Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: COc1cccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)c1

Procedure:
The product of Example 1B and 2-(3-methoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 7.97-8.05 (m, 2H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 6.98-6.99 (m, 1H), 6.96 (d, J=7.6 Hz, 1H), 6.86 (dd, J=8.2, 2.6 Hz, 1H), 3.81-3.83 (m, 4H), 3.77 (s, 3H), 3.63 (s, 2H), 3.03-3.13 (m, 4H); MS (ESI−) M/Z 393 (M−H)−.
Reaction SMILES: [C:1]([C:3]1([CH3:12])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5](=O)[CH2:4]1)#[N:2].[NH3:13]>>[C:1]([C:3]1([CH3:12])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5](=[NH:13])[CH2:4]1)#[N:2]
Reactant: CC1(C)CC(=O)CC(C)(C#N)C1
Reactant: N
Product: CC1(C)CC(=N)CC(C)(C#N)C1

Procedure:
imination of 3-cyano-3,5,5-trimethylcyclohexanone with ammonia in the presence of an imination catalyst at temperatures ranging from 20° to 150° C. and pressures ranging from 1.5 to 30 MPa to form 3-cyano-3,5,5-trimethylcyclohexanone imine followed by
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:36])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)=[N:30][CH:31]=1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(F)cn5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(F)cn5)cc4)CC3)n2CCS1
Yield: 108.9 %

Procedure:
A solution of the compound (367 mg, 0.68 mmol) obtained in Example 54-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (304 mg, quant.) as a colorless solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:55])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([N:42]3[CH2:46][CH2:45][CH2:44][C@H:43]3[C:47](=[O:53])[NH:48][CH:49]3[CH2:52][CH2:51][CH2:50]3)=[O:41])[C:35]3[C:30](=[CH:31][C:32]([CH3:54])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:55])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([N:42]3[CH2:46][CH2:45][CH2:44][C@H:43]3[C:47](=[O:53])[NH:48][CH:49]3[CH2:52][CH2:51][CH2:50]3)=[O:41])[C:35]3[C:30](=[CH:31][C:32]([CH3:54])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.5 g 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-naphthalene-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester in 10 ml dichloromethane were added 1.1 g TFA. After 3 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. The crude product was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). Yield: 970 mg MS (ES+): m/e=708.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O=[C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:34])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19])[C@H:12]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:64][N:65]1[C:69]([SH:70])=[N:68][N:67]=[N:66]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][C:18]([C@@H:15]1[C:14](=[O:35])[N:13]2[C@@H:16]1[CH2:17][C:11]([S:70][C:69]1[N:65]([CH3:64])[N:66]=[N:67][N:68]=1)=[C:12]2[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)=[O:37])([O:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:34]
Reactant: Cn1nnnc1S
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nnnc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.3 %

Procedure:
A solution of N,N-diisopropyl-N-ethylamine (0.0386 ml) in methylene chloride (0.347 ml) was added to a solution of 4-nitrobenzyl (2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (100 mg) and 4-(N,N-dimethylamino)pyridine (2.3 mg) in methylene chloride (5 ml) at -30° C. A solution of trifluoromethanesulfonic anhydride (0.0326 ml) in methylene chloride (0.293 ml) was then added thereto at -30° C. After the mixture was stirred at the same temperature for an hour, a solution of N,N-diisopropyl-N-ethylamine (0.129 ml) in methylene chloride (1.16 ml) and a solution of 1-methyl-1H-tetrazole-5-thiol (42.9 mg) in methylene chloride (2.15 ml) were added successively at -30° C. The mixture was stirred at -30° C. for 30 minutes and allowed to warm to ambient temperature over a period of 30 minutes. After stirring at ambient temperature for 2 hours, the mixture was allowed to stand at 4° C. for 2 days. After removal of the solvent, the residue was dissolved in ethyl acetate. The solution was washed three times with water and an aqueous sodium chloride, dried over magnesium sulfate and then evaporated in vacuo. The residue was chromatographed on deactivated silica gel with 10% water (2 g), eluting with a mixture of benzene and acetone (50:1 to 10:1) to give 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(1-methyl-1H-tetrazol-5-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (89 mg) as an oil.
Reaction SMILES: [Br-].O([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].CC(C)([O-])C.[K+].[F:32][C:33]1[CH:34]=[C:35]([C@H:39]2[CH2:44][CH2:43][C@H:42]([CH:45]=O)[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1.O>C1COCC1.C1(C)C=CC=CC=1>[F:32][C:33]1[CH:34]=[C:35]([C@H:39]2[CH2:44][CH2:43][C@H:42]([CH:45]=[CH:3][CH2:4][CH2:5][CH3:6])[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1
Reactant: O=C[C@H]1CC[C@H](c2cccc(F)c2)CC1
Reactant: CCCCO[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCCC=C[C@H]1CC[C@H](c2cccc(F)c2)CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Well-dried butoxyltriphenylphosphonium bromide (58.1 g) and THF (200 ml) were mixed under a nitrogen atmosphere and cooled to −30° C. Then, potassium t-butoxide (t-BuOK; 16.3 g) was put in thereto in twice in the temperature range of −30° C. to 20° C. After the mixture had been stirred at −20° C. for 30 minutes, the compound (37) (20.0 g) dissolved in THF (100 ml) was added dropwise thereto in the temperature range of −30° C. to −20° C. After the reaction mixture had been stirred at −10° C. for 30 minutes, it was poured into a mixture of water (400 ml) and toluene (400 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The eluent obtained was concentrated under reduced pressure. The residue was mixed with sodium benzenesulfonate dihydrate (31.0 g) and Solmix A-11 (100 ml), and heated under reflux for 8 hours. The reaction mixture was cooled to 30° C., and then water (200 ml) and toluene (200 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and heptane (volume ratio; toluene: heptane=1:1) as the eluent and silica gel as the stationary phase powder. The residue was further purified by means of recrystallization from Solmix A-11, and dried, giving 15.8 g of 1-(3-fluorophenyl)-trans-4-(1-pentenyl)cyclohexane (40). The yield based on the compound (37) was 66.2%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.O.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Solvent: O
Product: Cc1cc(N2CCCC2)ncc1[N+](=O)[O-]
Yield: 100 %

Procedure:
A solution of 2-chloro-4-methyl-5-nitropyridine (3.0 g, 17.3 mmol) in pyrrolidine (50 mL) was stirred at 80° C. for 12 hr. The mixture was concentrated in vacuo to give a residue which was poured into water and extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (3.6 g, 17.3 mmol, 100%) as a yellow solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([OH:10])[C:7]#[C:8][CH3:9].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[CH2:6]([O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[CH2:7][CH:8]=[CH2:9]
Reactant: CC#CCO
Reactant: C1=COCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of phosphoryl chloride (0.5 ml in 10 ml of DCM) was added with care to a solution of but-2-yn-1-ol (8.75 g, 125 mmol) and dihydropyran (10.50 g, 125 mmol) in DCM (80 ml). The reaction mixture was stirred at room temperature for 16 h, washed with sodium hydrogen carbonate solution (3 times), dried (MgSO4) and the solvent removed in vacuo to yield a colorless oil. The crude product was purified by column chromatography [silica gel, euted with hexane/ethyl acetate (4:1), Rf: 0.36] to yield a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]2[O:21][CH:20]=[C:19]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[C:15]=2[N:16]=[CH:17][N:18]=1.[ClH:35].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:35].[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]2[O:21][CH:20]=[C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2coc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCNCC4)coc23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-butyl 4-(4-{[2-fluoro-4-(methylsulfonyl)phenyl]amino}furo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate was suspended in ethyl acetate (3 mL), 4 N hydrochloric acid/ethyl acetate (3 mL) was added slowly under ice-cooling, followed by stirring at room temperature for 1 hour. After separation by filtration, washing was conducted by using ethyl acetate and diethyl ether to give N-[2-fluoro-4-(methylsulfonyl)phenyl]-7-(piperidin-4-yl)furo[3,2-d]pyrimidine-4-amine hydrochloride (267 mg) as a brown solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34](O)[CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:30][CH:29]=1>C(Cl)Cl>[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([I:25])[CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:30][CH:29]=1
Reactant: II
Reactant: COC(=O)CCC(O)c1ccc(F)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCC(I)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (419 mg, 1.6 mmol) in anhydrous 20 mL DCM was added imidazole (224 mg, 3.3 mmol) and iodine (406 mg, 1.6 mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and then methyl 4-(4-fluorophenyl)-4-hydroxybutanoate (212 mg, 1 mmol) in 10 mL DCM was added to the mixture. The resulting mixture was stirred at 0° C. for 2 h and the temperature was slowly raised to room temp over a period of 3 h. Evaporation of solvent left the crude product as an oil from which the product was isolated by Flash column chromatography eluting with 0% to 10% ethyl acetate/hexane to give the title compound, 161 mg, as a light yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]=[N+:16]=[N-:17])[O:11][C:10]2=[O:18])=[CH:5][CH:4]=1.[C:19]12CC(CC1)=C[CH:20]=2>O1CCOCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:20]=[CH:19][N:17]=[N:16]3)[O:11][C:10]2=[O:18])=[CH:5][CH:4]=1
Reactant: CSc1ccc(N2C[C@H](CN=[N+]=[N-])OC2=O)cc1
Reactant: C1=C2CCC(=C1)C2
Solvent: C1COCCO1
Product: CSc1ccc(N2C[C@H](Cn3ccnn3)OC2=O)cc1

Procedure:
(5R)-3-(4-Methylthiophenyl)-5-azidomethyloxazolidin-2-one (1.62 g, 6.14 mM) was dissolved in dioxane (30 ml), treated with norbornadiene (2.98 g, 31.5 mM) and heated under reflux for 6 hours. After removal of the solvent, the residue was dissolved in the minimum of hot ethyl acetate, filtered, cooled, then diluted with isohexane to precipitate the desired product (600 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=[CH:15][CH:16]=3)[NH:11][C:10](=[O:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.CC(C)([O-])C.[Na+].C(=[NH:48])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[NH2:48][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=[CH:15][CH:16]=3)[NH:11][C:10](=[O:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=c1nc(-c2cccc(Br)c2)c2ccc3ccccc3c2[nH]1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: Nc1cccc(-c2nc(=O)[nH]c3c2ccc2ccccc23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.5 %

Procedure:
The mixture of 4-(3-bromophenyl)-1H-benzo[h]quinazolin-2-one (950 mg, 2.71 mmol), 1,4-dioxane (95 mg, 1.08 mmol), sodium tert-butoxide (650 mg, 6.76 mmol), benzophenone imine (681 μL, 4.06 mmol), and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (101 mg, 0.16 mmol) was heated under reflux for 16 hours under N2 atmosphere. The solvent was removed under reduced pressure. To the residue was added methanol (50 mL) and 2M hydrochloride (50 mL), and stirred at room temperature for 16 hours. The reaction mixture was filtered to give the titled compound as a yellow solid (191 mg, yield 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:28])=[CH:16][C:17]([N:18]3[CH2:27][CH2:26][C:21]4(OCC[O:22]4)[CH2:20][CH2:19]3)=[C:12]2[C:11]([CH3:29])=[C:10]1[CH3:30].C(=O)([O-])O.[Na+]>Cl.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:28])=[CH:16][C:17]([N:18]3[CH2:27][CH2:26][C:21](=[O:22])[CH2:20][CH2:19]3)=[C:12]2[C:11]([CH3:29])=[C:10]1[CH3:30]
Reactant: Cc1cc(N2CCC3(CC2)OCCO3)c2c(C)c(C)n(-c3ccc(Cl)cc3Cl)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(N2CCC(=O)CC2)c2c(C)c(C)n(-c3ccc(Cl)cc3Cl)c2n1
Reaction time: 8 h
Yield: 81.6 %

Procedure:
After 1-(2,4-dichlorophenyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]-pyridine(5.21 g) was stirred in a mixture of 4 M hydrochloric acid (60 mL) and tetrahydrofuran (60 mL) at room temperature for 2.5 hours, 6 M hydrochloric acid (30 mL) was added thereto and the resulting mixture was stirred overnight. After completion of the reaction, the reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, after which the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The crystals thus obtained were washed with ethyl acetate to obtain 1-(2,4-dichloropheny1)-4-(4-oxopiperidin-1-yl)-2,3,6-trimethy1-1H-pyrrolo[2,3-b]pyridine (3.83 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][S:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[CH:12]=[C:11]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:10]=2)=[CH:5][CH:4]=1.[N:25]([O-])=O.[Na+]>C(O)(=O)C>[NH2:25][C:12]1[C:11]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:10][C:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=2)=[N:14][C:13]=1[NH:15][CH3:16]
Reactant: CNc1cc(N2CCOCC2)nc(SCc2ccc(OC)cc2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CNc1nc(SCc2ccc(OC)cc2)nc(N2CCOCC2)c1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.6 %

Procedure:
2-(4-methoxybenzylsulfanyl)-4-methylamino-6-morpholinopyrimidine (5.0 g, 14.4 mmol) was dissolved in acetic acid (50 ml), and an aqueous solution (10 ml) of sodium nitrite (1.49 g, 21.6 mmol) was added drop-wise under water cooling and stirred at room temperature for 5 hours. After distilling away acetic acid under reduced pressure and dissolving the residue in ethyl acetate, washing was performed in the order of 2N—NaOH solution and water, then dried with MgSO4 and the solvent was distilled away under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), 1.0 g of Pd/C was added and catalytic hydrogenation was performed under normal pressure for 4 hours. Celite was used to filter off Pd/C and the filtrate was distilled away under reduced pressure. Separation and purification were performed by silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain 1.28 g (25% yield) of 5-amino-2-(4-methoxybenzylsulfanyl)-6-methylamino-4-morpholinopyrimidine. Melting point: 79.5 to 84° C. MS m/z: 361 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11](I)=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[C:3]1=[O:19].[Cu](C#N)[C:22]#[N:23]>CN(C)C=O>[CH3:1][C:2]1([CH3:20])[C:3](=[O:19])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:22]#[N:23])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[C:5](=[O:7])[NH:6]1
Reactant: CC1(C)NC(=O)N(c2ccc(I)c(C(F)(F)F)c2)C1=O
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reaction time: 1 h
Yield: 75.5 %

Procedure:
184 g of the product of Example 2 is introduced at 20°±2° C. and 66.15 g of copper cyanide and 420 ml of dimethylformamide are added under agitation the whole is heated while distilling the methylene chloride until a temperature of 130° C. is obtained in the reaction medium and then it is maintained for 5 hours under agitation at this temperature. The medium is cooled down to 20°±2° C. under agitation, maintained for 1 hour under these conditions followed by separation and washing with 3×0.3 vol of dimethylformamide. Then 700 ml of pure 22°Be ammonium hydroxide and 700 ml of demineralized water are added to the mixture agitated at 20°±2° C. Agitation is carried out for 1 hour at 20°±2° C. then the whole is cooled down to 0°±5° C., maintained for 1 hour under agitation at 0°±5° C., followed by separating and washing with 2×140 ml of pure 22°Be ammonium hydroxide at 20°±2° C. then with 4×140 ml of demineralized water then drying. Purification is carried out by adding 1105 ml of ethyl acetate then taking to reflux under agitation and then 12.3 g of acticarbon black CX is added. The reaction medium is maintained under agitation under reflux for 30 minutes, then filtered, followed by washing with 3×61 ml of boiling ethyl acetate, concentration under agitation, cooling down under agitation to 0°±2° C. and maintaining under these conditions for 2 hours. Separation, washing with 3×37 ml of ethyl acetate at 0°±2° C. and drying are carried out. In this way 103.7 g of expected product (clear beige powder) is obtained.
Reaction SMILES: C([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])=[CH:25][CH:24]=3)[N:13]=2)=[N:6]1)(C)(C)C>C(O)=O>[CH3:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:26]1[CH:25]=[CH:24][C:23]([N:14]2[N:13]=[C:12]([NH:11][C:7]3[CH:8]=[C:9]([CH3:10])[NH:5][N:6]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:22])=[CH:28][CH:27]=1
Reactant: Cc1ccccc1-c1ccc(-n2nc(Nc3cc(C)n(C(C)(C)C)n3)c3ccccc3c2=O)cc1
Solvent: O=CO
Product: Cc1cc(Nc2nn(-c3ccc(-c4ccccc4C)cc3)c(=O)c3ccccc23)n[nH]1
Yield: 83 %

Procedure:
4-(1-tert-Butyl-5-methyl-1H-pyrazol-3-ylamino)-2-(2′-methyl-biphenyl-4-yl)-2H-phtalazin-1-one was deprotected with formic acid as described in Method O to give the title compound (0.036 g, 83% yield). 1H-NMR: (400 MHz, D6-DMSO) 9.29 (1H, s), 8.52 (1H, d), 8.40 (1H, d), 8.17 (1H, s), 7.97 (1H, t), 7.93 (1H, t), 7.82 (2H, d), 7.48 (2H, d), 7.30 (4H, m), 6.29 (1H, s), 2.33 (3H, s), 2.20 (3H, s); MS (ESI+)=408.16 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[F:8][C:9]1[CH:22]=[CH:21][C:12]([C:13](/[C:15](=[C:18](/[OH:20])\[CH3:19])/[C:16]#[N:17])=[O:14])=[CH:11][CH:10]=1>C(OCC)C>[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:13](/[C:15](=[C:18](/[OH:20])\[CH3:19])/[C:16]#[N:17])=[O:14])=[CH:21][CH:22]=1
Reactant: CCN(CC)CC
Agent: C/C(O)=C(/C#N)C(=O)c1ccc(F)cc1
Solvent: CCOCC
Product: CC[NH+](CC)CC
Reaction time: 1 h

Procedure:
A solution of 1.3 ml. of triethyl amine in 10 ml. of diethyl ether is added dropwise to a solution of 1.5 g. of 2-(p-fluorobenzoyl)-3-hydroxycrotononitrile in 20 ml. of diethyl ether. After stirring for 1 hour, a yellow oil separated which crystallizes upon evaporation of the solvent. The product was filtered, washed with ether and dried, providing the title compound.