Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])=O>>[F:20][C:17]([F:18])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:21][C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: N#Cc1cccc(C=O)c1
Product: N#Cc1cccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-formylbenzonitrile was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,4-diazepan-1-yl]methyl]benzonitrile.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([N:19]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]4[C:20]3=[O:29])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][CH2:39][CH2:40]Br.O>CN(C)C=O>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:40][CH2:39][O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)[C:10](=[O:18])[CH:9]([N:19]3[C:20](=[O:29])[C:21]4=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]4[C:23]3=[O:24])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCOC1CCCCO1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1CCOC1CCCCO1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a solution of (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepine-2-one (1.90 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (62% suspension in mineral oil; 0.20 g) gradually with stirring under cooling in an ice-bath (<3° C.). The mixture was stirred for 10 minutes under the same conditions. To the resultant mixture was added 2-[(tetrahydropyran-2-yl)oxy]ethyl bromide (1.60 g) in one portion. The mixture was stirred at ambient temperature for one hour and at 45° C. for 4.5 hours and allowed to stand overnight. The resultant reaction mixture was poured into water and extracted with ethyl acetate twice. The extract was washed with water and dried over magnesium sulfate. Removal of the solvent gave light yellow powder, which was washed with a mixture of ethyl acetate and diethyl ether and collected by filtration to afford a mixture (1.48 g) of (3RS)-1,3-dihydro -5-phenyl-3-phthalimido-1-{2-((RS)-2-tetrahydropyranyloxy) ethyl}-2H-1,4-benzodiazepine-2-one and (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-{2-((SR)-2tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine-2-one.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH3:5])[CH2:2]1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([Mg]Br)[CH:11]=[CH:12][CH:13]=1>C1COCC1.[Cu]I>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:2][CH:3]([OH:1])[CH2:4][CH3:5])[CH:11]=[CH:12][CH:13]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: CCC1CO1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCC(O)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirred suspension of CuI (0.40 g, 2.08 mmol) in 3-methoxyphenylmagnesium bromide in THF (31.2 mL, 1.0M THF solution, 31.2 mmol) at −20° C. was slowly added a solution of 1,2-epoxybutane (1.50 g, 20.8 mmol) in THF (1 mL). The mixture was allowed to warm up to room temperature and stirred at room temperature overnight. The reaction mixture was cooled in an ice bath and quenched with saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate (3×70 mL). The combined organic phase was washed with 1 N NaOH, brine, dried (Na2SO4) filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (4:1) to give 3.50 g (94%) of compound (51) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.00 (t, J=7.4 Hz, 3H), 1.50-1.65 (m, 2H), 2.62 (dd, J1=13.5 Hz, J2=8.6 Hz, 1H), 2.82 (dd, J1=13.5 Hz, J2=4.1 Hz, 1H), 3.74-3.79 (m, 1H), 3.80 (s, 3H), 6.75-6.85 (m, 3H), 7.20-7.25 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[C:9]([CH3:11])[N:10]=[C:4]2[CH:3]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]>>[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH:32]([OH:33])[C:8]3[N:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]4=[N:10][C:9]=3[CH3:11])[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: Cc1nc2cc(Br)ccn2c1I
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C)nc4cc(Br)ccn34)cc2COc2cc(F)ccc21
Yield: 100.8 %

Procedure:
[step 3] Using 7-bromo-3-iodo-2-methylimidazo[1,2-a]pyridine (3.2 g, 9.5 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (1.7 g, 5.9 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 14A, step 3, (E)-2-{3-fluoro-8-[hydroxy(7-bromo-2-methylimidazo[1,2-a]pyridin-3-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (3.0 g, 99%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=N1.N1CCCC1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([C:27]([N:37]5[CH2:38][CH2:43][CH2:42][CH2:41]5)=[O:28])[CH2:25][CH2:26]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Product: O=C([C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1)N1CCCC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[trans-4-carboxycyclohexylamino]pyrimido[5,4-d]pyrimidine by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and pyrrolidine. Melting point: 206°-209° C.; Rf : 0.52 (silica gel; petroleum ether/ethyl acetate/methanol=10:8:3)
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([Br:13])=[N:9][CH:10]=[CH:11][CH:12]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.O>C(O)C>[Br:13][C:8]1[C:7]([CH2:6][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: CS(=O)(=O)OCc1cccnc1Br
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Brc1ncccc1Cn1ccnc1
Temperature: 50 °C
Yield: 63.5 %

Procedure:
To a solution of (2-bromo-3-pyridyl)methyl methanesulfonate (2.5 g, 9.39 mmol) in ethanol (46.97 mL) at room temperature, potassium carbonate (2.62 g) and 1H-imidazole (1.31 g) are added. The mixture is stirred at 50° C. A thick sort of emulsion is formed and 10 mL of ethanol is added and the kind of emulsion is stirred at 50° C. overnight. Water is added until all solids are dissolved. Then, it is concentrated under reduced pressure and the residue is diluted with ethyl acetate and washed with sodium bicarbonate (saturated aqueous solution). Organic layer is decanted, dried over magnesium sulfate and solvent evaporated in vacuo. Crude material is purified by normal phase Isco chromatography using as eluent dichloromethane and methanol (98/2 to 90/10) to yield 1.42 g of the title compound. MS (m/z): 238, 240 (M+1, M+3).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.[CH2:19]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](Br)[CH:26]=1)(=[O:24])=[O:23])[CH3:20]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:27]2[CH:26]=[C:25]([S:22]([NH:21][CH2:19][CH3:20])(=[O:23])=[O:24])[CH:30]=[CH:29][C:28]=2[CH3:31])[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCNS(=O)(=O)c1ccc(C)c(Br)c1
Product: CCNS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and N-ethyl 3-bromo-4-methylbenzenesulfonamide (Combi-Blocks), the title compound was obtained as a beige solid after purification by preparative HPLC.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]([CH3:27])[C:15]1[CH:16]=[CH:17][C:18]([CH3:26])=[C:19]([CH:25]=1)[C:20]([N:22]([CH3:24])C)=[O:21].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)C#N>C1COCC1>[CH3:27][N:14]([CH3:13])[C:15]1[CH:25]=[C:19]2[C:18]([CH:26]=[C:24]([C:36]3[CH:35]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:37]=3)[NH:22][C:20]2=[O:21])=[CH:17][CH:16]=1
Reactant: Cc1ccc(N(C)C)cc1C(=O)N(C)C
Reactant: COc1cccc(C#N)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cccc(-c2cc3ccc(N(C)C)cc3c(=O)[nH]2)c1
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
To a solution of diisopropylamine (1.5 g, 15 mmol) in dry THF (10 mL) was added n-BuLi (6 mL of 2.5 M in hexane, 15 mmol) at −78° C. After 30 min, a solution of 5-dimethylamino-2,N,N-trimethylbenzamide (2.06 g, 10 mmol) in THF (15 mL) was added dropwise at −78° C., the red orange solution was stirred at the same temperature for 1 h. The solution of 3-methoxybenzonitrile (1.7 g, 13 mmol) in dry THF (10 mL) were added and the reaction mixture was stirred at −78° C. for 2 h. The reaction solution was quenched with water and extracted with ethyl acetate and dried over sodium sulfate. After removing the solvent, the residue was purified by column chromatography with n-hexane-ethyl acetate (3:1) to afford compound I as yellow solid (596 mg, 20%). 1H NMR (300 MHz, CDCl3) δ: 9.73 (s, 1H), 7.61 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.38 (m, 1H), 7.23-7.22 (m, 3H), 6.96 (m, 1H), 6.74 (s, 1H), 3.90 (s, 3H), 3.09 (s, 6H).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:17][N:18]([CH3:23])[S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:17][N:18]([CH3:23])[S:19]([N:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1)(=[O:21])=[O:20]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1nc2c([nH]1)CCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1cnc2c1CCCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76.9 %

Procedure:
To solution of 4,5,6,7-tetrahydro-1H-benzoimidazole (1.9992 g, 16.4 mmol) and triethylamine (4.60 mL, 32.8 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise a solution of dimethyl sulfamoyl chloride (1.76 mL, 16.4 mmol) in CH2Cl2 (10 mL). The reaction was warmed to room temperature and stirred for 3.5 hours. CH2Cl2 (80 mL) was added and the organic phase was washed with distilled water (1×80 mL). The aqueous washing was extracted with CH2Cl2 (2×40 mL), and the combined organic extracts were washed with brine (1×80 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (2:1 hexanes-EtOAc) provided 2.89 g (77%) of 4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide as a white solid. 1H NMR (CDCl3) δ 1.77-1.86 (m, 4H), 2.58-2.61 (m, 2H), 2.72 (t, 2H, J=6 Hz), 2.87 (s, 6H), 7.77 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].I[CH2:26][CH2:27][CH3:28]>>[CH2:26]([O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:27][CH3:28]
Reactant: Cc1cc2c(cc1-c1ccc(O)c(C=O)c1)C(C)(C)CCC2(C)C
Reactant: CCCI
Product: CCCOc1ccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Yield: 97.3 %

Procedure:
In a similar manner to Example 10(b), by reaction of 2 g (6.2 mmol) of 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) benzaldehyde [prepared in Example 16(a)] with 670 μl (6.8 mmol) of 1-iodopropane, 2.2 g (88%) of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][Mg]Cl.[C:4]([NH:12][C:13]1([CH2:17][CH:18]=[O:19])[CH2:16][CH2:15][CH2:14]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH4+].[Cl-]>C1COCC1>[C:4]([NH:12][C:13]1([CH2:17][CH:18]([OH:19])[CH3:1])[CH2:16][CH2:15][CH2:14]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CCC1(NC(=O)c2ccccc2)CCC1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)CC1(NC(=O)c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
Methyl magnesium chloride (14.0 mL, 3M solution in THF) was added to a stirred solution of [1-(benzoylamino)cyclobutyl]acetaldehyde (2.82 g, 13.0 mmol) in THF (30 mL) at −0° C., and the mixture was stirred at room temperature for 5 hours. Saturated aqueous NH4Cl (10 mL) was added to the mixture 0° C., and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (hexane:AcOEt=2:1) of the residue gave the title compound as a colorless oil (2.65 g, 87%). 1H-NMR (400 MHz, CDCl3) δ 1.25 (3H, d, J=6.1 Hz), 1.77-2.12 (5H, m), 2.28-2.40 (1H, m), 2.52 (1H, q, J=10.4 Hz), 2.75-2.85 (1H, m), 3.26 (1H, d, J=3.7 Hz), 3.97-4.07 (1H, m), 6.91 (1H, brs), 7.39-7.46 (2H, m), 7.46-7.53 (1H, m), 7.75-7.82 (2H, m).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][NH2:43]>>[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][NH:43][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:35][CH:36]=2)=[CH:7][CH:8]=1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: NCc1ccco1
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CNCc3ccco3)cc2)cc1

Procedure:
The same procedure as in Example 16-(2) was performed using (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.12 g) as obtained in Example 16-(1) and 1-(furan-2-yl)methanamine (34 mg), whereby (2S)-2-[{4-[(4-{[(furan-2-ylmethyl)amino]methyl}phenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow oil) was obtained (93 mg, 67%).
Reaction SMILES: [C:1]([NH:4][C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])[NH2:2].S(=O)(=O)(O)[OH:14].OO>>[C:1]([NH:4][C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]([O:11][OH:14])=[O:10])(=[O:3])[NH2:2]
Reactant: NC(=O)NC(=O)CCCC(=O)O
Reactant: O=S(=O)(O)O
Agent: OO
Product: NC(=O)NC(=O)CCCC(=O)OO

Procedure:
87 g (0.5 mol) of N-(carbamoyl)glutaramic acid, 175 g of sulfuric acid and 102 g (1.5 mol) of hydrogen peroxide (50% strength by weight) are reacted and worked up as described in Example 3.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][OH:12].Cl[C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:25]3[N:26]=[C:27]([N:55]4[CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[N:28]=[C:29]([C:30]4[CH:31]=[N:32][C:33]([N:36]([CH2:46][C:47]5[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=5)[CH2:37][C:38]5[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=5)=[N:34][CH:35]=4)[C:24]=3[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[H-].[Na+]>O>[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][O:12][C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:25]3[N:26]=[C:27]([N:55]4[CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[N:28]=[C:29]([C:30]4[CH:31]=[N:32][C:33]([N:36]([CH2:46][C:47]5[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=5)[CH2:37][C:38]5[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=5)=[N:34][CH:35]=4)[C:24]=3[CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(OCCN(C)C)nc3)cn2)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
To a toluene solution (2 ml) of N,N-dimethylethanolamine (139 μl, 0.138 mmol) and {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (150 mg, 0.23 mmol) obtained in Step A in Example 1-D-48, 60% oily NaH (46 mg) was added, followed by refluxing for 4 hours. The reaction mixture was cooled to room temperature, and diluted with water, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, followed by filtering off the magnesium sulfate, and subsequently the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1), to obtain a crude product of (5-{7-[6-(2-dimethylamino-ethoxy)-pyridin-3-yl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-bis-(4-methoxy-benzyl)-amine as a yellow solid (67 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-72) as a yellow powder (12 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([CH2:19][C:20]3[CH:21]=NC=[CH:24][CH:25]=3)=[C:16]([OH:18])[CH:17]=2)=[CH:4][CH:3]=1.CC(C)([O-:29])C.[K+]>C(O)(C)(C)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([CH2:19][CH:20]3[CH2:25][CH2:24][O:29][CH2:21]3)=[C:16]([OH:18])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2ccc(Cc3cccnc3)c(O)c2)c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Nc1ccc(-c2ccc(CC3CCOC3)c(O)c2)c2ccccc12
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 19 %

Procedure:
To a solution of 200 mg of tert-butyl naphthyl carbamate (Example 6) (0.59 mmol, 1 equiv.) in 1.6 mL anhydrous tert-butanol was added 200 mg of 3-tetrahydrofuroic aldehyde from above (excess) and 1.78 mL potassium tert-butoxide solution in tert-butanol (1.0 M, 1.78 mmol, 3 equiv.). The mixture was heated to 40° C. overnight, then cooled and quenched with NH4Cl saturated aqueous solution. The product was extracted with a dichloromethane/MeOH mixture (3×100 mL). The combined extracts were washed with brine, dried over MgSO4, and concentrated. 1H NMR analysis revealed that only 10% of the enone was consumed. The residue (300 mg) was dissolved in 4.0 mL dichloromethane and treated with 4 mL of a 1:1 mixture dichloromethane: TFA. The mixture was stirred for 1.5 h, then neutralized with saturated NaHCO3 aqueous solution, basified with 4 N NaOH solution and extracted with dichloromethane/MeOH (3×100 mL). The combined organic extracts were washed with brine, dried (MgSO4) and filtered and concentrated. The crude product was purified by column chromatography on silica gel using 10 to 50% EtOAc in hexane eluent mixtures to give the title compound (35 mg 0.11 mmol, 19% of theoretical yield).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCN(Cc2ccccc2)CC1
Yield: 89 %

Procedure:
The experimental protocol used is the same as that described for compound 6.1, 2-fluoro-5-nitrobenzonitrile replacing 2-fluoro-5-nitrotoluene and 1-benzylpiperazine replacing tert-butyl 1-piperazinecarboxylate. A light ochre-coloured solid is obtained (yield 89%). Melting point: 124.0° C.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].FC(F)(F)C(O)=O.[OH:13][CH2:14][C@@H:15]1[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][CH:4]([O:13][CH2:14][C@@H:15]1[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16]1)[CH3:5])[CH3:2]
Reactant: O=C1CCC[C@H](CO)N1
Reactant: C=COCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(C)OC[C@H]1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
Ethyl vinyl ether (1.68 mL, 17.5 mmol) and trifluoroacetic acid (0.1 mL) were added sequentially to a solution of (R)-6-hydroxymethylpiperidin-2-one (prepared from D-α-aminoadipic acid according to Huang, et al., Synth. Commun. 1989, 19, 3485–3496, 1.62 g, 12.5 mmol) in CHCl3 (10 mL) at rt. The reaction mixture was stirred at rt for 18 h, then saturated aqueous NaHCO3 (100 mL) was added and the mixture was extracted with CH2Cl2 (3×75 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→4% MeOH/CH2Cl2, gradient) afforded 2.03 g (80%) of (R)-6-(1-ethoxyethoxymethyl)-piperidin-2-one.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.[C:16]([C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:21](N(OC)C)=[O:22])#[N:17]>C1COCC1>[CH3:31][O:30][C:29]1[CH:28]=[CH:27][C:20]([C:21](=[O:22])[C:7]#[C:6][C:4]([CH3:8])([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])[CH3:5])=[CH:19][C:18]=1[C:16]#[N:17]
Reactant: C#CC(C)(C)O[Si](C)(C)C
Reactant: COc1ccc(C(=O)N(C)OC)cc1C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C#CC(C)(C)O[Si](C)(C)C)cc1C#N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
To a −78° C. stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (1.9 g, 12.501 mmol) in dry THF (25 mL), n-BuLi (2.80 mL, 4.50 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction was stirred for 30 min at −78° C., and then a solution of 3-cyano-N,4-dimethoxy-N-methylbenzamide (1.10 g, 5.01 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 3 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc in hexanes to afford 2-methoxy-5-(4-methyl-4-(trimethylsilyloxy)pent-2-ynoyl)benzonitrile (0.8 g, 56%) as a pale yellow oil.