Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[O:9]=[C:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH:8]1[NH:4][C:3](=[O:10])[CH2:2][CH2:1]1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C1CCC2CCC(=O)N12
Solvent: ClCCl
Product: O=C(CCC1CCC(=O)N1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a solution of tetrahydro-pyrrolizine-3,5-dione (5 g, 36 mmol) in CH2Cl2 (320 mL) at 0° C. was added benzyl magnesium chloride (1M solution in THF, 39 mL, 39 mmol) dropwise. The solution was stirred at 0° C. for 3 h and was quenched with saturated aqueous ammonium chloride. After warming to room temperature, the aqueous solution was extracted with CH2Cl2 (3×). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2) to yield 5.9021 g of 5-(3-oxo-4-phenyl-butyl)-pyrrolidin-2-one. 1H NMR (CDCl3) δ 87.35-7.18 (m, 5H), 3.69 (s, 2H), 3.56 (m, 1H), 2.50 (t, 2H), 2.27 (m, 2H), 2.15 (m, 1H), 1.73 (m, 2H), 1.61 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(F)cc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 548.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][CH:15]=O)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:2].Cl>C1COCC1.CO>[CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccccc2NC=O)c(OC)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccccc2NC)c(OC)c1
Temperature: 0 °C
Yield: 122.1 %

Procedure:
To a solution of N-[2-(4-ethyl-2-methoxyphenoxy)phenyl]formamide (0.21 mmol; 72 mg), under argon, in dry THF was added at 0° C., borane dimethylsulfide complex (0.51 mmol, 49 μL). The reaction was stirred at reflux for 3 h 30. After cooling to 0° C., the mixture was diluted with 1 mL of dry methanol and stirred 1 hour. HCl (4M in dioxane) was added at 0° C. until pH 2, then the mixture was refluxed 1 hour. After cooling to room temperature, the reaction was diluted with 5 mL of methanol and concentrated in vacuo. The crude was treated with 5 mL of NaOH (1N), until pH 12, and extracted with ethyl acetate (3*2 mL). Combined organic phases were dried over Na2SO4 and concentrated in vacuo to yield the title compound (66 mg, quantitative) as a red oil used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[O:7])=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:9]([F:15])=[CH:10][CH:11]=[CH:12][C:13]=2[F:14])=[O:7])=[CH:16][CH:17]=1
Reactant: Cc1ccc(C(=O)c2c(F)cccc2F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)c1c(F)cccc1F
Yield: 55 %

Procedure:
A mixture of 233 mg (1 mmol) of 4-methyl-2′,6′-difluorobenzophenone, 178 mg (1 mmol) of recrystallized N-bromosuccinimide, 17 mg benzoyl peroxide, and 3 mL CCl4 were refluxed under argon for 3 hours. The hot solution was filtered through a glass sintered filter and rinsed with 20 mL of hot CCl4 until the crystals became colorless. The crystals were washed with 6 mL of cold CCl4 and the solution was concentrated under vacuum. The crude product was purified by column chromatography on a silica gel flash column (13 cm×55 mm) eluted with ethyl acetate/hexane (15:85) and then concentrated under vacuum. The product was allowed to dry under high vacuum overnight. The resultant yield was 55%. Rf=0.3 (ethyl Acetate/hexane; 15:85). 1H-NMR: δ 7.84 (d, 2H, aromatic), 7.50 (d, 2H, aromatic), 7.46 (t, 1H, aromatic), 7.01 (m, 2H, aromatic), 4.51 (s, 2H). 13C-NMR (CDCl3): δ 188.1 (carbonyl); 160.8, 158.8, 143.9, 136.6, 132.0, 130.0, 129.4, 111.9 (aromatic), 31.8 (alkyl bromide).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([N:33]2[C:38](=[O:39])[NH:37][C:36](=[O:40])[C:35]([C:41]#[N:42])=[N:34]2)[CH:30]=[C:29]([Cl:43])[C:3]=1[O:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:14])[N:7]([CH2:15][O:16][P:17](=[O:28])([O:23]C(C)(C)C)[O:18]C(C)(C)C)[N:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:32]=[C:31]([N:33]2[C:38](=[O:39])[NH:37][C:36](=[O:40])[C:35]([C:41]#[N:42])=[N:34]2)[CH:30]=[C:29]([Cl:43])[C:3]=1[O:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:12])[CH3:13])[C:8](=[O:14])[N:7]([CH2:15][O:16][P:17](=[O:18])([OH:28])[OH:23])[N:6]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COP(=O)(O)O)c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
A solution of phosphoric acid di-tert-butyl ester 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester (44.0 mg, 0.067 mmol) in methylene chloride (1.0 mL, 0.067M) at 25° C. was treated with trifluoroacetic acid (0.2 mL). The reaction mixture was stirred at 25° C. for 20 min. At this time, the reaction mixture was concentrated in vacuo, azeotropically dried with benzene and concentrated from absolute ethanol followed by lyophilization from acetonitrile and water to afford phosphoric acid mono-{3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl}ester (31.4 mg, 86%) an off-white solid. Present in the product was 0.95 moles of residual ammonium from the ammonium acetate used in the supercritical fluid purification of the precursor. ES+-HRMS m/e calcd for C18H15N6O8PCl2 (M+Na+) 566.9958, found 566.9962.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:12])=[CH:5][C:6]=1[CH2:7][CH2:8][C:9]([OH:11])=O.[Li][CH3:14]>CCOCC>[Cl:1][C:2]1[S:3][C:4]([Cl:12])=[CH:5][C:6]=1[CH2:7][CH2:8][C:9](=[O:11])[CH3:14]
Reactant: [Li]C
Reactant: O=C(O)CCc1cc(Cl)sc1Cl
Solvent: CCOCC
Product: CC(=O)CCc1cc(Cl)sc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-(2,5-dichloro-3-thienyl)propanoic acid (0.225 g) in Et2O (5 mL) was added 1.05M MeLi in Et2O (2.0 mL) at 0° C. under nitrogen. After stirring at 0° C. for 30 minutes, the mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched by the addition of phosphate buffer solution (pH=7), and the resulting mixture was extracted with Et2O (30 mL). The organic layer was washed with water, brine, dried over MgSO4, and concentrated in vacuo. Chromatographic purification of the residue eluting with hexane-ethyl acetate (4:1) to give the title compound (0.173 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=2[C:18]2([CH:23]=[CH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.S(Cl)([Cl:27])=O>CN(C=O)C.C(Cl)Cl>[Cl:27][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=2)=[C:11]([C:18]2([CH:23]=[CH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: C=CC1(c2cc(CO)ccc2-c2cc(OC)ncc2F)CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC1(c2cc(CCl)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-vinylcyclopentyl)phenyl)methanol (47.0 mg, 144 μmol) in DMF (0.01 mL) and DCM (4.0 mL) was slowly added thionyl chloride (14.7 μL, 201 μmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed, and the product thus obtained was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 8.01-8.11 (1H, m), 7.98 (1H, m), 7.47 (1H, s), 6.94 (1H, d, J=7.8 Hz), 6.69-6.82 (1H, m), 5.80 (1H, dd, J=17.2, 10.6 Hz), 4.89 (1H, d, J=10.2 Hz), 4.52-4.69 (3H, m), 3.89 (3H, s), 1.68-1.84 (4H, m), 1.49-1.67 (4H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=1.[NH2:15][CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][CH2:16][NH:15][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH:8]=3)=[O:14])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: O=C(O)C1=NN=C(c2ccccn2)C1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(-c4ccccn4)n[nH]3)n2)cc1Cl
Yield: 22.7 %

Procedure:
The title compound was prepared using the method of Example 53 but starting from 5-pyridin-2-yl-4H-pyrazole-3-carboxylic acid (38 mg; 0.20 mmol) and 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (50 mg; 0.20 mmol). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% MeOH/DCM) to obtain 19 mg (23%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.70-3.74 (m, 2H), 4.38 (t, 2H), 6.96 (d, 1H), 7.23-7.40 (m, 2H), 7.82-8.02 (m, 5H), 8.09 (s, 1H), 8.48, (broad s, 1H), 8.62 (d, 1H), 13.89 (broad s, 1H).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:24]=[C:23]([CH:25]2[CH2:27][CH2:26]2)[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=1>>[CH:25]1([C:23]2[CH:24]=[C:19]([C:18]([F:17])([F:37])[F:38])[CH:20]=[CH:21][C:22]=2[C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)[CH2:26][CH2:27]1
Reactant: CCC(=O)N[C@@H]1CCCc2c(Br)cncc21
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2C2CC2)OC1(C)C
Product: CCC(=O)N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)cc3C3CC3)cncc21
Yield: 84 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (R)—N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-16) was reacted with 4-trifluoromethyl-6-cyclopropylphenylboronic acid pinacol ester acid to give the title compound as colorless oil in 84% yield. MS: 389.2 (M+H+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][NH:29][CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:15])[F:14])[C:5]=12.[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)CC)C>C(Cl)Cl>[C:33]([N:29]1[CH2:30][CH:27]([C:20]2[C:21]([CH3:26])=[C:22]([CH:25]=[C:18]([CH:16]([N:10]3[C:6]4=[N:7][CH:8]=[N:9][C:4]([NH2:3])=[C:5]4[C:12]([CH:13]([F:14])[F:15])=[N:11]3)[CH3:17])[C:19]=2[O:31][CH3:32])[C:23]#[N:24])[CH2:28]1)(=[O:35])[CH3:34]
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitrile dihydrochloride (21 mg, 0.043 mmol, racemic intermediate from Example 129, Step 2), acetyl chloride (3.4 μL, 0.048 mmol), and triethylamine (18 μL, 0.13 mmol) in methylene chloride (0.3 mL) was stirred overnight at room temperature. The solvents were evaporated and the crude material was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C22H24F2N7O2 (M+H)+: m/z=456.2; Found: 456.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:30]([NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccccc4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) in THF (3 mL) was added phenyl isocyanate (33 uL, 0.3 mmol) and the solution stirred at room temperature overnight. The reaction was concentrated in vacuo, diluted with EtOAc, and filtered to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-phenylurea (63 mg, 0.15 mmol, 50%). 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 7.61-7.56 (m, 2H), 7.48-7.35 (m, 4H), 7.32-7.21 (m, 3H), 7.02-7.89 (m, 2H), 3.99 (s, 6H); LC-MS (ESI) m/z 417 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CS(C)=O>[CH2:13]([C:8]1[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]3[N:33]=[N:34][NH:35][N:2]=3)[CH:4]=2)[N:9]=1)[CH:14]([CH3:15])[CH3:16]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(C#N)cc23)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4nn[nH]n4)cc23)cc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 57.4 %

Procedure:
A mixture of tert-butyl [6-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (0.60 g, 1.4 mmol), sodium azide (0.18 g, 2.8 mmol), ammonium chloride (0.30 g, 3.6 mmol) and dimethyl sulfoxide (810 ml) was stirred at 70° C. for 2 days. The reaction mixture was partitioned between ethyl acetate and 0.1N hydrochloric acid. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from n-hexane-ethyl acetate to give tert-butyl [2-isobutyl-4-(4-methylphenyl)-6-(2H-tetrazol-5-yl)quinolin-3-yl]methylcarbamate (0.38 g, yield 57%) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]2[N:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][C:24]=3[O:33][CH3:34])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].N1C=CC=CC=1.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([N:11]1[C@@H:10]([CH3:12])[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:21])[N:7]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][C:24]=2[O:33][CH3:34])[C:6]2[CH:35]=[CH:36][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a 0° C. solution of tert-butyl(3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (448 mg, 921 μmol) in CH2Cl2 (9.21 ml) was added pyridine (375 μl, 4.6 mmol), followed by acetyl chloride (78.8 μl, 1.1 mmol), dropwise. The reaction was stirred at 0° C. for 1 h, then allowed to warm to rt and stirred for an additional 20 h, then quenched by the addition of H2O and extracted with CH2Cl2. The combined organic layers were washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (316 mg, 65%) as a white solid. MS m/z 551 (MNa)+.
Reaction SMILES: [C:1]([CH:4]([CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:5]([NH:7][CH:8]([C:11]1[C:12](=[O:28])[NH:13][C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[N:15][N:16]=1)[CH2:9][CH3:10])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:4]([C:5]1[N:16]2[C:11]([C:12](=[O:28])[NH:13][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)=[N:15]2)=[C:8]([CH2:9][CH3:10])[N:7]=1)[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:3])[CH3:2]
Reactant: CCC(NC(=O)C(CCCc1ccccc1)C(C)=O)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C(CCCc2ccccc2)C(C)=O)n2nc(Cc3ccc(OC)c(OC)c3)[nH]c(=O)c12

Procedure:
Analogously to Example 1, 530 mg (1.04 mmol) of 2-acetyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-5-phenylpentanamide and 610 mg (4.00 mmol) of phosphorus oxychloride are reacted to give 7-(1-acetyl-4-phenylbutyl)-2-(3,4-dimethoxybenzyl)-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][N:14]=2)=[CH:9][CH:8]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>O>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:35][C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[N:14]=2)=[CH:9][CH:8]=1
Reactant: CN(C)CCCOc1ccc(-c2n[nH]c3ncccc23)cc1
Reactant: O=C(CCl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc(-c2nn(CC(=O)OCc3ccccc3)c3ncccc23)cc1
Reaction time: 4 h

Procedure:
To a suspension of 9 g of 3-[4-(3-dimethylaminopropoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine, 30 ml of dimethylformamide and 6.2 g of potassium carbonate was added dropwise 6.6 g of benzyl chloroacetate at 50° C. over the period of 2 hours. The mixture was kept at the same temperature for 4 hours. After the completion of the reaction, the reaction mixture was cooled. Water was added thereto, and the mixture was extracted with toluene. The extract was washed with water. After toluene was distilled off, diisopropyl ether was added to the residue for crystallization. The resulting crystals were recrystallized from diisopropyl ether - ethyl acetate to give benzyl 3-[4-(3-dimethylaminopropoxy)phenyl]-1H-pyrazolo[3,4-b]pyridin-1-ylacetate, m.p. 90°-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([CH:17]=O)[C:6]=2[C:19]=1[F:20].[CH2:21]([NH2:24])[CH2:22][NH2:23].C(=O)([O-])[O-].[K+].[K+].II>CC(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]3[NH:23][CH2:22][CH2:21][N:24]=3)[C:6]=2[C:19]=1[F:20]
Reactant: O=Cc1c(-c2ccc(F)cc2)oc2ccc(Cl)c(F)c12
Reactant: NCCN
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Fc1ccc(-c2oc3ccc(Cl)c(F)c3c2C2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
A mixture of 5-chloro-4-fluoro-2-(4-fluorophenyl)benzofuran-3-carbaldehyde (1.2 g, 4.10 mmol) and ethylenediamine (0.277 m, 4.10 mmol) in t-BuOH (15 ml) under a N2 atmosphere in a 50 ml RB flask was stirred at room temperature for 30 minutes. Potassium carbonate (0.567 g, 4.10 mmol) followed by iodine (1.041 g, 4.10 mmol) were then added and the reaction mixture was heated at 70° C. for 2 hours. The solvent was removed and the residue diluted with ethyl acetate. The mixture was washed with 10% sodium thiosulfate solution. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by using combiflash silica column using 8% methanol in chloroform as an eluent. The desired fractions were collected and concentrated to give the titled product (0.7 g, 52%). 1H NMR (400 MHz, CDCl3): δ 7.77-7.75 (m, 2H), 7.37-7.34 (m, 1H), 7.27-7.16 (m, 3H), 3.90 (s, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH2:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([N+:35]([O-:37])=[O:36])[C:29]=1[Cl:38])(=O)=O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2)[CH2:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([N+:35]([O-:37])=[O:36])[C:29]=1[Cl:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2cccc(NC(=O)OC(C)(C)C)c2n1
Reactant: CS(=O)(=O)OCc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(N(Cc3c(Cl)ccc([N+](=O)[O-])c3Cl)C(=O)OC(C)(C)C)c2n1
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a solution of 8-tert-butoxycarbonylamino-2-methylquinoline (258 mg) in N,N-dimethylformamide (3 ml) was added sodium hydride (44 mg) in an ice-water bath cooling, and the mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 2,6-dichloro-3-nitrobenzyl methanesulfonate (300 mg) in an ice water bath cooling, and the mixture was stirred for 80 minutes at the same temperature and then for 15 minutes at ambient temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with methylene chloride, and crystallized with n-hexane to give 8-[N-tert-butoxycarbonyl-N-(2,6-dichloro-3-nitrobenzyl)amino]-2-methylquinoline (352 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:16]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:16][C:6]=1[CH3:7]
Reactant: Cc1cc(C(=O)c2ncccn2)oc1C
Reactant: N
Solvent: CO
Product: Cc1cc(O)c(-c2ncccn2)nc1C
Temperature: 160 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(2-pyrimidyl)-methanone (220 mg), methanol (2 ml), and a 28% aqueous ammonia solution (2 ml) were placed in a sealed tube, and the mixture was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give 5,6-dimethyl-2-pyrimidin-2-yl-pyridin-3-ol (129 mg, yield 59%).