Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[C:11](=[O:14])([O-])[O-].[K+].[K+].[CH3:17]N(C)C=O>C(OCC)(=O)C.C(OCC)C>[I:10][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:17][O:14][CH3:11])=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: COc1cc(O)ccc1I
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCOc1ccc(I)c(OC)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 19 %

Procedure:
A mixture of 5-hydroxy-2-iodoanisole (Reference Compound No. 5, 4.30 g, 17.2 mmol), chlorodimethylether (2.46 mL, 32.4 mmol), and potassium carbonate (5.94 g, 43.0 mmol) was suspended in anhydrous N,N-dimethylformamide (80 mL) and stirred at 50° C. for 1.5 hours. After cooling down, the reaction mixture was diluted with ethyl acetate (100 mL) and diethylether (200 mL). It was washed with water (300 mL), then the aqueous layer was extracted with diethylether (100 mL). After the organic layers were combined, washed with water (200 mL, twice) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (958 mg) as a coloreless oil. (Yield 19%)
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:42]2[CH:46]=[C:45]([N:47]3[CH2:52][CH2:51][N:50]([C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[C:54]=4[CH3:60])[C:49](=[O:61])[C:48]3=[O:62])[N:44]=[CH:43]2)C=CC=CC=1.[Cl:75]CCl>>[ClH:75].[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:44]2[C:45]([N:47]3[CH2:52][CH2:51][N:50]([C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[C:54]=4[CH3:60])[C:49](=[O:61])[C:48]3=[O:62])=[CH:46][N:42]=[CH:43]2)=[CH:5][CH:4]=1)#[N:2].[ClH:75]
Reactant: Cc1cccc(N2CCN(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(=O)C2=O)c1C
Reactant: ClCCl
Reactant: N#Cc1ccc(CO)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(c3cncn3Cc3ccc(C#N)cc3)C(=O)C2=O)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-cyanobenzyl alcohol from Step A (153 mg, 0.291 mmol) in 1.0 mL of dichloromethane at -78 ° C. was added diisopropylethylamine (0.066 mL, 0.379 mmol), followed by triflic anhydride (0.053 mL, 0.316 mmol). After 20 minutes, a solution of diketopiperazine from Step F of Example 8 (153 mg, 0.291 mmol) in 1.0 mL dichloromethane was added dropwise via syringe. The reaction was allowed to warm to room temperature over 30 minutes, then concentrated in vacuo. The solution was taken up in 2 mL of methanol and heated to reflux for one hour, then cooled to room temperature, poured into EtOAc, washed with sat, NaHCO3 soln. and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. The product was purified by flash chromatography on silica gel (2-5% MeOH/CH2Cl2), taken up in CH2Cl2 and treated with excess 1M HCl/ether solution, and concentrated in vacuo to provide the titled product hydrochloride (30.8 mg) as a white powder.
Reaction SMILES: [CH:1]1([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]#[N:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.C(N(S(F)(F)[F:28])CC)C.C([O-])(O)=O.[Na+]>>[CH:1]1([CH:6]([F:28])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]#[N:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(C(O)C3CCCC3)cc2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CC1(c2ccc(C(F)C3CCCC3)cc2)CC1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
1-{-4-[Cyclopentyl(hydroxy)methyl]phenyl}cyclopropanecarbonitrile (600.0 mg, 0.002486 mol) was dissolved in methylene chloride (10 mL, 0.2 mol), cooled to −78° C., and to the solution was added diethylaminosulfur trifluoride (0.328 mL, 0.00249 mol) (DAST). The resulting reaction mixture was warmed to rt and stirred at rt for 18 h. The reaction mixture then was poured into ice-water containing NaHCO3 and the resulting mixture was extracted with CH2Cl2 (3×). The combined organic phase was dried over Na2SO4, and concentrated to afford the product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.FC(F)(F)S([O-])(=O)=O.[CH3:23][C:24]1[N:25]([S:30](N2C=CN=C2C)(=[O:32])=[O:31])[CH:26]=[CH:27][N+:28]=1C.C(#N)C.C(N(CC)CC)C>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([S:30]([N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH3:23])(=[O:32])=[O:31])[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1nccn1S(=O)(=O)n1cc[n+](C)c1C
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cc1nccn1S(=O)(=O)N1CC=C(c2ccc(F)cc2)CC1
Yield: 52 %

Procedure:
A solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (150 mg, 700 μmol), 2,3-dimethyl-1-[(2-methyl-1H-imidazol-1-yl)sulfonyl]-1H-imidazol-3-ium trifluoromethanesulfonate (410 mg, 1.05 mmol), acetonitrile (5 mL) and triethylamine (98 μL, 700 μmol) was stirred at 25° C. for 24 h. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative LCMS to yield the desired product (117 mg, 52%). MF=C15H16FN3O2S; LCMS found for C15H17FN3O2S(M+H)+: m/z=322.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([OH:22])([CH2:20][CH3:21])[CH2:18][CH3:19])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:25]([Cl:36])(=[O:35])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[ClH:36].[CH2:20]([C:17]([O:22][C:25](=[O:35])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:18][CH3:19])[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)[CH3:21]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CCC(O)(CC)CCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OC(CC)(CC)CCN1CCC(c2noc3cc(F)ccc23)CC1
Product: Cl
Reaction time: 96 h
Yield: 76.4 %

Procedure:
To a solution of 6-fluoro-3-[1-(3-hydroxy-3-ethylpentyl)-4-piperidinyl]-1,2-benzisoxazole (2.5 g, 7.48 mmol) in DCM (100 ml) was added decanoyl chloride (1.5 ml, 7.48 mmol) at 0 C., under nitrogen. The reaction mixture was stirred for 4 days at which time it was poured into NaHCO35 (sat., 50 ml). The layers were separated and the aqueous phase was extracted with DCM (2×). The combined organics were dried, filtered and concentrated to give the crude product which was purified via flash column chromatography (silica gel, 20-40% EtOAc/DCM). The product containing fractions were concentrated to give 3.0 g (81%) of the desired product as a yellow oil. The hydrochloride salt was prepared in anhydrous ether (60 ml) and isopropanol (1 ml) with ethereal HCl. The white salt was filtered and washed with anhydrous ether, m.p.=159°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:37])[CH2:26]C(NC2C=CC(F)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15]CCN2CCOCC2)C=1.[CH2:38]([O:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.COCCOCCOC>O>[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]([NH:50][C:13]2[N:12]=[CH:11][N:15]=[C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25](=[O:37])[CH3:26])=[CH:3][C:2]=3[F:1])[CH:14]=2)=[CH:51][CH:52]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1)Nc1ccc(F)cc1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Solvent: COCCOCCOC
Solvent: O
Product: CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Temperature: 160 °C
Yield: 45 %

Procedure:
A mixture of N-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)acetamide (Compound B of Example 13, 281 mg, 1.00 mmol), 4-benzyloxyaniline (Aldrich, 398 mg, 2.00 mmol), and 2-methoxyethyl ether (2 mL) was heated at 160° C. for 45 min. The cooled mixture was treated with H2O (50 mL) and extracted with EtOAc (100 mL). The EtOAc extract was washed with brine (3×25 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (200 mg, 22%) as a purple solid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.43 (s, 1H), 8.23 (s, 1H), 7.72 (dd, 1H, J=12.5, 2.0 Hz), 7.44-7.42 (m, 4H), 7.38 (dd, 2H, J=8.0, 6.9 Hz), 7.33-7.23 (m, 3H), 6.98 (d, 2H, J=9.0 Hz), 6.07 (s, 1H), 5.07 (s, 2H), 2.05 (s, 3H); MS(ESI+) m/z 445.13 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.N1C=CC=C[CH:34]=1.[C:39]1(=[O:49])[O:44][C:42](=[O:43])[C@H:41]2[CH2:45][CH2:46][CH2:47][CH2:48][C@@H:40]12>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH:40]1([C:39]([O:20][CH2:19][C@H:17]2[O:16][N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]4[CH:6]=[CH:5][C:4]([N:21]5[CH2:25][C@H:24]([CH2:26][N:27]6[CH:31]=[CH:30][N:29]=[N:28]6)[O:23][C:22]5=[O:32])=[CH:3][C:2]=4[F:1])=[CH:9][N:10]=3)[CH2:18]2)=[O:49])[CH2:48][CH2:47][CH2:46][CH2:45][CH:41]1[C:42]([O:44][CH3:34])=[O:43]
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: c1ccncc1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)C1CCCCC1C(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydro-3-isoxazolyl]-3-pyridinyl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 60 mg, 0.13 mmol) was suspended in 2 mL of anhydrous dimethylformamide. Anhydrous pyridine (1 mL, 12 mmol), 4-dimethylaminopyridine (MAP) (10 mg, 0.08 mmol) and cis-hexahydrophthalic anhydride (85 mg, 0.55 mmol) were added and the solution was stirred for 16 hours at room temperature during which the mixture became a clear solution. The reaction was quenched with 1 mL of methanol and purged with diazomethane generated from 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG) in a diazomethanegenerator (Aldrich, cat. No. Z41,173-6) until all product was converted into its methyl ester as judged by LCMS and the solution turned yellow by excess diazomethane. The solvent was removed and the product purified by chromatography on silica using a gradient from 0–20% methanol in dichloromethane that yielded 40 mg (48%) of the title compound as an off white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[F:25])=[O:17]>C(O)C>[CH2:7]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH3:15])=[C:19]([F:25])[CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1ccc(OCc2ccccc2)cc1F

Procedure:
Potassium carbonate (5.5 g, 40.0 mmol) and benzyl bromide (4.6 ml, 38.9 mmol) were added to a solution of 2-fluoro-4-hydroxyacetophenone (5.0 g, 32.4 mmol) in ethanol (50 ml), and the mixture was heated at reflux temperature for 16 h. The reaction mixture was evaporated to a residue to which 2 N HCl (100 ml) was added. This mixture was extracted with ethyl ether (3×60 ml) and the combined extracts were washed with brine (10 ml), dried (MgSO4), and evaporated to a residue, which was crystallized from ethyl acetate (7.4 g, 93%): MS(ES) m/z 245 (M+).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[N:5][OH:6])[NH2:4].Cl.[C:8]1(N=CC(OCC)=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:21](O)[CH3:22]>>[Cl:1][CH2:2][C:3]1[N:4]=[C:21]([CH2:22][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:6][N:5]=1
Reactant: CCO
Reactant: NC(CCl)=NO
Reactant: CCOC(=O)C=Nc1ccccc1
Agent: Cl
Product: ClCc1noc(Cc2ccccc2)n1

Procedure:
A mixture of chloroacetamide oxime, 11.0 g. (0.10 mole), and ethyl phenyliminoacetate hydrochloride, 22 g. (0.11 mole), in 80 ml. of absolute ethanol is refluxed for one hour. After cooling, the ammonium chloride which precipitates is filtered off and the alcohol is removed in vacuo. Upon steam distillation of the residue, 7.0 gm. of 3-chloromethyl-5-benzyl-1,2,4-oxadiazole is obtained, n20 1.5386.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:20][C:21](=O)[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([NH:8][C:9]2[S:10][CH:20]=[C:21]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:11]=2)=[N:6][CH:7]=1
Reactant: O=C(CBr)CCc1ccccc1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Product: Brc1cnc(Nc2nc(CCc3ccccc3)cs2)c(Oc2ccccc2)c1

Procedure:
Prepared according to the method of Example 7 Step E from 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea and 1-bromo-4-phenylbutan-2-one. 1H NMR (d6-DMSO) δ 8.26 (m, 1H), 7.45 (m, 3H), 7.31-7.11 (m, 8H), 6.74 (s, 1H), 2.92 (m, 4H). Mass spectrum (apci) m/z=452.3 (M+H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>CCO>[C:13]([C:14]1[CH:15]=[C:16]([NH2:17])[N:10]([C:5]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([CH3:2])[CH:4]=2)[N:11]=1)([CH3:20])([CH3:19])[CH3:12]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(NN)cc1C
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1C
Yield: 89.6 %

Procedure:
A black solution of 3,4-dimethylphenyl hydrazine hydrochloride (Apollo, 1.73 g, 10.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.38 g, 11.0 mmol) in EtOH (20 mL) was stirred at reflux for 5 h. The cooled solution was concentrated in vacuo, redissolved in diethyl ether (20 mL) and washed with aqueous NaOH solution (1M, 20 mL). The aqueous was extracted with diethyl ether (2×20 mL), then the combined organics washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave the title compound (2.18 g, 90%). LCMS (Method 3): Rt 2.75 min, m/z 244 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2([C:23]([OH:25])=[O:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[H-].[Na+].IC.[OH2:30].[CH3:31]N(C)P(=[O:40])(N(C)C)N(C)C>>[C:23]([OH:25])(=[O:24])[C:10]([OH:40])=[O:30].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2([C:23]([O:25][CH3:31])=[O:24])[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1
Reactant: O
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC(=O)C1(Nc2ccc(OC)cc2)CCN(Cc2ccccc2)CC1
Product: O=C(O)C(=O)O
Temperature: 15 °C
Reaction time: 2 h

Procedure:
55 Parts of 4-[(4-methoxyphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxylic acid are dissolved in 400 parts of dry hexamethylphosphoric triamide at 95° C. The solution is cooled to 15° C and 4.8 parts of sodium hydride dispersion 78% are added. After stirring for 2 hours at room temperature, 26.5 parts of iodomethane are added dropwise at a temperature below 20° C. Upon completion, stirring is continued for 24 hours at room temperature. The reaction mixture is poured onto 600 parts of water and the product is extracted with methylbenzene. The extract is washed once with a sodium hydroxide solution 10% and twice with water, dried, filtered and evaporated. The residue is converted into the ethanedioate salt in 2-propanol. The salt is filtered off and crystallized from 2-propanol, yielding methyl 4-[(4-methoxyphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxylate ethanedioate; mp. 177°-185° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:32])[C:18]([OH:31])([C:23]3[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=3)[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:33])[CH:12]=2)=[CH:7][C:6]=1[Cl:34])=[O:4].Cl.[OH-].[Na+]>O1CCOCC1.O1CCCC1.CO>[Cl:34][C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:32])[C:18]([OH:31])([C:23]3[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=3)[C:19]([F:21])([F:20])[F:22])=[C:13]([Cl:33])[CH:12]=2)[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(c1ccc(-c2ccc(C(=O)O)c(Cl)c2)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F

Procedure:
In analogy to Example 175, step 6, 3,3′-dichloro-4′-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxy-pyridin-3-yl)-1-methyl-propyl]-biphenyl-4-carboxylic acid methyl ester (Example 178) was treated first with aqueous HCl in dioxane, followed by aqueous NaOH in tetrahydrofuran/methanol to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=484.1 [M−H+].
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:30]=[CH:31]/[C:32](O)=[O:33]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32](=[O:33])/[CH:31]=[CH:30]/[C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:28])([F:27])[F:29])[C:20]=3[F:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1F
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3cccc(C(F)(F)F)c3F)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-fluoro-3-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Cl.[F:12][C:13]([F:17])([F:16])[CH2:14][NH2:15].O>CN1CCCC1=O>[F:12][C:13]([F:17])([F:16])[CH2:14][NH:15][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(NCC(F)(F)F)nc1
Temperature: 230 °C
Reaction time: 0.75 h
Yield: 34.9 %

Procedure:
A mixture of 1-(6-chloropyridin-3-yl)ethanone (1.0 g, 6.43 mmol) and 2,2,2-trifluoroethanamine hydrochloride (1.57 g, 11.8 mmol) in 1-methylpyrrolidin-2-one (10 mL) is stirred at 230° C. for 45 minutes under microwave irradiation. The reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (4:1 to 1:1) to give 490 mg (35% yield) of the title compound as a yellow solid.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])=[O:5].[OH:18]S(O)(=O)=O>>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=1)[NH:6][C:4](=[O:5])[C:3]2=[O:18]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(NC(=O)C=NO)c([N+](=O)[O-])c1
Product: COc1cc2c(c([N+](=O)[O-])c1)NC(=O)C2=O
Temperature: 80 °C

Procedure:
2-Hydroxyimino-N-(4-methoxy-2-nitro-phenyl)-acetamide (5 g, 22 mmol) was added portion wise to a hot solution of conc. H2SO4 (20 mL, 4 vol) at 60° C. After completion of the addition, temperature was raised to 80° C. and maintained the same for one hour. After completion of the reaction, the reaction mixture was poured on to the crushed ice and the resulting precipitate separated was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as brick red colored solid which was used directly for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:19])[C:12]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH2:13]>S(=O)(=O)(O)O>[CH:14]1([CH:12]2[CH2:13][C:4]3[C:3](=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=3)[C:11]2=[O:19])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)C1CCCC1
Agent: O=S(=O)(O)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)C2
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
2',3'-Dichloro-4'-methoxy-2-cyclopentylacrylophenone (33.3 g.) is dissolved in 98° sulfuric acid (150 ml.) and stirred at 20° C. for 1.5 hours. The solution then is added dropwise with stirring to ice water. The aqueous phase is decanted from the gummy product and fresh water is added. After 20 hours the gum solidifies and is crystallized from hexane-benzene (3:1) to obtain 2-cyclopentyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 116°-117° C.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:13]([C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19])([O-:15])=[O:14].Cl>C(O)C.C(OCC)C.C(Cl)(Cl)(Cl)Cl>[N+:13]([C:16]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:17]=1[C:18]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:19])([O-:15])=[O:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Mg]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 96.2 %

Procedure:
A mixture of magnesium turnings (4.94 g) and carbon tetrachloride (2 ml) in ethanol (35 ml) was warmed to 50° C. until the reaction started. Diethyl ether (150 ml) was then added cautiously, with stirring. A solution of diethyl malonate (32.5 g) in diethyl ether (50 ml) was then added dropwise, then stirred and heated at reflux for 2 hours. After cooling the mixture, diethyl ether (150 ml) was added. A solution of 2-nitro-4-trifluoromethylbenzoyl chloride (50.7 g) in diethyl ether (100 ml) was added dropwise. The mixture was heated at reflux for 2 hours. After cooling, hydrochloric acid (2M,200 ml) was added and the layers were separated. The organic layer was washed with water, dried (anhydrous sodium sulphate), and filtered. The filtrate was evaporated to dryness, to give diethyl 2-nitro-4-trifluoromethylbenzoylmalonate (72.6 g), in the form of an off-white solid, m.p. 60° C.
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[S:6][CH2:5][CH2:4]1)=O.[CH3:22][NH2:23]>C1C=CC=CC=1.CO>[CH3:22][N:23]=[CH:1][CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: O=CC1CCSc2c1c1ccccc1n2-c1ccccc1
Reactant: CN
Solvent: CO
Solvent: c1ccccc1
Product: CN=CC1CCSc2c1c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-formyl-9-phenyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (1.4 g) in absolute benzene (20 ml) is added a 30% solution (1.5 ml) of methylamine in methanol. The mixture is stirred at room temperature for 3 hours and evaporated to give 4-methyliminomethyl-9-phenyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole as orange solid. The product is dissolved in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) and sodium borohydride (274 mg) is added thereto. The mixture is stirred at room temperature for 1 hour and evaporated.