Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][C:9]([Cl:18])=[C:10]([F:17])[CH:11]=2)[N:6]=1)[CH3:4].C(C1C(C)=[C:29]([O:32]C(C2CC2)=O)[C:28]2C(=CC(F)=C(F)C=2)N=1)C.[CH2:40]([C:42]1[C:51]([CH3:52])=[C:50]([O:53][C:54]([CH:56]2CC2)=[O:55])[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([F:60])[C:48]=2F)[N:43]=1)[CH3:41]>O1CCCC1.O>[CH2:3]([C:5]1[C:14]([CH3:15])=[C:13]([O:16][C:29](=[O:32])[CH3:28])[C:12]2[C:7](=[CH:8][C:9]([Cl:18])=[C:10]([F:17])[CH:11]=2)[N:6]=1)[CH3:4].[CH2:40]([C:42]1[C:51]([CH3:52])=[C:50]([O:53][C:54](=[O:55])[CH3:56])[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([F:60])[C:48]=2[Cl:18])[N:43]=1)[CH3:41]
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Reactant: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Reactant: CCc1nc2cc(Cl)c(F)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2cc(Cl)c(F)cc2c(OC(C)=O)c1C
Product: CCc1nc2ccc(F)c(Cl)c2c(OC(C)=O)c1C
Reaction time: 1 h

Procedure:
3-Chloro-4-fluoroaniline (2.91 g) and 3.16 g of ethyl-2-methylpropionyl acetate were refluxed in toluene (60 ml) in the presence of 0.3 ml of boron trifluoride etherate for 3 hr. The reaction mixture was then washed with a saturated sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation. The resultant intermediate was refluxed in diphenyl ether for 30 min. The reaction solution was allowed to stand for cooling, and the precipitate was then collected by filtration under the reduced pressure to give 820 mg of a mixture of 2-ethyl-3-methyl-4-hydroxy-6-fluoro-7-chloroquinoline with 2-ethyl-3-methyl-4-hydroxy-5-chloro-6-fluoroquinoline. In 10 ml of tetrahydrofuran was suspended 90.3 mg of 60% sodium hydride. The mixture of 2-ethyl-3-methyl-4-hydroxy-6-fluoro-7-chloroquinoline with 2-ethyl-3-methyl-4-hydroxy-5-chloro-6-fluoroquinoline (starting material 1) (400 mg) was suspended in 10 ml of tetrahydrofuran, and this suspension was added dropwise to the above suspension under ice cooling. The mixture was stirred for one hr. Acetyl chloride (starting material 2) (180 μl) was then added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 17.5 mg of 2-ethyl-3-methyl-4-acetyloxy-6-fluoro-7-chloroquinoline (compound 18) and 44.6 mg of 2-ethyl-3-methyl-4-acetyloxy-5-chloro-6-fluoroquinoline (compound 19). 1H-NMR data are shown in Table 3.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:41]([CH3:44])[CH2:42][CH3:43])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17][CH2:18][C:19]([C:21]1[CH:22]=[CH:23][C:24]2[C:33]3[CH:32]=[C:31]4[CH2:34][CH2:35][CH:36](Br)[C:37](=[O:38])[C:30]4=[CH:29][C:28]=3[O:27][CH2:26][C:25]=2[CH:40]=1)=[O:20])=[O:16])=[O:8])=[O:4].[C:45]([O:49][C:50]([N:52]1[C@@H:56]([CH3:57])[CH2:55][CH2:54][C@H:53]1[C:58]([OH:60])=[O:59])=[O:51])([CH3:48])([CH3:47])[CH3:46].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[CH3:57][C@@H:56]1[N:52]([C:50]([O:49][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:51])[C@H:53]([C:58]([O:60][CH:36]2[CH2:35][CH2:34][C:31]3=[CH:32][C:33]4[C:24]5[CH:23]=[CH:22][C:21]([C:19](=[O:20])[CH2:18][O:17][C:15]([C@@H:10]6[CH2:11][CH2:12][C@H:13]([CH3:14])[N:9]6[C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C@@H:41]([CH3:44])[CH2:42][CH3:43])=[O:16])=[CH:40][C:25]=5[CH2:26][O:27][C:28]=4[CH:29]=[C:30]3[C:37]2=[O:38])=[O:59])[CH2:54][CH2:55]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(OC(=O)[C@@H]1CC[C@H](C)N1C(=O)OC(C)(C)C)C3=O
Temperature: 50 °C
Yield: 43 %

Procedure:
To a solution of (2S,5S)-2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl 1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carboxylate (5.95 g, 8.88 mmol) in THF (60 mL) was added (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (3.05 g, 13.3 mmol) and Cs2CO3 (2.31 g, 7.09 mmol). The resulting solution was heated to 50° C. for 18 h. The solution was cooled to room temperature and diluted with EtOAc and washed with aqueous HCl (0.5 M). The aqueous layer was backextracted with EtOAc (2×), and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 25-100% EtOAc (5% MeOH)/Hexanes) to provide (2S,5S)-1-tert-butyl 2-(3-(2-((2S,5S)-1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl) 5-methylpyrrolidine-1,2-dicarboxylate (3.116, 43% over 2 steps) as a orange foam. LCMS-ESI+: calc'd for C44H55N3O12: 817.38 (M+). Found: 817.65 (M+).
Reaction SMILES: C1N(CCS(O)(=O)=O)CCN(CCS(O)(=O)=O)C1.ClCC([NH:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O.C(O)(=O)C>O>[NH2:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CCl)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)CCN1CCN(CCS(=O)(=O)O)CC1
Solvent: CC(=O)O
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.25 h

Procedure:
Ten microliters of 0.2 M piperazine-N,N'-bis(2-ethanesulfonic acid) [=PIPES] buffer, pH 7.3, and 10 μl of 100 mM N-chloroacetyl-L-phenylalanine (adjusted to pH 6-7 with NaOH) are dissolved in 20 μl of water. After 10 μl of an enzyme solution (30-50 μg/ml) is added, the mixture is incubated at 37° C. for 15 minutes. Then, 50 μl of 50% acetic acid is added to stop the enzymatic reaction. The amount of L-phenylalanine produced from the substrate in the reaction solution is determined by the Yemm-Cocking ninhydrin colorimetric method (E. W. Yemm & E. C. Cocking: Analyst, Vol. 80, page 209, 1955) or with an amino acid automatic analyzer (Model 835-50, Hitachi Limited).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[NH2:17])=[N:3][C:4]=2[CH:10]=1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Reactant: Nc1ccccc1CCl
Agent: Cl
Product: Nc1ccccc1CSc1nc2cc(Cl)ccc2[nH]1
Yield: 63 %

Procedure:
The title compound was prepared by the method of Example 1 using 2.50 g of 2-mercapto-5-chlorobenzimidazole instead of 2-mercaptobenzimidazole and 2.42 g of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. The basic extraction used 5% sodium hydroxide instead of sodium carbonate. Washing the solid residue from the dichloromethane extract with additional dichloromethane gave 2.47 g of the title compound. Analysis. Calc'd. for C14H12N3ClS: C, 58.03; H, 4.17; N, 14.10; S, 11.06; C1, 12.23. Found: C, 57.33; H, 4.06; N, 14.27; S, 10.99; C1, 12.74.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].CS(O[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[S:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[N:23]=2)[N:13]=1)(=O)=O.[C:29](OCC)(=O)C>CN(C=O)C.O>[CH2:1]([S:4][CH2:29][C:12]1[N:13]=[C:14]([C:18]2[S:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[N:23]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH3:3]
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)Oc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
n-Propyl mercaptan (0.25 g, 3.30 mmol) and sodium hydride (60% in oil, 0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs, combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.20 g, 20%) as pale yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[N:26]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:42]>O1CCOCC1>[ClH:42].[C:30]([C:28]1[CH:29]=[C:25]([NH:24][C:22]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:20][CH:19]=2)=[O:23])[N:26]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:27]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(CC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Reactant: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(CC3CCNCC3)cc2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(carboxy-benzyl)-piperidine-1-carboxylic acid tert-butyl ester (1.595 g, 5.0 mmol) in THF (25 mL) at room temp is added TEA (0.77 mL, 5.5 mmol) followed by DPPA (1.18 mL, 5.5 mmol). The mixture is refluxed for 1 hour and 3-amino-4-tert-butyl-2-tolylpyrazole (1.26 g, 5.5 mmol) is added and the reaction is refluxed overnight. The reaction is cooled and partitioned between ether-aqueous NH4Cl, and the organic layer is washed with brine, then dried over MgSO4, filtered and evaporated. The residue is chromatographed on silica gel using ethyl acetate/heptane (3:7) chloride to yield 1.22 grams of 4-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-benzyl}-piperidine-1-carboxylic acid tert-butyl ester. 4-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-benzyl}-piperidine-1-carboxylic acid tert-butyl ester (3.24 g, 5.94 mmol) is dissolved in methylene chloride (20 mL) under nitrogen at 0° C. and 4N HCL in dioxane (3 ml) is added. After 10 minutes the cooling bath is removed and the reaction is stirred for 3 hours at room temp. The solution is concentrated to a foam which solidified after stirring in ether for a few hours. The solid is filtered and air dried to give 2.8 grams of 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3(4-piperidin-4-ylmethyl-phenyl)-urea hydrochloride. Intermediate 4, LCMS M+1 446, RT=2.82 minutes.
Reaction SMILES: O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C)(C)[N:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][Si](C(C)(C)C)(C)C)=[CH:31][CH:32]=2)[C:27]([CH2:42][CH3:43])=[CH:26]1)(C)(C)C>C1COCC1.C(OCC)(=O)C>[CH2:42]([C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[NH:25][CH:26]=1)[CH3:43]
Reactant: CCc1cn([Si](C)(C)C(C)(C)C)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCc1c[nH]c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.7 %

Procedure:
Tetrabutylammonium fluoride hydrate (1.4 g, 4.3 mmol) was added to an ice-cooled solution of 1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-3-ethyl-1H-indole (840 mg, 2.2 mmol) in THF (8 ml). The reaction mixture was stirred for 45 min at ambient temperature, diluted with ethyl acetate and washed with 1 N HCl and water. The organic phase was concentrated under reduced pressure and the crude product purified by column chromatography (silica gel, ethyl acetate/heptane 1:2) to give 258 mg (1.6 mmol, 74%) 3-ethyl-1H-indol-5-ol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:27]=[CH:26][C:22]2[NH:23][N:24]=[N:25][C:21]=2[CH:20]=1.Cl.N1C=CC=CC=1.[CH2:35]([O:37]CCO)C>>[N:23]1[C:22]2[CH:26]=[CH:27][C:19]([NH:18][C:2]3[C:11]4[C:6](=[C:7]([O:37][CH3:35])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]#[N:17])=[CH:20][C:21]=2[NH:25][N:24]=1
Reactant: CCOCCO
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc2[nH]nnc2c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc4nn[nH]c4c3)c(C#N)cnc2c(OC)c1OC

Procedure:
Using an analogous procedure to that described in Example 150, 278.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 161.3 mg (1.2 mmol) of 5-aminobenzotriazole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed for 10 min. The work up gave 246.3 mg (65.4%) of the product as a yellow solid, m.p. 205° C. (dec.), mass (electrospray, m/e): M+H 376.9. HRCIMS: calcd 376.128 for C19H16N6O3(M+), obsd 376.1264.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]1=[O:29].CC([O-])(C)C.[K+].CO>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[N:3]=[C:2]2[N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]1=[O:29]
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2nc(-c3cccnc3)nc(-n3c(=O)[nH]c4ccccc43)c2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a 50-mL two-neck round bottom flask equipped with a reflux condenser was added a mixture of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (50 mg, 0.18 mmol, 1 eq.) and 1H-benzo[d]imidazol-2(3H)-one (27 mg, 0.21 mmol, 1.1 eq.) in 5 mL of dry 1,4-dioxane. Pd(PPh3)4 (10.6 mg, 0.009 mmol, 0.05 eq) and t-BuOK (41 mg, 0.36 mmol, 2 eq.) were added. The resulting mixture was stirred at 100° C. under N2 atmosphere overnight. After cooling, 20 mL of methanol was added. The mixture was filtered, the filtrate was concentrated in vacuo and then was purified with chromatography on silica gel (ethyl acetate/petroleum ether from 1:4 to 1:2) to give the crude product, which was further purified with reverse phase HPLC to afford 4.8 mg of vi-e as a pale yellow solid (7%). MS m/z=370.1 (M+1) (Method B) (retention time=1.680 min). 1H NMR (400 MHz, DMSO-d6): δ 11.51 (s, 1H), 8.78 (d, J=8.0 Hz, 2H), 8.17 (d, J=9.2 Hz, 1H), 7.80 (dd, J=9.2, 2.8 Hz, 1H), 7.70-7.64 (m, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.20 (d, J=4.0 Hz, 2H), 7.16-7.08 (m, 1H), 3.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-])=O)[C:5]([O:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[H][H]>O1CCOCC1.[Ni]>[NH2:22][C:4]1[C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:20][CH:21]=2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2N)cc1
Yield: 95.9 %

Procedure:
190.8 g (0.541 mole) of methyl 2-[4-(5-chloro-3-nitropyridin-2-yloxy)phenoxy]propionate are dissolved in 1.9 l of dioxan. 40 g of Raney nickel catalyst are added and hydrogenation is effected with hydrogen at 20°-25° C. The catalyst is then removed by filtration, the solvent is distilled off and the still warm oily residue is crystallised by stirring it in hexane. The crystalline precipitate is isolated by filtration and dried, affording 167.4 g (96% of theory) of methyl 2-[4-(3-amino-5-chloropyridin-2-yloxy)phenoxy]propionate with a melting point of 92°-94° C.
Reaction SMILES: C[O:2][C:3](=[O:21])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[N:5]/[OH:6].CO.[OH-].[Na+].Cl>O>[OH:6]/[N:5]=[C:4](\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)/[C:3]([OH:21])=[O:2]
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Oc2ccccc2/C(=N\O)C(=O)O)cc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To E-α-hydroxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (1.00 g, 0.0035 mole) were added methanol (3.5 ml), water (3.5 ml), sodium hydroxide (0.31 g, 0.0077 mole) and the mixture was heated under reflux for one hour. After cooling to room temperature, the resultant was adjusted to pH 1 with 5% of hydrochloric acid. After stirring at room temperature, the crystals were filtered off and washed with water to obtain colorless crystals of E-α-hydroxyimino-2-(4-methylphenoxy)phenylacetic acid (0.90 g, yield: 94.7%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:21]=[CH:20][C:12]3[O:13][C:14]([CH3:19])([CH3:18])[C:15]([CH3:17])=[CH:16][C:11]=3[CH:10]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O>[Si:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:21]=[CH:20][C:12]3[O:13][C:14]([CH3:18])([CH3:19])[C:15]([CH3:17])=[CH:16][C:11]=3[CH:10]=2)=[CH:6][CH:7]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1=Cc2cc(Sc3ccc(O)cc3)ccc2OC1(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1=Cc2cc(Sc3ccc(O[Si](C)(C)C(C)(C)C)cc3)ccc2OC1(C)C
Temperature: 40 °C
Reaction time: 18 h
Yield: 83.5 %

Procedure:
6-(4-Hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (5.799 g) (see Preparation 8) was dissolved in dry dimethylformamide (12 ml) and imidazole (2.768 g) and tert-butyidimethylsilyl chloride (2.923 g) were added. The flask was fitted with a calcium chloride drying tube and the mixture was stirred at 40° C. for 18 hours. The solvent was then removed under reduced pressure and the residue was partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the crude product chromatographed on silica using 1:1 hexane:dichloromethane as the eluent to yield 6-(4-tert-butyldimethylsilyloxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (6.681 g) as an oil. LRMS m/z=413 (m+1)+.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2CC)=[CH:6][C:5]=1[Br:19].[CH3:21][CH:22](C[AlH]CC(C)C)C.Cl.CCOCC>C1(C)C=CC=CC=1>[Br:19][C:5]1[CH:6]=[C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:21][CH3:22])=[CH:15][CH:16]=2)[CH:8]=[CH:9][C:4]=1[CH2:3][OH:20]
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CCc1ccccc1Oc1ccc(C(=O)OC)c(Br)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCc1ccc(Oc2ccc(CO)c(Br)c2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
Under a nitrogen stream, to a solution of 2-bromo-4-(ethylphenoxy)-benzoic acid methyl ester (90 mg, 0.269 mmol) in anhydrous toluene (2 ml), a toluene solution of DIBAL (1M, 0.537 ml, 0.537 mmol) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hours and at room temperature for 1.5 hours. The reaction mixture was cooled again to −78° C., followed by addition of 1N hydrochloric acid (0.2 ml) and ether (3.5 ml). The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:5)) to give the titled compound (78 mg, 94%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC1C=CC(CN[C:34](C2C(C(F)(F)F)=NC3C(C=2)=CC=CN=3)=[O:35])=CC=1>>[CH3:34][O:35][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: O=C(NCc1ccc(F)cc1)c1cc2cccnc2nc1C(F)(F)F
Product: COc1ccc(-c2ccc(C(C)NC(=O)OC(C)(C)C)cc2)cc1

Procedure:
The title compound was synthesized from tert-Butyl 1-(4-bromophenyl)ethylcarbamate and phenyl boronic acid, following the general procedure for the coupling of aryl bromides with boronic acids (see above and c.f. scheme 27). Purification was done by flash column chromatography using Pet. ether/EtOAc 5:1→100% EtOAc as eluent. The fractions containing product were further purified by size exclusion chromatography Sephadex LH20, CHCl3/MeOH 1:1 yielding the title compound (68%).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][OH:10])[CH3:7].[C:15](O)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[CH2:6]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][O:10][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:7]
Reactant: CC(C)CCCCC(=O)O
Reactant: CCCCC(CC)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)CCCCC(C)C

Procedure:
2 g concentrated sulfuric acid were added to a solution of 130 g (1 mol) 2-ethylhexanol and 144 g (1 mol) "isooctanoic acid" (isomeric mixture from Ruhrchemie A. G., Oberhausen) in 300 ml toluene and heated to boiling with water separation until the equimolar amount of water separates (about 2 hours). After cooling it was washed with water and then with 10% sodium bicarbonate solution. The remaining end-product gave after distillation over a 15 cm Vigreux column 230 g (90%) isooctanoic acid-2-ethyl-hexylester as a colorless oil of medium viscosity.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:25])[N:5]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[N:7][C:8]=1[CH3:9])[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[CH2:1]([C:3]1[C:4](=[O:25])[N:5]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:26])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(C)nc(-c2ccccc2O)n(CCc2ccccc2)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1c(C)nc(-c2ccccc2OC)n(CCc2ccccc2)c1=O
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a solution of 5-ethyl-2-(2-hydroxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one (0.19 g, 0.50 mmol) was dissolved in THF (10 mL) that contained potassium carbonate (0.80 g) and iodomethane (3 mL). The mixture was refluxed for 40 h under an argon atmosphere. After cooling to room temperature, hexanes (100 mL) were added and the salts were filtered off. The filtrate was evaporated in vacuum, and the residue was purified by flash chromatography on silica gel (40 g) eluting with ethyl acetate-hexanes (2:3) to give 5-ethyl-2-(2-methoxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one (110 mg, 56%) as a white solid after final crystallization from hexanes.