Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]2[C:10]=1[S:9][N:8]=[N:7]2.C1C(=O)N([I:19])C(=O)C1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([I:19])[C:5]([NH2:11])=[C:6]2[C:10]=1[S:9][N:8]=[N:7]2
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(Br)c2snnc12
Solvent: C1CCOC1
Product: Nc1c(I)cc(Br)c2snnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A mixture of 7-bromo-1,2,3-benzothiadiazol-4-amine (80.0 mg, 0.348 mmol) and NIS (117.3 mg, 0.522 mmol) in THF (6 ml) was stirred at RT overnight. The solution was adsorbed onto silica gel and purified by ISCO chromatography (10 to 30% EtOAc:heptane) to afford 95 mg (77%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 6.89 (s, 2 H), 8.05 (s, 1 H).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.C(O)C=C.[C:24]([O:28][C:29](=[O:57])[CH:30]([NH:45][S:46]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)(=[O:48])=[O:47])[CH:31]([CH2:42][CH:43]=[CH2:44])[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])([CH3:27])([CH3:26])[CH3:25]>O1CCCC1>[C:24]([O:28][C:29](=[O:57])[CH:30]([N:45]([CH2:6][CH:1]=[CH2:2])[S:46]([C:49]1[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=1)(=[O:48])=[O:47])[CH:31]([CH2:42][CH:43]=[CH2:44])[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])([CH3:27])([CH3:25])[CH3:26]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=CCC(C(=O)OCc1ccccc1)C(NS(=O)(=O)c1ccc(OC)cc1)C(=O)OC(C)(C)C
Solvent: C=CCO
Solvent: C1CCOC1
Product: C=CCC(C(=O)OCc1ccccc1)C(C(=O)OC(C)(C)C)N(CC=C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triphenylphosphine (1 g, 3.9 mmol) are solved in 60 ml Tetrahydrofuran (THF) and cooled to 0° C. Diazopropyl dicarboxylate (DIAD) (0.77 ml, 3.9 mmol) are added via syringe and the reaction mixture is stirred for 30 min. Allyl alcohol (16 μl, 0.23 mmol) is added to the yellow suspension and then after 10 min., 2-Allyl-3-(4-methoxy-benzenesulfonylamino)-succinic acid 1-benzyl ester 4-tert-butyl ester (1.4 g, 2.6 mmol) is added. The reaction mixture is stirred for 30 min. at 0° C. and is then allowed to warm to room temp. After evaporation of most of the THF and flash-chromatography with Hexane/Ethylacetate (2:1) the desired product is obtained: 1H NMR (CDCl3 400 MHz), ppm: 7.80 (d, 2H), 7.38 (m, 5H), 6.95 (d, 2H), 5.75 (m, 2H), 5.10 (m, 6H), 3.95 (m, 2H), 3.90 (s, 3H), 3.21 (ddd, 1H), 2.50 (ddd, 1H), 2.35 (ddd, 1H), 1.40 (s, 9H).
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15]([CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18]O)[CH3:16]>C1(C)C=CC=CC=1>[C:1]([O:14][CH2:18][CH:17]([CH2:15][CH3:16])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CCCCC(CC)CO
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 80 °C
Reaction time: 13 h
Yield: 83.2 %

Procedure:
In a three-necked flask, 19.5 g (0.1 mole) of ferulic acid, 13.0 g (0.1 mole) of 2-ethylhexanol, and 200 ml of toluene as a solvent were placed, and 1.0 g of paratoluenesulfonic acid as an acid catalyst was added. This reaction mixture was stirred at 80° C. for 13 hours. After cooled, the mixture was washed with saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and decolored by activated carbon. The solvent toluene was fully evaporated off from the organic layer under reduced pressure to obtain 25.5 g (yield: 85%) of 2-ethylhexyl ferulate.
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:37][CH2:38][Cl:39]>C(#N)C>[Cl:39][CH2:38][CH2:37][O:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=1
Reactant: ClCCBr
Reactant: Oc1cc(-c2cccs2)n[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCOc1cc(-c2cccs2)n[nH]1
Yield: 29.2 %

Procedure:
5-Hydroxy-3-(2-thienyl)pyrazole (2.49 g), potassium carbonate (3.11 g) and 18-crown-6-ether (0.13 g) is suspended in acetonitrile (31 ml), to which 1-bromo-2-chloroethane (2.15 g) is added drop by drop and the reaction mixture is refluxed for 5 hours by heating. After the reaction is completed, it is extracted with ethyl acetate, washed with aqueous solution of sodium hydrogen carbonate and dried with anhydrous magnesium sulfate. Dichloromethane is added to the residue obtained by distilling off ethyl acetate and the insoluble matter is filtered off. Dichloromethane is added and distilled off to obtain the objective 5-(2-chloroethoxy)-3-(2-thienyl)pyrazole (1.0 g). mp. 134-138° C.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl)=[O:25]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:29][C:28]2[CH:27]=[C:26]([CH:33]=[CH:32][CH:31]=2)[C:24]([O:23][CH3:22])=[O:25])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: COC(=O)c1cccc(CCl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Product: COC(=O)c1cccc(CN2C(=O)C(CCO)Oc3ccccc32)c1
Yield: 87 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by methods F and G, alkylating with 3-(methoxycarbonyl)benzyl chloride, and isolated as a white powder in 87% yield, mp 73°-75° C.; 1H NMR (CDCl3) δ 7.92-7.95 (m, 2H), 7.38-7.43 (m, 2H), 6.96-7.03 (m, 2H), 6.91 (dt, J=2.3, 7.3 Hz, 1H), 6.81 (dd, J=1.4, 7.7 Hz, 1H), 5.23 (d, J=16.3 Hz, 1H), 5.16 (d, J=16.3 Hz, 1H), 4.87 (dd, J=5.7, 7.4 Hz, 1H), 3.92-3.95 (m, 2H), 3.91 (s, 3H), 2.21-2.37 (m, 3H containing one exchangeable hydrogen). 13C NMR (CDCl3) δ 166.9, 166.7, 144.2, 136.5, 130.9 (CH), 130.7, 129.1 (CH), 128.7 (CH), 128.5, 127.7 (CH), 124.3 (CH), 122.9 (CH), 117.4 (CH), 115.4 (CH), 75.3 (CH), 58.9 (CH2), 52.2 (CH2), 45.1 (CH2), 33.3 (CH2). IR 3569, 2948, 1709, 1676, 1502 cm-1. MS 342 (MH+). Anal. Calc'd. for C19H19NO5 : C, 66.85; H, 5.61; N, 4.10. Found: C, 66.37; H, 5.62; N, 3.97.
Reaction SMILES: [C@H:1]1([C:9]([OH:11])=[O:10])[CH2:5][CH2:4][C@@H:3]([C:6]([OH:8])=O)[CH2:2]1>C(OC(=O)C)(=O)C>[CH:1]12[CH2:2][CH:3]([CH2:4][CH2:5]1)[C:6](=[O:8])[O:11][C:9]2=[O:10]
Reactant: O=C(O)[C@@H]1CC[C@H](C(=O)O)C1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2CCC1C2
Yield: 78.9 %

Procedure:
A solution of 1.63 g of cis-cyclopentane-1,3-dicarboxylic acid in 8.2 ml of acetic anhydride was heated in an oil bath at ca. 100° C. for 45 minutes. The excess acetic anhydride and acetic acid were removed by evaporation in vacuo to give a solid which was triturated under diethyl ether. This afforded 1.14 g (79% yield) of the title anhydride.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5]CCCCCCCCCC(O)=O.[C:20]1(=[O:33])[O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CC(CC)C[Mg]Br.C([Mg]Br)(CC)C>>[CH3:1][CH:2]([CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([OH:32])=[O:33]
Reactant: CCC(C)CCCCCCCCCCCCC(=O)O
Reactant: O=C1CCCCCCCCCCCO1
Agent: CCC(C)C[Mg]Br
Agent: CCC(C)[Mg]Br
Product: CCC(C)CCCCCCCCCCCCCCC(=O)O
Yield: 84 %

Procedure:
16-Methyloctadecanoic acid was synthesized by the same operation, except that in the step (a) of the synthesis process for 14-methylhexadecanoic acid described above, 12-dodecanolide was changed to 15-pentadodecanolide, and in the step (b), 2-methylbutylmagnesium bromide was changed to sec-butylmagnesium bromide. Thus, 16-methyloctadecanoic add was obtained from 15-pentadodecanolide at a total yield of 84%. The purity was 95%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:23]=[C:24]([OH:26])[CH:25]=3)[C:13]([N:15]3[CH2:21][CH2:20][C:19](=[O:22])[NH:18][CH2:17][CH2:16]3)=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C([O:35][C:36](=[O:61])[CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]Br)[C:42]=1[CH2:54][CH2:55][C:56]([O:58]CC)=[O:57])C.Cl>CC(C)=O.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:25]=[C:24]([CH:23]=[C:12]([C:13]([N:15]4[CH2:21][CH2:20][C:19](=[O:22])[NH:18][CH2:17][CH2:16]4)=[O:14])[CH:11]=3)[O:26][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C:43]3[C:42]([CH2:54][CH2:55][C:56]([OH:58])=[O:57])=[C:41]([CH:46]=[CH:45][CH:44]=3)[O:40][CH2:39][CH2:38][CH2:37][C:36]([OH:61])=[O:35])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: O=C1CCN(C(=O)c2cc(O)cc(-c3ccc4c(c3)OCO4)c2)CCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCNC(=O)CC3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)O
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of 1-(3-benzo[1,3]dioxol-5-yl-5-hydroxy-benzoyl)-[1,4]diazepan-5-one (0.58 mmol) in a mixture of acetone and DMF (2:1, 2 mL) were added potassium carbonate (10 eq.) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.1 eq). The resulting mixture was stirred at 75° C. for 2 days. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and used for the next step without further purification. The total amount of material from the previous step was dissolved in 1,2-dichloroethane (4 mL), followed by addition of trimethyltin hydroxide (433 mg). The resulting reaction mixture was stirred at 70° C. for 7 days. Then it was neutralized with 5% HCl and extracted into ethyl acetate. The organic extract was washed with water and brine and dried over anhydrous sodium sulfate. The crude material was purified by reverse-phase HPLC to yield the title compound.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=1)[CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18].Cl.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].CN(C=O)C.CCOC(C)=O.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:19]([CH:17]([NH:18][CH:6]1[C:5]2[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:16][C:15]1[CH:22]=[CH:23][CH:24]=[C:13]([CH3:12])[CH:14]=1)([OH:21])=[O:20]
Reactant: Cc1cccc(C[C@H](N)C(=O)O)c1
Reactant: O=C1OCc2ccc(I)cc21
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(CC(NC2OC(=O)c3ccccc32)C(=O)O)c1

Procedure:
A solution of 6-iodophthalide (1.0 g, 3.85 mmol), (S)-3-methylphenylalanine.HCl (0.83 g, 3.85 mmol) K2CO3 (0.53 g, 3.85 mmol), CuI (73 mg, 0.38 mmol), TEBA (0.32 g, 1.3 mmol), tri-o-tolylphosphine (0.23 g, 0.77 mmol), Pd(OAc)2 (86 mg, 0.38 mmol), triethylamine (2.14 mL, 15.38 mmol) and water (1.2 mL) in DMF (12 mL) is heated to 100° C. for 12 h. After cooling, the solution is diluted with EtOAc, and washed with 1 N HCl (100 mL), sat'd LiCl (50 mL) and water (100 mL), evaporated and chromatographed (2% MeOH/CH2Cl2, 0 to 0.05% acetic acid) to yield (S)-6-[(1-carboxy-2-(3-methylphenyl)-ethylamino]-phthalide, as a light brown foam.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO>N1C=CC=CC=1>[C:9]([NH:6][C:5]1[CH:7]=[CH:8][NH:1][C:2](=[O:3])[N:4]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Reaction time: 0.08 h

Procedure:
Cytosine (5.55 g) is suspended in dry pyridine (100 ml). Using a syringe, benzoyl chloride (6.4 ml) is then added dropwise. A virtually clear solution is formed from which a precipitate separates out after approximately 5 minutes. Stirring is continued for approximately 2 hours at room temperature, methanol (100 ml) is then added, and the mixture is concentrated in vacuo. The residue is stirred with isopropanol, filtered, washed with a small amount of methanol and diethyl ether, and dried in vacuo.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=2[CH3:19])=[CH:13][CH:14]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2c(F)cccc2F)cc1

Procedure:
Compound (100) was prepared from compound (20) and (2,6-difluorophenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.83 mins, m/z (ES−)=343 (M−H for C19H14F2O4).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Cl>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Cl)cc2nc2n1CCCCC2
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)N=C1CCCCCN1C2

Procedure:
To a solution of 2 g of 3-chloro-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one, dissolved in 50 mL of glacial acetic acid was stirred 25 g of zinc dust with vigorous mechanical stirring. The mixture was heated to 55° C.-60° C. and concentrated hydrochloric acid was added dropwise (approximately 20 mL). The reaction was checked by TLC. Usually between 20 minutes to 5 hours were required for completion. The excess zinc was filtered off, the solution concentrated in vacuo, and basified with 20% sodium hydroxide solution. The product was extracted with tetrahydrofuran. Then the free base was chromatographed using 300:25:1 CHCl3 :MeOH:28% aqueous ammonia. The corresponding fractions were combined, concentrated in vacuo, and dried in high vacuum providing the 3-chloro-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline as a white crystalline solid; m.p. 102° C.-104° C. To convert to its hydrochloride salt, the base was treated with one equivalent of 4N HCl in 50 mL absolute ethanol. The solution was concentrated in vacuo, redissolved in absolute ethanol, and concentrated in vacuo. Then the hydrochloride was recrystallized from absolute ethyl alcohol with little ethyl acetate, giving white crystals, m.p. 270° C.-271° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:26])=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:14]=1)=[O:8].[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][C:33]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:34])=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:13]([C:15]([CH3:18])([CH3:16])[CH3:17])[N:14]=1)=[O:8]
Reactant: CC(C)(C)C(=O)c1sc(NC(=O)c2cc(Cl)ccc2O)nc1C(C)(C)C
Reactant: O=C(Cl)N1CCOCC1
Product: CC(C)(C)C(=O)c1sc(NC(=O)c2cc(Cl)ccc2OC(=O)N2CCOCC2)nc1C(C)(C)C
Yield: 93.1 %

Procedure:
Using 5-chloro-N-{4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]-thiazol-2-yl}-2-hydroxybenzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]([CH3:35])[CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: CI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc5ccccc5c4)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4ccc5ccccc5c4)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(naphth-2-ylmethyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(naphth-2-ylmethyl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.95-7.34,(14H, m), 4.87-4.71,(2H, m), 2.99-2.94,(3H, m), 2.55,(3H, s), 2.33-2.28,(3H, m). LCMS; retention time 3.66 min, MH+ 448.
Reaction SMILES: [CH3:1]N(C)CCN(C)C.Cl[Si](C)(C)C.Cl[C:15]12[C:22](=[O:23])[CH2:21][CH:20]1[CH:19]=[CH:18][CH2:17][CH2:16]2>O1CCCC1.[Cu].[Zn]>[CH3:1][C:15]12[C:22](=[O:23])[CH2:21][CH:20]1[CH:19]=[CH:18][CH2:17][CH2:16]2
Reactant: O=C1CC2C=CCCC12Cl
Reactant: CN(C)CCN(C)C
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC12CCC=CC1CC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2.7 ml of tetramethylethylenediamine and 2.0 g of zinc-copper couple in 30 ml of tetrahydrofuran was stirred at room temperature, and a solution of 11.3 ml of chlorotrimethylsilane and 950 mg of 6-chlorobicyclo[4.2.0]oct-2-en-7 one, prepared as shown in Preparation 7, in 30 ml of tetrahydrofuran added dropwise. The mixture was stirred overnight at room temperature, then the precipitate filtered off, washed with ether and the combined filtrates evaporated under reduced pressure. The residue was treated with a mixture of diethylether and hexane, the precipitate filtered off and solvent removed from the filtrate under reduced pressure. The residue was dissolved in 10 ml of tetrahydrofuran, cooled to -78° C., 4 ml of 1.5M methyllithium added, stirred at -78° C. for 10 minutes, then at -30° C. for 10 minutes, recooled to -78° C. and a mixture of 5.1 g of methyl iodide and 2.1 ml of hexamethylphosphoramide added. The temperature was allowed to rise to room temperature while stirring. The mixture was poured into water, extracted with ether and the solvent removed from the extract carefully under moderately reduced pressure. The residue was chromatographed on silica gel, eluting with 10% ether in pentane, giving 400 mg of 6-methylbicyclo[4.2.0]oct-2-en-7-one, the compound of formula (8) where Y is hydrogen.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11][CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[OH:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([S:11][CH3:12])[CH:4]=1
Reactant: CSc1cc(C(=O)O)ccc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1cc(CO)ccc1O
Temperature: 60 °C
Reaction time: 21 h

Procedure:
With ice-cooling, a solution of 7d (1.37 g; 7.4 mmol) in abs. tetrahydrofuran (THF; 15 ml) was added to a suspension of 95% pure LiAlH4 (0.55 g; 14 mmol) in absolute THF (10 ml) in a three-necked flask (which had been dried by heating and flushed with argon) such that there was only a moderate evolution of gas. After the addition had ended, cooling was removed and the reaction mixture was stirred at room temperature for 30 min and at 55-65° C. for a further 21 h. With ice-cooling, ice-water was added to the reaction mixture. The precipitate of Al(OH)3 was dissolved by adding 10% strength sulfuric acid, and the aqueous-acidic solution (pH 1) was extracted with diethyl ether (3×50 ml). The combined ethereal extract was extracted with 10% strength aqueous sodium hydroxide solution (2×25 ml). The combined sodium hydroxide solution was neutralized with 20% strength hydrochloric acid. The precipitate (8c) was filtered off, washed with H2O and dried. A further charge of 8c was obtained by extraction of the neutral aqueous solution with diethyl ether. The ethereal extract was washed with saturated NaCl solution, dried over Na2SO4 and concentrated: crystalline white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(=[O:12])[CH2:11][CH2:10][CH2:9]1.C([Li])CCC.C(NC(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1
Reactant: Brc1cccnc1
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC1(c2ccncc2Br)CCC1
Yield: 55.6 %

Procedure:
3-bromopyridine (1 g, 6.329 mmol) was reacted with cylcobutanone (0.93 mL, 6.369 mmol), n-butyl lithium (4.02 mL, 7.64 mmol) and diisopropyl amine (0.99 mL, 7.005 mmol) in dry THF to afford the crude product. Purification by column chromatography on silica gel (40% ethyl acetate in hexane) afforded 802 mg of the product (55% yield). LCMS Purity: 79%, m/z=227.9 (M+1)
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:43])[CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[O:16][C:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC3C=CC=CC=3)=[C:22]([O:34]CC3C=CC=CC=3)[CH:21]=1)=[CH:14][C:13]2=[O:42])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([NH:5][CH2:6][CH:7]([OH:43])[CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[O:16][C:15]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:34])[CH:21]=1)=[CH:14][C:13]2=[O:42])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1ccc2oc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)cc(=O)c2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc2oc(-c3ccc(O)c(O)c3)cc(=O)c2c1

Procedure:
6-(3-tert-Butylamino-2-hydroxy-propoxy)-3′,4′-dibenzyloxy-flavone, 39 (1.16 g, 2 mmol) was debenzylated in dry methanol (40 mL) with 10% Pd/C (30 mg) under hydrogen atmosphere as described for 48 to provide 52. Yield 740 mg (93%); mp 193° C. (decomposes); MS (FAB) 400 (M++1); IR (KBr) 3399, 1616; 1H NMR (200 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.55 (d, J=9.5 Hz, 1H), 7.53 (s, 1H), 7.39 (d, J=9.8 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.62 (s, 1H), 4.41-4.12 (m, 3H), 3.07-2.93 (m, 2H), 1.33 (s, 9H). Analysis. Calcd for C22H25NO6: C, 66.15; H, 6.31; N, 3.51. Found: C, 66.26; H, 6.47; N, 3.61.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>ClCCl.O>[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of ethyl 3-aminobenzoate (996 mg) and triethylamine (0.85 ml) in dichloromethane (10 ml) was added benzoyl chloride (0.70 ml). The mixture was stirred at room temperature for 15 minutes, poured into a mixture of ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give ethyl 3-benzoylaminobenzoate (1.36 g).