Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=2)[CH2:5][CH2:4]1)C.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:23]1([O:22][C:20]([N:3]2[CH2:8][CH2:7][CH:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=3)[CH2:5][CH2:4]2)=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN1CCC(c2cccc(OC(C)C)c2)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)Oc1cccc(C2CCN(C(=O)Oc3ccccc3)CC2)c1
Temperature: 45 °C
Yield: 61.8 %

Procedure:
To N-ethyl-4-(3-(1-methylethoxy)phenyl)piperidine (Preparation 45, 2.0 g, 8.10 mmol) in toluene (20 ml) at 85° C. was added phenyl chloroformate (1.0 ml, 9.70 mmol) and the mixture was heated at reflux for 4 h. The solution was cooled to 45° C. and aqueous sodium hydroxide solution (1 ml of 50% aqueous sodium hydroxide solution in 8 ml of water) was added. The reaction mixture was cooled to room temperature and the organic layer was separated and washed with methanol: 1N aqueous hydrochloric acid (1:1, 2×20 ml), methanol: 1N aqueous sodium hydroxide solution (1:1, 25 ml) and water (20 ml). The organic extract was dried (MgSO4), filtered and concentrated in vacuo to give the crude product. This was purified by silica column chromatography eluting with ethyl acetate:hexane (1:5) to give the title compound as an oil (1.7 g, 62%).
Reaction SMILES: C([C@H](NC([C:34]1[C:35]2C=[CH:37][NH:38][C:39]=2[CH:40]=[CH:41][CH:42]=1)=O)[C@H](O)C(N1[C@H](C(=O)NCC2C=CC=CC=2C)C(C)(C)SC1)=O)C1C=CC=CC=1.[C:43](Cl)(=O)[C:44](Cl)=O>>[CH2:44]1[CH2:43][CH2:40][CH:39]([N:38]=[C:37]=[N:38][CH:39]2[CH2:35][CH2:34][CH2:42][CH2:41][CH2:40]2)[CH2:35][CH2:34]1
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc3[nH]ccc23)CSC1(C)C
Reactant: O=C(Cl)C(=O)Cl
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
The synthesis of compounds with the general structure 27 is as follows. The boc-protected thiazolidine carboxylic acid 1 is converted to amino-ketones 26 with requisite grignard reagents 25 in the presence of oxalyl chloride. Final compounds 27 are obtained by a DCC-mediated coupling of 26 and 4 followed by deprotection of the P2 phenol. Final compounds were purified either by flash chromatography or preparative HPLC. Specific Method D
Reaction SMILES: [BrH:1].C([N:9]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([OH:26])[CH:20]=2)[C:16]2[C:11](=[C:12]([N+:28]([O-])=O)[C:13]([OH:27])=[CH:14][CH:15]=2)[CH2:10]1)C1C=CC=CC=1>C(O)C>[BrH:1].[NH2:28][C:12]1[C:13]([OH:27])=[CH:14][CH:15]=[C:16]2[C:11]=1[CH2:10][NH:9][CH2:18][CH:17]2[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([OH:26])[CH:20]=1
Reactant: O=[N+]([O-])c1c(O)ccc2c1CN(Cc1ccccc1)CC2c1ccc(O)c(O)c1
Agent: Br
Solvent: CCO
Product: Nc1c(O)ccc2c1CNCC2c1ccc(O)c(O)c1
Yield: 112.9 %

Procedure:
700 mg of 2-benzyl-4-(3,4-dihydroxyphenyl)-7-hydroxy-8-nitro-1,2,3,4-tetrahydroisoquinoline hydrobromide was dissolved in 14 ml of ethanol, and by adding thereto 0.07 g of 10% paradium-carbon, hydrogenation reaction was performed at 40° C. The reaction was over, the reaction mixture was filtered, and concentrated. The residue obtained was changed to precipitates by treatment with chloroform, the precipitates were collected by filtration, and dried, affording 590 mg of 8-amino-4-(3,4-dihydroxyphenyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[NH:8].[OH-].[Na+].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1)([O-:13])=[O:12].[N-]=C=O>C1C=CC=CC=1.O>[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[N:8][C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=1)=[O:22]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCCC1=N
Agent: Cl
Agent: [N-]=C=O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h

Procedure:
To a suspension of 6.73 g. (0.05 mole) of 1-methyl-2-iminopyrrolidine hydrochloride in 100 ml. of benzene is added 2 ml. of water followed by 5 ml. of 50% NaOH. After stirring for 5 min., the benzene layer is decanted onto excess anhydrous potassium carbonate. The process is repeated twice with 75 ml. portions of fresh benzene. The combined extracts are filtered rapidly from drying agent (dicalite pad and suction). To the filtrate is added in one portion with stirring 8.21 g. (0.05 mole) of p-nitrophenylisocyanate as a solution in benzene (the isocyanate solution is filtered prior to use). After stirring one hour, the solid, 1-(1-methyl-2-pyrrolidylidene)-3-p-nitrophenylurea, is collected and dried, m.p. = 180°-182° C. Recrystallization from acetone-methanol gives pure product, m.p. = 182°-183° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH2:33][CH3:34])=[CH:4][CH:3]=1.[O:35]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[O:38][CH2:37][CH2:36]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[C:39]2([CH2:44][CH2:43][N:42]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:13](=[O:14])[C:12]([CH2:15][C:16]5[CH:21]=[CH:20][C:19]([C:22]6[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=6)=[CH:18][CH:17]=5)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]4[CH2:33][CH3:34])=[CH:4][CH:3]=3)[CH2:41][CH2:40]2)[O:38][CH2:37][CH2:36]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCCc1nc(CC)n(-c2ccc(Br)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1nc(CC)n(-c2ccc(N3CCC4(CC3)OCCO4)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 61.3 %

Procedure:
To a solution of 4′-{[1-(4-bromophenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.6 g), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine)(0.29 g), 1,4-dioxa-8-azaspiro[4.5]decane (0.9 g) and sodium tert-butoxide (0.45 g) in toluene (40 mL) was added tris(dibenzylideneacetone)dipalladium (0.14 g), and the mixture was stirred at 100° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.1 g, 60%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Ni].CCO>[NH:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][O:14]2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCC3(CC2)OCc2ccccc23)cc1
Agent: [Ni]
Solvent: CCO
Product: c1ccc2c(c1)COC21CCNCC1
Reaction time: 19 h
Yield: 80.6 %

Procedure:
1′-Benzyl-3H-spiro[2-benzofuran-1,4′-piperidine] (119 g, 425.9 mmol) was dissolved EtOH (1 L) under argon and treated with Raney nickel (12 g) at ambient temperature for 1 h to absorb impurities which tended to poison the catalyst. Raney nickel was filtered off and the filtrate was hydrogenated in a steel autoclave over 10% Pd/C (Degussa Nr. 1835) (12 g) at 5 bar hydrogen pressure and 40° C. for 19 h. According to HPLC there was still 2.7% of starting material present. Thus the catalyst was filtered off, fresh 10% Pd/C (4 g) was added to the filtrate, and hydrogenation under the same condition was continued for 24 h. Filtration of the catalyst and evaporation of EtOH gave a light yellow oil, which crystallized spontaneously upon stirring with heptane (1 L) to give a white solid (65 g, 80%). MS: m/z=190 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][NH:5][C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[N:9][N:10]=1.[Li+].[OH-]>C1COCC1.O>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:8]1[O:7][C:6]([NH:5][CH2:4][C:3]([OH:26])=[O:2])=[N:10][N:9]=1
Reactant: COC(=O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of {5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,3,4]oxadiazol-2-ylamino}-acetic acid methyl ester (262 mg, 0.56 mmol, 1 eq) in THF-H2O (1:1) (2 mL) LiOH (27 mg, 1.12 mmol, 2 eq) was added. The reaction mixture was stirred at RT for 2 hrs. The solvent was removed partially and more water was added. The mixture was washed with ether and the pH of the aqueous layer was adjusted to 3 with 1N HCl. A solid precipitated and filtered to afford the desired product (190 mg). LC/MS (Method A) [4.83 min; 456(M+1)]
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:32][C:29]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:28][CH2:27][N:26]([C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])[CH2:31][CH2:30]1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2OCc2ccccc2)CC1
Yield: 59 %

Procedure:
2-Benzyloxybromobenzene (242.3 g) was reacted with 1-benzyloxycarbonyl-4-piperidone (214.7 g) according to the method described for Example 2e to afford 4-hydroxy-4-(2-benzyloxyphenyl)-N-Cbz-piperidine (226.75 g) after extraction and chromatography using 10-30% ethyl acetate in hexanes. 1H NMR (300 MHz, CDCl3) δ 7.40-7.21 (m, 12H), 6.98 (m, 2H), 5.12 (s, 4H), 4.11 (br s, 3H), 3.35 (br s, 2H), 2.03 (br s, 4H). A sample of this material (235 g) was reacted with triethylsilane (405 mL) and trifluoroacetic acid (195 mL) according to the method described for Example 2f. Following extraction and chromatography (10-25% ethyl acetate in hexane), residual triethylsilane was removed by distillation (50-60° C., 800-900 millitorr) to afford 4-(2-benzyloxyphenyl)-N-Cbz-piperidine (179.3 g). A solution of this material (4.01 g) in ethanol (60 mL) was shaken for 24 h with palladium hydroxide on carbon [Pearlman's catalyst] (2.2 g) under hydrogen (50 psi). The catalyst was removed by filtration, the filtrate was concentrated and triturated with acetone to afford 4-(2-hydroxyphenyl)-piperidine (0.75 g) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.02 (m, 2H), 6.82 (d, 1H), 6.72 (t, 1H), 3.20 (br d, 2H), 3.02 (m, 1H), 2.85 (tt, 2H), 1.74 (m, 4H). Using standard reductive amination conditions N-[2-(S)-(3,4-dichlorophenyl)]-4-oxobutyl-N-methyl-3-cyano-1-naphthamide (0.213 g) was reacted with 4-(2-hydroxyphenyl)-piperidine to afford N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[2-hydroxyphenyl]-1-piperidinyl]butyl]-N-methyl-3-cyano-1-naphthamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.C(O)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH:13]([CH3:18])[CH3:14]
Reactant: COC(=O)c1ccc(C)cc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)cc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 112 %

Procedure:
To a mixture of 2-hydroxy-4-methyl-benzoic acid methyl ester (1.0 g, 6.0 mmol), triphenylphosphine (1.9 g, 7.2 mmol), and isopropanol (0.72 g, 12.0 mmol) in THF (10.0 mL) is added DIAD (1.45 g, 7.2 mmol) dropwise at 0° C. The mixture is stirred at room temperature overnight. The mixture is evaporated to dryness under reduced pressure. The residue is partitioned between EtOAc (50 mL) and water (50 mL). The organic phase is washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as white solid (1.4 g, 96%). LC-ES/MS m/e 209.0 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CC(C)CC([O:10][C:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13](=[O:19])[CH:12]=1)=O.Cl>ClCCl.[Cl-].[Na+].O>[C:11]([OH:10])(=[C:12]1[C:11](=[O:10])[CH2:16][C:15]([CH3:17])([CH3:18])[CH2:14][C:13]1=[O:19])[CH2:16][CH:15]([CH3:17])[CH3:14]
Reactant: CC(C)CC(=O)OC1=CC(=O)CC(C)(C)C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(C)CC(O)=C1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 187.3 %

Procedure:
N-(ivDde)-D-serine (FIG. 3, structure C) was prepared from D-serine and ivDde-OH which was synthesized by O-acylation of dimedone with isovaleryl chloride in the presence of pyridine followed by the rearrangement of formed 5,5-dimethyl-3-oxocyclohex-1-enyl 3-methylbutanoate with aluminum chloride using a previously reported method (Akhrem, A. A., et al. Synthesis 1978, 925). In particular, a solution of isovaleryl chloride (13.5 mL, 13.3 g, 110 mmol) in dichloromethane (50 mL) was added dropwise over period of 15 min to a stirred solution of dimedone (14 g, 100 mmol) and pyridine (9.7 mL, 9.5 g, 120 mmol) in dichloromethane (150 mL). The reaction mixture was stirred for 1.5 h, and washed with 2N aqueous hydrochloric acid (2×50 mL), water, and saturated aqueous sodium bicarbonate (50 mL), and then dried over magnesium sulfate. The solvent was removed by rotary evaporator under vacuum to give 5,5-dimethyl-3-oxocyclohex-1-enyl 3-methylbutanoate (22.4 g, 100% yield) which appeared as a light yellow oil. To a stirred suspension of aluminum chloride (16.0 g, 120 mmol) in dichloromethane (100 mL) cooled on ice-bath was added dropwise a solution of 5,5-dimethyl-3-oxocyclohex-1-enyl 3-methylbutanoate (11.2 g, 50 mmol) over period of 30 min. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. Then the reaction mixture was slowly poured into a mixture of 37% aqueous hydrochloric acid (50 mL) and ice (150 g) with cooling on ice so the temperature did not exceed 5° C. Brine (200 mL) was added to the mixture and the product was extracted with dichloromethane (6×50 mL, completeness of the extraction was checked by TLC). The extract was washed with brine (2×50 mL), dried over magnesium sulfate, and concentrated on rotary evaporator under vacuum. The crude product was purified by column chromatography on silica gel using gradient of hexanes going to ethyl acetate:hexanes (1:10) to give ivDde-OH (10.5 g, 94%) which appeared as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([F:8])[CH:3]=1.[Li+].CC([N-]C(C)C)C.[Cl:17][CH2:18][CH2:19][CH2:20]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([F:8])[C:3]=1[CH2:20][CH2:19][CH2:18][Cl:17]
Reactant: Fc1cc(Cl)ccn1
Reactant: ClCCCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1nccc(Cl)c1CCCCl
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 76.9 %

Procedure:
To a cooled (−78° C.) solution of 4-chloro-2-fluoro-pyridine (2.0 g, 15 mmol) in THF (15 mL) is added LDA solution (9.1 mL, 18 mmol, 2.0 M in THF). After the mixture is allowed to stir at −78° C. for 90 min, 1-chloro-3-iodo-propane (4.9 mL, 46 mmol) is added and the mixture is allowed to slowly warm to room temperature for 16 hrs. Then reaction is quenched with saturated NH4Cl and the mixture is extracted with DCM (3×). The combined organic layers are washed with brine, dried over Na2SO4 and concentrated to give the crude product. Purification by flash column chromatography affords 2.4 g of 4-chloro-3-(3-chloro-propyl)-2-fluoro-pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:13](=[O:16])[CH2:14][CH3:15])=[CH:7][CH:8]=2)[CH:3]=1.C(OC(=O)C)(=[O:19])C.[Br-].[NH4+]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C(O)(=O)C>[C:13]([O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH:1]=[O:19])=[CH:3]2)=[CH:8][CH:7]=1)(=[O:16])[CH2:14][CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)Oc1ccc2ccc(C)cc2c1
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCC(=O)Oc1ccc2ccc(C=O)cc2c1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
The same reactor as used in the second half of Example 1 was charged with 11.4 parts of the resulting 2-methyl-7-propionyloxynaphthalene crystals, 90 parts of acetic acid, 10 parts of acetic anhydride, 0.249 part (Co=5990 we. ppm) of cobalt acetate tetrahydrate, 0.245 part (Mn=550 wt. ppm) of manganese acetate tetrahydrate, and 0.250 part (Br=2040 wt. ppm) of ammonium bromide, and pressurized to 8 kg/cm2 -G. The mixture was heated to 180° C., and air was introduced into the reactor at a rate of 10 Nl/hr. The reaction was terminated when the absorption of oxygen ceased. The reaction time was 2 hours. The reactor was cooled, and the contents were withdrawn and analyzed. The conversion of 2-methyl-7-propionyloxynaphthalene was 100 mole %, and the yield of 7-propionyloxy-2-naphthoic acid was 51.0 mole % (selectivity 51 mole %). At this time, 19 mole % of 7-propionyloxy-2-naphthaldehyde was formed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1.[N-:19]=[C:20]=[O:21].[K+].FC(F)(F)C(O)=O>C1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:20](=[O:21])[NH2:19])=[CH:9][CH:8]=1
Reactant: [N-]=C=O
Reactant: OCCc1ccc(OCc2cccc(F)c2)cc1
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCCc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
Under an argon atmosphere and at room temperature, a suspension of 1.0 g of 2-[4-(3-fluoro-benzyloxy)-phenyl]-ethanol and 0.66 g of potassium isocyanate in 2 ml of benzene was treated dropwise under stirring with 0.62 ml of trifluoroacetic acid. After stirring for 18 h at room temperature, the reaction mixture was diluted with water, then extracted three times with dichloromethane. The combined organic layers were dried over potassium carbonate and evaporated. There were obtained 0.52 g (44% of theory) of carbamic acid 2-[4-(3-fluoro-benzyloxy)-phenyl]-ethyl ester as a white solid; MS: m/e=290 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[Cl:11][C:6]1[N:5]=[C:4]([CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: Nc1ccc(CCO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(Cl)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred solution of 4,6-dichloro-2-methyl-5-nitro-pyrimidine (Albert et al., J. Chem. Soc., 1954, 3832, 7.5 g, 36.1 mmol) in THF (150 ml) was added 4-aminophenylethyl alcohol (2.47 g, 18.0 mmol), triethylamine (3.65 g, 36.1 mmol), and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 ml), and the mixture was extracted with ethyl acetate (100 ml×3). The organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) to afford 4.0 g (72%) of the title compound as a yellow solid.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=O)=O.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)CCC.CCCC(C)C.C(OCC)(=O)C.O>[CH2:28]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([CH2:6][C@@H:7]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2)[CH2:40][CH2:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](COS(C)(=O)=O)C1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCC#N
Product: CC(C)(C)OC(=O)N1CCO[C@@H](CN2CCN(C(=O)OCc3ccccc3)CC2)C1
Yield: 68 %

Procedure:
tert-Butyl (2R)-2-{[(methylsulfonyl)oxy]methyl}morpholine-4-carboxylate (75 g, 0.25 mol), sodium iodide (11.4 g, 76 mmol), potassium carbonate (38 g, 0.28 mol) and benzyl-1-piperazine carboxylate (54 mL, 0.28 mol) were heated together in butyronitrile (1.5 L) at 115° C. for 24 hours. Water (1.8 L) was added and the layers separated, the aqueous phase was washed with ethyl acetate (1 L) and the combined organics were washed with brine (1 L), dried (MgSO4) and evaporated to give crude product as a yellow oil. Chromatography (5 kg column: 20% ethyl acetate to 50% ethyl acetate in isohexane) gave product as pale yellow gum (73 g, 0.17 mol, 70%).
Reaction SMILES: N[N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1.[O:12]=[C:13]1[CH2:18][C:17](=O)[CH2:16][CH2:15][NH:14]1>C(O)C>[CH2:3]1[N:2]2[C:17]3[CH2:16][CH2:15][NH:14][C:13](=[O:12])[C:18]=3[C:8]3=[CH:9][CH:10]=[CH:11][C:6](=[C:7]23)[O:5][CH2:4]1
Reactant: NN1CCOc2ccccc21
Reactant: O=C1CCNC(=O)C1
Solvent: CCO
Product: O=C1NCCc2c1c1cccc3c1n2CCO3
Reaction time: 2 h
Yield: 197.4 %

Procedure:
A solution of 4-amino-3,4-dihydro-2H-1,4-benzoxazine (1.0 g) and 2,4-dioxopiperidine (753 mg) in absolute ethanol (40 ml) was stirred under nitrogen for 1.5 h. The solvent was removed in vacuo and the residue was dissolved in diethylene glycol (30 ml) and heated at 100° for 1 h, then at 150° for 2 h. The solution was allowed to cool, poured into water (200 ml) and extracted with dichloromethane (3×100 ml). The combined, dried organic extracts were evaporated to give a semi-solid (ca. 3 g) which was purified by FCC eluting with System A (400:10:1) to give the title compound (740 mg) as a solid, m.p. 298°-300°.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[OH-].[Na+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH2:7]([O:3][CH2:2][CH2:1][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCO
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOCc1ccccc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Ethylene glycol (742.5 g, 11.96 mol) was added to a solution of sodium hydroxide pellets (475.2 g, 11.88 mol) in 450 ml of water kept at 80° C. Benzyl chloride (302.8 g, 2.39 mol) was then added at 65° C., and the resulting suspension was vigorously stirred at 120° C. overnight. After cooling to room temperature, the mixture was poured into ice-water and extracted five times with diethyl ether. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The remaining residue was then distilled under vacuum and the relevant fractions (bp. 95-125° C. at 0.1-1 mbar) collected.