Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>[H][H].[Pd]>[C:13]1([C:8]2[C:7]3[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=3)[NH:10][N:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(-c3ccccc3)n[nH]c2c1
Agent: [Pd]
Product: Nc1ccc2c(-c3ccccc3)n[nH]c2c1
Yield: 71.5 %

Procedure:
To a solution of 2-chloro-5-nitro-benzophenone (1.0 g) in THF (tetrahydrofuran) (15 ml) was added anhydrous hydrazine (120 mg). The resulting reaction mixture was kept stirring at room temperature for 2-4 hours. The solvent was removed in vacuo and the residue dissolved in EtOAc, washed with water and brine, dried over Na2SO4. Removal of the solvent afforded (0.8 g, 88%) product 6-Nitro-3-phenyl-1H-indazole (5). 6-Nitro-3-phenyl-1H-indazole was hydrogenated over H2/Pd and gave 0.5 g of 3-phenyl-1H-indazol-6-ylamine (71.5%). M/z: 210.0. 1H NMR (CD3OD): 7.86 (d, 2H, J=7.9 Hz), 7.47 (t, J=8.1 Hz), 7.35 (t, 3H, J=8.7 Hz), 7.01 (d, 1H, J=8.7 Hz).
Reaction SMILES: C([O:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[C:9]([Br:16])[CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)(=O)C.[OH-].[K+]>CO>[Br:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]([CH3:17])[CH:6]=[C:5]([OH:4])[C:14]2=[O:15]
Reactant: CC(=O)Oc1cn(C)c2c(Br)cccc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(O)c(=O)c2cccc(Br)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a suspension of 8-bromo-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl acetate (3.68 g, 10.56 mmol) in methanol (100 mL) was added aqueous 2 M KOH (15 mL), the mixture turned into a brown solution and was stirred at room temperature for 1 h. The reaction mixture was concentrated, and was then partitioned between dichloromethane and brine. The organic phase was separated, the aqueous phase was extracted with dichloromethane for several times. The combined organic extracts were dried (Na2SO4), filtered and the solvent was removed in vacuo. The residue was then absorbed onto silica gel and purified by automatic silica gel column chromatography (Combiflash RF), eluting with MeOH/dichloromethane (0-5%) to afford 8-bromo-3-hydroxy-1-methylquinolin-4(1H)-one (2.47 g, 9.24 mmol, 87% yield) as a brown solid. LCMS: (M+H)+: 254.1
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[I-:22].[Na+]>CC(C)=O>[I:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [I-]
Reactant: BrCCCCCCCCCCCCOCc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCCCCCCCCCOCc1ccccc1
Yield: 104.7 %

Procedure:
First, 12.4 g of 1-bromo-12-benzyloxydodecane, 6.3 g of sodium iodide, and 125 ml of acetone were placed in a 200 ml flask whose content was replaced with argon. Then, the mixture was stirred under reflux for 5 hours. An insoluble matter was filtered away and a filtrate was concentrated. Thereafter, ether was introduced into the residue. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/1) to obtain 14.7 g of 1-iodo-12-benzyloxydodecane (Y: 100%). The compound thus obtained had a purity of 96.1% by GC.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH:11]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])[N:10]3[C:22](=[O:34])[CH:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:9]3[S:8]2)[CH2:4][CH2:3]1>[Pd].C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH:11]([C:12]([OH:14])=[O:13])[N:10]3[C:22](=[O:34])[CH:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:9]3[S:8]2)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CC1)S[C@@H]1C(NC(=O)Cc3ccccc3)C(=O)N1C2C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC2(CC1)S[C@@H]1C(NC(=O)Cc3ccccc3)C(=O)N1C2C(=O)O
Reaction time: 1 h
Yield: 4.5 %

Procedure:
Under a hydrogen pressure of 3.2 kg/cm2 and in the presence of 4.4 g of palladium on carbon (10% Pd), a solution of 4.4 g (0.091 mole) of benzyl 1'-methyl-6-(2-phenylacetamido)-spiro[penam-2,4'-piperidine]-3-carboxylate prepared in I.1.a) in 800 ml of ethanol are hydrogenolyzed in a Parr's apparatus for 1 hour. After filtering, the precipitate is digested in 1.5 liter of a 9:1 v/v methanol-water mixture for 1 hour. Evaporation of the filtrate to dryness gives 1.6 g of 1'-methyl-6-(2-phenylacetamido)-spiro[penam-2,4'-piperidine]-3-carboxylic acid. Yield: 44.8%; M.P. 189°-190° C. (decomposition).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].[C:23](Cl)(=[O:33])[C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH2:28]1[O:29][C:30]2[CH:31]=[CH:32][C:24]([C:23]([O:20][CH2:19][N:15]3[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]4[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:23](=[O:33])[C:24]5[CH:32]=[CH:31][C:30]6[O:29][CH2:28][O:27][C:26]=6[CH:25]=5)[C:4](=[O:22])[CH2:5]4)[CH2:17][C:16]3=[O:18])=[O:33])=[CH:25][C:26]=2[O:27]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(OCN1C(=O)CN(CCN2CC(=O)N(COC(=O)c3ccc4c(c3)OCO4)C(=O)C2)CC1=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.7 %

Procedure:
To a mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (0.94 g, 3.0 m mol) and pyridine (10 ml), piperonyloyl chloride (1.00 g, 6.0 m mol) dissolved in pyridine (10 ml) was added, and then the mixture was stirred for 20 hours at room temperature. To the reaction mixture, chloroform (250 ml) was added and the solution was washed with 10% sulfuric acid solution and successively with water, further was washed with aqueous sodium bicarbonate solution and successively with water. Then, the solvent was removed under reduced pressure to give the titled compound (1.12 g; yield 61%).
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[Cl:6][CH2:7][CH:8]1[CH2:12][O:11][C:10]([C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=2[C:21](OC)=[O:22])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9]1>CCOCC>[Cl:6][CH2:7][CH:8]1[CH2:12][O:11][C:10]([C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=2[C:21](=[O:22])[CH2:4][C:3]#[N:5])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:9]1
Reactant: COC(=O)c1ccccc1C1(c2ccccc2)OCC(CCl)O1
Reactant: CC#N
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: N#CCC(=O)c1ccccc1C1(c2ccccc2)OCC(CCl)O1

Procedure:
To a stirring solution of 75 ml of liquid ammonia was added a small piece of sodium and a few crystals of ferric nitrate. A total of 1.15 g (0.0502 mol) of sodium was added over a 20 min period, and after 5 mins a solution of 2.9 ml (0.050 mol) of acetonitrile in 10 ml of ether was added dropwise. A solution of 6.6 g (0.0198 mol) of the end product of Example 12 in 40 ml of ether was added dropwise, and after 2 hrs 100 ml of ether was added and the ammonia was allowed to evaporate. About 100 g of ice was added to the reaction, which was then acidified with acetic acid, followed by neutralization with a saturated solution of sodium bicarbonate. The water layer was separated and extracted once more with ether. The combined ether layers were washed with 100 ml of water, dried over sodium sulfate and evaporated. The oil was dissolved in 15 ml of dichloromethane and filtered through 100 g of Florisil. Elution with dichloromethane, and evaporation gave 2-[4-(chloromethyl)-2-phenyl-1,3-dioxolan-2-yl]-β-oxo-benzenepropanenitrile which was used without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:9]([S:11]SCC)[CH3:10].C(S)C>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[CH2:9]([S:11][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH3:10]
Reactant: CCSSCC
Reactant: Oc1ccccc1
Agent: [Zr+4]
Agent: Cl
Agent: [Cl-]
Solvent: CCS
Product: CCSc1ccccc1O
Temperature: 156 °C
Yield: 41.3 %

Procedure:
Zirconium tetrachloride (23.4 g, 0.1 mole) was added to phenol (141.2 g, 1.5 moles). The mixture was slowly heated to 156° C. under nitrogen and maintained at this temperature overnight while allowing HCl to escape. The mixture was cooled to ca. 100° C. and ethyl disulfide (122.3 g, 1 mole) was added. The mixture was heated under nitrogen while ethyl mercaptan was removed continuously by distillation. Heating was continued for a total of 7 hours during which temperature slowly increased to 198° C. Distillation of the mixture at 0.4 mm mercury to a maximum head temperature of 101° C. yielded 134.7 g of distillate. GC analysis indicated the distillate contained 53.4 g of phenol (38% recovered) and 63.7 g of ortho-(ethylthio)phenol (41% yield). Fractional distillation through a 5 inch Vigreux column yielded, after removal of phenol, a main fraction of 99.2% pure ortho-(ethylthio)phenol distilling at 125°-127° C. at 30 mm mercury.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24]([C:26]1[S:27][C:28]([CH2:31][CH2:32]OS(C)(=O)=O)=[CH:29][CH:30]=1)=[O:25]>CN(C=O)C>[CH3:22][O:23][C:24]([C:26]1[S:27][C:28]([CH2:31][CH2:32][N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]2=[O:15])=[CH:29][CH:30]=1)=[O:25]
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: COC(=O)c1ccc(CCOS(C)(=O)=O)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCn2ccc(OCc3ccccc3)cc2=O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.20 g (5.96 mmol) 4-benzyloxy-1H-pyridin-2-one in DMF is added subsequently 3.89 g (11.9 mmol) cesium carbonate and 1.58 g (5.96 mmol) 5-(2-methanesulfonyloxy-ethyl)thiophene-2-carboxylic acid methyl ester (preparation 11a). The reaction mixture is stirred overnight at RT. After filtration, the residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7]CC)=[O:6])=[C:2]=[O:3].Cl.O1CCOCC1.[CH3:17][C:18]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Na+]>ClCCl.CO>[CH3:17][C:18]1([O:23][C:2]([NH:1][CH2:4][C:5]([OH:7])=[O:6])=[O:3])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC1(O)CCCC1
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CC1(OC(=O)NCC(=O)O)CCCC1
Reaction time: 0.5 h

Procedure:
500 mg (3.87 mmol) of ethyl isocyanatoacetate was dissolved in 5 ml of dichloromethane. 0.05 ml of 4 N hydrochloric acid/1,4-dioxane solution was added to the obtained solution. 465 mg (4.64 mmol) of 1-methylcyclopentanol was added to the resultant mixture, and they were stirred for 3 hours 30 minutes. 10 ml of methanol and 12 ml of 1 N aqueous sodium hydroxide solution were added thereto and they were stirred for 15 minutes. The organic solvent was evaporated under reduced pressure. After extracting with dichloromethane twice, the aqueous layer was neutralized with 1 N aqueous hydrochloric acid solution. The product was extracted with dichloromethane 3 times and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound. The product was subjected to the next reaction without any purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[C@@H:16]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)(C)(C)C>C(Cl)Cl>[C:22]1([C@H:16]2[C:17](=[O:21])[CH2:18][CH2:19][CH2:20][NH:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (4 mL) is added to a stirred, cooled (0° C.) solution of (2S)- 1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (40 mg) in methylene chloride (2 mL) and the mixture is stirred at room temperature for 3 h. The solvent is evaporated under reduced pressure and the residue is partitioned between aqueous saturated sodium bicarbonate (50 ml) and ethyl acetate (3×50 ml). The combined organic fractions are washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo to give (2S)-2-phenylpiperidin-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:16][C:17]([F:28])([F:27])[N:18]1[CH:23]=[C:22]([CH:24]=[CH2:25])[CH:21]=[CH:20][C:19]1=[O:26].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:22]3[CH:21]=[CH:20][C:19](=[O:26])[N:18]([C:17]([F:28])([F:16])[F:27])[CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(=O)n(C(F)(F)F)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(=O)n(C(F)(F)F)c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 1-(trifluoromethyl)-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].[Na][Na].Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Cl:29])[CH:25]=2)[N:20]=1.C1C=CC([O-])=CC=1.[Na+].Cl>CS(C)=O.O>[Cl:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1)[CH:28]=[CH:27]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [Na][Na]
Solvent: CS(C)=O
Solvent: O
Product: CC(Oc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1)C(=O)O
Temperature: 125 °C

Procedure:
2-(4-Hydroxyphenoxy)propionic acid (2.85 gm, 0.0156 mole) was dissolved in 60 ml of dimethylsulfoxide. A solution of sodium hydroxide (1.25 gm, 0.031 mole) in 2.0 ml of water was added and the mixture stirred for a few minutes to insure complete conversion to the disodium salt. 2,6-Dichloroquinoline (3.1 gm, 0.0126 mole) was dissolved in 50 ml of DMSO and then added all at once to the sodium phenate solution. The reaction mixture was then heated to about 125° C. and stirred at this temperature for 3.0 hours. At the end of this time it was cooled, poured into 350 ml of cold water and acidified with concentrated hydrochloric acid. The precipitated crude product was collected on a filter, washed with fresh water, sucked damp dry and taken up in hot toluene. It was then dried over sodium sulfate, treated with "Norite", filtered and the filtrate concentrated and chilled to precipitate the white crystalline 2-(4-((6-chloro-2-quinolinyl)oxy)phenoxy)propionic acid.
Reaction SMILES: [CH:1]12[CH2:14][CH2:13][CH:5]([CH:6]3[C:11](=[O:12])[O:10][C:8](=O)[CH:7]31)[CH:4]1[CH:2]2[CH2:3]1.C1CC=CC=CC=1.C1(=O)OC(=O)C=C1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:34]=[C:35]([Cl:37])[CH:36]=1)[NH2:33]>C1(C)C=CC=CC=1>[Cl:29][C:30]1[CH:31]=[C:32]([N:33]2[C:8](=[O:10])[CH:7]3[CH:6]([CH:5]4[CH2:13][CH2:14][CH:1]3[CH:2]3[CH:4]4[CH2:3]3)[C:11]2=[O:12])[CH:34]=[C:35]([Cl:37])[CH:36]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C1OC(=O)C2C3CCC(C4CC43)C12
Agent: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Solvent: C1=CC=CCC=C1
Product: O=C1C2C3CCC(C4CC43)C2C(=O)N1c1cc(Cl)cc(Cl)c1

Procedure:
19.2 g of tricyclo-[3.2.2.02.4 ]-nonane-6,7-dicarboxylic acid anhydride (prepared from the cycloheptatriene/maleic acid anhydride adduct (see Ex. 1a) by catalytic hydrogenation, K. Alder, Ber. 86, 1528-39 (1953) and 19.4 g of 3,5-dichloroaniline are refluxed in 1000 ml of toluene for 16 hours, whereby thewater forming during the reaction is separated with a water separator. After cooling, the toluene is removed in vacuum, and the residue recrystallised from ethyl acetate, M.P. 145° - 153° C.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH2:9]([C:14]1[CH:15]=[CH:16][C:17]([C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])=[CH:18][CH:19]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C1CCCC(=O)O1
Reactant: CCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCc1ccc(C(=O)CCCC(=O)O)cc1
Temperature: 0 °C

Procedure:
Glutaric anhydride (10 g; 0.1mole) is reacted with pentylbenzene (100 ml) and aluminum chloride (29 g; 0.22 mole) at room temperature for 4 hours. The reaction mixture is poured into a mixture of ice-water (500 ml) and concentrated hydrochloric acid (50 ml) with vigorous stirring. The crude product is collected by filtration and recrystallized from aqueous ethanol to give 4-(4-n-pentylbenzoyl)butanoic acid (16.2 g) as colorless crystals, m.p. 104°-106° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:18](OC)=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.CO.[BH4-].[Li+].Cl.[OH-].[Na+]>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[O:13][C:14]([CH2:18][OH:19])=[C:15]([CH3:17])[N:16]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(OCCCCl)cc2)oc1CO
Temperature: 70 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of methyl 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-oxazole-5-carboxylate ax60 (390 mg, 1.26 mmol, 1 eq) and methanol (165 μl, 4.08 mmol, 1.8 eq) in tetrahydrofuran (13 ml) is treated with lithium borohydride (49 mg, 2.27 mmol, 1.8 eq) and the mixture is stirred at 70° C. for 1 h. After cooling back to 0° C., the mixture is treated dropwise with 1 N aqueous hydrochloric acid (1 ml). The mixture is then made basic (pH 10) with 2 N aqueous sodium hydroxide and extracted with ethyl acetate. The organic phase is then dried over magnesium sulfate and concentrated to give 330 mg of {2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-oxazol-5-yl}methanol ax61 as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[NH:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[O:14])[NH:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)c1cc(C(=O)O)[nH]c1C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1cc(C(=O)Nc2ccc(C(=O)O)cc2)[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4,5-diisopropylpyrrole-2-carboxylic acid (78 mg, 0.400 mmol) and methyl 4-aminobenzoate (181 mg, 1.20 mmol) in dichloromethane (5 ml) was added with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.00 mmol) under an argon atmosphere, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was treated in a conventional manner, and then the resultant was purified by silica gel chromatography (0.5% methanol-chloroform) to obtain the desired condensate (27 mg, 21%) from the low polarity portion, and the acid anhydride (30 mg, 40%), the starting material, from the high polarity portion.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]1[N+:7]([O-:17])=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(n1)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc2c([n+]1[O-])COC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A solution of 2-methyl-7H-furo[3,4-b]pyridin-5-one (150 mg, 1.0 mmol) in chloroform (5 mL) and dichloromethane (1 mL) is treated with m-chloroperoxybenzoic acid (258 mg, 1.5 mmol). The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated and the residue is purified by chromatography (silica gel). The product containing fractions are concentrated to give the title compound as a solid (122 mg, 73%).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:27][CH2:26][C@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].[S:33](Cl)(=[O:36])(=[O:35])[NH2:34]>CN(C)C(=O)C>[S:33](=[O:36])(=[O:35])([O:28][C@:25]1([C:29]([F:32])([F:31])[F:30])[CH2:24][C@@H:4]2[CH2:5][CH2:6][CH2:7][C:8]3[C:9](=[CH:10][C:11]4[CH:12]=[N:13][N:14]([C:17]5[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=5)[C:15]=4[CH:16]=3)[C@@:3]2([CH2:1][CH3:2])[CH2:27][CH2:26]1)[NH2:34]
Reactant: NS(=O)(=O)Cl
Reactant: CC[C@]12CC[C@@](O)(C(F)(F)F)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Solvent: CC(=O)N(C)C
Product: CC[C@]12CC[C@@](OS(N)(=O)=O)(C(F)(F)F)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 74 %

Procedure:
(3S,4aS,12bS)-12b-Ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.125 g, 0.280 mmol) in N,N-dimethylacetamide (3 mL) was stirred and treated with sulfamoyl chloride (0.105 g, 0.91 mmol). After about 3 h sulfamoyl chloride (0.080 g, 0.69 mmol) was added and the mixture was stirred for about 14 h at rt. The reaction mixture was purified without manipulation in one portion by preparative reverse phase HPLC using a Hypersil HS C18 column (250 mm×21.2 mm, 8 um particle size) with a gradient of 25-100% MeCN in 0.05 N aq. ammonium acetate pH 4.5 buffer. Product fractions were concentrated under reduced pressure then diluted with water (15 mL). The solids were collected by filtration then washed with water (5 mL) and dried to yield (3S,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-yl sulfamate (109 mg, 74%); LC/MS, method 2, Rt=2.86 min, MS m/z 526 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=0.8 Hz, 1H), 8.02 (s, 2H), 7.86 (s, 1H), 7.81-7.78 (m, 2H), 7.57 (s, 1H), 7.45-7.37 (m, 2H), 3.23-3.18 (m, 2H), 2.98-2.92 (m, 1H), 2.45-2.18 (m, 4H), 2.16-1.95 (m, 3H), 1.94-1.61 (m, 4H), 1.42-1.27 (m, 1H), 0.43 (t, J=7.3 Hz, 3H).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)=CC=1>Cl.O1CCOCC1>[N:19]1([C:15]2[CH:14]=[C:13]3[C:18]([C:9](=[O:8])[NH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: COc1ccc(COc2ncnc3cc(N4CCOCC4)ccc23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]cnc2cc(N3CCOCC3)ccc12
Reaction time: 3 h
Yield: 129.7 %

Procedure:
178 g (0.15 mol) of 4-(4-methoxybenzyloxy)-7-morpholin-4-ylquinazoline were dissolved in 250 ml of hydrogen chloride/dioxane (4 N) at room temperature and stirred for 3 h. Conventional work-up gave 45.0 g of 7-morpholin-4-yl-3H-quinazolin-4-one as solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[N:10][C:9]=2[CH3:20])=[CH:4][C:3]=1S(N)(=O)=O.BrC(C1C=CC(Cl)=C(S(N)(=O)=O)C=1)C(=O)C.BrC(C1C=CC=C([N+:52]([O-:54])=[O:53])C=1)C(=O)C>>[CH3:20][C:9]1[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[S:12][C:8]=1[C:5]1[CH:6]=[CH:7][CH:2]=[C:3]([N+:52]([O-:54])=[O:53])[CH:4]=1
Reactant: CC(=O)C(Br)c1cccc([N+](=O)[O-])c1
Reactant: Cc1nc(Nc2cnccn2)sc1-c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: CC(=O)C(Br)c1ccc(Cl)c(S(N)(=O)=O)c1
Product: Cc1nc(Nc2cnccn2)sc1-c1cccc([N+](=O)[O-])c1

Procedure:
The titled compound is prepared by the same procedure described for the preparation of 33c, replacing 5-(1-Bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide (33b) in this procedure with 1-Bromo-1-(3-nitro-phenyl)-propan-2-one (42a)