Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[C:12]([C:22]#[N:23])[CH:11]=3.C(O)C.[BH4-].[Na+]>O>[OH:7][CH:6]1[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]=2[C:2]1([CH3:24])[CH3:1])=[CH:14][C:13]([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[C:12]([C:22]#[N:23])[CH:11]=3
Reactant: CC1(C)C(=O)Oc2ccc3cc(C#N)c(Cn4cncn4)cc3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)c2c(ccc3cc(C#N)c(Cn4cncn4)cc23)OC1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1,2-dihydro-1,1-dimethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]furan-7-carbonitrile (0.07 g), ethanol (2 ml) and sodium borohydride (0.05 g) was stirred at room temperature for 18 h. Water (10 ml) was added, and the mixture was extracted with chloroform, and the extract was dried and evaporated to dryness under reduced pressure. The residue was recrystallised from ethyl acetate to give 1,2-dihydro-2-hydroxy-1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]furan-7-carbonitrile, m.p. 219°-222°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15](OCC)=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=2)=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH2:15][OH:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1-c1ccc(OC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(SC)ncc2CO)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 67.8 %

Procedure:
To a solution of ethyl 4-(4-methoxyphenyl)-2-(methylsulfanyl)pyrimidine-5-carboxylate (23.1 g) in toluene (500 mL) was added diisobutylaluminum hydride (15% toluene solution, 131 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hr, and quenched with acetic acid. The reaction mixture was extracted with ethyl acetate, and the extract was washed successively with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (13.5 g).
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[C:8]([F:10])[C:7]([Br:11])=[CH:6][C:5]=1[F:12].[Li]CCCC.[C:18](=O)=[O:19].S(C)C>CCOCC.CC(=O)OCC.Cl.C1COCC1.O>[Br:11][C:7]1[C:8]([F:10])=[CH:9][C:4]([CH2:18][OH:19])=[C:5]([F:12])[CH:6]=1
Reactant: O=C=O
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CSC
Product: OCc1cc(F)c(Br)cc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1,4-dibromo-2,5-difluorobenzene (600 mg, 2.21 mmol) in dry Et2O (8 mL) was added to a n-BuLi (0.88 mL of a 2.5M solution in hexanes, 2.20 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 2 h before solid CO2 was added. The reaction mixture was stirred at −78° C. for 10 min and then allowed to warm up to rt. The mixture was then diluted with EA and aq. 1N HCl was added. The layers separated and the org. layer dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the crude carboxylic acid as a pale yellow solid. The crude material (530 mg, 2.24 mmol) was dissolved in dry THF (20 mL) and treated with BH3.Me2S complex (1.0 M in THF, 4.5 mL, 4.50 mmol) at 0° C. The reaction mixture was then warmed to 50° C. and stirred at this temperature until completion of the reaction. The mixture was cooled to 0° C. and water was added followed by EA. The layers were separated and the aq. layer extracted with EA (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 3:1 to 1:1) to give the title compound as a white solid. TLC:rf (1:1 EA-hept)=0.53.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][C:7]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([N+:21]([O-])=O)=[CH:13][N:12]=1)([CH3:10])[C:8]#[N:9].[OH-].[Na+]>CC(=O)OCC>[NH2:21][C:14]1[CH:15]=[C:16]([C:17]([F:20])([F:18])[F:19])[C:11]([C:7]([CH3:10])([CH3:6])[C:8]#[N:9])=[N:12][CH:13]=1
Reactant: CC(C)(C#N)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1ncc(N)cc1C(F)(F)F
Reaction time: 4 h
Yield: 40.8 %

Procedure:
Tin(II) chloride dihydrate (449 mg, 1.991 mmol) was added to a solution of 2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (129 mg, 0.498 mmol) in EA (15 mL). The mixture was at 60° C. for 4 h. Then the solution was adjusted to pH=8-9 with 2N NaOH. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, basic condition) to yield a white solid of 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropanenitrile (46.48 mg, 0.203 mmol, 40.7% yield). TLC (PE/EA=1:1, Rf=0.3): 1H NMR (400 MHz, DMSO-d6) δ 8.04-8.17 (m, 1H), 7.31 (d, J=2.43 Hz, 1H), 5.97 (s, 2H), 1.70 (s, 6H); ES-LCMS m/z 230.1 (M+H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]1[CH:17]=[C:18]([OH:25])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C.CCOC(C)=O>[CH2:7]([O:25][C:18]1[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([F:15])[CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reaction time: 8 h

Procedure:
K2CO3 (8.97 g) and benzylbromide (4.25 mL) were added to a solution of 3-fluoro-4-nitrophenol (5.10 g) in anhydrous DMF (30 mL) at room temperature, and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over magnesium sulfate and concentrated. The residual solid was crystallized from EtOAc/hexane to yield 7.31 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[N:4]=1)#[N:2].C(O)(C(F)(F)F)=[O:22]>>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]([CH2:13][C:14]([OH:16])=[O:15])[N:4]=1)(=[O:22])[NH2:2]
Reactant: Cc1cc2c(C#N)nn(CC(=O)OC(C)(C)C)c2cn1
Reactant: O=C(O)C(F)(F)F
Product: Cc1cc2c(C(N)=O)nn(CC(=O)O)c2cn1

Procedure:
A solution of tert-butyl 2-(3-cyano-5-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (250 mg, 0.92 mmol) in TFA (4 mL) was subjected to microwave irradiation at 140° C. for 90 min. The reaction mixture was concentrated in vacuo, the residual solid was suspended in MeOH and concentrated again in vacuo. MS: 235.0 [M+H]+; tR (HPLC conditions d): 0.24 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([Br:20])=[CH:9][N:8]=1)(=O)=O.[CH:23]#[C:24][CH:25]([OH:27])[CH3:26].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:13]([C:11]1[C:10]([Br:20])=[CH:9][N:8]=[C:7]([C:23]#[C:24][CH:25]([OH:27])[CH3:26])[CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Oc1cc(Cc2ccccc2)c(Br)cn1)C(F)(F)F
Reactant: C#CC(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)C#Cc1cc(Cc2ccccc2)c(Br)cn1
Reaction time: 1 h
Yield: 79 %

Procedure:
650 mg of 4-benzyl-5-bromo-2-pyridyl trifluoromethanesulfonate (Production Example 1), 115 mg of 1-butyne-3-ol, 100 mg of tetrakis(triphenylphosphine)palladium(0), 30 mg of cuprous iodide and 1 ml of triethylamine were mixed with 5 ml of N,N-dimethylformamide, followed by stirring for one hour in an oil bath kept at 60° C. After cooling as it was, aqueous ammonia was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine and then evaporated. The residue was subjected to silica gel column chromatography and eluted with 30% ethyl acetate/hexane, to give 410 mg of the target compound.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[OH:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:25]([NH2:34])[C:24]=2[N:23]=[C:22]1[CH2:35][CH2:36][CH3:37].[OH-].[Na+]>ClCCl>[NH2:34][C:25]1[C:24]2[N:23]=[C:22]([CH2:35][CH2:36][CH3:37])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][N:16]([OH:15])[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:33]=2[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:26]=1
Reactant: CC(C)N=C=O
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCCNO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCN(O)C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
Isopropyl isocyanate (0.67 mL, 6.85 mmol) and triethylamine (2.38 mL, 17.1 mmol) were added to a solution of 1-[4-(hydroxyamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (prepared as described in Parts A-D of Example 43, 2.00 g, 5.71 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 2 hours, then 10% aqueous sodium hydroxide (2 equivalents) was added. After the mixture was stirred for 1 hour at room temperature, the layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, eluted with 3% methanol in dichloromethane). The appropriate fractions were combined and concentrated under reduced pressure. The resulting solid was slurried in 1:1 saturated aqueous sodium bicarbonate/water and was isolated by filtration, washed with water, and dried overnight in a vacuum oven at 80° C. to provide 0.327 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-hydroxy-N′-isopropylurea as beige needles, mp 158-160° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.CN(C)C=O>[CH2:16]([O:8][C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1CCCOC1
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A cooled (0° C.) solution of tetrahydro-pyran-3-carboxylic acid (2.831 g, 21.752 mmol) in dichloromethane (60 mL) and N,N-dimethylformamide (5 drops) was treated with oxalyl chloride (2.0 mL, 23.927 mmol). After stirring at room temperature for 2 h, benzyl alcohol (2.5 mL, 23.927 mmol) was added. After stirring at room temperature for 2 h and standing overnight, the volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (4.587 g, 96%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.58-1.88 (m, 3H), 2.03-2.13 (m, 1H), 2.62-2.72 (m, 1H), 3.47 (ddd, J=11.4, 9.6, 3.4 Hz, 1H), 3.63 (dd, J=11.4, 9.1 Hz, 1H), 3.85 (app dt, J=11.1, 3.8 Hz, 1H), 4.06 (ddd, J=11.4, 4.0, 1.6 Hz, 1H), 5.12, 5.17 (ABq, JAB=12.5 Hz, 2H), 7.31-7.46 (m, 5H).
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:35][CH3:36])=[C:25]([NH:28][C:29](=[O:34])[CH:30]=[CH:31][CH2:32]Cl)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[F:16].CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:35][CH3:36])=[C:25]([NH:28][C:29](=[O:34])[CH:30]=[CH:31][CH2:32][N:5]4[CH2:6][CH2:7][CH2:8][CH:3]([F:2])[CH2:4]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: FC1CCCNC1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCCC(F)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
99 mg 3-Fluoro-piperidine hydrochloride, 300 mg 4-Chloro-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide and 0.37 ml of DIEA were dissolved in 5 ml THF stirred at 70° C. overnight. The mixture was then diluted with ethyl acetate, washed with water and brine and dried over Na2SO4. The resulting solids were flash chromatographed with 0-4% methanol in chloroform to give 275 mg of 4-(3-Fluoro-piperidin-1-yl)-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1.CCOCC>C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.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>[N+:8]([C:7]1[C:2]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1ccc(B(O)O)cc1
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: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: Cc1ccc(-c2ncccc2[N+](=O)[O-])cc1
Yield: 81.4 %

Procedure:
A stirred mixture of 2-chloro-3-nitropyridine (10.6 g), p-tolylboronic acid (19.69 g) and tetrakis(triphenylphosphine)palladium (O) (0.16 g) in 2N sodium carbonate solution (100 ml) and dimethoxyethane (100 ml) was heated to reflux under nitrogen. After 64 h the mixture was cooled then filtered through hyflo eluting with more dimethoxyethane. The filtrate was evaporated in vacuo to give an oil which was redissolved with ether (300 ml) and washed with 5N sodium hydroxide solution (300 ml). The aqueous portion was further extracted with ether (300 ml×2). The combined organic extracts ware washed with water (200 ml), 1N hydrochloric acid (2×100 ml) and saturated brine. were dried (MgSO4) and evaporated in vacuo. The resultant crystalline solid was triturated with hexane to give the title compound as a yellow crystalline solid (11.66 g). T.l.c.(Hexanelethylacetate (2:1)), Rf 0.52,
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][C:14]3=[CH:16]S[CH:18]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br.C(O)(=O)CC.C1(O)C=CC=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][C:13]#[CH:18])[CH2:15][C:14]#[CH:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cscc3C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CCC(=O)O
Product: C#CCN(CC#C)S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C

Procedure:
A mixture of 5-[(4-methylphenyl)sulfonyl]-5,6-dihydro-4H-thieno[3,4-c]pyrrole (166 mg), hydrobromic acid (1.5 mL, 48% in water), propionic acid (0.26 mL) and phenol (182 mg) was heated at 100° C. for 8 h. The crude product obtained as such was passed through ion exchange resin (Strata-X-C) and eluted with methanol containing 10% ammonium hydroxide to yield the title compound.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[C:11]([O:13]C)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([NH:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OC)c(Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)cc1Nc1ccccc1
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A mixture of 3-(phenylamino)-4-methoxybenzoic acid, methyl ester (0.4 g, 1.6 mmol), methanol (10 mL), and 4N sodium hydroxide (15 mL) was stirred and heated to reflux. After 2 hours, the methanol was removed by rotary evaporator and the residual aqueous suspension stirred and acidified with 4N HCl. The precipitate was filtered off, rinsed with water, and dried to afford the product (0.35 g); m.p. 198-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]1=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:16]1[CH2:17][CH2:18][NH:13][C:14](=[O:19])[CH2:15]1)=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CN(c2nncc3cc(Br)ccc23)CCN1
Temperature: 190 °C
Yield: 83.2 %

Procedure:
A glass microwave reaction vessel was charged with 6-bromo-1-chlorophthalazine (Example 1, 0.11 g, 0.45 mmol), piperazin-2-one (0.090 g, 0.90 mmol), potassium carbonate (0.062 g, 0.45 mmol) and 5 mL acetonitrile. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 190° C. for about 12 min (watts, Powermax feature on, ramp time 1 min). The mixture was purified directly via flash chromatography (silica gel) eluting with 5% 2 M ammonia methanol/DCM to give the 4-(6-bromophthalazin-1-yl)piperazin-2-one (0.115 g) as a pale yellow solid. Found MS (ES+): 307, 309(M+H)+.
Reaction SMILES: CC1C=CC=C(C)C=1N.ICl.[CH3:12][O:13][C:14](=[O:29])[C@H:15]([CH2:27]O)[NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[CH3:12][O:13][C:14](=[O:29])[C:15](=[CH2:27])[NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: Cc1cccc(C)c1N
Agent: ClI
Product: C=C(NC(=O)OCc1ccccc1)C(=O)OC
Yield: 65 %

Procedure:
The synthesis of indazole amino acid B begins with the iodination of 2,6-dimethylaniline by the action of iodine monochloride (Scheme 3). This intermediate was temporarily set aside. N-CBZ-L-serine methyl ester undergoes a one-pot methanesulfonylation/elimination reaction to afford N-CBZ-dehydroalanine methyl ester. With the iodide and dehydroalanine in hand, they are efficiently coupled using palladium (II) acetate in a Heck coupling to afford the product in 65% yield. At this point, the chiral center is installed using a catalytic asymmetric hydrogenation utilizing (−)-1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I) tetrafluoroborate and hydrogen (60 psi) to give the chiral amino acid in ˜96% ee. The indazole ring is then formed by the action of iso-amyl nitrite. The resulting indazole is highly crystalline. One recrystallization from acetone/hexanes affords the indazole amino acid in excellent purity and with an improved 99.8% ee. Removal of the CBZ protecting group under hydrogenation conditions completes the preparation of fragment B. Indazole amino acid B can also be prepared using enzymatic resolution of the racemic amino acid or keto acid (Hanson, Ronald L.; Davis, Brian L.; Goldberg, Steven L.; Johnston, Robert M.; Parker, William L.; Tully, Thomas P.; Montana, Michael A.; Patel, Ramesh N. Process Research and Development, Bristol-Myers Squibb, New Brunswick, N.J., USA. Organic Process Research & Development (2008), 12(6), 1119-1129.).
Reaction SMILES: [CH3:1][C:2]([N:14]1[CH:18]=[C:17]([NH:19][C:20](=[O:26])[CH:21]([NH2:25])[CH2:22][CH2:23][CH3:24])[N:16]=[CH:15]1)([CH3:13])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[C:36]([F:38])[CH:37]=1)[CH2:34][C:33](=O)[CH2:32][CH2:31]2>>[CH3:1][C:2]([N:14]1[CH:18]=[C:17]([NH:19][C:20](=[O:26])[C@@H:21]([NH:25][CH:33]2[CH2:32][CH2:31][C:30]3[C:35](=[C:36]([F:38])[CH:37]=[C:28]([F:27])[CH:29]=3)[CH2:34]2)[CH2:22][CH2:23][CH3:24])[N:16]=[CH:15]1)([CH3:13])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CCNCc2ccccn2)cn1
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CCNCc2ccccn2)cn1

Procedure:
2-Amino-pentanoic acid (1-{1,1-dimethyl-3-[(pyridin-2-ylmethyl)-amino]-propyl}-1H-imidazol-4-yl)-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to afford the title: 525.5 m/z (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5](=[O:17])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:2].[Se]=[O:22]>C(O)C>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:17])[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:15])/[CH2:14][OH:22])[CH3:20]
Reactant: O=[Se]
Reactant: CCOC(OCC)C(=O)CCC=C(C)CCC=C(C)C
Solvent: CCO
Product: CCOC(OCC)C(=O)CC/C=C(\C)CC/C=C(\C)CO
Yield: 56.2 %

Procedure:
In 70 ml of 95% ethanol was dissolved 7.4 g of 1,1-diethoxy-6,10-dimethyl-2-oxo-5,9-undecadien, and the resulting solution was, after addition of 1.7 g of selenium oxide, refluxed for 15 minutes. The ethanol was removed by evaporation, and the residue was, after addition of water, extracted with ether. The ethereal extract was washed with an aqueous sodium hydrogencarbonate solution and dried. The solvent was then removed by evaporation to leave an oil, and the oil was purified by the silica gel column chromatography to yield 3.0 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH:31]([S:39](Cl)(=[O:41])=[O:40])=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1(/[CH:32]=[CH:31]/[S:39]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Product: O=S(=O)(/C=C/c1ccccc1)Nc1ccc(N2CCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
N-[2-({[(E)-2-Phenylethenyl]sulfonyl}amino)-5-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and β-styrenesulfonylchloride (48 mg, 0.239 mmol according to general method 3 to give before Boc-deprotection 160 mg of a purple solid. MS (posES-FIA) m/z=Found: 499.2; Calcd 499.14; 1H-NMR δ 8.26 (d, 1H), 8.04 (d, 1H), 7.75-7.38 (m, 8H), 7.22 (d, 1H, J=15.4 Hz), 7.16 (d, 1H), 6.97 (d, 1H), J=15.4 Hz), 6.78 (dd, 1H), 6.68 (d, 1H), 3.68 (app t, 2H), 3.39 (app t, 2H), 3.28-3.21 (m, 4H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-])=O)[CH:14]=1)[C:9]=2[NH2:22])(=[O:3])[CH3:2].C(OCC)(=O)C.CO.C([O-])=O.[NH4+]>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]([NH2:19])[CH:14]=1)[C:9]=2[NH2:22])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(N)c3ccc([N+](=O)[O-])cc3nc2c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc2c(N)c3ccc(N)cc3nc2c1
Yield: 29.4 %

Procedure:
To a 50 mL rbf equipped with a nitrogen bubbler were charged 3-acetamidyl-6-nitro-9-aminoacridine (110 mg, 0.37 mmol) and ethyl acetate (1.9 mL). Methanol (950 μL) and Pd/Alumina 10% (12 mg) were added and the reaction mixture was stirred to a fine suspension. Ammonium formate (47 mg, 0.74 mmol) was added and the mixture was stirred for 20 min at room temperature. A further portion of ammonium formate (70 mg, 1.11 mmol) was then added. Stirring was maintained overnight. The suspension was filtered and washed with ethyl acetate to afford the crude product (106 mg). The solid was dissolved in water and washed with ethyl acetate. The aqueous layer was concentrated in vacuo to afford 3-acetamidyl-6,9-diaminoacridine as a brown solid (29 mg, 29%). 1H NMR and LCMS analyses conformed to structure.