Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:17][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)COc1cccc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(CBr)c1
Temperature: 0 °C
Yield: 71.1 %

Procedure:
A solution containing ethyl 3-(hydroxymethyl)phenoxyacetate (2.6 g.) and carbon tetrabromide (8.3 g.) in DMF (30 ml.) was treated with a solution of triphenylphosphine (6.55 g.) in DMF (20 ml.) with stirring. The temperature was maintained below 15° C. during the addition using an ice bath. After 1 hour the mixture was poured into ice-water (300 ml.) and the aqueous mixture was extracted with ether (3×100 ml.). The combined extracts were washed with water (3×100 ml.) and saturated brine (100 ml.), dried (MgSO4) and concentrated. The resultant oil was purified by flash column chromatography, eluting with petrol (60°-80° )/ether (80:20 v/v) to give ethyl 3 (bromomethyl)phenoxyacetate (2.4 g.) as a colourless oil, NMR: 1.3 (3H,t), 4.25 (2H,q), 4.4 (2H,s), 4.6 (2H,s) and 6.7-7.4 (4H,m)ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH:10]2[CH2:13][O:12][CH2:11]2)[CH:8]=1)([O-:3])=[O:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:24][C:8]1[N:7]([CH2:9][CH:10]2[CH2:11][O:12][CH2:13]2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnn(CC2COC2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(CC2COC2)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a solution of 4-nitro-1-(oxetan-3-ylmethyl)pyrazole (3200 mg, 17.47 mmol) in THF (80 mL) was added LHMDS (1M solution in THF, 22.7 mL, 22.7 mmol) dropwise at −78° C. over a period of 15 min. The resulting mixture was stirred at −78° C. for 30 min. Hexachloroethane (5.38 g, 22.7 mmol.) in THF (20 mL) was added at −78° C. dropwise. The resulting mixture was stirred at −78° C. for another 40 min. The reaction mixture was quenched with aqueous ammonium chloride and extracted with Ethyl acetate (×3). Combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography with 0 to 75% ethyl acetate in heptane as eluent to give 5-chloro-4-nitro-1-(oxetan-3-ylmethyl)-1H-pyrazole (3.60 g, 95%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH3:6])[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(CCc2ccccc2OC[C@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CCc2ccccc2OC[C@H]2CCCN2C)c1
Yield: 94.8 %

Procedure:
Following a procedure similar to that described in Example 38(a), 1.00 g of (R)-1-t-butoxycarbonyl-2-{2-[2-(3-methoxyphenyl)ethyl]phenoxymethyl}pyrrolidine [prepared as described in Example 76(a)] was reacted with 0.184 g of lithium aluminum hydride dispersed in 10 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.750 g (yield 95%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1([F:18])C(=O)[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3]1.[CH3:19][O:20][CH:21](OC)[O:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:19][O:20][C:21]1([O:22][CH3:23])[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3][C:2]1([F:1])[F:18]
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1(F)F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC1(OC)CCN(c2ccc([N+](=O)[O-])cc2)CC1(F)F
Temperature: 45 °C
Yield: 84 %

Procedure:
The mixture of 4-(3,3-difluoro-4-oxo-piperidin-1-yl)-nitrobenzene (25 mmol), trimethylorthoformate (51 mmol), p-toluene-sulphonic acid monohydrate (27 mmol) in methanol was heated at 45° C. for 24 hours. Solvent was removed and residual mass was taken into ethyl acetate and saturated sodium bicarbonate solution mixture. The organic layer was dried and removal of the solvent afforded title compound as a solid in 84% yield.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:13]1([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>CO>[N:13]1([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[CH:11][C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[CH2:1][CH2:2][CH2:3]4)=[O:12])=[CH:20][CH:19]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CC(=O)c1ccc2c(c1)CCC2
Reactant: O=Cc1ccc(N2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccc(N2CCCC2)cc1)c1ccc2c(c1)CCC2

Procedure:
A solution of 1.47 g (9.14 mmoles) of 5, 1.60 g (9.14 mmoles) of p-pyrrolidinylbenzaldehyde and two pellets of sodium hydroxide (about 0.4 g) in 20 ml of methanol was stirred under nitrogen at room temperature for 112 hr. The reaction mixture was cooled in an ice bath and the precipitated solid 3-[4-(1-pyrrolidinyl)phenyl]-1-(2,3-dihydro-1H-inden-5-yl)-2-propen-1-one was filtered and washed with cold methanol. Yield: 1.2 g (41%); m.p. 162° to 164°. Evaporation of the filtrate gave a residue which was dissolved in methanol-toluene (9:1). The solution was filtered, evaporated to 100 ml, and cooled. The precipitated product was collected by filtration and washed with cold methanol. Yield: 0.9 g (31%); m.p. 177° to 179°. λmax (EtOH): 275 nm (ε=16,600); 328 nm (4170); 425 nm (37,800). Calcd for C 22 H23NO: C, 83.24; H, 7.30; N, 4.41. Found: C, 82.99; H, 7.49; N, 4.32.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][C:16]=1[O:28][CH3:29]>C1COCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][C:24](=[CH:7][C:5]([O:4][CH3:3])=[O:6])[CH2:25][CH2:26]2)=[CH:17][C:16]=1[O:28][CH3:29]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: COc1cc(N2CCC(=O)CC2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=C1CCN(c2ccc(Cl)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A suspension of 60% dispersion sodium hydride (65.1 mg, 1.627 mmol) in anhydrous THF (2.5 mL) was treated with a solution of trimethyl phosphonoacetate (235 μL, 1.627 mmol) in THF (1 mL) over 5 min. The mixture was stirred at RT for 30 min and then treated with a solution of 1-(4-chloro-3-methoxyphenyl)piperidin-4-one (300 mg, 1.252 mmol) in THF (3 mL). The reaction was stirred at RT for 1 h before it was partitioned between saturated NH4Cl and EtOAc. The extract was dried (Na2SO4) and concentrated to give the crude product, which was purified by flash chromatography (12 g silica gel cartridge and gradient elution from 0 to 30% EtOAc/hexanes) to afford methyl 2-(1-(4-chloro-3-methoxyphenyl)piperidin-4-ylidene)acetate (288 mg, 0.974 mmol, 78% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.19 (1 H, d, J=8.79 Hz), 6.49 (1 H, d, J=2.42 Hz), 6.44 (1 H, dd, J=8.79, 2.64 Hz), 5.73 (1 H, s), 3.88 (3 H, s), 3.70 (3 H, s), 3.26-3.34 (4 H, m, J=5.82, 5.49, 5.33, 5.33 Hz), 3.10 (2 H, t, J=5.38 Hz), 2.45 (2 H, t, J=5.27 Hz).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]>C(O)(=O)C>[NH2:3][C:4]1[CH:12]=[C:11]([Cl:13])[C:10]([Br:1])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: BrBr
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 2.65 mL (52.0 mmol) of bromine in 10 mL of acetic acid was added dropwise over 15 minutes to a solution of 8.89 g (52.0 mmol) of 2-amino-4-chloro-benzoic acid in 60 mL of acetic acid. The mixture was stirred at room temperature for 1 h and poured into 500 grams of ice. The solid was collected by filtration, washed with cold water and dried to produce 11.2 g (86%) of 2-amino-5-bromo-4-chloro-benzoic acid. LCMS: 251 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][C:39]#[N:40])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[C:39]([CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:34])=[O:35])#[N:40]
Reactant: N#CCCNS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: N#CCCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-Bromo-N-(2-cyano-ethyl)-benzenesulfonamide (example B.21) (376 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (254 mg, 45%). MS (ISP) 564.3[(M+H)+]; mp 174-182° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=3)[C:12]=2[O:23][C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][CH:25]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl.B(Br)(Br)Br.[Cl:44]CCl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.C(OCC)C.CO>[ClH:44].[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]([O:23][C:24]3[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: ClCCl
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(S(C)(=O)=O)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CS(=O)(=O)c1cccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
Dissolve the product of Example 15 in ethyl acetate (10 mL) and diethyl-ether (5 mL). Add 2M HCl in diethyl ether (1 mL, 2.0 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with an external ice bath and add 1M BBr3 in dichloromethane (1.0 mL, 1.0 mmol). After 20 minutes, dilute the reaction mixture with ethyl acetate (25.0 mL) and add saturated aqueous NaHCO3 in parts (2×10 mL). Separate the layers, wash the organic layer with brine (10 mL), dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting 6-(3-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol in dichloromethane (0 to 5%). Dissolve the free base in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and add 2M HCl in diethyl ether (1 mL, 2.0 mmol). Collect the precipitate on filter paper, rinse with diethyl ether and dry in vacuo (<2 mm of Hg) at 65° C. for 48 hours to give 73 mg of the title compound (26%): mass spectrum (ion spray): m/z=518.5 (M[free base]+1).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH3:8])[N:3]=1>C(N)CN>[CH3:8][C:4]1[N:3]=[C:2]([NH:3][CH2:2][CH2:7][NH2:6])[CH:7]=[N:6][CH:5]=1
Reactant: Cc1cncc(Br)n1
Solvent: NCCN
Product: Cc1cncc(NCCN)n1
Temperature: 150 °C

Procedure:
2-Bromo-6-methyl-pyrazine (220 mg, 1.44 mmol) was dissolved in ethylenediamine (2 ml) and stirred under microwave heating for 30 minutes at 150° C. in a closed vial. The reaction mixture was concentrated under reduced pressure, toluene was added and the volatiles were removed under reduced pressure. The last step was repeated two times. The remaining solid was used directly in the next step.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:21]([C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[C:18]([F:17])([F:27])[F:28])=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccccc3C(F)(F)F)nc(=O)c1-2
Temperature: 25 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.59 g, 2.65 mmol), 2-trifluoromethylbenzaldehyde (0.5 ml) and glacial acetic acid (25 ml) was refluxed overnight and then 0.5 equivalents of additional aldehyde was added and the mixture was refluxed for about 3 days. The reaction mixture was cooled to room temperature, the acetic acid was stripped and the residue was cooled and rinsed with ether to give a white solid which was collected by filtration and recrystallized from tert-butyl dimethyl ether/hexanes to afford 1-cyclopentyl-3-ethyl-6-(2-trifluoromethylphenyl)-pyrazolo[3,4-d]pyrimidin-4-one, m.p. 201°-202° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[C:3]=1[CH2:13][OH:14].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>C(Cl)Cl.O>[C:22]([O:14][CH2:13][C:3]1[C:4]([F:12])=[C:5]([CH:9]=[C:10]([F:11])[C:2]=1[Br:1])[C:6]([OH:8])=[O:7])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(F)c(Br)c(CO)c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCc1c(F)c(C(=O)O)cc(F)c1Br
Reaction time: 1 h

Procedure:
In 18 ml of methylene chloride was suspended 1.80 g of 4-bromo-2,5-difluoro-3-hydroxymethylbenzoic acid and to the suspension were added 1.64 g of triethylamine and 0.84 g of acetic anhydride with ice-cooling, after which the suspension was stirred for one hour. The temperature of the suspension was then elevated to room temperature, at which the mixture was stirred for a further 12 hours. The reaction mixture was added to a mixed solvent of 20 ml of methylene chloride and 50 ml of water and the pH was adjusted to 1 with 6N hydrochloric acid. Thereafter, the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluent: chloroform:ethanol=9:1), to obtain a colorless, oily 3-acetoxymethyl-4-bromo-2,5-difluorobenzoic acid. The oily product obtained was dissolved in 42 ml of anhydrous tetrahydrofuran, and 1.64 g of N,N'-carbonyldiimidazole was added to the solution with ice-cooling. The resulting mixture was stirred at room temperature for one hour. Subsequently, 1.45 g of magnesium ethoxycarbonylacetate was added thereto and the resulting mixture was stirred at the same temperature for 20 hours. The reaction mixture was added to a mixed solvent of 80 ml of ethyl acetate and 100 ml of water, and the pH was adjusted to 1 with 6N hydrochloric acid. Thereafter, the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluent: n-hexane:ethyl acetate=20:1), to obtain 1.32 g of colorless, crystalline ethyl 3-acetoxymethyl-4-bromo-2,5-difluorobenzoylacetate.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:33])=[C:15]([CH:32]=2)[C:16]([NH:18][C:19]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=2)=[O:17])[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-:35].[K+].[K+].OO.Cl>CS(C)=O.O>[C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:33])=[C:15]([CH:32]=2)[C:16]([NH:18][C:19]2[N:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:22]=[C:21]([C:30]([NH2:31])=[O:35])[CH:20]=2)=[O:17])[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)c(C(=O)Nc3cc(C#N)nn3-c3ccccc3)c2)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1cccc(-c2ccc(Cl)c(C(=O)Nc3cc(C(N)=O)nn3-c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62.2 %

Procedure:
To a solution of 5-(6-acetamidopyridin-2-yl)-2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)benzamide (Example 88, 100 mg, 0.22 mmol) in dimethylsulfoxide (3 mL) was added potassium carbonate (60 mg, 0.44 mmol) followed by hydrogen peroxide (30% w/w solution in water, 441 μL, 4.4 mmol) and the reaction was stirred at room temperature for 2.5 hours. Additional hydrogen peroxide was added (882 μL, 8.8 mmol) and the reaction was stirred for 1 hour. The reaction was diluted with water (5 mL) then neutralised with 2M aqueous hydrochloric acid and extracted into ethyl acetate (3×10 mL). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 80% ethyl acetate in heptanes to furnish the title compound as a colourless solid (65 mg, 62%).
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C@@:8]2([CH3:41])[N:12]3[C:13]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([NH:26][C@H:27](C)[C:28]([OH:30])=O)=[O:25])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=3)[C:9]2=[O:40])=[CH:5][CH:4]=1)#[N:2].[CH3:44]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NC[C@@H](O)C>C(Cl)Cl>[OH:30][C@@H:28]([CH3:44])[CH2:27][NH:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[S:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:42]=[CH:43][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([CH3:41])[C:9](=[O:40])[N:10]([C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)[C:11]2=[N:15][CH:14]=1)(=[O:18])=[O:17])=[O:25]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Agent: C[C@H](O)CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](O)CNC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
To a stirred solution of (S)-1-[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (see Example 5) (82 mg, 0.14 mmol) in anhydrous methylene chloride (1 mL) and HATU (82 mg, 0.21 mmol) was added DIPEA (73 μL, 0.42 mmol) and the mixture was stirred for 10 min at room temperature under nitrogen. (S)-1-Amino-propan-2-ol (0.21 mmol) was added and the mixture was stirred for 2 h at room temperature under nitrogen. The material was purified by column chromatography over silica gel to provide 62 mg of the title compound as a white solid (M+1, 631.2).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:28]=[O:29].[Se](=O)=[O:31]>C(OCC)(=O)C.CCCCCC>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:31])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:28]=[O:29]
Reactant: O=[Se]=O
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCCBr)c(OC)cc23)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCBr)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 6-(3-bromo-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (70 mg, 0.15 mmol) was added selenium dioxide (132 mg, 1.20 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL), saturated sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-(3-bromo-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (62 mg, 88% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[N:11]=2)O)[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([Cl:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[N:11]=2)[N:7]=1
Reactant: COc1cccc(C(O)c2cccc(Br)n2)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cccc(C(Cl)c2cccc(Br)n2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (6-bromopyridin-2-yl)(6-methoxypyridin-2-yl)methanol (5.11 g, 17.31 mmol) in CH2Cl2 (56 mL) @ 0° C. under N2 was added SOCl2 (3.09 g, 25.97 mmol). The mixture was then allowed to warm to rt and stirred for 3 hr. The mixture was then cooled back to 0° C. and quenched with saturated aqueous sodium bicarbonate. The resulting mixture was extracted 3× with CH2Cl2. The combined organics were dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography (25-35% CH2Cl2 in Hexanes) to give 2-bromo-6-[chloro(6-methoxypyridin-2-yl)methyl]pyridine. 1H NMR (500 MHz, CDCl3) δ 7.76 (d, 1H, J=7.8), 7.61-7.54 (m, 2H), 7.41 (d, 1H, J=7.8), 7.12 (d, 1H, J=7.1), 6.66 (d, 1H, J=8.3), 6.02 (s, 1H), 3.86 (s, 3H), LRMS m/z (M+H) Calcd.: 313.0, found: 312.9.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[CH:14]=[CH:13][CH:12]=[N:11][C:5]=1[NH:6]2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:15]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2[CH:14]=[CH:13][CH:12]=[N:11][C:5]=2[NH:6]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cccc2[nH]c3ncccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(-c2cccc3[nH]c4ncccc4c23)cc1
Temperature: 150 °C
Yield: 20.2 %

Procedure:
Compound 4 (20 mg, 0.081 mmol) was mixed with phenylboronic acid (20 mg, 0.16 mmol) and Tetrakis Pd(0) catalyst (19 mg, 0.016 mmol) in a solution comprising dioxane (3 ml) and a saturated K2CO3 solution (1 ml). The mixture was heated in a microwave reactor at 150° C. for 20 minutes. Purification by HPLC afforded the title compound as a tan solid (4 mg, 22%). 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H) 8.10 (d, J=7.84 Hz, 1H) 7.67 (m, 2H) 7.60 (m, 5H) 7.27 (m, 2H). [M+H] calc'd for C17H12N2, 245; found 245.