Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[C:28]([NH2:31])=[N:29][CH:30]=1)[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[F:36][C:37]([F:44])([CH:41]([F:43])[F:42])[C:38](Cl)=[O:39]>>[F:35][C:2]([F:1])([C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[C:28]([NH:31][C:38](=[O:39])[C:37]([F:44])([F:36])[CH:41]([F:43])[F:42])=[N:29][CH:30]=1)[C:3]([F:23])([F:24])[C:4]([F:21])([F:22])[C:5]([F:19])([F:20])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1ncc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(F)(F)C(F)F
Product: O=C(Nc1ncc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1[N+](=O)[O-])C(F)(F)C(F)F

Procedure:
5-(Perfluorooctyl)-3-nitro-2-aminopyridine is reacted with 2,2,3,3-tetrafluoropropionyl chloride to obtain 5-(perfluorooctyl)-3-nitro-2-(2,2,3,3-tetrafluoropropionamido)pyridine, which when hydrogenated yields 6-(perfluorooctyl)-1-hydroxy-2-(1,1,2,2-tetrafluoroethyl)-1H-imidazo(4,5-b)pyridine.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:4]1=[O:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C([O-])(O)=O.[Na+]>ClCCl>[O:18]=[C:4]1[CH:3]([CH2:2][O:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:7][CH2:6][N:5]1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C(CO)CCN1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCN(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 113.6 %

Procedure:
A mixture of 3-hydroxymethyl-1-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one obtained in step 3 (0.17 g, 0.6 mmol), dichloromethane (8 ml) and triethyl amine (0.085 g, 0.84 mol) was cooled to 0° C. and stirred for 15 min at that temperature. Methane sulfonyl chloride (0.090 g, 0.78 mmol) was added to the mixture over a period of 5 min and the reaction mixture was stirred for 1.5 hrs at 10-15° C. To this reaction mixture saturated NaHCO3 solution (10 ml) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated brine solution, dried over Na2SO4 and evaporated to obtain methanesulfonic acid 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl ester as a brown oil (0.23 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([OH:21])=O)[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:21])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A suspension of 5-chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.1 g, 0.00963 mole) and 1,1'-carbonyldiimidazole (1.56 g, 0.00963 mole) in tetrahydrofuran (100 ml) was refluxed for 3.25 hours under nitrogen, cooled to room temperature, a stream of nitrogen was bubbled through the solution for 0.75 hr then a solution of dipropylamine (2.92 g, 0.0289 mole) in tetrahydrofuran (4 ml) was added. The reaction mixture was refluxed overnight under nitrogen and evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate, the layers were separated, sodium chloride was added to the aqueous layer and it was re-extracted with ethyl acetate. The combined organic layers were washed twice with a saturated sodium chloride solution, dried over magnesium sulfate, charcoaled, filtered and evaporated under reduced pressure to a solid (3.7 g, 95% yield). The solid was recrystallized from isopropyl alcohol/water and dried under high vacuum at 58° C. to give 2.11 g of title compound, mp 170°-173.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[Cl:43])[NH2:39]>CN(C=O)C>[Cl:35][C:36]1[CH:37]=[C:38]([NH:39][C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:40]=[CH:41][C:42]=1[Cl:43]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(O)c1)Nc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a solution of 3-hydroxyphenyl acetic acid (5.0 g, 0.03 mol) in DMF (50 ml) was added 1-hydroxybenzotriazole hydrate (4.86 g, 0.03 mol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.9 g, 0.036 mol). To the flask was added 3,4-dichloroaniline (4.86 g, 0.03 mol). The reaction was allowed to stir overnight. Solvent was removed and the reaction was diluted with ethyl acetate. The reaction mixture was washed with 1N HCl, 10% sodium carbonate solution, and brine. The organic layer was dried over MgSO4, filtered and concentrated to provide the title compound (5.5 g, 62% yield): ES-MS (m/z) 296 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[F:12][C:13]1[CH:25]=[CH:24][C:16]([CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:15]([C:26]([F:29])([F:28])[F:27])[CH:14]=1>>[F:12][C:13]1[CH:25]=[CH:24][C:16]([CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:2]3[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[CH2:22][CH2:23]2)=[C:15]([C:26]([F:29])([F:27])[F:28])[CH:14]=1.[CH2:3]([OH:11])[CH2:2][CH2:13][CH3:14]
Reactant: Cn1nc(Br)c(=O)n(C)c1=O
Reactant: Fc1ccc(CC2CCNCC2)c(C(F)(F)F)c1
Product: CCCCO
Product: Cn1nc(N2CCC(Cc3ccc(F)cc3C(F)(F)F)CC2)c(=O)n(C)c1=O
Yield: 43 %

Procedure:
The compound 77 (oil) is prepared from the triazine 1b and from the intermediate 9b according to the synthesis method 1 in n-butanol (yield: 43%).
Reaction SMILES: [CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[CH:40]1([C:46]([OH:48])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C1CCC(N=C=NC2CCCCC2)CC1.C(OCC)C>ClCCl.C(OCC)(=O)C>[CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[CH2:42]1[CH2:43][CH2:44][CH2:45][CH:40]([C:46]([O-:48])=[O:47])[CH2:41]1
Reactant: O=C(O)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C([O-])C1CCCCC1
Temperature: 25 °C

Procedure:
To a mixed solution of maytansinol (103.2 mg. 0.183 m mole) and cyclohexanecarboxylic acid (140 mg, 1.094 m moles) in 5 ml of dry dichloromethane was added DCC (267 mg, 1.296 m moles), and after stirring at room temperature for a short while until insolubles began to separate out, DMAP (50.8 mg, 0.416 m mole) was added. The mixture was stirred at room temperature overnight. Then, the insolubles were filtered off, the filtrate washed with 0.5 N-HCl (ca. 10 ml) and saturated aqueous sodium hydrogen carbonate (ca. 10 ml) in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was chromatographed on a column of silica gel (75 g.). Elution was carried out with ethyl acetate, the eluate being collected in 16 g. fractions, and fractions No. 14 through No. 30 were pooled and concentrated to remove the solvent, whereupon 59 mg of crude product was obtained. This crude product was dissolved in ethyl acetate, followed by addition of diethyl ether. By the above procedure there was obtained 24.3 mg of maytansinol 3-cyclohexanecarboxylate as crystals melting at 202°-106° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[N:6]([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:19]=4[CH:20]=3)[CH:13]=[CH:12][N:11]=2)[C:5](=[O:28])[NH:4][C:3]1=[O:29].[H][H]>CO.[Pd]>[CH3:1][C:2]1([CH3:30])[N:6]([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:19]=4[CH:20]=3)[CH:13]=[CH:12][N:11]=2)[C:5](=[O:28])[NH:4][C:3]1=[O:29]
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc3cc([N+](=O)[O-])ccc3s2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc3cc(N)ccc3s2)n1
Yield: 26.8 %

Procedure:
5,5-Dimethyl-1-(2-(4-(5-nitrobenzothiophen-2-yl)pyrimidin-2-ylamino)ethyl)imidazo-lidine-2,4-dione (1.2 g, 2.82 mmol) was suspended in methanol (120 mL), 20% palladium on carbon (120 mg) was added, and the mixture placed on a Parr shaker under 50 psi of hydrogen gas for a total of 7 days. The reaction mixture was filtered through a thick bed of celite and washed with methanol (5×50 mL) to give a bright yellow solution. The crude material was purified by flash chromatography (MeOH/DCM) to give the title compound as a light yellow powder (300 mg, 63%). MS (M+H)+ 411.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:11]([CH2:30][CH2:31][CH3:32])[CH:10]=1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:17][C:16]=1[CH2:15][CH2:14][O:13][C:12]1[CH:28]=[CH:29][C:9]([OH:8])=[CH:10][C:11]=1[CH2:30][CH2:31][CH3:32]
Reactant: CCCc1cc(OCc2ccccc2)ccc1OCCc1nc(-c2ccccc2)oc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cc(O)ccc1OCCc1nc(-c2ccccc2)oc1C
Yield: 78 %

Procedure:
A solution of 4-[2-(4-benzyloxy-2-propylphenoxy)ethyl]-5-methyl-2-phenyloxazole. (1.2 g, 2.8 mmol) in THF (50 mL) was treated with 5% Pd/C (0.15 g) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated. The crude product was purified by radial chromatography using 15% ethyl acetate in hexanes to give a tan solid (0.74 g, 78%): 1H. NMR (400 MHz, CDCl3) δ 7.99 (dd, J=7.8 Hz, 2.4 Hz, 2H), 7.44-7.39 (m, 3H), 6.65-6.47 (m, 3H), 4.11 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.43 (t, J=7.8 Hz, 2H), 2.39 (s, 3H), 1.46 (q, J=7.2 Hz, 2H), 0.85 (t, J=7 Hz, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=O)=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[N:6]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(CC)CC)C>ClCCl>[CH2:44]([O:51][NH:52][C:11]([C:10]1[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[N:6][C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[C:8]([F:14])[CH:9]=1)=[O:13])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NOCc1ccccc1
Reactant: CN1CCN(c2nc(NC3CC3)c(C(=O)O)cc2F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2nc(NC3CC3)c(C(=O)NOCc3ccccc3)cc2F)CC1
Yield: 59.8 %

Procedure:
Following the procedure of Example 1-2, the reaction of 2-cyclopropylamino-5-fluoro-6-(4-methylpiperazinyl)-3-pyridinecarboxylic acid (Example H-2, 200 mg, 0.67 mmol) and HOBT (99.5 mg, 0.74 mmol) with EDCI (154.6 mg, 0.81 mmol) in dichloromethane (10 mL) followed by adding O-benzylhydroxylamine hydrochloride (0.81 mmol) and triethylamine (0.113 mL. 0.81 mmol) gave a crude oil. Purification of the oil by flash chromatography on a silica gel column with 5% of MeOH in dichloromethane provided 160 mg of the title compound as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)(=[O:21])=[O:20])[CH2:9][CH2:8][CH2:7]2)(=O)[CH3:2].[CH2:40]([NH2:44])[CH:41]([CH3:43])[CH3:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH:17]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=2)(=[O:21])=[O:20])[CH2:16][C:15]([NH:14][CH:10]2[C:11]3[C:6](=[CH:5][C:4]([CH:1]([NH:44][CH2:40][CH:41]([CH3:43])[CH3:42])[CH3:2])=[CH:13][CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:39])=[CH:33][CH:34]=1
Reactant: CC(C)CN
Reactant: CC(=O)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CNC(C)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of N-(6-acetyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(4-fluoro-phenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (161 mg, 0.286 mmol, 1.0 eq), isobutylamine (Aldrich, 126 mg, 1.72 mmol, 6.0 eq), NaBH(OAc)3 (Aldrich, 182 mg, 0.858 mmol, 3.0 eq) and glacial HOAc (J, T. Baker, 34 mg, 0.572 mmol, 2.0 eq) in ClCH2—CH2Cl (3 mL) was stirred at RT for 5 days. The reaction was quenched with saturated NaHCO3 (60 mL). The crude was extracted with CH2Cl2 (60 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-10% MeOH—CH2Cl2) afforded the title compound as a colorless thin film. MS (ESI, pos. ion) m/z: 620 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17]C(=O)N(C)C)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)CCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH2:17]
Reactant: CN(C)C(=O)Nc1ccc(OCCc2ccccc2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Cl
Product: Nc1ccc(OCCc2ccccc2)c(Cl)c1
Yield: 140.7 %

Procedure:
A mixture of 3-[3-chloro-4-(phenethyloxy) phenyl]-1,1-dimethylurea (16.68 g; 0.0523 mol), n-butanol (300 ml) and 50% aqueous sodium hydroxide (50 ml) is refluxed for 1.5 hours, and then poured onto 500 ml crushed ice. The resultant mixture is extracted with ether (2×200 ml). The ether solution is washed with brine, dried over potassium carbonate and cooled in an ice bath. Dry hydrochloric acid gas is bubbled through the solution. The precipitated amine hydrochloride is collected to afford 10.46 g (0.0368 mol) of product, a white solid, m.p. 198°-204° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[O:20][N:19]=[C:18]([CH2:21][NH2:22])[CH:17]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[O:20][N:19]=[C:18]([CH2:21][NH:22][C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NCc1cc(-c2ccco2)on1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NCc1cc(-c2ccco2)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.5 %

Procedure:
To a solution of 7 mg of phenylacetic acid and 5 mg of C-(5-furan-2-yl-isoxazol-3-yl)-methylamine in DMF were added 8 mg of HOBt, 9 mg of EDC and 0.02 mL of TEA. After stirring at room temperature for 18 hrs, the reaction mixture was concentrated in vacuo. The concentrate was purified by preparative HPLC to produce 4 mg of the isoxazole derivative (Yield: 35%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[F:6][C:7]1[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([F:13])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:14][C:9]1[CH:8]=[C:7]([F:6])[CH:12]=[C:11]([F:13])[CH:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Oc1cc(F)cc(F)c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1cc(F)cc(F)c1

Procedure:
A solution of 1-bromobutane (11.0 g, 0.08 mol) in acetone (30 ml) was added dropwise to a stirred, refluxing mixture of 3,5-difluorophenol (9.1 g, 0.07 mol) and potassium carbonate (30 g, 0.2 mol) in acetone (200 ml). The stirred mixture was heated under reflux for 24 h (glc analysis revealed absence of starting material). The product was extracted into ether (twice), and the combined ethereal extracts were washed with water, 5% sodium hydroxide, water and dried (MgSO4). Most of the solvent was removed in vacuo, and after the removal of the final amount of solvent and the excess of 1-bromobutane at atmospheric pressure, the residue was distilled to yield a colourless liquid.
Reaction SMILES: [CH:1]1[C:2]2[CH:22]=[CH:21][C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH:13]=[CH:12][C:11]=3[C:3]=2[O:4][C:5]=1[C:6](OCC)=[O:7].[BH4-].[Li+].C1COCC1.Cl>O>[CH:1]1[C:2]2[CH:22]=[CH:21][C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH:13]=[CH:12][C:11]=3[C:3]=2[O:4][C:5]=1[CH2:6][OH:7]
Reactant: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2o1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2ccc3c4ccccc4ccc3c2o1
Yield: 90.3 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet tube with bubbler was added ethyl phenanthro[1,2-b]furan-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc., 7.9 g, 27.2 mmol), lithium borohydride (Aldrich, 0.65 g, 30 mmol) and dry THF (400 mL). The mixture was stirred at reflux for 6 h and then poured into H2O (1 L). The reaction mixture was acidified with 1N HCl and the resulting white solid and filtered, washed with additional H2O (1500 mL) then dissolved in CH2Cl2 (500 mL), dried (Na2SO4), filtered, concentrated to 200 mL and diluted to 500 mL with hexane. The resulting material was filtered, washed with hexane (100 mL) and placed in a vacuum oven overnight. A total of 6.1 g (90.1%) of phenanthro[1,2-b]furan-2-methanol, mp 125°-126° was obtained (C,H).
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.[NH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[OH:21]>C1COCC1>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[OH:21])=[O:5]
Reactant: Nc1cc(OCc2ccccc2)ccc1O
Reactant: O=C(O)CBr
Solvent: C1CCOC1
Product: O=C(CBr)Nc1cc(OCc2ccccc2)ccc1O
Yield: 505.7 %

Procedure:
Bromoacetic acid (13.9 g, 0.01 mole) and dicyclohexyldicarbodiimide (DCCD, 20.6 g, 0.01 mole) were added at room temperature under stirring to the amine ((b), 21.5 g, 0.01 mole) in THF (200 ml). After 1 hour the reaction mixture was filtered and the liquid evaporated to dryness under vacuum. The residue was crystallized from acetic acid (50 ml) to give the bromoamide ((c), 17 g, 50%) as white prisms. The product structure was confirmed by NMR analysis.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:18][C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]=[N:25][NH:26][CH:27]=5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Br[CH2:40][CH2:41][OH:42]>O.C(OCC)(=O)C>[CH:1]([N:4]1[C:8]([C:9]2[S:18][C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C:23]5[CH:27]=[N:26][N:25]([CH2:40][CH2:41][OH:42])[CH:24]=5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(-c3cn[nH]c3)cc1OCC2
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(-c3cnn(CCO)c3)cc1OCC2
Temperature: 110 °C
Yield: 39.6 %

Procedure:
A solution of 1-Isopropyl-5-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl]-1H-[1,2,4]triazole (0.23 g, 0.61 mmol) and cesium carbonate (0.40 g, 0.0012 mol) in N,N-dimethylformamide (1.8 mL, 0.023 mol) was stirred at room temperature for 5 minutes. 2-Bromoethanol (0.086 mL, 0.0012 mol) was added and the reaction was heated to 110° C. overnight. The mixture was cooled to room temperature. Ethyl acetate and water were added and the aqueous layer was extracted 3× with ethyl acetate. The organic phases were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 101.8 mg of 145 as a colorless solid. MS(ESI+) 422.1. 1H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.66 (d, J=8.2, 1H), 7.52 (s, 1H), 7.32 (dd, J=8.2, 1.6, 1H), 7.27 (d, J=1.5, 1H), 5.10-4.95 (m, 1H), 4.90 (t, J=5.3, 1H), 4.34 (t, J=5.0, 2H), 4.15 (t, J=5.6, 2H), 3.77 (q, J=5.5, 2H), 3.29-3.24 (m, 2H), 1.48 (d, J=6.5, 6H)
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[C:9]1([CH:19]=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>C(O)C>[C:9]1([CH:19]2[C:2]3[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=3[NH:21][C:22]3=[CH:26][CH:25]=[N:24][N:23]23)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1cccc2ccccc12
Solvent: CCO
Product: O=C1CCCC2=C1C(c1cccc3ccccc13)n1nccc1N2
Temperature: 25 °C
Yield: 44.4 %

Procedure:
A solution of 1,3-cyclohexanedione (0.11 g, 1 mmol), 1-naphthaldehyde (0.16 g, 1 mmol), and 3-aminopyrazole (0.11 g, 1.27 mmol) in ethanol (10 mL) were heated at 80° C. in a sealed 20 mL vial for 3 days. After the reaction mixture was allowed to cool to ambient temperature, the solvent was evaporated at reduced pressure and the resulting residue was chromatographed on silica gel, eluting with 5% ethanol/methylene chloride to provide 0.14 g (44%) of the title compound.
Reaction SMILES: [S:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][O:14]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][OH:23]>C(OCC)C.O=P(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][O:23][C@@H:15]1[O:14][C@@H:13]([CH2:12][O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:3])=[O:2])[CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Reactant: OCc1ccc(Cl)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3ccc(Cl)cc3Cl)O2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 81.8 %

Procedure:
To a solution of 1.34 g of 2-tosyloxymethyl-3,4-dihydro-2H-pyran in 25 ml of diethyl ether were added 1.06 g of 2,4-dichlorobenzyl alcohol, followed by a catalytic amount (2-3 drops) of phosphorus oxytrichloride. The mixture was then stirred at room temperature for 4 days, after which 3 drops of triethylamine were added to the mixture, which was then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel as in Example 1(a), to give 1.82 g of trans-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran (having the lesser polarity), 144 mg of cis-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran (having the greater polarity) and 200 mg of a cis/trans mixture.