Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=[O:18])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:22][C:21]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[O:13][CH2:11][CH3:12])[CH:3]=1
Reactant: CCOc1cc(C=O)ccc1O
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Yield: 85.4 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.40 g, 2.6 mmol), 3-ethoxy-4-hydroxybenzaldehyde (0.43 g, 2.6 mmol) and cesium carbonate (0.84 g, 2.6 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 20 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10% sodium carbonate solution (1×), 0.5N sodium hydroxide solution (1×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(2-ethoxy-4-formylphenoxy)benzonitrile (0.67 g, 86%) as a yellow solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2([C:51]3[C:42](=[CH:43][C:44]4[O:49][CH2:48][CH2:47][O:46][C:45]=4[CH:50]=3)[O:41][CH2:40]2)[C:32]1=[O:52].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[CH3:19][C:15]1([CH3:18])[O:14][C@@H:13]([CH2:12][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]3([C:51]4[C:42](=[CH:43][C:44]5[O:49][CH2:48][CH2:47][O:46][C:45]=5[CH:50]=4)[O:41][CH2:40]3)[C:32]2=[O:52])[CH2:17][O:16]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC1(C)OC[C@H](CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)O1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 1′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (98%): mp 55-57° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.30-6.99 (m, 4H), 6.47-6.20 (m, 2H), 4.88-4.84 (m, 1H), 4.63-4.59 (m, 1H), 4.48-4.40 (m, 1H), 4.17-3.77 (m, 8H), 1.35-1.28 (m, 6H); MS (ES+) m/z 410.1 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[C:13]=2[F:22])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(O)(=[O:25])C.OO.S([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:25])=[C:14]([F:21])[C:13]=2[F:22])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(-c2ccc(B(O)O)c(F)c2F)cc1
Reactant: CC(=O)O
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(-c2ccc(O)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (19) (10.0 g) and acetic acid (50 ml) were put in a reaction vessel under a nitrogen atmosphere, hydrogen peroxide (31% aqueous solution; 4.5 ml) was added dropwise thereto in the temperature range of 25° C. to 30° C., and the mixture was stirred for another 2 hours at room temperature. Then, the reaction mixture was poured into a vessel containing an aqueous solution sodium hydrogensulfite (100 ml) and ethyl acetate (200 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, giving 8.9 g of 4′-butoxy-4-hydroxy-2,3-difluoro-1,1′-biphenyl (20). The yield based on the compound (19) was 97.9%.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:17]([N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:9]1[CH:8]=[C:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:26]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
3-[(2,4-Dichloro-benzoyl)-phenyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (55 mg, 0.11 mmol) was dissolved in a mixture of THF-MeOH—H2O (3:2:1) (15 mL) and then 0.66 ml of LiOH 1N was added to it. After 60 min of stirring at room temperature, solvents were removed and then partitioned between 15 ml of H2O, 4 ml of KHSO4 5% and 15 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×10 mL). The combined ethyl acetate layer was dried (MgSO4), concentrated and the residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 32 mg (60%) of 3-[(2,4-Dichloro-benzoyl)-phenyl-amino]-5-phenyl-thiophene-2-carboxylic acid. NMR 1H (DMSO, 400 MHz): Rotamer: 7.75 ppm (d, 1H, Haro); 7.68 ppm (2H, Haro); 7.53 ppm (d, Haro, minor rotamer); 7.51-7.23 ppm (m, 11H, Haro, minor rotamer); 7.17 ppm (Haro, minor rotamer).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C.Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)[C:21]([OH:23])=[O:22])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=C(C(=O)O)c2ccc(O)cc2)cc(OC)c1
Temperature: 135 °C
Reaction time: 6 h
Yield: 47 %

Procedure:
To a mixture of 3,5-dimethoxybenzaldehyde, 5, (500 g, 3.0 mol) and 4-hydroxyphenyl acetic acid, 6, (457 g, 3.0 mol) was added acetic anhydride (1.0 L, 10.60 mole) and triethylamine (420 mL, 3.0 mol). After stirring at 130-140° C. for 6 h, the mixture was cooled to room temperature. Concentrated HCl (1 L) was added to the reaction mixture slowly over 50 min while keeping the temperature between 20-30° C. The light yellow precipitate obtained was filtered and washed with water. The solid was dissolved in 3N NaOH (5 L) and stirred for 1 h and filtered. The filtrate was acidified to pH 1 with concentrated HCl while maintaining a temperature at 25-30° C. The precipitated product was filtered and washed with water to give crude product that was recrystallized from MeOH—H2O and dried at 40° C. for 6 h to yield 7 (428 g, 47%): mp 225-227° C. (lit. 226-228° C.)17; 1HNMR (360 MHz, DMSO-d6) δ12.48 (br s, 1H), 9.42 (s, 1H), 7.59 (s, 1H), 6.95 (d, J=8.0 Hz, 2H), 6.76 (d, J=8.0 Hz, 2H), 6.35 (t, J=2.2 Hz, 1H), 6.27 (d, J=2.2 Hz, 2H), 3.56 (s, 6H); MS (EI) m/z 299[M]−.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=2[S:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1cc(F)ccc1S(=O)(=O)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(=O)(=O)N1CCCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
(Step 2) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.87 g), 1-[5-fluoro-2-(pyrrolidin-1-ylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 1 (1.15 g) and potassium carbonate (1.54 g) in ethanol (10 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.20 g).
Reaction SMILES: [C:1](O)(=O)[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][CH2:16][CH2:17]C.C[C:22]1(C)[O:27][C:26](=[O:28])[CH2:25][C:24](=[O:29])O1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C(Cl)Cl>[O:29]=[C:24]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:25][C:26]([O:27][CH3:22])=[O:28]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Stearic acid (5.0 g, 17.6 mmoles) is suspended in methylene chloride (88 mL) and 2,2-dimethyl-1,3-dioxane-4,6-dione (2.7 g, 18.5 mmoles), triethylamine (6.7 mL, 48.0 mmoles) and diethyl cyanophosphonate (2.7 mL, 17.6 mmoles) are added. All solids dissolve quickly. The solution is stirred for 16 hours at ambient temperature. The reaction mixture is then diluted with methylene chloride (100 mL) and carefully washed three times with aqueous hydrochloric acid (3 M, 50 mL each), three times with water (50 mL each) and once with saturated aqueous sodium chloride (50 mL). The reaction mixture is then dried over anhydrous sodium sulfate, filtered and evaporated. The resulting syrup is dissolved in anhydrous methanol (100 mL) and heated to reflux for 16 hours. The methanol is evaporated and the crude product dissolved in hexanes with slight heating. The crude product was then loaded on silica gel (150 mL bed volume) eluting with hexanes (500 mL) then hexane:acetone (98:2 [v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to dryness. The resulting oil is dried well in vacuo. The yield is 5.2 g (87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[O:29])=[CH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][S:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:9]2=[O:29])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1C(CCSc2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1ccc(C2C(CCSc3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1-(4-fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-(4-hydroxyphenyl)azetidin-2-one (Method 13; 0.800 g, 1.944 mmol), t-butyl bromoacetate (0.32 ml, 2.17 mmol) and caesium carbonate (0.700 g, 2.15 mmol) in MeCN (15 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between water (20 ml) and DCM (20 ml). The water layer was extracted once more with DCM (10 ml) and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography using heptane:EtOAc (4:1) as eluent The title compound was obtained as a colourless oil (0.884 g; 87%). NMR (400 MHz) 1.45 (s, 9H), 2.00-2.30 (m, 2H), 2.90-3.10 (m, 2H), 3.15-3.25 (m, 1H), 4.50 (s, 2H), 4.60 (d, 1H), 6.85-7.00 (m, 6H), 7.15-7.35 (m, 6H); m/z: 526.2.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].[NH2:19][C:20]([CH:30]([F:32])[F:31])([CH2:24][C:25]1[NH:29][CH:28]=[N:27][CH:26]=1)[C:21](Cl)=[O:22]>C(OCC)(=O)C>[NH2:19][C:20]([CH:30]([F:32])[F:31])([CH2:24][C:25]1[NH:29][CH:28]=[N:27][CH:26]=1)[C:21]([NH:14][CH:10]1[C:9](=[O:15])[N:8]2[CH:11]1[S:12][CH2:13][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:7]2[C:16]([OH:18])=[O:17])=[O:22]
Reactant: NC(Cc1cnc[nH]1)(C(=O)Cl)C(F)F
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)(Cc3cnc[nH]3)C(F)F)C2SC1

Procedure:
A mixture of 1 g of 3-acetyloxymethyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 g of 2-amino-2-difluoromethyl-3-(5-imidazolyl)propionic acid chloride wherein the free amino groups are protected with tertiary-butoxycarbonyl in 50 ml of ethyl acetate is refluxed for 2 hours after which the solvent is removed leaving a residue which is chromatographed on silica gel using benzene-acetone as the eluant to give 7-[[2-amino-2-difluoromethyl-3-(5-imidazolyl)propionyl]amino]-3-acetoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid wherein the amino groups are protected with tert-butoxycarbonyl. The protected cephalosporin compound is treated with trifluoroacetic acid for 1/2 hour at 25° C. under nitrogen atmosphere then diluted with ether until precipitation stops and filtered to give the di-trifluoroacetic acid salt of the title cephalosporin which can be converted to free base by use of ion exchange resin.
Reaction SMILES: Br[CH2:2][C:3](=[O:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(C)=O>[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3](=[O:5])[CH3:4])[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
Bromoacetone (0.336 ml, 4.00 mmol) and potassium carbonate (1.38 g, 10.00 mmol) were added to a solution of 1-(2-fluoro-4-nitrophenyl)piperazine (compound of Reference Example 52; 0.390 g, 2.00 mmol) in acetone (10 ml) under ice cooling, and the mixture was stirred at room temperature for 18 hours. The residue obtained by evaporation of the solvent under reduced pressure was washed with water to give the title compound (0.467 g, 83%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][N:3]=1.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:25](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]([C:10](=[O:12])[CH3:11])[N:25]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(=O)Nc1cnc(Cl)nc1C
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1ncc2nc(Cl)ncc21
Yield: 77.3 %

Procedure:
A solution of N-(2-chloro-4-methylpyrimidin-5-yl)acetamide (9 g, 46.06 mmol, 1.00 equiv, 95%), potassium acetate (3.3 g, 32.95 mmol, 0.72 equiv, 98%), acetic anhydride (17.27 g, 165.78 mmol, 3.60 equiv) and isoamyl nitrite (13.6 g, 116.24 mmol, 2.52 equiv, 98%) in chloroform (180 mL) was reflux overnight. The resulting mixture was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum to give 7 g (73%) of 1-[5-chloro-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethan-1-one as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([CH2:15][N:16]([CH3:18])[CH3:17])[C:6]=1O)[CH3:3].[OH-:20].[Na+].[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([CH2:15][N:16]([CH3:18])[CH3:17])[C:6]=1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:8]1[C:7]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:10][C:9]=1[CH2:11][N:12]([CH3:14])[CH3:13])[CH3:3]
Reactant: CCCCCCCCBr
Reactant: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)Cc1cc(CN(C)C)c(CCCCCCCCOCCCCCCCCc2c(CN(C)C)cc(CN(C)C)cc2CN(C)C)c(CN(C)C)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
106.16 g (0.4 mol) of 2,4,6-tris(dimethylaminomethyl)phenol and 13.58 g (0.04 mol) of tetrabutylammonium hydrogen sulfate are placed in 200 ml of toluene in a 750 ml sulfonating flask having an anchor mixer, thermometer, reflux condenser and dropping funnel and at RT 80 g (1.0 tool) of a 50% aqueous NaOH solution are added dropwise in the course of 30 minutes. The suspension is then stirred for 30 minutes at 80° C. and then at the same temperature 154.5 g (0.8 mol) of octyl bromide are added in the course of 45 minutes. After a subsequent reaction period of 2 hours the mixture is cooled and filtered, and the filtrate is washed once with 30 ml of H20, dried over MgSO4, filtered and concentrated by evaporation, yielding 137.4 g of 2,4,6-tris(dimethylaminomethyl)phenyloctyl ether in the form of a brown, highly viscous liquid which no longer has an 0H band in the IR spectrum and of which the NMR analysis is in agreement with the said structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:11])[C:9]#N)[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-:18].[Na+].[OH2:20].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:11])[C:9]([OH:20])=[O:18])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:11][CH:8]([C:9]([OH:20])=[O:18])[C:6]1[CH:5]=[CH:4][C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:2]([F:1])[CH:7]=1
Reactant: O
Reactant: CC(C#N)c1ccc(-c2ccccc2)c(F)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Yield: 98 %

Procedure:
A mixture of 3.8 g (16.9 mmol) of the propionitrile (5) prepared according to the procedure of Example 11 (melting point 69°-72° C.), 3.5 g (87 mmol) of NaOH, 25 ml of H2O and 25 ml of CH3OH was allowed to reflux for 16 hours. The resulting clear, colorless solution was acidified with HCl and extracted with Et2O. The resulting Et2O solution was dried and concentrated to yield 4.0 g (98%) of the propionic acid (6) as a colorless solid having a melting point of 109°-113° C. According to the Merck Index, Ninth Edition, 1976, pure Flurbiprofen melts at 113°-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[O-:19][Mn](=O)(=O)=O.[K+].[OH2:25]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)[C:5]([C:18]([OH:19])=[O:25])=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(Cl)cc1-c1ccc(C(F)(F)F)cc1
Reactant: O
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(Cl)cc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a solution of 5′-chloro-2′-methyl-4-trifluoromethyl-biphenyl (27 g) in a mixture of t-butanol (100 mL) and H2O (200 mL) was added portionwise KMnO4 (46.9 g). At the end of the addition, the mixture was heated under reflux for 16 hours, cooled to room temperature and filtered on celite. The filtrate was then acidified with concentrated HCl and the aqueous layer was extracted with AcOEt. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound (24 g) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:39])=[C:14]([C:34](OCC)=[O:35])[C:15](=[O:33])[N:16]3[CH2:19][CH2:20][N:21]([CH3:32])[C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C([O:42][CH2:43][CH2:44][NH2:45])C>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:39])=[C:14]([C:34]([NH:45][CH2:44][CH2:43][OH:42])=[O:35])[C:15](=[O:33])[N:16]3[CH2:19][CH2:20][N:21]([CH3:32])[C:22](=[O:23])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][OH:39]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(=O)OCc2ccccc2)c1=O
Reactant: CCOCCN
Solvent: CCO
Product: CN(CCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21)C(=O)OCc1ccccc1
Product: NCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate(0.022 g, 0.041 mmol) in EtOH (3 mL) under nitrogen was treated with Ethoxyethylamine (0.012 mL, 0.20 mmol) for 15 min.@150° C. in a microwave vessel then@150° C. for an additional 1 h. After the reaction was cooled to ambient temperature the resulting suspension was filtered, and the filtered solid was washed with EtOH and Et2O then thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6 (90° C.) δ ppm 2.62 (t, J=5.67 Hz, 2 H), 2.87 (s, 3 H), 3.38 (t, J=7.14 Hz, 2 H), 3.43-3.49 (m, 2 H), 3.55 (t, J=5.95 Hz, 2 H), 3.60 (s, 3 H), 4.07-4.15 (m, 3 H), 4.41 (t, J=5.67 Hz, 3 H), 4.64 (s, 1 H), 4.87 (s, 2 H), 7.08 (t, J=8.97 Hz, 2 H), 7.16 (s, 2 H), 7.28 (d, J=2.20 Hz, 2 H), 7.29-7.34 (m, 3 H), 7.87 (s, 1 H), 8.48 (s, 1 H), 10.30 (s, 1 H); ES+ MS: 549 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([I:10])=[CH:4][C:3]=1[O:11][CH3:12].[CH:13](I)([CH3:15])[CH3:14].[H-].[Na+].O>CN(C)C=O>[I:10][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([O:1][CH:13]([CH3:15])[CH3:14])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc(I)cc(OC)c1O
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(I)cc(OC)c1OC(C)C
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 83.4 %

Procedure:
To a solution of 25.0 g (89.3 mmol) of 4-hydroxy-1-iodo-3,5-dimethoxybenzene in dimethylformamide (125 mL) were added 26.7 mL (267 mmol) of isopropyl iodide and 4.7 g (108 mmol) of a 55 wt. % sodium hydride dispersion in mineral oil. The reaction mixture was stirred at 50° C. for 2.5 hours. With ice cooling, water (125 mL) was added and the mixture was extracted with toluene-hexane (2:1). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield crude crystals. The crude crystals were recrystallized from methanol, whereby 24.0 g of 1-iodo-4-isopropoxy-3,5-dimethoxybenzene was obtained as a colorless crystalline powder (mp: 56.0 to 57.0° C., yield: 83%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[CH:4]=1.[NH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1.N1C2C(=CC=CC=2)C=C1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](OC)=[O:35])=[CH:26]1>>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[NH:10][C:34]([C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:25]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[CH:4]=2)[CH:26]=1)=[O:35]
Reactant: Nc1nccs1
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: c1ccc2[nH]ccc2c1
Product: O=C(Nc1nccs1)c1cn(Cc2cccc(Cl)c2)c2ccccc12

Procedure:
R5X=1-Bromomethyl-3-chloro-benzene; NH2A=2-aminothiazole; Indole starting material=methyl indole 3-carboxylate