Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([C:5](=[NH:7])[NH2:6])[CH2:4][CH2:3]1.[OH-:8].[Na+]>CC#N.O>[CH:2]1([C:5]2[N:6]=[CH:4][C:2]([CH:5]=[O:8])=[CH:3][N:7]=2)[CH2:4][CH2:3]1
Reactant: N=C(N)C1CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=Cc1cnc(C2CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a mixture of a1 (ca. 0.095 mol) in CH3CN (300 mL) was added cyclopropanecarboximidamide hydrochloride (12.5 g, 0.105 mol), then sodium hydroxide (7.6 g, 0.19 mol) in water (7.6 mL) was added drop-wise at 0° C. After addition was complete, the resulting mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated to remove CH3CN under reduced pressure and the residue water phase was extracted with DCM (3×300 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a red oil, which was purified by column chromatography on silica gel (petroleum ether: EtOAc=2:1) to afford 2-cyclopropylpyrimidine-5-carbaldehyde (7.6 g, yield: 53.5%). 1H NMR (CDCl3 400 MHz): δ 10.06 (s, 1H), 8.99 (s, 2H), 2.41-2.35 (m, 1H), 1.32-1.21 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:21])[F:22])=[CH:17][CH:16]=1)=[O:20])[CH3:2]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(CN)OCC
Product: CCOC(CNC(=O)Nc1ccc(C(F)(F)F)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To aminoacetoaldehyde diethylacetal (7.8 ml, 53.6 mmol) was added dropwise 10 g (53.4 mmol) of 4-trifluoromethylphenylisocyanate at 0° C. during five minutes. The reaction solution was stirred for one hour at room temperature. The crystals thus produced was collected by filtration and washed with hexane to give 16.2 g of 1-(2,2-diethoxyethyl)-3-(4-trifluoromethylphenyl)urea (95%) as a colorless powder.
Reaction SMILES: NC1C=C(OC)C(OC)=CC=1C(C1C=CC=CC=1OC)=O.NC1C(C)=NN(CC=C)C=1Cl.[CH3:33][O:34][C:35]1[C:36]([O:61][CH3:62])=[CH:37][C:38]2[N:44]=[C:43]3[N:45](CC=C)[NH:46][C:47]([CH3:48])=[C:42]3[N:41]=[C:40]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[O:58][CH3:59])[C:39]=2[CH:60]=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:33][O:34][C:35]1[C:36]([O:61][CH3:62])=[CH:37][C:38]2[N:44]=[C:43]3[NH:45][NH:46][C:47]([CH3:48])=[C:42]3[N:41]=[C:40]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[O:58][CH3:59])[C:39]=2[CH:60]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3OC)c3cc(OC)c(OC)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COc1cc(N)c(C(=O)c2ccccc2OC)cc1OC
Product: COc1cc2c(cc1OC)C(c1ccccc1OC)=NC1=C(C)NNC1=N2

Procedure:
1,2-dihydro-7,8-dimethoxy-5-(2-methoxyphenyl)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVaa) was prepared by reacting 0.0023 moles of (2-amino-4,5-dimethoxyphenyl)-(2-methoxyphenyl)-methanone (Xaa) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 1,2-dihydro-7,8-dimethoxy-5-(2-methoxyphenyl)-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVaa) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=365.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:21]I>CN(C)C=O.O>[CH3:21][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
17.5 g of cis-4,5-diphenyl-imidazolidine-2-thione are dissolved in 200 ml of dimethylformamide and first a solution of 3.2 g of sodium hydroxide in 20 ml of water and then 11.6 g of methyl iodide are added. The mixture is stirred for 6.5 hours at room temperature and evaporated to dryness, the residue is stirred with 350 ml of water and, after leaving to stand for some time, the mixture is filtered with suction, the solid material from the mixture is dissolved, whilst still moist, in 350 ml of ethanol and 50 ml of 2 N sodium hydroxide solution and 170 ml of water are added. The crystalline precipitate is filtered off with suction, filtered through silica gel using chloroform as the eluant and recrystallised from isopropanol/petroleum ether. cis-2-Methylthio-4,5-diphenyl-imidazoline with a melting point of 132°-134° is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[C:13]([C:15]([C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)=[O:22])([CH3:17])[CH3:16])#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]([C:15]([C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])[CH:25]=1)=[O:22])([CH3:17])[CH3:16])#[N:14]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(O)c2)c1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cc3C#N)c2)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
To a solution of 3-cyano-4-fluoronitrobenzene (1.76 g, 10.5 mmol) and 3-(1-cyano-1-methylethyl)-N-(3-hydroxyphenyl)benzamide (2.97 g, 10.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (2.17 g, 15.7 mmol), and the mixture was stirred at 70° C. for 12 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off, water (100 ml) was added to the filtrate, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, and insoluble material was filtered off. The obtained organic layer was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (4.21 g, 94%) as a yellow oil.
Reaction SMILES: CN(CCN(C)C)C.C([Li])(CC)C.C1COCC1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29](Cl)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O.C(OCC)(=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]2[CH:27]1[CH2:28]2)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(Cl)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2CC21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
TMEDA (0.11 mL) was slowly added dropwise at −78° C. to a mixture of sec-butyllithium (1.4 M; 0.52 mL) and THF (1.8 mL). Then it was stirred for a further 30 min at −78° C. and then a solution of 4-chloro-piperidine-1-carboxylic acid tert-butyl ester (160 mg) in a little THF was slowly added dropwise. The reaction mixture was stirred for 2 h at −78° C., then it was allowed to return slowly to room temperature. Ethyl acetate and water were added to the reaction mixture and the aqueous phase was extracted several times with ethyl acetate. The organic phases were combined, dried over sodium sulfate and the solvent was removed in vacuum.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[N:9]=[C:8]([C:10]2[S:14][C:13]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[O:7][N:6]=1.[CH2:23]([N:30]=[C:31]=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([NH:30][C:31]([NH:3][CH2:4][C:5]1[N:9]=[C:8]([C:10]2[S:14][C:13]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[O:7][N:6]=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=NCc1ccccc1
Reactant: NCc1noc(-c2ccc(CN3CCCCCC3)s2)n1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)NCc1noc(-c2ccc(CN3CCCCCC3)s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
770 mg (2.63 mmol) of the free form compound obtained in Example 8 was dissolved in 20 ml of DMF, and 5 ml of DMF solution containing 369 mg (2.77 mmol) of benzyl isocyanate was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under a reduced pressure, and the resulting residue was dissolved in chloroform, washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was subjected to a silica gel column chromatography, which was eluted with chloroform-methanol (50:1) to give 1.0 g of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:54]=[CH:53][C:10]([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[C:25]([N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[CH:24]=[CH:23][C:22]=4[NH:33][C:34]([C:36]4[CH:37]=[C:38]([CH:50]=[CH:51][CH:52]=4)[CH2:39][S:40][CH2:41][CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])=[O:35])[CH:16]=3)=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:54]=[CH:53][C:10]([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[C:25]([N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[CH:24]=[CH:23][C:22]=4[NH:33][C:34]([C:36]4[CH:37]=[C:38]([CH:50]=[CH:51][CH:52]=4)[CH2:39][S:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:35])[CH:16]=3)=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(N4CCOCC4)cc3)ccn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(N4CCOCC4)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(3-(2-(4-(4-morpholinobenzylcarbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenylcarbamoyl)-benzylthio)propanoate (170 mg, 0.20 mmol, 1.00 equiv, 86%) in dichloromethane (20 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The solution was adjusted to pH 7-8 with NaHCO3 (aq). The resulting solution was extracted with 3×30 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×30 mL of brine, dried over NaSO4 and concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 17 mg (13%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 8.96 (s, 1H), 8.49 (m, 1H), 8.34 (s, 1H), 7.79 (m, 4H), 7.54 (m, 3H), 7.16 (m, 2H), 6.89 (m, 2H), 4.42 (s, 2H), 3.86 (s, 2H), 3.70 (m, 5H), 3.49 (s, 4H), 3.04 (m, 4H), 2.60 (m, 2H), 1.78 (m, 6H). MS (ES, m/z): 694 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:7][C:6](=[O:23])[N:5]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[N:4]=1)#[N:2].[ClH:34].O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:34].[CH3:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([N:5]2[C:6](=[O:23])[CH:7]=[C:8]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:3]([C:1]#[N:2])=[N:4]2)=[CH:29][CH:28]=1)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)nc2C#N)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirring solution of tert-butyl 4-(3-cyano-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (700 mg, 1.475 mmol) in DCM (10 mL) at room temperature under argon was added 4 M HCl in dioxane (3.69 mL, 14.75 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (2 mL×2). After drying under vacuum for 2 hours, 567 mg (90%) of 1-(4-(methylsulfonyl)phenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt was obtained as an off-white solid. MS (ESI) 375 (M+H).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([O:13][CH3:14])[CH:7]=1)[C:3](=O)[CH3:4].[C:15]([NH:18][C:19]([NH2:21])=[S:20])(=[O:17])[CH3:16]>C(O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:20][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[N:21][C:3]=2[CH3:4])=[CH:7][C:8]=1[O:13][CH3:14]
Reactant: CC(=O)NC(N)=S
Reactant: COc1cc(C(Br)C(C)=O)ccc1F
Solvent: CCO
Product: COc1cc(-c2sc(NC(C)=O)nc2C)ccc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-Bromo-1-(4-fluoro-3-methoxy-phenyl)-propan-2-one (161b) (0.72 g, 2.74 mmol) is dissolved in ethanol (20 ml) and N-acetylthiourea (0.324 g, 2.72 mmol) is added in one portion. The mixture is stirred at 80° C. overnight then allowed to cool whereupon the product crystallised. Filtration affords the title compound as a white solid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:11][CH2:10][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:8]#[N:9])[CH2:6][CH2:5]1.[ClH:18].S(Cl)([Cl:21])=O>C(Cl)Cl>[ClH:21].[Cl:18][CH2:2][CH2:3][N:4]1[CH2:11][CH2:10][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:8]#[N:9])[CH2:6][CH2:5]1
Reactant: O=S(Cl)Cl
Reactant: N#CC1(c2ccccc2)CCN(CCO)CC1
Agent: Cl
Solvent: ClCCl
Product: N#CC1(c2ccccc2)CCN(CCCl)CC1

Procedure:
A solution is prepared from 5.9 parts of the nitrile obtained in the preceding paragraph and 134 parts of methylene chloride. This solution is saturated with hydrogen chloride gas at below 10° C. and 5.1 parts of thionyl chloride is added. The mixture is refluxed for 1 hour and then cooled and volatile material is removed under reduced pressure. The residue is dissolved in 88 parts of benzene, and the solution evaporated under reduced pressure. The residue is then crystallized from a mixture of ethanol and ether to give 1-(2-chloroethyl)-4-phenylisonipecotonitrile hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([O:21][CH3:22])[C:3]=1[OH:23].[C:24](Br)(=[O:26])[CH3:25]>FC(F)(F)C(O)=O>[C:24]([O:23][C:3]1[C:4]([O:21][CH3:22])=[C:5]([S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][C:7]=2[C:2]=1[Cl:1])(=[O:26])[CH3:25]
Reactant: COc1c(O)c(Cl)c2c(c1Sc1ccccc1)CCN(C)CC2
Reactant: CC(=O)Br
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OC(C)=O)c(Cl)c2c(c1Sc1ccccc1)CCN(C)CC2

Procedure:
A mixture of 0.45 g. (0.0013 mole) of 9-chloro-8-hydroxy-7-methoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine and 0.2 ml. (0.0026 mole) of acetyl bromide in trifluoroacetic acid is heated to reflux on a steam bath for 2 hours. The reaction mixture is concentrated and the residue is taken up in 100 ml. of methylene chloride. This solution is dried and evaporated to give 8-acetoxy-9-chloro-7-methoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=5[F:38])[CH:33]=O)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:50]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)(=[O:52])[CH3:51]>>[C:50]([N:53]1[CH2:58][CH2:57][N:56]([CH2:33][C:32]2[CH:35]=[CH:36][C:37]([F:38])=[C:30]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:39][C:40]6[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=6)[CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)[CH:31]=2)[CH2:55][CH2:54]1)(=[O:52])[CH3:51]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C=O)ccc3F)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(CN4CCN(C(C)=O)CC4)ccc3F)cn2)cc1

Procedure:
In the same manner as Example 1-D-151, using a crude product of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-benzaldehyde (130 mg) and 1-acetylpiperazine (50 mg) instead of 1-ethylpiperazine, a crude product of 5-{7-[5-(4-acetyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine was obtained as colorless solid (63 mg). Using the crude product (63 mg) of 5-{7-[5-(4-acetyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine, according to the above Deprotection method 2,1-(4-{3-[4-(2-amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-4-fluoro-benzyl}-piperazin-1-yl)-ethanone was obtained as a colorless powder (30 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([C:22]([O:24][CH2:25]C)=[O:23])[CH3:21]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([C:22]([O:24][CH3:25])=[O:23])[CH3:21]
Reactant: CCOC(=O)C(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br
Solvent: CO
Product: COC(=O)C(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br

Procedure:
A solution of 2.5 g. of N-[4-bromo-3-(1-ethoxycarbonylethyloxy)phenyl]-3,4,5,6-tetrahydrophthalimide in 30 ml. of methanol was prepared and HCl gas was bubbled at room temperature for 0.5 hour and then, the reaction mixture was kept for one night. The precipitate was separated by a filtration and washed with methanol to obtain 2.21 g. of Compound No. 16 shown in Table 1.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].N[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.CO>C(O)(=O)C>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([S:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:16]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)[CH:21]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3nc(C)ccc23)c1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To a solution of the product from Example 10B (100 mg, 0.575 mmol) and the product from Example 9c (146 mg, 0.632 mmol) in acetic acid (1 mL) was heated at 130° C. for 1 hour. The mixture was then allowed to cool to room temperature, then methanol (5 mL) added to the solution and the resulting solid collected and washed with methanol to provide the title compound (120 mg, 56%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.29 (s, 3H), 2.66 (s, 3H), 6.73 (d, J=8.8 Hz, 2H), 6.93 (m, 1H), 7.03 (m, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.26, (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 8.53 (s, 1H), 8.77 (m, 1H), 9.76 (bs, 1H), 9.96 (bs, 1H); MS (ESI)+ m/z 375 (M+H)+.
Reaction SMILES: [N+:1](C1C=C(C=CC=1C)C(O)=O)([O-:3])=[O:2].FC1C=C(C=CC=1C)C(O)=O.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=[CH:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][C:42]=1F)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=[CH:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][C:42]=1[N+:1]([O-:3])=[O:2])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(C=Cc2ccccc2OCc2ccccc2)c(F)c1
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cc1ccc(C(=O)O)cc1F
Product: COC(=O)c1ccc(C=Cc2ccccc2OCc2ccccc2)c([N+](=O)[O-])c1

Procedure:
Methyl 4-[2-(2-benzyloxyphenyl)ethenyl]-3-nitrobenzoate was prepared from 3-nitro-4-methylbenzoic acid using the methods described in Example 8 for the conversion of 3-fluoro-4-methylbenzoic acid to methyl 4-[2-(2-benzyloxyphenyl)ethenyl]-3-fluorobenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(=O)C1(c2ccc(Br)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-bromo-phenyl)-cyclopropanecarboxylic acid (5.0 g, 20.7 mmol) in toluene (30 mL) was slowly added thionyl chloride (17.7 mL, 243 mmol), and the reaction was refluxed for 4 hours. The mixture was concentrated, and the crude material was dissolved in toluene (50 mL). Methanesulfonamide (11.41 g, 120 mmol) was added, followed by triethylamine (15 mL), and the reaction was refluxed for 3 hours. After cooling to room temperature, the mixture was poured in CH2Cl2 (200 mL) and washed with H2O (150 mL). The organic layer was dried over MgSO4, filtered, and concentrated, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=1)[C@H:3]([OH:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:34]=[C:35]([C:42]([N:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][CH3:47])=[O:43])[CH:36]=[C:37]([CH:41]=1)[C:38](O)=[O:39].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][C@H:2]([NH:1][C:38](=[O:39])[C:37]1[CH:41]=[C:33]([CH3:32])[CH:34]=[C:35]([C:42]([N:44]([CH2:45][CH2:46][CH3:47])[CH2:48][CH2:49][CH3:50])=[O:43])[CH:36]=1)[C@H:3]([OH:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(OC)c2)c1

Procedure:
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol (VIII, EXAMPLE 6) is dissolved in anhydrous DMF (3 mL) and cooled to 0°. Triethylamine (500 μL, 3.6 mmol) and 5-methyl-N, N-dipropylisophthalamic acid (IX, 156 mg, 0.59 mmol) are added with stirring. The mixture is warmed to 20-25° briefly to allow for complete dissolution of the carboxylic acid, before recooling to 00. 1-Hydroxybenzotriazole (157 mg, 1.2 mmol) is added with stirring, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (229 mg, 1.2 mmol). The resulting mixture is stirred at 0° for 5 min, then warmed to 20-25° for 15 hr. The mixture is then quenched with aqueous citric acid (10%), and the mixture extracted three times with ethyl acetate. The combined organic extracts are washed with saturated sodium bicarbonate, saline, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound in crude form. This material is purified by flash chromatography (2-10% methanol/methylene chloride gradient elution) to give purified title compound, MS (ES) MH+=582.3.