Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11][CH3:12])[N:6]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[CH3:17][N:18]([CH3:20])[CH:19]=[C:4]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11][CH3:12])[N:6]=1)[C:3](=[O:13])[CH:2]([CH3:14])[CH3:1]
Reactant: CSc1nccc(CC(=O)C(C)C)n1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CSc1nccc(C(=CN(C)C)C(=O)C(C)C)n1
Temperature: 90 °C

Procedure:
To a solution of 3-methyl-1-(2-methylsulfanyl-pyrimidin-4-yl)-butan-2-one (4.3 g, 20.5 mmol) in anhydrous toluene (20 mL) is added N,N-dimethylformamide dimethylacetal (15.0 mL, 112.9 mmol). The reaction is heated at 90° C. for 4 h. The mixture is concentrated in vacuo to give the crude product, 1-dimethylamino-4-methyl-2-(2-methylsulfanyl-pyrimidin-4-yl)-pent-1-en-3-one. The crude product is used as it is.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:21]=[CH:22]\[CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:21]=[CH:22]\[CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(/C=C\CO)cc2c1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(/C=C\CO)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N-(4-chlorobenzyl)-6-[(1Z)-3-hydroxy-1-propenyl]-4-hydroxy-3-quinolinecarboxamide from Preparation No. 11 (0.184 g), K2CO3 (0.276 g) and iodomethane (0.062 mL) in DMF (2 mL) is heated in a stoppered flask at 90° C. for 1 h. Water is added and the mixture is allowed to cool and stir at room temperature for 16 h during which a precipitate formed. The precipitate is filtered and dried in vacuo at 60° C. for 48 h to give a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.085 g of the title compound as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10](O)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C.O>[N:27]([C@H:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:11])=[N+:28]=[N-:29]
Reactant: C[C@@H](O)c1cccc([N+](=O)[O-])c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](N=[N+]=[N-])c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 38 h
Yield: 130.1 %

Procedure:
To a solution of (1R)-1-(3-nitrophenyl)ethanol (12 g, 72 mmol) in tetrahydrofuran (220 mL), cooled to 0° C., was added diphenylphosphoryl azide (31 mL, 145 mmol) in one portion followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (22 mL, 145 mmol) dropwise over 30 minutes. The reaction mixture was allowed to warm slowly to room temperature and was stirred for 38 hours after which time the mixture was diluted with ethyl acetate (100 mL) and water (100 mL), the two phases separated and the aqueous phase extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (100 mL), dried (MgSO4) and concentrated under reduced pressure to give a black liquid. The crude liquid was purified by flash chromatography (silica, ethyl acetate/hexanes) to give 1-[(1S)-1-azidoethyl]-3-nitrobenzene (18 g) as a yellow liquid in acceptable purity.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>>[C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Agent: CCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCO
Temperature: 60 °C

Procedure:
700 g of catalyst produced in accordance with formulation 3. above were introduced into a continuous recycle-gas pilot plant having a reactor volume of 1 liter and activated as described above. Thereafter, 100 ml/h of pure lauric acid, which had been preheated to 240° C., was passed over the catalyst in the presence of hydrogen recirculated at a rate of 16 l/h under a pressure of 250 bars (corresponding to 4 m3 /h in the absence of pressure; equal to a 178.5-fold molar excess) at 270° C. Most of the lauric acid evaporated on the catalyst. The hydrogen leaving the reactor was cooled to about 60° C., the hydrogenation product separating and being relieved of pressure. 1 kg of lauric acid produced 920 g of pure lauryl alcohol which accumulated in colorless form with a saponification number of 0.5, an acid number of 0.06, a paraffin content of 0.96% and a low water content. After drying, its hydroxyl number was 299. The aldehyde content of 215 ppm of CO was very low. After about 140 hours' operation under the described conditions, the saponification number rose to 5.2. Because of this, the reactor entry temperature (reaction temperature) was increased to 300° C., as a result of which the saponification number fell below 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.[OH-].[Na+]>C1(C)C=CC=CC=1.COCCOCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:6][CH:7]=1
Reactant: Cn1ncc(C=O)c1-c1ccc(F)cc1
Reactant: O=C(O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: COCCOCCOC
Product: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Temperature: 92.5 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a mixture of 5-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (3.00 g), malonic acid (1.99 g) and bis(2-methoxyethyl) ether (9 mL) was added dropwise piperidine (1.89 mL) over about 10 min. The mixture was stirred at 90-95° C. for 1 hr. and further at 105-110° C. for 4 hrs. After cooling to 25° C., toluene (12 mL) and 1N aqueous sodium hydroxide solution (15 mL) were added and the mixture was stirred. The aqueous layer was separated and the organic layer was extracted with 1N aqueous sodium hydroxide solution (6 mL). The aqueous layers were combined and washed with toluene. The layers were adjusted to pH 3.5-4.0 with 2N hydrochloric acid at 20-30° C. and water (9 mL) was added dropwise. After stirring at 25° C. for 1 hr., the precipitated crystals were collected by filtration and washed with 20% ethanol to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (3.24 g, yield 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[CH:13][C:11]=1[NH2:12].[CH:26](=O)[CH3:27].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[C:14]1[CH:15]=[CH:16][C:10]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C:26]([CH3:27])=[N:12][C:11]=2[CH:13]=1
Reactant: COc1ccccc1Nc1ccc(-c2nc3ccccc3o2)cc1N
Reactant: CC=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(C)nc2cc(-c3nc4ccccc4o3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
To a solution of 2-(2-(2-methoxyphenyl)aminoanilin-5-yl)benzoxazole (see Working Example 30-1) (48.0 mg, 0.135 mmol) in dimethylformamide (2 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 20.5 μL, 0.405 mmol) and oxone (53.9 mg, 0.0878 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (18.2 mg, 38% yield) as white crystals.
Reaction SMILES: Cl.[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[Cl:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32](O)=[O:33])[CH:30]=2)[CH:25]=[CH:24][N:23]=1>CN(C)C1C=CN=CC=1>[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][N:17]([C:32]([C:29]4[CH:30]=[C:31]5[C:26]([CH:25]=[CH:24][N:23]=[C:22]5[Cl:21])=[CH:27][CH:28]=4)=[O:33])[CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Reactant: O=C(O)c1ccc2ccnc(Cl)c2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)c3ccc4ccnc(Cl)c4c3)CC1)C2

Procedure:
The title compound was prepared by a method analogous to that described for Example 2, using 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (Intermediate 4) and 1-chloroisoquinoline-7-carboxylic acid, and omitting 4-dimethylaminopyridine. +ESI (M+H) 452.3; 1H NMR (400 MHz, CDCl3, δ): 8.37 (s, 1H), 8.32 (d, J=5.7 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.75-7.79 (m, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.39 (s, 1H), 6.42 (s, 1H), 3.43-3.73 (m, 4H), 2.87 (s, 2H), 1.64-2.01 (m, 4H), 1.61 (s, 9H).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:14])([F:13])[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>CO>[F:4][C:5]([F:13])([F:14])[C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1cccc(OCc2ccc3ccccc3n2)c1
Yield: 15 %

Procedure:
To a solution of sodium methoxide (1.67 g, 30.84 mmol) in 100 ml of methanol is added 3-trifluoromethylphenol (3.75 ml, 30.84 mmol). After thirty minutes the solvent is removed in vacuo and replaced by 150 ml dimethylformamide. After addtion of 2-(chloromethyl)quinoline (5.48 g, 30.85 mmol) the reaction mixture is stirred overnight. The solvent is then removed and the residue is partitioned between water and chloroform. The organic layer is dried over sodium sulfate and the solvent is removed. The residue is passed through a silica gel column (eluting with 5:1 hexane-ethyl acetate) and then recrystallized from toluene to afford white crystals (1.4 g, 15%), m.p. 77°-78° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13]2[N:18]3[C:19]([C:23](OCC)=[O:24])=[C:20]([CH3:22])[N:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.O>CN(C=O)C>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]2[C:13]3[N:18]4[C:17](=[N:21][C:20]([CH3:22])=[C:19]4[C:23]2=[O:24])[CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(C)nc2cccc(NCCc3ccc(N)cc3)n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc3n(CCc4ccc(N)cc4)c(=O)c1n23
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a suspension of 80 mg (2.0 mmol) of 60% sodium hydride (dispension in oil) in 10 ml of DMF was added, while stirring at room temperature, 338 mg (1.0 mmol) of 5-[2-[4-(amino)phenyl]ethan-1-ylamino]-3-ethoxycarbonyl-2-methylimidazo[1,2-a]pyridine. The mixture was stirred for 30 minutes. The reaction mixture was poured into water, extracted with ethyl acetate. The extract was washed with an aqueous saline solution, dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to give 151 mg of the desired compound (51.7%, pale brown solid).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:16](=[O:17])[N:15]2[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:14]2=[N:13][C:12]=1[CH:23]([N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:22][C:18]1[N:15]2[C:16](=[O:17])[C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:12]([CH:23]([N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[CH3:24])[N:13]=[C:14]2[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc2nc(C(C)N3C(=O)c4ccccc4C3=O)c(Br)c(=O)n12
Reactant: OB(O)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2nc(C(C)N3C(=O)c4ccccc4C3=O)c(-c3ccccc3)c(=O)n12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of phenylboronic acid (0.177 g, 1.45 mmol), 2-(1-(3-bromo-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione (Prepared in Example 6, 0.40 g, 0.97 mmol) and potassium carbonate (0.402 g, 2.91 mmol) in a mixture of water (0.5 mL) and dioxane (9 mL) was added dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium (II) (0.040 g, 0.049 mmol) under an argon atmosphere. The mixture was stirred at 90° C. for 3 h then was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-3% MeOH in DCM) to afford 2-(1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]-pyrimidin-2-yl)ethyl)isoindoline-1,3-dione as a yellow solid. Mass Spectrum (ESI) m/e=410.1 (M+1).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11](=O)[CH2:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[Cl:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([Cl:20])=[C:13]([CH2:12][C:11]2[S:31][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:9][CH:10]=2)[CH:18]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(CNC(=O)c1ccccc1)Cc1cc(Br)ccc1Cl
Solvent: Cc1ccccc1
Product: Clc1ccc(Br)cc1Cc1cnc(-c2ccccc2)s1
Yield: 72.5 %

Procedure:
To a solution of the above 1-(3-benzoylamino-2-oxopropyl)-5-bromo-2-chlorobenzene (710 mg) in toluene (20 ml) was added Lawesson reagent (2.35 g), and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10) to give the desired 5-bromo-2-chloro-1-(2-phenyl-5-thiazolylmethyl)benzene (512 mg) as a colorless solid. APCI-Mass m/Z 364/366 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12]1([S:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-]>S(Cl)(Cl)=O.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:15]2[CH:16]=[CH:17][C:12]([S:18][CH3:19])=[CH:13][CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CSc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
4-Bromophenylacetic acid (10.8 g, 0.050 mol) was disolved in thionyl chloride (50 mL) and stirred for 30 min at 90° C. The mixture was concentrated and the residual oil was disolved in carbon disulfide (100 mL) and thioanisole (12.5 g, 0.10 mol) was added and the mixture was cooled to 0° C., and AlCl3 (14.7 g, 0.11 mol) was added portionwise. The mixture was stirred at room temperature for 16 h. The resultant dark green suspension was poured into ice water (150 mL) and extracted with CH2Cl2 (150 mL×2), washed with aqueous saturated NaHCO3 (50 mL), dried over MgSO4, and concentarted in vacuo gave the solid. The solid was suspended in ether and collected by filtration to give the title compound (8.4 g, 46%).
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([Cl:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC(C([C:17]1[CH:30]=[CH:29][CH:28]=[C:19]([C:20](C2C=CC=CC=2)=[O:21])[CH:18]=1)C)=O.S(Cl)(Cl)=O.[Cl-].[OH:36][C:37]([CH:39]([C:41]1[CH:54]=[CH:53][CH:52]=[C:43]([C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:45])[CH:42]=1)[CH3:40])=[O:38]>>[C:20]([C:3]1[CH:2]=[C:1]([CH:7]([CH3:11])[C:8]([Cl:10])=[O:9])[CH:6]=[CH:5][CH:4]=1)(=[O:21])[C:19]1[CH:28]=[CH:29][CH:30]=[CH:17][CH:18]=1.[OH:38][C:37]([CH:39]([C:41]1[CH:54]=[CH:53][CH:52]=[C:43]([C:44]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:45])[CH:42]=1)[CH3:40])=[O:36]
Reactant: CC(C(=O)Cl)c1ccccc1
Agent: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: CC(C(=O)Cl)c1cccc(C(=O)c2ccccc2)c1
Yield: 99 %

Procedure:
The procedure is identical to that for the synthesis of α-phenylpropionic acid chloride. Starting with 4.69 g (M=254.3 g, 18.4 mmol) of ketoprofen and 13.4 ml (10 eq) of thionyl chloride, 5.26 g (M=272.8 g, 18.2 mmol) of ketoprofen chloride are obtained, i.e. a yield of 99%.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:18](=[O:20])[CH3:19])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:22].[Na+].[Na+].O>C(O)(=O)C>[C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:18](=[O:20])[CH3:19])=[CH:11][CH:12]=3)[C:7](=[O:22])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(=O)c1ccc2c(c1)Cc1cc(C(C)=O)ccc1O2
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc2oc3ccc(C(C)=O)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 133.1 g (0.5 mole) of 2,7-diacetylxanthene in three liters of glacial acetic acid was added slowly over 11/2 hours 149.0 g (0.5 mole) of sodium dichromate. The resulting mixture was stirred for 2 hours at room temperature and then heated on a steam bath for 4 hours, then cooled, after which the reaction mixture was poured into 9 liters of water. The solid was filtered off and recrystallized from benzene to give the desired product. M.P. 226°-228°C.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:42][CH2:43]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:33]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:34]=[CH:35][C:30]([C:28]2[O:29][C:25]([CH3:24])=[C:26]([CH2:42][CH2:43][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=4)([CH3:14])[C:4]([OH:3])=[O:23])=[CH:8][CH:9]=3)[N:27]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CC(C)(Oc2cccc(F)c2)C(=O)O)cc1

Procedure:
A mixture of 2-(3-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 20, Part C), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 1, Part I) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionic acid 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 2H, J=8.2 Hz), 7.71 (d, 2H, J=8.2 MHz), 7.63 (d, 2H, J=7.0 Hz), 7.47 (t, 2H, J=7.6 Hz), 7.41–7.38 (m, 1H), 7.21–7.15 (m, 3H), 6.82 (d, 2H, J=8.6 Hz), 6.76–6.60 (m, 3H), 4.22 (t, 2H, J=6.3 Hz), 3.27 (d, 1H, J=14.1 Hz), 3.13 (d, 1H, J=14.1 Hz), 3.08 (t, 2H, J=6.3 Hz), 2.45 (s, 3H), 1.44 (s, 3H). MS (ES+) m/z exact mass calcd for C34H30FNO5 552.2186, found 552.2183.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=C(O)[CH:6]=[CH:7][CH:8]=1.Cl.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH:20]([C:25]([O:27][CH3:28])=[O:26])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[OH-].[NH4+]>S(=O)(=O)(O)O>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]2[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:28]=3[O:27][C:25](=[O:26])[C:20]=2[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: COc1cccc(O)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.1 %

Procedure:
A mixture of 3-methoxyphenol (28.3 g, 227 mmol) and methyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride (46.1 g, 162 mmol) is cooled in ice and treated dropwise with a solution prepared from 38 mL of water diluted to 150 mL with concentrated sulfuric acid. The mixture is stirred at room temperature for 48 hours, then added slowly to 500 g of ice and 100 mL of concentrated ammonium hydroxide. Additional ice and ammonium hydroxide are added until the pH of the mixture is 10 to 11. Stirring is continued until the initially gummy precipitate becomes granular. The solid is filtered, then stirred in 400 mL of 2.5% aqueous sodium hydroxide solution followed by 400 mL of 10% methanol in water. The solid is again filtered and recrystallized from 2-propanol to yield 24.5 g (47%) of final product; mp 118°-120° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:3])[NH2:2].[O:19]1CCOC[CH2:20]1>>[Cl:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:11])[N:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:20](=[O:19])[NH:2][C:1]2=[O:3]
Reactant: C1COCCO1
Reactant: CCOC(=O)CNc1cc(Cl)c(Cl)cc1C(N)=O
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2cc(Cl)c(Cl)cc21
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
Ethyl N-(2-carbamoyl-4,5-dichlorophenyl)aminoacetate (4.6 g) and N,N'-carbonyldiimidazole (5.12 g) were dissolved in dioxane (50 ml). The solution was evaporated to give a residue, which was stirred at 140° C. for 30 minutes. After cooling, the precipitates were collected by filtration and washed with ethanol to give ethyl 2-(6,7-dichloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl)acetate (4.40 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28](=[O:43])[NH:29][C:30]1[C:39]2[CH2:38][CH:37]([N:40]=[N+]=[N-])[CH2:36][CH2:35][C:34]=2[CH:33]=[CH:32][CH:31]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1COCC1>[CH2:20]([O:27][C:28](=[O:43])[NH:29][C:30]1[C:39]2[CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35][C:34]=2[CH:33]=[CH:32][CH:31]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [N-]=[N+]=NC1CCc2cccc(NC(=O)OCc3ccccc3)c2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC1CCc2cccc(NC(=O)OCc3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.4 %

Procedure:
Polymer supported triphenylphosphine (9.5 g, 28 mmol) was added to the product of Example 20B (4.6 g, 14 mmol) in THF (100 mL) containing 1.3 g (71 mmol) H2O. The mixture was stirred for 48 hours at ambient temperature, then diluted with THF and filtered through a pad of celite. The filter cake was washed with 3 solvents systems sequentially comprising 100% CH3OH, 1:1 CH3OH:CH2Cl2, and 100% CH2Cl2. The filtrate was concentrated under reduced pressure to provide 3.5 g (83%) of the title compound. 1H NMR (DMSO-d6) δ 8.81 (s, 1H), 7.45-7.30 (m, 5H), 7.13 (d, J=8 Hz, 1H), 7.05 (t, J=7 Hz, 1H), 6.90 (d, J=7 Hz, 1H), 5.12 (s, 2H), 3.00-2.65 (m, 4H), 2.23 (m, 1H), 1.84 (m, 1H), 1.59 (br s, 2H), 1.37 (m, 1H); MS (ESI+) m/z 297 (M+H)+.