Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=O.[I-].[Na+].[CH2:18]([N:20]([CH2:28][CH3:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:27])=[S:26])[CH3:19]>CC(C)=O.C(=O)([O-])O.[Na+].O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2([C:3]3[N:27]=[C:25]([NH:24][CH2:23][CH2:22][CH2:21][N:20]([CH2:18][CH3:19])[CH2:28][CH3:29])[S:26][CH:2]=3)[CH2:8][CH2:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: CCN(CC)CCCNC(N)=S
Reactant: O=C(CCl)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCN(CC)CCCNc1nc(C2(c3ccc(Cl)cc3)CCC2)cs1
Temperature: 50 °C
Yield: 86.8 %

Procedure:
A solution of 2-chloro-1-[1-(4-chlorophenyl)cyclobutyl]ethanone (120 mg, 0.494 mmol) and sodium iodide (74 mg, 0.494 mmol) in acetone (2.5 mL) was stirred at room temperature for 5 minutes. Next (3-diethylaminopropyl)thiourea (94 mg, 0.494 mmol) was added. The resulting mixture was heated at 50° C. for 1 h. After the mixture was allowed to cool to room temperature, it was diluted with 5% sodium hydrogen carbonate in water and then extracted with ethyl acetate (2×50 mL). The extracts were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a colorless oil. The oil was purified by column chromatography on silica gel using dichloromethane/2 N ammonia in ethanol (90:10) to give 162 mg of N′-{4-[1-(4-chlorophenyl)cyclobutyl]thiazol-2-yl}-N,N-diethylpropane-1,3-diamine, 19, as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 1.02 (t, 6H, J=7.2 Hz); 1.71–1.80 (m, 2H); 1.82–1.91 (m, 1H); 2.08–2.20 (m, 1H); 2.48–2.59 (m, 8H); 2.67–2.76 (m, 2H); 3.27 (t, 2H, J=6.3 Hz); 5.91 s (s, 1H); 6.17 (bs, 1H); 7.25 (s, 4H); 13C NMR (CDCl3, 75 MHz): δ 11.8, 16.9, 26.2, 34.3, 45.8, 47.1, 49.1, 51.9, 100.3, 128.2, 128.3, 131.5, 147.1, 159.8, 169.9.
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[Cl:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[Cl:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)[CH2:18][CH2:17]1.[CH2:14]([OH:15])[CH2:13][CH2:25][CH3:24]
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: Cn1nc(Br)c(=O)n(C)c1=O
Product: CCCCO
Product: Cn1nc(N2CCC(Oc3ccccc3Cl)CC2)c(=O)n(C)c1=O
Yield: 60 %

Procedure:
The compound 27 (solid) is prepared from the triazine 1b and from the intermediate 8a according to the synthesis method 1 in n-butanol (yield: 60%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:8]=[CH:9][C:10]=1[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([O-:4])=[O:3].[F:22][CH:23]([F:26])[CH2:24]I.C(NC(C)C)(C)C>CN(C)C=O.ClCCl>[F:22][CH:23]([F:26])[CH2:24][N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:6][C:5]=2[N+:2]([O-:4])=[O:3])[CH2:13][CH2:14]1
Reactant: NS(=O)(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Reactant: FC(F)CI
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: NS(=O)(=O)c1ccc(NC2CCN(CC(F)F)CC2)c([N+](=O)[O-])c1
Temperature: 85 °C

Procedure:
3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide hydrochloride (0.100 g), 1,1-difluoro-2-iodoethane (0.063 mL) and diisopropylamine (0.156 mL) were stirred together in N,N-dimethylformamide (3 ml) and heated to 85° C. The reaction was diluted with dichloromethane (50 mL) and washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was loaded onto silica gel (GraceResolve 12 g) and eluted using a gradient of 0.5% methanol/dichloromethane to 3% methanol/dichloromethane over 30 minutes to give the title compound.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH:13]3[O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]4[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=4[CH:45]=3)=[CH:8][CH:7]=2)[CH2:2]1.Cl[C:47]1[O:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1>C(Cl)(Cl)Cl>[O:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[CH2:14][CH:13]3[O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]4[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=4[CH:45]=3)=[CH:8][CH:7]=2)[CH2:2]1
Reactant: Clc1nc2ccccc2o1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CNC4)cc3)cc21
Solvent: ClC(Cl)Cl
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CN(c5nc6ccccc6o5)C4)cc3)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 0.382 g of benzyl 4-[4-(azetidin-3-yloxy)phenyl]-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 10 ml of chloroform is admixed at 0-5° C. with 0.156 ml of 2-chlorobenzoxazole. The reaction solution is stirred at room temperature over 20 hours and subsequently poured onto an ice-water mixture. The reaction mixture is extracted with ethyl acetate (2×50 ml) and the combined organic phases are washed with 50 ml of brine, dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (2:1 EtOAc-heptane); Rt=4.99.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][O:18][CH2:19][CH:20]=C)=[O:14].CSC.C(Cl)Cl.C[OH:40]>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][O:18][CH2:19][CH:20]=[O:40])=[O:14]
Reactant: C=CCOC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Reactant: CO
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)[C@H](COCC=O)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-propenyl-L-serine, methyl ester (13 g, 29.8 mmol ) in methylene chloride/methanol (10:1, 220 mL). Cool to -78° C. and sparge with a mixture of ozone/oxygen for approximately 10 minutes until a blue color persists. Sparge with nitrogen for 10 minutes at -78° C. to remove excess ozone. Treat with methylsulfide (60 mL, 0.82 mol) and allow to warm to room temperature. Stir at room temperature for 2.5 hours, evaporate the solvent in vacuo and dissolve the residue in ethyl acetate (200 mL). Wash with water, saturated sodium chloride, dry (Mg SO4) and evaporate the solvent in vacuo to give the intermediate N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester as a foam (13.6 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@:9]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1([O-])O[O:27]1.O.O.O.O.[Na+]>O1CCCC1.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C@:9]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C@H:10]1[CH2:12][CH2:13][OH:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-]B1OO1
Reactant: C=C[C@@H]1C[C@@]1(C(=O)OCC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@]1(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H]1CCO
Temperature: -15 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To (1R,2S)-ethyl 1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate (10 g, 39.2 mmol) and Boc anhydride (22.73 mL, 98 mmol) dissolved in tetrahydrofuran (25 mL) at room temperature was added portionwise DMAP (3.83 g, 31.3 mmol) and the mixture was stirred for 3 h. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with 0.1 N HCl followed by saturated aqueous sodium chloride solution, separated, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluting with a 5-15% ethyl acetate/hexane gradient to provide (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate (13.2 g, 37.1 mmol, 95% yield) as a clear oil. MS (ESI): m/z=378.0 [M+Na]. To a solution of (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-vinylcyclopropane carboxylate (13.2 g, 37.1 mmol) in tetrahydrofuran (50 mL) at -15° C. was added dropwise 1 N borane tetrahydrofuran complex (74.3 mL, 74.3 mmol) and the mixture was stirred for 2 h at −15° C. To the resulting mixture stirring at 0° C. was added dropwise water (100 mL) followed by sodium perborate tetrahydrate (11.43 g, 74.3 mmol), and the mixture was stirred for 16 hr at rt. The reaction mixture was diluted with ethyl acetate and water, and the resulting organic layer was washed with saturated aqueous sodium chloride solution, separated, dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The residue was purified via flash chromatography on silica gel (10-20% acetone/hex). The resulting impure material was repurified by flash chromatography on silica gel (eluting with a 25%-50% ethyl acetate/hexane gradient) to give (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-(2-hydroxyethyl)cyclopropanecarboxylate (9.15 g, 24.50 mmol, 66.0% yield) as an oil. MS (ESI): m/z=396.0 [M+Na].
Reaction SMILES: [O:1]=[S:2]([Cl:4])Cl.[OH2:5].[F:6][C:7]1[CH2:8][C:9](=[N+]=[N-])[CH:10]=[C:11]([F:14])[C:12]=1[F:13]>>[F:6][C:7]1[CH:8]=[C:9]([S:2]([Cl:4])(=[O:1])=[O:5])[CH:10]=[C:11]([F:14])[C:12]=1[F:13]
Reactant: O=S(Cl)Cl
Reactant: O
Reactant: [N-]=[N+]=C1C=C(F)C(F)=C(F)C1
Product: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
The flask containing the SOCl2/H2O solution is cooled again to −10° C. and a catalytic amount of Cu(I)Cl (˜50 mg) was added. The solution turns dark green in color. The flask was fitted with a 500 mL addition funnel (previously chilled to 0° C.) and the 3,4,5-trifluorodiazobenzene solution was quickly transferred to the funnel. The solution was immediately added dropwise over a period of 3 min. After addition, the reaction mixture slowly turns darker green in color, but after stirring for 5 min becomes bright, lime green. The reaction was stirred for an additional hour while warming to room temperature. The reaction mixture was transferred to a separatory funnel and extracted with CH2Cl2 (3×200 mL). The organic phases are combined and dried over anhydrous Na2SO4, filtered, and concentrated to give a dark-bronze oil (79.5 g, 83%).
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=1)[C:7]#[N:8].[C:23]([NH:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:29]2[C:30]([O:32][C:33](=O)[C:28]=12)=[O:31])(=[O:25])[CH3:24]>C(O)(=O)C.CCOC(C)=O>[C:7]([CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=1)[N:5]1[C:33](=[O:32])[C:28]2[C:29](=[CH:35][CH:36]=[CH:37][C:27]=2[NH:26][C:23](=[O:25])[CH3:24])[C:30]1=[O:31])#[N:8]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: COc1ccc(C(N)C#N)cc1OC1CCCC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C#N)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Yield: 65 %

Procedure:
A mixture of 2-amino-2-(3-cyclopentyloxy-4-methoxyphenyl)ethanenitrile acetate (3.5 g, 11.0 mmol) and 3-acetamidophthalic anhydride (2.3 g, 11.0 mmol) in glacial acetic acid (40 mL) was heated to reflux for 17 hours. The mixture was concentrated in vacuo to give an oil. The oil was dissolved in EtOAc and washed with water, brine and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 98:2) to give 3.1 g (62%) of N-{2-[cyano(3-cyclopentyloxy-4-methoxyphenyl)methyl]-1,3-dioxoisoindolin-4-yl}acetamide as white solid; mp 124-126° C.; 1H NMR (CDCl3) δ 9.44 (s, 1H), 8.76 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.03-6.99 (m, 2H), 6.84 (d, J=8.0 Hz, 1H), 5.60-5.53 (dd, J=6.2 and 10.4 Hz, 1H), 4.79-4.74 (m, 1H), 3.86-3.75 (m, 1H), 3.82 (s, 3H), 3.29-3.20 (dd, J=6.4 and 17 Hz, 1H), 2.72 (s, 3H0, 1.97-1.56 (m, 8H); 3C NMR (CDCl3) δ 169.58, 169.11, 167.18, 150.61, 147.98, 137.72, 136.28, 130.89, 128.66, 125.09, 119.80, 118.29, 116.78, 114.19, 111.90, 80.68, 56.02, 51.10, 32.73, 24.92, 24.03, 21.07. Analy. Calculated for C25H25N3O5: C, 67.10; H, 5.63; N, 9.39. Found: C, 66.89; H, 5.42; N, 9.26.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:30][CH:31]([F:33])[F:32])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.CO.O.[OH-].[Li+]>C(O)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1)=[C:8]2[O:30][CH:31]([F:32])[F:33]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
A solution of [8-chloro-4-difluoromethoxy-2-ethyl-3-(4-methanesulfonylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.10 g), methanol (5.0 mL), water (1.0 mL) and saturated aqueous lithium hydroxide solution (0.5 mL) was stirred at room temperature for 45 minutes. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the methanol removed under reduced pressured. The residue was diluted with water (2.0 mL) and the resulting precipitate collected by filtration, washed with water and dried to afford title compound as a white solid, 0.075 g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:26](=[O:27])[N:12]2[C:13]([C:23]([OH:25])=[O:24])=[C:14]([CH:17]([O:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8].C(Cl)Cl.[C:31]1([C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N+]=[N-])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO.CCOCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:26](=[O:27])[N:12]2[C:13]([C:23]([O:25][CH:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:24])=[C:14]([CH:17]([O:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)OC(C)C1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CC(=O)OC(C)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-3-cephem-4-carboxylic acid (stereoisomer A: 88 mg) in mixture (5 ml) of methanol and methylene chloride (1:1) is added a solution of diphenyldiazomethane in ether until the red color of the solution does no more disappear at 55° C on standing. After 3 hours, the reaction mixture is concentrated to give the residue which is stirred in a mixture of ether and petroleum ether. The supernatant is removed, and resulting precipitate is recrystallized from petroleum ether to give diphenylmethyl 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-3-cephem-4-carboxylate (stereoisomer A: 85 mg). m.p. 161-163° C. Yield: 70%.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([C:14]2(O)[CH2:17][CH:16]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:15]2)[CH:11]=[CH:10][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.COCCN(S(F)(F)[F:36])CCOC.C(Cl)[Cl:40]>>[ClH:40].[F:1][C:2]1[CH:13]=[C:12]([C:14]2([F:36])[CH2:17][CH:16]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:15]2)[CH:11]=[CH:10][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: ClCCl
Reactant: O=C(C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1)N1CCCC1
Reactant: COCCN(CCOC)S(F)(F)F
Product: Cl
Product: O=C(C1CC(F)(c2ccc(CN3CCCC3)c(F)c2)C1)N1CCCC1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A 2-L 3-neck RB flask, equipped a magnetic stirring bar, thermometer, addition funnel and nitrogen gas inlet was charged with Example 8, N-{2-fluoro-4-[1-hydroxy-3-(pyrrolidin-1-ylcarbonyl)cyclobutyl]benzyl}-pyrrolidine (43.0 g, 0.124 mol) and 1 L of anhydrous DCM under nitrogen. The mixture was cooled to −75° C. with a dry ice/acetone bath, then Deoxo-Fluor (Aldrich, 33.0 g, 27.5 mL, 0.149 mol) was added dropwise. The mixture was warmed to 0° C. and stirred for 30 min at this temperature. Then the mixture was quenched with 350 mL of sat. Na2CO3, and extracted with DCM (3×300 mL). The extract was dried over Na2SO4 and evaporated. The resulting crude oil was purified by column (silica gel, ether 60%, hexane 30%, MeOH 5%, Et3N 5%, Rf=0.37 in ether 60%, hexane 30%, MeOH 5%, NH4OH 5%) to give 29.0 g (67%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.39 (t, J=7.64 Hz, 1H), 7.21 (d, J=7.92 Hz, 1H), 7.14 (d, J=10.9 Hz, 1H), 3.67 (s, 2H), 3.40-3.61 (m, 5H), 2.66-3.00 (m, 4H), 2.50-2.55 (m, 4H), 1.80-2.00 (m, 4H), 1.75-1.80 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:3]1.C(N(CC)C(C)C)(C)C.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH:5]=2)=[CH:12][CH:11]=1)=[O:32]
Reactant: Cn1nc(-c2cccs2)cc1-c1ccc(N)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc(-c2cccs2)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a solution of 66 (20 mg, 0.08 mmol) in CH2Cl2 (10 ml) was added N,N-diisopropylethylamine (DIEA, 26 mg, 36 μL, 0.2 mmol), 4-dimethylaminopyridine (DMAP, 0.6 mg, 0.05 mmol). The 2,6-difluorobenzoyl chloride (15 mg, 0.08 mmol) was dropped into above solution. The mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (20 ml) and extracted with EtOAc. The dicarboxamide was hydrolyzed with 1M NaOH in THF and MeOH (1:1). The product was purified by HPLC and afforded 67 (20.5 mg, 65%) as yellow solid. LC-MS: calcd. for C21H15F2N3OS: 396 (M+1). 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 6.77 (s, 1H), 7.08-7.10 (m, 1H), 7.26-7.29 (m, 2H), 7.42 (dd, 1H, J=0.88, 3.5), 7.42 (dd, 1H, J=0.88, 4.9), 7.59 (d, 2H, J=8.6), 7.62-7.63 (m, 1H), 7.83 (d, 2H, J=8.6), 11.00 (s, 1H).
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:22][C:23]1[C:31]([F:32])=[CH:30][C:29]([O:33][Si](C(C)C)(C(C)C)C(C)C)=[CH:28][C:24]=1[C:25]([OH:27])=[O:26].O>O1CCCC1>[F:22][C:23]1[C:31]([F:32])=[CH:30][C:29]([OH:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]
Reactant: CC(C)[Si](Oc1cc(F)c(F)c(C(=O)O)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(O)cc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Tetrabutylammonium fluoride trihydrate (191 g, 731.8 mmol) was added in portions to a solution of 2,3-difluoro-5-(triisopropylsilyloxy)benzoic acid (99.13 g, 300.0 mmol) in tetrahydrofuran (500 mL), and the resulting mixture stirred overnight at room temperature. The reaction mixture was poured into water (1000 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with brine (2×500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 2,3-difluoro-5-hydroxybenzoic acid (50 g, 95%) as a light yellow solid. MS (ESI, neg. anion) m/z 173 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:27])[N:11]3[C:15]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)([C:16]=2[OH:17])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[C:6]([Cl:8])[CH:7]=1.P(OC)(OC)(O[CH3:31])=O.C([O-])([O-])=O.[K+].[K+]>O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[C:10](=[O:27])[N:11]3[C:15]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)([C:16]=2[O:17][CH3:31])[CH2:14][CH2:13][CH2:12]3)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COP(=O)(OC)OC
Reactant: N#Cc1ccc(CC23CCCN2C(=O)C(c2cc(Cl)cc(Cl)c2)=C3O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC1=C(c2cc(Cl)cc(Cl)c2)C(=O)N2CCCC12Cc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
4-[6-(3,5-Dichloro-phenyl)-7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrrolizin-7a-ylmethyl]-benzonitrile (24), (60 mg, 0.15 mmol) Trimethyl phosphate (4 ml) and K2CO3 were stirred under reflux for 10 hours then cooled to RT and diluted with water. The precipitate was filtered to afford after HPLC purification 4-[6-(3,5-Dichloro-phenyl)-7-methoxy-5-oxo-2,3-dihydro-1H,5H-pyrrolizin-7a-ylmethyl]-benzonitrile XII (18mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:3]1.[H][H]>C(O)(=O)C.[Pd]>[NH2:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[C:4]1[CH2:3][C:2]([CH3:28])([CH3:1])[CH2:7][CH:6]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH:5]=1
Reactant: [H][H]
Reactant: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(N2C(=O)c3ccccc3C2=O)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccncc2N)=CC(N2C(=O)c3ccccc3C2=O)C1
Yield: 89 %

Procedure:
A solution of 2-(5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (1 eq) in Acetic Acid (0.1M) was purged with nitrogen for 10 min. Then 10% Pd/C (0.10 eq) was added. The reaction mixture was stirred at room temperature overnight an atmosphere of hydrogen. Solids were removed by filtration over celite, then rinsed with EtOAc and MeOH. The filtrate was concentrated, diluted with EtOAc and washed 2× with sat. aq. 2M Na2CO3. Organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(3-(3-aminopyridin-4-yl)-5,5-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (89%). LC/MS (m/z): MH+=348.3, Rt=0.79 min.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](Cl)=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:15]([NH:17][N:18]([NH:22][CH2:23][CH3:24])[CH2:19][CH2:20][NH2:21])[CH3:16]>C(Cl)(Cl)Cl>[CH2:15]([NH:17][N:18]([NH:22][CH2:23][CH3:24])[CH2:19][CH2:20][NH:21][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[CH:13]=[CH:14][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=1)[CH3:16]
Reactant: CCNN(CCN)NCC
Reactant: [N-]=[N+]=Nc1ccc(C=CC(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Product: CCNN(CCNC(=O)C=Cc1ccc(N=[N+]=[N-])cc1)NCC

Procedure:
Subsequently, 8.5 g (40 millimoles) of the p-azidocinnamic acid chloride was dissolved in chloroform, and 4.8 g (40 millimoles) of N,N-diethylaminoethylenediamine was added thereto at a reaction temperature of 10° to 20° C., after which the resulting solution was further allowed to react for 1 hour. The chloroform was distilled off under reduced pressure, and 100 ml of water was added to the resulting oily substance, after which a solution of 1.7 g of sodium hydroxide in 20 ml of water was added thereto on an ice bath. The organic layer separated was extracted with chloroform, and the extract was further washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 11 g of an oily substance as the distillation residue. This oily substance decomposed at 130° C. with formation of bubbles and generation of heat. This oily substance was identified as the compound of this invention by analysis using the following spectral means: ##STR115##