Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCCC1>[F:35][C:20]([F:19])([F:34])[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]([Cl:1])=[O:4])[CH2:27][CH2:26]1
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cl)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A magnetically stirred mixture of triphosgene (365 mg, 1.23 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere was treated slowly with pyridine (485 mg, 6.15 mmol) via syringe. The resulting white suspension was then treated with a solution of 1-(3-Trifluoromethyl-benzyl) piperazine (1.0 g, 4.10 mmol) in tetrahydrofuran (10 mL) via addition funnel over 10 min. The reaction mixture was stirred at 25° C. overnight. At this time, the reaction was filtered to remove solids. The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60:40 hexanes/ethyl acetate afforded 4-(3-Trifluoromethyl-benzyl)-piperazine-1-carbonyl chloride (350 mg, 28%) as a clear oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:11]=[C:3]2[CH:2]=[O:1])[CH:13]=1
Reactant: OCc1cc2ccccc2n1-c1cccnc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=Cc1cc2ccccc2n1-c1cccnc1

Procedure:
A solution of 3.3 g of 2-hydroxymethyl-N-(3-pyridyl)indole in 33 ml of dry toluene under nitrogen is refluxed with 16.5 g of silver carbonate for 24 hours. Filtration through celite and evaporation yields an oil which is purified by preparative layer chromatography on silica with methylene chloride-ethyl acetate (8:2) as the eluent to yield N-(3-pyridyl)indole-2-carboxaldehyde, m.p. 101°-103° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[S:26][C:17]2=[N:18][CH:19]=[C:20]([C:23]([OH:25])=O)[C:21]([OH:22])=[C:16]2[CH:15]=1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.CC(O)=O>CN(C=O)C>[Br:13][C:14]1[S:26][C:17]2=[N:18][CH:19]=[C:20]([C:23]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][CH:30]=3)=[O:25])[C:21]([OH:22])=[C:16]2[CH:15]=1
Reactant: O=C(O)c1cnc2sc(Br)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(Br)cc2c1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of ethyl 4-hydroxythieno[2,3-b]pyridine-5-carboxylate (J. Heterocyclic Chem. 1977, 14, 807) (1.00 g) in CHCl3 (26 mL) is added bromine (0.23 mL) dropwise. The reaction is stirred at rt for 2 h. The reaction mixture is poured into 2N HCl (30 mL), and the aqueous layer is extracted with CHCl3 (3×30 mL). The combined organic layers are washed with H2O (100.mL), dried with MgSO4, filtered and concentrated in vacuo to yield 0.840 g (62%) of the bromide as a yellow solid. This material (0.757 g) is suspended in 10% aqueous NaOH (7 mL) and heated to reflux. The reaction is stirred at reflux for 1 h. The reaction mixture is cooled to rt, and H2O (26 mL) is added. Conc. HCl is added until a precipitate forms. The precipitate is filtered off to yield 0.597 (87%) of the acid as a brown solid. Carbonyldiimidazole (0.530 g) is added to a solution of 2-bromo-4-hydroxy-thieno-[2,3-b]pyridine-5-carboxylic acid (0.597 g) in DMF (20 mL). The reaction is heated to 60° C. and stirred for 18 h. The reaction mixture is cooled to rt, and 4-chlorobenzylamine (1.01 mL) is added. The reaction is stirred at rt for 7 h. The reaction mixture is poured into 20% aqueous HOAc (180 mL), and the resulting white solid is filtered off. This material is recrystallized from methanol then toluene to yield 2.095 g (74%) of the title compound as a white solid.
Reaction SMILES: C(N(C1C2N=C([N:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH2:28][CH2:27]3)N=C(N3CCOCC3)C=2N=CN=1)C)C1C=CC=CC=1.ClC1N=C(N2CCOCC2)C2N=CN=C(N(CC3C=CC=CC=3)C)C=2N=1>>[N:32]1([CH:29]2[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(N3CCC(N4CCCCC4)CC3)nc12
Agent: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(Cl)nc12
Product: C1CCN(C2CCNCC2)CC1
Yield: 54 %

Procedure:
8-(N-benzyl-N-methyl-amino)-2-[4-(piperidino)-piperidin-1-yl]-4-morpholino-pyrimido [5,4-d]pyrimidine From 2-chloro-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine and 4-piperidino-piperidine Yield: 54% of theory, Melting point: 106° C. C28H38N8O (502.67)
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH:18]1([N:13]2[C:12]([C:37]3[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 67.3 %

Procedure:
The title compound (68 mg) was prepared as in Example 177, Steps C and D, using 130 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 132 mg of 4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated for C20H24F3N3, 363.19; found, m/z 364.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.90-7.84 (m, 2H), 7.57-7.50 (m, 2H), 4.64 (br s, 2H), 3.94-3.85 (m, 1H), 3.33-3.05 (m, 4H), 2.93-2.72 (m, 2H), 2.00-1.76 (m, 6H), 1.67 (br s, 1H), 1.38-1.17 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[C:27]([CH3:35])([CH3:34])[CH2:26]2)=[CH:21][C:20]=1[O:36][CH3:37]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([N:31]([CH3:32])[CH3:33])[C:27]([CH3:34])([CH3:35])[CH2:26]3)=[CH:21][C:20]=2[O:36][CH3:37])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCC(N(C)C)C(C)(C)C2)ccc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCC(N(C)C)C(C)(C)C2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 1-(4-amino-3-methoxyphenyl)-N,N,3,3-tetramethylpiperidin-4-amine (INTERMEDIATE 45).
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[C:13]([OH:14])=[C:12]([F:15])[C:11]([CH3:16])=[CH:10][CH:9]=1.C1OCCOCCOCCOCCOCCOC1.[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42](F)[CH:43]=1)[C:39]#[N:40]>C1COCC1.CS(C)=O.O>[Cl:7][C:8]1[C:13]([O:14][C:42]2[CH:41]=[C:38]([CH:37]=[C:36]([F:35])[CH:43]=2)[C:39]#[N:40])=[C:12]([F:15])[C:11]([CH3:16])=[CH:10][CH:9]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: N#Cc1cc(F)cc(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccc(Cl)c(Oc2cc(F)cc(C#N)c2)c1F
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
KOtBu (6.23 ml of a 1M solution in THF, 6.23 mmol) was added to a solution of 6-chloro-2-fluoro-3-methylphenol (1.00 g, 6.23 mmol) and 18-CROWN-6 (0.823 g, 3.11 mmol) in DMSO (12 ml) at RT. After 20 mins, 3,5-difluorobenzonitrile (0.87 g, 6.23 mmol) was added and the solution was heated at 120° C. overnight. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (2×20 mL). The organic layer was dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (0-25% EtOAc/hexs) to provide 3-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-5-fluorobenzonitrile (1.15 g, 66%) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21 (dd, J=8.42, 1.46 Hz, 1H), 7.06-7.14 (m, 2H), 6.87-6.95 (m, 2H), 2.33 (d, J=2.11 Hz, 3H).
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[H-].[Na+].[CH3:10][N:11]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]1S(C)(=O)=O>CN(C)C=O>[CH3:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[S:1][C:12]1[N:11]([CH3:10])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=1
Reactant: Cn1c([N+](=O)[O-])cnc1S(C)(=O)=O
Reactant: Cn1ccnc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1ncc([N+](=O)[O-])n1C

Procedure:
A solution of 11.4 g of 2-mercapto-1-methyl-imidazole in 60 ml of dimethylformamide is added dropwise over the course of 15 minutes to a suspension of 4.8 g of 50% strength sodium hydride in 100 ml of dimethylformamide at 20° to 30° C, whilst stirring. The resulting solution is then added dropwise over the course of 30 minutes to a solution of 20.5 g of 1-methyl-2-methylsulphonyl-5-nitro-imidazole in 80 ml of dimethylformamide at 20° to 30° C whilst stirring. Thereafter the reaction mixture is stirred for a further hour at 100° C and is evaporated. The evaporation residue is extracted by shaking with 200 ml of methylene chloride and 200 ml of water and the methylene chloride extract is separated off, washed with 50 ml of water, dried over anhydrous magnesium sulphate and evaporated. After two recrystallisations from ethyl acetate the evaporation residue yields pure 1-methyl-2-[(1-methyl-5-nitro-2-imidazolyl)mercapto]-imidazole of melting point 123°-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][CH2:9]2)[CH:3]=1.[N+:20]([O-])([O-:22])=[O:21].[K+].[OH-].[Na+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[C:7]([N+:20]([O-:22])=[O:21])=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)C(=O)N1CCN(c2cc(Cl)ccn2)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=O)N1CCN(c2cc(Cl)c([N+](=O)[O-])cn2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 1-[4-(4-chloro-pyridin-2-yl)-piperazin-1-yl]-2,2-dimethyl-propan-1-one (1.6 mmol, 0.4 g) in sulfuric acid (2.3 mL) and cool the solution down to 0° C. Add potassium nitrate (1.6 mmol, 0.2 g) and stir the mixture allowing to reach room temperature overnight. Dilute the mixture with water and add sodium hydroxide 10% until basic pH. Extract in ethyl acetate. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue of 1-[4-(4-chloro-5-nitro-pyridin-2-yl)-piperazin-1-yl]-2,2-dimethyl-propan-1-one. Subject residue to silica gel chromatography eluting with a mixture hexanes/ethyl acetate as (from 30% up to 60%). MS(ES): m/z=327 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH2:23]Cl)[N:14]=2)[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]([CH3:12])[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH2:23][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(N(C)c2nc(CN3C(=O)c4ccccc4C3=O)nc3ccccc23)cc1Cl
Temperature: 50 °C

Procedure:
A mixture of (3-chloro-4-ethoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-methyl-amine (119 mg, 0.328 mmol) and potassium phthalimide (79 mg, 0.43 mmol) in DMF (2 mL) was heated at 50° C. for 3.5 h. EtOAc (25 mL) was added and this was washed with water (4×5 mL) then satd NaCl (2×5 mL). The organic layer was dried (MgSO4), filtered through a pad of silica with an EtOAc wash then concd. The title compound was obtained as an off-white solid (124 mg; 80%) after MPLC (SiO2/0-50% EtOAc in hexanes). 1H NMR (CDCl3) δ 7.96-7.90 (m, 2H), 7.78-7.73 (m, 2H), 7.72 (m, 1H), 7.53 (m, 1H), 7.22 (d, J=2.4 Hz, 1H), 7.05-6.95 (m, 2H), 6.91 (dd, J=2.4, 8.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 5.14 (s, 2H), 4.10 (q, J=6.9 Hz, 2H), 3.24 (s, 3H), 1.48 (t, J=6.8 Hz, 3H); LC-MS (ESI+; 473 ([M+H]+)).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[C:5](Cl)(=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(Cl)(Cl)Cl>[C:5]([NH:1][CH2:2][CH2:3][OH:4])(=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: NCCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)NCCO

Procedure:
2-Aminoethanol (13.76 g, 225.3 mmol) was dissolved in CHCl3 (750 ml). To the solution was added dropwise palmitoyl chloride (15.48 g, 56.3 mmol) with stirring under ice cooling. Thereafter, the mixture was stirred at room temperature for 19 hours.
Reaction SMILES: [BH4-].[Na+].CC(O)C.[CH3:7][C:8]1([CH3:18])[CH2:15][C:14]2([CH3:16])[CH:11]([CH2:12][CH2:13]2)[C:10](=[O:17])[CH2:9]1.Cl>O.C1(C)C=CC=CC=1>[CH3:7][C:8]1([CH3:18])[CH2:15][C:14]2([CH3:16])[CH:11]([CH2:12][CH2:13]2)[CH:10]([OH:17])[CH2:9]1
Reactant: CC1(C)CC(=O)C2CCC2(C)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC1(C)CC(O)C2CCC2(C)C1
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a 2-liter 3-necked flask fitted with a mechanical stirrer, additional funnel, reflux condenser and drying tube was added 15 g. (0.39 mole) of sodium borohydride and 500 ml. 2-propanol. To this solution was slowly added 218.6 g. (1.317 moles) of 4,4,6-trimethylbicyclo[4.2.0]octane-2-one in 50 ml. of 2-propanol. After 2 hours, about 200 ml. of water was added. The mixture was stirred an additional 1 hour, then about 35 ml. concentrated hydrochloric acid was added. After another 1 hour of stirring, 400 ml. of toluene and 500 ml. of water were added. The layers were separated and the organic layer was washed three times with 100 ml. of water. The combined water layers were extracted with toluene. The toluene layers were combined and dried over potassium carbonate. The solution was concentrated in vacuo and the residue distilled through a 25 cm. Vigreux--column to yield 215.8 g. (1.284 moles, 97.5 % yield) of 4,4,6-trimethylbicyclo [4.2.0]octane-2-ol. IR: 3360 cm-1.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[C:6]([OH:14])(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNOC
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
N,O-dimethyl hydroxyl amine hydrochloride (4.393 g, 45.037 mmol) was added to a stirred solution of benzoic acid (5.0 g, 40.943), EDC.HCl (9.418 g, 49.132) and N-methyl morpholine (4.141 g, 40.943 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at rt for 4 h. After completion of the reaction, the reaction mixture was concentrated. Diethyl ether was added and the mixture was extracted with water and brine. The organic layer was dried over Na2SO4 and filtrated. Concentration of the organic layer furnished the title compound as a colorless liquid (4.933 g, 73%). [1H-NMR (CDCl3, 300 MHz) δ 7.72-7.64 (m, 2H), 7.52-7.36 (m, 3H), 3.58 (s, 3H), 3.38 (s, 3H); HPLC RtA=6.281 min. (98%); LCMS RtA=0.38 min; [M+H]+=166.1]
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH:35]=O>>[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH2:35][N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:27])[F:28])=[N:19]3)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ncc[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Product: COc1ccc(N2CCN(Cc3ncc[nH]3)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Yield: 27 %

Procedure:
Prepared using the same procedure described in Example 75 from 5-((S)-3-benzyl-piperazin-1-yl)-8-methoxy-2-trifluoromethyl-quinoline and 1H-imidazole-2-carbaldehyde to afford the title compound as a yellow solid (39 mg, 27%). LC/MS (Method B) 2.85 min, [M+1]+ 482.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]4[C:19](=[O:20])[N:18]([CH2:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:17](=[O:29])[C:15]4=3)[N:10]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:46]1([S:52](Cl)(=[O:54])=[O:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:10]2[C:11]3=[N:12][CH:13]=[C:14]4[C:19](=[O:20])[N:18]([CH2:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:17](=[O:29])[C:15]4=[C:16]3[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:52]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)(=[O:54])=[O:53])[CH:7]=[CH:6][CH:5]=3)=[N:9]2)=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(Cn2nc(-c3cccc(N)c3)c3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(-c3cccc(NS(=O)(=O)c4ccccc4)c3)c3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17.6 %

Procedure:
To an ice cooled solution of 1-(3-aminophenyl)-3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (synthesized according to General Procedure B) (200 mg) in dichloromethane (6 ml), triethylamine (0.08 ml, 0.59 mmol) was added followed by phenylsulphonyl chloride (0.08 ml, 0.59 mmol). The reaction mixture was warmed to room temperature and stirred for 2-3 hours. After completion of reaction (TLC, LCMS), the reaction mixture was diluted with dichloromethane (15 ml) and was washed with water (10 ml). The dichloromethane layer was dried over sodium sulfate and evaporated under reduced pressure. The crude compound was passed through a plug of silica (eluent 20% ethyl acetate in hexanes) and then purified by reverse phase HPLC on C-18 column to give N-(3-(3-(4-methoxybenzyl)-6,8-dioxo-7-phenethyl-3,6,7,8-tetrahydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridin-1-yl)phenyl)benzenesulfonamide (45 mg, 18%) as a solid. 1HNMR (400 MHz, CDCl3): δ 9.04 (s, 1H), 7.83 (d, J=7.6 Hz, 2H), 7.56-7.20 (m, 14H), 6.84 (d, J=7.6 Hz, 2H), 6.57 (s, 1H), 5.73 (s, 2H), 3.91 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 2.96 (t, J=7.2 Hz, 2H); LCMS: [M+H] 643.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:15]([C:17]1[CH:28]=[CH:27][C:20]2[N:21]([CH3:26])[C:22]([CH2:24][NH2:25])=[N:23][C:19]=2[CH:18]=1)=[O:16].C(N(C(C)C)C(C)C)C.Cl[C:46]1[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][N:47]=1.Cl>O>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:15]([C:17]1[CH:28]=[CH:27][C:20]2[N:21]([CH3:26])[C:22]([CH2:24][NH:25][C:46]3[N:47]=[CH:48][C:49]([C:52]#[N:53])=[CH:50][CH:51]=3)=[N:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN)n2C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cn1)n2C)c1ccccn1
Temperature: 100 °C

Procedure:
1.5 g (3.25 mmol) of 1-methyl-2-aminomethylbenzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide trifluoroacetate were stirred into 10 mL of N-ethyldiisopropylamine and heated to 100° C. for 15 minutes. After the addition of 720 mg (5.25 mmol) of 2-chloro-5-cyanopyridine, the reaction mixture was heated to 125° C. for 2 hours. After cooling to ambient temperature and stirring with about 20 mL of water, the pH was adjusted to 4 by the addition of 1N hydrochloric acid and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed with saline solution and dried over sodium sulfate. After evaporation of the solvent, the crude product was chromatographed on silica gel, eluting first with methylene chloride, later with methylene chloride/ethanol (25:1) and (19:1). The desired fractions were combined and evaporated down. Yield: 1.05 g (67% of theory), C26H25N7O (483.6); mass spectrum: (M+H)+=484.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.[NH2:13][C:14]1[CH:15]=[N:16][N:17](COCC[Si](C)(C)C)[C:18]=1[C:19]1[C:20]([O:27][CH3:28])=[N:21][CH:22]=[C:23]([CH:26]=1)[C:24]#[N:25].ClC1(OC)N=C(OC)N=CN1.CN1CCOCC1>C(#N)C>[C:24]([C:23]1[CH:26]=[C:19]([C:18]2[C:14]([NH:13][C:10]([C:3]3[CH:2]=[N:1][N:5]4[CH:6]=[CH:7][CH:8]=[N:9][C:4]=34)=[O:12])=[CH:15][NH:16][N:17]=2)[C:20]([O:27][CH3:28])=[N:21][CH:22]=1)#[N:25]
Reactant: COc1ncc(C#N)cc1-c1c(N)cnn1COCC[Si](C)(C)C
Reactant: O=C(O)c1cnn2cccnc12
Agent: COC1=NC(Cl)(OC)NC=N1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COc1ncc(C#N)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 48 h
Yield: 15.3 %

Procedure:
To a suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (22.0 mg, 0.135 mmol, 6.56 equiv), 5-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-methoxynicotinonitrile (7.1 mg, 0.020 mmol, 1 equiv), and 2-chloro-2,4-dimethoxy-1,3,5-triazine (23.7 mg, 0.135 equiv, 6.56 equiv) in acetonitrile (2 mL) was added 4-methylmorpholine (23 uL, 0.21 mmol, 10 equiv) at 24° C. After 2 days, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (2 mL), saturated aqueous sodium chloride solution (2 mL), and ethyl acetate (5 mL). The organic was separated, and the aqueous was extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was dissolved in ethanol (3 mL) and 6 N aqueous hydrochloric acid (1 mL) and heated to 50° C. After 5 h, the reaction mixture was concentrated in vacuo and purified by preparative HPLC to afford a white solid (1.1 mg, 15% yield). 1H NMR (400 MHz, CDCl3), δ: 9.72 (s, 1H), 8.80 (dd, J=7.0, 1.6 Hz, 1H), 8.74 (s, 1H), 8.66 (m, 1H), 8.54 (d, J=2.2 Hz, 1H), 8.47 (s, 1H), 8.22 (d, J=1.9 Hz, 1H), 7.04 (dd, J=7.0, 4.2 Hz, 1H), 4.11 (s, 3H). LCMS (ESI): M+H=361.1
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:37](I)[CH3:38]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:37][CH3:38])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CCI
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1

Procedure:
To a mixture of 6-bromo-2-(4-hydroxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (200 mg), potassium carbonate (89 mg) and DMF (4.0 ml) was added ethyl iodide (41 μl) at room temperature with stirring, and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (110 mg) as colorless crystals.