Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[C@@:19]2([CH3:20])[C:6]([CH2:7][C@@H:8]([CH3:22])[C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])=[CH:5][C:4](=[O:23])[CH2:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:1][C:2]1[C@@:19]2([CH3:20])[C:6]([CH2:7][C@@H:8]([CH3:22])[C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])=[CH:5][C:4](=[O:23])[CH:3]=1
Reactant: C[C@@H]1CC2=CC(=O)C[C@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC1=CC(=O)C=C2C[C@@H](C)[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]12C
Yield: 60.4 %

Procedure:
30 g of 1α,7α-dimethyl-4-androstene-3,17-dione is heated under reflux in 700 ml of dioxane with 30 g of dichlorodicyanobenzoquinone for 8 hours. After cooling, the product is suctioned off from undissolved matter, washed with dioxane, and the filtrate concentrated under vacuum. The residue is chromatographed on silica gel and recrystallized from acetone/hexane, thus obtaining 18 g of 1,7α-dimethylandrosta-1,4-diene-3,17-dione, mp 148°-151° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:21][C:18]1[CH:19]=[C:20]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:15]=[CH:16][C:17]=1[F:22]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Fc1ccc(Br)cc1F
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(F)c(F)c2)C1=O
Yield: 83.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with 4-bromo-1,2-difluoro-benzene (163.5 mg, 0.8474 mmol), 1,4-dioxane (5 mL), copper iodide (16.14 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (29.10 mg, 0.253942 mmol) and potassium carbonate (234.3 mg, 1.6948 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 205 mg of the product (84.01% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][NH:6][C:7](=[O:46])[CH:8]([NH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:26][CH:25]=[CH:24]2)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:19])[CH2:17]C)=[CH:11][CH:10]=1.C(OC(N(C(OC(C)(C)C)=O)C1C2C(=CC(NC(C3C=CC(CC(O)C)=CC=3)C(NCC3C=CC=C([N+]([O-])=O)C=3)=O)=CC=2)C=CN=1)=O)(C)(C)C>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][NH:6][C:7](=[O:46])[CH:8]([NH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])=[N:26][CH:25]=[CH:24]2)[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([OH:19])[CH3:17])=[CH:13][CH:14]=1
Reactant: CCC(O)Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc(N)c2)cc1
Agent: CC(O)Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc([N+](=O)[O-])c2)cc1
Product: CC(O)Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc(N)c2)cc1
Yield: 80 %

Procedure:
According to the procedure for the preparation of 70G, 77F (38 mg, 0.055 mmol) afforded 29 mg (80%) of 77G as a white solid. MS (ESI) m/z 656.5 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A80) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1.S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:20])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc(-c2ccc(Cl)nn2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2ccc(Cl)nn2)c(O)c1
Yield: 46.3 %

Procedure:
i. 3-Chloro-6-(2,4-dihydroxyphenyl)pyridazine (4.0 g, 0.18 mole), dimethyl sulphate (2.55 g, 0.0201 mole), potassium carbonate (10.0 g, 0.072 mole) and dry acetone (100 ml) were stirred at room temperature for 20 hours. The reaction mixture was filtered and the inorganic residue was washed with more acetone. Evaporation of the combined filtrates gave a brown residue which was extracted wth dilute sodium hydroxide solution. The aqueous extract was washed with dichloromethane, treated with charcoal, filtered and acidified. The resulting precipitate was collected, washed with water and crystallised from ethanol to give 3-chloro-6-(2-hydroxy-4-methoxyphenyl)-pyridazine (2.2 g, 49%; m.p. 156°-157°).
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25]C)=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:16]=2[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:10][CH:9]=1)(C)(C)C.[ClH:38].[N:39](=[CH:47]CCl)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][Cl:46]>>[ClH:46].[ClH:38].[N:39]1([CH2:47][CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]3[C:16]([C:27]4[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=4)=[CH:17][CH:18]=[C:19]4[C:24]=3[CH:23]=[CH:22][C:21]([OH:25])=[CH:20]4)=[CH:12][CH:13]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=[CH:45]1
Reactant: ClCC=NCCCCCCCl
Reactant: COc1ccc2c(Oc3ccc(NC(=O)OC(C)(C)C)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(NCCN3C=CC=CC=C3)cc2)cc1
Yield: 33 %

Procedure:
Using procedures similar to Preparation 18 and Example 58, convert {4-[2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenyl}-carbamic acid tert-butyl ester (200 mg, 0.39 mmol) and 2-(hexamethyleneimino)-ethyl chloride hydrochloride (140 mg, 0.70 mmol) to 77 mg of the title compound (37%). Mass spectrum (ion spray): m/z=531 (M+H).
Reaction SMILES: [N:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7](OC)=[C:6](OC)[CH:5]=1)=[N+:2]=[N-].NC1C=CC=CC=1.C(O)(=O)C>CN(C)C=O>[NH:1]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[N:2]1
Reactant: COc1cc(C=O)c(N=[N+]=[N-])cc1OC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: Nc1ccccc1
Product: c1ccc2[nH]ncc2c1
Reaction time: 1 h
Yield: 169.3 %

Procedure:
A solution containing 51.8 g (0.25 mole) 6-azidoveratraldehyde (Example XII), 26.0 g (0.28 mole) aniline, 4 ml galcial acetic acid, and 300 ml dimethylformamide was stirred at 90-100° for 1 hr, then refluxed for 1 hr until the gaseous evolution was complete. After the mixture was cooled and poured slowly in 1.5 l. iced water, the product was filtered, washed with two 150 ml portions cold water, and air dried to give 50 g of crude indazole, m.p. 130°-138°. Recrystallization from ethyl acetate - hexane followed by ethyl acetate gave 26 g (41%) of the product, m.p. 149°-152°. Recrystallization from ethyl acetate - hexane gave the analytical sample, m.p. 149°-152°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](Cl)=[N:6][N:5]2[CH:11]=1.O1C[CH2:15][CH2:14][CH2:13]1.C([Mg]Br)CC.Cl>Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br-].[Zn+2].[Br-].O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:13][CH2:14][CH3:15])=[N:6][N:5]2[CH:11]=1
Reactant: C1CCOC1
Reactant: Clc1cn2nc(Cl)ccc2n1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC[Mg]Br
Agent: Cl
Solvent: O
Product: CCCc1ccc2nc(Cl)cn2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen stream, 2,6-dichloroimidazo[1,2-b]pyridazine (1.00 g, 5.32 mmol), bis(triphenylphosphine)nickel(II) dichloride (0.10 g, 0.16 mmol) and zinc bromide (0.04 g, 0.16 mmol) were added to tetrahydrofuran (8.0 ml), and a solution of n-propylmagnesium bromide in tetrahydrofuran (2 M, 3.99 ml, 7.98 mmol) was added dropwise over 10 minutes to the mixture under ice-cooling. The reaction mixture was stirred for 10 minutes under ice-cooling, and warmed to room temperature and stirred for 4 hours at room temperature. Cold water (100 ml) was added to the reaction mixture which was then acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, a saturated saline, an aqueous saturated sodium bicarbonate solution and a saturated saline in this order. The resulting organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated. The concentrated residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7) to give the title compound as pale yellow crystals. The yield was 0.76 g (73.1%).
Reaction SMILES: Cl.NCC1C=C(C(C)(C)C)C=C(I)C=1[OH:15].Cl.N[CH2:18][C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:21]([S:29][CH3:30])[C:20]=1[OH:31]>>[CH3:30][S:29][C:21]1[CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=[C:19]([CH:18]=[O:15])[C:20]=1[OH:31]
Reactant: CC(C)(C)c1cc(I)c(O)c(CN)c1
Reactant: CSc1cc(C(C)(C)C)cc(CN)c1O
Agent: Cl
Product: CSc1cc(C(C)(C)C)cc(C=O)c1O

Procedure:
This compound is prepared essentially by the same procedure as described in Example 3, Step A, except that the 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride is replaced by 2-aminomethyl-4-(1,1-dimethylethyl)-6-(methylthio)phenol hydrochloride. Thereby is obtained 3-methylthio-5-(1,1-dimethylethyl)salicylaldehyde.
Reaction SMILES: [NH2:1]N.[C:3]1(=[O:24])[N:7](CCCCON=C(OCC)C)[C:6](=[O:19])[C:5]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:4]12>>[C:3]1(=[O:24])[C:4]2[C:5](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:6](=[O:19])[N:1]=[N:7]1
Reactant: NN
Reactant: CCOC(C)=NOCCCCN1C(=O)c2ccccc2C1=O
Product: O=C1N=NC(=O)c2ccccc21

Procedure:
Briefly, N-(4-bromobutyl)phthalimide was treated with the anion of ethyl N-hydroxyacetimidate in tetrahydrofuran to yield ethyl N-[(4-phthalimidobutyl)oxy]acetimidate. The product was then treated with hydrazine to release the desired amine, ethyl N-[(4-aminobutyl)oxy]acetamidate, from the phthalimide. The desired amine was isolated from the crude product by removal of phthalazine-1,4-dione by filtration, and was coupled to biotin using dicyclohexyl carbodiimide and N-hydroxy succinimide in dimethylformamide. Acidic hydrolysis of the coupled product, ethyl N-[(4-biotinamidobutyl)oxy]acetamidate, gave the final product, N-(4-aminooxybutyl)biotinamide, V. Other analogous aminooxy linkers may be prepared by variations of the above synthetic procedure. The synthesis of biotin aminooxy linker V is described in more detail and summarized in the reaction scheme presented in Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:7]([S:8]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1nc(C)cnc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
4-Dimethylaminopyridine (0.1 g) was added to a solution of 2-chloropyridine-3-sulphonyl chloride (1.06 g), 2-amino-3-methoxy-5-methylpyrazine (0.695 g) and pyridine (0.424 ml) in dichloromethane (5 ml) and the mixture was stirred at ambient temperature for 18 hours. The solution was then transferred to a silica gel Mega Bond Elut column. Elution with 0-40% ethyl acetate/hexane gave 2-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.47 g) as an oil; 1H NMR (d6-DMSO): 2.3 (s, 3H), 3.9 (s, 3H), 7.5 (s, 1H), 7.65 (dd, 1H), 8.45 (dd, 1H), 8.7 (dd, 1H); mass spectrum (+ve CI): 315 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][C:3]=1[N:11]1[C:15]([CH:16]2[CH2:18][CH2:17]2)=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[N:12]1.[CH3:24][NH2:25]>S(Cl)(Cl)=O.C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:25][CH3:24])=[O:10])=[CH:4][C:3]=1[N:11]1[C:15]([CH:16]2[CH2:17][CH2:18]2)=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[N:12]1
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2cc(C(=O)O)ccc2Cl)c1C1CC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cc(C(=O)NC)ccc2Cl)c1C1CC1
Reaction time: 6 h
Yield: 77.1 %

Procedure:
A solution of ethyl 1-(2-chloro-5-hydroxycarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate (1.32 g, 3.73 mmol) in thionyl chloride (7.5 mL) was heated at reflux for 2 h under a nitrogen atmosphere. The resulting solution was concentrated in vacuo. A solution of the residue in anhydrous CH2Cl2 (10 mL) under a nitrogen atmosphere was treated with methylamine (2 M solution in THF, 9.33 mL, 18.7 mmol) followed by a catalytic amount of 4-dimethylaminopyridine. The resulting mixture was stirred for 6 h and partitioned between ethyl acetate and HCl (1 M aq). The organic layer was washed with brine, NaHCO3 (sat aq sol), and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash 40M™ chromatography (75:25 ethyl acetate/hexanes) to afford 1.00 g (77% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([CH:31]=[CH:32][C:33]([O:35][CH3:36])=[O:34])[CH:28]=[CH:27][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:26])[C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[C:16]([N+:23]([O-])=O)[CH:15]=1.[Cl-].[NH4+].CO.O>[Zn].CO>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([CH:31]=[CH:32][C:33]([O:35][CH3:36])=[O:34])[CH:28]=[CH:27][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:26])[C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([NH2:23])[CH:15]=1
Reactant: COC(=O)C=Cc1ccc(OCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC(=O)C=Cc1ccc(OCCCCCCOC(=O)c2cc(N)cc(N)c2)c(OC)c1
Yield: 95.4 %

Procedure:
1.0 g (1.99 mmol) of 3,5-dinitrobenzoic acid 6-[2-methoxy-4-(2-methoxycarbonylvinyl)phenoxy]hexyl ester and 0.42 g (7.96 mmol) of ammonium chloride were suspended in 20 ml of a mixture consisting of methanol : water 9:1. 2.6 g (39.8 mmol) of zinc were then added in portions in the course of 30 minutes. After 2 hours at room temperature 20 ml of methanol were added. After a further 17 hours the reaction suspension was partitioned between methylene chloride and water and the organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water. The organic phase was then dried over magnesium sulphate, filtered and concentrated by evaporation. Chromatography of the residue on 150 g of silica gel using ethyl acetate yielded 0.84 g of 3,5-diaminobenzoic acid 6-[2-methoxy-4-(2-methoxycarbonylvinyl)phenoxy]hexyl ester.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:47][CH:48]1[C@H:52]2[C@H:53](OC3CCCCO3)[N:54](C(OC(C)(C)C)=O)[C:55]3[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:56]=3[C:57](=[O:58])[N:51]2[CH2:50][CH2:49]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[C@H:20]2[C@H:21](OC3CCCCO3)[N:22](C(OC(C)(C)C)=O)[C:23]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:24]=3[C:25](=[O:26])[N:19]2[CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:47][CH:48]1[C@@H:52]2[CH:53]=[N:54][C:55]3[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:56]=3[C:57](=[O:58])[N:51]2[CH2:50][CH2:49]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[C@@H:20]2[CH:21]=[N:22][C:23]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:24]=3[C:25](=[O:26])[N:19]2[CH2:18][CH2:17]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 85 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15e (200 mg, 0.2 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16e (100 mg, 0.17 mmol, 85%) as a solid: [α]20D=+484° (c=0.15, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.39-1.56 (m, 6H, 14-H, 14′-H, 15-H), 1.83-1.94 (m, 4H, 13-H, 13′-H), 2.00-2.10 (m, 4H, 2-H, 2′-H), 2.26-2.38 (m, 4H, 1-H, 1′-H), 3.54-3.63 (m, 2H, 3-H, 3′-H), 3.70-3.77 (m, 2H, 11a-H, 11a′-H), 3.79-3.91 (m, 2H, 3-H, 3′-H), 3.93 (s, 6H, 7-OMe, 7′-OMe), 4.00-4.18 (m, 4H, 12-H, 12′-H), 6.79 (s, 2H, 9-H, 9′-H), 7.51 (s, 2H, 6-H, 6′-H), 7.65 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.8, 28.8, 29.0, 46.6, 53.7, 56.1, 68.9, 110.4, 111.6, 120.0, 140.6, 147.8, 150.9, 162.3, 164.6; IR (neat): 3317, 2936, 1620, 1599, 1505, 1453, 1430, 1381, 1261, 1216, 1092, 1020 cm−1; MS (FAB) m/z (relative intensity) 653 ([M+2×MeOH]+., 4), 621 ([M+MeOH]+., 3), 589 (M+., 100).
Reaction SMILES: [OH:1][N:2]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][C:12]3[C:13]2=[C:4]([CH:5]=[C:6]2[C:11]=3[CH2:10][O:9]C[O:7]2)[C:3]1=[O:20].BrBr.O>O1CCOCC1>[OH:1][N:2]1[C:3](=[O:20])[C:4]2[CH:5]=[C:6]([OH:7])[C:11]([CH:10]=[O:9])=[C:12]3[C:13]=2[C:14](=[CH:17][CH:18]=[CH:19]3)[C:15]1=[O:16]
Reactant: O=C1c2cccc3c4c(cc(c23)C(=O)N1O)OCOC4
Agent: BrBr
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1c(O)cc2c3c(cccc13)C(=O)N(O)C2=O
Yield: 84.8 %

Procedure:
To a suspension of 360 mg (1.33 mmol) of 5-hydroxy-11H-8,10-dioxa-5-aza-benzo[de]anthracene-4,6-dione (from Example 45) in 20 mL dioxane was added 0.36 mL (6.98 mmol) of bromine. The reaction mixture was refluxed for 1 hour and poured into 150 mL water. The precipitate was isolated and dried to yield 290 mg of the title compound, mp 237-253° C. (dec.)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]C)[C:6]=1[CH2:13][CH2:14][CH3:15])[CH3:3].Br>C(O)(=O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[CH2:13][CH2:14][CH3:15])[CH3:1]
Reactant: CCCc1c(CN(C)C)cccc1OC
Agent: Br
Solvent: CC(=O)O
Product: CCCc1c(O)cccc1CN(C)C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
The 1-(N,N-dimethylamino)methyl-3-methoxy-2-propylbenzene was then converted to the 3-hydroxy equivalent by adding the 1-(N,N-dimethylamino)methyl-3-methoxy-2-propylbenzene (238 g, 1.15 moles) to acetic acid (2.35 L) and then adding hydrobromic acid (1 L of a 48% solution). This mixture was then stirred at reflux for thirty hours. The acetic acid was removed and the residue was redissolved in ethanol. The ethanol was then removed and the residue was again redissolved in ethanol. Diethyl ether was added under a precipitate formed. Precipition was allowed to proceed overnight and the precipitate was collected by filtration to yield 216.2 grams (78.9%) of 1-(N,N-dimethylamino)methyl-3-hydroxy-2-propylbenzene hydrobromic salt.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16](OC)=[O:17])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of methyl 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionate (1.40 g) in tetrahydrofuran (80 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 10.3 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 2N hydrochloric acid, concentrated and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-hexane to give 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propan-1-ol (970 mg, yield 76%) as a colorless needle. melting point: 85–86° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH:30]4[CH2:32][CH2:31]4)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:38]([O:37][CH2:36][N:9]1[C:10]([CH:13]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH:30]3[CH2:31][CH2:32]3)(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:11][CH:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1)C1CC1
Reactant: ClCOCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)n2COCc2ccccc2)cc1)C1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 5-bromo-2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (3.00 g) in N,N-dimethylformamide (25 mL) was added sodium hydride (60%, oil, 279 mg) under ice-cooling, and the mixture was stirred at 0° C. for 10 min. To the reaction solution was added [(chloromethoxy)methyl]benzene (0.970 mL), and the mixture was stirred at 0° C. for 3 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50, volume ratio) to give the title compound (2.91 g, yield 79%) as a colorless amorphous solid.