Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[N:14]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N[C@@H]2CCCC[C@H]2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@@H]2CCCC[C@H]2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a solution of 1.146 g (3.1 mmol) of the product from Example 3 in 31 mL of DMF was added 0.137 g (3.42 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at 25° C. and then 0.42 mL (3.50 mmol) of benzyl bromide was added all at once. This reaction mixture was stirred for 10 hr at 55° C. and then poured into water and extracted with ether. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid which was recrystallized from ethyl acetate/Hexanes to provide 1.364 g (95%) of the desired product. 1H NMR(CDCl3): 7.7 ppm (dd, 2H, Ar), 7.1-7.4 (m, 5H, Ar), 6.9 ppm (dd, 2H, Ar), 4.5-4.7 ppm (AB quartet, 2H, CH2—Ar), 3.9 ppm (s, 3H, OMe), 4.0 ppm (m, 1H, N—CH), 2.9 ppm (m, 1H, CH—CO2—), 1.0-2.3 ppm (m, 17H, hydrocarbon protons).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]([O:12][CH:13]2[CH:17]([OH:18])[CH2:16][O:15][CH2:14]2)=[O:11])=[CH:6][C:5]([N:19]2[C:23](=[O:24])[C:22]3[CH2:25][CH2:26][CH2:27][CH2:28][C:21]=3[C:20]2=[O:29])=[C:4]([F:30])[CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C1C=CC=CC=1>[C:38]([O:18][CH:17]1[CH2:16][O:15][CH2:14][CH:13]1[O:12][C:10]([CH2:9][O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:30])=[C:5]([N:19]2[C:20](=[O:29])[C:21]3[CH2:28][CH2:27][CH2:26][CH2:25][C:22]=3[C:23]2=[O:24])[CH:6]=1)=[O:11])(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: O=C(COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl)OC1COCC1O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)OC1COCC1OC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
In 15 ml of benzene were dissolved 0.66 g of N-(4-chloro-2-fluoro-5-(4-hydroxytetrahydrofuran-3-yloxycarbonylmethoxy)phenyl)-3,4,5,6tetrahydrophthalimide and 0.20 g of triethylamine, followed by dropwise addition of a solution of 0.14 g of acetyl chloride in benzene. After stirring at room temperature for 4 hours, the reaction mixture was washed with water and subsequently with aqueous saturated sodium chloride solution, and 'dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane=2/3), to obtain 0.55 g of a compound described in Table 1 (No.3) (76%).
Reaction SMILES: [C:1]1([CH:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.O.[OH:47]S([O-])(=O)=O.[K+]>CCOC(C)=O>[C:1]1([CH:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)([C:29]([F:30])([F:31])[F:32])[C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=2)[CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]=[O:47])=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)([O-])O
Reactant: COc1ccc(COC(c2ccc(OC(COc3ccc(C)cc3)c3ccccc3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(COC(c2ccc(OC(COc3ccc(C=O)cc3)c3ccccc3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Yield: 48 %

Procedure:
90 mg (0.15 mmol) of rac 1-(1-phenyl-2-p-tolyloxy-ethoxy)-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-benzene in 3 ml of a mixture of acetonitrile:water (9:1) were treated with 100 mg (0.18 mmol) of ceric ammonium nitrate at room temperature overnight. An additional 100 mg (0.18 mmol) of ceric ammonium nitrate were added and stirring was continued. EtOAc and 1M KHSO4 were added and the phases were separated. The inorganic one was extracted with EtOAC, the combined organic phases were washed with brine, dried (Na2SO4) and evaporated. Column chromatography on silica gel gave 44 mg (48%) of rac 4-(2-phenyl-2-{4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-benzaldehyde, MS: 663 (M+OAc)−.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=1.C(=O)(O)[O-].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(OCC)(=O)C>[O:17]=[C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH:4]=[C:3]([NH:2][C:25](=[O:26])[CH2:24][Cl:23])[CH:16]=[CH:15][C:14]=2[NH:13]1
Reactant: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
To a suspension of HCl salt of 2-amino-6(5H)-phenanthridinone (3.4 g, 0.014 mol) in ethyl acetate (200 mL) was added saturated solution of sodium bicarbonate (200 mL), followed by addition of chloroacetyl chloride (5.6 mL, 0.07 mol). The reaction mixture was stirred at room temperature for 2 days. The solid that separated out was filtered and washed thoroughly with cold water. It was then dried under vacuum to give N-(6-oxo-5, 6-dihydro-phenanthridin-2-yl)-chloroacetamide (3.35 gm, 85%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)OCC2C=CC=CC=2)=[C:11]([C:26]([N:28]([O:30][CH3:31])[CH3:29])=[O:27])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCCC1>C(O)C.[C].[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])=[CH:10][C:11]=1[C:26]([N:28]([O:30][CH3:31])[CH3:29])=[O:27]
Reactant: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
To a solution of benzyl (4-{[tert-butyl(dimethyl)silyl]-oxy}-2-{[methoxy(methyl)amino]carbonyl}phenyl)carbamate (91 g, 0.20 mol) in ethanol (250 ml)-tetrahydrofuran (250 ml) was added 5% palladium-carbon (25 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was crystallized from n-hexane to give 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide (44 g, yield 70%) as white crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[C:9](#[N:12])[CH:10]=[CH2:11]>>[C:9]([CH2:10][CH2:11][NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8])#[N:12]
Reactant: NC1CCCCC1N
Reactant: C=CC#N
Product: N#CCCNC1CCCCC1N

Procedure:
1,2-diaminocyclohexane (1) is cyanoethylated with acrylonitrile in the presence of an acid catalyst (Equation 1) with one mole ##STR17## of acrylonitrile the monocyanoethylated product, N-(2-Cyanoethyl)-1,2-cyclohexanediamine, (2), is formed, two moles of acrylonitrile react to give the dicyanoethylated product, N,N'-di-(2-cyanoethyl)-1,2-diaminocyclohexane, (3).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#N.[H-].C([Al+]CC(C)C)C(C)C.[O:22]1CCOCC1.O.Cl>CCOCC.CCCCCC>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)=[O:22]
Reactant: C1COCCO1
Reactant: N#Cc1cccc2[nH]ccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: O=Cc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Two grams of 4-cyanoindole, prepared by the method of Uhle J.A.C.S., 71, 761 (1949), were dissolved in 20 ml of anhydrous ether. 15 Milliliters of a 20% solution of diisobutylaluminum hydride (DiBAl) in hexane were added in dropwise fashion. The reaction mixture was stirred at room temperature for about 30 minutes and then heated to refluxing temperature for about three hours. The reaction mixture was then cooled and 10 ml of a 4:1 dioxane-water solution added with stirring over a period of five minutes. 30 Milliliters of 1 N HCl were added over a 30 minute period with stirring. The aqueous mixture was extracted with several portions of ethyl acetate and the ethyl acetate extracts combined. The combined extracts were washed with 10 percent aqueous sodium carbonate and with saturated aqueous sodium chloride and were then dried. Evaporation of the solvent yielded 2.24 g of 4-formylindole. 4-Formylindole was purified by chromatography over Florisil using a hexane-ether solvent mixture (2:1) as the eluant. Recrystallization of the chromatographed 4-formylindole from an ether-hexane solvent mixture yielded yellow needles of 4-formylindole melting at 136°-137° C. Infrared spectrum; peak at 1670 cm-1 ; nmr (D6 acetone) δ 10.35 (s, 1H, CHO), 7.2-7.9 (m, 6H, Ar.); mass spectrum; molecular ion at 145.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][C:57]=2[S:59](Cl)(=[O:61])=[O:60])[CH:52]=[CH:51][CH:50]=1.O>ClCCl>[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][C:57]=2[S:59]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:61])=[O:60])[CH:52]=[CH:51][CH:50]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)[C@@H](CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](CCCOS(=O)(=O)c1cccc2cccnc12)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of di-tert-butyl (4S)-4-(3-hydroxypropyl)-N-trityl-L-glutamate (203.4 mg, 0.36 mmol) and triethylamine (150 μL, 1.09 mmol) in dichloromethane (5.0 mL) was added quinoline-8-sulfonyl chloride (124.1 mg, 0.55 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and at room temperature for overnight and then water was added. The organic layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/CH2Cl2=1/99) to give the desired product (140 mg, 51%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[N:9][N:8]=1)C.[OH-].[Na+]>CO>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:7]([CH2:6][CH2:5][C:4]([OH:24])=[O:3])=[N:8][N:9]=[C:10]2[C:19]1[S:20][CH:21]=[CH:22][N:23]=1
Reactant: CCOC(=O)CCc1nnc(-c2nccs2)c2cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(CCC(=O)O)nnc(-c3nccs3)c2c1
Yield: 82.9 %

Procedure:
Operating analogously to what described in example 118 starting from 3-(6-methoxy-4-thiazol-2-yl-phthalazin-1-yl)-propionic acid ethyl ester (1.05 g, 3.06 mmoles), prepared as described in example 122, CH3OH (25 ml) and 10% NaOH (2.5 ml, 6.25 mmoles), 0.8 g of the title compound were obtained (yield: 82.9%). m.p.: 228-229° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[Li][CH2:13][CH2:14][CH2:15]C.C(Br)C=C>C1COCC1>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([CH2:15][CH:14]=[CH2:13])[C:8]([O:10][CH3:11])=[O:9]
Reactant: [Li]CCCC
Reactant: COC(=O)CN1CCCC1=O
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(C(=O)OC)N1CCCC1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.2 %

Procedure:
Step A (1): To a solution of the methyl 2-(2-oxopyrrolidin-1-yl)acetate (15 g, 95.5 mmol, TCI-America) in THF (600 mL) at −78° C. was added n-BuLi (42.0 mL, 105 mmol, 2.5 M in hexane, Aldrich). After 10 min, allyl bromide (9.7 mL, 115 mmol, Aldrich) was added. The mixture was stirred at −78° C. for 1 h and warmed to room temperature over 2 h. The reaction was then quenched with saturated ammonium chloride. After 15 min the mixture was extracted with EtOAc (3×200 mL). The combined organic layers were dried with Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (20-80% EtOAc/hexanes linear gradient) to afford methyl 2-(2-oxopyrrolidin-1-yl)pent-4-enoate 4.0 g (21% yield) as pale yellow oil: LC-MS (M+H)+=198.2; 1H NMR (400 MHz, CDCl3) δ 5.67-5.69 (m, 1H), 5.04-5.14 (m, 2H), 4.88 (dd, J=10.70, 5.16 Hz, 1H), 3.70 (s, 3H), 3.44-3.69 (m, 1H), 3.34-3.37 (m, 1H), 2.68-2.75 (m, 1H), 2.36-2.46 (m, 3H), 1.94-2.07 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13].ON1C2C=CC=CC=2N=N1.[CH:26]1([N:32]=[C:33]=NC2CCCCC2)CCCCC1.CNC>O1CCCC1>[CH3:26][N:32]([CH3:33])[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:15])=[O:13]
Reactant: COC(=O)CCCCCCCCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCCC(=O)N(C)C
Reaction time: 8 h

Procedure:
To a solution of the decandioic acid mono methyl ester (2 mmol) in dry tetrahydrofuran (20 ml) was added 1-hydroxybenzotriazole (1 mmol), N,N′-dicyclohexylcarbodiimide (1.1 mmol) and N,N-dimethylamine (2M solution in tetrahydrofuran, 2 ml). The mixture was stirred overnight and then filtered. The solvent was removed in vacuo and the residue redissolved in ethyl acetate. The ethyl acetate solution was washed sequentially with saturated sodium hydrogen carbonate solution, 1M potassium hydrogen sulphate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate and removal of the solvent, the product was purified by preparative layer chromatography on silica plates in ethyl acetate to afford methyl 9-(N,N-dimethylcarbamoyl)nonanoate.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH2:25][CH2:26][C:16]=3[N:15]=2)=[CH:23][C:22]([C:27]2[CH:28]=[C:29]3[C:53](=[CH:54][CH:55]=2)[C:33]2[NH:34][C:35]([C@@H:37]5[CH2:41][CH2:40][CH2:39][N:38]5[C:42](=[O:52])[C@@H:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:46])[CH3:45])=[N:36][C:32]=2[CH:31]=[CH:30]3)=[CH:21][CH:20]=4)[C@@H:12]2[CH2:56][C@H:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.Cl.[CH3:58][O:59][C:60]([NH:62][C@@H:63]([CH:67]1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1)[C:64]([OH:66])=O)=[O:61].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CN(C=O)C>[CH3:51][O:50][C:48]([NH:47][C@@H:43]([CH:44]([CH3:46])[CH3:45])[C:42]([N:38]1[CH2:39][CH2:40][CH2:41][C@H:37]1[C:35]1[NH:34][C:33]2[C:53]3[C:29]([CH:30]=[CH:31][C:32]=2[N:36]=1)=[CH:28][C:27]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:17]1[NH:18][C:14]([C@@H:13]4[C@@H:12]5[CH2:56][C@@H:9]([CH2:10][CH2:11]5)[N:8]4[C:64](=[O:66])[C@@H:63]([NH:62][C:60](=[O:61])[O:59][CH3:58])[CH:67]4[CH2:72][CH2:71][O:70][CH2:69][CH2:68]4)=[N:15][C:16]=1[CH2:26][CH2:25]2)=[CH:55][CH:54]=3)=[O:52])=[O:49]
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c4-5)ccc3c2[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)C6CCOCC6)[nH]c4-5)ccc3c2[nH]1)C(C)C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To (1R,3S,4S)-tert-butyl-3-(2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (307 mg, 0.41 mmol) in DCM (5 mL) and MeOH (1 mL) was added HCl (4M in dioxane, 1 mL). The solution stirred for 2 h, and the solvent was removed. The intermediate (133 mg, 0.2 mmol) was dissolved in DMF (2.5 mL). ((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (43 mg, 0.2 mmol), HATU (76 mg, 0.2 mmol), and DIPEA (0.18 mL, 1.0 mmol) were added sequentially. The solution stirred o/n and the mixture was purified by HPLC to yield product (100.8 mg). LCMS-ESI+: calc'd for C48H56N8O7: 857.01 (M+); Found: 857.42 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=1)=[O:2].BrC[C:29]1[CH:30]=[C:31]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])[CH:32]=[C:33]([C:35]([CH3:39])([CH3:38])[C:36]#[N:37])[CH:34]=1.C(#N)C.C(O)(=O)C>O>[CH:1]([C:3]1[N:4]([C:29]2[CH:34]=[C:33]([C:35]([CH3:38])([CH3:39])[C:36]#[N:37])[CH:32]=[C:31]([C:40]([CH3:43])([CH3:44])[C:41]#[N:42])[CH:30]=2)[CH:5]=[N:6][CH:7]=1)=[O:2]
Reactant: CC(C)(C#N)c1cc(CBr)cc(C(C)(C)C#N)c1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: CC(C)(C#N)c1cc(-n2cncc2C=O)cc(C(C)(C)C#N)c1

Procedure:
A mixture of 4-formyl-1-tritylimidazole (0.5 g), 2,2'-(5-bromomethyl-1,3-phenylene)di(2-methylpropiononitrile) and acetonitrile (2 ml) was heated under reflux for 30 h. The reaction mixture was treated with acetic acid (8 ml) and water (2 ml) and the mixture was then heated at 90° for 1 h. The mixture was diluted with water (20 ml) and washed with ether, the aqueous phase was basified with sodium carbonate, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried and evaporated to dryness, and the residue was purified by flash chromatography using methanol (2% by volume) in chloroform as eluant, to give 2,2'-[5-(5-formylimidazol-1-yl)-1,3-phenylene]di(2-methylpropiononitrile), mp 108°-111°.
Reaction SMILES: [C:1]1([C:7]2[C:17]([NH2:18])=[N:16][C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([N:23]=[C:24]=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[NH2:15][C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:17]([NH:18][C:24]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[N:16][C:10]=2[N:11]=1
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ncc2cc(-c3ccccc3)c(N)nc2n1
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1ccccc1

Procedure:
Following the procedure of Example 2, 0.246 g of 6-phenyl-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 81 was reacted with 0.128 mL of tert-butyl isocyanate. The product is purified by medium pressure chromatography using silica gel and eluting with a gradient of 1:1 CHCl3 :EtOAc to EtOAc to afford the title compound; mp >250° C., CIMS (1% ammonia in methane): m/z (relative intensity) 337 (MH+ +1, 64), 338 (MH+ +2, 11), 236 (100).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].[F:16][C:17]1[CH:18]=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=[C:21]([F:24])[C:22]=1F.OS(O)(=O)=O.O>CN(C=O)C>[C:7]([C:9]([C:22]1[C:21]([F:24])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[F:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)C(C)C#N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C#N)c1c(F)cc([N+](=O)[O-])cc1F
Temperature: 150 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A stirred suspension of anhydrous K2CO3 (79.5 g, 575 mmol) in anhydrous DMF (365 mL) is heated to 150° C. and treated with ethyl 2-cyanopropionate (71.8 g, 564 mmol) via addition funnel over 20 min. The reaction is allowed to cool gradually to ambient temperature over 90 min, and then cooled further (to ca. 12° C.) with a mild ice bath. The yellow reaction mixture is at this point treated with 3,4,5-trifluoronitrobenzene (94.8 g, 535 mmol) via addition funnel over 20 min. The deep purple reaction mixture is stirred overnight at ambient temperature. The deep green reaction mixture is then poured into ice/water (950 mL) and made acidic (from pH 11 to pH 5) with 20% v/v H2SO4/H2O while stirring vigorously and ensuring ample cooling with ice bath. The mixture is then chilled in a refrigerator for 2 h. The amber-brown liquid is extracted with Et2O (1.2 L), taking care to dissolve the large clumps of green-black solid (which accounts for a significant amount of the product). The ethereal layer is washed with H2O (250 mL), saturated aqueous NaHCO3 (2×150 mL), and H2O (2×150 mL), dried over MgSO4, and concentrated under reduced pressure. Trituration (cold hexanes) affords the title compound as a pale tan solid in 77% yield; 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 4.35 (q, 2H), 2.06 (t, 3H), 1.31 (t, 3H).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:2]([CH3:5])([CH3:4])[CH3:3])[CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1cccc(I)c1
Product: C[Si](C)(C)c1cccc(Br)c1

Procedure:
1-Bromo-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1-bromo-3-iodobenzene as the dihalo compound of formula (III).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[OH:25][C@H:26]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:27](O)=[O:28].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:25][C@H:26]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:27]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:28]
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.8 %

Procedure:
2-(7-Methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.74 mmol) was suspended in anhydrous DMF (5 mL) and cooled to 0° C. internal temperature. Under an N2 atmosphere, (R)-2-hydroxy-4,4-dimethylpentanoic acid (125.4 mg, 0.858 mmol) was added followed by triethylamine (0.218 mL, 1.56 mmol). To this stirring solution was added HATU (356 mg, 0.936 mmol). After the complete addition of HATU, the mixture was allowed to warm to 10° C. After 45 min the reaction was complete, and it was quenched with an equal portion of ice water. A yellow precipitate formed which was collected by vacuum filtration and dissolved in CH2Cl2. This solution was desiccated with Na2SO4, filtered, and concentrated to give a viscous yellow-orange oil. The crude material was purified via silica gel chromatography using 88% CH2Cl2-hexanes (1:1) and 12% EtOAc to afford (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4,4-dimethylpentan-1-one as a faint yellow foam (265 mg, 76%). LC/MS: m/z 449.3 (M+H)+ at 2.75 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J=8.2, 1.8 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.41-7.37 (m, 2H), 6.97-6.93 (m, 2H), 4.89 (d, J=7.2 Hz, 1H), 4.49-4.44 (m, 1H), 4.06-3.67 (m,8), 2.52 (s, 3H), 1.56 (dd, J=14.3, 3.0 Hz, 1H), 1.42 (dd, J=14.3, 8.8 Hz, 1H), 0.97 (s, 9H)