Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]2[CH:18]=[C:17]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[N:16]=[N:15]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:27]>CCOC(C)=O.CO>[ClH:27].[NH2:7][C@@H:8]1[CH2:9][CH2:10][C@H:11]([N:14]2[CH:18]=[C:17]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[N:16]=[N:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](n2cc(C(=O)N3CCCC3)nn2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@@H](n2cc(C(=O)N3CCCC3)nn2)CC1

Procedure:
{cis-4-[4-(Pyrrolidine-1-carbonyl)-[1,2,3]triazol-1-yl]-cyclohexyl}-carbamic acid tert-butyl ester (406 mg) was stirred 1 h in a mixture of 4.6 M HCl in EtOAc (3.6 ml) and MeOH (0.84 ml). The solvent was evaporated to yield the product (335 mg, quant.) as white foam after drying on the high vacuum. MS 264.3 (100, [M+H]+).
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4]1.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl>[Cl:12][CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4]1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccn(CO)c1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccn(CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The obtained 1-hydroxymethyl-3-cyano-1H-pyrole was dissolved to 3 ml of chloroform, and 2 ml of thionyl chloride was added, followed by stirring at room temperature for 1 hour. After the reaction mixture was cooled to 0° C., it was poured into ice-water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 290 mg of 1-chloromethyl-3-cyano-1H-pyrole.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F-].[K+].CN(C=O)C.[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH:22]=[CH:23][C:24]=1[OH:25]>O>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[O:31])[N:28]([CH3:29])[CH3:30])[CH:22]=[CH:23][C:24]=1[O:25][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)Nc1ccc(O)c(Cl)c1
Reactant: O=C(CCl)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1ccc(OCC(=O)c2ccccc2)c(Cl)c1
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
A mixture of α-chloroacetophenone (4,64 g; 0.03 mol), anhydrous potassium fluoride and DMF (200 ml) is stirred for 15 minutes. Next, 3-(3-chloro-4-hydroxyphenyl)-1,1-dimethylurea (6.44 g; 0.03 mol) is added and the mixture stirred for 20 hours at room temperature and then for 24 hours at 80° C. The mixture is then drowned in water, and extracted with methylene chloride. The organic layer is separated, washed with water and filtered through a 5 cm pad of neutral alumina. The pad is washed with acetonitrile, filtrate and washings are combined and evaporated under vacuum to give a brown-yellow oil (7.0 g, 70.1%). This oil is purified by chromatographing on silica gel (eluent: methylene chloride) to afford the title compound: 6.75 g of a cream colored solid, m.p. 148°-150° C.
Reaction SMILES: [CH2:1]([C:5]12[CH2:18][C:17](=[O:19])[CH:16]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([O:14]C)=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:5]12[CH2:18][C:17](=[O:19])[CH:16]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([OH:14])=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CC(=O)C=C1c1ccc(OC)cc1C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC12CC(=O)C=C1c1ccc(O)cc1C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
A solution of 8a-butyl-6-methoxy-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (37 mg, 0.14 mmol) in anhydrous CH2Cl2 (1.4 mL) was placed under a nitrogen atmosphere, cooled in a dry ice-acetone bath, and treated over two minutes with 1M BBr3 in CH2Cl2 (0.42 mL, 0.42 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 3 hours. Additional 1M BBr3 in CH2Cl2 (0.1 mL, 0.1 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was partitioned between EtOAc and aqueous 1N HCl. The organic phase was washed with 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum to provide a solid residue. Recrystallization of this material from hot EtOAc gave pure 8a-butyl-6-hydroxy-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (11 mg). Concentration of the mother liquors gave additional product contaminated with ˜5% of starting material.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3C=CC=CC=3)=[CH:11][CH:10]=[CH:9][C:8]=2O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([OH:26])C=CC=CC=1>>[CH:6]1[C:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][O:26][C:2]=2[CH:3]=[CH:4][CH:5]=1
Reactant: Oc1ccccc1
Reactant: Oc1cccc(-c2ccccc2)c1-c1ccccc1
Product: c1ccc2c(c1)COc1ccccc1-2

Procedure:
2,3-diphenylphenol is a typical example of a phenol which will form a dibenzopyran but cannot isomerize to the fluorenol because the meta position involved in the isomerization reaction is already substituted with a phenyl group. A solution of 1.0 g. of 2,3-diphenylphenol, 1.0 g. of acetone, 25 ml of trifluoroacetic acid and 1.5 ml of trifluoroacetic anhydride were heated at reflux in dry air for 3.25 hours by which time a sample which was worked up with hexane in water to remove the acidic materials was shown by vpc to be free of the starting phenol. Approximately 98 percent of the material was insoluble in Claisen's alkali and 2 percent of the material was soluble in Claisen's alkali. Apparently the latter was the trifluoroacetic of 2,3-diphenylphenol. Heating of the reaction mixture at reflux was continued for 18 hours, but caused no detectable change in the reaction mixture. Extraction with hexane and washing with water of the reaction mixture and evaporation of the solvent isolated 0.99 g. of 1-phenyl-6,6-dimethyl- 6H-dibenzo[b,d]pyran, corresponding to formula A where X is oxygen, R1 and R2 are each methyl, R3 is phenyl and R4, R5 and R6 are each hydrogen, as a viscous liquid which on standing in hexane for several days was isolated as a white crystalline compound. Its structure was confirmed by nmr spectroscopy. A sample of this material dissolved in anhydrous trifluoroacetic acid and refluxed for 23 hours did not produce any rearranged product. The phenyl substituent in the meta position of the initial phenyl had effectively prevented any rearrangement of the dibenzopyran to the fluorenol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:16][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1cccc(Br)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)CCCc1cccc(Br)c1

Procedure:
Important starting materials for the synthesis of the preferred compounds of the invention are 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F), 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G), and the isomeric bromo compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H). Compound G can be obtained as described in J. Mez Chem. 1995, 38, 4764-4767, and as shown in Reaction Scheme 1. Thus, referring now specifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). The isomeric compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can be obtained, starting with ethyl (4-bromophenyl)acetate, in accordance with the sequence of reactions illustrated in Reaction Scheme 1 for Compound G. 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can also be obtained in accordance with the published literature procedure: Mathur et al. Tetrahedron, 41, 1509-1516 (1985).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH2:9]([CH2:13][C:14](=O)[CH3:15])[C:10]([CH3:12])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:14]([CH3:15])=[CH:13][CH:9]=[C:10]2[CH3:12])=[N:3][CH:4]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(Cl)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Cl)cn1
Yield: 100.5 %

Procedure:
2-Amino-5-chloropyridine (10.0 g, 77 mmol), acetonyl acetone (8.8 g, 77 mmol) and a catalytic amount of p-toluenesulphonic acid in anhydrous toluene (250 ml) was heated to reflux for 5 h under Dean and Stark conditions. The solvent was removed in vacuo, the residue slurried in hexane (250 ml), filtered through celite and the solvent removed in vacuo to give the title compound as a yellow oil (16.0 g): δH (CDCl3) 8.57 (1H, dd, J 2.7, 0.6 Hz), 7.78 (1H, dd, J 8.4, 2.7 Hz), 7.17 (1H, m, J 7.5, 0.5 Hz), 5.91 (2H, s), 2.14 (6H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35][OH:36])([CH3:29])([CH3:28])[CH3:27].[H-].[Na+].[NH4+].[Cl-].Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:36][CH2:35][CH2:34][CH2:33][NH:32][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:37])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(Cl)n3)cc(C)c21
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(OCCCNC(=O)OC(C)(C)C)n3)cc(C)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
To a solution of [6-(2-chloro-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.5 g, 1.37 mmol) and (3-hydroxy-propyl)-carbamic acid tert-butyl ester (0.48 g, 2.75 mmol) in DMF at 0° C. was added NaH (0.2 g, 4.13 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. Saturated NH4Cl (10 mL) was added at 0° C. and the solution acidified to pH˜5 with dilute HCl. The mixture was extracted with EtOAc (2×10 mL) and the organic extracts washed with water (10 mL), dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM:MeOH 95:5) to give {6-[2-(3-tert-butoxycarbonylamino-propoxy)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester (0.45 g, 65%). 1H NMR (400 MHz, DMSO): δ 9.10 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.22 (d, J=5.6 Hz, 1H), 7.24 (s, 1H), 7.09 (s, 1H), 5.51 (d, J=9.6 Hz, 1H), 4.02 (q, J=7.2 Hz, 2H), 3.93 (t, J=6.0 Hz, 2H), 3.07-3.02 (m, 3H), 2.28-2.27 (m, 1H), 2.26 (s, 3H), 1.77 (t, J=6.4 Hz, 2H), 1.33 (s, 12H), 1.11 (t, J=6.8 Hz, 3H). MS (ESI) m/z=502 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=O)[CH2:8]1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=[N:22][NH:21][C:18]([NH2:20])=[NH:19])[CH2:8]1
Reactant: Cc1n[nH]c2c1C(=O)CC(c1sccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1sccc1Cl)C2
Yield: 148.5 %

Procedure:
A mixture of 6-(3-chloro-2-thienyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (1.2 g), aminoguanidine hydrochloride (0.6 g), concentrated hydrochloric acid (1.1 ml), water (1.1 ml) and ethanol (50 ml) was refluxed for 3 hours. Under reduced pressure, the solvent was evaporated, and the residue was washed with ethanol to give 6-(3-chloro-2-thienyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 119) (1.2 g) as colorless crystals.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[C@H:28]1[N:36]2[C@@H:31]([CH2:32][CH2:33][CH:34](P(=O)(OCC)OCC)[C:35]2=[O:37])[CH2:30][CH2:29]1.C(O)C>O1CCCC1>[F:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[C@H:28]1[N:36]2[C@@H:31]([CH2:32][CH2:33]/[C:34](=[CH:8]\[C:7]3[CH:10]=[CH:11][C:12]([N:13]4[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]4)=[C:5]([O:4][CH3:3])[CH:6]=3)/[C:35]2=[O:37])[CH2:30][CH2:29]1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3cc(F)c(F)cc3F)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4cc(F)c(F)cc4F)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
Lithium hydroxide (0.265 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.60 g) and diethyl [(3S,8aR)-3-(2,4,5-trifluorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (2.0 g) in tetrahydrofuran (4 mL)-ethanol (16 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.97 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:27][CH:28]=[CH:29][C:7]=4[C:6]=2[CH:30]=1)[N:10](S(C1C=CC(C)=CC=1)(=O)=O)[C:11]=3[I:16].[OH-].[Na+].O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:27][CH:28]=[CH:29][C:7]=4[C:6]=2[CH:30]=1)[NH:10][C:11]=3[I:16]
Reactant: Cc1ccc(S(=O)(=O)n2c(I)c3c4c(ccnc42)-c2cc(F)ccc2N(C)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN1Cc2c(I)[nH]c3nccc(c23)-c2cc(F)ccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of Example 41D (2.0 g, 3.75 mmol) in dioxane (30 mL) was added 1M aqueous sodium hydroxide (15 mL, 15 mmol) and the mixture was stirred at 50° C. overnight. Water was added and the precipitate was filtered, washed with water and hexanes and dried in vacuo to afford the title compound. LC-MS: 380 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1([CH2:13][CH2:14][O:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)[CH:12]=[CH:11][N:10]=[CH:9]1>>[N:8]1([CH2:13][CH2:14][O:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(OCCn3ccnc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1cn(CCOC2CCC3(CCNCC3)CC2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (6.25 ml) was added to a solution of tert-butyl 9-(2-(1H-imidazol-1-yl)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (2.28 mmol, 1.0 eq.) in MC (25 ml) at 0° C. and the mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was azeotroped with MC to give the crude product which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)C.[OH-].[Na+].O.Cl>C(OCC)(=O)C.C(OCC)C.CO>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:24])=[O:3])=[CH:15][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCCCOc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)CCCCOc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a 1 L round bottom flask, equipped with a reflux condenser, was added 5-(4-Benzyloxy-phenoxy)-pentanoic acid ethyl ester (15.13 g, 46 mmol) and 2N aqueous sodium hydroxide (47 mL). The mixture was allowed to stir for 30 minutes. Water (200 mL) was added. The mixture was stirred for 20 minutes then heated to reflux for 2 hours to form a brown solution. The solution was quickly cooled to room temperature by the addition of ice. The cooled solution was acidified with 2N aqueous hydrochloric acid (50 mL) and the resulting white precipitate was collected by suction filtration, washed with water (2×100 mL), hexanes (2×100 mL), and dried under vacuum over night. The powder was finely ground and washed with hexanes (1×250 mL) and diethyl ether (1×250 mL) to yield a white powder. This powder was dissolved in a mixture of ethyl acetate (300 mL) and diethyl ether (200 mL) in a 1 L beaker. The solution was heated for 10 minutes, methanol (5 mL) added, heated an additional 10 minutes, and then filtered through a Celite plug to yield a clear yellow solution. The product was crystallized by slow addition of hexanes. The first crop of crystals was collected by filtration and hexanes (200 mL) was added to the mother liquor. The solution was then concentrated under reduced pressure to a volume of 400 mL and allowed to rest. The second batch of crystals was collected by filtration and combined with the first. The product (8.92 g, 65%) was isolated as a white crystalline material, mp 127-128° C. Combustion analysis: Found: C, 71.01; H, 6.98%; C18H20O4 requires C, 71.98; H, 6.71%;
Reaction SMILES: [NH2:1][C:2]1[C:7](CO)=[CH:6][N:5]=[C:4]([S:10][CH2:11][CH3:12])[N:3]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:10][CH2:11][CH3:12])[N:3]=1
Reactant: CCSc1ncc(CO)c(N)n1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCSc1nccc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-5-hydroxymethyl-2-(ethylthio)pyrimidine (5-1a) (9.6 g, 51.89 mmol) in CHCl3 (1 L) was added MnO2 (86.9 g, 415 mmol, 8 equiv). The suspension was stirred at rt overnight. The mixture was filtered through celite and washed with CHCl3. The combined filtrate was concentrated to give the titled compound (5-2a). 1H-NMR (500 MHz, CDCl3) δ 9.78 (s, 1H), 8.42 (s, 1H), 8.20 (broad, 1H), 5.74 (broad, 1H), 2.55 (q, 2H), 1.38 (t, 3H). LRMS m/z (M+H) Calcd. 184.24, found 184.16.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15]Br)=[C:8]([O:17][CH3:18])[CH:7]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25]>>[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:15][CH2:14][CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([O:19][CH3:20])[C:3]([O:2][CH3:1])=[O:21])=[CH:7][C:8]=3[O:17][CH3:18])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)C(Cc1ccc(OCCCBr)c(OC)c1)OC
Product: COC(=O)c1ccc(-c2ccc(OCCCOc3ccc(C[C@H](OC)C(=O)OC)cc3OC)cc2)cc1

Procedure:
3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid methyl ester (Step A) and 4′-hydroxy-biphenyl-4-carboxylic acid methyl ester (Example 197, Step A) were treated under Mitsunobu standard condition B. The crude was purified by chromatography on silica gel (hexanes/ethyl acetate 7:3) to afford the title compound.
Reaction SMILES: B(O)(O)O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:16])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1.C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O.[OH:32][CH2:33]C(CO)O>>[OH:16][C:8]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=[C:6]([CH3:5])[C:7]=1[CH:33]=[O:32]
Reactant: Cc1cc(O)c2c(c1)CCCC2
Reactant: OCC(O)CO
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Agent: OB(O)O
Product: Cc1cc2c(c(O)c1C=O)CCCC2
Temperature: 170 °C
Reaction time: 0.25 h

Procedure:
A suspension of boric acid (5.88 g) in glycerol (20 ml) was heated at 170° C. for 30 minutes. Temperature of the reaction mixture was lowered at 155° C. and 5,6,7,8-tetrahydro-3-methyl-1-naphthol (5.00 g) was added dropwise over 10 minutes. After 15 minutes, hexamethylenetetramine (4.35 g) was added dropwise below 180° C. and stirred at 170° C. for 30 minutes. The mixture was cooled to 110° C. and 24% aqueous sulfuric acid (20 ml) was added. The mixture was steam distilled and AcOEt was added to the distillate. The organic phase was washed with brine and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give 5,6,7,8-tetrahydro-1-hydroxy-3-methylnaphthalene-2-carbaldehyde as a solid (2.15 g). A pure sample was obtained by recrystallization from EtOH-H2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][CH:10]([O:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]([O:13]CC1C=CC=CC=1)=[O:12]>C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][CH:10]([O:21][C:22](=[O:30])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(Cc1ccccc1)OC(Nc1c(Cl)cccc1Cl)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(Cc1ccccc1)OC(Nc1c(Cl)cccc1Cl)C(=O)O
Temperature: 40 °C
Yield: 51 %

Procedure:
32 g (0.072 moles) of benzyl 2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetate prepared above were dissolved in 1000 ml of acetic acid, and the resulting mixture was mixed with 5 g of Pd/C 10% and then hydrogenated at a pressure of 3 atmospheres under heating to a temperature of 40° C. for a period of 10 hours. The catalyst was filtered, and the resulting solution was concentrated and then washed with toluene to remove acetic acid. The product was then recrystallized from cyclohexane, thus obtaining 13 g (50%) of 2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetic acid, in the form of white crystals having a melting point of 149°-150° C., Rf=0.51 (acetone 100/acetic acid 2.5). Spectral data and elemental analysis of the product were as follows.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17]C)=[O:16])[C:7]=2[O:6][CH2:5]1.[OH-].[Na+].Cl>CO>[OH:1][CH2:2][CH2:3][CH:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])[C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)COc1cccc2c1OCC2CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc2c1OCC2CCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
Methyl 3-(2-hydroxyethyl)-2,3-dihydrobenzofuran-7-yloxyacetate (7.80 g) was dissolved in methanol (100 ml), and a 2N sodium hydroxide aqueous solution (20 ml) was added to the resultant solution, and the mixture was stirred at room temperature for 4 hours. 1N hydrochloric acid (45 ml) was added to the reaction solution, and the mixture was concentrated. The residue was dissolved in ethyl acetate (200 ml), washed with water and saturated brine, and then dried over sodium sulfate. After sodium sulfate was filtered off, the filtrate was concentrated, and the residue was recrystallized from ethyl acetate/n-hexane to obtain the object compound (6.21 g, yield 84%).