Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH3:24])=[O:4].[Br:25]N1C(C)(C)C(=O)N(Br)C1=O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH2:24][Br:25])=[O:4]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(F)cc12
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
A mixture of 1-benzenesulfonyl-5-fluoro-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (13.9 g, 39.9 mmol), 1,3-dibromo-5,5-dimethylhydantoin (12.6 g, 39.9 mmol) and 1,1-azobis(cyclohexanecarbonitrile) (1.95 g, 8.0 mmol) in 1,2-dichloroethane (150 mL) was heated under reflux for 90 minutes then stirred at ambient temperature for 16 hours. The reaction mixture was washed with saturated aqueous sodium thiosulfate solution. The organic layer was dried (Na2SO4) then filtered. The filtrate was stirred with flash silica gel, filtered and the filtrate evaporated under reduced pressure. The resultant residue was triturated with diethyl ether/pentane (1:1) to afford the title compound as a cream solid (15.9 g, 93%). 1H NMR (400 MHz, CDCl3): 8.47-8.44 (m, 2H), 8.32 (dd, J=2.8, 1.1 Hz, 1H), 8.04 (dd, J=8.5, 2.8 Hz, 1H), 7.64-7.64 (m, 1H), 7.54-7.53 (m, 2H), 5.68 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:25])[CH:17]=2)[N:12]=1)=[O:4].[OH-].[Na+].O>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:25])[CH:17]=2)[N:12]=1)=[O:4]
Reactant: COC(=O)c1ccccc1-c1cc(C(=O)OC)c2cc(C)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccccc1-c1cc(C(=O)O)c2cc(C)ccc2n1
Reaction time: 24 h
Yield: 67.6 %

Procedure:
In 2 ml of methanol were dissolved 377 mg (1.23 mmol) of methyl 2-(2-methoxycarbonylphenyl)-6-methyl-4-quinolinecarboxylate obtained in Example 3 and 49 mg (1.2 mmol) of sodium hydroxide. 3 ml of water were added thereto and the resulting mixture was stirred for 24 hours. After concentrated under reduced pressure, water was added to the residue, the aqueous layer was acidified and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate followed by distillation under reduced pressure. The resulting residue was purified by flash silica gel chromatography using a mixed solvent of chloroform and methanol (70/1) to obtain 267 mg of 2-(2-methoxycarbonyl-phenyl)-6-methyl-4-quinolinecarboxylic acid. NMR (270 MHz, CD3OD):
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCOC(C)=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:7]([S:9]([N:25]2[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(C)c(Oc2ccc(C#N)cc2S(=O)(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C)c(Oc2ccc(C#N)cc2S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 42 %

Procedure:
A solution of sulfonyl chloride 32 (0.160 g, 0.50 mmol), tert-butyl piperazine-1-carboxylate (0.121 g, 0.65 mmol), and TEA (0.066 g, 0.65 mmol) in DCM (5 mL) was stirred overnight at room temperature. The reaction was monitored with TLC (25% EtOAc in hexanes). The reaction mixture was concentrated in vacuo and the residual was redissolved with a minimal amount of DCM and chromatographed on normal-phase silica to produce compound 33 as a white powder (0.099 g, 42.0% yield, 100.0% pure). 1H NMR (500 MHz, DMSO-d6): δ 8.24 (d, J=2 Hz, 1H), 8.00 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 6.98 (s, 1H), 6.78 (d, J=8 Hz, 1H), 3.39 (m, 4H), 3.22 (m, 4H), 2.29 (s, 3H), 2.07 (s, 3H), 1.37 (s, 9H); MS (ESI, EI+): m/z=372 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:25])[CH:5]=[CH:4][C:3]=1[OH:26].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: Cc1cc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1O
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CCCOc1ccc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-methyl-4-(2-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}ethyl)phenol (intermediate 7, 0.08 g ) in acetonitrile (2 ml) was added methyl 4-bromobutyrate (0.090 g) and cesium carbonate (0.194 g). The mixture was stirred at room temperature for 24 hours then partitioned between water and ethyl acetate. The organic layer was dried, the solvent removed and the resulting oil was purified by SPE(Si cartridge). Elution with cyclohexane:ethyl acetate (20:1) gave the title compound as an oil which crystallised on standing.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH2:23][O:22][C:21]3=[O:30])[CH2:16][CH2:15]2)=[C:10]([Cl:31])[CH:9]=1.C(N(CC)CC)C>ClCCl>[Cl:31][C:10]1[CH:9]=[C:8]([NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:13]=[CH:12][C:11]=1[N:14]1[CH2:15][CH2:16][CH:17]([N:20]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][O:22][C:21]2=[O:30])[CH2:18][CH2:19]1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1

Procedure:
Isobutyryl chloride (0.017 ml) was added to a stirred solution of the product from example 120 step (ii) (0.05 g) and triethylamine (0.07 ml) in dichloromethane (1 ml) at room temperature. After 2 h the mixture was partitioned between ethyl acetate and water, the organics separated, washed with water, dried, and evaporated under reduced pressure. Trituration with ether gave a solid, yield 0.048 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH:12]=O.[CH:14]([CH:16]=[CH2:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.ClCCl>[O:9]1[C:4]2=[C:3]3[C:2](=[CH:11][CH:10]=[C:5]2[O:6][CH2:7][CH2:8]1)[O:1][CH2:17][C:16]([CH:14]=[O:15])=[CH:12]3
Reactant: C=CC=O
Reactant: O=Cc1c(O)ccc2c1OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=CC1=Cc2c(ccc3c2OCCO3)OC1

Procedure:
3 g (16.6 mmol) of the compound obtained in Step B and 1.4 g (25 mmol) of acrolein are added to a suspension of 3.48 g (25 mmol) of potassium carbonate in 40 ml of 1,4-dioxane; the medium is then heated at reflux under argon for 3 hours. After cooling and filtering off the salts, the solvent is evaporated in vacuo. The residue obtained is taken up in dichloromethane and then washed with water. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. Chromatography on a silica column (eluant:ethyl acetate/petroleum ether 10/90) allows the title compound to be obtained in the form of a yellow solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]1([C:19]2[CH:28]=[C:27]([C:29](O)=[O:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][CH2:44][CH2:45][CH2:46][N:47]1[C:59]2[C:58]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[N:52]=[C:51]([NH2:60])[C:50]=2[N:49]=[C:48]1[CH2:61][CH2:62][O:63][CH3:64]>ClCCl.N1C=CC=CC=1>[NH2:60][C:51]1[C:50]2[N:49]=[C:48]([CH2:61][CH2:62][O:63][CH3:64])[N:47]([CH2:46][CH2:45][CH2:44][CH2:43][NH:42][C:29]([C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:28]=3)=[O:30])[C:59]=2[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[N:52]=1
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccccc12
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1cc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Yield: 44.6 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.57 g, 3.0 mmol) was added dropwise to a chilled (0° C.) solution of 2-phenyl-4-quinolinecarboxylic acid (0.5 g, 3.7 mmol), 1-hydroxybenzotriazole (0.5 g, 3.7 mmol), pyridine (2.2 ml), and dichloromethane (20 ml). The reaction was maintained for 15 min followed by the dropwise addition of 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.8 g, 2.55 mmol) in dichloromethane (100 ml). The reaction was maintained at room temperature overnight. The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol). The fractions containing product were combined, washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filtered, and concentrated to provide 0.62 g of N4-[4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenyl-4-quinolinecarboxamide as a yellow crystalline solid, m.p. 118° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.88 (t, J=5.7 Hz, 1H), 8.24-8.21 (m, 2H), 8.13-8.01(m, 4H), 7.83-7.78 (m, 1H), 7.62-7.48 (m, 5H), 7.36 (m, 1H), 7.20 (dt, J=7.6, 1.2 Hz, 1H), 6.54 (broad s, 2H), 4.62 (t, J=7.2 Hz, 2H), 3.83 (t, J=6.7 Hz, 2H), 3.45 (m, 2H), 3.29-3.20 (m, 5H), 1.96 (m, 2H), 1.79 (m, 2H); MS (EI) m/e 544.2589 (544.2587 calcd for C33H32N6O2).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=[CH:28][N:27]=4)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[CH:31]=[C:30]([C:32]([CH3:34])([CH3:33])[CH3:35])[CH:29]=[CH:28][N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:12][CH2:13]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)c1ccnc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)cn3COCC[Si](C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccnc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(C#N)CC4)C4CC4)c3n2)c1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 63.4 %

Procedure:
In a round-bottomed flask, 2-(4-tert-butyl-pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (62 mg, 0.091 mmol) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.28 mL) was added. The yellow reaction mixture was stirred at room temperature for 2.75 h then concentrated under reduced pressure. The residue was dissolved in dichloromethane (0.5 mL) and ethylenediamine (0.37 mL) was added. The reaction mixture was stirred at room temperature for 1.25 h then quenched with 5 mL water and extracted with EtOAc (2×). The combined organic layers were washed with 5 mL water and 5 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 8 g SiO2 with MeOH/CH2Cl2/0.5% NH4OH (gradient: 0-4% MeOH). All fractions containing product were combined and concentrated to afford 28 mg (61%) of 2-(4-tert-butyl-pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a yellow foamy solid. MS: (M+H)+=486.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([N:19]1[C@@H:26]2[C@@H:21]([CH2:22][CH2:23][NH:24][CH2:25]2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.CC(C)([O-])C.[Na+]>>[CH2:12]([N:19]1[C@@H:26]2[C@@H:21]([CH2:22][CH2:23][N:24]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:25]2)[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(CN2C[C@@H]3CCNC[C@@H]32)cc1
Reactant: Brc1cccnc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Product: c1ccc(CN2C[C@@H]3CCN(c4cccnc4)C[C@@H]32)cc1
Yield: 57 %

Procedure:
The product from Example 33E and 3-bromopyridine were processed according to the procedure of Example 1E, except that a larger amount of sodium tert-butoxide (384 mg, 4.0 mmol) was used. The residue was purified by chromatography (SiO2, hexanes: ethyl acetate, 20:80, Rf. 0.2) to provide the title compound (0.16 g, 57% yield). 1H NMR (CD3OD, 300 MHz) δ2.04 (m, 2H), 2.56 (m, 1H), 3.00 (m, 2H), 3.22 (m, 2H), 3.55 (m, 1H), 3.60 (d, J=12.5 Hz, 1H), 3.70 (d, J=12.5 Hz, 1H), 3.55 (m, 1H), 3.70 (m, 1H), 7.04 (ddd, J=8.8, 3.0, 1.3 Hz, 1H), 7.17 (d, J=4.8 Hz, 1H), 7.24 (m, 5H), 7.80 (dd, J=4.7, 1.3 Hz, 1H), 7.84 (d, J=3.0 Hz, 1H); MS (DCI/NH3) m/z 280 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C@@H:6]([CH2:11][N+:12]([O-])=O)[CH2:7][CH:8]([CH3:10])[CH3:9])C.[OH-].[K+].[H][H]>O.[Ni]>[CH3:10][CH:8]([CH2:7][C@H:6]([CH2:11][NH2:12])[CH2:5][C:4]([OH:15])=[O:3])[CH3:9]
Reactant: [H][H]
Reactant: CCOC(=O)C[C@H](CC(C)C)C[N+](=O)[O-]
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)C[C@H](CN)CC(=O)O
Yield: 80 %

Procedure:
150 g of (S)-5-methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl; assay: 97.2%) were suspended in 300 mL of H2O. KOH (90.1.g, assay 86.1%, 2.05 eq.) was added. The initially turbid reaction mixture became clear which indicated that the reaction was nearly completed. After complete conversion (as determined by HPLC) the reaction mixture was transferred to a hydrogenation reactor. 90.0 g of an aqueous slurry of Raney Nickel were added. At a hydrogen pressure of 12 bar and a temperature of 45° C. the mixture was stirred until complete conversion was detected by HPLC giving 88.0 g of pregabalin in an aqueous solution.
Reaction SMILES: [Br-:1].[Br-].[CH3:3][C:4]1[CH:9]=[CH:8][N+:7]([CH2:10][CH2:11][CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1.[CH2:17]([N:21]([CH2:30][CH2:31][CH2:32][CH3:33])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]>>[Br-:1].[Br-:1].[CH2:17]([N:21]([CH2:30][CH2:31][CH2:32][CH3:33])[C:22]1[CH:23]=[CH:24][C:25](/[CH:26]=[CH:3]/[C:4]2[CH:5]=[CH:6][N+:7]([CH2:10][CH2:11][CH2:12][N+:13]([CH3:14])([CH3:16])[CH3:15])=[CH:8][CH:9]=2)=[CH:28][CH:29]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Reactant: Cc1cc[n+](CCC[N+](C)(C)C)cc1
Agent: [Br-]
Product: CCCCN(CCCC)c1ccc(/C=C/c2cc[n+](CCC[N+](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a dry vial was added the salt 6 (708 mg, 2 mmol), 4-dibutylaminobenzaldehyde (467 mg, 2 mmol) and the vial was purged with N2. Ethanol (10 ml) was added via syringe, followed by piperidine (1 ml). Within 5 minutes the color began changing to deep red. The mixture was stirred at room temperature for 12 hours, concentrated and the salt was precipitated with dry ether. Following solvent removal, the salt was again dissolved in EtOH (8 ml) and precipitated with ether. The resulting fluorophore was filtered under a nitrogen atmosphere and dried. Yield: 1.04 g (91%). MS (dual ESI+): 204.69186 (M+H+)2+ HRMS calc. 409.3457. H-NMR (DMSO-D6): 0.92 (t, J=12 Hz, 6H); 1.38 (m, 4H); 1.48 (m, 4H); 2.24 (m, 2H); 3.22l-3.35 (m, 11 H); 3.85 (t, J=9 Hz, 4H); 4.25 (t, J=12 Hz, 2H); 6.8 (d, J=8 Hz, 2H); 6.97 (s, 2H); 7.75 (d, J=8 Hz, 2H); 8.05 (d, J=6 Hz, 2H); 8.95 (d, J=6 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]1[O:15][CH:16]=[C:17]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:24]([CH2:25][S:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[N:30]3)=[CH:23][CH:22]=2)[N:18]=1.ClC1C=C(C(OO)=[O:44])C=CC=1>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]1[O:15][CH:16]=[C:17]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:24]([CH2:25][S:26]([CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[N:30]3)=[O:44])=[CH:23][CH:22]=2)[N:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cc(C(F)(F)F)ccc1/C=C/c1nc(COc2ccc(CSCCn3ccnn3)cc2)co1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3F)n2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of 101 mg (0.20 mmol) 1-[2-(4-{2-[2-(E)-(2-fluoro-4-trifluoromethylphenyl)-vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 8 ml dichloromethane at −30° C. were added drop by drop during 20 min 54 mg (0.24 mmol) 3-chloro-benzenecarboperoxoic acid dissolved in 2 ml ethyl acetate. After 1 hour stirring at 30° C. the mixture was allowed to warm up over night, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate/methanol 9:1 furnished 73 mg (71%) title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.C[O-].[Na+].C(O)(=O)C[C:33](CC(O)=O)(C(O)=O)[OH:34]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([O:34][CH3:33])[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(F)cc32)c(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc2c(cc1[N+](=O)[O-])c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-7-fluoro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (60 mg) was added to a mixed liquid of a 28% sodium methoxide solution (135 mg) and pyridine (0.5 ml), and the mixture was stirred at 40° C. for 2 hours. The reaction mixture was acidified with a 3% aqueous solution of citric acid, and solids formed were collected by filtration. The solids were subjected to azeotropic distillation with ethanol and toluene. Hexane was added to the residue to conduct filtration, thereby obtaining the title compound (20 mg) as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.C([Li])CCC>C1COCC1>[CH3:16][C:15]([O:14][C:12]([N:8]1[CH2:7][C:6]2[CH:19]=[C:2]([B:20]([OH:25])[OH:21])[CH:3]=[CH:4][C:5]=2[O:11][CH2:10][CH2:9]1)=[O:13])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A solution of 1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (30.0 g, 91.4 mmol) and triisopropyl borate (22.4 g, 119 mmol) in THF (300 mL) was cooled to −78° C., and a 2.5M solution of n-butyllithium in hexanes (47.6 mL, 119 mmol) was added dropwise over 40 min at this temperature. The reaction mixture was stirred at −78° C. for an additional 30 min, then quenched by dropwise addition of 2 N hydrochloric acid (80 ml), and allowed to warm up to room temperature. Ethyl acetate (100 mL) and water (100 mL) were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water, dried over sodium sulfate, and concentrated. Hexane (200 mL) was added to the residue and the mixture was stirred overnight. The precipitate was filtered, washed several times with hexane, and dried to give (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (23.4 g, 87%) as a colorless solid. MS (EI) for C14H20BNO5: 294 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([C:42]#[N:43])[CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1.C(O)(=O)/C=C/C(O)=O>CS(C)=O.C(O)C>[CH3:24][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:25][CH2:26][CH:13]([CH2:12][N:27]1[CH2:28][CH:29]=[C:30]([C:33]2[C:41]4[C:36](=[CH:37][CH:38]=[C:39]([C:42]#[N:43])[CH:40]=4)[NH:35][CH:34]=2)[CH2:31][CH2:32]1)[O:14]3
Reactant: N#Cc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4ccc(C#N)cc24)CC1)CO3
Temperature: 77.5 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.60 g, 1.6 mmole) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-5-carbonitrile (0.85 g, 3.8 mmole) were combined in 70 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 30% hexanelethyl acetate to remove impurities. Ethyl acetate eluted the product, which was a yellow oil (0.24 g, 42%). The oil was crystallized from ethanol with the addition of a solution of fumaric acid (0.12 g, 1.02 mmole) in hot ethanol to give 0.20 g of the (S)-nantiomer of the title compound as a yellow solid difumarate.0.50 hydrate, m.p. 119° C. MS (ESI) m/z 427 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]1[CH3:11])=[O:4].[S-:12][C:13]#[N:14].[K+].[I-].[Na+]>C(O)C>[S:12]([CH2:2][C:3]([N:5]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]1[CH3:11])=[O:4])[C:13]#[N:14]
Reactant: CC1CCC(C)N1C(=O)CCl
Reactant: N#C[S-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC1CCC(C)N1C(=O)CSC#N
Reaction time: 2 h

Procedure:
1-(α-Chloroacetyl)-2,5-dimethylpyrrolidine (10 grams; 0.057 mol), potassium thiocyanate (10.1 grams), sodium iodide (a few crystals) and ethanol (100 ml) were charged into a glass reaction flask equipped with mechanical stirrer and reflux condenser. The reaction mixture was heated at reflux, with stirring, for a period of about 2 hours. After this time the reaction mixture was cooled and filtered. The filtrate was stripped of ethanol under reduced pressure resulting in a solid product. The solid was extracted with two 125 ml portions of hot benzene. The benzene extracts were combined and were evaporated to yield 1-(α-thiocyanoacetyl)-2,5-dimethylpyrrolidine as a light brown oil having a refractive index at 25° C. of 1.5185 and having the following elemental analysis as calculated for C9H14N2OS.