Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[CH:22]=3)([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1ccc(C2C(=O)Nc3cc(Cl)ccc32)cc1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)cc1C
Temperature: 70 °C

Procedure:
A mixture of rac-6-chloro-3-(3,4-dimethyl-phenyl)-1,3-dihydro-indol-2-one (0.18 g, 0.66 mmol) (from Example 52b supra), 3-chlorobenzyl bromide (0.16 g, 0.77 mmol) (Aldrich), potassium iodide (0.13 g, 0.78 mmol) and potassium carbonate (0.197 g, 1.42 mmol) in acetone (5 mL) was heated at 70° C. for 4 hours. After cooling, mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate three times. The combined organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated. Residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-(3,4-dimethyl-phenyl)-1,3-dihydro-indol-2-one as yellow solid. (Yield 0.08 g, 30.8%).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>CO.C(N(CC)CC)C>[OH:19][CH2:18][CH2:17][CH2:16][NH:15][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: NCCCO
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCCCO
Temperature: 50 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
To a solution of methyl 2-chloro-3-nitrobenzoate (100 g, 0.463 mol) in methanol (800 mL) and triethylamine (129 mL) was added 3-amino-1-propanol (52.2 g, 0.696 mol), and the mixture was stirred at 50° C. for 6 hr. The mixture was concentrated and the residue was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50% ethyl acetate/n-hexane mixture (short column). The filtrate was concentrated in vacuo to give the title compound as a brown oil (86.6 g, 0.341 mol, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH3:15])[CH2:6]2.Br[CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH2:17][C:18]#[N:19])[CH3:15])[CH2:6]2
Reactant: N#CCBr
Reactant: CNC[C@H]1Cc2cc(OC)c(OC)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COc1cc2c(cc1OC)[C@@H](CN(C)CC#N)C2
Reaction time: 8 h

Procedure:
At ambient temperature, 1.04 g (5 mmol) of {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}methylamine, 0.35 mL (5 mmol/1 eq.) of bromoacetonitrile and 2.16 g (20 mmol/4 eq.) of sodium carbonate are mixed into 16 mL of methyl isobutyl ketone. Refluxing is carried out overnight, followed by drying. The residue is taken up in water and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulphate to yield, after concentration, the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10].[OH-].[Li+]>O.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cccc(Cc2cccc(F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Cc2cccc(F)c2)c1
Temperature: 60 °C
Yield: 79 %

Procedure:
A mixture of methyl 3-(3-fluorobenzyl)benzoate and lithium hydroxide (0.227 g; 5.42 mmol) in water (5 mL) and THF (5 mL) was heated at 60° C. for 3 hours and concentrated under reduced pressure. The resulting aqueous solution was acidified with a 6N solution of hydrochloric acid in water. The resulting precipitate was filtered off to give 0.198 g (79%) of 3-(3-fluorobenzyl)benzoic acid which was used without further purification.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([I:30])=[N:26][NH:27]2)=[CH:23][CH:22]=1>C1COCC1>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C@:13]12[CH2:2][C@H:20]1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([I:30])=[N:26][NH:27]2)=[CH:23][CH:22]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C1Nc2ccc(F)cc2/C1=C/c1ccc2c(I)n[nH]c2c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Temperature: 50 °C
Reaction time: 7 h
Yield: 53.9 %

Procedure:
Trimethylsulfoxonium iodide (173.8 mg, 0.789 mmol) was added to a suspension of sodium hydride (94.76 mg, 4.12 mmol) (60% dispersion in oil) in THF (4.0 mL) at room temperature. The mixture was stirred for 15 min after which time a solution of (Z)-5-fluoro-3-((3-iodo-1H-indazol-6-yl)methylene)indolin-2-one (160 mg, 0.394 mmol) in THF (2.4 mL) was added. The solution was stirred at 50° C. for 7 h prior to quenching the reaction mass over 10% NH4Cl solution (15 mL) at room temperature. The product was extracted using ethyl acetate (15 mL×2) and the organic layer was dried over Na2SO4 and evaporated in vacuo. Trituration with hexane (5 mL) gave the title compound as a cream solid (89 mg, 53.7%). 1H NMR (400 MHz, d6-DMSO) δ 13.50 (s, 1H), 10.65 (s, 1H), 7.50 (s, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.85-6.81 (m, 2H), 5.81 (d, J=8.4 Hz, 1H), 3.22 (m, 1H), 2.43 (m, 1H), 2.01 (m, 1H); MS ESI 420.0 [M+H]+, calcd for [C17H11FIN3O+H]+ 420.0.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:42]2[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=2[F:49])[S:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:42]2[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=2[F:49])[S:22]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (0.180 g, 0.226 mmol) in 4 mL of DCM at 0° C. was added TFA (1 mL). The mixture was stirred for 1 hour at 0° C. for 3 hours then concentrated in vacuo. The residue was partitioned between EtOAc (20 mL) and saturated NaHCO3 solution (20 mL) and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo to afford the desired product as a yellow gum, 0.157 g, 100%.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:19]([NH:29][C:30](=[O:47])[CH2:31][N:32]2[C:36]3[C:37]([F:42])([F:41])[C@@H:38]4[CH2:40][C@@H:39]4[C:35]=3[C:34]([C:43]([F:46])([F:45])[F:44])=[N:33]2)[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][CH:5]=[C:6]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=1>C(O)C.O.NN>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([C@@H:19]([NH:29][C:30](=[O:47])[CH2:31][N:32]2[C:36]3[C:37]([F:42])([F:41])[C@@H:38]4[CH2:40][C@@H:39]4[C:35]=3[C:34]([C:43]([F:44])([F:45])[F:46])=[N:33]2)[CH2:20][C:21]2[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=2)=[N:4][CH:5]=1
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cnc([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of Compound 41B (100 mg, 0.14 mmol) in 15 ml of ethanol, 0.05 ml of hydrazine monohydrate was added and the reaction mixture was stirred at room temperature for 10 min. The solvent was removed and the residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title product. MS (m/z) 592.20 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH2:24][CH2:25][OH:26])=[CH:11][CH:10]=1)C1C=CC=CC=1>[C].[Pd]>[OH:26][CH2:25][CH2:24][C:20]1[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH:23]=[CH:22][N:21]=1
Reactant: OCCc1nccn1CCCCc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Product: OCCc1nccn1CCCCc1ccc(O)cc1
Yield: 66.9 %

Procedure:
Using 2-(1-{4-[4-(benzyloxy)phenyl]butyl}-1H-imidazol-2-yl)-1-ethanol (10.67 g) and 10% palladium carbon (1.6 g), the same reaction as Reference Example 11-(v) was carried out to yield the titled compound (5.3 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:30]([F:33])([F:32])[F:31])[N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21](=O)[O:22]C4C=CC=CC=4)=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH2:44])(=[O:43])=[O:42]>>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH:44][C:21]([NH:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:10]2[CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]2[C:30]([F:31])([F:32])[F:33])=[CH:17][CH:16]=1)=[O:22])(=[O:43])=[O:42]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: O=C(NCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1)Oc1ccccc1
Product: O=C(NCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1)NS(=O)(=O)c1ccccc1Cl

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[4-phenyl-2-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 2-chlorobenzenesulfonamide. MS (ESI) m/z 549 [M+H]+, 547 [M−H]−, 1H-NMR (CDCl3) δ 2.86 (2H, t, J=7.3 Hz), 3.48-3.55 (2H, m), 6.58 (1H, br), 7.25-7.28 (1H, m), 7.31-7.36 (3H, m), 7.25-7.28 (1H, m), 7.39-7.47 (4H, m), 7.58-7.61 (2H, m), 7.82 (2H, dd, J=8.4, 1.4 Hz), 8.00 (2H, d, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1.[Cl:37]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[Cl:37]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nccc1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (110 mg, 0.202 mmol)[prepared in Example 25] and N-chlorosuccinimide (35 mg, 0.263 mmol) in THF (2 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification: LCMS (ES) m/z=578 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[ClH:35]>C(Cl)Cl.CCOCC>[ClH:35].[NH2:27][C:23]1([C:20]2[CH:21]=[CH:22][C:17]([C:3]3[C:2](=[O:1])[C:10]4[C:5]([C:4]=3[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:18][CH:19]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C3=C(c4ccccc4)c4ccccc4C3=O)cc2)CCC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: NC1(c2ccc(C3=C(c4ccccc4)c4ccccc4C3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of tert-butyl 1-(4-(1-oxo-3-phenyl-1H-inden-2-yl)phenyl)cyclobutylcarbamate (6 mg, 0.0133 mmol) in DCM (1.0 mL) was added 2 M HCl in ether (2.0 mL). The reaction mixture was stirred at RT for 24 h and concentrated in vacuo to give the title compound (3 mg, 64%). 1H NMR (500 MHz, CD3OD): 7.65-7.10 (m, 13H), 2.75-2.60 (m, 2H), 2.55-2.45 (m, 2H), 2.20-2.05 (m, 1H), 1.95-1.80 (m, 1H). LCMS (Method I): [M+H]+=353.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][C@@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][C@@H:25]2[OH:33])[C:8]([F:11])=[CH:9][CH:10]=1.[C:35](Cl)(Cl)=[O:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]2[C@@H:24]3[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH2:26][C@@H:25]3[O:33][C:35]2=[O:36])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1
Reactant: O=C(Cl)Cl
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H]3Cc4ccccc4[C@H]32)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 5, using the following starting materials: {6-fluoro-2′-[((1R,2S)-2-hydroxy-indan-1-ylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and phosgene (1.9M in toluene).
Reaction SMILES: [C-:1]#[N:2].[Na+].O.Cl[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH3:14]>C(O)C>[F:13][C:11]1[CH:10]=[CH:9][C:8]([CH3:14])=[C:7]([CH2:6][C:1]#[N:2])[CH:12]=1
Reactant: Cc1ccc(F)cc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(F)cc1CC#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred and refluxing mixture of 71 parts of sodium cyanide, 99 parts of ethanol and 85 parts of water is added dropwise a solution of 134 parts of 2-(chloromethyl)-4-fluoro-1-methylbenzene in 99 parts of ethanol. Upon completion, stirring is continued first for 6 hours at reflux and further overnight at room temperature. The ethanol is evaporated and the residue is taken up in 4-methyl-2-pentanone and water. The layers are separated and the aqueous phase is extracted three times with 4-methyl-2-pentanone. The combined organic phases are washed twice with water, dried, filtered and evaporated. The residue is distilled, yielding 98 parts of 5-fluoro-2-methylbenzeneacetonitrile; bp. 124°-128° C. at 10 mm. pressure.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](O)=[O:6].[CH2:34]([NH2:36])[CH3:35]>>[CH2:34]([N:36]1[CH:2]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=4)[CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[CH2:3][CH2:4][C:5]1=[O:6])[CH3:35]
Reactant: CCN
Reactant: O=C(O)CCC(=O)c1ccc(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Product: CCN1C(=O)CCC1c1ccc(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1

Procedure:
4-Oxo-4-[4-(4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)butyl)phenyl]butyric acid and ethylamine are reacted together to give N-ethyl-5-[4-(4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)butyl)phenyl ]pyrrolidin-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:17][O:11][C:5]1[C:6](=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N)cc1C(=O)O

Procedure:
A solution of 10 g of 5-aminosalicyclic acid, 100 ml of methanol and 5 ml of sulfuric acid are refluxed overnight. The reaction mixture is cooled, basified with sodium carbonate and the methanol is evaporated. The resulting solid is washed with water and dried giving 4.0 g of methyl-5-aminosalicylic acid.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>C1COCC1.O>[F:30][C:31]1[CH:38]=[CH:37][C:34](/[CH:35]=[CH:10]/[CH2:9][CH2:8][OH:7])=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OCC/C=C/c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 47.6 %

Procedure:
n-Butyllithium (1.6M in H, 100 ml) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (32.1 g) in dry THF (200 ml) cooled to 0° under nitrogen. A solution of 4-fluorobenzaldehyde (9.93 g) in dry THF (100 ml) was added dropwise and the mixture stirred under nitrogen at 0° C. for 30 min and at room temperature for a further 1.5 h. The mixture was carefully diluted with water (25 ml), the solvent evaporated in vacuo at 40° and the residue partitioned between EA (200 ml) and water (200 ml). The aqueous phase was re-extracted with EA (200 ml), the organic phase combined, dried and evaporated in vacuo to give a brown oil. Purification by FCC eluting with CX-ER (1:1) gave the title compound as a colourless oil (6.33 g). T.l.c. (CX-ER 1:1) Rf 0.13
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[OH:15].[CH3:20][N:21]1CCCC1=O>>[C:20]([C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[OH:15])#[N:21]
Reactant: CN1CCCC1=O
Reactant: COc1ccc(O)c(CC=Cc2ccccc2Br)c1
Product: COc1ccc(O)c(CC=Cc2ccccc2C#N)c1
Yield: 39 %

Procedure:
Cuprous cyanide (1.03 g; 11.5 mM) and 2-(o-bromocinnamyl)-4-methoxyphenol (1.03 g; 3.23 mM) were combined in 12 ml of anhydrous N-methylpyrrolidinone. Nitrogen was bubbled through the resulting suspension for five minutes and it was then heated to 175° under positive nitrogen pressure for 2 hours. The reaction was poured into 50 ml of conc. NH4OH and 50 ml of water. The emulsion was extracted three times with ether and the ether extracts were washed once with water. Drying over magnesium sulfate was followed by solvent removal leaving a brown oil. This crude product was purified by flash chromatography with 35% ethyl acetate in hexane on a 30 mm×6" column of silica gel. Recrystallization from ethyl acetate/hexane gave 2-(o-cyanocinnamyl)-4-methoxyphenol as a tan solid (335 mg, 39% yield) m.p. 72-74°.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+:13].[S:14](=[O:18])(=[O:17])([OH:16])[OH:15]>O>[K+:13].[K+:13].[OH:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[OH:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([S:14]([OH:16])(=[O:18])=[O:15])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1cccc(O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cc(S(=O)(=O)O)cc(O)c1O
Temperature: 20 °C

Procedure:
2,3-Dihydroxybenzoic acid (15.4 g, 0.1 moles) was dissolved in small portions at 5° C. in 80 ml of sulfuric acid containing 30% sulfur trioxide. The mixture was allowed to warm to 20° C. over 1 h and was then poured slowly into 1L of vigorously stirred ice water. The pH was adjusted to 4.5 with 30% potassium hydroxide and the solid formed was removed by filtration. The filtrate was diluted with a 1.5 fold volume of methanol and filtered again. This filtrate was evaporated to 200 ml and the pH was adjusted to 6.0 with potassium hydroxide. Acetone (500 ml) was added and the resulting white precipitate was filtered and dried to give 18 g of crude product. Chromatography of this solid on HP20 in water gave 12.8 g of pure title compound after lyophilization.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[O:28]1[CH2:30][C@H:29]1[CH2:31][O:32][C:33]1[CH:34]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:36]=[CH:37][CH:38]=1>C(Cl)(Cl)Cl.CO>[CH2:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:30][C@H:29]([OH:28])[CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:34]=3)=[CH:27][CH:26]=2)[CH2:10][CH2:11]1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)Nc1cccc(OC[C@@H]2CO2)c1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3cccc(NC(C)=O)c3)cc2)CC1
Yield: 28.9 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide 0.421 g, 1.0 mmol) was reacted with N-{3-[(2S)oxiranylmethoxy]phenyl}acetamide (0.207 g, 1.0 mmol) according to Procedure G (eluant. 20:1 chloroform-methanol) to give the title compound (0.168 g, 0.289 mmol).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CO>[O:30]1[CH2:31][CH2:32][N:27]([CH2:2][C:3]2([OH:1])[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:7][CH2:8]2)[CH2:28][CH2:29]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: C1COCCN1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CN4CCOCC4)CC3)c(F)c2)C(=O)O1
Yield: 82 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with morpholine (2.05 mmol) in methanol (15 ml) at a temperature 25° C. for 14 hours and by purifying the compound by silica gel column chromatography in 82% yield.