc(C#N)ccc3N2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
At room temperature a solution containing 3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole]-8′-carbonitrile in methanesulfonic acid was stirred for 1.5 h. The reaction was poured carefully onto crushed ice (100 mL), basified with concentrated NH4OH and extracted with CH2Cl2. The combined organic extracts were washed with H2O (1×), dried (Na2SO4) and purified on Biotage KP-Sil eluting with 40% acetone/hexane to give 0.119 g (94%) of the title compound as a yellow solid. Anal. Calc'd. for C14H13N3O 0.2H2O: C; 69.23; H, 5.56; N, 17.30. Found: C, 69.59; H, 5.44; N, 17.05. NMR (400 Mz, DMSO-d6): consistent. MS: (ES+) m/z 240 [M+H, 100]. m.p.: 178-184° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Oc1cc(F)c(F)cc1Br
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc(Br)c(Oc2ccccn2)cc1F
Temperature: 120 °C
Yield: 58.5 %

Procedure:
To a solution of 2-bromo-4,5-difluoro-phenol (1 g, 4.78 mmol) in N,N-dimethylformamide were added K2CO3 and 2-fluoropyridine (0.46 g, 4.78 mmol) and heated at 120° C. for overnight. One more equivalent of 2-fluoropyridine was added and heated at 150° C. for 12 h. The reaction mixture was dissolved in ethyl acetate, washed with 1M NaHCO3, concentrated and purified by flash column chromatography using 0%, 5% and 10% of ethyl acetate in hexanes to yield 0.8 g (59%) of product. MS (ESI+) m/z 286 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([S:18]([C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[CH:23][C:22]=1[Cl:29])(=[O:20])=[O:19])[CH2:3][CH2:4]OS(C1C=C(Cl)C(Cl)=CC=1Cl)(=O)=O.[F:30][C:31]1[CH:45]=[CH:44][C:34]2[NH:35][C:36]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[N:37][C:33]=2[CH:32]=1>>[Cl:29][C:22]1[CH:23]=[C:24]([Cl:28])[C:25]([Cl:27])=[CH:26][C:21]=1[S:18]([N:2]([CH2:3][CH2:4][N:41]1[CH2:42][CH2:43][N:38]([C:36]2[NH:35][C:34]3[CH:44]=[CH:45][C:31]([F:30])=[CH:32][C:33]=3[N:37]=2)[CH2:39][CH2:40]1)[CH3:1])(=[O:19])=[O:20]
Reactant: CN(CCOS(=O)(=O)c1cc(Cl)c(Cl)cc1Cl)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl
Reactant: Fc1ccc2[nH]c(N3CCNCC3)nc2c1
Product: CN(CCN1CCN(c2nc3cc(F)ccc3[nH]2)CC1)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl

Procedure:
The title compound was prepared using the procedure described in Example 1 using 2,4,5-Trichlorobenzenesulfonic acid 2-(methyl-(2,4,5-trichlorobenzenesulfonyl)-amino)-ethyl ester (D4) and 1-(5-fluoro-1H benzimidazol-2-yl) piperazine. MH+ 520/522/524/526.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(OO)(=[O:24])C>CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH3:14])=[O:24])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OO
Reactant: CCCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCS(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1

Procedure:
A solution of 3.0 g. of 1-acetamido-2-nitro-4-n-propylthiobenzene in 30 ml. chloroform is cooled to -15° C. and treated with a solution of 2.5 g. of 40% peracetic acid in 4 ml. methanol. After the addition the temperature is allowed to rise slowly to 20° C whereupon the solution is washed with sodium bisulfite solution and then with sodium bicarbonate solution. The product is isolated by evaporation of the solvent and purified by treatment with ether to afford 1-acetamido2-nitro-4-n-propylsulfinylbenzene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-])=O)=[CH:13][CH:14]=2)[C:9]1=[O:21]>CO.[Pd]>[NH2:18][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:21])=[CH:14][CH:13]=1
Reactant: Cc1ccncc1N1CCc2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CO
Product: Cc1ccncc1N1CCc2ccc(N)cc2C1=O
Yield: 81.9 %

Procedure:
Using analogous reaction conditions as described in Example 25, 2-(4-methyl-pyridin-3-yl)-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (I-30a: 150 mg, 0.53 mmol) in methanol (100 mL) was reacted with 10% Pd/C (30 mg) to afford 110 mg of the product (82.02% yield).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]2([NH:10][C:1](=[O:9])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[O:4]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)c1ccccc1O
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC2(CCN(Cc3ccccc3)CC2)Oc2ccccc21
Temperature: 25 °C

Procedure:
Salicylamide (7.24 g), 1-benzylpiperidin-4-one (10.0 g) and p-toluenesulfonic acid hydrate (500 mg) were suspended in toluene (200 mL), and the suspension was stirred under reflux overnight while removing the water in the reaction system using a Dean-Stark tube. The mixture was cooled to room temperature, and the resulting precipitate was collected by filtration and washed with water, ethanol and diethyl ether to give 1′-benzylspiro[1,3-benzoxazine-2,4′-piperidin]-4(3H)-one as a crude product (9.7 g). The obtained crude 1′-benzylspiro[1,3-benzoxazine-2,4′-piperidin]-4(3H)-one (5.0 g) and 10% palladium-carbon (1.0 g) were suspended in ethanol (50 mL), and the suspension was stirred at 50° C. for 5 hr under a hydrogen atmosphere. The catalyst was removed by filtration through celite and the solvent was evaporated under reduced pressure. The resulting precipitate was collected by filtration, and washed with ethanol and diethyl ether to give the object product (2.7 g, 77%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=5)=[CH:25][C:23]=4[CH:24]=3)=[O:17])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:44][N+:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[C:3]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[CH2:19][CH2:20][O:21][C:22]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)=[CH:25][C:23]=3[CH:24]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4ncccc4O)cc2)CCO3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4c(O)ccc[n+]4[O-])cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.3 %

Procedure:
To a suspension of N-[4-(3-hydroxypyridin-2ylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (400mg) in tetrahydrofuran (30 ml) was added 3-chloroperbenzoic acid (70%, 0.32 g) at 0° C, and the mixture was stirred at room temperature for 15 hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate, concentrated under reduced pressure and recrystallized from ethanol to give N-[4-(1-oxido-3-hydroxypyridin-2-ylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 175) (262 mg) as pale yellow crystals.