Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH2:31][NH:30][CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]=O>>[CH:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH2:31][N:30]([CH3:32])[CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CCC4CCCCC4)n2)CNCC3)cc1
Reactant: C=O
Product: Cc1nccn1-c1ccc(Nc2nc(CCC3CCCCC3)c3c(n2)CCN(C)C3)cc1
Yield: 10.4 %

Procedure:
4-(2-Cyclohexylethyl)-6-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (20.0 mg, 10.4%) was synthesised from 4-(2-cyclohexylethyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and formaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 431.4 (M+H)+
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([CH2:28]O)=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([N:38](CC)CC)C.CS(Cl)(=O)=O.O.N>C(#N)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([CH2:28][NH2:38])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCN(CC)CC
Reactant: OCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: O
Solvent: CC#N
Product: NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
[6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-(trifluoromethyl)pyridin-3-yl]methanol (1.55 g) and triethylamine (0.4 g) were added to acetonitrile (30 ml), and an acetonitrile solution (10 ml) of methanesulfonyl chloride (0.4 g) was added dropwise thereto under ice cooling. Upon the completion of the dropwise addition, the reaction liquid was stirred at room temperature for 1 hour, and then the resulting solution was added dropwise to a mixture solution containing 28% ammonia water (30 ml) and acetonitrile (50 ml), which had been prepared separately, under ice cooling. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure and the purified by silica gel chromatography to obtain 1-[6-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-(trifluoromethyl)pyridin-3-yl]methanamine (1.0 g).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.O1CCOCC1.O.[F-].[Cs+].[C:34]1(B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37][CH2:36][CH:35]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:34]4[CH2:38][CH2:37][CH2:36][CH:35]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3=CCCC3)ccc12
Yield: 4.1 %

Procedure:
2,6-Dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (300 mg, 0.74 mmol, 1.00 eq) in 1,4-Dioxane (6 mL, 69.44 mmol, 20 V)/Water (2 mL, 111.02 mmol, 6.67 V) was taken in a microwave vial and to this were added Cesium fluoride (338.80 mg, 2.23 mmol, 3.00 eq) and 2-Cyclopent-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (172.97 mg, 0.89 mmol, 1.20 eq). The reaction mixture was purged with nitrogen for 15 min and bis(triphenyl phosphine)palladium (II) dichloride (25.16 mg, 0.04 mmol, 0.05 eq) was added and heated under microwave at 130 OC for 1 h. The reaction mixture was concentrated and the crude obtained was purified by flash column chromatography to afford the title compound (12 mg, 0.03 mmol, 3.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.85 (t, J=5.64 Hz, 1H), 7.95-7.98 (m, 3H), 7.75 (d, J=9.0 Hz, 1H), 6.88 (s, 1H), 3.26-3.29 (m, 2H), 2.85-2.89 (m, 2H), 2.60 (s, 2H), 1.96-2.04 (m, 4H), 1.81-1.86 (m, 3H), 1.74-1.77 (m, 2H), 1.23-1.33 (m, 2H). m/z: 405 [M+H]+
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:26])[C:11]1[N:12]=[C:13]([C:16]2[CH:17]=[N:18][N:19]([CH3:25])[C:20]=2[C:21]([O:23][CH3:24])=[O:22])[S:14][CH:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:15]1[S:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([CH3:25])[C:20]=2[C:21]([O:23][CH3:24])=[O:22])=[N:12][C:11]=1[CH:10]([F:9])[F:26]
Reactant: COC(=O)c1c(-c2nc(C(F)F)cs2)cnn1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2nc(C(F)F)c(Br)s2)cnn1C
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 106.3 %

Procedure:
N-bromosuccinimide (391 mg) was added to an N,N-dimethylformamide (3.6 ml) solution of the methyl 4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (200 mg) obtained in (Example 1.3) <Step 1>, and the obtained mixture was then stirred in a nitrogen atmosphere at 80° C. for 40 minutes. Thereafter, N-bromosuccinimide (391 mg) was further added to the reaction solution, and the obtained mixture was then stirred in a nitrogen atmosphere at 80° C. for 15 hours. Thereafter, a sodium thiosulfate aqueous solution (40 ml) and a saturated sodium hydrogen carbonate aqueous solution (60 ml) were successively added to the reaction solution, and the reaction mixture was then extracted with ethyl acetate (60 ml) twice. Organic layers were gathered. The gathered organic layer was washed with a saturated saline (100 ml) three times, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then dried under reduced pressure, so as to obtain the title compound (274 mg) in the form of a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:22][CH:21]=[CH2:20])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2
Reactant: Cc1cc2ccc(=O)oc2cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc2oc(=O)ccc2cc1C

Procedure:
A mixture of 6-methyl-7-hydroxycoumarin (I) (14.5 g), anhydrous K2CO3 (5 g), allyl bromide (15 ml) and acetone (400 ml) was refluxed for 12 h under stirring. From the refluxed mixture the solid was filtered and washed several times with acetone. The acetonic solution and the pooled washings were concentrated to dryness and the residue crystallized from MeOH, yielding 6-methyl-7-allyloxycoumarin (IV) (11.4 g; m.p. 124°-5° C.). ##STR9##
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH:19]([NH:37][OH:38])[CH2:20][S:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:16][C:11]=2[O:10][CH2:9]1>C1COCC1.C(O)=O>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH:19]([N:37]([OH:38])[CH:1]=[O:3])[CH2:20][S:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[CH2:28][CH2:29]3)(=[O:23])=[O:22])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: O=S(=O)(CC(C#Cc1ccc2c(c1)OCO2)NO)N1CCN(c2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CN(O)C(C#Cc1ccc2c(c1)OCO2)CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
Acetic anhydride (1.00 mL; 10.59 mmol) was added dropwise to formic acid (5 mL) at 0° C. and the mixture was stirred for 30 min. 1 mL of this solution was then added to a solution of N-[3-(1,3-benzodioxol-5-yl)-1-({[4-(4-fluorophenyl)-1-piperazinyl]sulfonyl}methyl)-2-propynyl]hydroxylamine (150.0 mg; 0.34 mmol) in THF (3 mL) and formic acid (0.7 mL) and the mixture was stirred overnight. The reaction mixture was then evaporated to dryness, the residue dissolved in MeOH and heated at 60° C. for 3 h. The solution was allowed to cool down to rt and the precipitate obtained was filtered. It was redissolved in EtOAc and precipitated again in pentane, filtered and dried under reduced pressure to give the title compound (1) (80 mg, 50% yield) as a white solid. HPLC, Rt: 3.58 min (purity: 96.9%). LC/MS, M+(ESI): 476.3, M−(ESI): 474.3. 1H NMR (CDCl3) δ: 9.55 (s, 0.5H), 9.12 (s, 0.5H), 8.1 (m, 1H), 6.90-7.09 (m, 7H), 6.05 (s, 2H), 4.81 (s, 0.5H), 4.61 (s, 0.5H), 3.62 (m, 2H), 3.31 (m, 4H), 3.14 (m, 4H).
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)=O.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=C)=[CH:17][CH:16]=1.C(N(C)C)C1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:2][C:4]2[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=2)=[CH:17][CH:16]=1
Reactant: N#CC=Cc1ccc(C(=O)Cl)cc1
Reactant: C=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: N#CC=Cc1ccc(C=Cc2ccc(Br)cc2)cc1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 11 %

Procedure:
2.13 g (11.1 mmols) of 4-chloroformylcinnamonitrile, 2.24 g (11.1 mmols) of 4-bromostyrene, 1.51 g (11.1 mmols) of N-benzyldimethylamine and 0.0246 g (0.11 mmol) of palladium acetate are added under argon to 30 ml of p-xylene, and the reaction mixture is stirred at 130° C. for 1.5 hours. The crude product which has been precipitated is filtered off at room temperature and is recrystallised from methanol and then from carbon tetrachloride. 0.38 g (11% of theory) of 4-bromostilbene-4'-acrylonitrile are obtained; melting point 258° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].N1C=CC=C[CH:22]=1>>[CH3:22][S:13][CH2:12][C@@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: c1ccncc1
Product: CSC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O

Procedure:
When glutathione was complexed with Cr(II), no measurable oxidation of the Cr(II) was observed until the appropriate pyridine derivative was added to the complex mixture. At this time, the 280 nm-340 nm charge transfer peak also appeared. At no time were the 450 nm and 585 nm peaks attributable to Cr--S observed. Replacing glutathione with S-methylglutathione gave identical results.
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]1=[O:16])([CH3:3])[CH3:2].[CH:17]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[CH2:10]([C:9]1[N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:16])[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1)[CH3:17]
Reactant: CCOC(=O)c1ccc(C)n(C(C)C)c1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1ccc(CC)n(C(C)C)c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
To a stirred solution of ethyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in Example 1(5) (515 mg, 2.0 mmol) in tetrahydrofuran (3 mL) was added a solution of lithium diisopropylamide (2.0M, 1.0 mL, 1.0 mmol) dropwise at −30° C. over 40 min. After addition, the mixture was stirred at 0° C. for 3 h. Then, methyl iodide (426 mg, 3.0 mmol) was added at 0° C., and the mixture was stirred at room temperature for 16 h. The mixture was quenched with water (5.0 mL), and extracted with dichloromethane (30 mL×3). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified with plate TLC eluting with n-hexane/ethyl acetate (v/v=2/1) to give 110 mg (23%) of the title compound as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](F)[N:17]=3)[C:13]([Cl:23])=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[F:24][C:25]1[CH:26]=[C:27]([CH2:31][NH2:32])[CH:28]=[CH:29][CH:30]=1>CS(C)=O>[NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:32][CH2:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=4)[N:17]=3)[C:13]([Cl:23])=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: NC[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Reactant: NCc1cccc(F)c1
Solvent: CS(C)=O
Product: NC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 105 °C
Reaction time: 40 h

Procedure:
A mixture of N-(trans-4-(aminomethyl)cyclohexyl)-5′-chloro-6-fluoro-2,4′-bipyridin-2′-amine (15 mg, 0.045 mmol), DMSO (0.35 ml), TEA (0.012 ml, 0.090 mmol) and (3-fluorophenyl)methanamine (50.5 mg, 0.403 mmol) reaction mixture was flushed with argon and then stirred at about 105° C. for about 40 hours. The excess (3-fluorophenyl)methanamine was removed under reduced pressure to yield a crude material, which was mixed with 0.5 ml DMSO, filtered, purified by prep LC, and then lyapholized to yield 11.2 mg of the title compound, as a TFA salt. LCMS (m/z): 440.2 (MH+), retention time=0.62 min. 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.11-1.28 (m, 2H) 1.28-1.47 (m, 2H) 1.67 (ddd, J=10.92, 7.40, 3.66 Hz, 1H) 1.92 (d, J=11.72 Hz, 2H) 2.14 (d, J=10.55 Hz, 2H) 2.83 (d, J=6.74 Hz, 2H) 3.57-3.69 (m, 1H) 4.63 (s, 2H) 6.84 (d, J=8.79 Hz, 1H) 6.90 (s, 1H) 6.94 (d, J=7.03 Hz, 1H) 6.96-7.03 (m, 1H) 7.10 (d, J=9.96 Hz, 1H) 7.18 (d, J=7.62 Hz, 1H) 7.29-7.39 (m, 1H) 7.69-7.77 (m, 1H) 8.01 (s, 1H)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11](C2CCCCO2)[N:10]=[C:9]3[C:21]2[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=2)=[N:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[N:59]1[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][OH:66])[CH:60]=1.Cl>O1CCCC1>[NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:14]=[C:13]([O:66][CH2:65][C:61]3[CH:60]=[N:59][CH:64]=[CH:63][CH:62]=3)[CH:12]=[C:8]([C:9]3[C:21]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:11][N:10]=3)[CH:7]=2)=[N:2]1
Reactant: OCc1cccnc1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4nc[nH]n4)cc23)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cncc(COc2cc(-c3nc[nH]n3)cc(-c3n[nH]c4ccccc34)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
The title compound was prepared from 3-(5-(1H-1,2,4-triazol-3-yl)-1-perhydro-2H-pyran-2-yl-1H-indazol-3-yl)phenol (0.394 g, 0.65 mmol), triphenyl phosphine (0.685 g, 2.61 mmol), diethyl azodicarboxylate (0.41 mL, 2.61 mmol), 3-pyridylcarbinol (0.26 mL, 2.67 mmol) in tetrahydrofuran (2.5 mL) and was allowed to stir at room temperature overnight. To this mixture 6 N hydrogen chloride (20 mL) was added and allowed to stir at room temperature for 5 hours. This reaction was extracted with diethyl ether (3×), basified to pH˜11 with 6 N sodium hydroxide (aqueous), extracted with ethyl acetate (3×). The organic fractions were combined and dried with sodium sulfate, filtered, and condensed. The compound was purified by column chromatography (SiO2, 100% ethyl acetate in hexanes to 95% ethyl acetate in 5% methanol) and preparative HPLC (15–80% acetonitrile to H2O, 30 min.) (0.028 g, 12% yield over 2 steps): 1H NMR (CD3OD) δ 8.72 (m, 2H), 8.51 (dd, 1H), 8.11 (br s, 1H), 8.03 (dd, 1H), 7.68 (m, 3H), 7.50 (m, 2H), 7.13 (ddd, 1H), 5.30 (s, 2H); ES-MS (m/z) 369 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[C-:30]#[N:31].[Na+]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=1[C:30]#[N:31]
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(N)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
A mixture of 5.0 g (0.0151 mole) of 2-(3,4-dichlorophenoxy)-5-(methylsulfonyl)benzenamine (Example 16), 75 ml of glacial acetic acid, 37.5 ml of water and 3.0 g (0.0306 mole) of concentrated sulfuric acid was cooled to 0° C. and 1.5 g (0.0217 mole) of sodium nitrite dissolved in 15 ml of water was added slowly. The mixture was stirred at 0° C. for 20 minutes and then added slowly to a mixture of 7.5 g (0.0838 mole) of cuprous cyanide and 30 g (0.612 mole) of sodium cyanide dissolved in 150 ml of water at 0° C. The mixture was stirred at 0° C. for 45 minutes and allowed to warm to room temperature. The mixture was then heated at 50° C. for 1 hr. The mixture was poured into water and the crystalline product collected by filtration, washed with water and dried, to obtain 4.95 g (96.1% yield) of product. Purification was accomplished by column chromatography using silica gel as the support and chloroform as the eluent followed by recrystallization from ethyl acetate, which gave purified 2-(3,4-dichlorophenoxy)-5-(methylsulfonyl)benzonitrile, mp 162°-163° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([CH2:59][C:60]([OH:62])=[O:61])=[CH:55][CH:54]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:18])[NH:52][C:53]1[CH:54]=[CH:55][C:56]([CH2:59][C:60]([OH:62])=[O:61])=[CH:57][CH:58]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)Cc1ccc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (F.W.=249.27, 1.5 g, 4.0 mmol), HATU (1.6 g, 3.9 mmol), and DIEA (0.7 mL, 4.97 mmol) in DMF (30 mL) was stirred at room temperature for 1 h. (4-Amino-phenyl)-acetic acid (FW=151.17, 0.5 g, 3.31 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered and separated by reverse phase HPLC (0-100% of buffer B; buffer A: water containing 0.1% TFA; buffer B: MeCN containing 0.1% TFA). The combined fraction was evaporated to furnish the desired product (S)-2-(4-Carboxymethyl-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][C@H:11]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:18]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([S:7]([CH2:10][C@H:11]2[N:15]([CH3:18])[C:14](=[O:16])[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2C)cc1
Temperature: -70 °C
Yield: 40 %

Procedure:
(5S)-5-(p-Toluenesulphonylmethyl)-2-pyrrolidinone (0.8 g, 3 mmol) was dissolved in dry THF and cooled to −70° C. Lithium diisopropylamide was slowly added and the reaction stirred for 20 minutes before addition of methyl iodide (2 ml, excess). The reaction was allowed to warm to ambient temperature for over 2 hours. The reaction was partitioned between ethyl acetate and water, the organic layer separated, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography eluting from methylene chloride to 5% methanol/95% methylene chloride and the product evaporated to give (5S)-5-(p-toluenesulphonyl-methyl)-1-methyl-2-pyrrolidinone (340 mg, 40%) as a brown oil.
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[C:12]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:19]([O:22]C(=O)C)(=[O:21])[CH3:20]>>[CH2:1]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:22][C:19](=[O:21])[CH3:20])[C:12]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCOc1ccnc(C)c1C
Product: CCCCCCCCCOc1ccnc(COC(C)=O)c1C
Yield: 54.3 %

Procedure:
To 41.4 g (0.1 mol, 1.0 eq.) of 4-nonyloxy-2,3-dimethylpyridine, 40.8 g (0.4 mol, 4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 7 hours at 88 to 92° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 16.7 g of 4-nonyloxy-2-acetoxymethyl-3-methylpyridine as a black brown oily matter (total yield of two processes 54.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=O)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:15]([NH2:18])[C:16]#[CH:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(N(CC)CC)C>[CH2:15]([NH:18][C:12]([C:9]1[O:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=2[CH:10]=1)=[O:14])[C:16]#[CH:17]
Reactant: C#CCN
Reactant: COc1cccc2oc(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC(=O)c1cc2c(OC)cccc2o1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
4-Methoxybenzo(b)furan-2-carboxylic acid (44.0 g) and propargylamine (12 g) were dissolved in dimethylformamide (200 ml), and WSC (48.0 g), HOBt (43.0 g) and triethylamine (50 ml) were added thereto at room temperature. The mixture was stirred for 4 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as yellow crystals (45.0 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8]O)[CH3:2].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([OH:17])=[O:16].CCCCCCCC(O[Sn](OC(CCCCCCC)=O)(CCCC)CCCC)=O>C1(C)C(C)=CC=CC=1>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([O:17][CH2:2][CH2:1][O:3][CH2:4][CH2:5][O:6][CH2:7][CH3:8])=[O:16]
Reactant: O=C(O)c1ccco1
Reactant: CCOCCOCCO
Agent: CCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCC
Solvent: Cc1ccccc1C
Product: CCOCCOCCOC(=O)c1ccco1

Procedure:
2-(2-Ethoxyethoxy) ethanol, carbitol solvent, 129 g (0.96 m), 90 g (0.8 m) furoic acid and 1 g dibutyltin dioctoate were heated with xylene to remove water by azeotropic distillation to acid number 1.4. Zylene removed by distillation at a pot temperature of 200° and product distilled. Carbitol furoate was collected in fraction 2, 121°-125°, 91% carbitol furoate by gc. Yield of carbitol furoate 144 g, 79%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([Sn:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([Sn:10]([CH3:12])([CH3:11])[CH3:13])[CH:7]=[CH:8][CH:9]=1)(=[O:17])=[O:16]
Reactant: C[Sn](C)(C)c1cccc(CCN)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NCCc1cccc([Sn](C)(C)C)c1

Procedure:
The title compound was prepared by the method of example 17, part A, from 3(2′-aminoethyl)phenyl trimethylstannane and methanesulfonyl chloride.