Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:13][C:14](=[O:16])[CH3:15].[Cl-].[NH+]1C=CC=CC=1>Cl.C(OCC)(=O)C>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:13][C:14](=[O:16])[CH3:15]
Reactant: COc1ccc([N+](=O)[O-])c(CC(C)=O)c1F
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Temperature: 180 °C
Reaction time: 1.25 h
Yield: 96 %

Procedure:
A mixture of 1-(2,3-difluoro-6-nitrophenyl)-propan-2-one (183 g) and potassium carbonate (100 g) in methanol (1 L) was heated at reflux for 3 h. The reaction mixture was then cooled and concentrated in vacuo to remove most of the methanol. The residue was diluted with ethyl acetate (1 L), filtered and washed with water. The separated aqueous layer was neutralized with 2N HCl and extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give a brown solid. The solid was triturated with diethyl ether and filtered to provide 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one (121 g, 71%) as a yellow solid. LC/MS; (M+H)+=228.2. N. A mixture of 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one from previous step (454 mg, 21 mmol) and pyridinium chloride (0.9 g, 7.8 mmol) was stirred at 180° C. for 75 min. The reaction was cooled to room temperature, diluted with 1N HCl (3 mL) and ethyl acetate (10 mL) and filtered. The filtrate was washed with brine (2×), dried and concentrated in vacuo to give 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (410 mg, 96%) as a grey solid, which was used without further purification for the next step. LC/MS; (M+H)+=214. 1HNMR (CDCl3): δ 2.37 (s, 3H), 4.22 (s, 2H), 6.95 (dd, 1H), 7.95 (d, 1H, J=9.35 Hz). O. 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one from previous step (50 g, 0.234 mol) was added to 2 liter round bottom flask. Water (1 L) was added, and the yellow suspension was stirred at RT. Sodium dithionite (225 g, 5.5 eq) was added in one portion and the reaction mixture was stirred and kept <30° C. until HPLC analysis indicated no starting material remained (typically less than 1 hour). Upon completion, the reaction mixture was cooled to 0° C. and the tan solid product was collected by vacuum filtration. The wet product was dried at <50° C. under house vacuum to afford 4-fluoro-2-methyl-1H-indol-5-ol (31.4 g, 81% yield) which was isolated as a tan crystalline powder. The material had an HPLC purity of >99.8. 1H NMR (CDCl3, 400 MHz) δ 7.8 (s, 1H), 6.9-6.7 (m, 2H), 6.2 (s, 1H), 4.7 (s, 1H), 2.4 (s, 3H). 13C NMR (CDCl3, 100MHz) δ 145.7, 143.4, 137.5, 136.7, 134.4, 120.1, 112.7, 106.8, 95.4, 13.3.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])[C:10](=[O:16])[N:11]1[CH2:15][CH2:14][S:13][CH2:12]1)(C)(C)C>C(OCC)(=O)C>[ClH:1].[NH2:8][CH:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])[C:10]([N:11]1[CH2:15][CH2:14][S:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(=O)N1CCSC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(Cc1ccccc1F)C(=O)N1CCSC1

Procedure:
HCl was bubbled into a solution of [1-(2-fluoro-benzyl)-2-oxo-2-thiazolidine-3-yl-ethyl]-carbamic acid tert-butyl ester (0.39 g, 1.1 mmol) in ethyl acetate (15 mL). The solution was concentrated, the residue was triturated in ether, the solid was filtered and dried (0.27 g, 84%, mp 217-218° C.).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])[C:14]3=[O:27])[CH:10]=[N:9]2)=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][O:30][CH2:31][CH2:32]Br>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:32][CH2:31][O:30][CH3:29])[C:14]3=[O:27])[CH:10]=[N:9]2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3O)C2=O)cn1
Reactant: COCCBr
Product: COCCOc1ccccc1CN1CC(=O)N(c2cnn(Cc3c(C)noc3C)c2)C1=O
Yield: 19 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(2-hydroxybenzyl)imidazolidine-2,4-dione (example 10-11) and 2-bromoethyl methyl ether. Yield 19%. 1H NMR (DMSO, 400 MHz): δ2.11 (s, 3H), 2.08 (s, 3H), 3.25 (s, 3H), 3.64 (t, J=3.6, 2H), 4.00 (s, 2H), 4.11 (t, J=3.2, 2H), 4.27 (s, 2H), 5.17 (s, 2H), 6.90 (m, 1H), 7.00 (m, 1H), 7.26 (m, 2H), 7.76 (s, 1H), 8.15 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.1 uM.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]4[S:19][C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[CH:27](Cl)[O:28]C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[C:20]1([C:18]2[S:19][C:12]3[C:11]([NH:10][C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[NH:1][CH:2]=[C:3]5[CH:27]=[O:28])=[N:16][CH:15]=[N:14][C:13]=3[CH:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1c[nH]c2ccc(Nc3ncnc4cc(-c5ccccc5)sc34)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of (1H-Indol-5-yl)-(6-phenyl-thieno[3,2-d]pyrimidin-4-yl)-amine (481 mg, 1.4 mmol) in 3 mL of methylene chloride in a 3-neck flask with dropping funnel under nitrogen at 0° C. was added titanium tetrachloride (461 mL, 4.2 mmol) dropwise. The mixture was stirred for 30 minutes and then dichloromethoxy methane (380 mL, 4.2 mmol) was added dropwise. The reaction was warmed to room temperature and concentrated in vacuo. The resulting residue was pre-absorbed onto silica gel (10 gm) and purified by flash chromatography using a 5% methanol/methylene chloride to afford the title compound in 92% yield. RP18-HPLC RT: 4.80 minutes; API MS: 371.20 (M+1); MP: 174-175° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(Cl)Cl.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH:35]1[CH3:40])[CH3:33].[BH4-].[Na+]>CC(O)=O>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:28][CH:27]=2)[CH2:36][CH:35]1[CH3:40])[CH3:33]
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CCN1CCNCC1C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccccc3)cc2)CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (86 mg, 0.23 mmol) in dryness DCM (15 mL) was added HOAc followed by 1-ethyl-2-methylpiperazine (90 mg, 0.7 mmol), after the addition the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. Sodium borohydride (85 mg, 1.4 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC to give the title compound as white solid (90 mg, yield 71%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.30 (t, 3H), 1.42 (m, 3H), 3.23 (s, 1H), 3.47-3.56 (m, 6H), 3.80 (t, 2H), 4.46 (m, 3H) 4.91 (m, 10H), 7.20-7.29 (m, 3H), 7.30-7.32 (m, 3H), 7.46-7.48 (m, 3H), 7.59 (m, 1H), 7.69 (t, 1H). LC-MS (ESI) m/z: 552 (M+1)+.
Reaction SMILES: Br.[CH3:2][C:3]1[NH:4][CH:5]=[C:6]([C:8](=O)[CH2:9][Br:10])[N:7]=1.C(=O)(O)[O-].[Na+].CC(C)=O.[C:21]([NH:24][C:25]([NH2:27])=[S:26])(=[NH:23])[NH2:22]>O>[BrH:10].[NH:24]([C:25]1[S:26][CH:9]=[C:8]([C:6]2[N:7]=[C:3]([CH3:2])[NH:4][CH:5]=2)[N:27]=1)[C:21]([NH2:23])=[NH:22]
Reactant: Cc1nc(C(=O)CBr)c[nH]1
Reactant: N=C(N)NC(N)=S
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc(-c2csc(NC(=N)N)n2)c[nH]1
Yield: 79.3 %

Procedure:
2.8 g (9.86 mmol) of 1-(2-methyl-4-imidazolyl)-2-bromo ethanone hydrobromide was dissolved in 10 ml water. Saturated sodium bicarbonate solution was added to pH 10 and the resultant solid was collected by filtration and washed with 15 ml water. The dried free base was heated at reflux in 50 ml acetone. To the refluxing clear acetone solution was added 1.2 g (9.86 mmol) of amidinothiourea. Solution occurred immediately and within a minute a solid began to form. After 1 hour reflux the slurry was cooled and the solid was collected by filtration and was washed with acetone followed by ether to give 2.37 g (79%) of 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole hydrobromide, mp 158° (dec.); nmr (DMSO-d6) (δ): 7.71 (s shoulder on broad s, 1H); 7.56 (broad s, 4H); 4.32 (s, 1H); 2.51 (s, 3H); calcd. for C8H10N6S.HBr: C, 31.69; H, 3.66; N, 27.72; found: C, 31.46; H, 4.30; N, 27.28.
Reaction SMILES: Br.Br.[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.[O-2].[Ca+2].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[C:25]=[S:26]>CO>[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][NH:21][C:25]([NH:24][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[S:26])[CH2:18][CH2:19]1
Reactant: COc1ccc(N=C=S)cc1
Reactant: NCC1CCN(CC2COc3ccccc3O2)CC1
Agent: Br
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Product: COc1ccc(NC(=S)NCC2CCN(CC3COc4ccccc4O3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.4 parts of (1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinemethanamine dihydrobromide, 4 parts of calcium oxide and 80 parts of methanol was stirred for 3 hours at room temperature. Then there were added 5 parts of 1-isothiocyanato-4-methoxybenzene and the whole was stirred for 3 hours at room temperature. The whole was filtered and the filtrate was evaporated. The sticky residue was suspended in a mixture of 1,1'-oxybisethane and 2,2'-oxybispropane, the latter was decanted (the residue was set aside) and allowed to crystallize, yielding a first fraction of 1 part of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N'-(4-methoxyphenyl)thiourea (intermediate 91). The residue, which was set aside, yield a second fraction of 5 parts of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N'-(4-methoxyphenyl)thiourea (intermediate 91). Total yield: 6 parts (93.5%) of N-[[ 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N'-(4-methoxyphenyl)thiourea; mp. 147.9° C. (intermediate 91).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:21][C:20]2[C:19]([F:18])=[CH:26][CH:25]=[CH:24][C:23]=2[F:27])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncc(Cl)cc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
33 g of 5-chloro-2-nitropyridin-3-ol (Example 15A; 189 mmol, 1 equivalent) and 61.6 g of caesium carbonate (189 mmol, 1 equivalent) were initially charged in 528 ml of DMF, 40.4 g of 2,6-difluorobenzyl bromide (189 mmol, 1 equivalent) were added and the mixture was stirred at RT overnight. The reaction mixture was stirred into water/1N aqueous hydrochloric acid and the solid was filtered off, washed with water and air-dried. This gave 54.9 g (97% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[CH3:18][NH:19][CH3:20]>C(Cl)Cl.CN(C)C=O>[CH3:18][N:19]([CH3:20])[C:4](=[O:5])[C:3]1[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(Br)ccc1F
Reaction time: 3 h

Procedure:
A suspension of 2-fluoro-5-bromobenzoic acid (680 mg, 3.10 mmol) in methylene chloride (20 ml) was treated with oxalyl chloride (0.35 ml, 4.04 mmol), followed by four drops of N,N-dimethylformamide. The resulting clear solution was stirred for about three hours. The solvents were removed in vacuo and the residue was redissolved in methylene chloride and treated with dimethylamine (4.6 ml, 9.3 mmol). Stirring was continued for 18 hours. The reaction mixture was diluted with methylene chloride, and washed with saturated sodium bicarbonate and brine. The organic fraciton was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title product was further purified by liquid chromatography.
Reaction SMILES: [NH4+:1].[OH-].[Br-].[CH2:4]([N+:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9]C=1)[CH:5]=[CH2:6].O>C(O)C>[CH2:6]([NH:1][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:7][CH2:4][CH:5]=[CH2:6])[CH:5]=[CH2:4]
Reactant: [NH4+]
Reactant: C=CC[n+]1csc2ccccc21
Agent: [Br-]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCNc1ccccc1SSc1ccccc1NCC=C
Reaction time: 96 h

Procedure:
NH4OH (28° Be, 100 ml) was added to N-allylbenzothiazolium bromide (10 g, 0.04 mole) in ethanol (100 ml). The resulting solution was held four days at room temperature, then poured into cold water (500 ml) and extracted twice with ethyl ether (2×100 ml). The organic solution was dried over anhydrous Na2SO4, then evaporated to dryness. The oily residue was purified by column chromatography silica gel, eptane:CH2Cl2 1:1) to give the product (yield 5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])([CH3:17])[C:7](=[O:16])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][C:3]=1[NH:19][C:20](=O)/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29].CC(O)C.Cl>O>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[CH:22]=[CH:21]/[C:20]1[NH:19][C:3]2=[CH:4][C:5]3[C:6]([CH3:18])([CH3:17])[C:7](=[O:16])[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]=3[CH:10]=[C:2]2[N:1]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)/C=C/c3ccccc3N)c(N)cc21
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(/C=C/c4ccccc4N)nc3cc21
Yield: 93.2 %

Procedure:
(E)-N-(6-Amino-3,3-dimethyl-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-3-(2-amino-phenyl)-acrylamide (0.82 g) is dissolved in water, 2-propanol and concentrated hydrochloric acid and heated for 3 h under reflux. After re-cooling the mixture is concentrated in vacuo. The residue is taken-up in EtOAc and saturated K2CO3 solution. After an aqueous work-up the desired compound (0.73 g) is obtained as a yellow solid. A small amount was treated with hydrochloric acid (2 N) to give the hydrochloric salt which precipitated in a pure form.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])[NH:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:5][CH:4]=1>Cl>[NH:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:4][CH:5]=2)=[O:25])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCNCC1

Procedure:
tert-butyl 4-(3-(4-(trifluoromethyl)phenyl)ureido)piperidine-1-carboxylate (1.6 g, 4.13 mmol) was dissolved in HCl solution (2 M, MeOH, 100 mL). The resulting solution was refluxed for 2 h. The solvent was removed under vacuo and the crude was basified to pH 12 by NaOH solution (6N). The final precipitates (0.9 g, 3.13 mmol, 78%) were filtered and dried under high vacuum. The final product (PTU/2) was served as a scaffold for the following urea inhibitors synthesis. 1H NMR (d6-DMSO, 300 Mhz): ∂ 8.77 (s, 1H), 7.57 (s, 4H), 6.30 (d, J=7.8 Hz, 1H), 3.55 (m, 1H), 2.91 (d, J=12.6 Hz, 2H), 2.48 (d, J=11.1 Hz, 2H), 1.77 (d, J=11 Hz, 2H), 1.22 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][CH2:12][S:13]([NH2:16])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].O>N1C=CC=CC=1>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:17][CH:10]([CH2:11][CH2:12][S:13](=[O:15])(=[O:14])[NH2:16])[CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NS(=O)(=O)CCC(O)COCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(CCS(N)(=O)=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of hydroxyl-sulfonamide 5 (77 g, 0.30 mol) in pyridine (730 mL, 9.5 vol) was cooled to <10° C. in a 2 L round bottom flask. Tosyl chloride (56.6 g, 0.30 mol) is added to the solution over 5 minutes maintaining the internal temperature below 10° C. The reaction was allowed to warm to room temperature with stirring overnight. The completed reaction was poured into water (10 vol, 770 mL) to give an orange solution which was extracted with iPrOAc/MTBE (1:1, 2×1.5 L). The combined organics were washed with brine (2×500 mL), aqueous HCL (2M, 2×500 mL) then brine (1×500 mL). The organic portion was dried (Na2SO4), filtered and evaporated to give sulfonate 6 as an orange oil (78 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](=O)[CH3:16])[O:7][CH2:6]1)[CH2:2][CH3:3].[CH2:21](OCC)C>>[CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15]([CH3:21])=[CH2:16])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1COc2cccc(C(C)=O)c2C1
Reactant: CCOCC
Product: C=C(C)c1cccc2c1CC(N(CCC)CCC)CO2

Procedure:
3-Dipropylamino-5-acetylchroman (Example 7; 0.40 g, 1.45 mmol) was dissolved in dry diethyl ether (2.0 ml) and this solution was added to the previously formed Wittig-reagent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[CH2:11].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH2:11][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: c1c[nH]cn1
Reactant: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(C)cc1
Solvent: CCO
Product: Cc1ccc(C(Cn2ccnc2)C(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
A mixture of 1-(2,4-dichlorophenyl)-2-(4-methylphenyl)propen-1-one (660 mg) and imidazole (770 mg) in ethanol (10 ml) were stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield a gum. The gum was chromatographed on silica gel in methanol: dichloromethane (1:24) to yield 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-(4-methylphenyl)propan-1-one (450 mg) (Found: C, 78.25; H, 5.88; N, 9.53; C19H18N2O requires C, 78.62; H, 6.21; N, 9.66) which was treated with ethereal hydrogen chloride to yield the hydrochloride salt of 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-(4-methylphenyl)propan-1-one m.p. 92°-96° C. (Found: C, 54.79; H, 4.33; N, 6.59; C19H17Cl3N2O.H2O requires C, 55.16; H, 4.38; N, 6.77) having the formula: ##STR25##
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[O:18][C:19]=3[CH:20]([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:31])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CC(C)=O>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][O:31][C:5]1[CH:6]=[CH:7][C:8]2[C:9]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[O:18][C:19]=3[CH:20]([CH3:22])[CH3:21])=[N:10][O:11][C:12]=2[C:4]=1[CH2:1][CH:2]=[CH2:3])[CH3:44]
Reactant: C=CCc1c(O)ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1c(OCC(=O)OCC)ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc12
Reaction time: 20 h
Yield: 80.7 %

Procedure:
The obtained 7-allyl-6-hydroxy-3-[2-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-1,2-benzisoxazole (45 mg, 0.098 mmol) and potassium carbonate (20 mg, 0.147 mmol) was suspended in acetone (5.0 mL). An acetone solution of ethyl bromoacetate (25 mg, 0.147 mmol) was added to the suspension while cooling with ice. The mixture was allowed to room temperature, and stirred for 20 hours. After insoluble was filtered off, the filter cake was washed with acetone. The filtrate and washings were combined, and concentrated. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (4/1) to give the desired compound (43 mg) as colorless oil (yield 80%).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2=[O:21].Br[CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][O:26][CH3:27].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:9][O:8][C:7]1[C:2]([O:1][CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][O:26][CH3:27])=[C:3]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:4]=[CH:5][C:6]=1[O:10][CH3:11]
Reactant: COCC(C)(C)CBr
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Temperature: 100 °C

Procedure:
Compound 303 (0.02 g, 0.07 mmol) and 1-bromo-3-methoxy-2,2-dimethyl-propane (0.12 g, 0.56 mmol) were dissolved in dry DMF (0.8 mL). K2CO3 (0.1 g, 0.68 mmol) were added. The suspension was heated at 100° C. for 18 h. H2O was added and the mixture was extracted with EtOAc (×2). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC afforded the title compound as an oil.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH2:9]([C:12]1[C:13]([OH:24])=[C:14]([CH:19]=[C:20]([Cl:23])[C:21]=1[NH2:22])[C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH2:11]>CC(C)=O>[CH2:9]([C:12]1[C:13]([O:24][CH3:1])=[C:14]([CH:19]=[C:20]([Cl:23])[C:21]=1[NH2:22])[C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH2:11]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(N)c(Cl)cc(C(=O)OC)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1c(N)c(Cl)cc(C(=O)OC)c1OC

Procedure:
A mixture of potassium carbonate (19 g), methyl iodide (8 g) and the phenolic compound of step 2 above (3.4 g) in acetone (100 ml) is stirred under reflux for about 6.4 hours. The mixture is partitioned between CH2Cl2 and H2O, and the organic layer is separated and washed with 10% aqueous HCl, dried (MgSO4) and evaporated affording an oil which chromatographed on silica gel affording the desired product which is used in the next step.