Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([Cl:25])[CH:18]=4)[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1.O>CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:25])[CH:18]=4)[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1Cl
Agent: CS(=O)(=O)O
Solvent: O
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(-c3ccc(O)c(Cl)c3)c(=O)c12
Temperature: 145 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
7-Chloro-2-(3-chloro-4-methoxyphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridazino-[4,5-b]quinoline-1,10-dione (previously prepared in Example 37 1.00 g, 2.47 mM) was stirred in methanesulfonic acid (20 mL) to give a black solution. This solution was heated to 145° C. for 6 hours and cooled to room temperature. Water (60 mL) was added to give a tan suspension which was stirred for 3 hours and filtered. The collected solids were washed with water and ether to give the title compound as a gold powder (0.98 g, 76%), mp 350°-353° C.; MS(CI): 390.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH:7]2[C:5]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)([CH2:6]2)[CH2:4]1)=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23]>C(O)C>[CH:1]([N:3]1[CH2:8][CH:7]2[C:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:22][CH3:23])=[CH:11][CH:10]=3)([CH2:6]2)[CH2:4]1)=[O:2]
Reactant: O=CN1CC2CC2(c2ccc(O)cc2)C1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1ccc(C23CC2CN(C=O)C3)cc1
Yield: 27.2 %

Procedure:
To a stirred mixture of 1.0 g of 3-formyl-1-(p-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane and 0.7 g of potassium carbonate in 25 ml of absolute ethanol is added a solution of 3.2 g of ethyl iodide in 10 ml of absolute ethanol. The mixture is refluxed for 2 hours and then is filtered and evaporated. The residual mixture of crystals and liquid is combined with water and this is extracted with chloroform and the extract is dried over magnesium sulfate and evaporated to give 1.0 g of a colorless, viscous liquid, which crystallizes on standing. Recrystallization from hexane gives 0.31 g of 3-formyl-1-(p-ethoxyphenyl)-3-azabicyclo[3.1.0]hexane as colorless crystals, m.p. 48°-51° C.
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].Br[C:13]1[CH:14]=[C:15]([S:19]([NH:22][CH2:23][CH2:24][OH:25])(=[O:21])=[O:20])[CH:16]=[N:17][CH:18]=1>>[OH:25][CH2:24][CH2:23][NH:22][S:19]([C:15]1[CH:14]=[C:13]([C:2]2[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=2[CH3:11])[CH:18]=[N:17][CH:16]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(NCCO)c1cncc(Br)c1
Reactant: CC(=O)Nc1nc(C)c(I)s1
Product: CC(=O)Nc1nc(C)c(-c2cncc(S(=O)(=O)NCCO)c2)s1
Yield: 23 %

Procedure:
Using an analogous method to that described in Example 7, N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide was reacted with 5-bromo-N-(2-hydroxyethyl)pyridine-3-sulfonamide to give the title compound (Method A HPLC: retention time 4.0 minutes; 10 mg, 23%); 1H NMR Spectrum: (DMSOd6) 12.22 (1H, br s); 8.92 (1H, d); 8.86 (1H, d); 8.16 (1H, t); 7.96 (1H, br s); 4.73 (1H, t); 3.39 (2H, br q); 2.89 (2H, br t); 2.40 (3H, s); 2.17 (3H, s); Mass Spectrum: M+H+ 357.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](/[CH:13]=C/N(C)C)[CH:5]=1.C1C[O:22]CC1.O>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH:13]=[O:22])[CH:5]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(/C=C/N(C)C)c1
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 40 °C

Procedure:
Compound 3 (11.81 g 47.2 mmol) and NaIO4 (30.3 g 141.6 mmol) was dissolved in 250 mL THF/H2O 1:1 at room temperature. The dark red solution was warmed to about 40° C. while heavy precipitation occurred and the color changed to light brown. After 1 h the precipitate was removed by filtration and washed with 200 mL ethyl acetate. The organic layer was washed three times with saturated NaHCO3, once with brine and dried with Na2SO4. The solution was evaporated to dryness and the resulting oil was purified on a silicagel pad eluting with DCM-hexane gradient (30% to 60% DCM) to yield after evaporation yellow Compound 4.
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[C:44]([F:46])[C:7]([O:8][C:9]2[CH:43]=[CH:42][C:12]([C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:41])([CH3:40])[C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[C:35]([F:36])=[CH:34][C:33]([N+:37]([O-])=O)=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)[CH:17]=3)([CH3:15])[CH3:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)(C)C>[NH2:37][C:33]1[CH:34]=[C:35]([F:36])[C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:13]([CH3:15])([CH3:14])[C:12]4[CH:42]=[CH:43][C:9]([O:8][C:7]5[C:44]([F:46])=[CH:45][C:4]([NH2:1])=[CH:5][CH:6]=5)=[CH:10][CH:11]=4)[CH:17]=3)([CH3:40])[CH3:41])=[CH:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: [H][H]
Reactant: CC(C)(c1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1)c1cccc(C(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2)c1
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)(c1ccc(Oc2ccc(N)cc2F)cc1)c1cccc(C(C)(C)c2ccc(Oc3ccc(N)cc3F)cc2)c1
Yield: 81 %

Procedure:
Successively, to a reduction vessel equipped with a thermometer, reflux condenser and stirrer, 115 g (0.184 mol) of 1,3-bis[4-(4-nitro-6-fluorophenoxy)-α, α-dimethylbenzyl]benzene, 250 g of isopropyl alcohol and 4.8 g of 5%-Pd/c having a moisture content of 50% were charged and reacted at 70°~80° C. for 4 hours in a hydrogen atmosphere. After finishing the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain 84.2 g (81% yield) of 1,3-bis[4-(4-amino-6-fluorophenoxy)-α, α-dimethylbenzyl]benzene as a light yellow crystal having a melting point of 130.4~132.9.
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[C:19]2[N:20]=[CH:21][C:22]3[N:23]([C:24]([CH3:27])=[N:25][CH:26]=3)[C:18]=2[CH:17]=[C:16]1[C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]([CH3:39])[CH:29]=1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[P:1]([OH:3])([OH:8])([O:13][CH2:14][N:15]1[C:19]2[N:20]=[CH:21][C:22]3[N:23]([C:24]([CH3:27])=[N:25][CH:26]=3)[C:18]=2[CH:17]=[C:16]1[C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]([CH3:39])[CH:29]=1)=[O:2]
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(C)n43)n1COP(=O)(OC(C)(C)C)OC(C)(C)C)cn2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(C)n43)n1COP(=O)(O)O)cn2C
Yield: 40.8 %

Procedure:
Di-tert-butyl (7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-6-yl)methyl phosphate (0.2 g, 0.361 mmol) was dissolved in DCM (5 mL) then TFA (0.2 mL, 2.60 mmol) was added. After about 20 min at rt the reaction mixture was concentrated under reduced pressure. The material was dissolved in DMF (7.5 mL) then the material was purified by preparative reverse phase HPLC (Table 2, Method i). The fractions were collected and concentrated under reduced pressure to remove most or all of the MeCN. The solid was collected by filtration and dried under vacuum to a constant weight at about 60° C. to provide (7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-6-yl)methyl dihydrogen phosphate (0.065 g, 41%): LC/MS (Table 2, Method a) Rt=1.42 min; MS m/z 442 (M+H)+.
Reaction SMILES: OC1C=CC(CC(CC2C=CC(O)=CC=2)=O)=CC=1.BrCCBr.BrCCC1C=C(C(=O)C)C=[CH:28][C:27]=1[O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][C:37]=1CCBr.[CH:48]([NH2:51])([CH3:50])[CH3:49]>>[C:42]([C:39]1[CH:38]=[CH:37][C:36]([O:35][CH2:27][CH2:28][NH:51][CH:48]([CH3:50])[CH3:49])=[CH:41][CH:40]=1)(=[O:44])[CH3:43]
Reactant: CC(C)N
Reactant: CC(=O)c1ccc(Oc2ccc(C(C)=O)cc2CCBr)c(CCBr)c1
Agent: O=C(Cc1ccc(O)cc1)Cc1ccc(O)cc1
Solvent: BrCCBr
Product: CC(=O)c1ccc(OCCNC(C)C)cc1

Procedure:
4-Hydroxyphenylmethyl ketone is reacted with 1,2-dibromoethane in the presence of base. The product of that reaction, 2-bromoethyl-4-acetylphenyl ether is then reacted with isopropylamine as in Preparation 1 to give the title compound.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([F:15])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([OH:4])=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccc(F)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Oc1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a stirred solution of 2.71 g of 1-acetoxy-4-fluoro-naphthalene in 142 ml of degassed methanol was added a solution of 9.2 g of potassium carbonate in 95 ml of degassed water. The mixture was stirred at room temperature for 5 h. The mixture was cooled with ice, acidified to pH1-2 with conc. HCL, extracted with dichloromethane, dried (magnesium sulphate), filtered and concentrated to an orange solid. The material was purified by chromatography on silica gel eluting with dichloromethane/heptanes/toluene to provide 1.98 g of 4-fluoro-1-hydroxynaphthalene as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:16][CH2:17][CH3:18])(=O)[CH3:2].ClC1C=CC=CN=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:41]([O:43][CH2:44][CH3:45])#[CH:42]>C(Cl)Cl>[CH2:41]([O:43][C:44]1[C:15]2[C:5](=[C:6]([O:16][CH2:17][CH3:18])[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:14]=2)[N:4]=[C:1]([CH3:2])[CH:45]=1)[CH3:42]
Reactant: C#COCC
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(OCC)c1
Agent: Clc1ccccn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(OCC)c2nc(C)cc(OCC)c2c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 8.2 %

Procedure:
To a nitrogen flushed vial were added ethyl 4-(acetylamino)-3-ethoxybenzoate (100 mg, 0.40 mmol), 2-chloropyridine (90 mg, 0.80 mmol) and CH2Cl2 (2 mL). Triflic anhydride (0.40 mmol) was added via a syringe at −78° C. The reaction mixture was stirred at −78° C. for 5 minutes. Ethyl ethynyl ether (0.174 mL, 40% in hexanes, 0.80 mmol) was added. The resulting reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 1 hour. The reaction was quenched by addition of Na2CO3 (5 mL, sat'd.), water (20 mL) and EtOAc (20 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified on a silica gel column eluting with a gradient of 10-20% EtOAc/hexanes to give the title intermediate (10 mg) as a light brown sticky material.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].CCN(CC)CC.CN(C1C=CC=CN=1)C.[CH3:27][O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl.O>[CH3:27][O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:32]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Cc1csc(N)c1C(N)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)Nc1scc(C)c1C(N)=O
Reaction time: 1 h
Yield: 43.6 %

Procedure:
A solution of 2-amino-4-methylthiophene-3-carboxamide (0.47 g, 3 mmol), Et3N (0.46 mL, 3.3 mmol), and dimethylaminopyridine (0.073 g, 0.64 mmol) in CH2Cl2 (10.0 mL) was cooled in an ice bath, and 2-methoxybenzoyl chloride (513 mg, 3.0 mmol) was added dropwise to this mixture. The reaction was stirred for 1 h, and water (20 mL) was added. The insoluble solids were filtered, and the layers were separated. The organic layer was dried and the solvent removed under vacuum to give a residue which was purified with silica gel using EtOAc-hexanes to give 2-(2-methoxybenzamido)-4-methylthiophene-3-carboxamide (0.38 g, 44% yield). LC/MS: m/z 291.1 (M+H)+ at 2.59 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[NH:10][CH:11]=O.P(Cl)(Cl)(Cl)=O>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([N+:10]#[C-:11])[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cc(F)ccc2F)cc1
Solvent: COCCOC
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: -5 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
To a solution of N-((2,5-difluorophenyl)(tosyl)methyl)formamide (5.92 g, 18.2 mmol) in DME (100 mL) at about −10° C. was added phosphorus oxychloride (Fluka, 5.09 mL, 54.6 mmol) followed by dropwise addition of TEA (12.7 mL, 91.0 mmol) in DME (10 mL). The reaction mixture was stirred at about −5° C. for about 3 h. The reaction mixture was poured into ice-cold water (250 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography using heptane/EtOAc (gradient; 1:0 to 1:1) to give the title compound (1.90 g, 34.0%) as a yellow solid. LC/MS (Table 1, Method a) Rt=2.94 min; MS m/z: 306.1 (M−H)−.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:13]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:22][C:23](OCC)=[O:24].O.[OH-].[Na+]>O1CCCC1>[NH2:7][C:8]1[C:13]([CH:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:22][CH2:23][OH:24]
Reactant: CCOC(=O)Cc1cccc(C(=O)c2ccccc2)c1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(CCO)cccc1C(O)c1ccccc1
Yield: 61.2 %

Procedure:
A suspension of 5.5 g (0.145 mole) of lithium aluminum hydride in 60 ml of dry tetrahydrofuran was treated with 19.4 g (0.0685 mole) of 2-amino-3-benzoyl benzeneacetic acid, ethyl ester dissolved in 120 ml of dry tetrahydrofuran stirred under nitrogen. After addition was complete, the mixture was continued at reflux for 2 hours. The mixture was then cooled, treated with successive additions of 5.5 ml of water, 5.5 ml of 15% sodium hydroxide and 16.5 ml of water. The mixture was then filtered, the filtrate stripped and the residue recrystallized from toluene. The titled compound (10.2 g) was obtained as pinkish needles,
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18](=O)[CH2:19][C:20](=O)[CH3:21].C([O-])(O)=O.[Na+]>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[C:20]([CH3:21])=[CH:19][C:18]([CH3:17])=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc3c(c2n1)CN(C(=O)OC(C)(C)C)C3
Yield: 98.9 %

Procedure:
A solution of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (700 mg; 3.12 mmol; 1 eq.) and pentane-2,4-dione (0.35 mL; 3.43 mmol; 1.1 eq.) in AcOH (3.1 mL) was stirred at room temperature for 1 hour then poured into sat. aq. NaHCO3. The precipitate was filtered off and dried to afford the title compound (890 mg, 97%) as a white solid. HPLC (max plot) 98.8%; Rt 3.32 min.
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]([F:18])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]([F:18])[C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Cl)c1F

Procedure:
To 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid (45, 1.50 g, 5.4 mmol) was added toluene (7.0 mL) and thionyl chloride (15.0 mL, 0.21 mmol). The reaction was heated to reflux for 3 hours. The reaction was concentrated to give crude compound that was used in the next step.
Reaction SMILES: COC1C=CC(C[N:8]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:21])=CC=1.C(#N)C.[N+]([O-])([O-])=O.[Ce+3].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O>[CH3:19][C:16]1([CH3:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:21])[NH:8][C:17]1=[O:18]
Reactant: COc1ccc(CN2C(=O)c3ccccc3C(C)(C)C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+3]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC1(C)C(=O)NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 297 %

Procedure:
The compound (6.0 g) obtained in step (b) just above was dissolved in a mixed solvent (acetonitrile:water=4:1) (40 ml). Diammonium cerium nitrate (26.6 g) was added to the solution. The mixture was stirred at room temperature for 3 hr. The reaction solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=8:2) to give 4,4-dimethyl-4H-isoquinoline-1,3-dione (10.9 g).
Reaction SMILES: [CH3:1][Mg]Br.[C:4]1([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][C:26]([C:28](N(C)OC)=[O:29])=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[C:4]1([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]([CH3:1])=[O:29])=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc2c(c1)ncn2-c1ccnc(N[C@@H](C)c2ccccc2)n1
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)ncn2-c1ccnc(N[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of methylmagnesium bromide (980 μL, 1.4 M, 13.8 mmol) in CH2Cl2 (0.5 mL) at 0° C. was added 2-[(S)-1-phenylethylamino]-4-[5-(N-methyl-N-methoxyaminocarbonyl)-benzimidazol-1-yl]pyrimidine (55.4 mg, 0.138 mmol) in CH2Cl2 (1.0 mL) slowly. The reaction mixture was warmed to room temperature slowly and continued stirring for 5 h. The reaction mixture was quenched with saturated aqueous NH4Cl then extracted with CH2Cl2. The combined extracts were washed with brine and dried over Na2SO4. The crude material was purified by preparative thin layer chromatography eluting with 3% MeOH/CH2Cl2 to obtain 38 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.5 (br s, 1H); 8.4 (s, 1H); 8.38 (d, J=5.5 Hz, 1H); 7.93 (br s, 1H); 7.79 (br s, 1H); 7.44-7.28 (m, 5H); 6.74 (d, J=5.2 Hz, 1H); 5.17 (br s, 1H); 2.68 (s, 3H); 1.63 (d, J=6.8 Hz, 3H). Mass spectrum 358.2 (CI, M+1).
Reaction SMILES: [NH4+:1].[OH-].N.[NH2:4][C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][C:7]([OH:9])=[O:8]>O>[NH2:4][C@H:5]([C:10]([O-:12])=[O:11])[CH2:6][C:7]([O-:9])=[O:8].[NH4+:1].[NH4+:4]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]

Procedure:
300 g NH4OH, containing 23.14% by weight of NH3, and 800 g of water were introduced into a 2 1 round-bottomed flask equipped with a magnetic stirrer. 543 g of L-aspartic acid were then added progressively such as to maintain the temperature of the mixture below 50° C. After cooling, a homogeneous 37.27% w/w ammonium aspartate aqueous solution was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.[BH3-]C#N.[Na+].O>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:25]4[CH2:26][O:23][CH2:24]4)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: O=C1COC1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3)cn2)c1=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 50 °C
Yield: 60.9 %

Procedure:
A mixture of 101j (2.75 g, 7.5 mmol), oxetan-3-one (1.6 g, 22.7 mmol), NaBH3CN (4.75 g, 22.5 mmol), and zinc chloride (3 g, 22.7 mmol) in methanol (125 mL) was stirred for hours at 50° C. The mixture was added to water and extracted with methylene chloride for three times. The organic layers were concentrated under reduced pressure. The residue was purified by column chromatography eluting with 25:1 methylene chloride/methanol to give 101k (1.92 g, 61%). MS: [M+H]+ 420. 1H NMR (500 MHz, DMSO) δ 8.58 (d, J=2.5, 1H), 8.55 (s, 1H), 7.94 (d, J=3, 1H), 7.54 (d, J=2.5, 1H), 7.39 (dd, J=3, 1H), 7.25 (d, J=4, 1H), 4.56 (t, J=6.5, 2H), 4.46 (t, J=6.5, 2H), 3.50 (s, 3H), 3.43 (m, 1H), 3.01 (m, 4H), 2.40 (m, 4H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21]([OH:23])([CH3:22])[C:20]3[C:15](=[C:16]([N+:24]([O-])=O)[CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:27])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>CO>[NH2:24][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[C:14](=[O:27])[N:13]([C:10]1[CH:11]=[CH:12][C:7]([C:3]([CH3:5])([CH3:4])[CH3:6])=[CH:8][CH:9]=1)[C:21]2([OH:23])[CH3:22]
Reactant: CC(C)(C)c1ccc(N2C(=O)c3c([N+](=O)[O-])cccc3C2(C)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(N2C(=O)c3c(N)cccc3C2(C)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaBH4 (0.091 g, 2.36 mmol) was added in small portions to the mixture of 2-(4-tert-butyl-phenyl)-3-hydroxy-3-methyl-7-nitro-2,3-dihydro-isoindol-1-one (0.20 g, 0.59 mmol, Step H) and NiCl2.6H2O (0.28 g, 1.18 mmol) in 10 mL of MeOH at 0° C. over 30 min. The mixture was stirred at RT for 30 min, filtered through Celite®, and condensed. The titled compound was obtained as a white solid after flash column chromatography (0 to 25% of EtOAc in CH2Cl2). MS (ES+): 311.1 (M+H)+. Calc'd for C19H22N2O2-310.39.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=[CH:18][N:19]=3)[N:16]=2)[CH:8]=[CH:7][C:3]=1C(N)=O.C([O:33][C:34](=[O:50])C1C=CC=C(B2OC(C)(C)C(C)(C)O2)C=1)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[N:27]1[C:28]2[C:23](=[CH:22][C:21]([CH2:20][C:17]3[N:15]4[N:16]=[C:11]([C:9]5[CH:10]=[C:2]([CH:3]=[CH:7][CH:8]=5)[C:34]([OH:50])=[O:33])[CH:12]=[CH:13][C:14]4=[N:19][CH:18]=3)=[CH:30][CH:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: NC(=O)c1ccc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1Cl
Reactant: CCOC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)c1

Procedure:
The title compound was prepared in analogy to the compound of Example 15 starting with 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid ethyl ester, using PdCl2(dppf)/CH2Cl2 (1/1) as catalyst and with an additional ester deprotection step afterwards (tR 3.14 min (conditions 11), MH+=380.9).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C)[CH:32]=3)(=[O:30])=[O:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)(=[O:30])=[O:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(OC)c2)cc1)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(O)c2)cc1)c1ccccc1

Procedure:
Prepared by treating 1u with boron tribromide (3 eq) in CH2Cl2 at room temperature. Yield (57%); 1H NMR (d6-DMSO) δ 12.15 (br s, 1H), 10.19 (s, 1H), 7.41–7.02 (m, 17H), 6.86 (d, J=8.0 Hz, 2H), 6.42 (d, J=15.7 Hz, 1H), 2.37 (q, J=7.4 Hz, 2H), 0.83 (t, J=7.4 Hz, 3H); APcI m/z: 510 (M+H+).