Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([C:7]([NH:9][C:10]1[S:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[N:13][N:14]=1)=[O:8])[NH2:6])[CH2:2][CH2:3][CH3:4].[CH2:19]=O.[OH-].[K+]>CO>[CH2:1]([N:5]1[C:7](=[O:8])[N:9]([C:10]2[S:11][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[N:13][N:14]=2)[CH2:19][NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(N)C(=O)Nc1nnc(S(C)(=O)=O)s1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1NCN(c2nnc(S(C)(=O)=O)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-n-Butyl-4-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 to 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-n-butyl-4-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1Br)=[O:3].[C:12]([OH:15])(=[O:14])[CH3:13].C(N(CC)CC)C>C(#N)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][O:15][C:12](=[O:14])[CH3:13])=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: CC(=O)c1ccc(Cl)cc1Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)c1ccc(Cl)cc1
Temperature: 4 °C
Yield: 90.1 %

Procedure:
To a cooled (4° C.) and stirred solution of 2-bromo-4-chloroacetophenone (5.0 g, 21.41 mmol) and glacial acetic acid (2.8 mL, 49.25 mmol) in acetonitrile was added triethylamine (6.1 mL, 44.97 mmol). The reaction mixture was warmed to room temperature, than refluxed for 3 hours. The reaction mixture was extracted with ether, acetate, washed with 1N hydrochloric acid, brine, dried, and concentrated to yield 4.1 g of acetic acid 2-(4-chlorophenyl)-2-oxo-ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:21]=[C:22]([CH2:25][C:26]#[N:27])[S:23][CH:24]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-:29].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:21]=[C:22]([CH2:25][C:26]([NH2:27])=[O:29])[S:23][CH:24]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: N#CCc1cc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cs1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)Cc1cc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of (4-(7-chloro-1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-thienyl)acetonitrile (69.4 mg) obtained in Example 152 and 2M aqueous potassium carbonate solution (0.431 mL) in DMSO (3 mL) was added 30% aqueous hydrogen peroxide (0.176 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 5 hr. The reaction mixture was allowed to be cooled to room temperature, water was added thereto under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was washed with ethyl acetate and diisopropyl ether to give the title compound (55.8 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:21])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[CH2:22](Br)[C:23]#[CH:24].C1(C)C=CC=CC=1>C1COCC1>[CH2:19]([OH:20])[CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:21][CH2:24][C:23]#[CH:22]
Reactant: C#CCBr
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCOCCOCCOCCOCCOCCOCCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Sodium hydride, 60% dispersion in mineral oil, (0.86 g, 21.4 mmol) was added in portions to the solution of hexaethylene glycol (5.5 g, 19.4 mmol) in anhydrous THF (40 mL) at 0° C. (FIG. 3). The reaction mixture was stirred at 0° C. for 15 minutes then propargyl bromide, 80% in toluene, (2.4 mL, 21.4 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 3 hours. The formed sodium bromide was removed by filtration and the solvent was evaporated. The crude product was purified on SiO2 column using methanol/dichloromethane gradient 0-100% to yield 3.4 g (54%) of 1 as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.45 (t, J=2.4 Hz, 1H), 2.74 (bs, 1H), 3.61-3.71 (m, 24H), 4.21 (d, J=2.4 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 58.4, 61.7, 69.1, 70.3-70.6, 72.5, 74.5, 79.7; MS ESI (m/z): [M+H]+ calcd. for C15H29O7, 321.38; found 321.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.[CH3:30][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH3:30])[C:5]1[N:6]=[CH:7][N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester (1.01 g, 2.63 mmol) in THF (25 ml) was cooled to -78° C. Lithium hexamethyldisilazide (2.76 ml of a 1 M solution in THF, 2.76 mmol) was added dropwise and the reaction stirred 30 min at -78° C. Methyl iodide (0.164 ml, 2.76 mmol) was added and the reaction stirred a furthur 1 hr at -78° C. and then at -20° C. for 4 hrs. The reaction was quenched with water (10 ml) and saturated NaHCO3 solutuon (10 ml) and extracted with EtOAc. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. Chromatography of the residue (SiO2, 2 to 3% MeOH in CH2Cl2, gradient elotion) afforded the product.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:30])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.C(OC)(=O)C.Cl.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15](=[O:30])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)CCC(C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1C
Agent: [Pd]
Agent: Cl
Solvent: COC(C)=O
Solvent: CO
Product: COC(=O)CCC(C(=O)c1cccc(O)c1)c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A solution of methyl (RS)-5-(3-benzyloxyphenyl)-5-oxo-4-(2-methylphenyl)-pentanoate (46 g) in methanol (250 mL), methyl acetate (250 mL) and concentrated hydrochloric acid (25 mL) is treated with palladium on carbon catalyst (5%; 1.5 g) and shaken under hydrogen at atmospheric pressure and room temperature for 2 hours. The suspension is filtered, and evaporated. The residue is dissolved in ethyl acetate, washed with water, dried and evaporated, and the residue is recrystallised from a mixture of ethyl acetate and cyclohexane, giving methyl (RS)-5-(3-hydroxyphenyl)-5-oxo-4-(2-methylphenyl)pentanoate as colourless crystals (21.7 g), m.p. 101-103° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[C@H:15]([CH2:20][CH2:21][S:22][CH3:23])[NH:16][C:17](=[O:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:17]([NH:16][C@H:15]([C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:24])[CH2:20][CH2:21][S:22][CH3:23])(=[O:19])[CH3:18]
Reactant: CSCC[C@H](NC(C)=O)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCC[C@H](NC(C)=O)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
To a solution of 8.6 g (0.024 mol) of 1-(t-butoxycarbonyl) -4-(N-acetyl-L-methionyl)piperazine in 60 ml of dichloromethane was added 10 ml of trifluoroacetic acid and the mixture was stirred at room temperature overnight. The solution was extracted with water and the resulting aqueous solution was made basic with sodium hydroxide. The product was extracted with dichloromethane, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 2.1 g of 1-(N-acetyl-L-methionyl)piperazine, as an oil: IR (film) 3304, 3051, 2917, 2861, 1645, 1546, 1448, 1377 cm−1; NMR (CDCl3) δ 1.95 (m, 2 H), 2.02 (s, 3 H), 2.10 (s, 3 H), 2.54 (m, 2 H), 2.98 (m, 4 H), 3.74 (m, 4 H), 5.10 (m, 1 H), 6.40 (b, 0.5 H), 6.48 (b, 0.5 H).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.CCCCCC>C(OCC)(=O)C>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=3)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Reactant: COc1cccc(B(O)O)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cccc(-c2ccc3c(c2)C2(CCCCC2)C(=NOCc2ccccc2)N3)c1
Yield: 73.1 %

Procedure:
Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol) and 3-methoxyphenyl boronic acid (0.79 g, 5.2 mmol) according to Example 45 procedure A. The product was purified by flash silica gel chromatography; (eluant: 10:0.5 hexane:ethyl acetate) to give the desired product (0.80 g, 1.9 mmol, 75%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.43-1.78 (8H, m), 1.95-2.00 (2H, q), 3.80 (3H, s), 5.00 (2H, s), 6.82-6.86 (2H, m), 7.10-7.16 (2H, m), 7.28-7.53 (10H, m), 9.57 (1H, s); MS (ESI(−ve)) m/z 411 (M−H)−.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:21])=[CH:10][C:11]=2[Cl:20])[N:6]=1)=[O:4].[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[Cl:21][C:9]1[CH:10]=[C:11]([Cl:20])[C:12]2[C:13](=[O:19])[C:14]3[C:15](=[O:17])[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:29]=[C:3]([OH:4])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: COC(=O)c1nc2cc(Cl)cc(Cl)c2c(O)c1C(=O)OC
Reactant: NNc1ccccc1
Solvent: CCO
Product: O=c1c2c(Cl)cc(Cl)cc2[nH]c2c(O)nn(-c3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
To a stirred suspension of dimethyl-5,7-dichloro-4-hydroxyquinoline-2,3-dicarboxylate (3.00 g, 9.09 mM) in ethanol (42 mL) was added phenylhydrazine (6.26 mL, 63.6 mM). The resulting green solution was heated to reflux for 16 hours during which time a small amount of red precipitate formed. This suspension was cooled to room temperature with stirring and additional precipitation occurred to give a thick tan suspension. The solids were collected and washed with ethanol (the ethanol washes were saved). The collected solids were recrystallized from ethanol (1.20 L) to give the phenylhydrazine salt of the title compound (1.17 g) as a tan powder. This material was stirred and refluxed in glacial acetic acid (15 mL) for 2.5 hours and then cooled to room temperature with stirring. The resulting orange suspension was filtered to give the title compound (0.629 g, 19%) as an orange powder which was slightly impure. An analytical sample of the title compound was obtained from the above saved ethanol washes by filtration of a precipitate which formed after these washes stood for several hours. Recrystallization of this collected tan powder (0.126 g) from glacial acetic acid (2 mL) gave the pure title compound (0.083 g) as an orange powder, mp 364-367° C.; MS(CI): 374 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:7]=1[Cl:17])=[O:4].[NH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.C1COCC1>[Cl:17][C:7]1[C:8]([N+:14]([O-:16])=[O:15])=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][NH:18][CH2:19][CH2:20][OH:21]
Reactant: N#Cc1cc(NC(=O)CBr)c(Cl)c([N+](=O)[O-])c1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1cc(NC(=O)CNCCO)c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a solution of 2-bromo-N-(2-chloro-5-cyano-3-nitrophenyl)acetamide (30 mg, 0.094 mmol) in DCM (2 mL) was added a solution of 2-aminoethanol (5.75 mg, 0.094 mmol) in THF (2 mL) then CESIUM CARBONATE (30.7 mg, 0.094 mmol) was added. After stirring at room temperature for 1.5 h, LC-MS indicated completion. After concentration purification via flash chromatography (0-100% EtOAc in Hexane, 12 g) gave N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)amino)acetamide as a yellow solid (15 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:21])=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7]([N+:14]([O-])=O)=[C:8]([CH:10]=[CH:11][C:12]=1[Cl:13])[NH2:9].O.O.[Sn](Cl)Cl.N#N>CO>[Br:1][C:2]1[C:3]([Cl:21])=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:8]([NH2:9])[C:7]=1[NH2:14]
Reactant: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2Cl)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: N#N
Solvent: CO
Solvent: O
Product: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2Cl)c1N
Temperature: 75 °C
Reaction time: 11 h

Procedure:
3-(3-bromo-2,5-dichlorophenoxy)-4-chloro-2-nitroaniline (2.68 g, 6.50 mmol) and tin(II) chloride dihydrate (7.33 g, 32.5 mmol) were suspended in MeOH (50 mL) and heated to 75° C. under a reflux condenser and N2. After 11 hours, the reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (150 mL), after which 10% aqueous sodium carbonate (250 mL) was added with vigorous stirring until the pH was 10. The resulting suspension was filtered through celite, the filtrate was extracted with ethyl acetate. The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to yield the title compound. LRMS (M+1)=382.5.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[O:32]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:33])[N:23]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2cccc(OC)c2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)c1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-(3-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 18 & 19, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:20]1([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)=[O:14])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)c1ccc(-c2ccc(Br)cc2)o1
Reactant: NCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(NCCCN1CCOCC1)c1ccc(-c2ccc(Br)cc2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.06 g of 5-(4-bromphenyl)-2-furancarboxylic acid chloride and 2.55 g of N-(3-aminopropyl)morpholine is refluxed 6 hr with 3.0 g of anhydrous potassium carbonate in 50 ml of acetonitrile. The mixture is allowed to stir at room temperature overnight. Solvents are then evaporated and the residue is triturated with ethyl ether followed by evaporation again. This process is repeated several times. A solution of the residue in ethyl ether is allowed to stand overnight whereupon crystals are formed. After three recrystallizations from ethyl acetate, the product, 2.47 g (37.5%), melts at 83°-100° The CI and EI mass spec. are consistent with the proposed structure. The latter showed M+ =393.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23]>>[CH3:20][N:21]([CH3:26])[S:22]([NH:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH:17]=[CH:18][C:9]([NH:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[N:10]2)(=[O:24])=[O:23]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)N(C)C)cccc3n2)o1

Procedure:
The title compound, MS: m/e=361.0 (M+H+), was prepared in accordance with the general method of example 19 from N2-(5-Methyl-furan-2-ylmethyl)-quinoline-2,5-diamine and dimethylsulfamoyl chloride.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][O:3]2.C1(C)C=CC=CC=1.C[Al](C)C.[Cl:20][C:21]1[C:22]2[N:23]([C:31]([C:34](OCC)=[O:35])=[N:32][N:33]=2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.Cl>C1COCC1>[C@H:2]12[CH2:8][C@H:5]([N:6]([C:34]([C:31]3[N:23]4[CH:24]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:26]=[C:21]([Cl:20])[C:22]4=[N:33][N:32]=3)=[O:35])[CH2:7]1)[CH2:4][O:3]2
Reactant: CCOC(=O)c1nnc2c(Cl)cc(C(F)(F)F)cn12
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: C[Al](C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(c1nnc2c(Cl)cc(C(F)(F)F)cn12)N1C[C@@H]2C[C@H]1CO2
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a mixture of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (100 mg) and anhydrous THF (4 mL) was added dropwise trimethylaluminium toluene solution (1.8 M, 0.410 mL) in an ice bath. The reaction solution was stirred at the same temperature for 1 hr under argon gas atmosphere, ethyl 8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (180 mg) was added thereto, and the mixture was stirred at room temperature for 2 days. The reaction mixture was slowly added to 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (47 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.C(O)(=O)C>[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1
Reactant: CC(C)(C)CC=O
Reactant: OC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)CCN1CCC(O)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Acetic acid (31 μL), pyrrolidin-3-ol (3.47 g, 39.8 mnol) and 3,3-dimethyl-butyraldehyde (3.99 g, 39.8 mmol) were dissolved in THF (100 mL) and stirred at room temperature for 40 min. The solution was then cooled to 0° C. on an ice bath. To the cold solution sodium triacetoxyborohydride (10.98 g, 51.8 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was basified with a 5.0 M solution of NaOH and extracted with CH2Cl2 (3×150 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford 1-(3,3-dimethyl-butyl)-pyrrolidin-3-ol in (6.34 g, 92.5%), which was used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2O)n1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(OC)cc2)n1
Temperature: 100 °C

Procedure:
To a solution of 1-(5-chloro-2-hydroxy-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 2 0.2 g (0.6 mmol) in DMF (5 mL) were added potassium carbonate (0.23 g, 1.7 mmol), potassium iodide (0.1 g, 0.6 mmol) and 4-methoxybenzyl chloride (0.1 ml, 0.7 mmol). The resulting mixture was heated at 100° C. in an Emrys microwave reactor for 30 minutes. The volatiles were removed in vacuo. The crude product was purified on silica to yield 1-[5-chloro-2-(4-methoxy-benzyloxy)-benzyl]-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 13 as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[C:9]([N:11]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])[C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CON=Cc1cc(N)c(Cl)cc1Cl
Solvent: O
Solvent: CC(=O)O
Product: CON=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(Cl)cc1Cl
Reaction time: 15 h

Procedure:
18 g (82 mmol) of 5-amino-2,4-dichlorobenzaldehyde (O-methyl)oxime were added to a solution of 12.5 g (82 mmol) of 3,4,5,6-tetrahydrophthalic anhydride in 300 ml of acetic acid, whereupon the mixture was stirred for 15 hours at reflux temperature. The reaction mixture was subsequently poured into 1 l water. The product was then extracted with 300 ml of methyl tert-butyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and finally concentrated. The residue was purified by means of silica gel chromatography (eluent: hexane/ethyl acetate=4:1). Yield: 20.9 g; m.p.: 122-124° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3](OC(=O)C(O)(C1C=CC=C(OC)C=1)C1C=CC=C(OC)C=1)[CH2:2]2.OC(C1C=CC=C(OC)C=1)(C1C=CC=C(OC)C=1)C(O)=O.[OH:51][C:52]([C:62]1[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:53]([OH:55])=[O:54]>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:54][C:53](=[O:55])[C:52]([OH:51])([C:62]1[CH:63]=[CH:64][C:65]([O:68][CH3:69])=[CH:66][CH:67]=1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[CH2:2]2
Reactant: COc1ccc(C(O)(C(=O)O)c2ccccc2)cc1
Reactant: COc1cccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2cccc(OC)c2)c1
Agent: COc1cccc(C(O)(C(=O)O)c2cccc(OC)c2)c1
Product: COc1ccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1

Procedure:
This compound is prepared by an analogous method to hydroxy-bis-(3-methoxy-phenyl)-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Intermediate K) by replacing hydroxy-bis-(3-methoxy-phenyl)-acetic acid (Intermediate J) with hydroxy-(4-methoxy-phenyl)-phenyl-acetic acid (Intermediate L).