Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]1=[C:25]3[N:26]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1.Br[CH2:28][C:29]([OH:31])=[O:30].[OH-].[Na+]>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[CH2:17][C:16]1=[C:25]3[N:26]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C(O)CBr
Reactant: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(O)CN1CCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C1
Reaction time: 24 h
Yield: 53.8 %

Procedure:
An IPA (0.1 mL) solution of (6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaene (Example 21, 5 mg, 0.014 mmol), 2-bromoacetic acid (2.9 mg, 0.021 mmol) and NaOH (1 N, 42 μL, 0.042 mmol) was heated at 60° C. in a sealed vessel overnight, then at 120° C. for 24 hours. After cooling, the reaction mixture was directly purified by reverse-phase column chromatography eluting with 0-50% acetonitrile/H2O to afford the title product (3.1 mg, 53% yield). MS (apci) m/z=412.2 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:6]=2[N:7]=1)[CH3:2].[Br:14]Br>CO>[Br:14][C:11]1[C:5]2[O:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=1
Reactant: CCc1nc2c(OC)cccc2o1
Reactant: BrBr
Solvent: CO
Product: CCc1nc2c(OC)ccc(Br)c2o1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
2-Ethyl-4-methoxybenzoxazole (2.81 g) was dissolved in methanol (80 ml) under nitrogen and the solution cooled to −78° C. Bromine (0.73 ml) was added dropwise. The mixture was allowed to warm gradually to room temperature and stirred for 3.5 h. The methanol was evaporated in vacuo and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate. The combined organic phases were washed with 5% aqueous sodium metabisulphite, evaporated onto silica and purified by flash chromatography eluting with 25%-50% ethyl acetate in hexane to give a mixture of the title compound and 2-ethyl-4-methoxybenzoxazole as a pale yellow liquid (2.28 g).
Reaction SMILES: [Br:1]Br.[C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[O:13][CH2:14][O:15][C:8]=12)#[N:4].C([O-])(=O)C.[K+]>C(O)(=O)C.O>[Br:1][C:12]1[C:7]([CH2:6][CH2:5][C:3]#[N:4])=[C:8]2[O:15][CH2:14][O:13][C:9]2=[CH:10][CH:11]=1
Reactant: N#CCCc1cccc2c1OCO2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CCCc1c(Br)ccc2c1OCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
16.4 ml of bromine dissolved in 35 ml of acetic acid are poured at 18° C. onto 53.6 g of nitrile obtained in Stage C dissolved in 179 ml of acetic acid. The mixture is stirred for 1 hour, then left overnight at room temperature and hydrolysed with 31.5 g of potassium acetate dissolved in 150 ml of water and 196.5 g of ice. The mixture is extracted with diethyl ether and the ethereal phase is washed several times with water and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C:7](Cl)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Ca+2].[Cl-].[C:14]([O:18][C:19](=[O:39])[NH:20][C@@H:21]1[C:24](=[O:25])[NH:23][C@@H:22]1[CH2:26][CH2:27][C:28](=[O:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:10])[C:7]([N:23]1[C:24](=[O:25])[C@@H:21]([NH:20][C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:39])[C@H:22]1[CH2:26][CH2:27][C:28](=[O:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N[C@@H]1CCC(=O)CO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)C(=O)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(C(=O)C(=O)OC(C)(C)C)[C@@H]1CCC(=O)CO[Si](C)(C)C(C)(C)C
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To a solution of 490.7 g (3.0 Mol) chloro-oxo-acetic acid tert-butyl ester (6) in 4.41 l methylene chloride was added 577 g (5.7 Mol) calcium chloride. The suspension was cooled to 0-5° C. A cold (0° C.) solution of 575 g (1.48 Mol) (2R, 3S)-[2-[4-(tert-butyl-dimethyl-silanyloxy)-3-oxo-butyl]-4-oxo-azetidin-3-yl]-carbamic acid tert-butyl ester (5) and 385 g (3.0 Mol) N,N-diisopropylethylamine was added at such a rate that the temperature does not rise above 5° C. (1.5 h). The reaction mixture was warmed to 23° C. and stirred for 1 h. The solids were removed by filtration and washed with 1.0 l methylene chloride. The combined filtrates were extracted with 1.5 l water, twice with 1.5 l sodium bicarbonate 5% and once again with 1.5 l water. The aqueous phases were extracted with 1.0 l methylene chloride. The combined organic phases were dried over 500 g sodium sulfate and filtered. The solids were washed with 1 l methylene chloride. The combined filtrates were concentrated to a volume of 5.0 l. To this solution 20 l n-hexane was added and the mixture was concentrated to a volume of 10 l. The product was allowed to crystallize while stirring at room temperature for 16 h. The precipitate was collected by filtration, washed with 4 l n-hexane and dried at 0.1 torr at 40° C. to yield 550 g of (2R, 3S)-{3-tert-butoxy carbonylamino-2-[4-(tert-butyl-dimethyl-silanyloxy)-3-oxo-butyl]-4-oxo-azetidin-1-yl}-oxo-acetic acid tert-butyl ester (7) as colorless crystals (69% Th.); m.p.: 102-103° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[CH2:22]([N:25]=[C:26]=[O:27])[CH2:23][CH3:24]>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:26]([NH:25][CH2:22][CH2:23][CH3:24])=[O:27])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: CCCN=C=O
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: CCCNC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
1,8-Diazabicyclo[5,4,0]-unded-7-ene (0.8 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) in acetonitrile (100 mL). The mixture was stirred for 30 minutes. Propyl isocyanate (0.3 g, 3.2 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with CH2Cl2 (60 mL) and 2N HCl (30 mL). The mixture was filtered and the solid was slurried with methanol (40 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-propyl-urea (0.3 g, 31%) as a white solid: mp 298-300° C.; 1H NMR (DMSO-d6) δ 0.82 (t, J=7.3 Hz, 3H, CH3), 1.32-1.41 (m, 2H), 1.99-2.04 (m, 1H), 2.37-2.65 (m, 2H), 2.86-2.99 (m, 3H), 4.29 (d, J=6.0 Hz, 2H), 4.37 (d, J=17.3 Hz, 1H), 4.45 (d, J=17.3 Hz, 1H), 5.11-5.18 (dd, J=5.1 and 13.2 Hz, 1H, CH), 6.00 (t, J=5.5 Hz, 1H, NH), 6.38 (t, J=5.9 Hz, 1H, NH), 7.47-7.62 (m, 3H, Ar), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 11.31, 22.62, 23.24, 31.18, 41.16, 46.13, 51.50, 121.36, 128.19, 130.24, 131.58, 136.29, 139.80, 157.97, 168.13, 171.01, 172.87; Anal. calcd. for C18H22N4O4: C, 60.32; H, 6.19; N, 15.63. Found: C, 59.93; H, 6.27; N, 15.40.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=3)(O)[CH3:13])[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=3)\[CH3:13])[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(C(C)(O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1F
Temperature: 0 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3-fluoro-4-methoxyphenyl)propan-2-ol (1 g, 2.48 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers, which were separated by HPLC. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.60 (m, 2H), 7.43 (m, 1H), 7.22-7.15 (m, 4H), 4.40 (m, 2H), 3.80 (s, 3H), 3.10 (m, 4H), 2.80 (s, 3H), 1.80 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:2].[C:11]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([O:24][C:25](Cl)=[O:26])[CH:21]=[CH:22][CH:23]=1)=[O:16])([CH3:14])([CH3:13])[CH3:12].CN(C)C1C=CC=CC=1>C(#N)C>[C:11]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([O:24][C:25](=[O:26])[N:4]([CH2:3][C:1]#[N:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:21]=[CH:22][CH:23]=1)=[O:16])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)C(=O)Nc1cccc(OC(=O)Cl)c1
Reactant: N#CCNc1ccccc1
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(OC(=O)N(CC#N)c2ccccc2)c1
Temperature: 0 °C

Procedure:
Into a solution of 13.2 g N-cyanomethylaniline in 150 ml acetonitrile is added 25.57 g chloroformic acid-[3-(tert.-butylcarbonylamino)-phenyl]-ester, then with further stirring 12.1 g N,N dimethylaniline is added dropwise and the mixture heated for an additional 15 minutes to boiling. The mixture is stirred after cooling in 1 l ice water, the substance which separates out is taken up and after drying in vacuum is recrystallized from a little acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:24]([CH3:26])[CH3:25])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:8])=[O:4].C1COCC1>CCCCCCC>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:24]([CH3:26])[CH3:25])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=[O:15])=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)C
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(S)-Benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylate (40 g) and 5% Pd/Alumina were charged to a Parr reactor followed by THF (160 mL). The reactor was sealed and purged with nitrogen (6×20 psig) followed by a hydrogen purge (6×30 psig). The reactor was pressurized to 30 psig with hydrogen and agitated at room temperature for approximately 15 hours. The resulting slurry was filtered through a GF/F filter and concentrated to approximately 135 g solution. Heptane (120 mL) was added, and the solution was stirred until solids formed. After an addition 2-3 hours, additional heptane (240 mL) was added drop-wise, the slurry was stirred for approximately 1 hour, then filtered. The solids were dried to afford the title compound (S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid.
Reaction SMILES: [NH2:1][OH:2].[CH2:3]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4]>CCO>[CH2:3]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8](=[N:1][OH:2])[NH2:9])[CH3:4]
Reactant: NO
Reactant: CCOc1ccccc1C#N
Solvent: CCO
Product: CCOc1ccccc1C(N)=NO
Temperature: 50 °C
Reaction time: 12 h
Yield: 97.2 %

Procedure:
Hydroxylamine (Fluka 55458; 50% in water; 4.08 mL; 67.95 mmol; 5 eq.) was added to a solution of 2-ethoxybenzonitrile (Fluorochem 18661; 2 g; 13.59 mmol; 1 eq.) in EtOH (30 mL) and the reaction mixture was stirred at 50° C. for 12 hours. Evaporation in vacuo gave a white solid, which was further dried under high vacuum to afford the title compound (2.38 g, 97%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CC(C)=O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]2[CH:2]=1)([O-:13])=[O:12]
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1-c1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
2-Bromo-2′-nitroacetophenone (7.65 g, 31.3 mmol) and 2-aminopyridine (2.95 g, 31.3 mmol) were dissolved in acetone (50 ml) and brought to reflux. After 10 minutes a light yellow/white precipitate forms in addition to strong boiling. Refluxing was continued for 3 hours and cooled to room temperature. The volume was reduced ½ by evaporation and the intermediate solids were collected by filtration and washed with acetone (20 ml) and air dried (7.26 g of intermediate). The intermediate (7.20 g) was dissolved in MeOH (100 ml) with HBr (4 drops, catalytic) and brought to reflux. The reaction was monitored by TLC (10% MeOH in CH2Cl2). After 70 minutes, the reaction mixture was cooled to room temperature, adjusted to pH=12 with 1M NaOH, and concentrated to remove the methanol. The yellow product was collected by filtration, washed with water and air dried. 5.54 g (74%) of 2-(2-Nitro-phenyl)-imidazo[1,2-a]pyridine was obtained as a yellow crystalline solid (MS, M++H=240.1).
Reaction SMILES: [F:1]/[C:2](/[Si](CC)(CC)CC)=[C:3](/[F:13])\[CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH3:12])[CH2:6][CH2:5]1.O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(OC)(C)C>[F:13]/[C:3](/[CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH3:12])[CH2:6][CH2:5]1)=[CH:2]/[F:1]
Reactant: CCCC1CCC(/C(F)=C(\F)[Si](CC)(CC)CC)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCCC1CCC(/C(F)=C\F)CC1

Procedure:
34.6 g (0.11 mol) of [(Z)-1,2-difluoro-2-(4-propylcyclohexyl)vinyl]triethylsilane are refluxed for 20 h in 900 ml of THF together with 45 ml of water and 160 ml of TBAF (0.16 mol, 1 M soln. in THF). The batch is diluted with MTBE and washed a number of times with water. The aqueous phases are extracted with MTBE, and the combined organic phases are washed with water and saturated sodium chloride solution. The solution is dried using sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (SiO2, pentane), giving 1-((E)-1,2-difluorovinyl)-4-propylcyclohexane as a colourless oil.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:9]([O-:12])(=[S:11])[CH3:10].[K+].C(OCC)C>CN(C=O)C>[O:6]1[CH2:7][CH2:8][CH:3]([CH2:2][S:11][C:9](=[O:12])[CH3:10])[CH2:4][CH2:5]1
Reactant: CC([O-])=S
Reactant: BrCC1CCOCC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)SCC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
To a solution of 0.97 g (5.4 mmol) of 4-bromomethyl tetrahydropyran in DMF (9.7 mL) were added 1.27 g (11.2 mmol) of potassium thioacetate. The reaction was stirred at room temperature for 3 h. Diethyl ether (100 mL) was added and the reaction mixture was washed with saturated aqueous NaHCO3 solution (2×25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, eluent: heptanes, 10% ethyl acetate) to afford 0.81 g of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl)ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]2)=[CH:20][CH:19]=1.[ClH:37]>CCOCC>[ClH:37].[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:19]=[CH:20][C:21]([CH:24]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C2CCCNC2)cc1
Yield: 77 %

Procedure:
Following General Procedure D1, tert-butyl 3-(4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)piperidine-1-carboxylate (50 mg, 0.10 mmol) was reacted with HCl in ether (2.5 mL) to afford the desired product (31 mg, 77%) as an off-white solid: ESI MS m/z 405 [C24H24N2O2S+H]+
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[CH:25])[C:22]34[O:26][C:17]3([C:18](=[O:27])[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[C:14]([O:28][CH3:29])[CH:13]=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:31]=[CH:32][C:33]#[C:34][Si:35]([CH3:38])([CH3:37])[CH3:36].C(N)CCC>[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:31]=[CH:32]\[C:33]#[C:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:22]34[O:26][C:17]3([C:18](=[O:27])[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[C:14]([O:28][CH3:29])[CH:13]=[CH:12][C:11]2=3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C#CC=CCl
Reactant: C#CC1N(C(=O)Oc2ccccc2)c2ccc(OC)cc2C23OC12CCCC3=O
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: COc1ccc2c(c1)C13OC1(CCCC3=O)C(C#C/C=C\C#C[Si](C)(C)C)N2C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
A solution of Compound 314 (5.69 g, 14.6 mmol) in dry degassed benzene (120 mL) was added to copper (I) iodide (0.666 g, 3.51 mmol), and to the resulting mixture was added 1-chloro-4-(trimethylsilyl)-but-1-en-3-yne (3.69 g, 23.4 mmol) followed by n-butylamine (2.89 mL, 29.2 mmol) and tetrakis(triphenylphosphine) palladium (0) (1.01 g, 0.877 mmol) in dry degassed benzene (60 mL). The reaction mixture was stirred at 25° C. for 2 hours, diluted with ethyl ether (200 mL), poured into saturated aqueous ammonium chloride (200 mL), and extracted with ethyl ether (2×70 mL). The combined organic layers were dried (MgSO4 )and evaporated in vacuo. The residue was purified by flash column chromatography (silica, 25 percent ethyl ether in petroleum ether) to give 5.43 g (73 percent) of Compound 315: white foam; Rf =0.29 (silica, 30 percent ethyl ether in petroleum ether); IR (CHCL 3) νmax 2958, 2836, 1717, 1609, 1590, 1493, 1380, 1299, 1251 cm-1 ; 1H NMR (300 MHz, CDCl3) δ7.94 (d, J=3.0 Hz, 1 H, aromatic), 7.38-7.06 (m, 6 H, aromatic), 6.89 (dd, J=8.9, 3.0 Hz, 1 H, aromatic), 5.92 (d, J=1.6 Hz, 1 H, H6), 5.86 (d, J=11.0 Hz, 1 H, olefinic), 5.65 (br d, J=11.0 Hz, 1 H, olefinic), 3.81 (s, 3 H, OCH 3), 2.78-2.62 (m, 2 H, H9), 2.37-2.25 (m, 2 H, H7), 2.05-1.85 (m, 2 H, H8), 0.20 (s, 9 H, Si(CH3)3) ;13C NMR (125 MHz, CDCl3) δ201.2, 157.2, 154.1, 151.0, 129.3, 128.6, 128.5, 125.7, 124.0, 121.4, 120.7, 118.9, 114.8, 114.8, 103.5, 101.5, 90.5, 83.0, 74.6, 57.4, 55.4, 48.4, 38.8, 23.8, 18.2, -0.17; MS (FAB+) m/e (rel intensity) 511 (M+, 100), 390 (8), 362 (9), 176 (11), 120 (10); HRMS for C30H29NO5Si (M+) , calcd 511.1815, found 511.1815.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][O:9]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][C:5]([CH3:30])([CH3:29])[C:4]1=[O:31])[CH3:2]>CO>[CH2:1]([N:3]1[CH:7]([CH2:8][OH:9])[CH2:6][C:5]([CH3:30])([CH3:29])[C:4]1=[O:31])[CH3:2]
Reactant: CCN1C(=O)C(C)(C)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Product: CCN1C(=O)C(C)(C)CC1CO
Reaction time: 96 h
Yield: 84.1 %

Procedure:
Amberlyst 15® (5.56 g, 26.1 mmol) was washed three times with methanol and then a solution of 1-ethyl-3,3-dimethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (1.08 g, 2.61 mmol) in methanol (50 ml) was added. The mixture was left to stand for 4 days at room temperature and then the resin was removed by filtration (washing with methanol). The combined methanol fractions were concentrated to give a crude oil (1.62 g) which was purified by automated flash silica-gel column chromatography (Biotage SP4), eluting with a 0-100% gradient of ethyl acetate in hexane, to give pure 1-ethyl-5-(hydroxymethyl)-3,3-dimethyl-2-pyrrolidinone (0.376 g) as an oil that solidified on standing.
Reaction SMILES: NC1C=CC=CC=1.[C:8]([C:12]1[CH:13]=[C:14]([CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])[C:15]([O:17][CH2:18][CH2:19][C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([NH2:30])[CH:24]=1)=[O:21])=[O:16])([CH3:11])([CH3:10])[CH3:9].[CH2:39]([O:43][C:44]1[CH:49]=[CH:48][C:47]([C:50](=[O:57])[CH2:51][C:52](OCC)=[O:53])=[CH:46][CH:45]=1)[CH2:40][CH2:41][CH3:42]>C1(C)C(C)=CC=CC=1>[C:35]([C:32]1[CH:31]=[C:14]([CH:13]=[C:12]([C:8]([CH3:10])([CH3:11])[CH3:9])[C:33]=1[OH:34])[C:15]([O:17][CH2:18][CH2:19][C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([NH:30][C:52](=[O:53])[CH2:51][C:50]([C:47]2[CH:48]=[CH:49][C:44]([O:43][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:45][CH:46]=2)=[O:57])[CH:24]=1)=[O:21])=[O:16])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCCCOc1ccc(C(=O)CC(=O)OCC)cc1
Reactant: CC(C)(C)c1cc(C(=O)OCCC(=O)Oc2ccc(Cl)c(N)c2)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1C
Solvent: Nc1ccccc1
Product: CCCCOc1ccc(C(=O)CC(=O)Nc2cc(OC(=O)CCOC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)ccc2Cl)cc1
Reaction time: 5 h
Yield: 82.2 %

Procedure:
A solution of the aniline from (c) (19.8 g, 44.2 mmole) and the β-ketoester from (e) (13.0 g, 44.2 mmole) in xylene (160 ml) were heated under reflux, using a Dean & Stark apparatus, for 5 hours. Over the final hour, the volume of the mixture was reduced to 75 ml by distillation. 60-80 petroleum ether (300 ml) was added with cooling and the solid collected by filtration. The product was isolated as a brown solid (24.2 g, 82%). m.p. 94-96%.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1.[OH-].[Na+].C(O)(C)C.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28].[CH3:12][N:10]1[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6][CH:5]([CH2:4][CH2:3][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:11]1
Reactant: C1COCCN1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Solvent: CC(C)O
Product: CN1CC(CCN2CCOCC2)Oc2ncccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one hydrochloride, 16 g (058 mole) was dissolved in morpholine (30 mL) and stirred overnight at room temperature. To the solution was added dilute sodium hydroxide solution (50 ml) and the resulting mixture extracted with chloroform (3×30 ml). The chloroform was removed on the rotary evaporator with aspiration. The residual morpholine was removed in vacuo at 50° C. (rotary evaporator). To the residual free base (15.5 g, 0.053 mole) was added isopropyl alcohol (1 liter) and maleic acid (9.24 g g, 0.080 mole). The mixture was heated to boiling and the clear solution cooled at 20° C. for several hours. The resulting crystals, 16 g (68.1%), were recrystallized from isopropyl alcohol, m.p. 163°-165° C.