Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH2:13][CH:14]=[O:15])[CH3:12].C[Si](C)(C)[C:18]([F:21])([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:19][C:18]([F:21])([F:20])[CH:14]([OH:15])[CH2:13][C:5]1([CH3:12])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC1(CC=O)CCOc2ccc(F)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(CC(O)C(F)(F)F)CCOc2ccc(F)cc21
Reaction time: 1 h
Yield: 105.7 %

Procedure:
To 1.7 g (8.16 mmol) of (6-fluoro-4-methylchroman-4-yl)acetaldehyde and 1.69 mL (11.4 mmol) of trimethyl(trifluoromethyl)silane in 15 mL of tetrahydrofuran was added 1 mL (1 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. The mixture stirred for 1 hour and then an additional 9 mL (9 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added. After 18 hours, the mixture was concentrated in vacuo and diluted with 1N aqueous HCl and extracted with three 50 mL portions of diethyl ether. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford 2.4 g of crude 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman4-yl)propan-2-ol as a mixture of diastereomers. The crude oil was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([CH2:8][C:9]([O:11]C)=O)[N:4]=1)[CH3:2].[CH2:13]([C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([CH2:39][CH3:40])=[N:31][N:32]3[CH:35]3[CH2:38][CH2:37][CH2:36]3)=[CH:28][CH:27]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:21][N:22]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([CH2:39][CH3:40])=[N:31][N:32]3[CH:35]3[CH2:36][CH2:37][CH2:38]3)=[CH:28][CH:27]=2)[CH2:23][CH2:24][N:25]1[C:9](=[O:11])[CH2:8][C:5]1[NH:4][C:3]([CH2:1][CH3:2])=[N:7][N:6]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Reactant: CCc1nc(CC(=O)OC)n[nH]1
Product: CCc1nnc(CC(=O)N2CCN(c3ccc4c(CC)nn(C5CCC5)c4c3)C[C@@H]2Cc2ccccc2)[nH]1
Yield: 16 %

Procedure:
Prepared by the method outlined for Example 275 using methyl (5-ethyl-1H-1,2,4-triazol-3-yl)acetate and 6-((S)-3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole as starting materials. Product was obtained as a light yellow solid (16%). LC/MS (Method B) 3.56 min, [M+1]+ 512.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CN1CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(CO)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)N1CCC(C=O)CC1
Reaction time: 3 h
Yield: 51.5 %

Procedure:
A solution of 1-isopropylpiperidine-4-methanol (0.40 g, 2.5 mmol) and N-methylmorpholine (0.46 g, 3.8 mmol) in methylene chloride (20 mL) was treated with tetrapropyl-ammonium perruthenate (0.089 g, 0.25 mmol). After 3 h, the mixture was concentrated and the residue purified by column chromatography (SiO2: 10% to 20% methanol:methylene chloride) affording 0.20 g (50%) of the title compound.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.FC(F)(F)C(O)=O.[Pd]>[NH2:13][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[N:9][CH:10]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(NC2CCCCC2)nc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NCc1ccc(NC2CCCCC2)nc1
Yield: 63.1 %

Procedure:
Charge a solution of 6-cyclohexylamino-nicotinonitrile (1.4 g, 7.1 mmol) in methanol (70 mL) and trifluoroacetic acid (5 mL) to a pressure vessel containing 10% Pd/C (Degussa type E101, 600 mg). Pressurize the vessel to 40 psi with hydrogen and stir for 2 h. Filter the mixture through Celite®, wash with warm ethanol, and dichloromethane. Concentrate the filtrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with dichloromethane/2M ammonia in methanol (99:1 to 90:10 gradient) to obtain the title compound (920 mg, 54%). MS (ES+) m/z: 206.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.[CH3:38][O:39][C:40]1[CH:45]=[C:44]([Br:46])[CH:43]=[CH:42][C:41]=1[CH2:47][CH2:48][NH2:49].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:38][O:39][C:40]1[CH:45]=[C:44]([Br:46])[CH:43]=[CH:42][C:41]=1[CH2:47][CH2:48][NH:49][C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:14][CH:15]=1)=[O:18]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: COc1cc(Br)ccc1CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Br)cc4OC)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1; 1.90 g; 5.04 mmol), 1-hydroxybenzotriazole hydrate (0.85 g; 5.55 mmol) and 2-(2-methoxy-4-bromophenyl)ethanamine (Preparation 6; 1.28 g; 5.55 mmol) in dry dimethylformamide (15 mL) was added 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.16 g; 6.05 mmol) at ambient temperature. After stirring at ambient temperature for 4 hours, the solution was diluted with 150 mL of water, stirred for 10 minutes longer and then extracted with ethyl acetate (3×15 mL). Aqueous HCl (1M, 50 mL) was added to enable layer separation. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with hexane and ethyl acetate to provide ethyl 7-(4-(2-methoxy-4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate as a light yellow solid (1.81 g). MS (apci, pos) m/z=590.
Reaction SMILES: [CH2:1]([C:16]1[NH:17][C:18]2[C:23]([C:24]=1C)=[CH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=S)=[CH:20][CH:19]=2)[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][CH3:15].[O:31]1CCOCC1>[Ni]>[CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:31])=[CH:20][CH:19]=2)[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][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1[nH]c2ccc(C(=S)OCC)cc2c1C
Reactant: C1COCCO1
Agent: [Ni]
Product: CCCCCCCCCCCCCCCc1cc2cc(C(=O)OCC)ccc2[nH]1

Procedure:
Raney nickel (5 g) was added to a solution of ethyl 2-(n-pentadecyl)-3-methylthioindole-5-carboxylate (0.5 g) in dioxan (25 ml) and the mixture was heated on a steam bath for 1 hour. The mixture was filtered hot and the filtrate was evaporated in vacuo to give a white solid. This solid was recrystallised from petroleum ether (b.p. 60°-80° C.) to give ethyl 2-(n-pentadecyl)indole-5-carboxylate (0.35 g), m.p. 89°-91° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:12])=[C:6]([CH:8]=[CH:9][C:10]=1[CH3:11])[NH2:7])([O-:3])=[O:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:1]([C:4]1[C:5]([CH3:12])=[C:6]([NH:7][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:8]=[CH:9][C:10]=1[CH3:11])([O-:3])=[O:2]
Reactant: Brc1ccccn1
Reactant: Cc1ccc(N)c(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Nc2ccccn2)c(C)c1[N+](=O)[O-]
Temperature: 20 °C
Yield: 41.4 %

Procedure:
3.3 g of 3-Nitro-2,4-dimethylaniline and 3.2 g of 2-bromo-pyridine are mixed and the resulting mixture heated for 8 hours to 170° C. After cooling to 20° C., the greasy mass formed was dissolved in water and the solution pH then raised by addition of sodium carbonate. The resulting precipitate was recrystallized from ethanol. 2 g of the product melting at 178° to 179° C. were obtained. Another 2.1 g of the substance were obtained from the aqueous phase by concentration.
Reaction SMILES: [CH:1](=[N:8][CH:9]([CH2:15][CH2:16][C:17]#[N:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Li+].Cl[CH:26]([F:28])[F:27]>O1CCCC1>[CH:1](=[N:8][C:9]([CH:26]([F:28])[F:27])([CH2:15][CH2:16][C:17]#[N:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)Cl
Reactant: CCOC(=O)C(CCC#N)N=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)(N=Cc1ccccc1)C(F)F
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To the solution of crude ethyl 2-benzylideneamino-4-cyanobutyrate (4) obtained above, was added 0.35 L of tetrahydrofuran (THF) and 28.0 g of lithium t-butoxide (1.6 eq) at 5° C. The mixture was stirred at ˜5° C. for 0.5 h, at 20–25° C. for 2 h, and then warmed to 40° C. Chlorodifluoromethane (34.2 g, 1.8 eq) was slowly bubbled into the reaction mixture, and the temperature maintained at 40–50° C. When the exotherm subsided, bubbling was continued for another ˜15 min. and then stopped. The reaction mixture was stirred at 40° C. for 1–2 h. After the reaction was complete, the solvent was removed under reduced pressure. The crude product 5 was ready for use in the next step.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:35])[C:18]=1[CH2:19][CH:20]([C:22]1[C:27]2[CH2:28][C:29]([CH3:32])([CH3:31])[O:30][C:26]=2[C:25]([O:33][CH3:34])=[CH:24][CH:23]=1)O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:35])[C:18]=1/[CH:19]=[CH:20]/[C:22]1[C:27]2[CH2:28][C:29]([CH3:32])([CH3:31])[O:30][C:26]=2[C:25]([O:33][CH3:34])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/c2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Yield: 62 %

Procedure:
p-Toluenesulfonic acid (0.8 g) was added to a suspension of Compound 45a (1.0 g) obtained in Step A of Example 45 in toluene (27 ml), followed by heating under reflux for 30 minutes. After being allowed to stand for cooling, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution for neutralization, followed by extraction with ether. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to give Compound 67 (0.59 g, 62.2%) as yellow crystals.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([N:17]3[N:18]=[C:19]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:26][CH:25]=4)[C:20]([C:21]([NH2:23])=[O:22])=[C:16]3[NH:15][CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.CC(O)=O.[OH-].[OH-].[Pd+2]>[O:30]([C:27]1[CH:26]=[CH:25][C:24]([C:19]2[C:20]([C:21]([NH2:23])=[O:22])=[C:16]3[NH:15][CH2:14][C:11]4([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:17]3[N:18]=2)=[CH:29][CH:28]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC21CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC21CCNCC1
Reaction time: 16 h
Yield: 51.4 %

Procedure:
A mixture of 1′-benzyl-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carboxamide (50 mg, 0.10 mmol), 10% w/w Pd(OH)2/C (5 mg) in MeOH (10 mL) and HOAc (1 drop) was stirred for 16 hr under H2. The mixture was filtrated and the filtrate was concentrated to give the crude product (20 mg 51.4%) as a yellow solid. MS (ESI, m/e) [M+1]+ 390.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:6][CH:7]=1.[S:18]1[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[N:19]1>CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:24][C:20]3=[N:19][S:18][N:22]=[C:21]3[N:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C(=O)c1cccc(F)c1)c1ccncc1
Reactant: Nc1nsnc1N
Solvent: CC(=O)O
Product: Fc1cccc(-c2nc3nsnc3nc2-c2ccncc2)c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A mixture of 1-(3-fluorophenyl)-2-pyridin-4-ylethane-1,2-dione (1.5 g, 6.5 mmol) and 1,2,5-thiadiazole-3,4-diamine (1.1 g, 9.8 mmol) in AcOH (30 mL) was stirred and heated at reflux for 1 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and a solution of NaHCO3 4%. The organic phase was dried (MgSO4) and evaporated to dryness to give the title compound as a dark oil (1.7 g, 82%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:19])[CH3:4].Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>>[ClH:1].[CH3:4][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8][C:7]1([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[OH:19])[CH3:2]
Reactant: COc1cccc(Br)c1
Reactant: CN(C)CC1CC(Oc2ccccc2)CCC1=O
Agent: Cl
Product: COc1cccc(C2(O)CCC(Oc3ccccc3)CC2CN(C)C)c1
Yield: 47 %

Procedure:
The base of compound (27) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with 6:1 ethyl acetate/methanol via a silica gel column and was taken up in 2-butanone. After adding trimethylchlorosilane/water, compound (24) was obtained in a yield of 47% theoretical.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH2:16]Br)[C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K]>CN(C=O)C>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH2:16][N:22]3[C:21](=[O:23])[C:20]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]4[C:18]3=[O:28])[C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)Oc1ccc2cc(CBr)c(=O)oc2c1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2cc(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1
Yield: 48.7 %

Procedure:
7-acetoxy-3-bromomethylcoumarin (630 mg) was stirred overnight with potassium phthalimide (432 mg, 2.33 mmol) in DMF (100 mL). The reaction solvent was evaporated and the reaction partitioned between CH2Cl2 and water, then washed several times with water, then with aqueous NaHCO3. The organic layer was dried with brine, then with anhydrous sodium sulfate and evaporated. The crude product was recrystallized in acetic acid to give 7-acetoxy-3-phthalimidomethylcoumarin (375 mg, >95% purity), an off-white solid. 1H NMR (CDCl3): δ 7.73-7.97 (m, 4H), 7.53 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.13 (s, 1H), 7.03 (dd, J=7.5, 2.1, 1H), 4.82 (s, 2H), 2.33 (s, 3H).
Reaction SMILES: CO.C([O:5][C:6]([C:8]1[C:9]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:15])=[N:10][CH:11]=[N:12][CH:13]=1)=[O:7])C.[OH-].[Na+]>O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:9]2[C:8]([C:6]([OH:7])=[O:5])=[CH:13][N:12]=[CH:11][N:10]=2)=[O:15])=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cncnc1C(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)c2ncncc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a methanol solution(15 ml) of 4-(4-methoxyphenylcarbonyl)pyrimidine-5-carboxylic acid ethyl ester was added 4N NaOH(4 ml). The solution was stirred at room temperature for 15 h. Water was added to the reaction solution to dissolve the resulting solid. After removal of methanol the aqueous layer was washed with AcOEt, made pH2 with 2N HCl and extracted with AcOEt. The organic layer was washed with brine and dried over Na2SO4. After removal of the solvent the residue was recrystallized from AcOEt and hexane(1:1) to give 4-(4-methoxyphenylcarbonyl)pyrimidine-5-carboxylic acid(1.06 g) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[I-:17].[Na+]>CC(C)=O.O>[I:17][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: CCOC(=O)c1ccc(OCCCCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(OCCCI)cc1
Yield: 94.3 %

Procedure:
The mixture of ethyl 4-(3-chloropropoxy)benzoate (26.5 g), sodium iodide (49.0 g) in acetone (300 ml) was heated under reflux for 24 hr. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with 5% aqueous sodium sulfite, water, saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (34.4 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:29]=1[N:37]=[C:38]=[O:39])([CH3:27])[CH3:26]>>[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:35])[CH3:36])[C:29]=1[NH:37][C:38](=[O:39])[N:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)([CH3:26])[CH3:27]
Reactant: CCCCCCCCc1ccc(NCc2cccc(OC)c2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCCc1ccc(N(Cc2cccc(OC)c2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 18.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (3-methoxyphenylmethyl)(4-octylphenyl)amine (1.5 g) and 2,6-diisopropylphenyl isocyanate (1.12 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(3-methoxyphenylmethyl)-N-(4-octylphenyl)urea (0.46 g) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:41])[C:29]([N:31]([CH3:40])[CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:25])([F:26])[F:27])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:41])[C:29]([N:31]([CH3:40])[CH2:32][C:33]([OH:35])=[O:34])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)OC(C)(C)C)C(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cccc(OC(F)(F)F)c3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)O)C(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cccc(OC(F)(F)F)c3)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.3 %

Procedure:
To an ice-cooled solution of tert-butyl 2-[(2-{1-benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indol-3-yl}-2-oxoacetyl)(methyl)amino]acetate (5.17 g, 9.13 mmol) in methylene chloride (60 mL) was added trifluoroacetic acid (30 mL, 390 mmol). The reaction mixture was stirred for 1.5 hours at room temperature and concentrated. The residue was treated with diethyl ether and the mixture was concentrated to the precipitation point. The solid was purified by HPLC using 70% acetonitrile/0.1% formic acid in water as the mobile phase. The acetonitrile was evaporated, and the aqueous phase was extracted with ethyl acetate and washed with water and brine. The organic phase was evaporated to dryness and the residue was dried for 15 hours at 91° C. to give the title compound as a light pink solid (2.81 g, 60%), mp 178–179° C. Mass spectrum (−ESI, [M−H]−) m/z 509; 1HNMR (500 MHz, DMSO-d6): δ12.8–13.2 (br, 1H), 8.45 (m, 1H), 8.35 (d, 1H, J=8.4 Hz), 7.7–7.8 (m, 3H), 7.55–7.65 (m, 2H), 7.4–7.45 (m, 2H), 7.25–7.35 (m, 5H), 5.6 (d, 2H, J=3.5 Hz), 4.15 (d, 2H, J=21.0 Hz), and 3.0 ppm (dd, 3H, J=22.0 Hz and 0.78 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=2)=[N:4][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH2:14][O:15]CC3C=CC=CC=3)[CH2:10][CH:9]=2)=[CH:6][N:7]=1.CO>C1COCC1.[Pd]>[NH2:1][C:2]1[C:3]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3=CCC(COCc4ccccc4)CC3)cnc2N)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(C3CCC(CO)CC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.5 %

Procedure:
Methyl 4-(3-amino-6-(4-((benzyloxy)methyl)cyclohex-1-en-1-yl)pyrazin-2-yl)-2-fluorobenzoate (381 mg, 0.851 mmol) was dissolved in THF (5 mL) and then MeOH (15 mL) was added and then Pd—C (10% wet) (550 mg, 0.517 mmol) was added. The mixture was put under vacuum and purged with hydrogen and this cycle was repeated thrice and then finally under hydrogen overnight. After 14 h, LCMS indicated alkene saturation but only partial benzyl deprotection, and therefore another Pd—C (10% wet) (700 mg) was added and the mixture stirred at room temperature for another 5 h after which complete benzyl deprotection observed. The reaction mixture was filtered and concentrated in vacuo to afford 215.6 mg of the desired product as a mixture of diasteromers (cis/trans unspecified) (70%). LCMS (m/z): 360.2 (MH+), 0.71, 0.72 min.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[CH3:20][Mg]Cl>C1COCC1>[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:7]1)(=[O:5])[CH3:20]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (3.320 g, 12.2 mmol) in THF (30 mL) was added 15 mL of 3.0 M MeMgCl in THF at −15° C. under N2. After 0.5 h, the mixture was allowed to warm to rt for 4 h. The reaction mixture was then quenched with 40 mL of 1 NHCl and extracted with ethyl acetate (3×), dried over Na2SO4. After the solvent was evaporated under reduced pressure, the crude (R)-tert-butyl 3-acetylpiperidine-1-carboxylate was directly used in the next step without further purification. MS ESI +ve m/z 250 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([C:12]([O-:14])=[O:13])[C:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([C:12]([OH:14])=[O:13])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C(=O)[O-])(C(=O)[O-])c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Yield: 93 %

Procedure:
To a stirred solution of 7.58 g (22.0 mmol) of diethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalonate VI in 50 ml of absolute ethanol, maintained under nitrogen gas at ~15° C. (ice bath) is added 8.72 g (109.0 mmol, 5.0 mol -equiv.) of 50% aqueous sodium hydroxide. The temperature is maintained at <25° C. for 6 hours. The resulting suspension is diluted with 150 ml water and the pH is adjusted to ~8.0 with dilute hydrochloric acid. The solution is transferred to a separatory funnel and is extracted with 3×60 ml of methylene chloride. The aqueous layer is acidified to pH <1 with concentrated hydrochloric acid and is then extracted with 200 ml of ethyl acetate in three portions. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo to give 5.9 g 2-(2-fluoro-4-biphenylyl)-2-methyl malonic acid. This material is dissolved in 15 ml of glacial acetic acid and the solution is heated to reflux for ~17 hours. Water (15 ml) is added and the solution is allowed to cool slowly with stirring and seeding. After 1 hour stirring at room temperature, the mixture is cooled with stirring to 0°-5° C., then let stand for ~15 hours. The product is isolated and washed with a few ml of cold 50% aqueous acetic acid then dried to give 4.67 g flurbiprofen Ib of melting point 113°-115° C.