Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:51]3[N:56]=[C:55]([CH2:57][CH2:58][C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=4[CH2:65][C:66]([O-])=[O:67])[C:54]([C:69]([F:72])([F:71])[F:70])=[CH:53][N:52]=3)=[CH:46][CH:45]=2)[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[Li+].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:2][C:66](=[O:67])[CH2:65][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=1[CH2:58][CH2:57][C:55]1[C:54]([C:69]([F:70])([F:72])[F:71])=[CH:53][N:52]=[C:51]([NH:50][C:47]2[CH:48]=[CH:49][C:44]([CH:41]3[CH2:42][CH2:43][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:38])[CH2:40]3)=[CH:45][CH:46]=2)[N:56]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Temperature: 25 °C
Reaction time: 23 h
Yield: 62.1 %

Procedure:
1-Hydroxybenzotriazole (38.0 mg, 0.28 mmol), EDCl (50.0 mg, 0.32 mmol) and N,N-diisopropylethylamine (187 uL, 1.08 mmol) were added to a solution of lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I140) (124 mg, 0.215 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. Ammonium carbonate (101 mg, 1.08 mmol) was added in one portion to the stirred reaction mixture after 10 minutes and the reaction was stirred at room temperature for 23 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (65 mL) and washed with saturated NaHCO3 (65 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL) and dried over MgSO4. The solvent was removed in vacuo to afford a pale yellow oil. The crude material was purified by column chromatography on silica gel (0-80% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I141) (76 mg, 62%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.02 (s, 1H), 7.56 (d, J=7.4 Hz, 2H), 7.29-7.20 (m, 4H, obscured by solvent), 5.36 (d, J=21.2 Hz, 2H), 3.89-3.76 (m, 1H), 3.66-3.51 (m, 2H), 3.45-3.27 (m, 4H), 3.15-3.04 (m, 4H), 2.29-2.25 (m, 1H), 2.01-1.94 (m, 1H), 1.49 (s, 9H). LCMS Method C: rt 6.37 min; m/z 570.1 [M+H]+, 568.2 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][N:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH:5]=[N:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncc2cc(Cl)ccc12
Product: Clc1ccc2c(Cl)nncc2c1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 6-chlorophthalazin-1 (2H)-one (10.0 g, 55.4 mmol) and phosphoryl trichloride (50.0 mL, 538 mmol, Aldrich) was heated to 105° C. for 8 h. After cooling to RT, the mixture was concentrated, re-dissolved in CH2Cl2 and neutralized with sat aq. NaHCO3. After stirring for 3 h, the organic layer was collected and the aqueous layer was extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4, filtered through a SiO2, eluting with EtOAc, and concentrated to give the title compound as a tan solid. MS (ESI, pos. ion) m/z: 199 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]([O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])=[C:6](B(O)O)[CH:7]=1.[CH2:18]([O:21][C:22]1([CH3:55])[CH2:27][CH2:26][N:25]([C:28]2[N:33]3[CH:34]=[C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39](Br)[CH:38]=4)[N:36]=[C:32]3[CH:31]=[C:30]([CH3:44])[C:29]=2[C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[CH2:24][CH2:23]1)[CH:19]=[CH2:20].C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=CC(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:18]([O:21][C:22]1([CH3:55])[CH2:23][CH2:24][N:25]([C:28]2[N:33]3[CH:34]=[C:35]([C:37]4[CH:38]=[C:39]([C:6]5[CH:7]=[C:2]([F:1])[C:3]([CH3:17])=[CH:4][C:5]=5[O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH:40]=[CH:41][CH:42]=4)[N:36]=[C:32]3[CH:31]=[C:30]([CH3:44])[C:29]=2[C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[CH2:26][CH2:27]1)[CH:19]=[CH2:20]
Reactant: C=CC[C@H](C)Oc1cc(C)c(F)cc1B(O)O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(F)c(C)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 72 %

Procedure:
Prepared in 72% yield from (S)-(5-fluoro-4-methyl-2-(pent-4-en-2-yloxy)phenyl)boronic acid and (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 2H), 7.96-7.92 (m, 1H), 7.56-7.51 (m, 1H), 7.48-7.41 (m, 1H), 7.32 (s, 1H), 7.14-7.09 (m, 1H), 6.81 (d, J=6.5 Hz, 1H), 6.14-5.96 (m, 2H), 5.72 (ddt, J=17.1, 10.2, 7.0 Hz, 1H), 5.43 (dd, J=17.3, 1.8 Hz, 1H), 5.12-4.95 (m, 3H), 4.22-4.10 (m, 1H), 4.07-3.94 (m, 3H), 3.82 (t, J=10.5 Hz, 1H), 3.69 (s, 3H), 3.02 (d, J=7.8 Hz, 1H), 2.73 (d, J=8.5 Hz, 1H), 2.47 (d, J=0.8 Hz, 3H), 2.40-2.33 (m, 1H), 2.31 (d, J=1.5 Hz, 3H), 2.28-2.17 (m, 1H), 1.98 (dd, J=13.9, 2.6 Hz, 2H), 1.86-1.72 (m, 2H), 1.33 (s, 3H), 1.27 (s, 9H), 1.14 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1): 698.35.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:10])([CH3:9])[C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[I-:11].[Na+]>C(#N)C>[I:11][CH2:2][Si:3]([CH3:10])([CH3:9])[C:4]1[O:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(CCl)c1ccco1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C[Si](C)(CI)c1ccco1

Procedure:
Combine chloromethyl(dimethyl)furylsilane (4.4 g, 23.1 mmol) obtained from Example 2, step (a) with acetonitrile (100 mL). Add sodium iodide (3.5 g, 23.1 mmol) and stir overnight under nitrogen. Filter the mixture and remove ~40 mL of solvent via distillation.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[CH2:15][C:16](=O)[CH3:17])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S(=O)(=O)(O)O.[OH-].[NH4+]>>[N:1]1([CH2:6][C:7]2[CH:12]=[C:11]3[C:10](=[CH:9][CH:8]=2)[NH:13][C:14](=[O:19])[CH:15]=[C:16]3[CH3:17])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)CC(=O)Nc1ccc(Cn2ccnc2)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(=O)[nH]c2ccc(Cn3ccnc3)cc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
7 Parts of N-[4-(1H-imidazol-1-ylmethyl)phenyl]-3-oxobutanamide were added dropwise to 73.6 parts of concentrated sulfuric acid (exothermic reaction, the temperature rose to 90° C.). Upon complete addition, the mixture was stirred for 1 hour at 70° C. The reaction mixture was poured into crushed ice and the whole was neutralized with an ammonium hydroxide solution to pH 9. The precipitated product was filtered off and taken up in water. The whole was extracted with dichloromethane. The aqueous layer was concentrated. The crystallized product was filtered off, washed with 2-propanone and dried in vacuo at 100° C., yielding 2.25 parts (34.8%) of 6-(1H-imidazol-1-ylmethyl)-4-methyl-2(1H)-quinolinone; mp. 266.0° C. (compound 1).
Reaction SMILES: C(O[C:4]([O:10][CH2:11][CH3:12])(OCC)[CH2:5][CH3:6])C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[CH2:23][S:22][C:21]2=[S:26])=[CH:16][CH:15]=1>C(OC(=O)C)(=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:24](=[O:25])[C:23](=[C:4]([O:10][CH2:11][CH3:12])[CH2:5][CH3:6])[S:22][C:21]2=[S:26])=[CH:18][CH:19]=1
Reactant: O=C1CSC(=S)N1c1ccc(Cl)cc1
Reactant: CCOC(CC)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(CC)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O

Procedure:
Following the procedures of Example 1, triethylorthopropionate is reacted with 3-(4'-chlorophenyl)-rhodanine in acetic anhydride for 51/2 hours to give 3-(4'-chlorophenyl)-5-(1'-ethoxypropylidene)-rhodanine. To a suspension of the latter (25 g., 0.0765 m.) in 200 ml. of dioxane and 200 ml. of water is added 50 ml. of 10% sodium hydroxide solution. The mixture is stirred at room temperature for 4 hours and then concentrated in vacuo at 40°-45°C. The residual solution is washed with ether, decolorized and acidified with dilute hydrochloric acid to yield 3-(4'-chlorophenyl)-5-(1'-hydroxypropylidene)-rhodanine, m.p. 145°-149°C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O)CO>CCOC(C)=O>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Solvent: CCOC(C)=O
Solvent: OCCO
Product: O=c1[nH]nc(N2CCOCC2)c2ccccc12
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of 4-chlorophthalazin-1-one (0.49 g, 2.7 mmol), morpholine (2.4 mL, 27 mmol), and ethylene glycol (1.5 mL) was microwaved at 190° C. for 1 hour, and 210° C. for 30 minutes, diluted with EtOAc, washed with sat NaHCO3 and water, concentrated, adsorbed onto silica, and chromatographed (30% EtOAc/DCM) to give 300.0 mg of product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.27-8.20 (m, 1H), 8.00-7.79 (m, 3H), 3.86-3.77 (m, 4H), 3.07 (dd, J=10.2, 5.6, 4H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]1[C:15](C)=[CH:14][N+:13]([O-])=[C:12](C)[C:11]=1[CH3:19]>C(Cl)(Cl)Cl>[C:5]([O:4][CH2:1][C:2]1[C:15]([CH3:14])=[C:10]([O:9][CH3:8])[C:11]([CH3:19])=[CH:12][N:13]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C)c[n+]([O-])c(C)c1C
Solvent: ClC(Cl)Cl
Product: COc1c(C)cnc(COC(C)=O)c1C

Procedure:
215 ml of acetic anhydride were added dropwise at room temperature to a solution of 81.5 g of 4-methoxy-2,3,5-trimethylpyridine 1-oxide in 290 ml of chloroform. After boiling under reflux for 4 hours the solution was evaporated, the residue was dissolved in 200 ml of toluene and again evaporated. The residue was taken up in 500 ml of ethyl acetate and extracted three times with 250 ml of saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The product which remains behind as the residue was chromatographed on 400 g of silica gel with ether. There was obtained (4-methoxy-3,5-dimethyl-2-pyridyl)methyl acetate in the form of an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>[Cl-].[Zn+2].[Cl-]>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([C:2]2[NH:17][C:11]3[C:16]([CH:1]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NNc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Oc1ccc(-c2cc3ccccc3[nH]2)cc1
Reaction time: 1 h
Yield: 42.2 %

Procedure:
4-Hydroxyacetophenone phenylhydrazine (47 g.) was fused with 250 g. zinc chloride (10 min. at 180° C.), poured into 3 1. of 0.3 N HCl, heated and stirred for one hour on the steam bath, cooled to 0° and filtered. The precipitant was extracted with boiling pet. ether and allowed to stand. 2-(4-Hydroxyphenyl)indole (17 g., m.p. 224°-229°) was isolated. A well-stirred mixture of 2-(4-hydroxyphenyl)indole (0.1 mole), iodoethane (0.1 mole) and sodium bicarbonate (0.12 mole) in 200 ml. of acetone was refluxed overnight. After 400 ml. of water was added, the product 2-(4-hydroxyphenyl)-1-ethylindole (A) was filtered out. Then A was reacted with 4,4'-bis(2-bromoethoxy)-2-hydroxybenzophenone as in Example 1 to produce Compound VII.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[C:5]([O:13][CH2:14][CH2:15]I)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)C(C)C)C.O>CN(C)C=O>[C:5]([O:13][CH2:14][CH2:15][S:1][CH2:2][CH2:3][OH:4])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCS
Reactant: O=C(OCCI)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCCSCCO)c1ccccc1

Procedure:
A solution of 2-mercaptoethanol (1.52 mL), 2-iodoethyl benzoate (6.00 g) and ethyldiisopropylamine (4.53 mL) in N,N-dimethylformamide (60 mL) was stirred at 40° C. for 3 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→3:7) to give the title compound (3.77 g) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3[S:24][CH:25]=[CH:26][C:20]=3[NH:19][C:18]2=[O:27])[CH2:11][CH2:10]1.[H-].[Na+].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3[S:24][CH:25]=[CH:26][C:20]=3[N:19]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:18]2=[O:27])[CH2:13][CH2:14]1
Reactant: CCOC(=O)Cl
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccsc3c2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(=O)n(CCN2CCN(c3ccccc3OC)CC2)c(=O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
A mixture of 3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[3,2-d]pyrimidine-2,4-dione (2.62 g, 6.77 mmol) and sodium hydride (60% in mineral oil, prewashed with pentane, 325 mg, 8.13 mmol) in N,N-dimethylformamide (50 ml) was allowed to equilibrate for one hour. Ethyl chloroformate (0.78 ml, 8.13 mmol) was added to the resultant solution, and stirred at room temperature for 16 hours. The solution was poured into ice water (200 ml) and the resultant solid was collected by filtration, washed with water and air dried. The solid was purified by flash chromatography on silica gel 60 (100 g) using 1% methanol in methylene chloride as eluant to give the product (0.88 g, 28% yield) as a colorless solid, mp 121°-122° C.
Reaction SMILES: Br[C:2]1[C:3](N)=[N:4][CH:5]=[C:6](Br)N=1.[CH2:10]([O:12][CH:13]([O:22][CH2:23][CH3:24])[C:14]1[CH:21]=[CH:20]C(C=O)=[CH:16][CH:15]=1)[CH3:11].[BH4-].[Na+]>CO>[CH2:23]([O:22][CH:13]([O:12][CH2:10][CH3:11])[C:14]1[CH:15]=[CH:16][C:6]([CH2:5][NH:4][CH:3]2[CH2:2][CH2:13][O:12][CH2:10][CH2:11]2)=[CH:20][CH:21]=1)[CH3:24]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: Nc1ncc(Br)nc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)c1ccc(CNC2CCOCC2)cc1
Reaction time: 1.25 h
Yield: 183.1 %

Procedure:
To a solution of tetrahydropyran-4-amine 1 (100 g, 988.7 mmol) in MeOH (3.922 L) was added 4-(diethoxymethyl)benzaldehyde (196.1 g, 941.6 mmol) over 2 min at RT. The reaction mixture was stirred at RT for 80 min, until the aldimine formation was complete (as seen by NMR). NaBH4 (44.49 g, 1.176 mol) was carefully added over 45 min, maintaining the temperature between 24° C. and 27° C. by mean of an ice bath. After 75 min at RT, the reaction has gone to completion. The reaction mixture was quenched with 1M NaOH (1 L). The reaction mixture was partitioned between brine (2.5 L) and TBDME (4 L then 2×1 L). The organic phase was washed with brine (500 mL) and concentrated in vacuo. The crude mixture was redissolved in DCM (2 L). The aqueous phase was separated, the organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a yellow oil (252.99 g, 91% Yield); 1H NMR (400 MHz, CDCl3) δ 1.26 (t, 6H), 1.43-1.52 (m, 2H), 1.85-1.89 (m, 2H), 3.40 (td, 2H), 3.53-3.66 (m, 4H), 3.85 (s, 2H), 4.00 (dt, 2H), 5.51 (s, 1H), 7.33 (d, 2H) and 7.45 d, 2H) ppm; MS (ES+) 293.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Reactant: OB(O)c1cccc(F)c1
Product: COC(=O)c1c(O)c2cc(-c3cccc(F)c3)ccc2sc1=O

Procedure:
6-(3-Fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 3-fluorophenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.549 (s, 1H), 7.814-7.664 (m, 2H), 7.463-7.249 (m, 3H), 7.132-7.042 (m, 1H), 4.028 (s, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:11][C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C@H:33]([C:40]([OH:42])=[O:41])[CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH2:7][C:8]([O:10][NH:32][C@H:33]([C:40]([OH:42])=[O:41])[CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1)=[O:9]
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)ON[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
To a diclofenac solution (3 g, 10.13 mmoles) in tetrahydrofuan (50 ml) cooled at 0° C., 1,1′-carbonyldiimidazol (1.69 g, 10.13 mmoles) is added under stirring. After 10 minutes the solution is treated with (L) histidine (1.57 g, 10.13 mmoles) and left under stirring at room temperature for 4 hours. The reaction mixture is concentrated under vacuum, treated with methylene chloride and then washed in sequence with HCl 1% and then with water. The organic phase is anhydrified with sodium sulphate and evaporated under vacuum. The obtained residue is purified by chromatography on silica gel column, eluting with ethyl acetate. [2-[(2,6-dichlorophenyl)amino]benzeneacetyloxy](L)-histidine is obtained.
Reaction SMILES: [BH4-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]>C(O)(C)C>[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a cooled (0° C.) mixture of NaBH4 (2.15 g, 0.057 mol) and isopropanol (70 mL) was added N-acetyl-4-piperidone (8.00 g, 0.057 mol). The mixture was allowed to warm to room temperature and stirred for 16 hours. CO2 was bubbled into the reaction mixture, EtOAc (120 mL) was added, and the precipitate was removed by filtration. The filtrate was concentrated to give 8.0 g (100%) of N-acetyl-4-hydroxypiperidine as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.C1(=O)O[CH2:14][CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:14][CH2:13][OH:12])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1O
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1OCCO
Temperature: 125 °C
Yield: 56.1 %

Procedure:
4-Bromo-2-hydroxybenzonitrile (1.00 g, 5.05 mmol), ethylene carbonate (467 mg, 5.30 mmol) and potassium carbonate (348 mg, 2.52 mmol) were suspended in DMF (2.00 mL) and heated to 125° C. for 4.5 h. The mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to give the title compound (686 mg, 56%). 1H NMR (300 MHz, d4-MeOD): 3.92 (2H, t, J=4.7 Hz), 4.21 (2H, t, J=4.7 Hz), 7.26 (1H, dd, J=8.2, 1.7 Hz), 7.44 (1H, d, J=1.6 Hz), 7.53 (1H, d, J=8.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([N:12]2[C@H:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15][C@H:14]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:13]2)[CH:3]=1.C[CH2:33][N:34](C(C)C)C(C)C.CN>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:34][CH3:33])[N:5]=[C:4]([N:12]2[C@H:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15][C@H:14]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:13]2)[CH:3]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C(F)(F)F)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: C1COCCO1
Product: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
Into a 100 mL RB flask was dissolved cis-1-[6-chloro-2-(methylsulfonyl)-4-pyrimidinyl]-N-(phenylmethyl)-6-(trifluoromethyl)-3-piperidinecarboxamide (400 mg, 0.839 mmol) in 1,4-dioxane (5 mL), then added Hunig's base (0.730 mL, 4.19 mmol), and the resulting mixture was stirred for 5 minutes. Methylamine (1.677 mL, 3.35 mmol, 2M in THF) was added, and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and then CH3OH (15 mL) was added. An insoluble solid was observed and the mixture was filtered. The filtrate was concentrated to afford the title compound (301 mg) as a clear oil. LC-MS (ES) m/z=428 [M+H]+.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][O:17]/[N:18]=[C:19](/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)\[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.Cl>O1CCCC1.CO>[CH2:4]([O:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][O:17]/[N:18]=[C:19](/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)\[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2ccccc2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
Lithium hydroxide monohydrate (70.7 mg) was added to a solution of methyl E-4-(4-benzyloxybenzyloxyimino)-4-phenylbutyrate (340 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-(4-benzyloxybenzyloxyimino)-4-phenylbutyric acid (238 mg, yield 72%) as colorless crystals. m.p. 86-87° C.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)(=O)=O)=CC=1.[I-:22].[Na+]>CC(C)=O>[I:22][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]1
Reactant: [I-]
Reactant: CC1(C)CCC(CCOS(=O)(=O)c2ccc(Br)cc2)CC1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)CCC(CCI)CC1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 2-(4,4-dimethylcyclohexyl)ethyl 4-bromobenzenesulfonate (Preparation 16, 410 mg, 1 mmol) in acetone (100 ml) was added sodium iodide (370 mg, 2.5 mmol), and the mixture was heated under reflux for 3 h. After allowing the reaction mixture to cool to room temperature, the mixture was filtered and the filtrate was diluted with water (500 ml) and extracted with diethyl ether (500 ml). The organic extract was dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (220 mg, 83%).