Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH2:34][O:35]COC)=[CH:17][CH:16]=1.S(=O)(=O)(O)O>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH2:34][OH:35])=[CH:17][CH:16]=1
Reactant: COCOCc1nc(-c2ccccc2)oc1CCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCc2oc(-c3ccccc3)nc2CO)cc1
Yield: 58.5 %

Procedure:
A mixture of 5-[2-[4-(5-methyl-2-phenyl-4-oxazolyl)methoxyphenyl]ethyl]-4-methoxymethoxymethyl-2-phenyloxazole (3.80 g), 10% sulfuric acid (10 ml) and tetrahydrofuran (100 ml) was refluxed for 2 hrs., and concentrated. Ethyl acetate was poured into the residue and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and [5-[2-[4-(5-methyl-2-phenyl-4-oxazolyl)methoxyphenyl]ethyl]-2-phenyl-4-oxazolyl]methanol (2.03 g, yield 59%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 142–143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[Br:44][C:45]1[CH:46]=[C:47]([C@H:51]([NH2:53])[CH3:52])[CH:48]=[CH:49][CH:50]=1>C(Cl)(Cl)Cl>[Br:44][C:45]1[CH:46]=[C:47]([C@H:51]([NH:53][C:36]([NH:20][C:19]2[CH:21]=[C:22]([CH3:23])[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[CH3:24])=[O:42])[CH3:52])[CH:48]=[CH:49][CH:50]=1
Reactant: C[C@@H](N)c1cccc(Br)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)N[C@H](C)c4cccc(Br)c4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (83 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(3-bromophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (63 mg, yield 45%).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1[C:23]2[CH2:22][C@@H:21]3[C:12](=[C:13]([OH:33])[C@@:14]4([OH:32])[C@@H:19]([CH2:20]3)[C@H:18]([N:24]([CH3:26])[CH3:25])[C:17]([OH:27])=[C:16]([C:28]([NH2:30])=[O:29])[C:15]4=[O:31])[C:11](=[O:34])[C:10]=2[C:9]2[O:8][C:7](=[S:35])[NH:6][C:5]=2[CH:4]=1.C(N(C(C)C)CC)(C)C.[CH2:46]([O:53][C:54](=[O:57])[CH2:55]Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C)C=O>[NH2:30][C:28]([C:16]1[C:15](=[O:31])[C@:14]2([OH:32])[C@@H:19]([CH2:20][C@H:21]3[C:12](=[C:13]2[OH:33])[C:11](=[O:34])[C:10]2[C:9]4[O:8][C:7]([S:35][CH2:55][C:54]([O:53][CH2:46][C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)=[O:57])=[N:6][C:5]=4[CH:4]=[C:3]([N:2]([CH3:36])[CH3:1])[C:23]=2[CH2:22]3)[C@H:18]([N:24]([CH3:25])[CH3:26])[C:17]=1[OH:27])=[O:29]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CN(C)c1cc2[nH]c(=S)oc2c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)c1cc2nc(SCC(=O)OCc3ccccc3)oc2c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Reaction time: 0.08 h

Procedure:
To a solution of (6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-dioxo-2-thioxo-2,3,6,6a,7,7a,8,11,11a,13-decahydrotetraceno[2,1-d][1,3]oxazole-10-carboxamide (Example 42) in N,N-dimethylformamide (DMF) is added 2 equivalents of diisopropylethylamine, after stirring for 5 min. 1.2 equivalent of benzyl-2-bromoacetate is added. The reaction mixture is stirred for 1 hr and mixture triturated with diethyl ether and solid is collected. It is purified by extraction.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8].C(OOC(C)(C)C)(C)(C)C>>[C:9]1([CH:7]([CH3:8])[O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCO
Reactant: CCc1ccccc1
Agent: CC(C)(C)OOC(C)(C)C
Product: CCCCCOC(C)c1ccccc1
Temperature: 90 °C
Yield: 48 %

Procedure:
Into a pressure vessel 1-pentanol (109 μL, 1 mmol, 1 eq) was added and diluted with ethylbenzene (1.225 mL, 10 mmol, 10 eq). To this stirring solution was added 1 mol % of a stock solution of {[Cl2NN]Cu}2(benzene) from the catalyst stock solution described in Example 4 (200 μL=0.01 mmol). After adding of tert-butyl peroxide (220 μL, 1.2 mmol), the pressure vessel was sealed and heated to 90° C. for 24 hr. The catalyst was separated by exposing the mixture to air and filtering through Celite®. After removing ethyl benzene under vacuum, the residue was analyzed by GC/MS and 1H NMR to determine the yield and consumption of starting materials. 1H NMR Yield: 48%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20].CI.[C:23](=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:23])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1Cl
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(N2C(=O)C3=CCCCN3C2=O)c(Cl)cc1Cl
Yield: 132.5 %

Procedure:
An acetonitrile (10 mL) solution of 2-(2,4-dichloro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.62 g, 2.0 mmol), methyliodide (0.25 mL, 4 mmol) and potassium carbonate (0.21 g, 1.5 mmol) was stirred for 2 hours under reflux. A saturated ammonium chloride solution (20 mL) was added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with diethyl ether (10 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (40 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by crystallization from dichloromethane to obtain a white solid of 2-(2,4-dichloro-5-methyloxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.65 g, yield:100%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.C(N1CCC2(CC3C=CC(Cl)=CC=3O2)CC1)C1C=CC=CC=1.[CH2:46]([O:48][C:49](Cl)=[O:50])[CH3:47]>C1C=CC=CC=1>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][C:11]3([O:14][C:15]=2[CH:21]=1)[CH2:10][CH2:9][N:8]([C:49]([O:48][CH2:46][CH3:47])=[O:50])[CH2:13][CH2:12]3
Reactant: Clc1ccc2c(c1)OC1(CCN(Cc3ccccc3)CC1)C2
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC2(CC1)Cc1ccc(Cl)cc1O2
Temperature: 25 °C

Procedure:
A stirred solution of 6.1 g of 2,3-dihydro-1'-benzyl-6-chlorospiro[benzofuran-2,4'-piperidine], free base of Example 5, and 2.5 g of ethylchloroformate in 150 ml of benzene is refluxed for 18 hours. Thereafter, the solution is successively permitted to cool to ambient temperature, washed with water, washed with a saturated sodium bicarbonate solution, washed with a saturated sodium chloride solution, dried and concentrated to dryness, leaving 2,3-dihydro-6-chloro-1'-ethoxycarbonylspiro[benzofuran-2,4'-piperidine] as a dark oil. The oil is taken up in a mixture of 50 ml of a 50% potassium hydroxide solution and 100 ml of ethyl alcohol and this mixture is refluxed for 18 hours and then permitted to cool to room temperature before removal of the ethyl alcohol under reduced pressure. The remaining aqueous suspension is extracted with ether and the combined ether extracts are washed with 3 N hydrochloric acid, the acidic wash is basified with 6 N sodium hydroxide and the basified solution is extracted with ether. The combined ether extracts are dried before being concentrated to dryness, leaving on off-white solid. The solid is dissolved in ether where it is converted to its hydrogen chloride salt which is recrystallized twice from ethyl alcohol providing the product, 2,3-dihydro-6-chlorospiro[benzofuran-2,4'-piperidine]hydrochloride, mp 281°-288° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH3:17])[CH:11]=2)[CH:5]=1.[C:19]([C:22]1C=C(B(O)O)C=CC=1)([OH:21])=[O:20].BrC1C=C(C)N=C(C)C=1.COC(=O)C1C=CC=C(C2C=CN=C(C)C=2)C=1.OO>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH2:17][O:21][C:19](=[O:20])[CH3:22])[CH:11]=2)[CH:5]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: COC(=O)c1cccc(-c2cc(C)nc(C)c2)c1
Agent: COC(=O)c1cccc(-c2ccnc(C)c2)c1
Agent: Cc1cc(Br)cc(C)n1
Agent: OO
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cccc(-c2cc(C)nc(COC(C)=O)c2)c1
Yield: 82 %

Procedure:
Oxidation of 3-(2,6-dimethyl-pyridin-4-yl)-benzoic acid methyl ester (28.8 g, 0.12 mol; prepared from commercially available 3-carboxyphenylboronic acid [CAS-No. 25487-66-5] and 4-bromo-2,6-dimethylpyridine [Chem. Pharm. Bull. 38 (1990) 2446 and J. Org. Chem. 27 (1962) 1665] as described for 3-(2-methyl-pyridin-4-yl)-benzoic acid methyl ester in example K12) with H2O2 (30%, 36.5 ml, 0.36 mol) in acetic acid (117 ml) at 70° C. for 27 h and subsequent reaction of the N-oxide in acetic acid anhydride (31 ml) at 135° C. for 30 min yielded after aqueous work-up 3-(2-acetoxymethyl-6-methyl-pyridin-4-yl)-benzoic acid methyl ester (29.2 g, 82%) as a brown oil.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:13](N)([NH2:16])(=[O:15])=[O:14]>O1CCOCC1>[N:12]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([S:13]([NH2:16])(=[O:15])=[O:14])[CH2:3][CH2:2]1
Reactant: NS(N)(=O)=O
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCN(c2ncccn2)CC1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 15 step i) using 2-piperazin-1-ylpyrimidine (3.0 g) and sulfamide (1.2 g) in dioxane (30 mL) to give the subtitle compound as a white solid. Yield: 2.06 g.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[CH2:47][CH3:48])[CH2:6][C@@H:7]([NH:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9])[CH3:2].O.[CH:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][C:51]=1[S:60]([OH:63])(=[O:62])=[O:61]>C(O)(C)C>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[CH2:47][CH3:48])[CH2:6][C@@H:7]([NH:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH2:14][CH2:15]1)=[O:9])[CH3:2].[CH:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][C:51]=1[S:60]([O-:63])(=[O:62])=[O:61]
Reactant: O=S(=O)(O)c1ccc2ccccc2c1
Agent: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Solvent: O
Solvent: CC(C)O
Product: O=S(=O)([O-])c1ccc2ccccc2c1
Temperature: 5 °C

Procedure:
0.25 g (0.38 mmol) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide and 86.2 mg (0.38 mmol) naphthalene-2-sulphonic acid monohydrate are suspended in 5 ml isopropanol and refluxed. The solution is cooled to ambient temperature within 6 days in 5° C. stages and filtered. The isolated solid is washed with isopropanol and dried for 12 hours at 60° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH2:14][CH3:15])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>CN(C=O)C.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][N:10]3[C:11]4[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH2:14][CH3:15])[C:7]=4[N:8]=[CH:9]3)=[CH:31][CH:30]=2)=[O:28])=[CH:37][CH:38]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: CCn1c(=O)c2[nH]cnc2n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(CC)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 54.5 %

Procedure:
To a solution of 1,3-diethylxanthine (190 mg), a synthetic process for which is described in Journal of American Chemical Society, 75, 114 (1953), in DMF (5 ml) were added potassium carbonate (189 mg) and 4-(4-chlorobenzoyl)benzyl bromide (282 mg) and the mixture was stirred at room temperature for 17 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and recrystallized (ether-hexane) to provide the title compound as colorless powder (217 mg, 54%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)=[CH:4][C:3]=1[CH3:18].Cl.[H][H]>[C].[Pd].C(O)C>[CH3:18][C:3]1[CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)[S:6][CH:2]=1
Reactant: Cc1cc(-c2n[nH]c(=O)c3ccccc23)sc1Br
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1csc(-c2n[nH]c(=O)c3ccccc23)c1
Yield: 90.6 %

Procedure:
300 mg of 4-(5-bromo-4-methyl-2-thienyl)-1-phthalazinone, 500 mg of 5% palladium carbon (Pd-C) and 1 ml of concentrated hydrochloric acid were added to 50 ml of ethanol, and hydrogen gas was reacted with the resulting mixture under ordinary pressure. After the end of the reaction, the mixture was filtered, and the filtrate was concentrated to obtain 205 mg of 4-(4-methyl-2-thienyl)phthalazinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][CH:26]([CH:30]([CH3:32])[CH3:31])[C:27]([OH:29])=[O:28])=[CH:20][CH:19]=1.[F:33][C:34]1[CH:48]=[CH:47][C:37]([O:38][C:39]2[N:44]=[C:43]([CH2:45]O)[CH:42]=[CH:41][CH:40]=2)=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH2:45][C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([O:38][C:37]3[CH:47]=[CH:48][C:34]([F:33])=[CH:35][CH:36]=3)[N:44]=2)=[O:12])=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][CH:26]([CH:30]([CH3:32])[CH3:31])[C:27]([O:29][CH2:45][C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([O:38][C:37]3[CH:47]=[CH:48][C:34]([F:33])=[CH:35][CH:36]=3)[N:44]=2)=[O:28])=[CH:22][CH:23]=1
Reactant: CC(C)C(C=Cc1ccc(Cl)cc1)C(=O)O
Reactant: OCc1cccc(Oc2ccc(F)cc2)n1
Reactant: CC(C)C(C=Cc1ccc(F)cc1)C(=O)O
Product: CC(C)C(C=Cc1ccc(Cl)cc1)C(=O)OCc1cccc(Oc2ccc(F)cc2)n1
Product: CC(C)C(C=Cc1ccc(F)cc1)C(=O)OCc1cccc(Oc2ccc(F)cc2)n1

Procedure:
By the procedure of Example 1, the acid chloride of each of 4-(4-fluorophenyl)-2-isopropyl-3-butenoic acid and 4-(4-chlorophenyl)-2-isopropyl-3-butenoic acid is reacted with [6-(4-fluorophenoxy)-2-pyridyl] methanol, yielding [6-(4-fluorophenoxy)-2-pyridyl]methyl 4-(4-fluorophenyl)-2-isopropyl-3-butenoate and [6-(4-fluorophenoxy)-2-pyridyl]methyl 4-(4-chlorophenyl)-2-isopropyl-3-butenoate, respectively.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=CC=1.[CH2:24]([O:26][PH:27](=[O:31])[O:28][CH2:29][CH3:30])[CH3:25]>>[CH2:24]([O:26][P:27]([CH2:21][CH2:22][CH2:23][CH2:18][NH:17][C:14]([C:11]1[CH:12]=[N:13][C:8]([C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)=[N:9][CH:10]=1)=[O:16])(=[O:31])[O:28][CH2:29][CH3:30])[CH3:25]
Reactant: CCO[PH](=O)OCC
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Reactant: Nc1ccccc1
Product: CCOP(=O)(CCCCNC(=O)c1cnc(-c2ccccc2)nc1)OCC

Procedure:
Following procedures similar to those of Example 5 but substituting 2-phenyl-pyrimidine-5-carboxylic acid for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting (4-aminobutyl)-phosphonic acid diethyl ester oxalate for aniline, there is prepared 14-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-butyl)-phosphonic acid diethyl ester as a solid. MS: 392 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.31 (t, 6H), 1.77 (m, 6H), 3.48 (q, 2H), 3.97-4.19 (m, 4H), 7.40-7.58 (m, 3H), 7.84 (bs, N—H), 8.40-8.57 (m, 2H), 9.23 (s, 2H); IC50=23.5 nM.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOC(C)=O>CN(C=O)C>[C:8]1([S:14]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cccc1
Reaction time: 1 h

Procedure:
To a solution of 1H-pyrrole (5 g, 74.5 mmol) in DMF (50 mL) was added NaH (4.5 g, 110 mmol) portionwise at 0° C., and the mixture was stirred at this temperature for 1 hour. Benzenesulfonyl chloride (19.4 g, 110 mmol) was added, and the mixture was stirred at room temperature overnight, followed by a standard aqueous/EtOAc workup and purified by column chromatography (PE:EtOAc=100:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.II.Cl>C1COCC1.CCOCC.[Zn]>[OH:19][CH:18]([C:17]1[CH:20]=[CH:21][C:14]([CH3:13])=[CH:15][CH:16]=1)[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: Cc1ccc(C=O)cc1
Reactant: COC(=O)Cc1ccccc1Br
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)C(O)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl 2-bromophenylacetate (473 mg; 2.065 mmol) and 4-methylbenzaldehyde (188 mg, 1.57 mmol) in dry THF (5 mL) under N2 was added powdered zinc (201 mg, 3.09 mmol). After stirring at reflux for 10 min, a few crystals of iodine were added. The mixture was refluxed under N2 for 4 hours, then allowed to stand at room temperature overnight. The next day the mixture was diluted in Et2O and 1N HCl was added. The biphasic mixture was stirred until the zinc had completely dissolved in the aqueous layer. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue which contained two diastereomers (Rf=0.22, 0.17 in 15% EtOAc/hexane), was purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane. A total of 283 mg (67%) of both diastereomers was isolated. The 300 MHz 1H NMR spectra of each diastereomer was consistent with its structure.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)(=[O:10])=[O:9])[C:3]([OH:5])=O.C1C=CC2N(O)N=NC=2C=1.[NH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CN1CCOCC1>CN(C=O)C.C(Cl)CCl>[O:41]1[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][NH:35][C:3](=[O:5])[CH:2]([OH:1])[CH2:6][CH2:7][S:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)(=[O:10])=[O:9])[CH2:39][CH2:40]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)C(O)CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCN1CCOCC1)C(O)CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1
Reaction time: 2 h
Yield: 45.4 %

Procedure:
Part G: A solution of 3.4 g (10 mmol) of 2-hydroxy-4-[(3-phenoxybenzyl)sulfonyl]butanoic acid from Part F and 2.1 g (15 mM) HOBT in 15 mL of anhydrous DMF was cooled in an ice bath and treated with 2.3 g (12 mM) of EDC. After 2 hours, the reaction was treated with a solution of 1.5 g (12 mM) of 4-(2-aminoethyl)morpholine and 3.3 mL (3.1 g, 30 mM) of N-methylmorpholine in 5 mL anhydrous DMF. After stirring for 66 hours, the reaction was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated to yield 3.5 g of crude product. The crude product was chromatographed on silica gel using 5% methanol/ethyl acetate followed by 20% ethanol/THF to yield 2.1 g of N1-(2-morpholinoethyl)-2-hydroxy-4-[(3-phenoxybenzyl)sulfonyl]butanamide suitable for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH2:39][OH:40].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8]
Reactant: OCCCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 338) (45 mg) was suspended in N,N-dimethylformamide (4 ml). Potassium carbonate (50 mg) and 4-bromo-1-butanol (55 mg) were added to the suspension, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (26 mg, yield 48%).