Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[N:8]=[O:9].C1N2CN3CN(C2)CN1C3.Cl.FC(F)(F)[C:24](O)=[O:25]>>[OH:10][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N:8]=[O:9])=[CH:6][C:5]=1[CH:24]=[O:25]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(O)ccc1N=O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: Cc1cc(O)c(C=O)cc1N=O
Reaction time: 0.25 h

Procedure:
In a 500 mL recovery flask, 5.0 g (36.5 mmol) of 3-methyl-4-nitrosophenol (manufacture by Aldrich Inc.) and 7.63 g (54.7 mmol, 1.5 eq) of hexamethylenetetramine (manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved in 100 ml of trifluoroacetic acid (manufactured by Kanto Chemical Co., Inc.) and reacted at 95° C. for 10 hours. After the reaction was completed, in an ice bath, 200 ml of 1 N hydrochloric acid was added thereto and the resultant was stirred for 15 minutes. After the stirring, the resultant was extracted with chloroform to obtain an extract. The extract was washed with hydrochloric acid and unsaturated saline, thereby obtaining 1.51 g (9.13 mmol) of 2-hydroxy-4-methyl-5-nitroso-benzaldehyde.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][C:34](=[O:36])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][CH:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CC(c2cccc(Br)c2)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1cccc(Br)c1)O2

Procedure:
2-(3-Bromophenyl)-chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 1.0 g of 2-(3-bromophenyl)-6-hydroxychroman-4-one. 1H NMR (300 MHz, d6-DMSO) δ: 8.83 (s, 1H), 7.63 (m, 1H), 7.53 (m, 1H), 7.46 (m, 1H), 7.37 (m, 1H), 6.88 (d, 1H, J 2.9 Hz), 6.62 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7, 2.9 Hz), 5.42 (d, 1H, J 7.0 Hz), 5.14 (d, 1H, J 10.5 Hz), 4.86 (m, 1H), 2.29 (m, 1H), 1.84 (m, 1H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Br[CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].C(N=C(N(C)C)N(C)C)(C)(C)C>CC#N>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: COC(=O)c1cccc(CBr)c1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: COC(=O)c1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a slurry of 3-iodo-4-nitro-1H-indazole (1.0 g, 3.46 mmol) and methyl 3-(bromomethyl)benzoate (1.59 g, 6.92 mmol) and CH3CN (12 mL) was added 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.697 mL, 3.46 mmol) dropwise and the mixture was allowed to stir overnight at ambient temperature. The mixture was concentrated and diluted with saturated aqueous NH4Cl (40 mL) and EtOAc (70 mL). The layers were mixed and separated and the aqueous phase was extracted with EtOAc (25 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (50% EtOAc/hexane) to provide 1.04 g (68%) of the product as a yellow/orange solid.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[O:50]1[CH:55]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:54][NH:53][C:52]2[CH:61]=[CH:62][CH:63]=[CH:64][C:51]1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:44]1([N:53]2[CH2:54][CH:55]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[O:50][C:51]3[CH:64]=[CH:63][CH:62]=[CH:61][C:52]2=3)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCOC(=O)C1CNc2ccccc2O1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1CN(c2ccccc2)c2ccccc2O1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Tris(dibenzylideneacetone)dipalladium (0) (4.3 mg, 0.0046 mmol), xantphos (8.2 mg, 0.014 mmol), and bromobenzene (40 □L, 0.381 mmol) were added to a solution of (±)-ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (65 mg, 0.31 mmol) in dioxane (2.5 mL). The solids were allowed to dissolve, and cesium carbonate (143 mg, 0.44 mmol) was added, and the suspension was stirred at 100° C. for 24 h. The mixture was cooled to ambient temperature, diluted with water (20 mL), and the product was extracted with 67% EtOAc/hexane (3×25 mL). The organic layers were combined, dried over sodium sulfate, and concentrated. Purification of the crude concentrate by flash column chromatography using 15% EtOAc/hexane afforded the title compound. MS m/z: 284 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C(O)C.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>C(O)(=O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:23][CH2:22][CH2:21][O:20][CH3:19])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: COCCN
Solvent: CCO
Solvent: CC(=O)O
Product: COCCN=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Yield: 72.7 %

Procedure:
A suspension of 6-nitroveratraldehyde (84 g, 0.4 mole), 600 ml of ethanol, and 1 ml of acetic acid was refluxed with 2-methoxyethylamine (30 g, 0.44 mole) for 1.5 hrs. After cooling overnight filtration gave 78 g of the product; m.p. 65°-66°.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26][NH2:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1.FC(F)(F)CS(Cl)(=O)=O>>[F:5][C:4]([F:7])([F:6])[C:2]([NH:27][CH2:26][CH2:25][CH:24]([C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:15]([C:12]1[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=1)[N:16]=[CH:17]2)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:1]
Reactant: NCCC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(Cl)CC(F)(F)F
Product: O=C(NCCC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Yield: 99.7 %

Procedure:
Prepared from 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropan-1-amine TFA salt (25 mg, 0.05 mmol) by adding 2,2,2-trifluoroethanesulfonyl chloride under the General Coupling Method B conditions. Obtained 22 mg (82%) of 2,2,2-trifluoro-N-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropyl)acetamide. MS found: (M+H)+=442.
Reaction SMILES: N1C=CC=CC=1.F.[CH3:8][O:9][C:10](=[O:57])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[C@@H:21](/[CH:22]=[CH:23]/[C@@H:24]([O:32][Si](C(C)(C)C)(C)C)[CH2:25][C@H:26]([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:20]([O:40][Si](C(C)(C)C)(C)C)[CH2:19][C:18]=1[O:48][C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH3:8][O:9][C:10](=[O:57])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[C@@H:21](/[CH:22]=[CH:23]/[C@@H:24]([OH:32])[CH2:25][C@H:26]([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:20]([OH:40])[CH2:19][C:18]=1[O:48][C:49](=[O:56])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OC(=O)c2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OC(=O)c2ccccc2)C[C@H]1O
Yield: 27.7 %

Procedure:
Using as the material and reagent a hydrogen fluoride-pyridine solution (0.7 ml) and methyl(11R,12S,13E,15S,17R)-9-benzoyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (734 mg), the same procedure as in Example 2 was performed to obtain methyl(11R,12S,13E,15S,17R)-9-benzoyloxy-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (141 mg, 28%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[CH3:28][C:29]([CH3:31])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(O)=O>[CH:29]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1)([CH3:31])[CH3:28]
Reactant: CC(C)=O
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCC(n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccccc32)CC1
Reaction time: 0.08 h
Yield: 24.4 %

Procedure:
To a mixture of (S)—N-(1-(1-(piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)ethyl)-9H-Aurin-6-amine from Example 113 (81 mg, 0.223 mmol) in anhydrous DCM (2 mL) was added acetone (49 μL, 0.67 mmol) followed by AcOH (1 drop). After stirring for 5 min, sodium triacetoxyborohydride (71 mg, 0.335 mmol) was added and stirring was continued for 19 h. The crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-40% 0.1% NH4OH in acetonitrile/water) followed by Isolute® SCX-2 purification. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording 131 as a pale yellow solid (22 mg, 24%). LCMS: RT 1.68 min [M+H]+ 405.1. 1H NMR (DMSO plus TFA, 400 MHz): δ 8.82 (1H, bs), 8.57 (1H, s), 8.22 (1H, d, J=8.16 Hz), 7.77 (1H, d, J=7.78 Hz), 7.64-7.52 (2H, m), 5.97 (1H, bs), 5.49-5.35 (1H, br), 3.79-3.58 (3H, m), 3.43-3.24 (2H, m), 3.00-2.78 (2H, m), 2.68-2.48 (3H, m), 2.38 (1H, bd, J=16.58 Hz), 1.89 (3H, d, J=6.93 Hz), 1.36 (6H, dd, J=6.61, 2.47 Hz)
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:11][C:12](=[O:15])[CH2:13][PH4:14]>[Na].CO>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][C:12](=[O:15])[CH2:13][PH4:14]
Reactant: O=C(C[PH4])CCl
Reactant: Oc1cccc(Cl)c1
Agent: [Na]
Solvent: CO
Product: O=C(C[PH4])COc1cccc(Cl)c1
Yield: 177.5 %

Procedure:
From 5.75 g (0.25 mole) of metallic sodium and 200 ml of methanol sodium methylate is prepared. 32 g (0.25 mole) of m-chloro-phenol are added, the mixture is refluxed for an hour and evaporated to dryness. The solid residue is suspended in 200 ml of benzene and 88 g (0.25 mole) of chloro acetonyl phosphorane are added. The reaction mixture is refluxed for 3 hours. The sodium chloride is removed by filtration of the hot mixture and the benzene filtrate is evaporated in vacuo. The residual solid crude product is rubbed with 50 ml of ether and the crystals formed are filtered and dried. Thus 97 g of the crystalline title compound are obtained, yield 87.2%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Na].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([N:35]1[CH2:40][CH2:39][N:38]([C:41]([C:43]2[C:44]3[C:58]([CH:59]=[CH2:60])=[N:57][N:56](C4CCCCO4)[C:45]=3[N:46]=[C:47]([C:49]3[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=3)[CH:48]=2)=[O:42])[CH2:37][CH2:36]1)=O)(C)(C)C>CN(C=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:60]=[CH:59]/[C:58]2[C:44]3[C:45](=[N:46][C:47]([C:49]4[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=4)=[CH:48][C:43]=3[C:41]([N:38]3[CH2:37][CH2:36][NH:35][CH2:40][CH2:39]3)=[O:42])[NH:56][N:57]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc(-c2ccc(O)cc2)nc2[nH]nc(/C=C/c3ccc(F)cc3)c12)N1CCNCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
0.25 mmol of 1-fluoro-4-iodo-benzene were weighted into a reaction tube. 2.5 mmol sodium hadrogencarbonate was added as solid, followed by 0.25 mmol tetrabutylammonium fluoride in 0.5 ml DMF and 0.1 mmol of 4-[6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester in 1 ml DMF. The tube was purged with Argon. 0.01 mmol palladium(II) acetate in 0.25 mmol DMF was added, the tube was closed with a screw cap and stirred for 8 h at 80° C. New palladium(II) acetate (0.01 mmol) was added and heating continued for 1 h at 100° C. The reaction mixture was diluted with 20 ml ethyl acetate and washed with 20 ml water, dried and evaporated. The residue was dissolved in 5 ml THF and 1 ml methanol and shaken with 100 mg silica-bound propane thiol scavenger for 4 h at RT. The mixture was filtered, the filter washed with THF, the filtrate evaporated and the residue submitted to SFC purification. The purified product was dissolved in 3 ml methanol and 0.5 ml 4N HCl in dioxane. The mixture was stirred for 30 min at 65° C. The cooled solution was diluted slowly with ml diethyl ether to precipitate the product, which was filtered off, washed with 1 ml diethyl ether, and dried in vacuo to afford [3-[(E)-2-(4-Fluoro-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone (18 mg, 37%).
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[C:21]([OH:24])(=[O:23])[CH3:22]>CS(C)=O.O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:9]2[C:2]([CH3:1])=[C:3]([CH:4]=[CH:4][CH2:3][CH2:2][CH2:9][CH2:8][CH2:22][C:21]([OH:24])=[O:23])[CH:6]=[CH:7][CH:8]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: CC(=O)O
Reactant: Cc1c(C=O)cccc1C(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1c(C=CCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 2 °C
Reaction time: 16 h

Procedure:
A solution of 2.585 g of 2-methyl-3-(4-chlorobenzoyl)benzaldehyde and 5.49 g of ω-carbethoxyhexyl triphenyl phosphonium bromide in 25 ml of a 1:1 dimethylsulfoxidetetrahydrofuran mixture was added with stirring in 3 minutes to 520 mg of a 60% oil suspension of sodium hydride in 15 ml of a 1:1 dimethylsulfoxide-tetrahydrofuran mixture cooled to 2° C. and stirring was continued for 16 hours at 24° C. after the temperature had risen. The mixture was then cooled to 5° C. and 2 ml of acetic acid were added thereto. The solvents were removed and the residue was empasted with isopropyl ether and then filtered to remove insolubles. The filtrate was evaporated and the residue was saponified in a mixture of 50 ml of methanol and 15 ml of a 2 N sodium hydroxide solution at 80° C. for 1 hour. The methanol was removed and water was added. The mixture was extracted with ether and the aqueous phase was treated with activated carbon, filtered and acidified with concentrated hydrochloric acid. The oily residue was extracted with ether and the ether phase was washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to obtain 2.98 g of 8-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-oct-7-enoic acid with an Rf=0.35 (8:2 CH2Cl2 -acetone mixture).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([CH2:13][OH:14])[CH2:8][O:7]2)([O-:3])=[O:2].[I:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.[H-].[Na+]>CN(C=O)C>[I:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:14][CH2:13][CH:9]1[CH2:8][O:7][C:6]2=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]2[CH2:10]1
Reactant: O=[N+]([O-])c1cn2c(n1)OCC(CO)C2
Reactant: BrCc1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)OCC(COCc1cccc(I)c1)C2
Temperature: 25 °C
Reaction time: 2.33 h
Yield: 43.9 %

Procedure:
A mixture of oxazine alcohol 180 (see Example 2MMM) (200.3 mg, 1.01 mmol) and 3-iodobenzyl bromide (406 mg, 1.37 mmol) in anhydrous DMF (7.5 mL) under N2 at 0° C. was treated with 60% NaH (57 mg, 1.43 mmol), then quickly degassed and resealed under N2. After stirring at room temperature for 140 min, the mixture was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (10 mL) and diluted with water (40 mL) to precipitate a crude solid, which was collected by filtration and washed with water and petroleum ether (0.49 g). The filtrate was extracted with EtOAc (3×80 mL), and then the extracts were washed with brine (50 mL). The combined extracts were evaporated to dryness and the residue was combined with the solid above and chromatographed on silica gel. Elution with 0-1% EtOAc/CH2Cl2 firstly gave foreruns, and then further elution with 1-2% EtOAc/CH2Cl2 gave 6-{[(3-iodobenzyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (182) (184 mg, 44%) as a cream solid: mp (CH2Cl2/hexane) 127-130° C.; 1H NMR (CDCl3) δ 7.69-7.62 (m, 2H), 7.40 (s, 1H), 7.24 (m, 1H), 7.10 (br t, J=8.0 Hz, 1H), 4.51 (dd, J=11.4, 3.1 Hz, 1H), 4.48 (d, J=12.3 Hz, 1H), 4.44 (d, J=12.2 Hz, 1H), 4.35 (dd, J=11.4, 7.7 Hz, 1H), 4.14 (dd, J=12.3, 5.5 Hz, 1H), 4.02 (dd, J=12.3, 7.4 Hz, 1H), 3.60 (dd, J=9.6, 5.8 Hz, 1H), 3.54 (dd, J=9.6, 6.7 Hz, 1H), 2.66 (m, 1H). Anal. (C14H14IN3O4) C, H, N.
Reaction SMILES: [Mg].Br[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH2:4][CH3:5].[C:14]([C:22]1[CH:39]=[CH:38][C:25]([N:26]([CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:24][CH:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.O>[CH2:36]([N:33]([CH2:34][CH3:35])[CH2:32][CH2:31][N:26]([S:27]([CH3:30])(=[O:28])=[O:29])[C:25]1[CH:38]=[CH:39][C:22]([C:14]([OH:21])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:3]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:4][CH3:5])=[CH:23][CH:24]=1)[CH3:37]
Reactant: CCC(Br)c1ccc(OC)cc1
Reactant: CCN(CC)CCN(c1ccc(C(=O)c2ccccc2)cc1)S(C)(=O)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(c1ccc(OC)cc1)C(O)(c1ccccc1)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1
Reaction time: 16 h

Procedure:
Magnesium turnings (10.0 g., 0.411 mole) are employed to prepare the Grignard reagent from 0.333 mole of p-(1-bromopropyl)anisole in 500 ml. of tetrahydrofuran which has been previously dried by distillation for lithium aluminum hydride. The Grignard reaction is initiated by adding a small portion of the p-(1-bromopropyl)anisole to a small portion of the magnesium turnings in a beaker and when the reaction commences as evidenced by a rise in temperature of the mixture it is transferred to the main reaction flask containing the remaining magnesium turnings and tetrahydrofuran solvent. A nitrogen atmosphere is maintained over the reaction mixture which is cooled at 0°-5°C. The main portion of the p-(1-bromopropyl)anisole dissolved in 700 ml. of similarly dried tetrahydrofuran is then added dropwise to the reaction flask during a period of 30 min. The mixture is then agitated overnight (16 hr.) with cooling and then employed for reaction in the same flask with the substituted benzoylmethanesulfonanilide reactant. 4'-Benzoyl-N-(2-diethylaminoethyl)methanesulfonanilide (25.0 g., 0.0667 mole) dissolved in 200 ml. of dried tetrahydrofuran is added dropwise during 45 min. to the reaction mixture with cooling and stirring which is continued for 24 hr. after the material has been added. The reaction product is then recovered by removing the excess magnesium by filtration and treatment of the filtrate first with water (18.0 g., 1.00 mole) and then with a solution of 50 g. of ammonium chloride in 500 ml. of water. Stirring is continued for 1/2 hr. and the organic layer is then separated and concentrated under reduced pressure. The residual oil is dissolved in ether, the solution washed first with water, the with saturated sodium chloride, and dried over magnesium sulfate. Excess hydrogen chloride gas is then introduced into the solution with stirring and the precipitated hydrochloride salt is collected on a filter and washed with ether; yield 35.2 g. (66%), m.p. 75°-140°C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]2[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>CCOCC>[OH:20][CH:19]([C:16]1[CH:17]=[CH:18][N:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)[CH:15]=1)[CH2:4][CH2:3][CH2:2][CH2:7][CH3:6]
Reactant: O=Cc1ccn(-c2cccc(Oc3ccccc3)c2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCC(O)c1ccn(-c2cccc(Oc3ccccc3)c2)c1
Reaction time: 1 h
Yield: 74.1 %

Procedure:
Grignard reagent was prepared (from 0.5 g of Mg) as described in Example 3. Then 1.8 g of 1-(3-phenoxyphenyl)pyrrole-3-aldehyde in 15 mL of ether was added. The reaction was stirred for 1 h and then poured into 300 mL of 1 N NH4Cl solution. The product was extracted with ether and the combined organic solution was washed with H2O, dried and evaporated to dryness. The crude product was purified by dry column chromatography to give 0.85 g of desired product as an oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.[CH3:15][S:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:21]([C:20]1[CH:23]=[CH:24][C:17]([S:16][CH3:15])=[CH:18][CH:19]=1)[OH:22])[CH3:5])[CH3:2]
Reactant: C#CCOC(C)OCC
Reactant: CSc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(C)OCC#CC(O)c1ccc(SC)cc1
Reaction time: 0.5 h

Procedure:
A solution of 8 g (62.4 mmol) of 1-(1-ethoxyethoxy)-2-propyne in 135 ml of tetrahydrofuran was treated at -78° under argon with 39 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -40° for 30 minutes and then a solution of 8.11 ml (62.4 mmol) of 4-(methylthio)benzaldehyde in 53 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was warmed to 0°, stirred at 0° for a further 1 hour and then treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 600 g of silica gel (elution agent ether/hexane 1:1). There was obtained 4-(1-ethoxyethoxy)-1- [4-(methylthio)phenyl]-2 -butyn-1 ol as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2.N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28].Cl>C(Cl)Cl>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[C:27](=[O:29])[CH3:28])=[CH:15][CH:16]=1
Reactant: COc1ccc2cc(Nc3ccc(O)cc3)ccc2c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2cc(N(C(C)=O)c3ccc(O)cc3)ccc2c1
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a solution of 190 mg (0.72 mmol) of 4-[(6-methoxy-2-naphthyl)amino]phenol (prepared as described in Example 2) and 0.50 ml of pyridine (dried over KOH) in 4 ml of dry CH2Cl2 at 0° was added dropwise over 5 minutes 55 ul (0.77 mmol) of acetyl chloride. The reaction mixture was stirred for 30 minutes then added to 25 ml of 1N aqueous HCl solution and extracted with 25 ml of warm ethyl acetate. The organic extract was washed with an additional 25 ml of 1M aqueous HCl solution, dried (MgSO4) and concentrated in vacuo to give a solid. The crude solid was purified by flash chromatography (silica gel, 10×3.0 cm, 1:1 EtOAc/petroleum ether) followed by recrystallization (EtOAc/petroleum ether) to afford 145 mg (66%) of title compound as white crystals, m.p. 187°-188°.