Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27])[CH3:22].C(N(CC)CC)C>C(O)(=O)C>[CH2:21]([O:23][C:24]([CH2:25][CH2:26][N:27]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])=[O:28])[CH3:22]
Reactant: CCOC(=O)CCN
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOC(=O)CCn1c(C)ccc1CN1C(=O)c2ccccc2C1=O

Procedure:
3.9 g (0.015 mol) of 6-phthalimido-2,5-hexanedione, 3.1 g (0.02 mol) of β-alanine ethyl ester hydrochloride and 3 ml (0.02 mol) of triethylamine are stirred in 80 ml of glacial acetic acid at 50° C. for 8 hours and the mixture is worked up as in Example 27.
Reaction SMILES: CO[C:3]1[CH:30]=C[C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[N:31]1C=CC=CC=1C=O>>[N:31]1[CH:30]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1ccccn1
Product: O=C(NCCNCc1ccccn1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 2-pyridinecarboxaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.27 (1H, s) 8.46 (1H, ddd, J=4.81, 1.66, 0.76 Hz) 8.07 (1H, t, J=5.61 Hz) 8.01 (1H, d, J=5.37 Hz) 7.77 (1H, d, J=5.47 Hz) 7.68 (1H, td, J=7.68, 1.73 Hz) 7.47 (1H, d, J=5.42 Hz) 7.39 (1H, d, J=7.71 Hz) 7.29 (1H, d, J=2.64 Hz) 7.20 (1H, ddd, J=7.47, 4.91, 0.90 Hz) 6.80 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.49, 1.98 Hz) 3.78 (2H, s) 3.36 (2H, q, J=6.12 Hz) 2.68 (2H, t, J=6.83 Hz)
Reaction SMILES: [C:1]([S:5](/[N:7]=[CH:8]/[CH2:9][C:10]1([C:23](OC)=[O:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[C:27]1([Li])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC>[C:1]([S:5]([N:7]1[CH:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:9][C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[C:23]1=[O:24])=[O:6])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)C1(C/C=N/S(=O)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(c1ccccc1)N(S(=O)C(C)(C)C)C2=O
Temperature: 0 °C
Yield: 12.5 %

Procedure:
To a −78° C. solution of 1-tert-butyl 4-methyl 4-{(2E)-2-[(tert-butylsulfinyl)imino]ethyl}piperidine-1,4-dicarboxylate (358 mg, 0.921 mmol) in ether (10 mL) was added phenyllithium (1.8 M, 1.6 mL, 3.1 mmol). The reaction was warmed to 0° C. After 1 h the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with dichloromethane (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of 2 to 55% ethyl acetate:hexanes to give the title compound (50 mg). MS: m/z=435.2 (M+1).
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21](N)=[O:22])=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:25].C1(OC)C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:25])=[O:22])=[CH:18][CH:19]=3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1nnc2ccc(Oc3ccc(CC(N)=O)cc3)cn12
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)c1nnc2ccc(Oc3ccc(CC(=O)O)cc3)cn12

Procedure:
A solution of Example 23 step b (44 mg, 0.12 mmol), TFA (1 mL) and anisole (1 mL) in DCM (1 mL) was stirred at RT for 1 H, then evaporated in vacuo. The resulting residue was suspended in diethyl ether (3 mL), filtered and dried in vacuo to give the title compound (38 mg, quant.). LCMS (Method 5): Rt 3.65 min, m/z 312 [MH+].
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)#[N:2].[CH3:26][NH:27][NH2:28]>CCO>[NH2:2][C:1]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]3)[N:27]([CH3:26])[N:28]=1
Reactant: CNN
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3cccc(F)c3C#N)ccc21
Solvent: CCO
Product: Cn1nc(N)c2c(-c3ccc4c(c3)CCN4C(=O)OC(C)(C)C)cccc21
Temperature: 100 °C

Procedure:
To a suspension of 1,1-dimethylethyl 5-(2-cyano-3-fluorophenyl)-2,3-dihydro-1H-indole-1-carboxylate (1.60 g, 4.73 mmol) in 30 mL of EtOH was added 7 mL of methylhydrazine in one portion. The mixture was heated in an oil bath at 100° C. for 24 h. LCMS showed conversion complete. The mixture was cooled and concentrated in vacuo. The residue was partitioned between DCM (60 mL) and water (30 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo to give 1,1-dimethylethyl 5-(3-amino-1-methyl-1H-indazol-4-yl)-2,3-dihydro-1H-indole-1-carboxylate as a cream-colored foamy solid (1.70 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:16]3[CH2:21][N:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)OCC)C3)cc1

Procedure:
Method as described for example 34 using 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 14) and ethyl chloroformate as starting materials.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[C:31](C#N)=[CH:30][CH:29]=[CH:28][C:27]=2C#N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:36][OH:37].Cl.[CH3:39][OH:40].O>C1(C)C=CC=CC=1>[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[C:27]([CH:36]=[O:37])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:39]=[O:40])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CO
Reactant: N#Cc1cccc(C#N)c1CCCCCCCCCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cccc(C=O)c1CCCCCCCCCc1ccccc1

Procedure:
A solution of diisobutylaluminium hydride in toluene (3.1 ml, 4.6 mmol) was added dropwise to a stirred solution of 2-(9-phenylnonyl)-1,3-benzenedicarbonitrile (0.70 g, 2.1 mmol) in dry toluene (30 ml) under nitrogen, cooled in an ice bath. After one hour at room temperature methanol (1 ml) was added cautiously, followed by methanol:water (1:1, 1 ml) and 5M hydrochloric acid (15 ml). The mixture was extracted with diethyl ether (20 ml) and the extracts dried, filtered and evaporated to a yellow oil (0.8 g). Chromatography on flash silica eluting with dichloromethane gave 2-(9-phenylnonyl)-1,3benzenedicarboxaldehyde as a colourless oil.
Reaction SMILES: I[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1.O(C(C)(C)C)[Li].O>O1CCOCC1.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:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(I)o3)n2)c1
Reactant: c1ccc2ocnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]OC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4nc5ccccc5o4)o3)n2)c1
Temperature: 100 °C
Yield: 12.3 %

Procedure:
A sealed tube with a teflon screw cap was charged with a mixture of [6-(2-iodo-oxazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine (100 mg, 0.264 mmol), benzoxazole (31 mg, 0.264 mmol), Pd(PPh3)4 (15 mg, 0.013 mmol) and LiOtBu (42 mg, 0.529 mmol) in dry dioxane (5 ml) and heated to 100° C. for 24 h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 eluting with 30% EtOAc in cyclohexane to afford the title compound as a beige solid (12 mg, 12%). 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.14-8.11 (m, 2H), 7.99-7.88 (m, 3H), 7.83 (t, J=7.9 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.61-7.51 (m, 2H), 7.46 (d, J=7.3 Hz, 1H), 6.80 (d, J=5.0 Hz, 1H), 2.41 (s, 3H). (ESI+) m/z 370 (M+H)+. Retention time=2.88 mins (method 1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[NH:4][C:3]1=[O:32].[CH:33](I)([CH3:35])[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+]>CC(CC)=O>[CH:33]([N:4]1[C:5]2=[N:11][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:17][CH:18]=3)[C:9]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3]1=[O:32])([CH3:35])[CH3:34]
Reactant: CC(C)I
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccn4)cc3)c(Nc3ccccc3)c2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CC(C)n1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(-c4ccccn4)cc3)nc21
Reaction time: 1 h

Procedure:
Methylethylketone (1.2 mL) is added into a 0.5˜5 mL reaction vessel containing 5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (25 mg, 0.0589 mmol), isopropyl iodide (0.0707 mmol) and Cs2CO3 (0.0707 mmol). The sealed vessel is put onto a Biotage Microwave instrument and the microwave reaction is carried out at 140° C. for 1 hour. The obtained crude product is then purified by silica-gel flash chromatography to give pure product MS (ESI) m/z 467.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]([OH:9])=[O:8].[CH2:15](OC(OCC)OCC)C>>[CH3:13][O:12][C:10]1[C:6]2[C:7](=[O:9])[O:8][CH:15]=[N:14][C:5]=2[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Product: COc1cc(OC)c2c(=O)ocnc2c1
Temperature: 140 °C
Yield: 76.2 %

Procedure:
A mixture of 1.0 g (5.07 mmol) of 4,6-dimethoxy-anthranilic acid, as prepared in Example 3, and 15 ml of triethylorthoformate (90.2 mmol) was heated to 140° C. for 4 h. The volatiles were evaporated under reduced pressure to give 0.8 g of 5,7-dimethoxy-3,1-benzoxazine-4-one as a yellow solid (76% yield), which was used without any further purification.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[CH3:40]
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)s1
Reactant: Cc1ccc(N)cc1O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(C)c(O)c3)cc2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 34, 40 mg, 0.093 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (14 mg, 0.1137 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜2 mL of i-prOH affording the title compound in 36% yield (0.028 g, 0.0521 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(C(F)(F)F)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 18.4 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(trifluoromethyl)phenylboronic acid (19.7 mg, 0.1 mmol). The mixture was heated under microwave at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(3-(trifluoromethyl)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (4.31 mg, 18%). 1H-NMR (CDCl3): 1.95 (d, 1H), 2.66 (t, 1H), 3.16 (d, 3H), 5.97 (d, 1H), 6.96 (s, 1H), 7.06 (m, 2H), 7.20 (s, 1H), 7.38 (m, 3H), 7.44 (m, 3H), 7.53 (m, 1H), 7.62 (m, 1H), 7.70 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[C:14]3[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F:78][C:79]1[CH:80]=[C:81]([C:99]([CH3:103])([CH3:102])[C:100]#[N:101])[CH:82]=[C:83]2[C:88]=1[C:87](=[O:89])[N:86]([C:90]1[C:95]([CH:96]=[O:97])=[C:94](I)[CH:93]=[CH:92][N:91]=1)[CH:85]=[CH:84]2.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O>[F:78][C:79]1[CH:80]=[C:81]([C:99]([CH3:103])([CH3:102])[C:100]#[N:101])[CH:82]=[C:83]2[C:88]=1[C:87](=[O:89])[N:86]([C:90]1[C:95]([CH:96]=[O:97])=[C:94]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:20]=[C:14]5[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]5[N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[CH:93]=[CH:92][N:91]=1)[CH:85]=[CH:84]2
Reactant: CN1CCn2nc(Nc3cc(Cl)nn(C)c3=O)cc2C1
Reactant: CC(C)(C#N)c1cc(F)c2c(=O)n(-c3nccc(I)c3C=O)ccc2c1
Agent: [Pd+2]
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1COCCO1
Solvent: O
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ccc6cc(C(C)(C)C#N)cc(F)c6c5=O)c4C=O)nn(C)c3=O)cc2C1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 77.9 %

Procedure:
6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one (511 mg, 1.73 mmol, 1 equiv.), bis(pinacolato)diboron (485 mg, 1.91 mmol, 1.1 equiv.) and potassium acetate (511 mg, 5.2 mmol, Eq: 3) were suspended in dioxane (25 ml). The reaction mixture was degassed under argon. X-PHOS (124 mg, 260 μmol, Eq: 0.15) and palladium(II) acetate (19.5 mg, 86.7 μmol, 0.05 equiv.) were added and the reaction mixture was stirred at 100° C. (external temperature) for 40 min. under an argon atmosphere until reaction was complete. Bath temperature was reduced to 80° C. Flask was raised out of the heating bath, but continued stirring. 2-(8-fluoro-2-(3-formyl-4-iodopyridin-2-yl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile (800 mg, 1.73 mmol, 1.0 equiv.) and potassium carbonate (719 mg, 5.2 mmol, 3 equiv.) were added, followed by 2.5 mL H2O. Tricyclohexylphosphine (48.6 mg, 173 μmol, 0.1 equiv.) and bis(dibenzylideneacetone)palladium (49.9 mg, 86.7 μmol, 0.05 equiv.) were added. The reaction mixture was heated with vigorous stirring at 80° C. and stirred for 1.5 h. The reaction mixture was poured onto water. Some brine was added to break up the emulsion and the mixture was extracted with DCM (4 times). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The resulting solid was triturated by adding 10 mL EtOAc followed by 75 mL ether. The solid was collected by filtration and washed several times with ether to give a pale green/grey solid (800 mg). (M+H)+=594 m/e. The product was used as is in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][OH:26])[S:23][CH:24]=1)=[CH:16][CH:15]=3.I[CH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][O:26][CH3:33])[S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Reactant: CI
Product: COCc1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cs1

Procedure:
The process is carried out as in Example 10 above, with the compound from Example 9, 3-(2,4-dichlorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodomethane
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]1[C:20]([Cl:21])=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:10])=[C:7]([OH:22])[CH:6]=1.Cl[CH2:24][C:25]#[N:26].[Br-].[Na+]>CN(C=O)C.C(Cl)Cl.O>[NH2:4][C:5]1[C:20]([Cl:21])=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[O:10])=[C:7]([O:22][CH2:24][C:25]#[N:26])[CH:6]=1
Reactant: N#CCCl
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC#N
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
To a stirred suspension of sodium hydride (420 mg of 60%, 10.5 mmoles, washed with n-pentane) in 10 ml DMF was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.612 g, 5 mmoles) and the mixture stirred for 20 minutes, followed by cooling (ice bath) and addition of chloroacetonitrile (418 mg, 5.5 mmoles) and sodium bromide (100 mg). The mixture was stirred in the cold for 1 hour and at ambient temperature for 16 hours, followed by pouring into a mixture of water and ice, and filtration of the resulting solid. The product was dissolved in methylene chloride and filtered over alumina, followed by concentration in vacuo to give crude product. This was recrystallized from methanol to give 930 mg (57%) of the title compound as white crystalline solid mp 188°-189°. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ 8.1 (s, 1H); 7.78 (bs, 1 H); 6.44 (s, 1H); 4.84 (s, 2H); 4.60 (s, 2H); 3.43 (m, 2H); 2.59 (m, 6H); 1.02 (t, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]2[O:7][C:8]([CH3:31])([CH3:30])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:28])[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:13][C:12]3=[O:29])[C:5]=2[CH:4]=1)#[N:2].[O:34]([C:41](Cl)=[S:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])O.[Na+]>C(#N)C.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:33]=[CH:32][C:6]2[O:7][C:8]([CH3:31])([CH3:30])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([O:28][C:41]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[S:42])[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:27])[CH3:25])([CH3:23])[CH3:22])=[CH:13][C:12]3=[O:29])[C:5]=2[CH:4]=1)#[N:2]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CC1(C)C=C(n2ccc(C(O)CCO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C#N)ccc2O1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)C=C(n2ccc(C(CCO[Si](C)(C)C(C)(C)C)OC(=S)Oc3ccccc3)cc2=O)c2cc(C#N)ccc2O1

Procedure:
In 30 ml of anhydrous acetonitrile, is dissolved 1.46 g of 6-cyano-2,2-dimethyl-4-{2-oxo-4-(1-hydroxy-3-t-butyldimethylsilyloxypropyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 38. Then, 0.73 g of 4-dimethylaminopyridine and 0.79 ml of phenoxythiocarbonyl chloride are added at room temperature, and reacted at that temperature for 6 hours. After stopping the reaction by adding 0.1M aqueous solution of sodium hydrogen carbonate, the reaction mixture is extracted with ether. The organic layer is washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/2 mixture of ethyl acetate/n-hexane as a developing solvent. Thus, 1.20 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-phenoxythiocarbonyloxy-3-t-butyldimethylsilyloxypropyl)-1-pyridinyl}-2H-benzo[ b]pyran is obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][C:5]#[CH:6].Cl[CH2:9][C:10]([N:12]1[CH2:31][CH2:30][C:15]2[N:16]=[C:17]([NH:20][CH:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)[N:18]=[CH:19][C:14]=2[CH2:13]1)=[O:11].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:3]([O:7][CH2:9][C:10]([N:12]1[CH2:31][CH2:30][C:15]2[N:16]=[C:17]([NH:20][CH:21]3[CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:29]3)[N:18]=[CH:19][C:14]=2[CH2:13]1)=[O:11])[CH2:4][C:5]#[CH:6]
Reactant: O=C(CCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: C#CCCO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCOCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
To sodium hydride (60 wt % in mineral oil, 1.58 g, 39.6 mmol) in tetrahydrofuran (50 mL) at 23° C., add 3-butyn-1-ol (7.93 g, 8.59 mL, 113.2 mmol) dropwise, then stir at 23° C. for 20 minutes. Add this solution to 2-chloro-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]ethanone (9.70 g, 28.3 mmol) in tetrahydrofuran (150 mL) at 23° C. and stir for one hour. Pour the reaction mixture into 50% saturated aqueous sodium bicarbonate solution. Separate the organic layer and further extract the aqueous layer with ethyl ether (×2) and ethyl acetate (×2). Combine the organic extracts and wash with brine, then dry over anhydrous sodium sulfate, filter, and concentrate. Purify the resulting crude product by silica gel column chromatography (gradient elution: 20% ethyl acetate in hexanes to 100% ethyl acetate) to give the title compound (8.16 g, 77%). MS (m/z): 377 (M+1).