Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[CH:13]2[N:16]([CH3:17])[CH:10]([CH2:11][CH2:12]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCOCC1>[CH2:1]([N:8]1[CH2:14][CH:13]2[N:16]([CH3:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C2CCC1C(=O)N(Cc1ccccc1)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CN1C2CCC1CN(Cc1ccccc1)C2
Reaction time: 18 h

Procedure:
To a solution of 3-benzyl-8-methyl-3,8-diazabicyclo[3.2.1]octane-2,4-dione (28.3 g, 0.116 mol) in 200 ml of absolute dioxane LiAlH4 (7.6 g, 0.2 mol) was added and the mixture boiled under argon for 18 h. Then a mixture of water (7.5 ml) and dioxane (40 ml) was added dropwise to the reaction mixture. The suspension was mixed for 20 min and filtered trough a dense glass filter. The filtrate was evaporated and the residue was distilled on Büchi oven for distillation at 120° C. and 0.1 mbar. Yield 17.6 g (70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:12]([O-])([OH:14])=[O:13]>CC(O)=O>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([OH:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: COc1ccc(O)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(O)c([N+](=O)[O-])cc1OC

Procedure:
In SCHEME 9 3,4-dimethoxyphenol (36) is selectively nitrated with 70% HNO3 in AcOH to give 4,5-dimethoxy-2-nitrophenol (37) which is further converted to the corresponding triflate (38) with trifluoromethylsulfonic anhydride (Tf2O) and pyridine in dichloromethane. Triflate (38) is reacted under inert conditions with a boronic acid of general type (31) under Suzuki-type basic conditions (Pd(PPh3)4 and aqueous potassium phosphate in toluene) to a biaryl of type (39). Biaryl (39) is further hydrolized with aqueous lithium hydroxide in THF and MeOH or MeCN to give the corresponding carboxylic acid (40) which is converted to a building block of type (41) by reaction with oxalyl chloride in anhydrous dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([O:22][CH:23]([CH3:28])[C:24](OC)=[O:25])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CC(C[AlH]CC(C)C)C>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:22][CH:23]([CH3:28])[CH2:24][OH:25])=[CH:29][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)Oc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(CO)Oc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 127.5 %

Procedure:
To a solution of methyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenoxy)propanoate (0.050 g, 0.12 mmol) in dichloromethane at 0° C. was added DIBAL (0.034 g, 0.24 mmol, 1.0 M in THF) over 15 min. Then, the mixture was stirred for 1 h at 0° C. and then warmed to rt for 15 min. After this time, the reaction was quenched with methanol, HCl (2 M) and water, and then extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate), followed by the formation of the hydrochloride salt to form the title compound (0.033 g, 66%) as a bright yellow gum. MW=431.35. 1H NMR (DMSO-d6, 500 MHz) δ 13.97 (s, 1H), 9.73 (s, 1H), 7.86 (t, J=1.8 Hz, 1H), 7.68-7.62 (m, 2H), 7.57 (t, J=7.9 Hz, 1H), 7.31-7.26 (m, 2H), 7.06-7.01 (m, 2H), 6.86 (s, 1H), 4.49-4.39 (m, 2H), 3.61-3.41 (m, 2H), 3.17-3.09 (m, 2H), 2.88 (s, 2H), 2.26-2.17 (m, 2H), 1.21 (d, J=6.2 Hz, 3H); APCI MS m/z 395 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:22][O:23][CH3:24])([S:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:25]OS([O-])=O.[K+].C(=O)(O)[O-].[K+]>C(#N)C.O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:22][O:23][CH3:24])([S:14]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1(Sc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=S([O-])OO
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COCC1(S(=O)c2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
A solution of N-tert-Butoxycarbonyl-4-methoxymethyl-4-(3-tolylsulfanyl)piperidine (0.26 g, 0.73 mmol; Example 107, Step A) in acetonitrile (10 mL) was treated with a solution of Oxone (0.99 g, 1.6 mmol) in water (10 mL) and potassium bicarbonate (0.56 g, 5.6 mmol) in water (10 mL), and stirred at room temp. for 1 h. The reaction mixture was diluted with dichloromethane and water. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 25% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[NH:12][C:13]([CH3:31])=[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=2)=[CH:5][CH:4]=1.[N:32]1[CH:37]=CC=C[CH:33]=1.[C:38](Cl)(Cl)=[O:39].CNC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[N:16]([C:38]([N:32]([CH3:37])[CH3:33])=[O:39])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:13]([CH3:31])[N:12]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Reactant: c1ccncc1
Agent: CNC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(C(=O)N(C)C)C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
A solution of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (0.5 g, 1.1 mmole) in 10 ml of dry tetrahydrofuran under argon at 0°-5° C. was treated with pyridine (1.0 ml, 12.6 mmole), then with phosgene (1.16 ml of 12.5% in benzene, 1.47 mmol). After 0.5 hours at 0°-5° C., dimethylamine (1 ml of 40% aqueous, excess) was added. Reaction was complete within 0.5 hours. The mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, water and saturated brine. The aqueous washes were back extracted with fresh ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to give 0.6 g of essentially homogeneous product.
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.C(P(CCCC)CCCC)CCC.[OH:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][CH:37]=[C:38]2[NH:41][C:42](=[O:55])[CH2:43][N:44]([CH2:52][CH2:53]O)[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[CH:33][CH:32]=1>O1CCCC1>[C:48]([O:47][C:45]([N:44]1[CH2:52][CH2:53][N:41]([C:38]2[C:39]3[C:34](=[CH:33][CH:32]=[C:31]([OH:30])[CH:40]=3)[CH:35]=[CH:36][CH:37]=2)[C:42](=[O:55])[CH2:43]1)=[O:46])([CH3:49])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(=O)Nc1cccc2ccc(O)cc12
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3ccc(O)cc23)C(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of di-tert-butylazodicarboxylate (10.81 g, 43.2 mmol) in 60 mL of tetrahydrofuran at 0° C. was added tributylphosphine (10.76 mL, 43.2 mmol) dropwise. After 10 minutes, a solution of the crude product from Step B (ca. 28.8 mmol) in 30 mL of tetrahydrofuran was added dropwise, and the reaction was allowed to warm to room temperature. After two hours, HPLC analysis showed partial conversion. The solution was cooled to 0° C., and additional portions of tributylphosphine (3.0 mL, 18 mmol) and di-tert-butylazodicarboxylate (4.6 g, 18 mmol) were added. The reaction was warmed to room temperature, and stirred for 16 hours. The solution was concentrated in vacuo, and the resulting product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to provide the titled product as a dark brown foam, contaminated with tributylphosphine oxide impurity. This material was used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[C@H:15]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[NH:16]C(OCC2C=CC=CC=2)=O)[C@@H:10]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:9]1=[O:41])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.CO>[H][H].[C].[Pd]>[C:6]([OH:42])(=[O:5])[CH3:7].[C:1]([O:5][C:6](=[O:42])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[C@H:15]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)[NH2:16])[C@@H:10]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:9]1=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COC(=O)C[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)[C@@H](N)Cc1ccc(O)cc1
Yield: 176.2 %

Procedure:
A mixture of 1.3 g of (S)-4-(N-benzyloxycarbonyl-L-tyrosyl)-3 -methoxycarbonylmethyl-2-oxopiperazine- 1-acetic acid tert-butyl ester thus obtained, 300 mg of 10% palladium-carbon, 180 mg of acetic acid and 20 ml of methanol was stirred for 30 minutes in hydrogen streams. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to afford 1.0 g of (S)-4-L-tyrosyl-3-methoxycarbonylmethyl-2-oxo-piperazine-1-acetic acid tert-butyl ester acetate as a colorless oily product. This product can be used in the subsequent reaction without purification.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1([C:27](=[O:32])C(=NO)C)C=CC=CC=1.C(=O)C1C=CC=C(OC)C=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:32][CH3:27])[CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: CC(=NO)C(=O)c1ccccc1
Agent: COc1cccc(C=O)c1
Product: COc1cccc(-c2nc(CI)c(-c3ccccc3)o2)c1

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 1-phenyl-1,2-propanedione-2-oxime and m-anisaldehyde gave 4-iodomethyl-2-(3-methoxyphenyl)-5-phenyloxazole.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11](O)(=O)[CH3:12].C(=O)(O)[O-].[Na+]>C1(=O)CCCCC1>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[CH2:11][CH2:5][CH2:4][CH2:3][C:8]2=1
Reactant: CC(=O)O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C1CCCCC1
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3

Procedure:
Cyclohexanone (1.16 mL, 11.2 mmol) and 4-bromo-phenylhydrazine hydrochloride (2.50 g, 11.2 mmol) were refluxed in cyclohexanone (18 mL) and acetic acid (AcOH) (12 L) for 24 h. The reaction mixture was treated with saturated sodium bicarbonate (Na2CO3) and extracted with ethyl acetate, dried (Na2CO3) and concentrated. The product was purified by column chromatography, giving 479 mg of compound 30 as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][O:33][C:34]3[N:35]=[N:36][C:37](Cl)=[CH:38][CH:39]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CO>[C].[Pd].O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][O:33][C:34]3[N:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(Cl)nn2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2cccnn2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
A mixture of 4-tert-butyl-N-[6-{2-(6-chloropyridazin-3-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide (150 mg), 10% palladium-carbon (30 mg), triethylamine (52 mg), methanol (8 ml) and tetrahydrofuran (6 ml) is stirred at room temperature for five hours under hydrogen atmosphere (1 atm), and the mixture is filtered to remove the catalyst. The filtrate is concentrated to dryness under reduced pressure. The residue is treated with aqueous citric acid solution, and extracted with chloroform. The extract is washed, dried and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate/diisopropyl ether to give 4-tert-butyl-N-[5-(3-methoxyphenoxy)-6-{2-(pyridazin-3-yloxy)ethoxy}pyrimidin-4-yl]benzenesulfonamide (111 mg) as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H][H]>[Pd]>[C:4]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([O:3][CH2:1][CH3:2])=[O:12]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Product: CCOC(=O)C1CCC(O)CC1
Reaction time: 5 h

Procedure:
Into an autoclave is placed ethyl-p-hydroxybenzoate (495 grams) and 5% palladium on carbon (4 grams). The reaction mass is hydrogenated at 150° C. and 50-75 psig hydrogen pressure. After five hours, a sample showed 40% ketone and 44% alcohol having the structure: ##STR24##
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[C:20]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1)(=[O:22])[CH3:21].C(O)(=O)C>O1CCCC1>[OH:29][CH:28]([C:27]1[CH:30]=[CH:31][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:25][C:26]=1[N+:32]([O-:34])=[O:33])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C#CC(=O)OCC
Reactant: CC(=O)Nc1ccc(C=O)c([N+](=O)[O-])c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: CCOC(=O)C#CC(O)c1ccc(NC(C)=O)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
To a solution of diisopropylamine (1.1 ml, 7.70 mmol) in tetrahydrofuran (12 ml) was added, at -78° C. under an argon atmosphere, 1.5 N butyllithium (4.8 ml, 7.22 mmol). The mixture was stirred for 30 min. Ethyl propiolate (0.9 ml, 8.66 mmol) and a solution of 4-acetylamino-2-nitrobenzaldehyde (1.0 g, 4.81 mmol) in tetrahydrofuran (6 ml) were added in that order, and the mixture was further stirred at -78° C. for one hr. A solution of acetic acid (0.9 ml, 14.91 mmol) in tetrahydrofuran (3 ml) was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution, and saturated brine in that order. It was then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(4-acetylamino-2-nitrophenyl)-2-butynoate (1.613 g) as an oil. Ethyl 4-hydroxy-4-(4-acetylamino-2-nitrophenyl)-2-butynoate thus prepared was dissolved in toluene (14 ml), 4-methoxybenzylazide (2.35 g, 14.4 mmol) was added to the solution, and the mixture was stirred at 10° C. for 18 hr. The reaction mixture was cooled to room temperature, and the resultant crystal as a precipitate was collected by suction filtration to give a 3:1 mixture (1.09 g, 48%) of ethyl 4-hydroxy-(4-acetylamino-2-nitrophenyl)methyl-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (a-1) and ethyl 5-hydroxy-(4-acetylamino-2-nitrophenyl)methyl-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (a-2).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:23]([CH2:25][C:26]([OH:28])=O)#[N:24].[CH3:29][C:30]([CH3:55])([CH3:54])[C:31]([C:33]1[C:41]2[C:36](=[N:37][CH:38]=[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([N:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)[CH:43]=3)[N:40]=2)[NH:35][CH:34]=1)=[O:32].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:29][C:30]([CH3:55])([CH3:54])[C:31]([C:33]1[C:41]2[C:36](=[N:37][CH:38]=[C:39]([C:42]3[CH:43]=[C:44]([N:48]4[CH2:53][CH2:52][N:51]([C:26](=[O:28])[CH2:25][C:23]#[N:24])[CH2:50][CH2:49]4)[CH:45]=[CH:46][CH:47]=3)[N:40]=2)[NH:35][CH:34]=1)=[O:32]
Reactant: N#CCC(=O)O
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCNCC4)c3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCN(C(=O)CC#N)CC4)c3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Dichloromethane (1 mL) was added to a mixture of EDCI (0.181 g, 0.945 mmol), HOBT monohydrate (0.128 g, 0.945 mmol), cyanoacetic acid (0.060 g, 0.71 mmol), and 2,2-Dimethyl-1-[2-(3-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (0.1718 g, 0.473 mmol) under argon. Diisopropylethylamine (DIPEA, 0.41 mL; 0.304 g, 2.36 mmol) was subsequently added and the reaction was stirred overnight at ambient temperature. The reaction was quenched with saturated aqueous NaHCO3 and extracted 3 times with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Preparative thin layer chromatography afforded 0.0402 g (20% yield) of 3-(4-{3-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazin-1-yl)-3-oxo-propionitrile as an off-white solid.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([NH:15][OH:16])=[NH:14])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([Cl:27])=O)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[ClH:27].[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[N:14]=[C:25]([C:24]3[CH:28]=[CH:29][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=3)[O:16][N:15]=2)[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCC(CC(=N)NO)CC1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CCC(CC)N1CCC(Cc2noc(-c3ccc(C(C)(C)C)cc3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 12, starting from 2-((1-ethylpropyl)piperidin-4-yl)-N-hydroxyacetamidine and 4-tert-butylbenzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[CH:5][N:4]=1.I[C:13]1[C:21]2[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:18]=[N:17][C:16]=2[NH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd]>[CH3:1][O:2][C:3]1[C:8]([C:13]2[C:21]3[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1B(O)O
Reactant: Ic1c[nH]c2ncnc(-c3ccccc3)c12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncccc1-c1c[nH]c2ncnc(-c3ccccc3)c12
Temperature: 170 °C

Procedure:
A mixture of (2-methoxypyridin-3-yl)boronic acid (36 mg, 0.23 mmol), 5-iodo-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.16 mmol), sodium carbonate (83 mg, 0.78 mmol) and SiliaCat® heterogeneous catalysts DPP-Pd (loading=0.28 mmol/g, 111 mg, 0.031 mmol) in dioxane (1.30 mL) and water (0.26 mL) was heated to 170° C. under the microwave irradiation for 15 minutes. The reaction mixture was concentrated, redissolved in DMSO, filtered and the resulting solution was reconcentrated. Purification by reverse phase HPLC using an acetonitrile gradient in water with 0.1% formic acid modifier afforded 5-(2-methoxypyridin-3-yl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine. LRMS (ESI) calc'd for C18H15N4O [M+H]+: 303, found 303. 1H NMR (600 MHz, DMSO-D6) δ 12.40 (s, 1H), 8.82 (s, 1H); 7.97 (dd, 1H, J=1.1, 4.3 Hz); 7.65 (s, 1H); 7.64 (dd, 1H, J=1.1, 5.6 Hz); 7.28 (d, 2H, J=6.6 Hz), 7.24 (t, 1H, J=6.1 Hz); 7.08 (dd, 2H, J=6.1, 6.6 Hz); 6.94 (dd, 1H, J=4.3, 5.6 Hz); 3.05 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1.[OH-].[Na+]>ClCCl.O>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])=[CH:7][N:6]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2CC2)cn1
Reaction time: 1 h

Procedure:
5-Amino-2-methoxy pyridine (12.4 g, 0.10 mol) and pyridine (10 ml) were mixed together in dichloromethane (200 ml) in a reaction flask. Cyclopropane carboxylic acid chloride (9.1 ml, 0.10 mol) was added to the reaction mixture over a period of 2 minutes. The reaction was exothermic and the temperature rose to 34° C. The reaction was allowed to stand for one hour at room temperature, after which the reaction mixture was wsahed with 5% sodium hydroxide (200 ml) and water (100 ml). The resulting organic phase was separated and dried over anhydrous magnesium sulfate. Crystals formed, so the mixture was filtered and washed with 300 ml of acetone and the filtrate evaporated in vacuo to give a solid that was triturated with hexane to yield 16.7 g, after drying. The product was identified by infrared (IR) and nuclear magnetic spectroscopy (NMR) analysis as the title compound, having a melting pont of 130°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]3[N:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][N:23]=3)=[O:21])[CH:16]([CH2:34][CH3:35])[CH2:15]1)(=[O:13])=[O:12])=[CH:5]2.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]3[N:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N+:29]=4[O-:44])=[CH:24][N:23]=3)=[O:21])[CH:16]([CH2:34][CH3:35])[CH2:15]1)(=[O:13])=[O:12])=[CH:5]2
Reactant: CCC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1ncc(-c2ccccn2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: CCC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1ncc(-c2cccc[n+]2[O-])cn1
Reaction time: 5 h
Yield: 18.3 %

Procedure:
To a methylene chloride solution (50 ml) of 4-[(5-chloroindol-2-yl)sulfonyl]-2-(ethyl)-1-[(5-(pyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine (234 mg) was added metachloroperbenzoic acid (1.58 g) at room temperature. The resulting mixture was stirred for 5 hours. An aqueous solution (20 ml) of sodium sulfite was added, followed by stirring for 1 hour. To the reaction mixture were added a saturated aqueous solution of sodium bicarbonate and methylene chloride. The water layer was extracted thrice with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol:methylene chloride=1:50). The oil thus obtained was solidified from ethanol-diethyl ether, whereby the title compound (44.1 mg) was obtained as a pale yellow solid. MS (FAB) m/z: 527 [(M+H)+, Cl35], 529 [(M+H)+, Cl37].
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]N[CH2:3][CH2:2]1.[NH:20]1[C:24]2=[CH:25][N:26]=[CH:27][CH:28]=[C:23]2[C:22]([CH:29]=O)=[CH:21]1>>[NH:20]1[C:24]2=[CH:25][N:26]=[CH:27][CH:28]=[C:23]2[C:22]([CH:29]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1c[nH]c2cnccc12
Product: FC(F)(F)c1nnc2ccc(N3CCC(c4c[nH]c5cnccc45)CC3)nn12
Yield: 68 %

Procedure:
Obtained in 68% yield by General Synthetic Method 5, starting from 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine and 1H-pyrrolo[2,3-c]pyridine-3-carboxaldehyde (obtained as described in J. Chem. Soc. (C) 1970, 498).