Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([NH:14][CH:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH2:35][CH2:36][CH2:37][OH:38]>>[OH:38][CH2:37][CH2:36][NH:35][C:16](=[O:18])[CH:15]([NH:14][C:12](=[O:13])[C:11]1[CH:31]=[CH:32][C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=2)=[CH:9][CH:10]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:22][CH:21]=1
Reactant: NCCO
Reactant: COc1ccc(Oc2ccc(C(=O)NC(Cc3ccc(OC(F)(F)F)cc3)C(=O)O)cc2)cc1
Product: COc1ccc(Oc2ccc(C(=O)NC(Cc3ccc(OC(F)(F)F)cc3)C(=O)NCCO)cc2)cc1
Yield: 89.3 %

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 2-{[4-(4-methoxyphenoxy)benzoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid (490 mg, 1.03 mmol) prepared in Example 49 (49a) and 2-aminoethanol (112 μL, 1.86 mmol) to give 477 mg of the title compound (white powder, yield: 89%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].S(=O)(=O)(O)O.CCOCC>O1CCOCC1>[O:14]=[C:3]1[C:2]2[N:1]=[C:19]([C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([CH3:15])[CH:17]=3)[O:20][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cccc(-c2nc3c(o2)C(=O)c2ccccc2C3=O)c1
Reaction time: 0.08 h
Yield: 43.2 %

Procedure:
To a solution of 5 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphthalene in 70 mL of dioxane, one adds, with protection from light, 32.00 mL (240 mmol) of 3-methylbenzoic acid chloride; after 5 min of stirring, 0.50 mL of concentrated sulfuric acid is added. After 45 min of reflux and complete cooling, 200 mL of ether are added, and the precipitate that forms is eliminated by filtration. The red filtrate is evaporated to dryness, redissolved in dichloromethane, washed several times with water, dried and purified on a flash column (support: silica; conditioning: heptane; eluant: dichloromethane/heptane, 50/50). The yellow crystals formed after evaporation of the solvent are uncolored and recrystallized in dichloromethane to produce 3 g of 4,9-dihydro-4,9-dioxo-2-(3-methylphenyl)-naphtho[2,3-d]oxazole in the form of yellow crystals.
Reaction SMILES: C1(N[C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)CCCCC1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32](Cl)=[O:33])[CH:28]=[CH:29][CH:30]=1>CCN(CC)CC>[CH:17]1([NH:9][C:32](=[O:33])[CH:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)[C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:12]=2[CH:13]=[CH:14][CH:15]=[CH:16]3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: CCN(CC)CC
Product: COc1cccc(C(C(=O)NC2CCCCC2)c2c3ccccc3nn2-c2ccccc2)c1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 3-methoxyphenyl acetyl chloride ([6834-42-0]) in the presence of Et3N to give the title compound as yellow foam. MS: m/e=440.4 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:8]=12)([O-])=O.[Sn](Cl)(Cl)(Cl)[Cl:17].[OH-].[Na+]>Cl>[ClH:17].[ClH:17].[NH2:1][C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:8]=12
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cccn2ncc([N+](=O)[O-])c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccn2ncc(N)c12

Procedure:
0.7 g of 3,4-dinitropyrazolo[1,5-a]pyridine was added to a suspension of 11.1 g of tin chloride in 80 ml of concentrated hydrochloric acid. The reaction was monitored by thin layer chromatography (TLC). The pH of the reaction mixture was adjusted to 12 using sodium hydroxide. The aqueous phase was extracted with ethyl acetate and the organic phase was dried over sodium sulfate. The organic phase was acidified with 3 ml of hydrochloric ethanol (2.5 N HCl). The precipitate was filtered off. This gave 0.55 g of pyrazolo[1,5-a]pyridine-3,4-diamine hydrochloride, whose 1H NMR analysis (DMSO-d6, 400 MHz) (δ ppm) was as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][C:22]3[CH:27]=[C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)[CH:25]=[CH:24][C:23]=3[NH:33]C(=O)OC(C)(C)C)=[O:20])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:33][C:23]1[CH:24]=[CH:25][C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[CH:27][C:22]=1[NH:21][C:19](=[O:20])/[CH:18]=[CH:17]/[C:14]1[CH:15]=[N:16][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2ccc(/C=C/C(=O)Nc3cc(-c4cccs4)ccc3NC(=O)OC(C)(C)C)cn2)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2ccc(/C=C/C(=O)Nc3cc(-c4cccs4)ccc3N)cn2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
To a solution of compound 41 (85.2 mg, 0.15 mmol) in DCM (2 mL) was added neat trifluoroacetic acid (0.7 mL). The reaction was allowed to stir at room temperature for 2 h then concentrated, diluted with AcOEt, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated to give title compound 42 (38 mg, 54% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1.[NH2:24][C:25]1[C:26]([C:32](O)=[O:33])=[N:27][C:28]([Br:31])=[CH:29][N:30]=1>C(#N)C>[NH2:24][C:25]1[C:26]([C:32]([NH:1][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=2[N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:12][CH2:11]2)=[O:33])=[N:27][C:28]([Br:31])=[CH:29][N:30]=1
Reactant: COc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(N)c1
Reactant: Nc1ncc(Br)nc1C(=O)O
Solvent: CC#N
Product: COc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(NC(=O)c2nc(Br)cnc2N)c1
Yield: 7 %

Procedure:
Following method 11, tert-butyl 1-(2-amino-4-methoxyphenyl)piperidin-4-ylcarbamate was coupled to 3-amino-6-bromopyrazine-2-carboxylic acid with TEA (3 eq) in ACN at 55° C. for 48 hours. Concentrated, triturated in cold ACN, filtered, and dried in vacuo yielding tert-butyl 1-(2-(3-amino-6-bromopyrazine-2-carboxamido)-4-methoxyphenyl)piperidin-4-ylcarbamate (7%). LCMS (m/z): 521.1 (MH+); LC Rt=3.63 min.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH:10]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:50]1[O:53][CH:51]1[CH3:52]>CO.Cl>[OH:53][CH:51]([CH3:52])[CH2:50][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:38])[F:39])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Reactant: CC1CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(O)CN1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.30 g, 0.5 mmol) from Example 2 in MeOH (10 mL) was added DIEA (0.17 mL, 1.0 mmol) and propylene oxide (1 mL, 13 mmol). The solution was stirred for 18 h at ambient temperature and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3:0.3 CH2Cl2 :MeOH:NH4OH as eluant. The free base was dissolved in MeOH containing 1.5 equivalents of 3 N aqueous HCl. The resulting solution was evaporated under reduced pressure and the residue was lyophilized from CH3CN:H2O to give the hydrochloride salt of the title compound as an amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)=[CH:3][C:2]=1[C:29]1[CH:30]=[N:25][CH:26]=[N:27][CH:28]=1
Reactant: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2ccccc21
Reactant: OB(O)c1cncnc1
Product: NC1=NC(c2ccncc2)(c2ccc(F)c(-c3cncnc3)c2)c2ccccc21
Yield: 41 %

Procedure:
The title compound was synthesized from 1-(3-bromo-4-fluorophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine (Scheme #11, G) as described in Example 67 (Scheme #10, D) in 41% yield using pyrimidin-5-ylboronic acid. 1H NMR (DMSO-d6) δ 9.02 (s, 1 H), 8.78-8.72 (m, 2 H), 8.30-8.23 (m, 2 H), 7.78-7.70 (m, 1 H), 7.66-7.58 (m, 1 H), 7.41-7.26 (m, 4 H), 7.20-7.08 (m, 3 H), 6.76 (br s, 2 H), 1.72 (s, 1.9 H); MS (ESI) m/z 382 [M+1]+.
Reaction SMILES: C([O:8][CH2:9][C:10]1([Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22]2[CH:21]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][C:13]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:14][CH:15]=2)C1C=CC=CC=1.C1COCC1>[Pd].CCO>[C:23]([C:20]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:27]([CH3:29])([CH3:30])[CH3:28])=[CH:14][CH:15]=3)[C:10]([Si:31]([CH3:34])([CH3:33])[CH3:32])([CH2:9][OH:8])[C:22]=2[CH:21]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc2c(c1)C(COCc1ccccc1)([Si](C)(C)C)c1cc(C(C)(C)C)ccc1-2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)C(CO)([Si](C)(C)C)c1cc(C(C)(C)C)ccc1-2
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 4.0 g of 2,7-di-tert-butyl-9-trimethylsilyl-9-fluorenylmethyl benzyl ether in 20 mL of freshly distilled THF and 80 mL of 100% EtOH was added 0.8 g of 5% palladium on charcoal. The heterogeneous mixture was shaken under hydrogen at a pressure of 45 psi in a Parr apparatus for 2 hours. The catalyst was removed by filtration and rinsed with ether (2×10 mL). The filtrate was evaporated under reduced pressure to give 3.23 g (100%) of the crude alcohol as a yellow oil which was chromatographed on silica gel (230-400 mesh, 4×45-cm packed column) with an eluant consisting of Skelly B--ether (3:1), to give 3.12 g (96.4%) of the alcohol as a white solid. Recrystallization from Skelly B gave 2.57 g (79.44%) of the pure alcohol as white needles, m.p. 131°-132° C.; IR (KBr): 3545, 3495 cm-1 (OH); 1H NMR (CDCl3): δ -0.18 (s, 9H, SiMe3), 1.20 (b, 1H, OH), 1.39 (s, 18H, t-Bu), 4.50 (s, 2H, CH2), 7.20-7.90 (m, 6H, aryl).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1.[ClH:61].[N:62]1([CH2:67][C:68](O)=[O:69])[CH:66]=[CH:65][N:64]=[CH:63]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[ClH:61].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([O:21][C:68](=[O:69])[CH2:67][N:62]2[CH:66]=[CH:65][N:64]=[CH:63]2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[O:32][C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)Cn1ccnc1
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(=O)Cn2ccnc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 72 h

Procedure:
A suspension comprising 422 mg (0.80 mmol) of N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12), 311 mg (1.51 mmol) of dicyclohexylcarbodiimide, 142 μl (1.76 mmol) of pyridine, 20 mg (0.16 mmol) of 4-(N,N-dimethylamino)pyridine and 156 mg (0.96 mmol) of 2-(1-imidazolyl)acetic acid hydrochloride in 10 ml of methylene chloride was stirred for 3 days. At the end of this time, insoluble materials were filtered off, and the filtrate was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 75 g of silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to give 507 mg (a quantitative yield) of the title compound as a colorless foam-like material.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1([NH2:32])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[C:27]=2[Cl:30])[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:32][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[C:27]=2[Cl:30])[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(N)Cc2ccc(Cl)c(Cl)c2C1
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(Cl)c(Cl)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76529.5 %

Procedure:
To a solution of 2-cyclobutoxy-3-methyl-benzoic acid (225 mg, 1.1 mmol), 2-amino-4,5-dichloro-indan-2-carboxylic acid ethyl ester (254) (360 mg, 1.3 μmol), HATU 622 mg, 1.64 mmol) in anhydrous DMF (10 mL) is added DIPEA (360 μL, 2.20 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is suspended in H2O (50 mL) and washed with EtOAc (3×50 mL). Organics are combined and washed successively with NaHCO3 and brine, and then the organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-20% EtOAc in heptane) to give a pure product (255) as white powder (460 mg, 90%).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:19][CH2:18][C:17]2[NH:16][C:15](=[O:20])[CH2:14][CH2:13][C:12]=2[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]I.[H-].[Na+]>O1CCCC1>[CH3:21][N:16]1[C:17]2[CH2:18][CH2:19][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][C:12]=2[CH2:13][CH2:14][C:15]1=[O:20]
Reactant: CI
Reactant: O=C1CCC2=C(CCC(OC(=O)c3ccccc3)C2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)CCC2=C1CCC(OC(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
46.5 g. of the isomer mixture containing about 60 percent of 6-benzoyloxy-3,4,5,6,7,8-hexahydro-1H-quinoline-2-one and 40% of the 3,4,4a,5,6,7-hexahydro isomer were dissolved in 400 ml. of tetrahydrofuran (THF). 80 ml. of methyl iodide were added and the resulting mixture cooled in an ice-water bath. 9.6 g of sodium hydride (as a 50 percent suspension in mineral oil) were added in portions. After all of the sodium hydride suspension had been added, the cooling bath was removed and the reaction mixture stirred at ambient temperature under a nitrogen atmosphere for about 4 hours. The reaction mixture was then diluted with water and the aqueous mixture thoroughly extracted with chloroform. The chloroform extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. The chloroform was removed by evaporation to dryness in vacuo leaving as a residue an orange oil weighing 47.3 g. Crystallization of the residue from an ether-hexane solvent mixture yielded crystals of 1-methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and the corresponding 3,4,4a,5,6,7-hexahydro isomer.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH2:26][CH2:27][OH:28])[N:20]=3)=[CH:15][C:14]=2[O:31][CH3:32])[N:10]=1.[CH2:34]([P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:34]/[P:43](=[O:50])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[CH:22][N:21]([CH2:26][CH2:27][OH:28])[N:20]=3)=[CH:15][C:14]=2[O:31][CH3:32])[N:10]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(CCO)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(CCO)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 9.8 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(2-hydroxyethyl)-1H-pyrazole-4-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.30 g) and N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 0.060 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (100:1, v/v) to give diethyl (E)-2-[3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.06 g, yield 15%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[CH:18]=[N:17][CH:16]=1.C1C=C(Cl)C=C(C(OO)=[O:37])C=1>C(Cl)Cl>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[CH:18]=[N+:17]([O-:37])[CH:16]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2cncc(Cc3ccc4oc5ccccc5c4c3)c2cc1OC
Solvent: ClCCl
Product: COc1cc2c[n+]([O-])cc(Cc3ccc4oc5ccccc5c4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To a solution of 4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxyisoquinoline 10 (600 mg, 1.62 mmol) in CH2Cl2 (40 mL) was added mCPBA (336 mg, 1.95 mmol) at RT under a nitrogen atmosphere. The reaction mixture was stirred at RT overnight and then this mixture was partitioned between CH2Cl2 (200 mL) and a 1 M K2CO3 aqueous solution (50 mL). The separated organic layer was washed with brine (50 mL), dried over MgSO4, filtered and evaporated to give 4-dibenzofuran-2-ylmethyl-6,7-dimethoxy-isoquinoline 2-oxide 35 (see table 7) as yellow solid (645 mg, quant. yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[OH:12].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([O:12][CH2:22][O:23][CH3:24])=[CH:4][C:5]=1[CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)c1cc(O)c(Br)cc1Br
Reactant: COCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C(C)C)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of 2,4-dibromo-5-isopropylphenol (512 g, 1.74 mol) in chloroform (1.74 L), N,N-diisopropylethylamine (364 mL, 2.09 mol) was added, and cooled on ice. Chloromethyl methyl ether (159 mL, 2.09 mol) was added dropwise over 60 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled on ice, and a 1M aqueous solution of sodium hydroxide (1.5 L) was added dropwise to separate the organic layer. The organic layer was washed with a 1M aqueous solution of sodium hydroxide (1.5 L) and water (1.5 L), and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure. The resulting residue was purified by distillation under reduced pressure (0.93 to 1.5 hpa, 122° C. to 137° C.) to give 1,5-dibromo-2-isopropyl-4-(methoxymethoxy)benzene (548 g, 96%) as a light yellow oil.
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH:4][CH2:3][CH2:2]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:22]([N:4]1[CH:5]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:6][CH2:7][N:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][CH2:3]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of Intermediate 3-2 (4.21 g) and TEA (2.0 g) in DCM (50 mL) was added benzoyl chloride (2.11 g) slowly. After stirring at room temperature for 1 hour and then the reaction was quenched with saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. Purification was achieved by chromatography on an ISCO column (RediSep 12, gradient elution with 10% to 70% EtOAc/Hex providing pure Intermediate 3-3 (2.82 g, 49% yield for the three steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:5]([NH:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)=[O:6].C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:5]([NH:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][CH:22]([O:25][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2ccc(N3CCC(O)CC3)cc2)cc1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Oc2ccc(N3CCC(OC(=O)c4ccccc4)CC3)cc2)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine (200 mg, 0.44 mmol) in dichloromethane (8 mL) were added with triethylamine (0.091 mL, 0.65 mmol), benzoyl chloride (74 mg, 0.53 mmol) and 4-(dimethylamino)pyridine (3 mg, 0.025 mmol), and the resulting solution was stirred for 2.5 days at room temperature. This reaction solution was purified by silica gel column chromatography (methanol:dichloromethane=7:93), to thereby yield 80 mg of the title compound.