Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].FC(F)(F)C(O)=O.ClCCl.CO>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(CCC(=O)O)ccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1

Procedure:
tert-Butyl 3-(4-(5-(3-Cyano-4 isopropyloxyphenyl)-1,2,4-thiadiazol-3-yl)-3-methylphenyl)propanoate (110 mg, 0.23 mmol, from Step D) was treated with 20% solution of trifluoroacetic acid in dichloromethane (10 mL) for 3 h at rt. The solvents were removed under reduced pressure, residual solids dissolved in toluene and concentrated again. Pure product was isolated by a column chromatography using a Biotage 40S column (eluent: dichloromethane/methanol=9/1): 1H NMR (500 MHZ, CDCl3) δ 1.49 (d, J=6.5, 6H), 2.65 (s, 3H), 2.77 (t, J=8.0, 2H), 3.03 (t, J=8.0, 2H), 4.79 (sep, J=6.5, 1H), 7.11 (d, J=9.0, 1H), 7.21 (d, J=9.0, 1H), 7.24 (s, 1H), 7.70 (d, J=8.0, 1H), 8.17 (d, J=2.0, 1H), 8.25 (dd, J=8.0, 2.0, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[NH:9][C:8](=[O:15])[N:7]=[C:6]2[CH3:16].C([O:19][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])C.Br>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[NH:9][C:8](=[O:15])[N:7]=[C:6]2[CH3:16].[C:20]([OH:24])(=[O:19])[CH2:21][CH2:22][CH3:23]
Reactant: COc1cc2[nH]c(=O)nc(C)c2cc1OC
Reactant: CCCC(=O)OCC
Agent: Br
Product: CCCC(=O)O
Product: Cc1nc(=O)[nH]c2cc(O)c(O)cc12
Yield: 80 %

Procedure:
When 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-butanoic acid ethyl ester is refluxed with excess 40% aqueous HBr for 24 hours the title compound is afforded in 80% yield, mp 288°-299° C.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:14]N1C(=O)C2=CC=CC=C2C1=O>C(O)(=O)C>[C:1]1([OH:14])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:1]1(=[O:14])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: CC(=O)O
Product: O=C1C=CC=C2C1=Cc1ccccc12
Product: Oc1cccc2c1Cc1ccccc1-2
Yield: 5 %
Yield: 30 %

Procedure:
To 25 ml of acetic acid were added 10 mmol of fluorene, 1 mmol of N-hydroxyphthalimide and a binary co-catalyst [0.03 mmol of acetylacetonatovanadium V(AA)3 and 0.02 mmol of acetylacetonatocopper Cu(AA)2 ]and the resultant mixture was stirred under an oxygen atmosphere at a temperature of 90° C. for 8 hours. The products in the reaction mixture were analyzed by gas chromatography, and, as a result, fluorene was converted into fluorenol (yield 5%) and fluorenone (yield 30%) with a conversion of 36%. The selectivity of such oxides (the alcohol and the ketone) was 97%.
Reaction SMILES: [C:1](O)(=O)CC(O)=O.[Cl:8][C:9]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:22]=[C:16]2[C:17]([O:19][C:20](=[O:21])[C:15]2=[CH:14][CH:13]=1)=[O:18].C(N(CC)CC)C.C(OCC)(=O)C>O>[Cl:8][C:9]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:22]=[C:16]2[C:15](=[CH:14][CH:13]=1)[C:20](=[O:21])[O:19][C:17]2([OH:18])[CH3:1]
Reactant: O=C(O)CC(=O)O
Reactant: O=C1OC(=O)c2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(O)OC(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Dried malonic acid (156 g, 1.5 mol) and 5-(2-chloro-4-trifluoromethylphenoxy)phthalic anhydride (342 g, 1.0 mol) were stirred with triethylamine (200 ml) under a nitrogen atmosphere and warmed slowly to 80° C. After 5 hours at 80° C., the reaction mixture was allowed to cool to room temperature and ethyl acetate (750 ml) and water (500 ml) were added. The organic phase was separated and washed with dilute hydrochloric acid then water. Ethyl acetate was distilled from the solution and the crude product purified by chromatography over silica gel. Finally, crystallisation from 40°-60° petroleum spirit/diethyl ether afforded the product as a white solid, m.p. 106°-108° C. Yield=154 g (43%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]2)=[CH:4][C:5]([NH:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:21][C:22]1[CH:36]=[CH:35][C:25]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:24][C:23]=1[N:37]=[C:38]=S.CC(C)N=C=NC(C)C>>[Cl:21][C:22]1[CH:36]=[CH:35][C:25]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:24][C:23]=1[NH:37][C:38]1[N:9]([CH3:10])[C:5]2[CH:4]=[C:3]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]([F:19])([F:20])[F:18])[CH2:13][CH2:12]3)[C:2]([Cl:1])=[CH:8][C:6]=2[N:7]=1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The sub-title compound was prepared in analogy to Example 76 using 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (508 mg, 1.65 mmol), tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate (493 mg, 1.65 mmol), DIC (208 mg, 1.65 mmol) and
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N:41]=[C:40]2[CH3:48])[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN(C=O)C>[CH3:48][C:40]1[N:39]([CH:36]2[CH2:35][CH2:34][N:33]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)=[O:16])[CH2:4]3)[CH2:38][CH2:37]2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: Cc1nc2ccccc2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4c(C)nc5ccccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 69.8 %

Procedure:
The title compound was prepared from 60 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxy-benzyl ester (prepared above as Aldehyde 5), 50 mg of 1-1-piperidin-4-yl-2-methyl-1-H-benzoimidazole (from Step B) and 80 mg of sodium triacetoxyborohydride in 4 mL THF and 1 mL of DMF, using a procedure analogous to that described in Example 95, Step D to provide 61 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Br:18][C:19]1[CH:32]=[CH:31][C:22]2[NH:23][C:24]([C@@H:26]([NH2:30])[CH2:27][O:28][CH3:29])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Br:18][C:19]1[CH:32]=[CH:31][C:22]2[NH:23][C:24]([C@@H:26]([NH:30][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][O:28][CH3:29])=[N:25][C:21]=2[CH:20]=1
Reactant: COC[C@H](N)c1nc2cc(Br)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(C)c1)c1nc2cc(Br)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[C:18](=[O:25])[NH:17][N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:26]1(Br)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[C:18](=[O:25])[N:17]([CH:26]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: BrC1CCCCCC1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCCCCC3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1

Procedure:
Prepared from compound 4 and cycloheptylbromide as described for compound 8. Crystallized from petroleum ether (60-80° C.) M.p.111-112° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.FC(F)(F)C(O)=O.[H][H]>[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nnc2ccc(-c3cccc([N+](=O)[O-])c3)nn12
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc2ccc(-c3cccc(N)c3)nn12

Procedure:
A mixture of 5.1 g. of 3-methyl-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine (prepared as in Example 19), 60 ml. of trifluoroacetic acid and 0.9 g. of 10% palladium catalyst on carbon is shaken in a Parr hydrogenator under about 35 pounds of hydrogen pressure until hydrogen uptake is complete. The catalyst is filtered off and the reaction mixture is concentrated. The residue is dissolved in water and adjusted to pH 5 by addition of 5N NaOH. The insoluble material is filtered off and washed with water to obtain 6-(m-aminophenyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine, m.p. 193° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9]1([C:15]2([O:19][CH2:18]2)[CH2:16]Cl)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[OH:19][CH2:18][C:15]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2][CH2:16]1
Reactant: Oc1ccccc1O
Reactant: ClCC1(c2ccccc2)CO1
Product: OCC1(c2ccccc2)COc2ccccc2O1

Procedure:
Catechol and 2-phenyl epichlorohydrin were reacted to give the intermediate 2-hydroxymethyl-2-phenyl-1,4-benzodioxan (method (a) of Example 2) which was converted to the imidazoline compound by method (b) of Example 2. The free base was recrystallised from light petroleum (60°-80°); m.p. 114.5°-116°.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]([C:12]1[O:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:19][CH:18]=3)=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:2]2.ClC1C=C(C=CC=1)C(OO)=[O:33]>ClCCl>[NH3:1].[N:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[N:4]([C:10]([C:12]1[O:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH+:23]([O-:33])[C:24](=[O:27])[CH:25]=[CH2:26])=[CH:19][CH:18]=3)=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(=O)Nc1ccc(-c2ccc(C(=O)N3CCN4CCC3CC4)o2)cc1
Solvent: ClCCl
Product: C=CC(=O)[NH+]([O-])c1ccc(-c2ccc(C(=O)N3CCN4CCC3CC4)o2)cc1
Product: N
Reaction time: 15 h

Procedure:
A mixture of N-{4-[5-(1,4-Diaza-bicyclo[3.2.2]nonane-4-carbonyl)-furan-2-yl]-phenyl}-acrylamide (175 mg; 0.479 mmol), m-chloroperoxybenzoic acid (165 mg; 0.958 mmol) and dichloromethane (5 ml) was stirred at room-temperature for 15 hours. The crude mixture was evaporated. Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound. Yield 180 mg (99%). Mp. 162° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1B(O)O.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: OB(O)c1c(F)cccc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2c(F)cccc2F)nc1-c1ccc(C)cc1
Yield: 26.8 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), 2,6-difluorophenylboronic acid (142 mg; 0.901 mmol), tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (10-80%) in heptane to give 33 mg (16%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:12]2=[N:13][NH:14][C:15](=[O:20])[C:16]3[CH:17]=[CH:18][CH:19]=[C:10]([C:11]=32)[NH:9][CH:8]1[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.[C:29](O)(=O)C.[BH3-][C:34]#[N:35].[Na+]>C(#N)C>[CH3:29][N:35]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([CH:8]2[NH:9][C:10]3[C:11]4[C:12](=[N:13][NH:14][C:15](=[O:20])[C:16]=4[CH:17]=[CH:18][CH:19]=3)[CH:7]2[C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[CH:22][CH:23]=1)[CH3:34]
Reactant: [BH3-]C#N
Reactant: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(C=O)cc1
Reactant: CC(=O)O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2nccn2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
A mixture of 4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (80 mg, 0.22 mmol), acetic acid (60 uL) and 27% dimethylamine alcohol solution (2.5 mL, 15 mmol) in acetonitrile (7 mL) was stirred at room temperature for 4 h. Then the mixture was cooled to 0° C. NaBH3CN (36 mg, 0.67 mmol) was added. After the addition, the mixture was stirred at room temperature for 4 hr. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate and filtered. The filtrate was concentrated to give 8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (30 mg, yield 34%) as a white solid. 1H-NMR: (400 MHz, DMSO-d6) δ (ppm): 2.11 (s, 6H), 3.36 (s, 2H), 3.37 (s, 3H), 4.65 (d, J=10.4 Hz, 1H), 4.92 (d, J=10.4 Hz, 1H), 6.76 (s, 1H), 6.89 (s, 1H), 7.20 (d, J=7.6 Hz, 3H), 7.35 (d, J=8.0 Hz, 2H), 7.43 (d, J=6.8 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H); LC-MS (ESI) m/z: 401 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:27])[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#N)=[CH:14][CH:13]=2)=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2].[OH-:30].[K+].CCO.[OH2:35]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:27])[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]([OH:35])=[O:30])=[CH:14][CH:13]=2)=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(NCc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C)c1O
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1ccc(NCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Temperature: 150 °C
Yield: 52 %

Procedure:
To 3-({4-[(4-Acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-hydroxy-methyl)-benzonitrile (160 mg, 0.41 mmol) in EtOH/H2O (6:1, 2.1 mL) in a microwave tube is added powdered KOH (140 mg, 2.0 mmol). The tube is sealed, placed in a microwave reactor, and heated at 150° C. for 30 min. The reaction mixture is acidified to pH=7 and concentrated. The residue is purified by reverse phase HPLC using 90:10 to 20:80 (H2O/0.1% TFA)/CH3CN. Obtained is the title compound as a brownish solid (86 mg, 52%). LC-MS (m/e): 404 (M−1); 1H NMR (DMSO-d6) δ 13.16 (1H, s), 12.85 (1H, bs), 7.90 (1H, m), 7.73 (1H, m), 7.56 (1H, m), 7.32-7.45 (2H, m), 7.27 (2H, d), 7.20 (2H, d), 6.76 (1H, t), 6.00 (1H, d), 5.69 (1H, s), 4.38 (2H, d), 2.35 (3H, s), 1.93 (3H, s).
Reaction SMILES: O=[C:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:18]([O:28][CH3:29])[N:17]=3)[N:15]=[C:8]12)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:29][O:28][C:18]1[N:17]=[C:16]([C:14]2[N:15]=[C:8]3[CH:7]([C:5]4[S:45][C:2]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:3][N:4]=4)[CH2:12][CH2:11][CH2:10][N:9]3[N:13]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1nc(-c2nc3n(n2)CCCC3C(=O)NCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1nc(-c2nc3n(n2)CCCC3c2ncc(-c3ccccc3)s2)ccc1-n1cnc(C)c1
Yield: 10.6 %

Procedure:
2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (2-oxo-2-phenylethyl)amide obtained in Example 172 (26.6 mg) was dissolved in THF (1 mL). Lawesson reagent (45.6 mg) was added and the mixture was stirred with heating under reflux for 11 hours. The reaction solution was ice-cooled. Then, chloroform and a saturated sodium bicarbonate solution were added and the organic layer was separated. The resulting organic layer was dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the organic layer was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (2.8 mg). The compound was further purified by CHIRALCEL™ IB (2 cm×25 cm; mobile phase:hexane:ethanol=30:70) to obtain the title compound (1.5 mg, racemate). The property values of the compound are as follows.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[N:14]=[CH:15][C:16]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[O:21])=[N:17][CH:18]=1.O.NN>CCO.CN(C=O)C>[NH2:3][CH2:12][C:13]1[N:14]=[CH:15][C:16]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[O:21])=[N:17][CH:18]=1
Reactant: COc1ccc(C)cc1NC(=O)Nc1cnc(CN2C(=O)c3ccccc3C2=O)cn1
Agent: NN
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: COc1ccc(C)cc1NC(=O)Nc1cnc(CN)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a stirred solution of 1-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyrazin-2-yl]-3-(2-methoxy-5-methyl-phenyl)-urea (16 mg, 38 μmol) in 380 μL 95% EtOH and 100 μL DMF at room temperature in a capped reaction vial was added hydrazine monohydrate (3.8 μL, 76 μmol). After stirring overnight at room temperature, a white precipitate formed. The precipitate was filtered off, dried and triturated with EtOAc to remove phthalimide based impurities to provide the product as a white solid (7.9 mg, 72%). 1H-NMR (400 MHz, d6-DMSO) δ 9.54 (s, 1H), 8.80 (s, 1H), 8.46 (s, 1H), 8.02 (s, 1H), 6.93 (d, 1H), 6.79 (d, 1H), 4.51 (d, 2H), 4.39 (br s, 2H), 3.89 (s, 3H), 2.23 (s, 3H). LRLCMS (ESI, Positive) m/e 288.2 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:20][C:21](OCC)=[O:22].O>CN(C=O)C>[C:3]1([N:9]2[CH2:20][C:21](=[O:22])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]2=[O:18])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(Cc1ccccc1)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CN(c2ccccc2)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred slurry of 500 mg (12 mmol) of a 60% oil dispersion of sodium hydride (which had been washed with hexane) in 12 ml dry DMF under argon atmosphere was added 1.06 g (5.0 mmol) of N-phenyl-2-phenyl acetamide (IVa) in 5 mL dry DMF. Gas evolution had ceased after 30 minutes and 0.560 mL(5.0 mmol) of ethyl bromoacetate was added via syringe. The solution was stirred at 25° C. for 30 minutes, then warmed to 80° C. for 4 hours. The cooled solution was carefully poured into 200 mL H2O, washed with ether, filtered over celite and acidified to pH=2. The white precipitate was filtered, washed well with H2O and dried under high vacuum to give 1.04 g (4.0 mmol, 80% yield) of 1,3-diphenyl-2,4-pyrrolidinedione Ia, mp 285°-287° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][CH2:41][C:42]#[N:43])[CH:39]=2)O1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[N:37][N:38]([CH2:40][CH2:41][C:42]#[N:43])[CH:39]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C
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: C1COCCO1
Solvent: CO
Solvent: O
Product: CC1Cc2ccc(-c3cnn(CCC#N)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (15 mg, 0.036 mmol; Peak 1, Example 49, Step 7), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (13 mg, 0.054 mmol), tetrakis(triphenylphosphine)palladium(0) (2.1 mg, 0.0018 mmol), and sodium bicarbonate (9.0 mg, 0.11 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was diluted with methanol, purified with RP-HPLC (pH=10) to afford 12.1 mg of the desired product. LCMS (M+H)+: m/z=458.3.