Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:26][CH2:27][C:28]([NH:30]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:29])[C:4]([NH:6][CH2:7][CH2:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:14]1)=[O:10])=[O:5].[C:50]1([C:56]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:57][C:58](O)=[O:59])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(N(CC)C(C)C)(C)C>[CH:20]1([CH2:19][N:15]2[CH2:16][CH2:17][CH2:18][C@H:13]([CH2:12][NH:11][C:9](=[O:10])[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C@@H:3]([NH:2][C:58](=[O:59])[CH2:57][C:56]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH2:26][CH2:27][C:28](=[O:29])[NH2:30])[CH2:14]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H](CCC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCC(=O)NC[C@H]1CCCN(CC2CCCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: NC(=O)CC[C@H](NC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCC(=O)NC[C@H]1CCCN(CC2CCCCC2)C1
Reaction time: 17 h
Yield: 50.8 %

Procedure:
To a solution of 84 mg of (2S)-2-amino-N5-triphenylmethyl-N1-(3-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}amino-3-oxopropyl)pentanediamide monohydrochloride in 1.5 ml of chloroform, 0.052 ml of N,N-diisopropylethylamine was added at room temperature, followed by an hour's stirring at the same temperature. Then 39 mg of 3,3,3-triphenylpropionic acid, 24 mg of 1-hydroxy-benzotriazole monohydrate and 31 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride were added at room temperature by the order stated, followed by 17 hours' stirring at the same temperature. The reaction liquid was rendered weakly basic with saturated aqueous sodium bicarbonate solution, extracted with chloroform and dried over anhydrous sodium sulfate. Distilling the solvent off, the resultant residue was dissolved in 1 ml of chloroform, and to the solution 1 ml of trifluoroacetic acid was added at room temperature, followed by 20 minutes' stirring at the same temperature. The reaction liquid was rendered weakly basic with saturated aqueous sodium bicarbonate solution, extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified with preparative thin layer chromatography (Kieselgel™60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=90/10/1) to provide 43 mg of the title compound as a white solid.
Reaction SMILES: CCOCC.O=O.C([O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)C(C)(C)C>>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[OH:13]
Reactant: CC(C)(C)COc1ccc2ccccc2c1
Agent: O=O
Solvent: CCOCC
Product: Oc1ccc2ccccc2c1

Procedure:
Silylations of aryl alkyl ethers at elevated temperatures were conducted under the conditions applied to diaryl ethers to probe the cleavage selectivity of sp2 versus sp3 C—O bond. At the elevated temperatures of these experiments, the reaction of 2-methoxynaphthalene gave 2-naphthol as the major product in moderate yield (Scheme 1). GC-MS analysis of the crude reaction mixture indicated the presence of trace amounts of naphthalene along with 2-methylnaphthalene and further reduced species, including products of partial aromatic reduction. Compounds presumably derived from 2-naphthol silylation were also detected. Likewise, cleavage of 2-ethoxynaphthalene under the same conditions gave 2-naphthol in slightly higher yield, but with the same or analogous side products. Sterically bulkier ethers were investigated to probe the versatility and possible mechanism of the C—O bond cleavage. Despite the large alkyl substituent adjacent to the ether oxygen, reaction of 2-neopentyloxynaphthalene provided 2-naphthol in approximately the same yield as with the less bulky substrates. Even 2-tert-butyloxynapthalene was cleaved to give the expected naphthol in 55% yield (Scheme 1). Control experiments performed at identical conditions but without triethylsilane provided 2-naphthol in cases of 2-ethoxy- and 2-tert-butyloxynapthalene albeit with substantially diminished yields. Since 2-methoxy- and 2-neopentyloxy-substrates remained intact in such silane-free cleavages, a b elimination mechanism is likely to be operative. When attempting to reduce 4-tert-butyl and 4-methyl anisoles under the standard conditions, the yields of the corresponding phenols were high, likely because of more challenging silylation of the substituted phenyl ring for the steric reasons (Scheme 2).
Reaction SMILES: O1CCO[CH2:3][CH2:2]1.Br[C:8]1[CH:33]=[N:32][C:11]2[O:12][C:13]([CH3:31])([CH3:30])[C:14](=[O:29])[N:15]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[CH:9]=1.CCCCCC.C([Zn]CC)C>O>[CH2:2]([C:8]1[CH:33]=[N:32][C:11]2[O:12][C:13]([CH3:30])([CH3:31])[C:14](=[O:29])[N:15]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[CH:9]=1)[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Oc3ncc(Br)cc32)CC1
Reactant: C1COCCO1
Agent: CC[Zn]CC
Solvent: CCCCCC
Solvent: O
Product: CCc1cnc2c(c1)N(C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(C)(C)O2
Reaction time: 8 h

Procedure:
At room temperature, to a 1,4-dioxane solution (10.0 ml) of tert-butyl 4-(7-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (Example 52-1) (150 mg) was added a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (69.5 mg), and then a hexane solution (1 M, 0.681 ml) of diethyl zinc was added dropwise, followed by stirring overnight. The reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (84.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:21]1[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[C:23]([Cl:30])[CH:22]=1>C1COCC1>[Br:9][C:7]1[CH:6]=[CH:5][C:3]([NH:4][C:21]2[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[C:23]([Cl:30])[CH:22]=2)=[C:2]([Cl:1])[CH:8]=1
Reactant: O=C(O)c1cnc(Cl)cc1Cl
Reactant: Nc1ccc(Br)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of 2-chloro-4-bromoaniline (6.776 g, 33.1 mmol) in 50 ml anhydrous THF was added LHMDS (50 ml, 50 mmol, 1M/THF) over a period of 15 min at −78° C. It was stirred for an additional 30 min., then a solution of 4,6-dichloronicotinic acid (3 g, 15.7 mmol) in 50 ml THF was added dropwise. After complete addition the mixture was gradually allowed to warm to room temperature and the reaction mixture was stirred for an additional 12 hours. The mixture was quenched with H2O and 1N HCl was added (pH 0-1) followed by brine. It was extracted using THF and dried with Na2SO4. The solvent was removed and the solid crude product was suspended in 200 ml EtOAc. The suspension was heated with stirring at the reflux temperature for 5 min. It was cooled to room temperature and the precipitate was filtered and washed with EtOAc and dried at 50° C. for 5 h in oil pump vacuo to obtain the title compound as an off-white solid (4.05 g, 72%). Rf (CHCl3/MeOH 10:1)=0.3. 1H-NMR (500 MHz, DMSO-D6): δ=10.12 (s, 1H), 8.65 (s, 1H), 7.88 (s, 1H), 7.62-7.57 (dd, 1H), 7.55-7.48 (dd, 1H), 6.67 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=3[OH:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(O)c(C=O)c1
Product: COc1ccc(O)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-hydroxy-5-methoxy-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 513.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:13][C:3]1[C:2]([NH:1][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:11][C:10]([Cl:12])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(N)c1Cl
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(NC2CCCC2)c1Cl
Reaction time: 3 h
Yield: 8.3 %

Procedure:
To a stirred solution of methyl 3-amino-2,5-dichlorobenzoate (2.5 g, 11.5 mmol) and cyclopentanone (4.8 g, 57.1 mmol) in methanol (5 mL) was added acetic acid (0.6 g, 11.3 mmol) and stirring was continued at room temperature for 3 h. Then sodium cyanoborohydride (1.4 g, 22.2 mmol) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the product was purified by column chromatography to afford methyl 2,5-dichloro-3-(cyclopentylamino)benzoate (0.275 g, 8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([NH2:15])[CH:11]=[CH:12][C:13]=2[CH3:14])=[C:5]([CH3:16])[CH:4]=1.CCO/[C:20](/[CH3:27])=[CH:21]/[C:22](OCC)=[O:23]>C(Cl)(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]3[N:15]=[C:20]([CH3:27])[CH:21]=[C:22]([OH:23])[C:11]3=[CH:12][C:13]=2[CH3:14])=[C:5]([CH3:16])[CH:4]=1
Reactant: CCOC(=O)/C=C(\C)OCC
Reactant: COc1ccc(-c2c(C)ccn2N)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2c(C)cc3c(O)cc(C)nn23)c(C)c1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
A mixture of 2-(4-methoxy-2-methylphenyl)-3-methyl-1H-pyrrol-1-amine (0.23 g, 1.06 mmol), ethyl trans-3-ethoxycrotonate (0.17 g, 1.06 mmol) and p-toluenesulfonic acid (0.01 g, 0.053 mmol) in CHCl3 (7.0 mL) was refluxed with a Dean-Stark tube charged with molecular sieves for 24 h. After cooling down to room temperature, the mixture was concentrated in vacuo to dryness and the residue was subjected to column chromatography (silica gel, 1/4 EtOAc/heptane) to give 0.194 g (65%) of beige foam as the desired product: mp 234–237° C.; 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J=8 Hz, 1H), 6.89–6.87 (m, 1H), 6.84–6.79 (m, 1H), 6.54 (br s, 1H), 5.94 (br s, 1H), 3.85 (s, 3H), 2.34 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H); MS m/z 283.2 (M++H).
Reaction SMILES: Br[C:2]1(Br)[CH2:4][C:3]1(Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C[Li].O>C(OCC)C>[CH2:5]([C:3]1[CH2:4][CH:2]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC1(Br)CC1(Br)Br
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: CCCCCCC1=CC1
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
A solution of 1.01 g (0.00278 mol) of 1,1,2-tribromo-2-hexyl-cyclopropane in 4 ml of diethyl ether was placed under a nitrogen atmosphere via use of a Firestone valve. While cooling in an ice water bath, 6.3 ml (0.00835 mol) of 1.4M methyl lithium in diethyl ether was added slowly by syringe. After 15 minutes, 2 ml of water was added via syringe. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo with a bath temperature under 20° C. to yield 0.300 g (87% of theoretical) of 1-hexyl-cyclopropene pure as an oil.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>>[CH3:10][O:11][CH2:12][CH2:13][NH:14][CH2:1][CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:9]
Reactant: COCCN
Reactant: c1ccc(C2CO2)cc1
Product: COCCNCC(O)c1ccccc1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
A mixture of styrene oxide (2.40 g 0.030 mole) and 2-methoxyethylamine (4.50 g, 0.060mole) was heated on a steam bath for 16 hours. After cooling to ambient temperature the oil began to crystallize. Trituration in isooctane followed by filtration gave a slightly impure solid. Recrystallization from isopropyl ether gave 1.52 g (39%) of the product, mp 77°-80° C.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[C:2]([C:23]3[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=3)=[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]3[N:4]=2)=[CH:12][CH:13]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Fc1ccc(-c2nn3ccccc3c2Br)cc1
Product: CSc1ccc(-c2c(-c3ccc(F)cc3)nn3ccccc23)cc1

Procedure:
By using 3-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (4.0 g, 13.8 mmol) and 4-methylsulphanyl-phenylboronic acid (3.07 g, 1.83 mmol) the title compound was obtained as a white solid (2.29 g 50%) in the manner described in Example 2. MH+: 335; NMR: (CDCl3) δ 2.53 (3H, s) 6.80 (1H, t) 7.00 (2H, t) 7.15 (1H, t) 7.25 (2H, d) 7.30 (1H, d) 7.50 (2H, d) 7.60 (2H, m) 8.50 (1H, d).
Reaction SMILES: [C:1]([N:14]([CH3:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(=O)(=O)(O)O.[CH:26](O)([CH3:28])[CH3:27]>>[CH:26]([O:18][C:17](=[O:19])[CH2:16][CH2:15][N:14]([C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:20])([CH3:28])[CH3:27]
Reactant: CC(C)O
Reactant: CCCCCCCCCCCC(=O)N(C)CCC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCC(=O)N(C)CCC(=O)OC(C)C

Procedure:
One hundred grams(100) of N-lauroyl-N-methyl-β-alanine and 750 ml of isopropanol were charged into a 1,000-milliliter flask. Further, 2 ml of conc. sulfuric acid were added as the catalyst. The mixture was heated under ref lux for reaction for 8 hours.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:18][CH2:19][CH2:20][CH3:21])[C:3](=[O:17])[CH:4]=[CH:5][O:6][S:7]([C:10]1[C:11]([CH3:16])=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8].[I-:23].[Na+].[I-].[Li+].S(=O)(=O)(O)O>CC(C)=O.C(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:22])([CH2:18][CH2:19][CH2:20][CH3:21])[C:3](=[O:17])/[CH:4]=[CH:5]/[I:23].[CH3:1][C:2]([CH3:22])([CH2:18][CH2:19][CH2:20][CH3:21])[C:3](=[O:17])[CH:4]=[CH:5][O:6][S:7]([C:10]1[C:11]([CH3:16])=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8]
Reactant: [I-]
Agent: CCCCC(C)(C)C(=O)C=COS(=O)(=O)c1ccccc1C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCC(C)(C)C(=O)/C=C/I

Procedure:
The sample of (25A) was dissolved in 250 ml of dry acetone and stirred overnight under argon with 25.2 g of sodium iodide and 1.0 g of lithium iodide. The (CHCl3) analysis the next day of the reaction mixture showed little or no reaction had taken place. A 0.25 ml portion of concentrated sulfuric acid was added to the dark colored reaction mixture and it was then heated to reflux using an oil bath. The mixture rapidly became very viscous and the analysis after a few minutes showed considerable amounts of (27A) had formed at the expense of (25A). After 1 hour of reflux the resultant very dark colored reaction mixture was evaporated in vacuo. The residue was mixed with ether and washed with aqueous sodium thiosulfate and then with saturated aqueous sodium bicarbonate. The resultant extract was dried (MgSO4) and evaporated in vacuo. The resultant 27.8 g of residue was distilled in vacuo to yield 18.7 g of (27A) as a yellow oil, bp 78°-88° (0.2 mm); Rf (CHCl3) 0.58; nmr (CDCl3) δ 0.90 (3H, broad t, J=6.0 Hz), 1.14 (6H, s), 1.0-1.8 (6H, m) 7.66 (1H, d, J=14.8 Hz) and 8.07 ppm (1H, d, J=14.8 Hz); ir (film) 940, 1040, 1080, 1470, 1560, 1688, 2860, 2930 and 2960 cm-1.
Reaction SMILES: [Si]([O:8][C@H:9]([C:69]1[CH:78]=[CH:77][C:76]([OH:79])=[C:75]2[C:70]=1[CH:71]=[CH:72][C:73](=[O:80])[NH:74]2)[CH2:10][N:11]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]1([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:68])[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([C:45]4[CH:46]=[C:47]5[C:52](=[C:53]([CH3:55])[CH:54]=4)[N:51]=[CH:50][C:49]([C:56](=[O:58])[NH2:57])=[C:48]5[NH:59][C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH3:67])[CH:61]=4)(=[O:44])=[O:43])[CH:37]=3)=[CH:30][CH:29]=2)[S:27][CH2:26][CH2:25][S:24]1)C(=O)OC(C)(C)C)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:8][C@H:9]([C:69]1[CH:78]=[CH:77][C:76]([OH:79])=[C:75]2[C:70]=1[CH:71]=[CH:72][C:73](=[O:80])[NH:74]2)[CH2:10][NH:11][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:35]([C:36]3[CH:37]=[C:38]([S:42]([C:45]4[CH:46]=[C:47]5[C:52](=[C:53]([CH3:55])[CH:54]=4)[N:51]=[CH:50][C:49]([C:56]([NH2:57])=[O:58])=[C:48]5[NH:59][C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH3:67])[CH:61]=4)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=3)=[O:68])=[CH:32][CH:33]=2)[S:24][CH2:25][CH2:26][S:27]1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C6(CCCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c7ccc(O)c8[nH]c(=O)ccc78)C(=O)OC(C)(C)C)SCCS6)cc5)c4)cc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C6(CCCCNC[C@H](O)c7ccc(O)c8[nH]c(=O)ccc78)SCCS6)cc5)c4)cc23)c1
Reaction time: 0.5 h

Procedure:
Intermediate 158 (90 mg, 0.08 mmol) was taken up in dichloromethane and treated with trifluoroacetic acid (0.50 mL). After 30 minutes of stirring, the mixture was concentrated to a residue under reduced pressure, taken up in tetrahydrofuran (1 mL) and treated successively with TBAF solution (1.0 M in THF, 1 mL) and glacial acetic acid (0.50 mL). The mixture was left overnight at room temperature and then concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (RP-HPLC, acetonitrile/water/0.1% TFA) to provide, after concentration, the trifluoroacetic acid salt of the title compound as a bright yellow foam (22 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22]C)=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Temperature: 0 °C

Procedure:
4-(6-Chloro-2,3-dihydro-indol-1-yl)-7-methoxy-quinazoline (7.596 g, 24.4 mmol; free-base from Example 64) was added in several portions over 5 minutes to molten pyridine hydrochloride (85 g) at 170° C. The stoppered mixture was heated 75 minutes and then poured into ice/water (~600 mL). The precipitated solid was filtered, dissolved in 10% i-PrOH/CHCl3, and the organic solution was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4(s), filtered and concentrated in vacuo to afford 3.14 g. of product. (M.P. 270°-280° C. (dec); LC-MS: 298 (MH+); anal. RP18-HPLC RT: 4.00 min.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:29]#[C:30][Si](C)(C)C)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:29]#[CH:30])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C#C[Si](C)(C)C)cccc4c3=O)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
A solution of {1-[4-(4-oxo-2-phenyl-8-trimethylsilanylethynyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (51 mg, 0.091 mmol) in MeOH (2 mL) and DCM (1 mL) was treated with potassium carbonate (15 mg, 0.109 mmol) and the reaction stirred at RT for 3 h. The reaction mixture was quenched with water, diluted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a foamy solid (45 mg, 100%). 1H NMR (400 MHz, CDCl3): δ 8.27 (dd, J=7.7 and 1.6 Hz, 1H), 7.86 (dd, J=7.5 and 1.6 Hz, 1H), 7.48 (d, J=7.5 Hz, 2H), 7.41-7.30 (m, 5H), 7.25-7.19 (m, 3H), 5.06 (s, 1H), 3.47 (s, 1H), 2.65-2.27 (m, 4H), 2.14-2.00 (m, 1H), 1.91-1.76 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][CH:21]([OH:23])[CH2:20][CH:19]3[C:24](O)=[O:25])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CO>O1CCCC1>[OH:23][CH:21]1[CH2:22][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[CH:19]([CH2:24][OH:25])[CH2:20]1
Reactant: O=C(O)C1CC(O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CC(O)CC1CO
Temperature: 25 °C

Procedure:
1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (13.3 g, 37.6 mmoles) is dissolved in anhydrous tetrahydrofuran (250 mL). The solution is stirred at ambient temperature, and borane-methyl sulfide complex in tetrahydrofuran (2 M, 40 mL, 80 mmoles) is added slowly via syringe. When the evolution of gas ceases, the flask is fitted with a condenser and Drierite drying tube and the solution is refluxed for 1 hour. During this time a white precipitate forms. Methanol (15 mL) is carefully added to the hot reaction mixture, which is refluxed for an additional 15 minutes, during which time the solid dissolves. The mixture is cooled and evaporated to a clear syrup. The syrup is coevaporated three times with methanol (100 mL each) to remove borate salts. The resulting brittle white solid is dried in vacuo. The yield is 12.7 g (99%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH:11]=O)[CH:5]=[CH:4][N:3]=[CH:2]1>O1CCCC1>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH3:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=CNCCCCn1ccnc1
Solvent: C1CCOC1
Product: CNCCCCn1ccnc1
Yield: 66.6 %

Procedure:
A solution of 58.8 g of N-[4-(1H-imidazol-1-yl)butyl]formamide in 480 ml of dry tetrahydrofuran was treated with 87.0 ml of 10 Molar borane methyl sulfide complex in tetrahydrofuran. The reaction mixture was heated to reflux for 18 hours under an argon atmosphere, cooled in an ice bath and quenched with 400 ml of methanol. The solvent was removed, the methanol addition and evaporation repeated, and the residue was made acidic with hydrochloric acid and was stirred over night. The mixture was made basic with sodium hydroxide solution and was extracted with dichloromethane. The combined organic layers were dried over potassium carbonate and evaporated to give an oil which was distilled to give 35.9 g (68%) of 4-(1H-imidazol-1-yl)-N-methylbutanamine, bp 130°-135° C./0.3 mm. The product was further characterized as the picrate, mp 111-113.