Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8][C:7]=2[C:6]([C:23](O)=[O:24])=[N:5][CH:4]=1.C1[CH:31]=[N:30][C:29]2N(O)N=NC=2C=1.CNC>C1COCC1.C(Cl)CCl>[CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:9][CH2:8][C:7]=2[C:6]([C:23]([N:30]([CH3:31])[CH3:29])=[O:24])=[N:5][CH:4]=1
Reactant: COc1ccc(CN2CCc3c(C(=O)O)ncc(OC)c3C2=O)cc1
Reactant: On1nnc2cccnc21
Agent: CNC
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COc1ccc(CN2CCc3c(C(=O)N(C)C)ncc(OC)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 250 mL THF suspension of 4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylic acid (11.0 g), 8.0 g EDC, 5.7 g HOAT, and 11.2 mL TEA was stirred at room temperature for 20 minutes, followed by addition of 45 mL of a 2M THF solution of dimethylamine and then stirring for 1.5 hours. The reaction was quenched with 200 mL of 1N aq HCl and stirred vigorously for 30 minutes. After concentrating in vacuo until an oil formed on the water layer, 200 mL chloroform was added. The water layer was washed again with chloroform then the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to pure product by HPLC/MS and NMR.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([S:12][C:13]#[N:14])[C:5]=2[N:6]=1.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C)C=O>[CH3:11][C:9]1[CH:8]=[C:7]([S:12][C:13]#[N:14])[C:5]2[N:6]=[C:2]([NH:1][C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=3)=[O:26])[S:3][C:4]=2[CH:10]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(SC#N)c2nc(N)sc2c1
Solvent: CN(C)C=O
Product: Cc1cc(SC#N)c2nc(NC(=O)Nc3ccc([N+](=O)[O-])cc3)sc2c1
Reaction time: 5 h

Procedure:
A mixture of 2-amino-6-methyl-4-thiocyanatobenzothiazole (35 g., 0.16 mole) in dimethylformamide (250ml.) was treated slowly with p-nitrophenyl isocyanate (27 g., 0.16 mole). The reaction was then heated under stirring on the steam bath for 5 hours. The mixture was then filtered hot. The solution was chilled in an ice bath and filtered. The product was combined with the solid initially filtered to give 40 g. (65%) of off-white solid.
Reaction SMILES: C(OC(=O)[CH:10]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:11]([C:16]([O:18]C(C)(C)C)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1.[CH3:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].FC(F)(F)[C:42](O)=[O:43]>CCOCC>[CH2:26]([O:25][C:23](=[O:24])[CH:10]([O:43][CH2:42][C:36]1[CH:35]=[CH:34][CH:39]=[CH:38][CH:37]=1)[C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)C[C@@H](C(=O)OC(C)(C)C)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCCCC
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)O)C(OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Then, 23.2 g of this 2-benzyloxycarbonyl-3(R)-t-butoxycarbonyl-5-methylhexanoic acid benzyl ester was dissolved in 75 ml of 95% trifluoroacetic acid aqueous solution and stirred overnight at room temperature. Trifluoroacetic acid was evaporated off in vacuo, the residue dissolved in 100 of methylene chloride, washed with saturated NaCl aqueous solution and dried over anhydrous magnesium sulfate. After concentration in vacuo, syrup thus obtained was dissolved in 70 ml of ether and, after addition of 200 ml of n-hexane, precipitated crystals were removed by filtration and the filtrate was concentrated in vacuo, yielding 12.5 g of 2-benzyloxy-3(R)-hydroxycarbonyl-5-methylhexanoic acid benzyl ester.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23](O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N1C=CC=CC=1>CN(C)C=O.O>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]([N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: CC(C)N1CCC(Oc2ccc(C3(C(=O)O)CCOCC3)cc2)CC1
Reactant: CCNCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C1(c2ccc(OC3CCN(C(C)C)CC3)cc2)CCOCC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 9.6 %

Procedure:
4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylic acid (86 mg, 0.2 mol), diethylamine (27 μL, 0.26 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (108 mg, 0.29 mmol), pyridine (53 uL, 0.66 mmol) were combined and dissolved in dimethylformamide (1.5 mL). The reaction mixture was stirred at 60° C. for 5 hours. Further diethylamine was added (500 μL). The reaction mixture was stirred at ambient temperature for 60 hours. The reaction mixture was diluted with water (25 mL), and extracted with ethyl acetate (2×35 mL). The combined organics were dried using Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography using 15 g of silica gel, eluting with dichloromethane:methanol:ammonia (96:4:0.4) to dichloromethane:methanol:ammonia (90:10:1) to give the title compound as a clear yellow oil (10 mg, 11%). 1H NMR (400 MHz, CD3OD) δ7.2 (d, 2H), 6.95 (d, 2H), 4.4 (m, 1H), 3.85-3.7 (m, 4H), 3.3 (m, 2H), 3.05-2.9 (m, 5H), 2.6 (m, 2H), 2.25 (d, 2H), 2.0 (m, 4H), 1.8 (m, 2H), 1.1 (m, 9H), 0.63 (m, 3H)
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH2:25][CH3:26])[CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].ClCCl.[C:30]1(C)[C:31]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=1.[CH:41](N(C(C)C)CC)(C)C>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH:22]([CH2:25][CH3:26])[CH2:23][O:24][S:36]([C:31]3[CH:30]=[CH:35][C:34]([CH3:41])=[CH:33][CH:32]=3)(=[O:37])=[O:38])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCC(CO)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Solvent: ClCCl
Solvent: O
Product: CCC(COS(=O)(=O)c1ccc(C)cc1)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 0.58 h
Yield: 77.6 %

Procedure:
Into a 10 mL round bottom flask was added the product of Example 3E (0.05 g, 0.13 mmol) followed by dichloromethane (2 mL). Toluenesulfonyl chloride (0.075 g, 0.39 mmol), 4-N,N-dimethylaminopyridine (0.048 g, 0.39 mmol) and diisopropylethylamine (0.05 g, 0.39 mmol, 68.7 μl) were then added in succession to the reaction mixture and this was stirred for 35 minutes. Water was then added to the mixture and the solution poured into a separatory funnel and the layers separated. The organic layer was washed with water and brine and dried over magnesium sulfate. The crude oil obtained after filtration and concentration was purified by silica gel flash chromatography (hexanes:ethyl acetate) to obtain 54 mg (77%) of the desired compound as a thick colorless oil. 1H (CDCl3) δ (ppm): 7.74 (3H, two singlets), 7.3 (m, 4H), 6.8 (d, 2H), 5.2 (s, 2H), 4.38 (p, 1H), 4.15 (m, 2H), 2.44 (s, 3H), 1.72 (m, 2H), 1.6 (s, 9H), 0.95 (t, 3H); 13C (CDCl3) δ (ppm): 159.2, 158.5, 153.9, 145.1, 133, 130, 129, 128.1, 127.2, 125.4, 118.5, 116.5, 71.9, 70.2, 66.6, 28.1, 24.2, 21.8, 9.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH3:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:50]=1[NH2:51]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:51][C:50]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[CH3:44])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccccc1N
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4C)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 55 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with o-tolylamine yielded the title compound (55% yield) as a pale red foam. MS (ISP): m/z=680.4 [M+H]+.
Reaction SMILES: C(O[CH2:5][O:6][CH:7]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.[I:26][C:27]1[C:28](=[O:34])[NH:29][C:30](=[O:33])[NH:31][CH:32]=1.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:19]([O:18][CH2:17][CH:7]([O:6][CH2:5][N:31]1[CH:32]=[C:27]([I:26])[C:28](=[O:34])[NH:29][C:30]1=[O:33])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: CC(=O)OCOC(COCc1ccccc1)COCc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=c1[nH]c(=O)n(COC(COCc2ccccc2)COCc2ccccc2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a suspension of 2-O-(acetoxymethyl)-1,3-di-O-benzylglycerol (44; prepared according to Martin J. C., Dvorak C. A., Smee D. F., Matthews T. R., Verheyden J. P. H. (1983) 9-[(1,3-Dihydroxy-2-propoxy)methyl]quanine: a new potent and selective antiherpes agent, J. Med. Chem. 26, 759–761) (2.038 g, 5.9 mmol) and 5-iodouracil (2.106 g, 8.85 mmol) in anhydrous CH2Cl2 (25 mL) at room temperature was added N,O-bis-(trimethylsilyl)acetamide (BSA, 5.46 mL, 22.13 mmol), and the mixture was stirred at room temperature under nitrogen for 2 h. The resulting clear solution was cooled to 0° C., and SnCl4 (1 M solution in CH2Cl2, 5.9 mL, 5.9 mmol) was added. The mixture was stirred at room temperature overnight, and then poured into a mixture of saturated aqueous NaHCO3 and CHCl3. The aqueous layer was extracted with CHCl3, and the combined organic phase was evaporated. The residue was purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (97:3) to give the title compound 45 as a yellow oil (2.935 g, 95%). 1H NMR (CDCl3) δ 8.59 (s, 1H, NH), 7.82 (s, 1H, H-6), 7.36–7.26 (m, 10H, arom.), 5.28 (s, 2H, CH2N), 4.50 (s, 4H, 2 CH2), 3.99 (m, 1H, CHO), 3.52 (m, 4H, 2 CH2O).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]=[CH2:29])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[CH2:30]([Zn]CC)C.CCCCCC.ICI.[Cl-].[NH4+]>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]2[CH2:30][CH2:29]2)[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CC[Zn]CC
Reactant: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: CCCCCC
Solvent: ClCCl
Product: CCC(OC1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
To a solution of 9-chloro-1-(2-chloro-4-methoxyphenyl)-6-[1-(ethenyloxy)propyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (170 mg, 0.39 mmol) in dichloromethane (4.0 mL) was added a solution of diethyl zinc in hexane (1.0 M, 2.0 mL, 2.0 mmol) and diiodomethane (0.31 mL, 3.84 mmol) at 0° C. After stirring at 0° C. for 1.5 hr, aqueous ammonium chloride was added to the reaction mixture at 0° C. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (87.7 mg, 0.196 mmol, 50%) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[C:17]3=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=[C:16]3[CH2:15][CH2:14][C:13]3[CH:23]=[C:24]([Cl:28])[CH:25]=[C:26]([Cl:27])[C:12]2=3)[CH2:7][CH2:6]1)=[O:4].CN1CCOCC1.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C(Cl)Cl>[Br:22][C:20]1[CH:21]=[C:16]2[CH2:15][CH2:14][C:13]3[CH:23]=[C:24]([Cl:28])[CH:25]=[C:26]([Cl:27])[C:12]=3[CH:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:1][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:6][CH2:7]3)[C:17]2=[N:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCC(=O)N1CCC(C2c3ncc(Br)cc3CCc3cc(Cl)cc(Cl)c32)CC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)NCC(=O)N1CCC(C2c3ncc(Br)cc3CCc3cc(Cl)cc(Cl)c32)CC1

Procedure:
The title compound of Example 3 (0.15 g, 0.31 mmol) was dissolved in CH2Cl2 (1.5 mL). 4-Methylmorpholine (102 uL), followed by mesyl chloride (36 uL, 0.47 mmol, 1.5 equiv.) was then added. Reaction mixture was stirred at room tempearture ovemite. The CH2Cl2 phase was washed twice with Sat. NaHCO3, brine and then dried over Na2SO4. CH2Cl2 was then removed by rotary evaporation and resulting residue was purified on silica gel column eluting with 30% EtOAc/CH2Cl2 to give the title compound as a white solid (0.109 9, mp=120-140° C., MH+==562.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[C:12]([OH:18])[CH:11]=2)[CH2:6][CH2:5]1.C[O:20][C:21](=O)[CH2:22][C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]2[CH:32]=1.C(#N)C.N1CCCCC1>C1C=CC=CC=1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]2[N:26]([CH:32]=[C:23]([C:22]3[C:21](=[O:20])[O:18][C:12]4[C:13]([CH:14]=3)=[CH:16][CH:17]=[C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][F:1])[CH2:5][CH2:6]3)[CH:11]=4)[N:24]=2)[CH:27]=1
Reactant: O=Cc1ccc(N2CCN(CCF)CC2)cc1O
Reactant: COC(=O)Cc1cn2cc(Cl)ccc2n1
Solvent: c1ccccc1
Solvent: CC#N
Solvent: C1CCNCC1
Product: O=c1oc2cc(N3CCN(CCF)CC3)ccc2cc1-c1cn2cc(Cl)ccc2n1
Temperature: 0 °C
Yield: 23.4 %

Procedure:
253 mg (1 mmol) 4-[4-(2-Fluoro-ethyl)-piperazin-1-yl]-2-hydroxy-benzaldehyde and 450 mg (2 eq.) (6-chloro-imidazo[1,2-a]pyridin-2-yl)-acetic acid methyl ester refluxed in 15 mL benzene and 7.5 mL acetonitrile in the presence of 0.395 mL (4 eq.) piperidine for 21 h. The reaction mixture is cooled to 0° C. and the precipitated material filtered, washed with diethyl ether and dried under high vacuum, yielding 100 mg (23%) desired product as a yellow solid. M.p.=265° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][C:15]1[N:19]=[CH:18][N:17](C)[N:16]=1)=[N:5][NH:6][C:7]2=[O:13].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.[C:30](#N)C>>[F:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4]([CH2:14][C:15]3[N:16]([CH3:30])[N:17]=[CH:18][N:19]=3)=[N:5][NH:6][C:7]2=[O:13])=[C:2](/[N:1]=[CH:26]/[C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)[CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC#N
Reactant: Cn1cnc(Cc2n[nH]c(=O)c3cc(F)cc(N)c23)n1
Product: Cn1ncnc1Cc1n[nH]c(=O)c2cc(F)cc(/N=C/c3ccc(F)cc3)c12
Yield: 52 %

Procedure:
To a suspended of 5-amino-7-fluoro-4-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)phthalazin-1-(2H)-one (7) (1.6 g, 5.8 mmol) in acetonitrile (50 mL) was added 4-fluorobenzaldehyde (2.2 g, 17.5 mmol). The mixture was stirred under reflux under nitrogen for 48 hours. The precipitate was filtered and washed with a mixture of solvents (ethyl acetate/hexane, 1:1, 10 mL). After drying in vacuum, it afforded the title compound as a yellow solid (1.2 g, yield 52%). LC-MS (ESI) m/z: 381 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[ClH:1].[Cl:24][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[O:22][CH3:23])[CH2:15][NH:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=2)[C:2]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[N:3][N:4]=1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Reactant: COc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nnc(NCc3ccc(OC)c(Cl)c3)c3cc(C#N)ccc23)cc1
Product: Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
423 mg of tetrakis(triphenylphosphine)palladium (0) was added to a mixture of 1.0 g 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine, 423 mg 4-methoxyphenylboric acid, 30 ml toluene, 30 ml tetrahydrofuran, and 30 ml of 2 M aqueous sodium carbonate in a nitrogen atmosphere. The mixture was stirred at 80° C. for 2 hr, and further at 10° C. for 15.5 hr. The reaction solution was returned to room temperature and extracted with aqueous ammonium chloride and ethyl acetate. The organic layer was washed with aqueous ammonia, water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography. The resulting coupled compound was dissolved in ethyl acetate/ethanol, 4 N hydrochloric acid/ethyl acetate solution was added thereto, and the resulting crystals were collected by filtration to give 460 mg of the title compound as a yellow powder.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:13]=[C:14]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])[CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)(=[O:26])=[O:25])[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[S:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[S:24]([N:21]1[CH2:22][CH2:23][N:18]([C:17]2[CH:16]=[CH:15][C:14]([C:32]([OH:41])([C:37]([F:39])([F:40])[F:38])[C:33]([F:34])([F:35])[F:36])=[CH:13][C:12]=2[C:11]#[C:10][CH2:9][NH:8][S:52]([CH3:51])(=[O:54])=[O:53])[CH2:19][CH2:20]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: NCC#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NCC#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
To a solution of 2-(3-(3-amino-1-propyn-1-yl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol trifluoroacetate (102 mg, 0.17 mmol, Example 159) in CH2Cl2 (4 mL) was added diisopropylethylamine (89 μL, 0.51 mmol) and methanesulfonyl chloride (14 μL, 0.19 mmol). The reaction mixture was stirred at room temperature for 20 min and then partitioned between CH2Cl2 (5 mL) and saturated aqueous sodium bicarbonate (5 mL). The layers were separated, the organic material was separated, washed with saturated aqueous sodium bicarbonate (5 mL), dried (Na2SO4), filtered, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (12 g of silica gel, 10% to 50% EtOAc in hexanes) to provide N-(3-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-propyn-1-yl)methanesulfonamide (57 mg) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (br s, 1H), 8.09 (br s, 1H), 7.48-7.78 (m, 4H), 7.32 (br s, 1H), 7.11 (d, J=7.63 Hz, 1H), 4.07 (br s, 2H), 3.41-3.32 (m., 4H), 3.21-3.05 (m, 4H), 2.93 (s, 3H); m/z (ESI, +ve ion) 606.0 (M+H)+. GK-GKRP IC50 (Binding)=0.783 μM. GK-GKRP EC50 (LC MS/MS-2)=0.412 μM.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O>[CH:30]1([NH:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:19][C:17]=4[CH:18]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NC1CCCCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNC4CCCCC4)cc2)CCO3)cc1

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g) and cyclohexylamine (0.17 ml) in dimethylformamide (10 ml) was stirred at room temperature for 2.5 hours. The solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give N-(4-((cyclohexylamino)methyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 114) (0.09 g) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=2)[CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:7]=1.[OH-:26].[Na+]>CO.O.OO>[OH:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([NH2:25])=[O:26])=[N:22][CH:23]=2)[CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:7]=1
Reactant: N#Cc1ccc(Nc2cc(O)cc(-c3cccc4[nH]ccc34)c2)cn1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(Nc2cc(O)cc(-c3cccc4[nH]ccc34)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a solution of 5-[3-hydroxy-5-(1H-indol-4-yl)-phenylamino]-pyridine-2-carbonitrile (83 mg, 0.25 mmol) in MeOH (1 mL) was added 50% NaOH solution in H2O (200 μL) and 30% H2O2 (500 μL), and the mixture was stirred for 16 h at room temperature. The solution was concentrated to half the volume with a gentle stream of nitrogen, and the solution was diluted by addition of water (2 mL). The aqueous solution was extracted with ethyl acetate (2 mL, three times). The combined solution of organic layer was dried and concentrated to give 5-[3-hydroxy-5-(1H-indol-4-yl)-phenylamino]-pyridine-2-carboxylic acid amide (58 mg, 0.168 mmol, 66%) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (dd, J=2.4, 0.4 Hz, 1H), 7.91 (dd, J=8.8, 0.4 Hz, 1H), 7.55 (m, 1H), 7.35 (dd, J=8.0, 0.4 Hz, 1H), 7.25 (d, J=3.2 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 7.06 (dt, J=7.2, 0.8 Hz, 1H), 6.97 (m, 1H), 6.82 (m, 1H), 6.67 (m, 1H), 6.63 (dd, J=2.4, 0.4 Hz, 1H).