Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[NH2:52][CH:53]([CH2:56][OH:57])[CH2:54][OH:55].OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:46])[NH:52][CH:53]([CH2:56][OH:57])[CH2:54][OH:55])([CH3:44])[CH3:43])=[CH:33][CH:32]=3)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(CO)CO
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)NC(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 2-amino-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)piperazine, respectively.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].[CH:7]1([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=3)[N:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:7]1([C:13]2[N:14]([CH2:2][C:3]([OH:5])=[O:4])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=3)[N:17]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Cc1cc(-c2c[nH]c(C3CCCCC3)n2)ccc1F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cn(CC(=O)O)c(C3CCCCC3)n2)ccc1F
Temperature: 25 °C

Procedure:
0.38 mL methyl bromoacetate was added to 940 mg 2-cyclohexyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazole and 1.52 g potassium carbonate in 10 mL DMF. The reaction was stirred over night at RT and evaporated. Methanol and 1 mol/L sodiumhydroxide solution was added and the mixture was stirred 2 h at RT. The solvent was removed. The residue was dissolved in water and acidified with 1 mol/L HCL solution. The precipitate was filtered and dried to give 700 mg desired product. Rt: 0.92 min (method B), (M+H)+: 317
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20](Cl)=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>ClCCl>[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:34][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
Triethylamine (38.6 mL, 0.277 mol) was added to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (72.9 g, 0.232 mol) in dichloromethane (1200 mL). Isobutylamine (25.24 mL, 0.2540 mol) was then added, and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with dichloromethane, washed sequentially with water (2×) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 67.4 g of (7-benzyloxy-3-nitroquinolin-4-yl)(2-methylpropyl)amine as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([OH:17])[CH:9]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
5-Bromo-2-methoxy-phenol was synthesized by dissolving 5-bromo-2-methoxy-benzaldehyde (50 g, 233 mmol), in CH2Cl2 (150 mL) was cooled with an ice bath to 0° C., and subsequently, 3-chloroperoxybenzoic acid (70-75% purity) (68.1 g, 276 mmol) in CH2Cl2 (500 mL) was added. The reaction mixture was allowed to warm slowly to room temperature and stirred for 72 h. The colorless solid was filtered off, and the filtrate was stirred for 2 h with a 2 N Na2SO3 solution (200 mL). The organic layer was evaporated and the remainder dissolved in diethyl ether and washed with 1 N Na2SO3 and a half saturated NaHCO3 solution. The organic phase was extracted with a 2 N aqueous NaOH solution. The combined basic extract was acidified (pH ˜3-4) with concentrated HCl and then extracted with diethyl ether. The combined organic extracts were dried over MgSO4, filtered, and the solvent evaporated to afford intermediate 5-bromo-2-methoxy-phenol (43.5 g, 90%). 1H NMR (CDCl3) 7.06 (d, J=2.3, 1H), 6.96 (dd, J=8.6, 2.3, 1H), 6.70 (d, J=8.6, 1H), 5.67 (s, 1H), 3.86 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[CH3:25][N:26]([CH3:35])[C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([NH2:34])=[CH:29][N:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:34][C:30]3[CH:29]=[N:28][C:27]([N:26]([CH3:25])[CH3:35])=[CH:32][C:31]=3[CH3:33])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: Cc1cc(N(C)C)ncc1N
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2cnc(N(C)C)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 43.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 472 mg, 1.27 mmol), N2,N2,4-trimethylpyridine-2,5-diamine (580 mg, 3.81 mmol) and p-toluenesulfonic acid monohydrate (241 mg, 1.27 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was irradiated by microwave at 180° C. for 135 min. After cooling, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (266 mg, 0.547 mmol, 43%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([CH2:17][C:18](OCC)=[O:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:17]=[C:18]2[OH:19]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Product: Oc1cc(-c2ccccc2)nc2ccc(Cl)cc12

Procedure:
From 100 g of p-chloroaniline and 138.5 ml of ethyl benzoylacetate treated according to Example 4(a) there was obtained 115.6 g of 6-chloro-2-phenyl-4-quinolinol, mp greater than 350°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH4+].[Cl-]>CCOCC>[C:2]1([C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(c2ccccc2)CCCCC1
Yield: 71 %

Procedure:
The Grignard reagent resulting from the action of 48.9 g (0.3M) of bromobenzene on 8.75 g (0.35M) of magnesium in the form of turnings is prepared in 300 ml of anhydrous ether. To it is added 19.6 g (0.2M) of cyclohexanone dissolved in 300 ml of anhydrous ether. Stirring takes place for 3 h on the reflux condenser and the complex is decomposed by a cold, saturated NH4Cl solution and then, after settling, the liquids are extracted with ether (3×200 ml). The ethers are dried (Na2SO4) and evaporated in vacuo to give a yellowish solid which, after two crystallizations in petroleum ether, give 25 g of white 1-phenyl-cyclohexanol melting at 60° to 61° C. (IR).
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:11][C:12]1[CH:13]=[C:14]([N:19]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[CH2:33])=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]>C1(C)C=CC=CC=1>[CH3:27][C:22]1[CH:21]=[C:20]([N:19]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][CH2:33][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:34][CH:35]=2)[C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=2)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: C=Cc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1
Reactant: CCO[SiH](OCC)OCC
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1)(OCC)OCC
Temperature: 25 °C
Yield: 94.2 %

Procedure:
Into a three-necked flask, 40 ml of toluene, 6.0 g (37 mmol) of triethoxysilane and 0.34 mmol of platinum (II) dichloro(h-cycloocta-1,5-diene) were placed, and 20 ml of a toluene solution containing 9.9 g of 4-[N,N-bis(3,4-dimethylphenyl)amino]styrene was added dropwise with stirring at room temperature. After the addition was completed, the mixture was stirred at 70° C. for 3 hours, and thereafter the solvent was removed under reduced pressure to obtain oily pale yellow 4-[N,N-bis(3,4-dimethylphenyl)amino]-[2-(triethoxysilyl)ethyl]benzene in an amount of 14.0 g (yield: 94.2%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])[CH:5]=[N:4][CH:3]=1.C[O-].[Na+].[C:22]([O-])(O)=[O:23].[Na+]>CO.CCOC(C)=O>[CH3:22][O:23][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])[CH:5]=[N:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1cncc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cncc(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of (1R,2S)-1-[(6-chloropyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol (2 g, 7.6 mmol) in MeOH (26 mL) was added a solution of NaOMe (1.3 g, 23 mmol) in MeOH (40 mL). The mixture was heated at reflux for 24 hr. Additional NaOMe (1.3 g) was added. Continue heating at reflux for 24 hr, and then add additional NaOMe (1.3 g). Continue heating at reflux for 24 hr and cool to rt. Dilute with EtOAc and was with sat. aq. NaHCO3. The solids were removed by filtration. Separate phases and wash organic extract with additional sat. aq. NaHCO3. Dry organic extracts over MgSO4, filter and concentrate. Purify by biotage MPLC (90 g column, 25% ethyl acetate/hexanes) to afford 1.4 g (71%) of (1R,2S)-1-[(6-methoxypyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol as an oil: 1H NMR (CDCl3) δ 3.04-3.08, 3.23-3.29, 3.91, 4.75-4.78, 5.18, 5.42-5.45, 7.25-7.34, 7.57-7.61; MS (ESI+) for C14H15N3O2 m/z 258 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[N:29]4[CH2:35][CH:34]5[N:36](C(OC(C)(C)C)=O)[CH:31]([CH2:32][CH2:33]5)[CH2:30]4)[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:31]12[NH:36][CH:34]([CH2:33][CH2:32]1)[CH2:35][N:29]([C:21]1[N:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:7]4([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]4)[CH2:15][CH2:16]3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=1)[CH2:30]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1nc3ccccc3n1C1CCN(C3(c4ccccc4)CCCCCC3)CC1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(C2(N3CCC(n4c(N5CC6CCC(C5)N6)nc5ccccc54)CC3)CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A mixture of t-butyl 3-{1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (57.8 mg, 0.099 mmol), trifluoroacetic acid (1 ml), and CH2Cl2 (3 ml) was stirred at room temperature for 0.5 hours. After evaporation of the solvent, the residue was treated with 10% HCl solution in MeOH (1.5 ml) at room temperature and allowed to stand for 0.5 hours. The reaction mixture was concentrated to give 44.6 mg (77.6%) of white amorphous solid as an HCl salt.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:23]=3)[O:20][C:19](=[O:38])[NH:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:39]1[O:41][CH2:40]1.[Cl-].C[NH3+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:23]=3)[O:20][C:19](=[O:38])[N:18]2[CH2:39][CH2:40][OH:41])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CO1
Reactant: COc1ccc([C@H]2NC(=O)O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Agent: C[NH3+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2[C@H](c3ccc(OC)c(OCc4ccccc4)c3)OC(=O)N2CCO)cc1OCc1ccccc1

Procedure:
Mixture: 100 mg of rel-(4R,5S)-4,5-bis(3'-benzyloxy-4'-methoxyphenyl)oxazolidin-2-one, 5 ml of ethylene oxide, 15 ml of tetrahydrofuran, 5 mg of methylammonium chloride.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Ic1ccc(N2CCNCC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(I)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a stirred solution of 1-(5-iodopyridin-2-yl)piperazine (CAS number 219635-89-9, 5.083 g, 17.6 mmol), and triethylamine (4.91 mL, 35.2 mmol) in CH2Cl2 (75 mL) at 0° C. was added methane sulfonyl chloride (2.04 mL, 26.4 mmol) dropwise and the resulting suspension stirred for 30 mins at room temperature. The reaction mixture was diluted with CH2Cl2 (200 mL) and washed twice with water (2×200 mL). The organic phase was washed with saturated brine solution (1×200 mL), dried (MgSO4), filtered and concentrated in vacuo to give a dark yellow solid. This was triturated with ether, filtered and dried to give 1-(5-iodopyridin-2-yl)-4-(methylsulfonyl)piperazine as a yellow solid (5.378 g, 83%).
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:11]([NH2:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH3:10][C:2]1[O:18][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][C:3]=1[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: NC(=O)c1ccccc1
Reactant: COC(=O)CC(=O)C(C)Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C
Temperature: 90 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A 500-ml 4-necked flask equipped with a mechanical stirrer, a thermometer, a Claisen head with a condenser and a receiver connected to a cold trap and a vacuum controller was charged with 52.26 g of crude methyl 4-bromo-3-oxovalerate (ca. 0.250 mol) and 46.5 g of benzamide. A vacuum of 400 mbar was applied and the suspension was stirred at 90° C. for 18 h. After ca. 3 h the suspension had become a clear orange oil. After cooling to rt 300 ml of methanol and 1.0 g of p-toluenesulfonic acid monohydrate were added and the brown solution was stirred at reflux (ca. 73° C.) for 1 h. After this time 50 ml of methanol were distilled off, 50 ml of methanol were added and the mixture was heated at reflux for additional 30 min. After cooling and rotary evaporation (50° C., 8 mbar, 30 min), the residue was treated under argon with 150 ml of toluene and 125 ml of sat. aqueous sodium bicarbonate solution. The resulting suspension was stirred in an ice bath for 1 h, the precipitated benzamide was filtered off with suction and the filter cake was washed twice with a small amount of ice-cold toluene and water. The combined aqueous phases were extracted in a separatory funnel with 100 ml of toluene. Thereafter the combined organic phases were washed twice with 30 ml, a total of 60 ml of deionized water, dried (Na2SO4) and rotary evaporated (50° C., 8 mbar,1 h) to give 49.22 g of crude Methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate (theor. amount 57.81 g) as a yellow oil, which was used without purification in the next step.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][N:12]=[C:11]2[S:15]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:11]([S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:17])=[N:12]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCCl)cccc12
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCCl)cccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
A mixture of 7-(3-chloro-propoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.7 g, 1.75 mmoles), 3-chloro-benzylbromide (0.28 mL, 2.17 mmoles), and cesium carbonate (0.7 g, 2.17 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 10 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.87 g, 1.66 mmoles).
Reaction SMILES: O1CCC1.Br[CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1.[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O.CN(C)C=O>[N:13]([CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1)=[N+:14]=[N-:15]
Reactant: OCC1(CBr)COC1
Reactant: [N-]=[N+]=[N-]
Agent: C1COC1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1(CO)COC1

Procedure:
The oxetane of the present invention has the formula: ##STR1## The oxetane of Formula I, 3-azidomethyl-3-nitratomethyloxetane (ANMO), is synthesized using 3-bromomethyl-3-hydroxymethyl oxetane (BMHMO) as the starting material. Reaction of 3-bromomethyl-3-hydroxymethyloxetane with sodium azide (NAN3) in acetone or dimethylformamide (DMF) gives the corresponding 3-azidomethyl-3-hydroxymethyloxetane in essentially quantitative yield. Subsequent reaction of 3-azidomethyl-3-hydroxymethyloxetane with acetyl nitrate gives the oxetane AMNO.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:20](=[O:22])[CH3:21])[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[O:7][C:6](=[O:23])[CH:5]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:20](=[O:22])[CH:21]=[CH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])=[CH:11][CH:12]=2)[O:7][C:6](=[O:23])[CH:5]=1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(C)cc(=O)oc12
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-(3-methylbut-2-enyloxy)-8-acetylcoumarin (2.14 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 1.34 g of product m.p. 114-16° C., 1H-NMR (CDCl3) δ: 1.69 (s, 3H); 1.72 (s, 3H); 2.44 (d, 3H, J=1.22 Hz); 4.65 (d, 2H, J=6.5 Hz); 5.34-5.38 (m, 1H); 6.16 (d, 1H, J=1.2 Hz); 6.95 (d, 1H, J=8.8 Hz); 7.00 (d, 1H, J=18 Hz); 7.10 (d, 1H); 7.30-7.40 (m, 3H); 7.45-7.52 (m, 12H); 7.61 (d, 1H, J=8.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:5]([CH:6]=[O:7])=[C:4]([OH:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C=O)C>[Cl:10][C:8]1[CH:9]=[C:2]([Cl:1])[CH:3]=[C:4]([O:11][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cc(Cl)cc1OCc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
A solution of 13.77 g (72.5 mmol) of 4,6-dichloro-2-hydroxybenzaldehyde in 100 ml of DMF was stirred and 12.02 g (87 mmol) of K2CO3 was added. This mixture was heated to ~70° C. for 60 minutes, then 11.7 ml of 4-fluorobenzyl bromide was added. The resulting solution was stirred at 70° C. for 3.5 hours, then this was poured onto ice H2O (1.5 1), filtered and washed with H2O, and recrystallized from Et2O/petroleum ether. Yield: 17.88 g (83%) of off-white crystals, m.p. 107°-108° C.
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH3:44][O:45][C:46]1[CH:51]=[C:50]([C:52]([OH:54])=O)[CH:49]=[C:48]([N:55]2[CH2:59][CH2:58][CH2:57][C:56]2=[O:60])[N:47]=1.[CH:61]12[CH2:67][CH:64]([CH2:65][CH2:66]1)[CH2:63][CH:62]2[NH:68][C:69](=[O:84])[C@H:70]([CH3:83])[CH2:71][C@H:72]([OH:82])[C@@H:73]([NH2:81])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>>[CH2:74]([C@H:73]([NH:81][C:52]([C:50]1[CH:49]=[C:48]([N:55]2[CH2:59][CH2:58][CH2:57][C:56]2=[O:60])[N:47]=[C:46]([O:45][CH3:44])[CH:51]=1)=[O:54])[C@@H:72]([OH:82])[CH2:71][C@H:70]([C:69](=[O:84])[NH:68][CH:62]1[CH2:63][CH:64]2[CH2:67][CH:61]1[CH2:66][CH2:65]2)[CH3:83])[C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1
Reactant: COc1cc(C(=O)O)cc(N2CCCC2=O)n1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: COc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCC2=O)n1

Procedure:
Prepared in an analogous manner to E6, from 2-methoxy-6-(2-oxopyrrolidin-1-yl)pyridine-4-carboxylic acid (D58) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>>[N:14]1([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1
Reactant: C1CSCCN1
Reactant: N#Cc1ccc(F)c2ccccc12
Product: N#Cc1ccc(N2CCSCC2)c2ccccc12
Yield: 20.2 %

Procedure:
The title compound (6 mg, 20% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and thiomorpholine (48 mg, 0.468 mmol).