Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.O[CH2:11][C:12]([CH3:24])([CH3:23])[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH2:16]([O:15][C:13]([C:12]([CH3:24])([CH3:23])[CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(CO)C(=O)OCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(COc1ccc(C=O)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (2.7 g), benzyl hydroxypivalate (4.7 g) and triphenylphosphine (6.4 g) in tetrahydrofuran (22 mL) was added diethyl azodicarboxylate (40% toluene solution, 11 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-4/1) to give the title compound (0.97 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]Cl)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:11]([O:14][CH2:15][C:16]1[N:17]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=1)(=[O:13])[CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(#N)C>[C:11]([O:14][CH2:15][C:16]1[N:17]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:18]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=1)(=[O:13])[CH3:12]
Reactant: ClSc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)OCc1nc(C(C)C)cn1Cc1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
To a solution of the compound (3) (0.97 g, 4.5 mmol) in toluene (1.88 g) was added dropwise a solution of the compound (10a) (0.87 g, 3.2 mmol) in acetonitrile (4 ml) under ice-cooling for 30 minutes. A solution of triethylamine (0.46 g, 4.5 mmol) in acetonitrile (0.5 ml) was added dropwise thereto for 15 minutes, and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The extract was washed with water, concentrated under reduced pressure and purified by column chromatography on silica gel (elution ethyl acetate) to yield the objective (11) (1.17 g) as a crystal. Yield 82%. Mp 133–135° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH3:9].[F:10][C:11]([F:26])([F:25])[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[C:15](Cl)=[O:16]>>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:9])[C:15](=[O:16])[C:14]1[CH:13]=[C:12]([C:11]([F:26])([F:25])[F:10])[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1I
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I

Procedure:
The title compound was prepared in analogy to example 25, intermediate a, from (4-iodo-pyridin-3-yl)-methyl-amine and 3,5-bis-trifluoromethyl-benzoyl chloride (CAS RN 785-56-8). Pale yellow liquid (15%). MS (ESI): m/z=475 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:38]([OH:40])=[O:39])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]3[C:30]4[C:29](=[O:31])[CH2:28][C:27]([CH3:33])([CH3:32])[CH2:26][C:25]=4[O:24][C:23]4[CH2:22][C:21]([CH3:35])([CH3:34])[CH2:20][C:19](=[O:36])[C:18]3=4)[C:10]=2[CH3:37])=[CH:7][CH:8]=1)#[CH:2].[H][H].ClCCl>CO.[C].[Pd]>[CH2:1]([C:3]1[C:4]([C:38]([OH:40])=[O:39])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]3[C:30]4[C:29](=[O:31])[CH2:28][C:27]([CH3:32])([CH3:33])[CH2:26][C:25]=4[O:24][C:23]4[CH2:22][C:21]([CH3:34])([CH3:35])[CH2:20][C:19](=[O:36])[C:18]3=4)[C:10]=2[CH3:37])=[CH:7][CH:8]=1)[CH3:2]
Reactant: C#Cc1ccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)nc1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)nc1C(=O)O
Yield: 36.1 %

Procedure:
A suspension of the 3-ethynyl-6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylic acid produced in Example 12-3 (100 mg, 0.19 mmol) and 10% palladium carbon (wet) (100 mg) in methanol (2 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at the same temperature as above under a hydrogen atmosphere for 2.5 hours. Thereafter, a solid was removed from the reaction solution by filtration, and the solvent was then distilled away from the filtrate thus obtained under reduced pressure. The residue thus obtained was purified by silica gel thin-layer chromatography (methanol:dichloromethane=1:10, v/v) to obtain the title compound (37.3 mg, yield: 37%).
Reaction SMILES: [NH:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:13](#[N:17])[CH2:14][C:15]#[N:16]>C(O)C.N1CCCCC1>[C:15]([C:14]([C:13]#[N:17])=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)#[N:16]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)Nc1ccc(C=C(C#N)C#N)cc1

Procedure:
32.6 g (0.2 mol) of 4-acetaminobenzaldehyde and 13.74 g (0.208 mol) of malononitrile are initially charged in 140 ml of ethanol, and 24 drops of piperidine are added. The mixture is stirred at reflux for 30 min. After cooling, the crystals are filtered off with suction and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CON)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Product: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Yield: 85 %

Procedure:
The same method as employed in the preparation of Intermediate 2, but starting from (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (Intermediate 1) and 1-[(aminooxy)methyl]-4-methoxybenzene (intermediate 6), gave the title compound as a gum in a 85% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:5].[CH2:24]([N:26]([CH2:38][CH3:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>O>[CH2:36]([N:33]([CH2:34][CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH2:38][CH3:39])[CH2:24][CH3:25])[CH:32]=[CH:31][C:30]=1[C:4]1([C:3]2[CH:15]=[CH:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:18][C:2]=2[CH3:1])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:5]1)[CH3:37]
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c(C)c1
Temperature: 40 °C

Procedure:
A mixture of 2-(2-methyl-4-(diethylamino)benzoyl)-benzoic acid (12.48 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (10.56 g.) and acetic anhydride (12 ml.) was warmed (at 40±8° C.) during one hour, diluted with water (50 ml., then 100 ml.), adjusted to pH 4.6 and filtered. The filtrate was clarified with water and adjusted to pH 5.5. Recrystallization of the resulting product (m.p. 134°-140° C.) from methanol afforded 3-(2,4-bis(diethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)phthalide (I: X= Y4 = (CH3CH2)2N, Y2 = CH3, Z4 = Z5 = Z6 = Z7 = H) (m.p. 149°- 151° C.).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:27][CH2:28][CH3:29]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:27][CH2:28][CH3:29])[CH2:18]1
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(CCC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and 1-iodopropane. LCMS (System A): tRET=0.69 min; MH+ 377
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:13]3[CH2:18][CH2:17][CH:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:15][CH2:14]3)=[CH:8]C=2CO)[S:4][C:3]=1[C:27]([NH2:29])=[O:28].[C-:30]#N.[K+].[C:33]([OH:36])(=[O:35])[CH3:34]>CO.O=[Mn]=O>[CH3:30][O:35][C:33]([C:34]1[C:10]2[C:2]([NH2:1])=[C:3]([C:27](=[O:28])[NH2:29])[S:4][C:5]=2[N:6]=[C:7]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21])[CH2:15][CH2:14]2)[CH:8]=1)=[O:36]
Reactant: CC(=O)O
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2cc(CO)c3c(N)c(C(N)=O)sc3n2)CC1
Agent: O=[Mn]=O
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)nc2sc(C(N)=O)c(N)c12
Reaction time: 48 h
Yield: 60 %

Procedure:
A mixture of 400 mg of the above amide, 298 mg KCN, 1.59 g MnO2 and 157 microL acetic acid was suspended in 16 mL MeOH and the reaction was capped and stirred 2 days. The reaction mixture was filtered through diatomaceous earth, concentrated, and flash-chromatographed eluting with 5% MeOH/CH2Cl2 to provide 254 mg (60%) 3-amino-6-[4-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-2-carbamoyl-thieno[2,3-b]pyridine-4-carboxylic acid methyl ester as determined by NMR(DMDO). Further elution with 25% MeOH/CH2Cl2/1% HOAc brought down 151 mg (36%) of the corresponding carboxylic acid as determined by NMR(DMDO).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCCN1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCCC2=O)cc1Cl
Temperature: 100 °C

Procedure:
A mixture of 500 mg of 2-chloro-4-florobenzonitrile, 821 mg of 2-pyrrolidinone and 3 g of cesium carbonate in 5 mL of DMF was heated to 100° C. in a sealed microwave reactor for 15 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (20-80% ethyl acetate/hexane) to afford 2-chloro-4-(2-oxopyrrolidin-1-yl)benzonitrile. 890 mg of 2-chloro-4-(2-oxopyrrolidin-1-yl)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2-oxopyrrolidin-1-yl)benzoic acid. 80 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-oxopyrrolidin-1-yl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopyrrolidin-1-yl)benzamide. MS (Q1) 426.2 (M)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[S:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[CH2:50][NH2:51].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:51][CH2:50][C:46]2[S:45][CH:49]=[CH:48][CH:47]=2)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:15]2[CH2:20][NH:19][CH2:18][C@@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NCc1cccs1
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CNC[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCc2cccs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
To a solution of 1-tert-butyl 3-methyl (3R*,5S*)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate (51.1 mg) and diisopropylethylamine (38 mg) in DMF (0.5 ml) was added a solution of 1-thiophen-2-ylmethanamine (23 mg) in DMF (0.5 ml) and the mixture was stirred at 80° C. overnight. 2% Aqueous sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate, and the extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower. The residue was dissolved in trifluoroacetic acid/acetonitrile solution (20% (V/V), 1.0 ml), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated by a nitrogen gas blower. The residue was neutralized with triethylamine (1 ml), and saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with ethyl acetate, and the extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower to give the object compound (3.1 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.[CH3:33][C:34]1[N:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](O)=[O:37].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][C:36]([C:35]2[C:34]([CH3:33])=[N:42][CH:41]=[CH:40][CH:39]=2)=[O:37])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]2[CH3:20]
Reactant: Cc1ncccc1C(=O)O
Reactant: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1NCc1c(-c2ccc(OC(=O)c3cccnc3C)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 6-(4-hydroxy-2-methoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 25.0 mg, mmol), 2-methylnicotinoic acid (8.0 mg, 0.058 mmol), N,N-diisopropylethylamine (20.2 μL, 0.116 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (24.3 mg, mmol) was dissolved in anhydrous N,N-dimethylformamide (0.5 mL), and then the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (70 mL). The mixture was washed with water (70 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (20.7 mg) as a colorless solid. (Yield 65%)
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:32]([C:36]#[C:37][Si](C(C)C)(C(C)C)C(C)C)=[CH:33][CH:34]=[N:35][C:11]2=3)(=O)=O)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:36]([C:32]1[C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[C:15]([C:19]4[CH:20]=[CH:21][C:22]([N:25]5[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]5)=[CH:23][CH:24]=4)[CH:14]=3)[NH:10][C:11]=2[N:35]=[CH:34][CH:33]=1)#[CH:37]
Reactant: CC(C)[Si](C#Cc1ccnc2c1c1cc(-c3ccc(N4CCN(C)CC4)cc3)ccc1n2S(=O)(=O)c1ccccc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccnc2[nH]c3ccc(-c4ccc(N5CCN(C)CC5)cc4)cc3c12
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 41 %

Procedure:
The precursor used in Example 43, 9-benzenesulfonyl-6-(4-(4-methylpiperazin-1-yl)phenyl)-4-((triisopropylsilyl)ethynyl)-9H-pyrido[2,3-b]indole, which was obtained in a similar fashion as the procedure of Example 37, was deprotected from both the benzenesufonyl and triisopropylsilyl group using the following procedure. Under an inert atmosphere, to a solution of 9-benzenesulfonyl-6-(4-(4-methylpiperazin-1-yl)phenyl)-4-((triisopropylsilyl)ethynyl)-9H-pyrido[2,3-b]indole (73.8 mg, 0.111 mmol) in anhydrous THF (2.8 mL, 0.05M), a solution of TBAF (1M in THF, 3 eq, 330 μL) was added dropwise. The reaction was stirred at 70° C. for 2.5 h. After cooling to R.T, the mixture was then quenched cautiously with water and brine. The aqueous layer was extracted with DCM (3×40 mL) The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was first purified by silica gel flash chromatography (DCM/MeOH 95:5 to 94:6) to afford the desired product contaminated by TBAF. A pale yellow solid was obtained in 41% yield after a double trituration of the previous mixture in MeOH and then in DCM followed by filtration. 1H NMR (300 MHz, DMSO) δ 12.07 (s, 1H), 8.59 (d, J=1.1 Hz, 1H), 8.42 (d, J=5.0 Hz, 1H), 7.76 (dd, J=8.5, 1.7 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.28 (d, J=5.0 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 5.09 (s, 1H), 3.25-3.09 (m, 8H), 2.24 (s, 3H); 13C NMR (101 MHz, DMSO) δ 152.29 (C), 149.93 (C), 145.94 (CH), 138.04 (C), 132.39 (C), 131.36 (C), 127.13 (CH), 126.07 (CH), 122.20 (C), 120.33 (C), 118.66 (CH), 117.79 (CH), 115.81 (CH), 114.71 (C), 111.80 (CH), 89.04 (C), 80.61 (CH), 54.55 (2CH2), 47.96 (2CH2), 45.75 (NCH3); HRMS calcd for C24H23N4 [M+H]+ 367.1917 found 367.1914.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[C:11](Br)[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:20](=[O:23])([O-])[O-].[Na+].[Na+].[CH2:26]1[CH2:30]O[CH2:28][CH2:27]1>C(OCC)(=O)C.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>[CH3:5][N:4]1[C@H:3]2[C@@:26]([CH3:30])([C:26]3[CH:30]=[CH:14][C:6]([C:11]4[C:10]5[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=5)[N:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:12]=4)=[CH:7][C:27]=3[CH2:28][CH2:2]2)[CH2:27][CH2:28][C:20]1=[O:23]
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1cc(Br)c2cccc(C(F)(F)F)c2n1
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc(C(F)(F)F)nc5c(C(F)(F)F)cccc45)cc3CC[C@@H]12
Yield: 48 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a-,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2,8-bis(trifluoromethyl)-4-bromoquinoline (224 mg, 0.65 mmol), 0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 153 mg (48%) of the title compound as an amorphous foam. mp 100°-106°. FDMS: m/e=492. α[D]589 =+51.86 (c=0.47, chloroform).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(O[CH:16]([C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34])[C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=1)=O)(C)(C)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42][CH:16]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]=2)=[CH:38][CH:37]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cn1c(C(OC(=O)OC(C)(C)C)c2cc(F)ccc2F)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cn1c(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
Trifluoroacetic acid (2.0 ml) was added to the 2-[(t-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole (204 mg, 0.545 mmol) obtained in Referential Example 13. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in thionyl chloride (1.0 ml). One drop of dimethylformamide was added to the resulting solution. The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue and the resulting mixture was concentrated further under reduced pressure. The residue was dissolved in dimethylformamide (5.0 ml). After addition of 4-chlorobenzenethiol (118 mg, 0.82 mmol) and potassium carbonate (451 mg, 3.27 mmol), the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was then allowed to stand at room temperature and ethyl acetate (60 ml) was added thereto. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 5:1) to give the title compound (195 mg, 89%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[N:19]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:26][CH2:25][CH2:24][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: NCCN1CCCC1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NCCN4CCCC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.8 mmol) in 2-propanol (40 mL) was added 2-(pyrrolidin-1-yl)ethanamine (226 mg, 2.0 mmol) followed by triethylamine (200 mg, 2.0 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford [3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-pyrrolidin-1-yl-ethyl)-amine. (Yield 500 mg, 78.1%).