Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C1CCNCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCCCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 160 °C
Reaction time: 5.5 h
Yield: 11.3 %

Procedure:
In a 200 ml autoclave were placed 5 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 5 g of piperidine and 45 ml of hexamethylphosphoric triamide and the mixture was stirred at 160° C. After 5.5 hours, the temperature was lowered to room temperature and disappearance of the starting materials was confirmed by thin layer chromatography followed by removing hexamethylphosphoric triamide using a vacuum pump (120° C./2 mm Hg). To the residue was added several drops of concentrated hydrochloric acid and then ethyl acetate. Crystals which formed were collected by filtration and washed with ethyl acetate. The crystals thus obtained were recrystallized from dimethylformamide-water and the resulting crystals were added sodium hydroxide and water so as to obtain an aqueous solution of pH 13 which then was treated with activated carbon and filtered. The filtrate was adjusted to pH 7 with acetic acid to precipitate crystals which then were collected by filtration and recrystallized from dimethylformamide-water to give 570 mg of 9-fluoro-8-(1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 258°-261° C., white rhombic crystals.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II.[CH2:10](O)[CH2:11][OH:12]>C(OCC)(=O)C>[O:7]1[C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:12][CH2:11][CH2:10]1
Reactant: O=C1CCCCC1
Reactant: OCCO
Agent: II
Solvent: CCOC(C)=O
Product: C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a solution of cyclohexanone (10 g, 0.102 mol) in ethylene glycol (50 mL) was added iodine (3.88 g, 15.3 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and extracted with saturated aqueous sodium thiosulfate. The organic phase was dried and concentrated to give a crude product, which was purified via silica gel chromatography eluting with ethyl acetate/petroleum ether (1:8) to give 1,4-dioxaspiro[4.5]decane (6.8 g, 46.9% yield) as light oil. 1H-NMR (CDCl3) δ 3.93(s, 4H), 1.58-1.59 (d, 8H), 1.39-1.41(m, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:11][C:10](=[O:12])[C@H:9]1[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.CCOC(C)=O>[CH2:24]([NH:31][C:32]([N:11]1[C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:9]([CH3:13])[C:10]1=[O:12])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H]1C(=O)N[C@H]1Cc1ccccc1
Reactant: O=C=NCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1C(=O)N(C(=O)NCc2ccccc2)[C@H]1Cc1ccccc1
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
To a solution of 4(S)-benzyl-3(S)-methylazetidin-2-one (50 mg, 0.28 mmol) in THF (4 mL) at −78°, lithium bis(trimethylsilyl)amide (280 μL, 280 mmol, 1 M in THF) was added. After 10 min, benzyl isocyanate (37.2 mg, 34.6 μL, 0.28 mmol) was added. Stirring was continued at −78° for 45 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with aqueous NaHSO4 (1M) and brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, 14% EtOAc in hexane) to give the title compound 4(S)-benzyl-3(S)-methyl-2-oxoazetidine-1-carboxylic acid benzylamide (23 mg, 27% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ7.38-7.19 (m, 10H), 6.94 (t, J=5.1 Hz, 1H), 4.53 (dd, J=14.9, 6.0 Hz, 1 H), 4.48 (dd, J=14.9, 6.0 Hz, 1H), 3.90 (ddd, J=8.6, 3.2, 2.9 Hz, 1H), 3.53 (dd, J=13.7, 3.5 Hz, 1 H), 2.95 (qd, J=7.6, 2.5 Hz, 1H), 2.92 (dd, J=13.3, 8.9 Hz, 1H), 1.14 (d, J=7.6 Hz, 3H); FAB MS m/z 309.3 (MH+); HRMS calcd for C19H21N2O2: 309.1603 (MH+); found: 309.1614.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C([Li])CCC.CN(C)[CH:25]=[O:26].O>O1CCCC1>[O:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:25]=[O:26])=[CH:13][CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-(2-t-butyldimethylsiloxyethyl)bromobenzene (4.29 g) in tetrahydrofuran (30 ml) was added n-butyllithium (1.64 mol/l solution in tetrahydrofuran, 9.0 ml) at -78° C., and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added N,N-dimethylformamide (1.3 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was concentrated to dryness under reduced pressure to give 4-(2-t-butyldimethylsiloxyethyl)benzaldehyde(3.59 g)To a solution of ethyl triphenylphosphranylidenebutylate (2.22 g), which was prepared from (3-carboethoxypropyl)triphenylphosphonium bromide and sodium bis(trimethylsilyl)amide, in tetrahydrofuran (25 ml) was added 4-(2-t-butyldimethylsiloxyethyl)benzaldehyde (1.57 g) at -78° C., and the mixture was stirred at the same temperature for 4 hours and allowed to stand at room temperature for 12 hours. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over anhydrous MgSO4, and the solvent was removed under reduced pressure. To a solution of the residue in acetonitrile (80 ml) was added a 47% hydrofluoric acid (1 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure. The residue was dissolved in chloroform, the solution was washed with a saturated aqueous NaHCO3 solution, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride, diethyl ether and methanol (1:1:1) as eluent to give 2-[4-(4-ethoxycarbonyl-1-butenyl)phenyl]ethyl alcohol (0.35 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH:23][CH3:24].CO>>[CH3:22][N:23]([CH3:24])[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CNC
Solvent: CO
Product: COc1ccc(N(C)c2nc(N(C)C)nc3ccccc23)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5 mmol), 2.0 M dimethylamine in methanol (2.0 ml, 4 mmol) in a sealed tube was stirred at 70-80° C. overnight. The mixture was filled and the filtration was concentrated by vacuum. The residue was extracted with ethyl acetate and was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel with acetate and hexane (1:9) as eluent, yielding 128 mg of title compound (83%). 1H NMR (CDCl3): 7.44 (d, J=7.8 Hz, 1H), 7.36-7.30 (m, 1H), 7.11-7.08 (m, 2H), 6.90-6.85 (m, 3H), 6.65-6.59 (m, 1H), 3.82 (s, 3H), 3.51 (s, 3H), 3.30 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13]C(C3C=CC=C4C=3N=C(NC(C)(C)C)C(C)=N4)=C[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:39][C:40]([C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[N:44]=[C:45]([NH:53][CH2:54][CH:55]([F:57])[F:56])[C:46]([CH3:52])=[N:47]2)=O.C(OC(NC1(C(=O)CC(OCC)=O)CC1)=O)(C)(C)C>CCO.CC(O)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:40]([C:42]3[CH:51]=[CH:50][CH:49]=[C:48]4[C:43]=3[N:44]=[C:45]([NH:53][CH2:54][CH:55]([F:57])[F:56])[C:46]([CH3:52])=[N:47]4)=[CH:39][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NCC(F)F
Agent: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)F)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Yield: 41 %

Procedure:
This compound (0.40 g, 41% yield) as a yellow amorphous solid was prepared according to the procedures described for Intermediate 324b, using 2-bromo-1-(34(2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)ethanone (617) (583 mg, 2.26 mmol), ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604) (650 mg, 1.89 mmol) as the starting materials, followed by the subsequent treatment of the resulting 331a (m/z (ESI, +ve) 535.2 (M+H)+) with NH4OAc (728 mg, 9.44 mmol) in 3 mL of EtOH and 1.5 mL of HOAc at 50° C. for 4 h. m/z (ESI, +ve) 516.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(O)(=O)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:22][N:23]3[C:24](=[O:33])[C:25]4=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]4[C:27]3=[O:28])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCl
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1COc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the red dye, 4-(4-nitro-phenylazo)phenol (0.5 g), in DMF was added sodium hydride (0.1 g of a 50% dispersion). After stirring for 5 minutes at room temperature, N-(chloromethyl)phthalimide (0.5 g) was added and stirring continued overnight. The solution was acidified with acetic acid and the product precipitated by pouring into ice water. The product recrystallized from ethyl acetate/cyclohexane, was obtained in 0.72 g yield, m.p. 182°-190° C.
Reaction SMILES: F[C:2]1[C:20]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[C:26]([NH:31][CH3:32])[N:25]=[CH:24]3)=[C:19]([CH3:33])[CH:18]=[CH:17][C:3]=1[C:4](=S)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1.O.[NH2:35][NH2:36]>C(O)CCC>[CH:13]([O:12][C:8]1[CH:7]=[C:6]([NH:5][C:4]2[C:3]3[C:2](=[C:20]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[C:26]([NH:31][CH3:32])[N:25]=[CH:24]5)[C:19]([CH3:33])=[CH:18][CH:17]=3)[NH:36][N:35]=2)[CH:11]=[CH:10][CH:9]=1)([CH3:15])[CH3:14]
Reactant: NN
Reactant: CNc1ncc2cc(-c3c(C)ccc(C(=S)Nc4cccc(OC(C)C)c4)c3F)ccc2n1
Solvent: CCCCO
Solvent: O
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(OC(C)C)c5)n[nH]c34)ccc2n1
Temperature: 150 °C

Procedure:
A mixture of 2-fluoro-N-(3-isopropoxyphenyl)-4-methyl-3-(2-(methylamino)quinazolin-6-yl)benzothioamide (54 mg, 117 μmol) and hydrazine hydrate (11 μL, 234 μmol) in n-butanol (6 mL) was heated in a microwave reactor at 150° C. for 33 min. Solvent was removed and the residue was purified by preparative TLC (50% EtOAc/hexane) to give the title compound. MS (M+H)+ 439.
Reaction SMILES: [NH2:1]N.Br[C:4]1[N:5]([C:14]2[N:15]=[C:16]([NH2:22])[NH:17][C:18](=[O:21])[C:19]=2[N:20]=1)[C@@H:6]1[O:13][C@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[CH2:7]1.CO>O>[NH2:1][C:4]1[N:5]([C:14]2[N:15]=[C:16]([NH2:22])[NH:17][C:18](=[O:21])[C:19]=2[N:20]=1)[C@@H:6]1[O:13][C@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[CH2:7]1
Reactant: Nc1nc2c(nc(Br)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: NN
Solvent: CO
Solvent: O
Product: Nc1nc2c(nc(N)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
Hydrazine is added to a suspension of 8-bromodeoxyguanosine in water:methanol (150 mL; 1:2) and the resulting solution is heated at reflux for 24 hours. The resulting precipitate is removed by filtration and the filtrate is evaporated to a solid. After repeated evaporations from ethanol, the product is recrystallized from methanol. The purified 8-azido-2'-deoxyguanosine (1.3 g) is dissolved in a mixture of methanol:water (160 mL, 5:3), Raney nickel (10.0 g) is added, and the mixture is heated at reflux for 18 hours. The catalyst is removed by filtration through celite and after washing with water and methanol the filtrate is evaporated to dryness. The resulting solid is recrystallized from methanol to yield 8-aminodeoxyguanosine.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:25]([O:27][C:28](=[O:31])[CH2:29][NH2:30])[CH3:26].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:25]([O:27][C:28](=[O:31])[CH2:29][NH:30][CH2:22][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]3)[CH:13]=2)[CH:18]=1)[CH3:26]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: CCOC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-(4-tert-butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (90 mg, 0.29 mmol), glycine ethyl ester hydrochloride (162 mg, 1.16 mmol), and triethylamine (0.16 mL, 1.16 mmol) in 1,2-dichloroethane (2 mL) was treated with sodium triacetoxyborohydride (129 mg, 0.58 mmol). The mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane and washed with aqueous sodium bicarbonate. The organic phase was dried over MgSO4 and concentrated. The residue was purified with a silica gel column eluted with ethyl acetate in hexane from 0 to 100% to give product (64 mg, yield: 55%). ESI-MS: 420.30 (M+23)+; 1H NMR (400 MHz, CDCl3) δ=7.66-7.70 (m, 3H), 7.41 (dd, 1H), 7.11-7.14 (m, 2H), 4.26 (m, 1H), 4.19 (q, 2H), 3.93 (s, 2H), 3.43 (s, 2H), 2.28 (d, 4H), 1.89 (d, 2H), 1.44 (q, 2H), 1.27 (t, 3H), 1.09-1.20 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: C([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([CH3:22])([CH3:21])[CH2:7]1)(=O)C=C.[C:23]([O:47][CH:48]1[CH2:53][C:52]([CH3:55])([CH3:54])[N:51]([OH:56])[C:50]([CH3:58])([CH3:57])[CH2:49]1)(=[O:46])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]1[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([OH:43])[C:37]([CH3:45])([CH3:44])[CH2:36]1)=[O:33]>>[C:23]([O:47][CH:48]1[CH2:49][C:50]([CH3:58])([CH3:57])[N:51]([O:56][CH2:17][C:16](=[C:15]=[O:14])[O:5][CH:6]2[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([CH3:22])([CH3:21])[CH2:7]2)[C:52]([CH3:55])([CH3:54])[CH2:53]1)(=[O:46])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]1[CH2:36][C:37]([CH3:44])([CH3:45])[N:38]([O:43][CH2:8][C:7](=[C:6]=[O:5])[O:5][CH:6]2[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([CH3:21])([CH3:22])[CH2:7]2)[C:39]([CH3:41])([CH3:42])[CH2:40]1)=[O:33]
Reactant: C=CC(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCC(=C=O)OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)C(C)(C)C2)CC(C)(C)N1OCC(=C=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1

Procedure:
The title compound is prepared from 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl acrylate and bis(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl) sebacate according to the general procedure of Example 2.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[C:48]#[N:49].N1C2C(=CC=CC=2)C=C1>C1COCC1.[Cl-].[Na+].O.[Cl-].[Cl-].[Zn+2].C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2].CC(C[AlH]CC(C)C)C.CCOCC>[C:48]([C:47]1[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:17]([CH3:18])[CH3:19])[CH:20]([CH3:21])[CH3:22])[CH:11]=[CH:10]2)#[N:49]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reactant: N#Cc1ccccc1Br
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(-c3ccccc3C#N)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
sec-Butyllithium (41 mmole, 31.5 ml) was added dropwise over 10 minutes to 5-bromo-1-triisopropylsilylindole (40 mmoles, 14.0 g) in 400 ml THF at -78° C. The solution was stirred for 15 minutes. A solution of anhydrous ZnCl2 in 50 ml THF was added. The solution was warmed to 0° C. and stirred for 40 minutes. In a separate flask nickel acetylacetonate (1.5 mmole, 0.385 g) and triphenylphosphine (6.0 mmoles, 1.60 g) were dissolved in 20 ml of THF and cooled to -78° C. DIBAL (1.5 mmole, 1.5 ml of 1.0M solution in hexane) was added. The solution was stirred for 10 minutes. 2-Bromobenzonitrile (39.9 mmoles, 7.26 g) was added. After stirring for 5 minutes, the indole solution was added over a 10 minute period. The mixture was allowed to warm to room temperature, stirred for 2 hours, and then added to ether and brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The product was chromatographed over silica gel eluted with 0-15% ether in hexane to yield 7.83 g of 5-(2-cyanophenyl)-1-triisopropylsilylindole. (MS)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH:22]2[OH:31])[N:3]=1.S(=O)(=O)(O)O.C(O)(C)C.C(=O)(O)[O-].[Na+]>CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O.[O-2].[Cr+6].[O-2].[O-2]>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:23][C:22]2=[O:31])[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2O)nc1N
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2=O)nc1N
Reaction time: 0.33 h

Procedure:
To a stirred solution of alcohol (65 mg, 0.14 mmol, Example 306) in acetone (4 mL), Jones reagent (made by adding 0.5 mL of concentrated sulfuric acid to a solution of chromium(VI) oxide, 0.67 g, Aldrich, in 2 mL of water) was slowly added until the orange color persisted for 20 minutes. The mixture was stirred for 1 hour and 2 mL of isopropanol was added. The mixture was again stirred for 30 minutes followed by slow addition of saturated sodium bicarbonate solution until pH=7. The mixture was extracted with ethyl acetate/tetrahydrofuran (2:1, 3×10 mL) and the extracts were combined and dried with sodium sulfate. The solvent was removed and the residue was chromatographed on HPLC (20–70%) to give a white solid, 4.3 mg, 7%. MS (ES) MH+=456.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22]>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:22][C:21]1[CH:23]=[CH:24][C:25]([F:26])=[C:19]([Cl:18])[CH:20]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OC(C)=O
Temperature: 88 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (2.52 g), 3-chloro-4-fluoroaniline (1.49 g) and isopropanol (60 mL) was stirred at 88° C. for 5 h. The reaction mixture was cooled to room temperature, filtered to afford the desired compound as a solid (2.51 g, 81.00%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([F:20])=[C:15]([CH:19]=2)[C:16](O)=[O:17])[CH:6]=[N:7][CH:8]=1)#[N:2].O.O[N:23]1C2C=CC=CC=2N=N1.N>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([F:20])=[C:15]([CH:19]=2)[C:16]([NH2:23])=[O:17])[CH:6]=[N:7][CH:8]=1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(C(=O)O)c2)c1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cncc(C#Cc2ccc(F)c(C(N)=O)c2)c1
Reaction time: 0.08 h
Yield: 42.2 %

Procedure:
Add N-(3-dimethylaminopropyl)-N-ethylcarbodiamide hydrochloride (128 mg, 0.66 mmol) to a solution of 5-(5-cyanopyridin-3-ylethynyl)-2-fluorobenzoic acid (prepared as described in EXAMPLE 120), (158 mg, 0.59 mmol) and 1-hydroxybenzotriazole hydrate (87 mg, 0.64 mmol) in N,N-dimethylformamide (5 mL) and stir for 5 min to form a gel. Add additional N,N-dimethylformamide (4 mL) to enable stirring of the reaction mixture and stir for 0.5 h. Bubble anhydrous ammonia gas through the reaction mixture for 1-2 min. and then stir for an additional 15 min. Dilute the reaction mixture with ethyl acetate and a saturated aqueous solution of sodium bicarbonate and separate the layers. Extract the aqueous phase once with ethyl acetate. Wash the combined organic phases once with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 20:80 ethyl acetate:dichloromethane, to give the title compound as a white solid (66 mg, 42%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=1)([O-:3])=[O:2].ON1C(=O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:44][O:45][C:46](=[O:53])[C@H:47]([CH2:49][CH2:50][S:51][CH3:52])[NH2:48]>CN(C=O)C.C(N(CC)CC)C>[CH3:44][O:45][C:46](=[O:53])[C@H:47]([CH2:49][CH2:50][S:51][CH3:52])[NH:48][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Reaction time: 1 h

Procedure:
4-Nitro-2-phenylbenzoic acid (50.0 g, 205 mmol) and 3-hydroxy1,2,3-benzotriazin-4(3H)-one (36.89 g, 226 mmol) were dissolved in 500 mL DMF. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47.3 g, 247 mmol) and methionine methyl ester hydrochloride (53.37 g, 267 mmol) were added followed by triethylamine (31.5 mL, 226 mmol). Additional triethylamine was added to raise the pH to 6˜7. After 1 hour at ambient temperature, the reaction mixture was concentrated to 200 mL, diluted with 500 mL ethyl acetate, washed with 1 M HCl, 5% NaHCO3, and brine, and dried over Na2SO4 to provide (4-nitro-2-phenylbenzoyl)methionine methyl ester which was used directly without further purification. MS m/e 389 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.78 (m, 2H), 2.01 (s, 3H), 2.60 (m, 2H), 3.69 (s, 3H), 4.69 (m, 1H), 6.02 (d, J=8 Hz, 1H), 7.48,(m, 5H), 7.85 (m, 1H), 8.27 (m, 2H).