Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:18](=[S:20])=[S:19].Cl.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CS(C)=O>[C:11]([C:7]1[CH:8]=[C:9]([CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])[C:18]([S:20][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[S:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: BrCc1ccccc1
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(C(=S)SCc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A flask was charged with 0.3 mol of 2,6-di-t-butylphenol and 150 ml of dimethylsulfoxide. To the flask, maintained at 10° C., was added dropwise an aqueous solution of 0.6 mol potassium hydroxide, followed by 0.3 mol carbon disulfide. The resulting reaction mixture was stirred at 10° C. for 1 hour and then allowed to warm to about 25° C. Concentrated hydrochloric acid (0.3 mol) was then added slowly to the reaction mixture, maintained at 0° C. Benzylbromide (0.3 mol) was then added and the reaction mixture heated at 50° C. for 1 hour. The reaction mixture was cooled, diluted with 600 ml ice water, and extracted with ether. The ether extracts were washed with water, dried over magnesium sulfate and evaporated to give the crude product. After recrystallization from hexane, the product melted at 110°-112° C. Elemental analysis of the product is tabulated in Table I. The product is believed to be novel.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].O.[NH2:14][NH2:15]>CCO>[CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:14][NH2:15])=[O:5]
Reactant: NN
Reactant: CCOC(=O)c1cccnc1C
Solvent: O
Solvent: CCO
Product: Cc1ncccc1C(=O)NN
Yield: 99.2 %

Procedure:
To a solution of ethyl 2-methylnicotinate (500 mg, 3.0 mmol) in EtOH (2.3 mL) was added hydrazine monohydrate (0.3 mL, 6.1 mmol). The reaction mixture was heated at reflux for 3 days and then concentrated to afford the desired product as a beige solid (450 mg, 98%). MS (ESI): mass calcd. for C7H9N3O, 151.1; m/z found, 152.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.57 (br s, 1H), 8.49 (dd, J=4.9, 1.8 Hz, 1H), 7.66 (dd, J=7.7, 1.7 Hz, 1H), 7.26 (ddd, J=7.7, 4.9, 0.5 Hz, 1H), 4.85-4.05 (bs, 2H), 2.50 (d, J=4.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:33])[N:10]3[CH2:25][CH:24]([O:26]C(=O)C(C)(C)C)[CH2:23][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](S(C)(=O)=O)[N:14]=2)=[CH:4][CH:3]=1.[C:34]1([O-:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:33])[N:10]3[CH2:25][CH:24]([OH:26])[CH2:23][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: [O-]c1ccccc1
Reactant: CC(C)(C)C(=O)OC1Cn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)c(=O)n2C1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(-c2ccc(F)cc2)c(-c2ccnc(Oc3ccccc3)n2)n2n1CC(O)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A solution of 2,2-dimethyl-propionic acid 6-(4-fluorophenyl)-7-(2-methane-sulfonyl-pyrimidin-4-yl)-5-oxo-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-2-yl ester, 35, (50 mg, 0.105 mmol) in THF (1 mL) is slowly cannulated into a solution of sodium phenolate in THF (1 mL) at 0° C. The cooling bath is removed and the reaction stirred at room temperature for 1 hour. The reaction is quenched with NH4Cl (sat. aq.) (500 μL). The reaction mixture is concentrated in vacuo and the residue diluted taken up in ethyl acetate (15 mL). The solution is washed with water (20 mL) and a 5% aqueous Na2CO3 (20 mL). The combined aqueous layers are extracted with ethyl acetate (25 mL) and brine (20 mL), dried, filtered and concentrated in vacuo. The crude material is purified over silica (100% ethyl acetate to 5% to 10% to 20% methyl alcohol/ethyl acetate) to afford 9 mg (21% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ8.43 (d, J=5.2 Hz, 1H), 7.46 (t, J=7.8 Hz, 2H), 7.31–7.27 (m, 3H), 7.19 (d, J=8.2Hz, 2H), 7.03 (t, J=8.6Hz, 2H), 6.80 (d, J=5.2 Hz, 1H), 5.41 (br s, 1H), 4.82 (m, 1H), 4.23 (d, J=12.4 Hz, 1H), 3.95–3.85 (m, 2H), 3.76 (dd, J=12.4, 4.4 Hz, 1H); HRMS m/z calcd for C22H18FN4O3 (MH+) 405.1363, found 405.1365.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]=1N1CCCC1.[O:28]1CCOCC1.Cl>CCCCCC.C(OCC)(=O)C>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=[O:28]
Reactant: BrCc1ccc2ccccc2c1
Reactant: C1COCCO1
Reactant: C1=C(N2CCCC2)CCc2ccccc21
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1CCc2ccccc2C1Cc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A mixed solution of 0.53 g (92.87 mmol) of 2-(bromomethyl)naphthalene, 20.36 g (102.16 mmol) of 1-(3,4-dihydronaphthalene-2-yl)pyrrolidine and 120 ml of dehydrated dioxane was stirred for 4 hours while heating and refluxing. After cooled down to room temperature, 100 ml of a 5% hydrochloric acid aqueous solution was dropwise added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic phase was dried on anhydrous sodium sulfate and filtered, and then the solvent was removed by distillation. A crude product obtained was refined by column chromatograph (silica gel: hexane/ethyl acetate=10/1) to obtain 16.05 g (yield: 60.5%) of 1-(naphthalene-2-ylmethyl)-3,4-dihydronaphthalene-2(1H)-one.
Reaction SMILES: C(SCCC#N)CCCCCCCCC.[CH2:16]([S:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:28])=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:34]O>CS(O)(=O)=O>[CH2:16]([S:26]([CH2:29][CH2:30][C:31]([O:33][OH:34])=[O:32])(=[O:27])=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCS(=O)(=O)CCC(=O)O
Reactant: OO
Agent: CCCCCCCCCCSCCC#N
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCS(=O)(=O)CCC(=O)OO
Temperature: 10 °C
Yield: 87.6 %

Procedure:
The product of Example 12 was converted to the corresponding carboxylic acid by alkaline hydrolysis followed by acidification and then to the corresponding sulfone carboxylic acid by oxidation in accordance with a procedure found in U.S. Pat. No. 3,857,875 to Brady et al. A stirred mixture of 5 g of 3-(n-decylsulfonyl)propionic acid and 50 mL of methanesulfonic acid was heated to 40°±3° C. The 3-(n-decylsulfonyl)propionic acid dissolved only partially in the methanesulfonic acid at this temperature. Then 2.04 g of 90% hydrogen peroxide was added dropwise via pipette over ten minutes. Before the addition of the hydrogen peroxide was completed, the reaction mixture became thick from precipitation of a solid. After the addition of the 90% hydrogen peroxide was completed, the heating of the reaction mixture was continued at 40°±3° C. until the reaction time totalled ninety minutes beginning at the start of the addition of the hydrogen peroxide. The reaction mixture was then cooled in an ice bath at 10° C. The solid was then filtered from solution using a coarse sintered-glass funnel, then transferred to a beaker containing 200 mL of ice water prepared from deionized water. The product was washed twice with ice water, filtered and dried to provide 4.63 g of the desired product (87.6% of theoretical based upon the weight of starting 3-(n-decylsulfonyl)propionic acid). The product was found to have 5.32% active oxygen. The product was stabilized with an equal weight of boric acid and put through a #30 polyethylene sieve which provided a particle size of less than 600 microns. The stabilized product contained 2.58% by weight active oxygen.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18](O)=[O:19])=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[F:15])=[C:4]([F:21])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)[N:40]=[N:39]C=2C=1.NN.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18]([NH:39][NH2:40])=[O:19])=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[F:15])=[C:4]([F:21])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)c(F)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)NN)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (70 mg, 0.195 mmol), EDCI (112 mg, 0.585 mmol), and HOBt (79 mg, 0.585 mmol) in DMF (3 mL) was stirred for 30 minutes. Hydrazine (19 mg, 0.585 mmol) was added followed by Et3N (0.082 mL, 0.585 mmol). After 3 hours, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to yield 64 mg (89%) desired product.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:58][O:59][CH3:60])[C:10]([NH:12][CH:13]2[C:56](=[O:57])[N:15]3[C:16]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:17]([CH:20]=P(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C=O.O1CCC[CH2:64]1.C(OCC)(=O)C>C(OCC)C>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:58][O:59][CH3:60])[C:10]([NH:12][CH:13]2[C:56](=[O:57])[N:15]3[C:16]([C:40]([O:42][CH:43]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[O:41])=[C:17]([CH:20]=[CH2:64])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Reactant: C1CCOC1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 12.5 h

Procedure:
A mixture of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-triphenylphosphoranylidenemethyl-3-cephem-4-carboxylate (syn isomer) (2.2 g), 36% aqueous formaldehyde (20 ml) and tetrahydrofuran (60 ml) were stirred at ambient temperature for 12.5 hours. After addition of ethyl acetate (100 ml) to the reaction mixture, the organic layer was separated out, washed with 10% hydrochloric acid and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diethyl ether, and chromatographed on silica gel using chloroform and then a mixture of chloroform and acetone (19:1 and 9:1 by volume) as an eluent. The fractions containing the desired compound were collected and evaporated to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (0.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[OH:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:13][CH2:14][CH2:15][CH2:16][O:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([CH2:8][OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1
Reactant: BrCCCBr
Reactant: COc1cc(O)c(Cl)cc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OCCCBr)c(Cl)cc1CO
Temperature: 75 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of 2-chloro-4-(hydroxymethyl)-5-methoxyphenol (intermediate 54; 0.5 g, 2.61 mmol), 1,3-dibromopropane (1.61 ml; 15.71 mmol) and potassium carbonate (737 mg; 5.23 mmol) in 12 ml acetone was heated to 75° C. in a sealed vessel and stirred for 16 hr. The solids were filtered and washed with acetone and the combined filtrates were concentrated to dryness and purified by preparative reversed-phase HPLC (hexane/EtOAc from 0 to 40%), affording the title compound (80%) as a light yellow oil.
Reaction SMILES: Cl.C([NH:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:16][CH2:15]1)=[O:12])(=O)C1C=CC=CC=1>[OH-].[Na+]>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH2:21][CH2:20][N:17]2[CH2:16][CH2:15][CH:14]([NH:13][C:11]([NH2:10])=[O:12])[CH2:19][CH2:18]2)=[CH:23]1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
1-benzoyl-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea hydrochloride (1.180 g.) was refluxed in 2 N sodium hydroxide solution (20 ml) for 1 hour. The reaction mixture was cooled and the title compound was filtered off, (0.678 g., 86%) m.p. 212.2° (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10]([OH:12])[CH3:11].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[NH:6])[O:12][CH2:10][CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Cl)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
An 100-mL round bottomed flask was charged with 3-chlorobenzonitrile (2.75 g, 20 mmol, 1 eq.), ethanol (1 g, 22 mmol, 1.1 eq.), HCl (4 N in dioxane, 20 ml, 80 mmol, 4 eq.). The resulting mixture was stirred at rt for 48 hr. The volatile material was removed under reduced pressure and the residue was treated ether. Solid was collected by filtration and washed with ether. The product thus obtained was forwarded to the next step without any further purification (2.87 g, 65% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[NH:25][C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[NH:25][C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH3:15])[CH2:10][CH2:9]1
Reactant: CC(c1nc2ccccc2c(=O)[nH]1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1nc2ccccc2c(=O)[nH]1)C1CCNCC1

Procedure:
A solution of 4-[1-(4-oxo-3,4-dihydro-quinazolin-2-yl)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester and TFA in CH2Cl2 was stirred at r.t. for 6 hr. The precipitated solid was filtered and dried to afford the product as a white solid. (2 g, 90%). 1H NMR (DMSO-d6) δ 8.51 (br, s, 1H), 8.18 (br, s, 1H), 8.06 (d, 1H, J=7.6), 7.74 (t, 1H, J=8.0), 7.57 (d, 1H, J=8.0), 7.44 (t, 1H, J=8.0), 3.29-3.18 (m, 2H), 2.88-2.76 (m, 2H), 2.61-2.57 (m, 1H), 1.95-1.92 (m, 2H), 1.61-1.57 (m, 1H), 1.42-1.25 (m, 2H), 1.25 (d, 3H, J=6.8); ESI-MS m/z 258.1 (M+1)+.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)(O)=O.[OH2:15].[CH2:16]=O>CN(C)C=O>[OH:15][CH2:16][C:5]1[CH:4]=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9]
Reactant: C=O
Reactant: O=C(O)c1ccc2c(c1)C(=O)NC2=O
Reactant: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CO)cccc21
Yield: 96 %

Procedure:
The 4-carboxyphthalimide (0.5 mol) was dissolved in dimethylformamide (200 ml) and H2O (600 ml) and treated with 37% aqueous formaldehyde (100 ml) and the mixture was heated on a steam bath until the solution became homogenous. The reaction was placed in an ice bath and cooled. A white solid crystallized and was collected and washed with cold water. The solid was dissolved in THF and dried with MgSO4 and concentrated to yield 96% of hydroxymethylphthalimide product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:29]1[N:28]=[C:27]([C:20]2[C:21]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:18][CH:19]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Nc1ccccc1O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Oc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 42.8 %

Procedure:
Using the procedure of example 1, 2-aminophenol (88 mg) was reacted with compound 1f (100 mg) to provide compound 30 (35 mg, 43%). 1H NMR (400 MHz, CD3OD) δ 8.83 (d, J=8.0 Hz, 1H), 8.28 (m, 2H), 8.25 (s, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.22 (m, 2H), 6.97 (m, 1H), 6.91 (m, 2H). MS (ESI) m/z: 304 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13])=[CH:5][CH:4]=1.Cl.[NH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>CCO>[CH3:13][C:12]1[N:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)CCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Cn1c(C)ccc1-c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Yield: 45.9 %

Procedure:
In a round bottomed flask, charged with 1-(4-(trifluoromethyl)phenyl)pentane-1,4-dione (3.18 g, 13.02 mmol) in EtOH (Ratio: 2, Volume: 13 mL) and ethyl 2-aminoacetate hydrochloride (1.818 g, 13.02 mmol) was added ethyl 2-aminoacetate hydrochloride (1.818 g, 13.02 mmol) and triethylamine (10.53 mL, 76 mmol). The reaction mixture was heated at 70° C. for 15.5 h (˜50% of SM remained by TLC and LCMS). The reaction was then concentrated and the residue was treated with water and extracted with DCM (3×). The organic layer was dried with MgSO4. The crude product was added to a 120 g ISCO silica gel column and was purified with a gradient of 0% to 50% EtOAc/hexanes. The product was obtained as a light yellow oil (1.8 g, 5.98 mmol, 45.9% yield). 1H NMR (CDCl3/400 MHz) δ (ppm) 7.62 (d, 2H), 7.42 (d, 2H), 6.23 (d, 1H), 6.05-6.02 (m, 1H), 4.55 (s, 2H), 4.25 (q, 2H), 2.24 (s, 3H), 1.28 (t, 3H). MS m/z: 312.22 (M+1).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.O>CS(C)=O>[CH:18]1([O:6][C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=2[O:8][CH3:9])[CH:2]=[O:1])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To the solution of 15.22 g (100 mmoles) of isovanilline in 125 ml of dimethylsulphoxide, 27 g of powdered anhydrous potassium carbonate are added. The suspension is stirred at 60° C. for 30 minutes and then 12.9 ml (120 mmoles) of cyclopentyl bromide are added at 60° C. during 60 minutes. Then the suspension is stirred at the same temperature 8 hours, cooled to 25° C. and poured into 500 ml of water. The aqueous emulsion is extracted four times with 100 ml of ether. The collected ethereal phases are washed twice with 20 ml of 1 N sodium hydroxide solution, dried over anhydrous magnesium sulphate and evaporated. To the oily residue 100 ml of benzene are added and the evaporation is repeated. The remained oil is fractionally distilled in vacuo to give 20.65 g (94%) of title compound, b.p. 136°-138° C./0.01 Hgmm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([CH2:27][CH:28]=[CH2:29])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.[OH-:41].[Na+].OO>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([CH2:27][CH2:28][CH2:29][OH:41])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCc1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCCO)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{2-[6-allyl-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (Example 4, Step 4E: 400 mg in 7.0 mL of dry tetrahydrofuran) at 0° C. was added 2.18 mL of a 1M solution of borane in tetrahydrofuran dropwise over 10 minutes. After 3 hours, the reaction was treated sequentially with sodium hydroxide (0.84 mL of a 3M solution) and hydrogen peroxide (0.29 mL of a 30% solution) and the mixture allowed to warm to room temperature. After 2 hours the mixture was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 8:2; then 7:3; then 3:2; then 1:1) gave the title compound (253 mg).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19](O)C)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].B(F)(F)F.[N+]([CH3:29])([O-])=O>C(Cl)Cl>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:4](=[CH:12][C:11]=1[O:10][CH3:9])[C:2]([CH3:29])([C:1]([O:6][CH2:7][CH3:8])=[O:5])[O:3][CH2:19][CH2:13]2
Reactant: CCOC(=O)C(C)=O
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C(C)O)cc1OC
Agent: FB(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C)OCCc2cc(OC)c(OC)cc21

Procedure:
Ethyl pyruvate (1.00 g, 0.0086 m), 3,4-dimethoxyphenylethanol (1.57 g, 0.0086 m), and, 1 ml of BF3 etherate are stirred at 25° C. in 20 ml of nitromethane for 45 minutes. The mixture is dissolved in methylene chloride and extracted with aqueous sodium bicarbonate. The organic phase is dried (sodium sulfate), concentrated, and chromatographed on silica gel to give 1.4 g of 6,7-dimethoxy-1-methyl-1-carboethoxyisochroman. A 0.5 g sample of this is dissolved in ether and treated with 100 mg of LAH. After 10 minutes, the mixture is quenched with ethyl acetate and partitioned between 1 N aqueous sodium hydroxide and CH2Cl2. The organic phase yields 0.34 g of 6,7-dimethoxy-1-methyl-1-hydroxymethylisochroman. This is dissolved in THF and treated sequentially with sodium hydride and then o-tetrahydropyranyl chloroethanol. The adduct, upon treatment with acid and water, yields 2-[(7,8-dimethoxy-1-methyl-isochroman-1-yl)methoxy]ethanol. In the manner of Preparation 7, this can be converted to its benzenesulfonates ##STR21## Furthermore, 2-[(1-methylisochroman-1-yl)methoxy]ethanols, with various substituents on the isochroman ring, can be prepared by using the appropriate phenyl ethanols whose substituents, R1 -R5 (vide supra), are analogous to those substituents of the isochromans of Table 3.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[S:3].Cl.[O-:11][Mn](=O)(=O)=O.[K+].[CH3:17][N:18]=[C:19]=[O:20]>>[CH2:8]([O:7][C:5]([CH2:4][N:1]1[C:2](=[O:11])[S:3][N:18]([CH3:17])[C:19]1=[O:20])=[O:6])[CH3:9]
Reactant: CCOC(=O)CN=C=S
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CN=C=O
Agent: Cl
Agent: [K+]
Product: CCOC(=O)Cn1c(=O)sn(C)c1=O

Procedure:
Reagents: Ethyl isothiocyanatoacetate (0.8 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), methyl isocyanate (0.38 ml, 6.5 mmol).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:8]=[CH:9][CH:10]=1)[CH3:3].[N+:16]([CH:19]=[C:20](SC)SC)([O-:18])=[O:17].[C:25](#[N:27])C>>[CH3:25][NH:27][C:20]([NH:15][CH2:14][CH2:13][S:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH:6]=1)=[CH:19][N+:16]([O-:18])=[O:17]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1cccc(CSCCN)c1
Reactant: CC#N
Product: CNC(=C[N+](=O)[O-])NCCSCc1cccc(CN(C)C)c1

Procedure:
2-[[3-(N,N-Dimethylaminomethyl)phenyl]methylthio]ethanamine (3 g) and 1-nitro-2,2-bis(methylthio)ethylene (2.2 g) were heated under reflux in acetonitrile for 7 hours. The solvent was removed and the residual oil used without further purification. The oil was treated with ethanolic methylamine (33%, 34 ml) and heated under reflux for 3 hours. The solvent was removed and the residual oil was purified by column chromatography on silica with methanol. The resultant orange oil was triturated with ether to give the title compound as a white crystalline solid (0.23 g) m.p. 62°-4°. TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2) Rf 0.36.