Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[C:4]([CH3:16])[CH:3]=1.N([O-])=O.[Na+].[I-:21].[K+]>Cl.O>[C:14]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([I:21])=[CH:3][C:4]=2[CH3:16])[CH:13]=[CH:12][CH:11]=1)#[N:15]
Reactant: Cc1cc(N)ccc1-c1cccc(C#N)c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(I)ccc1-c1cccc(C#N)c1
Reaction time: 0.33 h
Yield: 28.9 %

Procedure:
A suspension of 4-amino-l-(3-cyanophenyl)-2-methylbenzene (2.5 gm, 12.0 mmol) in conc. hydrochloric acid (13 mL) and water (16 mL) at 0° C., was treated with a solution of sodium nitrite (1.83 gm, 26.5 mmol) in water (10 mL) over 10 mins. The mixture was stirred for 20 mins and then a solution of potassium iodide (8.40 gm, 50.6 mmol) in water (20 mL) was added over 10 mins. The resultant mixture was heated at 80° C. for 2 h then cooled. The residue was extracted with dichloromethane and the combined organic extracts were washed with excess 5% aqueous sodium metabisulphite, to remove iodine. The organic solution was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane:ethyl acetate 20:1 to 10:1) to give 1-(3-cyanophenyl)-4-iodo-2-methylbenzene as a white solid (1.105 gm, 29%).
Reaction SMILES: B(Br)(Br)Br.C(NC(=O)[O-])C.CO[C:13]1[C:14]([Cl:26])=[CH:15][C:16]2[CH:17]([CH3:25])[CH:18]3[CH2:22][NH:21][CH2:20][CH:19]3[C:23]=2[CH:24]=1>C(Cl)Cl>[Cl:26][C:14]1[CH:13]=[CH:24][C:23]2[CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH:17]([CH3:25])[C:16]=2[CH:15]=1
Reactant: COc1cc2c(cc1Cl)C(C)C1CNCC21
Agent: BrB(Br)Br
Agent: CCNC(=O)[O-]
Solvent: ClCCl
Product: CC1c2cc(Cl)ccc2C2CNCC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BBr3 (3.7 mL, 1.0 M in CH2Cl2) was added to a solution of N-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 3, Step A) (0.49 g, 1.6 mmol) in CH2Cl2 (32 mL), and stirred overnight at room temperature. The excess BBr3 was quenched with the dropwise addition of H2O (10 mL), and washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL). The organic extract was dried over MgSO4 and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C15H18ClNO3+H: 296, observed: 296.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24](Br)[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:37][CH2:38]OC.O.B1(C=C)OB(C=C)OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH:37]=[CH2:38])[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOC
Reactant: CCCOc1nc(Br)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.8 %

Procedure:
Compound B (4.0 g), tetrakis(triphenyl-phosphine)palladium(0) (203 mg, 176 μmol) and 1,2-dimethoxyethane (100 Ml, 1 mol) were combined and stirred under nitrogen at room temperature for 20 minutes. Water (20.6 mL, 1.1 mol), 2,4,6-trivinylcyclotriboroxane pyridine complex (1.1 g, 44.4 mmol) and potassium carbonate (1.3 g, 9.3 mmol) were then added and the mixture was heated at 90° C. for 6-12 hours. The product was purified by flash chromatography in hexanes/EtOAc 0-75%) to yield compound C (3.2 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:4])=[O:3].[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([N:16]1[CH2:15][CH2:14][N:13]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[CH2:18][CH2:17]1)[CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc(N2CCNCC2)cc1S(C)(=O)=O
Reactant: CCCCBr
Product: CCCCN1CCN(c2ccc(OC)c(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine and n-Bu-Br, the title compound was recovered by the procedure described in Example 2; MS m/z (rel. intensity, 70 eV)) 326 (M+, 32), 284 (16), 283 (bp), 70 (58), 56 (23).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([O:32][C:33]1[CH:46]=[CH:45][C:36]2[CH:37]3[CH2:43][CH2:42][C:41](=O)[CH2:40][CH:38]3[O:39][C:35]=2[C:34]=1[F:47])[CH3:31].Cl>C1COCC1.O>[CH2:30]([O:32][C:33]1[CH:46]=[CH:45][C:36]2[CH:37]3[CH2:43][CH2:42][C:41](=[CH:2][O:3][CH3:4])[CH2:40][CH:38]3[O:39][C:35]=2[C:34]=1[F:47])[CH3:31]
Reactant: CCOc1ccc2c(c1F)OC1CC(=O)CCC21
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1F)OC1CC(=COC)CCC21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
58.3 g (170 mmol) of methoxymethyltriphenylphosphonium chloride are initially introduced in 500 ml of THF, and a solution of 19.1 g (170 mmol) of potassium tert-butoxide in 200 ml of THF is added at 0° C. After 30 min at this temperature, 7-ethoxy-6-fluoro-1,4,4a,9b-tetrahydro-2H-dibenzofuran-3-one as a solution in 300 ml of THF is added, and the batch is stirred at room temperature for 17 h. Water is added at 0° C., and the mixture is acidified using 2 N hydrochloric acid. The batch is extracted with MTBE, and the combined extracts are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. Purification of the crude product by column chromatography (SiO2, toluene) gives (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-3-[1-methoxy-methylidene]-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl.Cl>[CH3:18][S:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10])(=[O:21])=[O:20]
Reactant: N#CCc1ccccc1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccccc1CC#N
Temperature: 0 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To an ice-cold solution of 2-aminophenylacetonitrile (500 mg) in dichloromethane (20 ml) were added triethylamine (330 μl) and methanesulfonyl chloride (530 μl) and the mixture was stirred for 16 hours, under argon gas atmosphere. After confirming the completion of the reaction using TLC, the resulting mixture was diluted with 1 N aqueous hydrochloric acid solution (30 ml), and extracted with dichloromethane (50 ml×3). The organic layer was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by column-chromatography (ethyl acetate/hexane=1/2) to yield (2-methanesulfonylaminophenyl)acetonitrile (573 mg, 72%).
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12].[H][H]>C(O)C.[Ni]>[CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12]
Reactant: CC(=CCc1ccc(O)cc1O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCc1ccc(O)cc1O
Yield: 65 %

Procedure:
4-(3,7,11,15-Tetramethyl-2-hexadecenyl)-1,3-benzenediol (2.00 g: 5.14 mmole) was dissolved in ethanol (10 ml), a suspension of Raney's nickel W4 in ethanol (15 ml), was added thereto and then the mixture was reciprocatively shaken at 70° to 85° C. and a hydrogen pressure of 70 to 80 atm. for 2 days. After removing Raney's nickel by filtration, the filtrate was concentrated and the concentrate was chromatographed through a silica gel column. Thus, 1.30 g of the title compound was recovered from the fractions eluted with hexane-ethyl acetate (5:1). Yield=65%.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N1C=CN=C1)(N1C=CN=C1)=O.O[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>[H-].[Na+].O1CCCC1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: Oc1cccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Oc2cccnc2)cc1

Procedure:
A 6 g. (16.6 m moles) sample of 4-(hexadecylamino)-benzoic acid and 2.7 g. (16.6 m moles) 1,1'-carbonyldiimidazole in 50 ml. dry tetrahydrofuran is stirred for 2 hours. Then, 1.58 g. (16.6 m moles) 3-hydroxypyridine and a trace of sodium hydride catalyst is added and the reaction is refluxed for 3 hours. The solution is cooled, filtered, and evaporated. The product is crystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=O)=[O:9])=[CH:4][CH:3]=1.[C:19]([CH2:21][C:22]([NH2:24])=[S:23])#[N:20]>N1CCCCC1.C(Cl)(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([OH:9])[NH:24][C:22](=[S:23])[C:21]=2[C:19]#[N:20])=[CH:13][CH:14]=1
Reactant: O=C(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: N#CCC(N)=S
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: N#CC1=C(c2ccc(Cl)cc2)C(O)(c2ccc(Cl)cc2)NC1=S

Procedure:
A suspension of 22.3 g. 4,4'-dichlorobenzil, 6.5 g. 2-cyanothioacetamide, 20 drops of piperidine and 200 ml. chloroform is stirred for 20 hours at ambient temperature. The yellow precipitate obtained is filtered off with suction, well washed with chloroform and dried. There are obtained 22.0 g. of the desired compound in the form of yellow crystals; m.p. 213° C. (decomp.).
Reaction SMILES: CO[C:3](=[O:20])[C@H:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[NH2:5].[CH3:21][N:22]=[C:23]=[S:24]>>[CH2:13]([O:12][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH:4]1[NH:5][C:23](=[S:24])[N:22]([CH3:21])[C:3]1=[O:20])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN=C=S
Reactant: COC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Product: CN1C(=O)C(CCCNC(=O)OCc2ccccc2)NC1=S

Procedure:
Using an analogous procedure to Example 1 Nδ-benzyloxycarbonyl-L-ornithine methyl ester may be reacted with methyl isothiocyanate to give the title compound
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[CH3:17][C:18]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.O>[CH:17]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1)=[CH2:18]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Nc1nc2ccccc2c2ccc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(n1)c(N)nc1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-chlorobenzo[f][1,7]naphthyridin-5-amine (Example 20) (1.0 eq.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.2 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous potassium carbonate solution (2.0 eq.) in toluene/ethanol (4:1, 0.1 M) was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane to give a solid, which was then triturated in 10% ethyl acetate in hexane to give 3-vinylbenzo[f][1,7]naphthyridin-5-amine. 1H NMR (acetone d-6): δ 8.99 (d, 1H), 8.42 (d, 1H), 8.01 (d, 1H), 7.53-7.62 (m, 2H), 7.30-7.35 (dd, 1H), 7.03-7.10 (dd, 1H), 6.77 (br, 2H), 6.56 (d, 1H), 5.66 (d, 1H). LRMS [M+H]=222.1
Reaction SMILES: [H-].[Na+].[S:3]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6](=[O:16])[CH:5]=[CH:4]1.[CH3:17]I>CCCCCC.CN(C)C=O>[CH3:17][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[S:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]1=2
Reactant: CI
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cn1c2ccccc2c2sccc(=O)c21
Reaction time: 3 h

Procedure:
Sodium hydride (2.3 g of 50% suspension in mineral oil, 0.05 mole) is washed with hexane and suspended in 25 ml of dimethylformamide (DMF). Thiopyrano [3,2-b] indol-4(5H)-one, 10.0 g (0.05 mole) in 130 ml of DMF is added and the mixture stirred for 3 hours. Methyl iodide (14.2 g, 0.1 mole) is added and the mixture stirred for 3 hours and then poured over ice. The white precipitate is filtered, dried and recrystallized from hexane to give 9.3 g of product, mp 113°-114°C.
Reaction SMILES: [O:1]([C:8]1[C:9]2[N:16]([CH2:17][CH:18](O)O)[CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][S:22]([CH2:25][CH2:26][NH2:27])(=[O:24])=[O:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.C(O)(=O)C>[CH3:21][S:22]([CH2:25][CH2:26][NH:27][CH2:18][CH2:17][N:16]1[C:9]2[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH:14]=[CH:15]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)CCN
Reactant: OC(O)Cn1ccc2ncnc(Oc3ccccc3)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCNCCn1ccc2ncnc(Oc3ccccc3)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
2-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethane-1,1-diol (500 mg) and 2-(methylsulfonyl)ethylamine (341 mg) were dissolved in N,N-dimethylformamide (29 mL)/acetic acid (2.9 mL), and the mixture was stirred at room temperature for 1.5 hrs. Sodium triacetoxyborohydride (579 mg) was added, and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) to give the title compound (508 mg) as a candy-like substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=2)[NH:12][C:11]=1[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:37][OH:38]>C(O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[NH:20])[NH:37][OH:38])[CH:17]=2)[NH:12][C:11]=1[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C#N)cc3c2CCNC(=O)OC(C)(C)C)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=N)NO)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 32.3 %

Procedure:
A solution of {2-[5-cyano-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (300 mg in 5 mL ethanol) was added to a suspension of 725 mg potassium carbonate and 273 mg hydroxylamine hydrochloride in 7 mL ethanol and the whole heated to reflux on an oil bath. After 21 hours, the mixture was cooled to room temperature and filtered to remove solids. The filtrate was concentrated in vacuo then partitioned between ethyl acetate and water. The organic portion was washed with water, dried over sodium sulfate and the concentrate purified by flash chromatography on silica gel (methylene chloride:methanol, 92:8) to give the title compound (105 mg).
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=O)(=[O:3])[NH2:2].[OH-].[Na+].O>C(O)(=O)C>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[NH:2][C:1](=[O:3])[C:4]3[C:5](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:6]=2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(C(=O)Nc2ccccc2C(N)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1

Procedure:
A mixture of 2'-carbamoyl-p-toluanilide (66.97 g; 0.263 mol), sodium hydroxide (41.9 g) and water 837 ml) is stirred and heated at reflux for 0.5 hour. The resultant solution is cooled down, made acid with acetic acid. The reaction mixture is filtered, the isolated product is washed and dried to afford 58.16 g off white solid, mp 239°-241° C. Recrystallized from absolute ethanol, the product has a mp of 239°-240.5° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1cccc(C)c1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc([C@@H]2COc3cc(O)ccc3[C@@H]2c2ccc(OCCN3CCCC3)cc2)c1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-3-(3-methylphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane (0.360 g, 0.75 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white foam.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1C=CC=C[CH:18]=1.S(Cl)(Cl)=O>CN(C=O)C.C(O)C>[CH2:17]([O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:18]
Reactant: c1ccccc1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1Oc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 2-phenoxybenzoic acid (7.71 g; 0.036 mol) dry benzene (80 ml), thionyl chloride (4.76 g; 0.04 mol) and DMF (2 drops) were added, and the resultant mixture was stirred under reflux for 2 hours. The reaction mixture was dropwise added to dry ethanol (100 ml) under ice-cooling in 30 minutes, followed by allowing to stand overnight. The reaction mixture was concentrated under reduced pressure and, after addition of a 4% aqueous sodium hydrogen carbonate solution (150 ml) thereto, extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl-2-phenoxybenzoate (8.72 g, yield, 100%) as a colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[S:19](=[O:28])(=[O:27])[NH:18]2)=[C:9]1[CH3:29])(C)(C)C.[CH:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38]Br)=[CH:33][CH:32]=1>>[F:26][C:24]1[CH:23]=[CH:22][C:21]2[CH:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]=3[CH3:29])[N:18]([CH2:38][CH2:37][C:34]3[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=3)[S:19](=[O:28])(=[O:27])[C:20]=2[CH:25]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1c(C2NS(=O)(=O)c3cc(F)ccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(C2c3ccc(F)cc3S(=O)(=O)N2CCc2ccccc2)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 13, step e) and 2-phenethyl bromide. MS: ESI (negative): 477 (M−H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([NH:29][N:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[Cl:39])C)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[Cl:39][C:33]1[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=1[N:30]1[C:18](=[O:19])[C:11]2[C@@H:12]3[C:15]([CH3:17])([CH3:16])[C@@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:29]1[CH3:27]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CN(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1c2c(c(=O)n1-c1ccc(Cl)cc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 46.6 %

Procedure:
Triethylamine (450 μL, 3.2 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 361 mg, 1.68 mmol) in 1,2-dichloroethane (3 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N′-(2,4-dichloro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (310 mg, 1.07 mmol) in 1,2-dichloroethane (6 mL) was added over 2 min. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 30 min, and then in an oil bath at 50° C. for 2 h. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated in an oil bath at 100° C. for 1 h and then allowed to cool to room temperature. Dichloromethane (100 mL) was added and the mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 20-50% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and co-evaporated successively with methanol, diethyl ether and petroleum ether. The residue was triturated with hexanes, and the solid was dried overnight under high vacuum at 70° C. and then at 85° C. for 1 h to give (4S,7R)-2-(2,4-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (175 mg, 45%) as an off-white solid. ES(+)-MS (M+H) 351.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20].[CH2:21](Br)[CH:22]=[CH2:23].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[CH2:23]([O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:10]2[C:18](=[O:19])[C:13]3=[CH:14][CH2:15][CH2:16][CH2:17][N:12]3[C:11]2=[O:20])[CH:4]=1)[CH:22]=[CH2:21]
Reactant: Cc1cc(Cl)c(N2C(=O)C3=CCCCN3C2=O)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(N2C(=O)C3=CCCCN3C2=O)c(Cl)cc1C
Yield: 65 %

Procedure:
An acetonitrile (10 mL) solution of 2-(2-chloro-4-methyl-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.34 g, 1.11 mmol), allylbromide (0.11 mL, 1.22 mmol) and potassium carbonate (0.15 g, 1.11 mmol) was stirred for one hour under reflux. A saturated ammonium chloride solution (20 mL) was added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with diethyl ether (10 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (40 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane =1/2) to obtain a white solid of 2-(5-allyloxy-2-chloro-4-methylphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.24 g, yield:61.5%).