Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[NH:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@@H:16]([C:18]([N:20]([CH3:38])[C@H:21]([C:26]([N:28]([CH3:37])[C@H:29]([C:34](O)=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH3:17].[NH:46]([CH3:60])[C@H:47]([C:51]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:52])[CH:48]([CH3:50])[CH3:49].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@@H:16]([C:18]([N:20]([CH3:38])[C@H:21]([C:26]([N:28]([CH3:37])[C@H:29]([C:34]([N:46]([CH3:60])[C@H:47]([C:51]([CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:52])[CH:48]([CH3:49])[CH3:50])=[O:35])[CH2:30][CH:31]([CH3:32])[CH3:33])=[O:27])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:19])[CH3:17]
Reactant: CN[C@H](C(=O)Cc1ccccc1)C(C)C
Reactant: CC(C)C[C@@H](C(=O)N(C)[C@@H](CC(C)C)C(=O)O)N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@@H](C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@H](C(=O)Cc1ccccc1)C(C)C)N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
3.48 ml (3.18 g=31.5 m mol) N-methylmorpholine and 1.86 ml (1.8 g=15.0 m mol) pivaloyl chloride are added to a solution of 6.65 g (15.0 m mol) BOC-(D)-Ala-MeLeu-Me-Leu-OH in 60 ml chloroform, pre-cooled to -20° C. Conversion to the anhydride is completed after stirring for 2 hours at -20° C. (IR control). 3.35 g (15.0 m mol) H-MeVal-Bzl in 50 ml chloroform are then added dropwise to the reaction mixture at -20° C. The progress of the reaction is followed by means of thin-layer chromatography and IR-spectrometry and is complete after 41/2 days. The obtained solution is poured onto 200 ml 1N sodium bicarbonate on a shaker, and diluted with 300 ml chloroform. After separation of the organic phase, the aqueous phase is extracted with a further 100 ml chloroform, the combined chloroform phases dried over sodium sulphate, filtered and evaporated. The residue is chromatographed on 600 g silica gel (0.063-0.2 mm) using 2% methanol in methylene chloride as eluant to yield the title compound: rotation, [α]D25 =-143.7° (c=0.9 in chloroform).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:24]=[CH:23]4)[CH:3]=2)[NH:7][N:6]=1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1n[nH]c2ccc(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)cc12
Temperature: 25 °C
Yield: 25.2 %

Procedure:
5-bromo-3-methyl-1H-indazole (30.7 mg, 0.145 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (110.3 mg, 0.291 mmol), Fibercat palladium catalyst (Johnson-Matthey, 59.3 mg), and K2CO3 (2 M in water, 0.50 ml, 1.0 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.6 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 85 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (3×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified via silica gel (Biotage instrument, 13% EtOAc/hexanes->100% EtOAc). This crude material was then purified via HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (14.0 mg, 25%). MS (ESI pos. ion) m/z: 384 (M+H). Calc'd Exact Mass for C23H17N3OS: 383.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:34])[NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[C:28]2[CH:29]=[C:30]([OH:33])[CH:31]=[CH:32][C:27]=2[O:26][CH:25]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:9])[C:10]([NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[C:28]2[CH:29]=[C:30]([OH:33])[CH:31]=[CH:32][C:27]=2[O:26][CH:25]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:34]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)N1CCCC1Cc1coc2ccc(O)cc12)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)C(=O)NC(C(=O)N1CCCC1Cc1coc2ccc(O)cc12)C(C)C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a solution of 31 (0.04 g, 0.082 mmol) in DCM (5 mL) was added TFA (1 mL) at ambient temperature. After 1 h, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (10% MeOH/DCM) to afford 0.011 g (37%) of 32 as a white solid. 1H NMR (CDCl3, 300 MHz) 88.54 (d, 1H); 7.37 (s, 1H); 7.31 (d, 1H); 7.09 (d, 1H); 6.83 (dd, 1H); 4.64 (t, 1H); 4.56-4.51 (m, 1H); 4.09-3.93 (m, 2H); 3.73-3.65 (m, 1H); 3.36 (dd, 1H); 2.35 (t, 1H); 2.19-1.94 (m, 3H); 1.77-1.69 (m, 2H); 1.33 (d, 2H); 1.25-1.19 (m, 1H); 1.04-1.00 (m, 5H); 0.94 (t, 1H) ppm.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:22]2[C:23]([F:39])=[C:24]([NH:28]C(=O)OCC4C=CC=CC=4)[CH:25]=[CH:26][CH:27]=2)=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=3)(=[O:3])[NH2:2]>C1COCC1.CO.[Pd]>[NH2:28][C:24]1[C:23]([F:39])=[C:22]([C:7]2[C:8]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NC(=O)OCc4ccccc4)c3F)c12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3F)c12
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of benzyl 3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-fluorophenylcarbamate (0.6318 g, 1.195 mmol) and 10% Pd/C (0.191 g, 0.179 mmol) in THF (31.9 mL) and MeOH (47.8 mL) was hydrogenated. After 2 hr, the reaction was filtered through a wad of CELITE® and rinsed with THF and MeOH. The filtrate was concentrated in vacuo, dissolved in EtOAc (100 mL) and brine (25 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give the desired product (0.4462 g, 1.007 mmol, 84% yield) as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([O:26][C:27]([C:29]1[S:30][C:31]([CH:34]=O)=[CH:32][CH:33]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:16])/[CH:7]=[CH:34]/[C:31]1[S:30][C:29]([C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])=[CH:33][CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=O)OCc2ccccc2)s1
Reaction time: 0.5 h

Procedure:
Diethylphosphonoacetic acid tert-butyl ester (12 g, 48 mmol) was dissolved in tetrahydrofuran (50 ml), 60% sodium hydride (1.6 g, 41 mmol) was added at 0° C., and the mixture was stirred for 30 minutes. A solution of 5-formyl-2-thiophenecarboxylic acid benzyl ester (8.8 g, 36 mmol) in tetrahydrofuran (1 mL) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12]Br)[C:5]([C:8]([O:10]C)=O)=[N:6][CH:7]=1.[CH2:14]([NH2:16])[CH3:15].C1COCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][N:16]([CH2:14][CH3:15])[C:8](=[O:10])[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1ncc(Br)cc1CBr
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN1Cc2cc(Br)cnc2C1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (0.39 g, 1.3 mmol), ethylamine in THF (0.88 mL, 2.0 M, 1.8 mmol) and potassium carbonate (0.26 g, 1.9 mmol) in ethanol (5 mL) in a sealed reaction vial was stirred at 40° C. for 2 h. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.24 g). LCMS (M+H)+=240.9/242.9.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccncc1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4ccncc4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 4-bromomethyl-pyridine gave the title compound.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=O>C(O)C>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc([N+](=O)[O-])cc3)cs2)c1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A solution (8 mL) of the compound (1.0 g, 4.7 mmol) obtained in Example 1b and 2-bromo-1-(4-nitrophenyl)ethanone (1.4 g, 5.6 mmol) in ethanol was heated under reflux overnight, and cooled to room temperature. The solvent was evaporated under reduced pressure, and the resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (1.5 g, 89%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH:8]1([NH2:11])[CH2:10][CH2:9]1>C(O)C>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][N:11]([CH:8]1[CH2:10][CH2:9]1)[CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH3:7]
Reactant: NC1CC1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN(CCC(=O)OCC)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.7 %

Procedure:
A mixture of ethyl acrylate (300 mmol) and cyclopropyl amine (149 mmol) in absolute ethanol (45 mL) was stirred for 24 h at room temperature. The crude mixture was purified by fractionated distillation in vacuo (20 mbar). One fraction was collected (boiling point: 135° C. at 20 mbar), yielding to 20.58 g of the desired product as a colorless oil. MS (m/e): 274.3 (MH+, 100%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[I-:11].[Na+]>CC(C)=O>[I:11][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: [I-]
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCN1CCOCC1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A mixture of 4-(2-chloro-ethyl)-morpholine hydrochloride (5 g, 26.9 mmole), and sodium iodide (20 g, 134.4 mmole) in acetone (50 ml) was refluxed for 16 hours. After cooled to room temperature, the reaction was partitioned between CHCl3 and brine. The aqueous layer was extracted with CHCl3 (2×25 ml). The combined organic layers were washed with brine, and dried over anhydrous Mg2SO4. Removal of the solvent gave 4-(2-iodo-ethyl)-morpholine as a pale yellowish oil (3.84 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20][N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(Cl)cc2C1=O
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(Cl)ccc2-3)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
A solution of 370 mg (1.01 mmol) of 8-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 5 ml of N,N-dimethylformamide was treated with 0.42 ml (3.03 mmol) of dipropylamine and stirred at room temperature under argon for 2 hrs. The solution was evaporated and the residue was triturated in 10 ml of water. The white crystals were filtered off. The product was chromatographed on 20 g of silica gel (ethyl acetate/hexane 1:1, then ethyl acetate). There were obtained 259 mg of 8-chloro-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted with ethereal hydrochloric acid into the hydrochloride. By recrystallization from acetonitrile there were obtained 268 mg (54%) of 8-chloro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (1:1.6) of m.p. 180°-192° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.FC(F)(F)[C:13]([O:15]C(=O)C(F)(F)F)=[O:14]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:13]([OH:15])=[O:14]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Brc1cccc2cc[nH]c12
Solvent: CN(C)C=O
Product: O=C(O)c1c[nH]c2c(Br)cccc12

Procedure:
To a solution of 7-bromoindole (10 g, 51.0 mmol) in N,N-dimethylformamide (DMF) (100 cm3) was added trifluoroacetic anhydride (12.5 cm3, 89.6 mmol) over 5 min. The resultant solution was stirred at room temperature for 16 h. The solution was poured onto water (500 cm3) and the precipitate formed was isolated by filtration, washed with water and 4N sodium hydroxide (200 cm3) added. The suspension was heated at reflux for 1.5 h and allowed to cool before washing with diethyl ether (2×250 cm3). The aqueous layer was acidified to pH 1 with 5N hydrochloric acid and the resultant precipitate isolated by filtration, washed with water and dried over phosphorous pentoxide under reduced pressure at 60° C. for 16 h. This afforded the title compound LA) (8.94 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:17]2[CH:18]=[C:19]([C:24]([CH3:27])=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:14][C:15]=1[OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:29][CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:17]2[CH:18]=[C:19]([C:24]([CH3:27])=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:14][C:15]=1[O:16][CH2:29][CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2ccc(O)c(CNC(=O)OC(C)(C)C)c2)ccc1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOc1ccc(-c2ccc(C)c(C(=O)OC)c2)cc1CNC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
170 mg of Methyl 3-(3-{[(t-butoxycarbonyl)amino]-methyl}-4-hydroxyphenyl)-6-methylbenzoate was dissolved in 5 ml of acetonitrile, 0.5 ml of iodoethane and 500 mg of cesium carbonate were added successively thereto and the mixture was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate and successively washed with water and brine, dried over magnesium sulfate, filtered, and the solvent was concentrated, to give 185 mg of the title compound.
Reaction SMILES: [OH:1][N:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5](=NO)[CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CS(O)(=O)=O>O1CCCC1>[OH:1][N:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5]([O:28][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([O:28][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ON=C1CC(c2ccccc2)N(O)C(c2ccccc2)C1
Reactant: CCCCCCO
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CCCCCCOC1(OCCCCCC)CC(c2ccccc2)N(O)C(c2ccccc2)C1
Yield: 20.2 %

Procedure:
A solution of 10.0 g (0.035 mole) 1-hydroxy-2,6-diphenyl-4-piperidone oxime, 22.0 g (0.22 moles) 1-hexanol and 7.0 g (0.073 moles) methanesulfonic acid in 250 mL tetrahydrofuran is heated at 60° C. for 12 hours. The solution is then washed three times with 10% aqueous sodium carbonate solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. 3.2 g (20% yield) of the title compound is isolated as a clear oil after purification by LC (silica gel, ethyl acetate:hexane).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:8][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][CH2:5]2)[CH2:3][N:2]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][O:46][C:47]([NH:49][C@H:50]([C:54](O)=[O:55])[CH:51]([CH3:53])[CH3:52])=[O:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:45][O:46][C:47]([NH:49][C@H:50]([C:54]([N:6]1[CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][C:4]2([CH2:3][N:2]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:1]2)[CH2:5]1)=[O:55])[CH:51]([CH3:52])[CH3:53])=[O:48]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCOC(=O)C1CC2(CN1)CN(C(=O)OC(C)(C)C)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CC2(CN(C(=O)OC(C)(C)C)C2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To a solution of 2-(1,1-dimethylethyl) 7-ethyl 2,6-diazaspiro[3.4]octane-2,7-dicarboxylate (145) (500 mg, 1.76 mmol), HATU (735 mg, 1.93 mmol) and N-[(methyloxy)carbonyl]-L-valine (339 mg, 1.93 mmol) in anhydrous CH2Cl2 (10 mL) was added Hunig's base (0.68 mL, 3.87 mmol) and the reaction stirred at room temperature under nitrogen for 2 h. The reaction was concentrated in vacuo and purified by C18 reverse-phase chromatography eluting with 10-90% ACN/water/0.2% NH4OH to afford the title compound as an off-white solid (398 mg, 51% yield).
Reaction SMILES: C([N:8]1[C@@H:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:22])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:22][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:8]1
Reactant: C[C@H]1CCC[C@H](CCc2ccccc2)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CCC[C@H](CCc2ccccc2)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(2-phenylethyl)piperidine (1.4 g, 5.50 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 65 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(2-phenylethyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 148.3-151.0; 1H NMR (300 MHz) δ 9.3, (s, 2H), 7.28-7.11 (m, 5H), 3.43 (s, 1H), 3.19 (s, 1H), 2.67-1.27 (m, 13H); 13C NMR (75 MHz) 140.0 (s), 128.3 (s), 126.1 (s), 50.9 (s), 47.9 (s), 32.1 (s), 31.5 (s), 28.5 (s), 26.4 (s), 17.2 (s), 16.5 (s). FT-IR (neat): 3410, 3075, 2944, 1590, 1494, 1454, 1435, 1336, 1122, 1029, 751, 701. Elemental Analysis for C14H22NCl: C, 70.11%; H, 9.27%; N, 5.84%. Found: C, 69.95%; H, 9.19%; N, 5.79%.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:20])[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[CH3:21][O:20][C:3]1[C:2](=[O:1])[C:8]([NH:9][S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc(=O)c2O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccccc(NS(=O)(=O)c2ccc(C)cc2)c1=O

Procedure:
A mixture of 2-hydroxy-3-[N-[(4-methylphenyl)sulfonyl]-amino]-2,4,6-cycloheptatrien-1-one (14.5 g), potassium carbonate (12.5 g), dimethyl sulfate (12.5 g) and 2-butanone (145 ml) is heated at reflux for 1 hour. The mixture is filtered and the precipitate is washed with water and suspended in ethyl actate. Hydrochloric acid (10%) is added until the solution is acidic. The organic phase is collected and dried over sodium sulfate. Evaporation of the solvent and crystallization of the residue from ethyl acetate-hexane gives 2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-one, mp 163°-164° C. The above filtrate is evaporated and the residue is subjected to chromatography on silica gel using ethyl acetate-hexane (3:1). Evaporation of the eluates are crystallization of the residue from ethyl acetate gives 2-methoxy-3-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one, mp 101°-102° C and 2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one, mp 94.5° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([OH:12])=[N:3][CH:2]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][N:3]=[C:4]2[OH:12])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc2ncnc(O)c2c1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2ncnc(O)c2c1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of quinazoline-4,6-diol (20 g, 123 mmol) and acetic anhydride (186 mL, 1.97 mol) was heated to 100° C. in pyridine (30 mL) for 2 hours. After cooling to room temperature, ice (200 g) was slowly added to the reaction mixture. The precipitate was filtered, washed with cold water, and dried under high vacuum to provide the product (16.25 g, 65%) as pale yellow solid.