Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[CH3:19].[C-:20]#[N:21].[Na+].C(OCC)(=O)C>CN1C(=O)CCC1.[Ni](Br)Br>[C:20]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[CH3:19])#[N:21]
Reactant: [C-]#N
Reactant: Cc1nn(COCC[Si](C)(C)C)c2ccc(Br)cc12
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1nn(COCC[Si](C)(C)C)c2ccc(C#N)cc12
Temperature: 180 °C

Procedure:
To a solution of 5-bromo-3-methyl-N-(2-trimethylsilanylethoxymethyl)indazole 116 (0.5 g, 1.466 mmol) in NMP (10 mL) was added nickel bromide (0.321 g, 1.469 mmol) and sodium cyanide (0.144 g, 2.939 mmol). The reaction mixture was heated in a microwave reactor at 180° C. for 30 minutes. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-cyano-3-methyl-N-(2-trimethylsilanylethoxymethyl)indazole 117. (0.36 g, 1.254 mmol).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:10]([OH:12])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[C:7]([O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH:8]=1)[CH3:30]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCOc1ccc(C(=O)O)cc1OCC=C(C)C
Product: CCN1CCCC1CNC(=O)c1ccc(OCC=C(C)C)c(OCC=C(C)C)c1
Yield: 55 %

Procedure:
In a manner identical to Example 15, 3,4-diprenyloxybenzoic acid(1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.09 g(55%) of the aimed compound. m.p. 80.0-81.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:28])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([O:25]C)=O)=[CH:22][C:12]=2[N:11]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][CH:35]=1.C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:27])([CH3:28])[O:19][C:20]=3[C:21]([C:23]([NH:29][C:30]3[CH:35]=[N:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=3)=[O:25])=[CH:22][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)n(C)c2c2c1OC(C)(C)C2
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: C[Al](C)C
Product: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)Nc3ccc(C(F)(F)F)nc3)c3c(c21)CC(C)(C)O3
Yield: 19 %

Procedure:
The title compound was prepared by following the same procedure as described for Example-137 using methyl 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (step-7 of Intermediate-49, 0.100 g, 0.247 mmol), 5-amino-2-trifloromethylpyridine (0.162 g, 0.371 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) to afford 0.025 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 3.46 (s, 2H), 3.57 (s, 3H), 7.01 (m, 1H), 7.28 (s, 2H), 7.30 (d, 1H), 7.90 (d, J=8.7 Hz, 1H), 8.45 (d, J=7.8 Hz, 1H), 9.00 (s, 1H), 10.02 (s, 1H), 10.53 (s, 1H). MS [M−H]−: 532.19.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)=[C:35]([Cl:46])[CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=3)=[C:35]([Cl:46])[CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (6.5 mL, 22.6 mmol) was added to a THF (10 mL) and MeOH (5 mL) solution of ethyl 3-(5-(5-chloro-2-(((2,4′-dichloro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (3.8 g, 6.5 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off, dried in vacuo and purified via HPLC to yield the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[CH3:16][C:17]1[NH:21][N:20]=[C:19]([NH2:22])[CH:18]=1>CC(O)=O>[CH3:15][O:14][C:11]1[C:12]([CH3:13])=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[NH:2][C:1]([NH:22][C:19]1[CH:18]=[C:17]([CH3:16])[NH:21][N:20]=1)=[CH:3]2
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1ccc(C(=O)O)c(CC#N)c1C
Solvent: CC(=O)O
Product: COc1ccc2c(=O)[nH]c(Nc3cc(C)[nH]n3)cc2c1C
Temperature: 130 °C

Procedure:
A 10˜20 mL process vial was charged with 500 mg 2-Cyanomethyl-4-methoxy-3-methyl-benzoic acid and 5-Methyl-1H-pyrazol-3-ylamine in 15 mL AcOH. The vial was heated at 130° C. for 30 min under microwave irradiation. Most of the solvent was removed under reduced pressure, and the residue was poured into ice-water. The solid was collected and washed with water.
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]#[CH:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:14]1C=CC=C[C:15]=1OC#N>CCOCC>[C:6]1([C:12]#[C:13][C:15]#[N:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: N#COc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: N#CC#Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (21.6 mL, 2.5M in hexane) was added dropwise to a solution of phenylacetylene (5 g, 0.05 mol) in dry Et2O (200 mL) maintaining at −78° C. under inert atmosphere. A solution of 2-pyridyl cyanate (7.2 g, 0.06 mol) in dry Et2O (100 mL) was added dropwise keeping the temperature below −60° C. The mixture was stirred for 30 min at −78° C. then warmed to RT. The reaction was diluted with Et2O and quenched with 1N NaOH. The organic layer was washed once with 1N HCl and once with saturated NaHCO3. The solvent was removed under vacuum maintaining the temperature under 30° C. to give 3-phenyl-2-propynenitrile as a colorless crystalline solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=2[CH3:20])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=2[CH3:20])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCOc1ccc(CNc2cccc([N+](=O)[O-])c2C)cc1
Product: C=CCOc1ccc(CN(Cc2ccccc2)c2cccc([N+](=O)[O-])c2C)cc1

Procedure:
The product from Example 19A and benzyl bromide were processed as described in Example 6B to provide the title compound. MS (ESI+) m/z 389 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](C=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N+]#[C-])(C)(C)C.C(O)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cn1
Agent: [C-]#[N+]C(C)(C)C
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: c1ccc(COc2cccnc2)cc1

Procedure:
A solution of 4.22 g. (0.02 mol) of 5-benzyloxy-2-pyridinecarboxaldehyde in 100 ml. of chloroform is treated with 1.66 g. (0.04 mol) of t-butyl isocyanide and 2.40 g. (0.04 mol) of acetic acid and the solution is refluxed gently for five hours. The reaction mixture is washed with 5% sodium bicarbonate solution, dried and evaporated to dryness to give 2-[α-N-t-butylamido)-acetoxymethyl]-5-benzyloxypyridine.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:29]1[CH:34]=[CH:33][C:32]([O:35][C:36](Cl)=[S:37])=[CH:31][CH:30]=1>COCCOCCOC>[O:35]([C:36]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1)=[S:37])[C:32]1[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: S=C(Oc1ccccc1)Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice bath cooled solution containing 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole prepared as in Example 16 and 0.5 ml (3.6 mmole) of triethylamine in 10 ml of diglyme is added 0.48 ml (3.5mmole) of phenyl chlorothionoformate. The reaction is allowed to warm to room temperature and heated at 40° to 120° C. for several hours. Workup and chromatography in a manner analogous to that outlined in Example 18 affords the desired titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([N:23]([CH2:30][P:31](=[O:34])([OH:33])[OH:32])[CH2:24][C:25]([O:27]CC)=[O:26])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([N:23]([CH2:24][C:25]([OH:27])=[O:26])[CH2:30][P:31]([OH:34])([OH:33])=[O:32])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CN(CP(=O)(O)O)S(=O)(=O)c1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)N(CC(=O)O)CP(=O)(O)O)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.3 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-(2-ethoxy-2-oxoethyl)phenylsulfonamido)methylphosphonic acid (Intermediate 8.4) (180 mg, 0.33 mmol, 1.00 equiv) in tetrahydrofuran/water (5/5 mL). This was followed by the addition of lithium hydroxide (39 mg, 1.62 mmol, 4.97 equiv) in several batches at room temperature. The resulting solution was stirred for 4 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 6 with 1M hydrogen chloride. The resulting mixture was concentrated under vacuum. The crude product (150 mg) was purified by preparative HPLC giving 59.2 mg (35%) of the title compound as a TFA salt. 1H-NMR (300 MHz, DMSO+D2O, ppm): 7.73˜7.74 (m, 1H), 7.67˜7.68 (m, 1H), 7.58˜7.62 (m, 2H), 7.49 (s, 1H), 7.00 (s, 1H), 4.71˜4.75 (m, 1H), 4.49 (d, J=16.2 Hz, 1H), 4.33 (d, J=15.9 Hz, 1H), 4.07 (s, 2H), 3.62˜3.64 (m, 1H), 3.45˜3.54 (m, 2H), 3.31˜3.40 (m, 1H), 2.88 (s, 3H). MS (ES, m/z): 523 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[NH:9][C:10]3[CH:16]=[C:15]([N:17]4[CH2:22][CH2:21][CH2:20][C:19]5([CH2:27][CH2:26][CH2:25][NH:24][CH2:23]5)[CH2:18]4)[CH:14]=[C:13]([CH3:28])[C:11]=3[N:12]=2)=[C:6](I)[CH:5]=[CH:4][N:3]=1.[ClH:30].[O:31]1CCOCC1>O>[Cl:30][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:31])[C:7]=1[C:8]1[NH:9][C:10]2[CH:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C:19]4([CH2:27][CH2:26][CH2:25][NH:24][CH2:23]4)[CH2:18]3)[CH:14]=[C:13]([CH3:28])[C:11]=2[N:12]=1
Reactant: Cl
Reactant: C1COCCO1
Reactant: Cc1cc(N2CCCC3(CCCNC3)C2)cc2[nH]c(-c3c(I)ccnc3Cl)nc12
Solvent: O
Product: Cc1cc(N2CCCC3(CCCNC3)C2)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Temperature: 85 °C
Yield: 27 %

Procedure:
To a suspension of 2-[2-(2-chloro-4-iodo-pyridin-3-yl)-7-methyl-3H-benzoimidazol-5-yl]-2,8-diaza-spiro[5.5]undecane (144 mg, 0.28 mmol) in H2O (1.5 mL) was added a solution of HCl in dioxane (4 M, 20 mL, 80 mmol). After it was heated at 85° C. for 18 h, the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by chromatography (50:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (16 mg, 27%). 1H NMR (MeOH-d4) δ 1.35-1.82 (8H), 2.54 (s, 3H), 2.90-3.19 (8H), 6.60 (d, J=7 Hz, 1H), 6.89 (s, 1H), 6.96 (s, 1H), 7.58 (d, J=7 Hz, 1H). ESI-MS m/z 412 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:10][C:9](=[CH2:22])[S:8]1)=[O:5])[CH3:2].C[O-].[Na+]>CO>[CH2:1]([NH:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:10]=[C:9]([CH3:22])[S:8]1)=[O:5])[CH3:2]
Reactant: C=C1CN(c2cccc(C(F)(F)F)c2)C(=NC(=O)NCC)S1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)N=c1sc(C)cn1-c1cccc(C(F)(F)F)c1
Yield: 50 %

Procedure:
A solution of 2-(N-ethylcarbamoylimino)-3-(3-trifluoromethylphenyl)-5-methylenethiazolidine (0.2 g) and sodium methoxide (28 % methanolic solution; 0.2 g) in methanol (30 ml) was refluxed for 10 hours. After removal of the solvent, the residue was extracted with chloroform (100 ml), washed with water and dried over anhydrous magnesium. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.1 g of 2-(N-ethylcarbamoylimino)-3-(3-trifluoromethylphenyl)-5-methylthiazoline (Compound No. 44).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:25][NH2:26]>C(Cl)Cl>[ClH:11].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([NH:26][CH3:25])=[N:2][CH3:1])=[CH:6][CH:7]=1
Reactant: CNC(=O)Cc1ccc(Cl)cc1
Reactant: CN
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CN=C(Cc1ccc(Cl)cc1)NC
Product: Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.1 %

Procedure:
Using glass vessels dried at 125° C. before use, N-methyl-2-(4-chlorophenyl)acetamide (18.4 grams; 0.1 mole) is dispersed in a mixture of 150 milliliters of methylene chloride and triethyloxonium fluoroborate (19 grams; 0.1 mole). The reaction mixture is stirred at room temperature for 72 hours, then cooled in an acetone-Dry Ice bath while monomethylamine (10 grams; 0.33 mole) is added. The mixture is then stirred an additional 18 hours at room temperature. During the foregoing additions and mixing of reactants the mixture is maintained under a dry nitrogen blanket. The reaction mixture is then concentrated under vacuum and the residue is suspended in water, made strongly alkaline by addition of cold aqueous 20 percent sodium hydroxide, and extracted with ethyl acetate. The organic phase is separated and dried over anhydrous sodium sulfate. Excess dry gaseous hydrogen chloride is introduced into the mixture, and the resulting mixture is evaporated under reduced pressure, residual oil is taken up in methyl ethyl ketone, filtered and the filtrate evaporated. The product is obtained as a residue which is recrystallized from isopropanol. The 2-(4-chlorophenyl)-N,N'-dimethylacetamidine hydrochloride product is obtained in a yield of 4 grams; corresponding to a 17.1 percent yield based on the acetamide starting material. The product is found to melt at a temperature of 242.5°-243.5° C. Infrared and nuclear magnetic resonance analyses also confirm the named structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1(C(OC)=O)[NH:12][NH:11][CH:10]=[CH:9]1.[Cu]([C:20]#[N:21])C#N.C[CH2:23][O:24][C:25](C)=[O:26]>CN1C(=O)CCC1>[C:20]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:25]([O:24][CH3:23])=[O:26])[NH:11][N:12]=1)#[N:21]
Reactant: COC(=O)C1(c2ccccc2Br)C=CNN1
Reactant: CCOC(C)=O
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(-c2ccccc2C#N)n[nH]1
Reaction time: 0.33 h
Yield: 98 %

Procedure:
A mixture of methyl 5-(2-bromophenyl)-1H-pyrazole-5-carboxylate (0.225 g, 0.000800 mol) and copper cyanide (0.093 g, 0.0010 mol) in NMP (10 mL) was subjected to MWI at 170° C. for 20 min. The reaction mixture was diluted with EtOAc and filtered. The filtrate was evaporated to give methyl 3-(2-cyanophenyl)-1H-pyrazole-5-carboxylate (0.178 g, 98%) which was used without purification. LCMS: (AA) ES+ 228.1, ES-226.2.
Reaction SMILES: [F:1][C:2]1([CH2:18][OH:19])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1([CH2:18][O:19][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCC(F)(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of benzyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) in CH2Cl2 (10 mL) at RT was added methanesulfonyl chloride (0.29 mL, 3.7 mmol) and triethylamine (1.04 mL, 7.5 mmol). The reaction mixture was stirred at rt for 5 min, and partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, concentrated and purified on silica gel (10:1 to 1:2 hexanes:EtOAc) to give benzyl 4-fluoro-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate. M.S. (M+1): 346
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].OO.[OH:23]S(O)(=O)=O>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=1)[C:14]([OH:23])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OCc2ccccc2)cc1C=O
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(OCc2ccccc2)cc1C(=O)O
Temperature: 65 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred suspension of 5-(benzyloxy)-2-methoxybenzaldehyde (7, 1.12 g. 4.6 mmol) in MeOH (8 mL) at room temperature was added a solution of KOH (1.04 g, 18.5 mmol) in water (1.4 mL). The mixture was heated to 65° C. and H2O2 (35 wt %; 4.0 mL, 46 mmol) was added dropwise over 105 min. The reaction mixture was stirred at 65° C. for 1 h. Then it was cooled to room temperature and acidified to pH 2 with 6N H2SO4. The precipitate was collected, washed with water and dried in vacuo to afford the title compound (1.16 g, 97%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 10.94 (br s, 1H), 7.80 (d, J=3.3 Hz, 1H), 7.44-7.37 (m, 4H), 7.35-7.32 (m, 1H), 7.19 (dd, J=9.0, 3.3 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 5.08 (s, 2H), 4.04 (s, 3H); ESI MS m/z 257 [M−H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[OH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCO)CCO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-nitrobenzenesulfonyl chloride (10.5 g, 47.6 mmol) in anhydrous methylene chloride (25 mL) was added dropwise with stirring to a 0° C. solution of diethanolamine (5.00 g, 47.6 mmol) and triethylamine (4.92 g, 47.6 mmol) in anhydrous methylene chloride (50 mL). Reaction stirred three hours at 0° C. and then overnight at room temperature. Reaction mixture concentrated under reduced pressure. Residue dissolved in ethyl acetate, washed with 1N NaOH, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with ethyl acetate to afford the title compound. MS (ESI) m/z 291 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.O.C([O-])(=O)C.[Zn+2:16].C([O-])(=O)C>O>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[Zn:16]
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: CC(C)C[C@H](N)C(=O)O
Solvent: O
Product: [Zn]
Temperature: 48.888888888888886 °C

Procedure:
Anhydrous L-leucine, 5.2472 g, 0.0400 mole, was dissolved in 30 ml of deionized water and heated to 120° F. Ultra-pure zinc acetate dihydrate, Zn(C2H3O2)2.2H2O , 4.3900 g, 0.0200 mole, was added in small increments over one hour, with stirring. The solution did not clear, so another 20 ml of water was added and the mixture was heated in a boiling water bath to 190° F. for an additional 21/2 hours. Water was then added to a total volume of 75 ml, the mixture heated again to 190° F., and gravity filtered. The retained solid was dried at 150° F. for 12 hours, found to weigh 2.717 g, and was analyzed.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:37]1[C:33](=[O:43])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36]1=[O:38])=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CCl)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 87.1 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.15 g, 7 mmol) and potassium phthalimide (1.94 g, 10.5 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give 2-[[6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (3.42 g, 87.2%) as crystals.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>O1CCCC1>[CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([S:41]([CH3:44])(=[O:43])=[O:42])[C@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:32]=[N:31][C:30]([NH2:33])=[N:29][CH:28]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(N2CCN(S(C)(=O)=O)[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
5-{9-Isobutyl-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (140 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5 ml) followed by the addition of triethylamine (68 μl) and mesyl chloride (28 μl) with ice cooling and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=5:5 to 0:10) to give a white solid (135 mg, 62%).