Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>COCCOC>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[C:10]1[C:11]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: C1COCCN1
Solvent: COCCOC
Product: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (12 mg, prepared as in Example 26) and morpholine (0.2 mL) in DME was heated at 80° C. for 12 hours. Concentration in vacuo gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethyl pivalate (15 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H40ClN2O4: 539.3. Found: 539.4.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([O:6][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:5]
Reactant: CCCCCCCCCCCC(O)CC(=O)O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.00 g of 3-hydroxymyristic acid in 50 ml of DMF were added at room temperature 2.85 ml of triethylamine and 2.43 ml of benzyl bromide. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, ethyl acetate and water were added to the residue, and the organic layer was separated, washed twice with water and dried over anhydrous sodium sulfate. After the solvent was removed in vacuo, the crude product was purified by a silica gel column chromatography to afford 3.69 g of benzyl 3-hydroxymyristate (Intermediate 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12](Cl)[C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)cc(N2CCOCC2)c1[N+](=O)[O-]
Temperature: 115 °C
Yield: 46.6 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-nitro-3,5-dichlorobenzamide (12 g, 34 mmol) in DMSO (50 mL) was added morpholine (3.6 g, 41 mmol) followed by N,N-diisopropylethylamine (8.9 g, 69 mmol). The mixture was heated at 110-120° C. for 4 hours, then cooled to ambient temperature, quenched with water (50 mL) and extracted with ethyl acetate (3x100 mL). The combined organics were washed with brine (2×30 mL), dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 6.3 g (46% yield) of N-(5-chloropyridin-2-yl)-2-nitro-3-(morpholin-4-yl)-5-chlorobenzamide; NMR (CDCl3) 8.2 (m, 1), 7.7 (m, 1), 7.2-7.4 (m, 3), 3.8 (m, 4), 3.0 (m, 4) ppm.
Reaction SMILES: C([Li])CCC.[CH2:6]([CH:9]1[S:14][CH2:13][CH2:12][CH2:11][S:10]1)[CH2:7][CH3:8].[CH3:15][C:16]([CH3:56])([O:18][C:19]([NH:21][C@H:22]([C:30](N[C@H](C(NC(CC1CCCCC1)C(=O)C(=O)CCC)=O)CC(C)C)=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH3:17]>O1CCCC1>[CH:24]1([CH2:23][C@H:22]([NH:21][C:19](=[O:20])[O:18][C:16]([CH3:15])([CH3:17])[CH3:56])[CH:30]([OH:31])[C:9]2([CH2:6][CH2:7][CH3:8])[S:14][CH2:13][CH2:12][CH2:11][S:10]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCCC(=O)C(=O)C(CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CCCC1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC1(C(O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)SCCCS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
n-Butyl lithium (2.5M, 11.76 ml, 29.4 mmol) was added dropwise at -25° to a 40 ml tetrahydrofuran solution of 2-n-propyl-1,3-dithiane from part A (4.536 g, 28.0 mmol). After stirring for 2 hours at -20° to -25°, the solution was cooled to -78° and (S)-<α-[[(1,1-dimethylethoxy)carbonyl]amino]cyclohexanepropanal (3.57 g, 14.0 mmol) was added as a 20 ml tetrahydrofuran solution. A chromatography check after 1 hour revealed the formation of a complex reaction mixture. It was warmed gradually from -78° to -50° over a period of 18 hours, quenched with saturated ammonium chloride (50 ml) and the two layers separated upon warming to room temperature. The aqueous layer was diluted with water (75 ml, to dissolve the precipitated ammonium chloride) and reextracted with ethyl acetate (2×50 ml). Combined organic extracts were washed with saturated ammonium chloride (1×75 ml), dried over anhydrous sodium sulfate and concentrated to give 7.9 g crude product which upon flash chromatographic purification yielded 1.517 g of the title B compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1.C(N(CC)CC)C>CC#N>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1ccccc1CN(CCCCCCBr)Cc1ccccn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1CN(CCCCCCN1CCc2ccccc2C1)Cc1ccccn1
Reaction time: 48 h
Yield: 73 %

Procedure:
The compound 2 (0.44 g, 1.13 mmol), 1,2,3,4-tetrahydroisoquinoline (0.22 g, 1.69 mmol) and triethylamine (0.218 g, 1.69 mmol) were added to 300 mL CH3CN, and the solution was stirred for two days. Purification was carried out on a silica gel TLC plate that was developed in 4% methanolic NH3 (7 M NH3 in methanol)/96% CH2Cl2. The product was obtained as pale yellow oil (73%). 1H NMR (CDCl3) δ 8.488 (dd, 1H, Ar), 7.616 (ddd, 1H, Ar), 7.573 (dd, 1H, Ar), 7.497 (dd, 1H, Ar), 7.219 (ddd, 1H, Ar), 7.090 (m, 4H, Ar), 7.004 (d, 1H, Ar), 6.933 (ddd, 1H, Ar), 6.833 (d, 1H, Ar), 3.789 (s, 3H, —OCH3), 3.766 (s, 2H, —CH2—), 3.671 (s, 2H, —CH2—), 3.608 (s, 2H, —CH2—), 2.895 (t, 2H, —CH2—), 2.712 (t, 2H, —CH2—), 2.491 (t, 2H, —CH2—), 2.455 (t, 2H, —CH2—), 1.554 (m, 4H, —CH2—CH2—), 1.298 (m, 4H, —CH2—CH2—). Mass Spec.=443.62 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([C@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:35])[CH2:21][C@@H:22]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:23]1[CH:27]=[CH:26][O:25][N:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46]Cl)=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])([CH3:39])([CH3:38])[CH3:37].O>CN(C=O)C>[C:36]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][O:34][C:31]2[CH:32]=[CH:33][C:28]([C@@H:22]([C:23]3[CH:27]=[CH:26][O:25][N:24]=3)[CH2:21][C:20]([N:15]3[C@@H:14]([CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:18][O:17][C:16]3=[O:19])=[O:35])=[CH:29][CH:30]=2)=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)c1cc(CCl)ccc1C(C)(C)C
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 31 %

Procedure:
Cesium carbonate (360 mg, 1.1 mmol) was added to a mixture of 7.5 (40.0 mg, 0.10 mmol) and 26.5 (27.0 mg, 0.12 mmol) in DMF (2.0 mL). The resulting mixture was stirred at room temperature for 19 hours. The mixture was then treated with water (5 mL) and extracted with EtOAc (15 mL). The organic layer was separated, washed twice with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-30% EtOAc/hexane) to give (S)-3-((S)-3-(4-(4-tert-butyl-3-isopropylbenzyloxy)phenyl)-3-(isoxazol-3-yl)propanoyl)-4-benzyloxazolidin-2-one (18.0 mg, 30%) as a clear oil. The ester (18.0 mg, 0.031 mmol) was treated with THF/H2O (3/1, v/v, 2.0 mL) and hydrogen peroxide (30%, 0.021 mL, 0.19 mmol) and cooled to 0° C. LiOH (2.60 mg, 0.062 mmol) was added. The resulting mixture was stirred at 0° C. for 1 hour. A saturated solution of Na2SO3 was added to the mixture, and the reaction was stirred for 1 hour. The mixture was extracted with EtOAc (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-30% EtOAc/hexane) to give 26 (5.80 mg, 44%) as a colorless film. MS ESI (neg.) m/e: 420 (M−H). 1H NMR (500 MHz) (CDCl3) δ 8.28 (1H, s); 7.37-7.34 (2H, m); 7.20-7.17 (3H, m); 6.96-6.94 (2H, d, J=8.2 Hz); 6.07 (1H, s); 4.98 (2H, s); 4.56 (1H, dd, J=7.8, 7.4 Hz); 3.64 (1H, m), 2.36 (1H, dd, J=16.8, 7.8 Hz), 2.99 (1H, dd, J=16.8, 7.4 Hz), 1.43 (9H, s), 1.26 (6H, d, J=7.1 Hz).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:21][C:20]2[N:16]([N:17]=[N:18][C:19]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=2[CH2:13]1)=[O:11])(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[NH2:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:21][C:20]2[N:16]([N:17]=[N:18][C:19]=2[C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)N1Cc2ccccc2-n2nnc(-c3ccc(F)cc3)c2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CC(=O)N1Cc2ccccc2-n2nnc(-c3ccc(F)cc3)c2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of [3-[3-(4-fluoro-phenyl)-4H,6H-1,2,5,10b-tetraaza-benzo[e]azulen-5-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]carbamic acid tert-butyl ester (28.0 mg, 0.047 mmol) in DCM (2 mL), was added trifluoroacetic acid (0.18 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were evaporated in vacuo to afford a gummy solid which was crystallized from hexane to afford trifluoroacetic acid salt of (R)-3-amino-1-[3-(4-fluoro-phenyl)-4H,6H-1,2,5,10b-tetraaza-benzo[e]azulen-5-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one (25 mg, 87%).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])C.[Si:17]([O:34][CH2:35][CH:36]([OH:39])[CH2:37][SH:38])([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Si:17]([O:34][CH2:35][C@@H:36]1[O:39][C@@H:4]([CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])[S:38][CH2:37]1)([C:30]([CH3:33])([CH3:31])[CH3:32])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](OCC(O)CS)(c1ccccc1)c1ccccc1
Reactant: CCOC(CP(=O)(OCC)OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(C[C@@H]1O[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CS1)OCC
Temperature: 25 °C
Yield: 84.2 %

Procedure:
To a solution of diethylphosphonoacetaldehyde diethylacetal (12.23 g, 48.1 mmol, 1.2 eq.) and t-butyldiphenylsilyloxy-3-mercapto-2-propanol (13.63 g, 38.1 mmol, 1.2 eq.) in toluene (500 mL) was added pTSA (0.73 g, 3.8 mmol, 0.1 eq.). The mixture was stirred at reflux for 72 hr and was cooled to room temperature. A saturated solution of sodium bicarbonate was added and the aqueous phase was extracted with dichloromethane. The organic phase was dried with anhydrous magnesium sulphate and evaporated under reduced pressure. The crude material was purified by flash chromatography with ethyl acetate:hexane (2:1), and gave 16.31 g of the compound in a 87% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH:11]2[CH2:13][O:12]2)=[CH:4][CH:3]=1.[OH:14][CH2:15][C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>C(O)C>[C:8]([C:7]1[C:6]([CH3:10])=[C:5]([CH:11]([OH:12])[CH2:13][N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17][C@H:16]2[CH2:15][OH:14])[CH:4]=[CH:3][C:2]=1[F:1])#[N:9]
Reactant: Cc1c(C2CO2)ccc(F)c1C#N
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc(F)c1C#N
Temperature: 150 °C

Procedure:
A mixture of 6-fluoro-2-methyl-3-(oxiran-2-yl)benzonitrile (785 mg, 4.43 mmol) and (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1340 mg, 6.2 mmol) in ethanol (10 mL) was heated in microwave at 150° C. for 3 h. The volatile was evaporated and the residue was purified on Biotage using 40-100% ethyl acetate/hexane to give the title compound: LC/MS: (M+1)+: 394.19.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[Cl:15][C:16]1[CH:17]=[C:18]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Reactant: Clc1ccc(SCCCCBr)cc1Cl
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 4 from 6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichlorophenylmercapto)-butylbromide (B.p. 0.1 mb : 153°-160° C.).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH:16]([CH2:25]Cl)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[CH2:18]([O:17][CH:16]1[CH2:25][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:15]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCC(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(C(=O)OCC)CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 4.67 g, 0.117 mol) in 1,4-dioxane (69 mL) was added diethyl malonate (17.7 mL, 0.117 mol) dropwise. The mixture was stirred for 1.5 hours at ambient temperature after complete addition. To this mixture was added [2-bromo-1-(chloromethyl)ethoxy]methylbenzene (prepared according to the procedure found in Organic Letters (2004), 6(11), pp. 1853-1856; 32.0 g, 0.121 mol) dropwise and the resulting mixture was stirred for 1 hour at ambient temperature, then heated at reflux for 16 hours. The mixture was cooled briefly in an ice bath and sodium hydride (60% dispersion in mineral oil, 4.67 g, 0.117 mol) was added portionwise. The mixture was heated to reflux for a further 24 hours. Upon cooling to room temperature, the mixture was poured into pH 7 buffer and brine, and the product was extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated. Flash column chromatography, eluting with a gradient of 5-60% ethyl acetate in hexanes afforded product (26.9 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)[CH:14]=[C:13]([CH3:26])[C:3]=1[O:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH3:12])[CH2:7]1.C(O)C.[H][H]>[Pt]=O.C(OCC)(=O)C>[NH2:23][C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[C:13]([CH3:26])[C:3]([O:4][CH2:5][CH:6]3[CH2:11][CH2:10][CH2:9][N:8]([CH3:12])[CH2:7]3)=[C:2]([CH3:1])[CH:16]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(-c2cccc([N+](=O)[O-])c2)cc(C)c1OCC1CCCN(C)C1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cccc(N)c2)cc(C)c1OCC1CCCN(C)C1

Procedure:
A mixture of 3-[2,6-dimethyl-4-(3-nitrophenyl)phenoxymethyl]-1-methylpiperdine (785 mg, 2.21 mmol), ethanol (10 mL), and ethyl acetate (5 mL) was hydrogenated overnight with platinum oxide (50 mg) at 1 atmosphere of hydrogen. The reaction was purged with nitrogen and filtered through Celite. The solids were washed with methanol and ethyl acetate. The filtrate and the washings were concentrated to give 3-[4-(3-aminophenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine as a yellow oil (735 mg, quantitative).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[CH:14][C:15](=[O:17])[O:16][C:11]=2[CH:10]=1.C(N(CC)CC)C.C(C1[C:36]([OH:37])=[C:35]([C:38](C)(C)C)[CH:34]=C(C)C=1)(C)(C)C.C(Cl)(=O)C(C)=C>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:38][C:35](=[CH2:34])[C:36]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[CH:14][C:15](=[O:17])[O:16][C:11]=2[CH:10]=1)=[O:37]
Reactant: O=c1ccc2ccc(OCCCCCCO)cc2o1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCOc1ccc2ccc(=O)oc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.2 g (16 mmol) of 7-(6-hydroxy-hexyloxy)-2H-1 -benzopyran-2-one were dissolved in 40 ml of absolute tetrahydrofuran with the exclusion of moisture, treated with 1.82 g (18 mmol) of triethylamine, 0.004 g (0.3 mmol) of 4-dimethylaminopyridine and a spatula tip of 2,6-di-tert.-butyl-p-cresol and cooled to 0° C. 1.7 ml of methacryloyl chloride were added dropwise to this solution within 10 min. The mixture was stirred at 0° C. for one hour and at room temperature for a further hour. Subsequently, the white precipitate which separated was filtered off and rinsed with tetrahydrofuran. The filtrate was evaporated to dryness and the residue was chromatographed on silica gel with acetone/cyclohexane (1:4). In this manner there were obtained 4 g of 6-(2-oxo-2H-1-benzopyran-7-yloxy)-hexyl 2-methyl-acrylate as a colourless liquid. λmax. (in CH2Cl2)=322.7 nm (ε=15110 l/mol cm).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:23]O>N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)=[N:23][O:12][C:11]3=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1ncc2c(O)c(C(=O)c3ccc(F)cc3)cnc21
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4ccc(F)cc4)c3cnc21

Procedure:
1-Ethyl-5-(4-fluorobenzoyl)-4-hydroxy-1H-pyrazolo[3,4-b]pyridine (3.35 g) was refluxed overnight in 75 ml of pyridine containing 4.0 g of hydroxylamine hydrochloride. The solvent was then evaporated and the residue triturated with 5% hydrochloric acid The product thus obtained was washed with methanol and then chromatographed over silica gel (5% methanol/dichloromethane) to remove a trace of fluorescent impurity. After recrystallization from ethyl acetate/hexane, 2.83 g of product was obtained, mp 175°-176° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]([CH2:6][C:7](OC)=[O:8])=[CH2:5].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH3:1][O:2][C:3]([CH:4]1[CH2:6][C:7](=[O:8])[N:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5]1)=[O:11]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: NCc1ccccc1
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Yield: 96.7 %

Procedure:
A solution of 158.2 g (1.0 mole) of dimethylitaconate and 107.2 g (1.0 mole) of benzylamine in 750 ml of methanol was let stand at ambient temperature over the weekend. The solution was filtered and the filtrate was concentrated under reduced pressure to give an oil as residue. The oil crystallized when it was triturated with petroleum ether (30°-60° C.). The solid was collected by filtration and dried to yield 225.5 g (97%) of the title compound as a white powder. An analytical sample, m.p. 63°-65° C., was prepared from 2-propyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1>>[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(CO)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: Cc1ccc(COc2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)cc1

Procedure:
Mitsunobu coupling of phenol 58 with 4-methylbenzylalcohol followed by flash chromatography (5 to 30% EtOAc-hexanes gradient) gave 2-(3-(3-(4-methylbenzyloxy)phenyl)propyl)isoindoline-1,3-dione as a white waxy solid. Yield (2.6 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J=3.2 Hz, 2H), 7.67 (d, J=3.2 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 7.16 (dd, J=8.0 Hz, 3H), 6.75-6.85 (m, 3H), 4.98 (s, 2H), 3.74 (t, J=8.0, 2H), 2.67 (t, J=8.0 Hz, 2H), 2.35 (s, 3H), 2.04 (dddd, J=8.0, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=2)[O:5][C:4]([CH3:18])([CH3:17])[C@H:3]1[OH:19].C(N(CC)CC)C.[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33])([O-:29])=[O:28].C(N)(=O)C1C=CC=CC=1>ClCCl>[OH:19][C@H:3]1[C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[N+:27]([O-:29])=[O:28])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:14])[F:15])[CH:10]=2)[O:5][C:4]1([CH3:17])[CH3:18]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](N)[C@@H]1O
Agent: NC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](NC(=O)c2ccccc2[N+](=O)[O-])[C@@H]1O
Temperature: 15 °C
Yield: 47 %

Procedure:
(3S,4R)-4-Amino-2,2-dimethyl-6-(trifluoromethoxy)-chroman-3-ol [prepared by the method of Quagliato et al. Biorg. & Med. Chem. Let. 1991 1, 39; (2.75 g, 10 mmol)] and triethylamine (1.39 mL, 10 mmol) were stirred together in dichloromethane (25 mL) at 0° C. To this solution was added a solution of 2-nitrobenzoylchloride (1.32 mL, 10 mmol) in dichloromethane (10 mL). The ice bath was allowed to gradually warm to 15° C. overnight. The crude benzamide was diluted with dichloromethane (50 mL), washed with water (2×10 mL), dried (MgSO4) and concentrated to afford 2.0 g (47%) of white solid: m.p. 189°-190° C.; 1H NMR (DMSO-d6): δ 9.17 (d, 1H), 8.04 (d, 1H), 7.81 (m, 2H), 7.71 (t, 1H), 7.33 (s, 1H), 7.16 (d, 1H), 6.86 (d, 1H), 5.86 (d, 1H), 4.96 (br t, 1H), 3.64 (dd, 1H), 1.42 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][N:3]=1.[C:11]([NH:14][NH2:15])(=[O:13])[CH3:12].C(O)C>CCCCCC>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=[N:15][NH:14][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(=O)NN
Reactant: CC(=O)c1ccc(C)nc1
Solvent: CCO
Solvent: CCCCCC
Product: CC(=O)NN=C(C)c1ccc(C)nc1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
A mixture of 6.76 gm (0.05 mole) of 2-methyl-5-acetylpyridine, 3.7 gm (0.05 mole) of acetic acid hydrazide and 100 ml of ethanol was refluxed 5 hr. The solution was diluted with Skellysolve B until cloudy. The mixture was cooled to room temperature and then chilled in the freezer. The product was collected, washed ith Skellysolve B and dried to afford 7.93 gm (83%) of the title compound having a melting point of 178.5° C.