Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C([C@@H]1COC(=O)N1[C:16](=[O:44])[C@H:17]([CH2:21][S:22]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1)(=[O:24])=[O:23])[CH:18]([CH3:20])[CH3:19])C1C=CC=CC=1.O.[OH-].[Li+].S([O-])([O-])=[O:49].[Na+].[Na+]>O1CCCC1.O.[OH-].[Na+]>[F:43][C:40]1[CH:39]=[CH:38][C:37]([C:34]2[CH:35]=[N:36][C:31]([N:28]3[CH2:27][CH2:26][N:25]([S:22]([CH2:21][C@H:17]([CH:18]([CH3:19])[CH3:20])[C:16]([OH:49])=[O:44])(=[O:23])=[O:24])[CH2:30][CH2:29]3)=[N:32][CH:33]=2)=[CH:42][CH:41]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
Hydrogen peroxide (0.37 ml, 27.5 wt % in water) was added to an ice-cold solution of 4-(R)-Benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyryl)oxazolidin-2-one(0.67 g) in tetrahydrofuran (5 ml), followed by the dropwise addition of a solution of lithium hydroxide monohydrate (61 mg) in water (2.5 ml), and the mixture stirred in the ice-bath, allowing to slowly warm to ambient temperature. After 4 h, the mixture was re-cooled in ice, treated with sodium sulfite (0.68 g) as a solution in water (15 ml), and stirred for 10 min. The mixture was then reduced in vacuo and the residue diluted with 1 M sodium hydroxide (10 ml) and washed with ethyl acetate (2×30 ml). The combined organic washes were back-extracted with 1M sodium hydroxide (2×10 ml), and the combined aqueous phase was acidified with citric acid to pH 3-4. The resultant suspension was filtered, and the solids washed with water and dried under vacuum at 40° C. to yield the title compound as a white solid (0.36 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH:8]=O)=[O:5].[CH3:27][O:28][CH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[CH:14][CH:15]=1)[CH2:8][N:31]1[CH2:32][CH2:33][CH2:34][C@@H:30]1[CH2:29][O:28][CH3:27])=[O:5]
Reactant: CCCS(=O)(=O)c1ccc(C(C=O)NC(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: COC[C@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCS(=O)(=O)c1ccc(C(CN2CCC[C@@H]2COC)NC(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dichloro-N-{2-oxo-1-[4-(propylsulphonyl)phenyl]-ethyl}benzamide (135 mg, 0.33 mmol) in 1,2-dichloroethane (5 mL) under nitrogen was added (R)-2-(methoxymethyl)pyrrolidine (81 □L, 0.66 mmol) followed by sodium triacetoxyborohydride (138 mg, 0.65 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of satd. NaHCO3(aq) and the product extracted into ethyl acetate (×2). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. One diastereoisomer of the title compound was isolated in pure form following preparative HPLC. 1H NMR δ (400 MHz, CDCl3) δ 1.00 (3H, t, J=7.4 Hz), 1.32-1.40 (1H, m), 1.52-1.59 (2H, m), 1.71-1.82 (4H, m), 1.96-2.04 (1H, m), 2.37-2.42 (1H, m), 2.87 (1H, br s), 3.00 (3H, s), 3.03-3.07 (2H, m), 3.21-3.35 (3H, m), 5.15-5.19 (1H, m), 7.34 (1H, dd, J=1.9, 8.3 Hz), 7.47 (1H, d, J=1.9 Hz), 7.59-7.61 (3H, m), 7.87 (2H, d, J=8.3 Hz), 8.31 (1H, d, J=5.3 Hz); m/z (ES+) 515 (M+H), 513 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:16])[C:7]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Br:16][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1c(Br)cncc1Br
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1c(Br)cncc1-c1ccccc1
Temperature: 70 °C
Yield: 54.9 %

Procedure:
A mixture of 1,1-dimethylethyl (3,5-dibromo-4-pyridyl)carbamate (4.2 g; 12.0 mmol), phenylboronic acid (1.76 g; 14.4 mmol), sodium carbonate (3.1 g; 29.2 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.416 g; 0.36 mmol) in dioxane (24 ml) and water (12 ml) is heated at 70° C. under argon for 8 hours. The reaction mixture is concentrated under reduced pressure. The residue obtained is taken up in ethyl acetate (200 ml), washed with water (2×100 ml) and brine (100 ml), dried over sodium sulphate, filtered and then concentrated under reduced pressure. The residue is chromatographed on a column of silica, eluting with an ethyl acetate/cyclohexane gradient of from 0 to 5%. 2.3 g of 1,1-dimethylethyl (3-bromo-5-phenylpyrid-4-yl)carbamate are isolated in the form of a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[C:27]([CH3:28])[C:22]2=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=1)([CH3:3])[CH3:2].Br[CH2:43][C:44]([NH2:46])=[O:45].C(N(CC)CC)C>>[CH:1]([O:4][C:5]1[C:6]([NH:18][C:19]2[N:24]=[C:23]3[NH:25][N:26]=[C:27]([CH3:28])[C:22]3=[C:21]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=2)=[CH:7][C:8]([CH3:17])=[C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:43][C:44]([NH2:46])=[O:45])[CH2:13][CH2:12]2)[CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Reactant: NC(=O)CBr
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCN(CC(N)=O)CC1
Temperature: 100 °C

Procedure:
The mixture of N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (20 mg, 0.035 mmol), 2-bromoacetamide (0.1 N in DMF, 0.035 mmol, 0.35 mL) and triethylamine (0.1 N in DMF, 0.105 mmol, 1.05 mL) was heated at 100° C. for 10 min. The resulting reaction mixture was purified by RP-HPLC to afford 2-(4-(5-isopropoxy-4-(4-(2-(isopropylsulfonyl)phenylamino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylphenyl)piperidin-1-yl)acetamide. MS (ES+): 635.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][O:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:14][CH2:13][O:12][CH3:11])[CH:5]=[O:6]
Reactant: COCCBr
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
An amount of 3,4-dihydroxybenzaldehyde (5.0 g, 36.2 mmol) in 20 mL of N,N′-dimethylformamide is added 2-bromoethyl methyl ether (3.4 mL, 36.2 mmol), and sodium carbonate (5.0 g, 72.4 mmol). The reaction mixture is stirred at room temperature for 3 days. After removal solids by filtration, the solution is subsequently evaporated under high-pressure vacuum to dark brown liquid. The residue is added water and acidified with 12 N HCl solution to pH˜2, then extracted 4×100 mL of EtOAc. The combined organic layer is washed with brine, dried over Mg2SO4, stirred in darko, filtered and evaporated to give yellow liquid. Purification is performed by column chromatography over silica gel using 40% EtOAc/Hex as eluent to give 2.13 g of colorless solid: mp 74-75° C.; MS (ESI) m/z 195.1 (M+H)−1
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:22])=O>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:10]=1)[C:5]([Cl:22])=[O:6]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Cl)c1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (700 mg, 2.67 mmol) was placed into 100 ml round bottom flask equipped with a stir bar. 3.0 ml of anhydrous chloroform was added to the flask followed by 2.0 ml of thionyl chloride and 1 drop of anhydrous DMF. The reaction mixture was stirred at 35° C. for 3 hours and then at room temperature overnight. LCMS of the sample after quenching a small amount with MeOH showed that no acid left. The solvent and excess thionyl chloride was removed under vacuum to give SKC-03-071. SKC-03-071 was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:18]=[C:17]([NH2:19])[CH:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=1.CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:19][C:17]2[CH:16]=[C:15]([C:20]([F:22])([F:21])[F:23])[CH:14]=[C:13]([CH3:12])[N:18]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Cc1cc(C(F)(F)F)cc(N)n1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(F)(F)F)cc(NC(=O)Cc2ccc(Br)cc2)n1
Yield: 62.3 %

Procedure:
Dissolve 4-bromo-phenylacetic acid (660 mg, 3.07 mmol) and 6-methyl-4-trifluoromethyl-pyridin-2-ylamine (500 mg, 2.84 mmol) in 10 mL dry THF. Add 4-methyl morpholine (345 mg, 0.375 mL, 3.4 mmol), stir a few minutes under nitrogen atmosphere, then add DMTMM (865 mg, 3.12 mmol) and stir the pale yellow slurry overnight. Dilute slurry with 90 mL EtOAc, wash twice each with saturated aqueous NaHCO3 and aqueous saturated sodium chloride, then dry the organic layer over MgSO4 and concentrate to give an ivory crystalline solid. Purify this solid on a 120 g silica cartridge with 0→5% EtOAc in dichloromethane to give 660 mg (62%) of the title compound as a white crystalline solid. LCMS (ES) m/z 373/375 (M+1).
Reaction SMILES: C(OC(NC1C=C(F)C(F)=CC=1C(NCC(NC[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=O)=O)=O)(C)(C)C.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([O:40][CH2:41][CH3:42])=[C:36]([CH:39]=1)[CH:37]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[Br:31][C:32]1[CH:33]=[CH:34][C:35]([O:40][CH2:41][CH3:42])=[C:36]([CH:39]=1)[CH2:37][N:22]1[CH2:23][CH2:24][CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: CCOc1ccc(Br)cc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1ccc(Br)cc1CN1CCCCC1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 5-bromo-2-ethoxybenzaldehyde (0.15 mmol), methanol (1.2 mL), and acetic acid (0.030 mL) was added NaBH3CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. for 13 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×3). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material were added dichloromethane (1 mL) and trifluoroacetic acid (TFA) (0.50 mL) and the solution was stirred at room temperature for 10 min. The reaction mixture was concentrated, and the residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. Preparative TLC (SiO2, ethyl acetate/methanol=10/1) gave 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl)amino}methyl]-1-(5-bromo-2-ethoxybenzyl)piperidine (Compound No. 2052) (10.2 mg, 38%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 539.2 (M++H, C24H29BrF2N4O3).
Reaction SMILES: [Si:1]([C@:8]1([OH:19])[C@H:15]([CH3:16])[O:14][C@@H:11]([O:12][CH3:13])[CH2:10][C@@H:9]1[CH:17]=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[Si:1]([C@:8]1([OH:19])[C@H:15]([CH3:16])[O:14][C@@H:11]([O:12][CH3:13])[CH2:10][C@@H:9]1[CH2:17][OH:18])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CO[C@H]1C[C@H](C=O)[C@](O)([Si](C)(C)C(C)(C)C)[C@H](C)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CO[C@H]1C[C@H](CO)[C@](O)([Si](C)(C)C(C)(C)C)[C@H](C)O1
Yield: 99.5 %

Procedure:
1.2 g (4.15 mmoles) of 13 dissolved in 50 ml of methanol was reduced with sodium borohydride (0.1 g) at 0° C. for 20 minutes. The excess sodium borohydride was consumed by the addition of acetone. After addition of 25 ml of water the solution was neutralized with acetic acid and then extracted with methylene chloride. The organic extracts were evaporated to dryness to give 1.2 g (100%) of 14.
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH:9]([CH3:12])[CH2:10][CH3:11])=[N:7][C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][N:4]=1)[NH2:2].[NH:19]1[CH:23]=[C:22]([CH2:24][CH:25]([C:31](OCC)=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:21]=[CH:20]1>>[CH3:12][CH:9]([C:8]1[C:3]2[N:4]([C:31]([CH:25]([CH2:24][C:22]3[N:21]=[CH:20][NH:19][CH:23]=3)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:2][N:1]=2)[CH:5]=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:7]=1)[CH2:10][CH3:11]
Reactant: CCOC(=O)C(Cc1c[nH]cn1)C(=O)OCC
Reactant: CCC(C)c1nc(-c2cccnc2)cnc1NN
Product: CCOC(=O)C(Cc1c[nH]cn1)c1nnc2c(C(C)CC)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to Example 1, by condensing rac-2-hydrazino-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine with diethyl (imidazol-4-ylmethyl)malonate there is obtained ethyl (RS)-8-[(RS)-1-methylpropyl]-α-(imidazol-4-ylmethyl)-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 419 (M)+, which is converted into the above acid by alkaline saponification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[F:42])[C:36](Cl)=[O:37]>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:41]([F:42])=[C:33]([F:32])[CH:34]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(F)c(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3,4-difluorobenzoyl chloride (0.5 g, 2.8 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was quenched with MeOH (1 mL) and was filtered. The solid was rinsed with CH2Cl2 (5 mL) and then dissolved in acetone (4 mL). Ether (10 mL) and hexane (10 mL) were added to the solution and the resulting suspension was filtered to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3,4-difluoro-benzamide as a white solid (0.7 g, 75%): mp, 218-220° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.1 min. (99%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.51-2.64 (m, 2H), 2.87-2.93 (m, 1H), 4.95 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.55-8.01 (m, 6H), 9.26 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 39.20, 48.86, 116.77, 116.65, 116.89, 117.51, 117.74, 121.95, 124.75, 124.80, 124.85, 124.89, 127.18, 131.28, 131.32, 131.39, 131.53, 133.15, 134.82, 138.86, 147.42, 147.59, 149.70, 149.87, 150.68, 150.85, 153.02, 153.19, 164.45, 166.93, 167.49, 169.81, 172.74. Anal Calcd for C21H15F2N3O5: C, 59.02; H, 3.54; N, 9.83; F, 8.89. Found: C, 59.12; H, 3.60; N, 9.68; F, 8.86.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][CH2:10][C:11]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)C=Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 1-(4-bromo-phenyl)-4-methyl-pent-1-en-3-one (Compound 14, 7.98 g, 31.7 mmol) in 20 mL diethyl ether at 0° C. was slowly added lithium aluminum hydride (LAH) (1.20 g, 38.0 mmol). After stirring for one hour and subsequent warming to room temperature the reaction was quenched by 2 mL of saturated ammonium chloride solution at 0° C. with an ice bath and dried over anhydrous MgSO4. Solid was removed by filtration and the filtrate was concentrated at reduced pressure to obtain a crude colorless oil. 5 g of polyphosphoric acid (PPA) was then added to the crude oil and the mixture was heated at 120° C. for 15 min. After cooling to room temperature, the mixture was taken up in water (100 mL), extracted with diethyl ether (3×15 mL), washed with brine (1×15 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (hexane) afforded the title compound (6.70 g, 89% yield) as a light yellow oil:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2].P(Cl)(Cl)(Cl)=O.CN([CH:21]=[O:22])C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:21]=[O:22])=[C:6]([CH:10]([CH3:11])[CH3:12])[CH:5]=1)[CH3:2]
Reactant: CCOc1cccc(C(C)C)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CCOc1ccc(C=O)c(C(C)C)c1
Yield: 3.5 %

Procedure:
Using an analogous formylation procedure to that employed by Campaigne et al 3-ethoxycumene (5 g, 30.49 mmol) was added dropwise to a mixture of phosphorous oxychloride (2.84 mL, 30.5 mmol) and DMF (8.6 mL, 0.111 mol) at 0° C. and the resultant mixture was heated to 80-90° C. for 48 hrs before being poured onto crushed ice. The solution was taken to pH 7 with saturated sodium acetate, extracted with diethyl ether and upon drying and solvent removal a clear colourless oil was obtained. Column chromatography (silica, ethyl acetate/hexane, 1:9, Rf 0.44) gave the tide compound as a clear colourless oil (202.4 mg, 7.5% based on reacted material). 1H n.m.r. [400 MHZ, CDCl3] δ 10.11, s, 1H, CHO; 7.715, d, J 8.8 Hz, 1H, H6; 6.865, d, J 2.4 Hz, 1H, H3; 6.75, dd, J 8.55, 2.4 Hz, 1H, H5; 4.05, q, J 7 Hz, 2H, CH2; 3.95, septet, J 6.9 Hz, 1H, CH(CH3)2; 1.39, t, J 7 Hz, 3H, CH3; 1.225, d, J 7.1, 6H, CH(CH3)2. 13C n.m.r [100 MHZ, CDCl3] δ190.53, CHO; 163.42, C4; 153.87, C2; 134.77, C6; 126.37, C1, 112.42, C3; 110.87, C5; 63.48, OCH2CH3; 27.52, CH(CH3)2; 23.48, CH(CH3)2; 14.47, OCH2CH3. Mass spectrum (f.a.b.) calculated 192.115023, found 192.1151.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:8]=2[C:9]([CH3:25])([CH3:24])[C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[O:13]>C(O)(C(F)(F)F)=O.O>[OH:1][C:2]1[C:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:8]=2[C:9]([CH3:25])([CH3:24])[C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccncc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A mixture of tert-butyl 2-(5-hydroxy-8,8-dimethyl-7-oxo-7,8-dihydroisoquinoline-6-carboxamido)acetate (0.02 g, 0.06 mmol) in 2 mL TFA was stirred at room temperature for 1 hour, M+1=291. The mixture was diluted with 10 mL water. The solution was concentrated and dried to give 0.018 g of the product as a pale yellow solid. MS m/e: (M+H)+ 291.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][N:18]3[CH3:23])=[CH:10][C:9]1=[O:24])[C:5](O)=[O:6].[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)[CH2:29][O:28]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.O>[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH:38][C:5](=[O:6])[C@@H:4]([N:8]3[CH2:12][C:11]([O:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[CH:16]=[N:17][N:18]5[CH3:23])=[CH:10][C:9]3=[O:24])[CH2:3][CH:2]([CH3:25])[CH3:1])=[N:34]2)[CH2:29][O:28]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc3c2cnn3C)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc3c2cnn3C)=CC1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 57 %

Procedure:
A solution of (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (30 mg, 0.08 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (3.6 mg 0.08 mmol). The mixture was stirred at room temperature for 3.5 h and then partitioned between ethyl acetate and water. The aqueous phase was acidified with 1N aqueous hydrochloric acid (pH=1), and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid as an off-white solid. A mixture of (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid in dichloromethane (5 mL) was treated with 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.025 g, 0.13 mmol), N,N-diisopropylethylamine (0.033 g, 0.26 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.056 g, 0.13 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3.5 h. The mixture was partioned between dichloromethane and water. The organic layer was collected and concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 20% to 100% ethyl acetate/hexanes) which afforded (S)-4-Methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (0.025 g, 57%) as an off-white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH3:19])[S:15]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:17])=[O:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Imidazole (5.00 g, 73.6 mmol) was dissolved in toluene (80 ml), and thereto were added triethylamine (9.52 ml, 68.4 mmol) and dimethylsulfamoyl chloride (6.77 ml, 63.3 mmol), and the mixture was stirred at room temperature for 8 hours. The precipitates were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to azeotropic distillation with hexane to give the title compound (10.9 g, 98%).