Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[C:10]([NH:13][C:14]1[S:15][C:16]([C:19]2[CH2:26][S:25][CH:24]3[N:21]([C:22](=[O:28])[CH:23]3[NH2:27])[C:20]=2[C:29]([O:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:17][N:18]=1)(=[O:12])[CH3:11].C(N(CC)CC)C>O1CCCC1>[C:10]([NH:13][C:14]1[S:15][C:16]([C:19]2[CH2:26][S:25][CH:24]3[N:21]([C:22](=[O:28])[CH:23]3[NH:27][C:7](=[O:8])[CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[C:20]=2[C:29]([O:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])=[CH:17][N:18]=1)(=[O:12])[CH3:11]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1

Procedure:
A solution of (thien-2-yl)-acetyl chloride (0.55 cc) in dry tetrahydrofuran (5 cc) is added, in 5 minutes, to a solution of 3-(2-acetamido-thiazol-5-yl)-7-amino-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.27 g) in dry tetrahydrofuran (27.5 cc) at 2° C., and after 30 minutes a solution of triethylamine (0.63 cc) in dry tetrahydrofuran (5 cc) is added. After 1 hour's reaction at 2° C., the reaction mixture is filtered and the filtrate is diluted with a mixture of ethyl acetate (200 cc) and half-saturated sodium bicarbonate solution (200 cc). The organic layer is washed with water (100 cc) followed by a saturated sodium chloride solution (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is chromatographed on a column (height: 30 cm; diameter: 5 cm) of silica (0.04-0.06 mm), elution being effected under 0.4 bar (40 kPa) with a 30:70 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 15 to 22, containing the pure product, are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 3-(2-Acetamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.92 g) is obtained in the form of a yellow powder.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][O:12][C:4]1[CH:3]=[C:2]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(F)cc1OCCCNC(=O)OC(C)(C)C
Reactant: C1CCNC1
Product: COC(=O)c1ccc(N2CCCC2)cc1OCCCNC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 95.7 %

Procedure:
A mixture of methyl 4-fluoro-2-[3-(tert-butoxycarbonylamino)propoxy]benzoate (8.148 g, 25 mmol) and pyrrolidine (20.87 mL, 250 mmol) was purged with nitrogen and heated to 80° C. for 3 hours. The reaction was concentrated in vacuo. After diluting with EtOAc, the mixture was cooled to 0° C., acidified with satd citric acid, and extracted with EtOAc. The organic layer was washed with satd citric acid and water, dried (Na2 SO4), and concentrated. The resulting residue was absorbed onto silica gel and chromatographed (20% EtOAc/hexane to 35% EtOAc/hexane). The resulting product was triturated with Et2O/hexane to give the desired product as a white solid (9.05 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3F)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[O:30]=[C:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[N:35]3[CH2:34][CH2:33][NH:32][C:31](=[O:30])[CH2:36]3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1
Reactant: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2F)cn1)c1ccc(Cl)s1
Solvent: CS(C)=O
Product: O=C1CN(c2cc(-n3ccccc3=O)ccc2-n2cnc(CNC(=O)c3ccc(Cl)s3)c2)CCN1
Yield: 17.2 %

Procedure:
A solution of 5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide prepared in Example 11 (70 mg, 0.16 mmol) and 2-oxopiperazine (565 mg, 5.65 mmol) in DMSO (1 mL) was heated at 150° C. for 2 days. The mixture was purified by HPLC to give the title compound (14 mg). MS 509.0 and 511.0 (M+H, Cl pattern).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:14]([NH:16][CH2:17][CH2:18][CH:19]([OH:26])[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(OCC)(=O)C.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl.O>[C:1]12([CH2:11][CH2:12][N:13]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:14]([NH:16][CH2:17][CH2:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:15])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCC(O)c1ccncc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H-one (221 mg, 0.520 mmol) was added to a solution of 1-[2-(1-adamantyl)ethyl]-3-[3-hydroxy-3-(4-pyridyl)propyl]-1-pentylurea (100 mg, 0.234 mmol) in anhydrous dichloromethane (2 ml) under ice-cooling, the temperature was raised to room temperature, and the mixture was stirred for one hour. The reaction mixture was cooled with ice again, ethyl acetate (10 ml), a saturated aqueous sodium sulfite solution (5 ml) and a saturated aqueous sodium hydrogencarbonate solution (5 ml) were added to the reaction mixture, and the whole was stirred for 15 minutes. The reaction mixture was distributed with ethyl acetate (50 ml) and water (10 ml), and the organic layer was washed with a saturated aqueous sodium sulfite solution (5 ml), a saturated aqueous sodium hydrogencarbonate solution (5 ml) and a saturated aqueous sodium chloride solution (25 ml) successively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 87.3 mg (87.8%) of the titled compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C@H:12]([C:22](OC)=[O:23])[CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])(=[O:10])=[O:9])[S:5][C:6]=1[Cl:7].[BH4-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH:12]([CH2:22][OH:23])[CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:10])[S:5][C:6]=1[Cl:7]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1cc(Br)c(Cl)s1)C(C(F)(F)F)C(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1cc(Br)c(Cl)s1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of methyl N-[(4-bromo-5-chloro thien-2-yl)sulfonyl]-4,4,4,4′,4′,4′-hexafluorovalinate (1.45 g, 2.907 mmol) in THF (20 mL) was added lithium borohydride (LiBH4) (5.82 mL, 11.64 mmol) under N2 atmosphere at 0° C. The reaction was allowed to warm to 25° C. for 19 h. The reaction was cooled to 0° C., quenched with 2N HCl (slow addition), diluted in ether (40 mL) and the organic layer was washed sequentially with 1N aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (15 mL), then dried over MgSO4, filtered and concentrated to obtain a crude oil (1.3 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:6 EtOAc-hexanes, to afford 4-bromo-5-chloro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid (1.13 g, 84.32%).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][Br:11])=[O:4].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[Br-:11].[CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)C(=O)NC(=O)CCCCBr
Solvent: CC#N
Product: CC(C)(C)C(=O)NC(=O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A solution of 1.82 g. (6.80 mmoles) of the N-trimethylacetyl-5-bromovaleramide prepared above and 2.67 g. (10.2 mmoles) of triphenylphosphine in 18 ml. of acetonitrile was heated to reflux under nitrogen for 96 hours. The solution was concentrated and the resultant solid was triturated with benzene (4x). The triturated solid was purified by silica gel column chromatography using first ethyl acetate to remove high Rf impurities then with a 9:1 mixture of methylene chloride:methanol. The salt, [4-trimethylacetylaminocarbonylbutyl]triphenylphosphonium bromide, was obtained as crystals from methylene chloride:ethyl acetate weighing 0.750 g. melting at 133.5°-138°.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1>[Pd].C(O)C.O1CCOCC1>[CH2:25]([O:24][C:22]([CH2:21][O:20][C:14]1[C:13]2[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=2)[N:17]=[C:16]([CH3:19])[CH:15]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)COc1cc(C)nc2c(OCc3ccccc3)cccc12
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)COc1cc(C)nc2c(O)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
A mixture of 8-benzyloxy-4-ethoxycarbonylmethoxy-2-methylquinoline (1.30 g) and palladium on carbon (130 mg) in a mixture of ethanol (8 ml) and dioxane (7 ml) was stirred for 3 hours at ambient temperature under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 4-ethoxycarbonylmethoxy-8-hydroxy-2-methylquinoline (539 mg).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:16][C:17]([F:31])([F:32])[C:18]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=1[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2,4-bis(trifluoromethyl)phenylboronic acid (0.572 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 22 h to give 2-(2,4-bis(trifluoromethyl)phenyl)-4-chloro-5,7-difluoro-3-methylquinoline as a crystalline solid. Mass Spectrum (ESI) m/e=426.0 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:29])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.CO.O.[OH-].[Li+]>C(O)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1)=[C:8]2[CH3:29]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
A solution of [8-chloro-3-(4-methanesulfonylbenzyl)-2,4-dimethylquinolin-5-yloxy]-acetic acid methyl ester (0.11 g), methanol (5.0 mL), water (1.0 mL) and saturated aqueous lithium hydroxide solution (0.5 mL) was stirred at room temperature for 3 days. The pH of the solution was adjusted to 4 by the addition of glacial acetic acid and the methanol removed under reduced pressure. The resulting precipitate was collected by filtration, washed with water and dried to afford title compound as a white solid, 0.08 g.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][NH:3]1.Br[CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27](C(OC(C)(C)C)=O)[N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]=[C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([C:19]([F:20])([F:22])[F:21])[CH:5]=[CH:4][N:3]1[CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[NH:27][N:26]=1
Reactant: N#Cc1cc(C#N)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(C#N)cc(Oc2c(C(F)(F)F)ccn(Cc3n[nH]c4ncccc34)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}isophthalonitrile (0.076 g, 0.249 mmol), tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.078 g, 0.249 mmol) and potassium carbonate (0.034 g, 0.249 mmol) were combined and diluted with dimethylformamide (1 mL) and stirred at room temperature. After 16 hours, water (10 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (3×25 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting solid was dissolved in TFA. After 30 minutes, the solution was concentrated. The resulting solid was suspended in methanol and filtered to afford the title compound as a solid. 1H NMR (DMSO-d6) δ 8.52 (d, J=4.6 Hz, 1H), 8.17-8.17 (m, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.06 (d, J=7.1 Hz, 1H), 7.98 (m, 2H), 7.18 (dd, J=8.2 Hz, J=4.7 Hz, 1H), 6.65 (d, J=7.3 Hz, 1H), 5.52 (s, 2H). HRMS (M+1)=437.0981.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12].S(OC)(O[CH3:17])(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:17][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CN1C(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 67 %

Procedure:
A stirred mixture of sodium hydride (60%, 31 g, 0.79 mol) in dry xylene (500 mL), under a nitrogen atmosphere, was heated to reflux for 30 min. 1,3-Dihydro-indol-2-one 16a (100 g, 0.75 mol) was then slowly added via an addition funnel and stirred at reflux for 1.5 hours. Dimethyl sulfate (104 g, 0.83 mol) was added drop-wise, whereupon the resulting homogeneous solution was refluxed for an additional 2 hours. After cooling to room temperature, the reaction mixture was washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford 1-methyl-1,3-dihydro-indol-2-one 16b (74 g, 67.3%). 1H NMR (300 MHz, CDCl3) δ 7.23-7.31 (m, 2H), 7.04 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 3.52 (s, 2H), 3.21 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].[Na].[CH2:18]=[C:19]1[C:24](=[O:25])[CH:23]2[CH2:26][CH2:27][N:20]1[CH2:21][CH2:22]2>C(O)C.C(O)(=O)C>[O:25]=[C:24]1[CH:23]2[CH2:26][CH2:27][N:20]([CH2:21][CH2:22]2)[CH:19]1[CH2:18][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C=C1C(=O)C2CCN1CC2
Reactant: CCOC(=O)Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CC1C(=O)C2CCN1CC2)c1ccccc1
Reaction time: 16 h

Procedure:
Ethyl phenylacetate, 49.2 g was added to a solution of sodium ethoxide previously prepared from metallic sodium, 2.9 g and ethanol, 100 ml. The mixture was cooled to 5°, then a solution of 2-methylenequinuclidin-3-one, 39.4 g, in ethanol, 50 ml. was added dropwise and with stirring. After 16 hours at room temperature, the solution was neutralized with acetic acid then subjected to evaporation at reduced pressure. Water, 100 ml. was added to the residue and the mixture was extracted with chloroform. Evaporation of this solvent gave ethyl (3-oxoquinuclidin-2-yl)methylphenylacetate, 54 g (60%); b.p. 195°-200° at 1 mm Hg; m.p. of methiodide salt, 194.7°-195.6°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].I[CH2:13][CH3:14]>CN(C=O)C>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH2:13][CH3:14]
Reactant: COC(=O)C(C)(C)CO
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
60% Sodium hydride in mineral oil (1.6 g, 39.2 mmol) is added to a solution of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (2.0 mL, 15.7 mmol) in 30.0 mL of DMF, followed by the addition of iodoethane (3.1 mL, 39.2 mmol) and the reaction mixture is stirred at room temperature for 1 hour. After this time, the reaction mixture is quenched with saturated NH4Cl aqueous solution and then extracted with dichloromethane twice. The organics are combined and washed with water twice then brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield 2.512 g of the title compound. Yield: quantitative; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (3H, t, J=8.0 Hz), 1.20 (6H, s), 3.41 (2H, s), 3.48 (2H, q, J=8.0 Hz), 3.70 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[OH:18])[C:6](=[O:19])[C:5]=2[CH:4]=1.C[O-].[Na+].Cl.Cl[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>CO.ClC1C=CC=CC=1>[CH2:26]([N:27]([CH2:30][CH3:31])[CH2:28][CH2:29][O:18][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:13]1[C:14]([O:16][CH3:17])=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]2=[O:19])[CH3:25]
Reactant: CCN(CC)CCCl
Reactant: COc1cc(OC)c2c(c1)C(=O)c1cccc(O)c1-2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CO
Product: CCN(CC)CCOc1cccc2c1-c1c(OC)cc(OC)cc1C2=O
Yield: 64.9 %

Procedure:
Similar to example 3D1, prepare a solution of 2,4-dimethoxy-5-hydroxy-fluoren-9-one (0.33 g, 1.3 mmol) in methanol (8 mL) and 24 mL chlorobenzene with sodium methoxide (0.11 g, 2.0 mmole), and react the free base of 2-chloro-ethyl-diethyl amine hydrochloride 2.1 g (12 mmole) in order to obtain 0.30 g of the title compound as a reddish-orange powder. m.p. 178° C.-180° C. Analysis calculated for C21H25NO4.HCl: C, 64.36; H, 6.69; N, 3.58. Found: C, 63.99; H, 6.75; N, 3.62.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:7]([C:13]1[CH:27]=[CH:26][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].CO.[C:36](OC)(OC)(OC)[CH3:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:36][C:37]1[N:12]2[C:3]([C:4]3[CH:5]=[C:6]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:7]([C:13]4[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=4)=[N:8][C:9]=3[CH:10]=[CH:11]2)=[N:1][N:2]=1
Reactant: COC(C)(OC)OC
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccnc(NN)c3cc2-c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(CNC(=O)OC(C)(C)C)cc4)nc3ccn12
Temperature: 100 °C

Procedure:
To a stirred solution of 16-2 (5 g, 11.3 mMol) in 20 mL of 3:1 toluene:methanol was added trimethyl orthoacetate (1.8 g, 15.3 mMol) and p-toluenesulfonic acid monohydrate (0.1 g, 0.6 mMol). The reaction was heated to 100° C. in a microwave reactor for 35 minutes. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified using normal phase flash chromatography to yield 17-1 as a solid. LC/MS (M+1) calculated: 466.6 observed: 466.2
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28]Cl>CS(C)=O.O>[CH2:7]([NH:15][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCN
Reactant: ClCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCNCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-octylamine (0.37 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-octyl)-2-(napthalen-2-yloxy)ethylamine, solid, m.p. 105° C., (yield 0.64 gm, 87.6%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2[C:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30](=[O:38])(=[O:37])[NH:29][N:28]=1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CC#N.O.C(Cl)Cl>[C:44]([O:43][C:41](=[O:42])[CH2:40][N:22]1[C:23]2[C:19](=[CH:18][C:17]([F:16])=[CH:25][CH:24]=2)[C:20]([C:27]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30](=[O:37])(=[O:38])[N:29]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:28]=2)=[C:21]1[CH3:26])([CH3:47])([CH3:46])[CH3:45]
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: BrCCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: Cc1c(C2=NN(CCc3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2-Bromoethyl)benzene (9 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9]([CH3:12])[CH2:10]O)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:8](=[O:13])[CH:9]([CH3:12])[CH2:10]2
Reactant: CC(CO)C(=O)c1ccc(F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1Cc2cc(F)ccc2C1=O

Procedure:
A mixture of 18.2 g. (0.10 mole) of 4'-fluoro-3-hydroxy-2-methylpropiophenone and 12 g. of phosphorous pentoxide in 100 ml. of xylene is refluxed for 1 hour. The reaction is cooled, water is added and the xylene layer is washed with aqueous sodium hydroxide and water. The organic layer is then concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.