Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]O)=[CH:18][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C(/N=N/C(N(C)C)=O)=O)C>C1COCC1>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OCc1ccc(F)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.7 %

Procedure:
To a mixture of 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile (185 mg, 0.99 mmol), 4-fluorobenzyl alcohol (188 mg, 1.49 mol), PPh3 (391 mg, 1.49 mmol) and THF (4 mL) cooled in an ice-water bath, TMAD (257 mg, 1.49 mmol) was added. The reaction mixture was stirred overnight at rt, filtered, and concentrated before purification by prep-HPLC to give the title compound (40 mg, 13%). 1H NMR (400 MHz, CDCl3): δ 5.14 (2H, s), 5.68 (1H, s), 7.00-7.05 (2H, m), 7.33-7.36 (3H, m), 7.52 (1H, s), 7.96 (1H, s), 8.64 (1H, s). [M+H] Calc'd for C16H11FN4O, 295. Found, 295.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH3:22])=[O:20].[CH2:24]([N:26](CC)[CH2:27]C)C.CNC.Cl>CN(C=O)C>[F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:26]([CH3:27])[CH3:24])[C:4]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Reactant: CCN(CC)CC
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1N(C)C
Yield: 64.5 %

Procedure:
A solution of 3.46 g (0.010 mol) of the compound produced in Example 103, 0.97 g (0.010 mol) of triethylamine and 2.00 g (0.012 mol) of a 26% W/V solution of aqueous dimethylamine in 50 ml of DMF was stirred at room temperature for 18 hours. The reaction mixture was poured into 3.7% HCl and extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). The dry ether phase was con-centrated in vacuo to 2.6 g of a yellow solid. This crude product was purified using the HPLC in 5% ethyl acetate/cyclohexane, affording 2.39 g (67%) of a yellow solid; mp 80°-81° C.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[O:17]=[C:18]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:19][NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:63][C:64]1[CH:72]=[CH:71][CH:70]=[CH:69][C:65]=1[C:66](O)=[O:67]>CN(C=O)C.O>[CH3:63][C:64]1[CH:72]=[CH:71][CH:70]=[CH:69][C:65]=1[C:66]([N:38]1[CH2:39][CH2:40][N:35]([C:18](=[O:17])[CH2:19][NH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[O:22])[CH2:36][CH2:37]1)=[O:67]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: Cc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 63.8 %

Procedure:
DIPEA (152 mg, 0.66 mmol) was added to a stirred solution of biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt (116 mg, 0.26 mmol) in DMF (1 mL). HOBT (36 mg, 0.26 mmol) and EDCI.HCl (50 mg, 0.26 mmol) were then added. After 2 minutes 2-methylbenzoic acid (30 mg, 0.22 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water. The product was extracted with ethyl acetate and the ethyl acetate layer was washed with NaHCO3 solution, saturated brine solution, dried over sodium sulphate and concentrated under reduced pressure. The residue was washed with diethyl ether to afford 62 mg (72.9% yield) of biphenyl-4-carboxylicacid {2-[4-(2-methyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a pale yellow solid. LC-MS purity: 94.42%, HPLC Purity: 92.84%. 1H NMR: (DMSO) δ 8.7-8.6 (bs, 1H), 8.0 (d, 2H) 7.8 (m, 4H), 7.6-7.2 (m, 7H), 4.1-4.3 (dd, 2H), 3.8-3.4 (m, 6H), 3.2 (m, 2H), 2.2 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[OH:33])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[O:33][CH2:2][C:3]([N:5]1[CH2:10][CH:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH:6]1[CH3:20])=[O:4])[CH3:22]
Reactant: CCOC(=O)Cc1cc(Cl)ccc1O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(Cl)ccc1OCC(=O)N1CC(C)N(Cc2ccc(F)cc2)CC1C
Yield: 97.8 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (3.3 g, 11.0 mmol) in 2-butanone (100 mL) was added (5-chloro-2-hydroxy-phenyl)-acetic acid ethyl ester (2.3 g, 11.0 mmol), potassium carbonate (3.05 g, 22.1 mmol), and potassium iodide (1.83 g, 11.0 mmol). The reaction was heated at reflux for 48 hrs. The solution was cooled, diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by dissolving in dichloromethane and passing through a pad of silica gel. Concentration in vacuo gave the title compound (5.13 g).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N:20]=[C:19]([NH:30][CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[N:18]=1)[CH2:27][CH2:26][CH2:25]3.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N+:20]([O-:4])=[C:19]([NH:30][CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[N:18]=1)[CH2:27][CH2:26][CH2:25]3
Reactant: CCN(CC)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56.4 %

Procedure:
H2O2 (70%, 0.52 mL, ca. 10.4 mmol) was added dropwise to a stirred solution of TFAA (1.5 mL, 10.4 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 26 (312 mg, 1.0 mmol) and TFA (0.40 mL, 5.2 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 5° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 27 (179 mg, 54%) as a red gum: 1H NMR δ 8.11 (br s, 2H, H-5, H-9), 7.73 (br s, 1H, NH), 3.64-3.69 (m, 2H, CH2N), 3.01-3.10 (m, 4H, H-6, H-8), 2.81-2.85 (m, 2H, CH2N), 2.64-2.73 (m, 4H, 2×CH2N), 2.14-2.22 (m, 2H, H-7), 1.09 (t, J=7.1 Hz, 6H, 2×CH3); 13C NMR δ 156.0, 149.5, 145.8, 138.1, 129.8, 115.7, 111.7, 51.1, 46.6 (2), 38.5, 33.4, 32.3, 25.6, 11.0 (2); MS (FAB+) m/z 318 (MH+, 70%), 302 (20); HRMS (FAB+) calcd for C16H24N5O2 (MH+) m/z 318.1930, found 318.1933.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH2:16])[CH3:15]>>[CH2:14]([NH:16][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH3:15]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCN
Product: CCNc1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
In a manner similar to Example 31, 4-fluoro-3-nitrobenzoic acid was treated with ethylamine to give 4-ethylamino-3-nitrobenzoic acid, which was then esterified with anhydrous hydrogen chloride in methanol to give the title compound. 1H-NMR (CDCl3): δ 8.89 (1H, d), 8.28 (1H, br s), 8.06 (1H, dd), 6.87 (1H, d), 3.90 (3H, s), 3.42 (2H, m), 1.40 (3H, t).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([CH3:22])=[N:20][N:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:22][C:19]1[O:18][C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[N:21][N:20]=1
Reactant: [H][H]
Reactant: Cc1nnc(C2CCN(C(=O)OCc3ccccc3)CC2)o1
Agent: [Pd]
Solvent: CCO
Product: Cc1nnc(C2CCNCC2)o1
Yield: 981.2 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine (0.18 g) in ethanol (5 mL) was hydrogenated over 10% palladium on carbon (0.050 g) at a hydrogen pressure of 1 bar for 2 hours. The catalyst was then removed by filtration through diatomaceous earth, the filter cake was washed with ethanol and the solvent evaporated to afford the piperidine as a white crystalline solid (0.98 g); mp 64°-66° C.; NMR (CDCl3): 3.17 (m, 2), 2.98 (m, 1), 2.75 (dr,2, J=2.6, 12.0), 2.51 (s, 3), 2.01 (m, 2), 1.75 (m, 2); MS: m/z=196(M+1+28).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][S:5][N:4]=1)[CH3:2].C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:20][CH:1]([C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][S:5][N:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csnc1CC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1csnc1C(C)Br

Procedure:
Following generally the procedure of Example 28, ethyl 3-ethyl-4-isothiazolecarboxylate is reacted with NBS and benzoyl peroxide to give ethyl 3-(1-bromoethyl)-4-isothiazolecarboxylate, which is then reacted with sodium bicarbonate and DMSO and the resulting ethyl 3-acetyl-4-isothiazolecarboxylate is treated with lithium hydroxide monohydrate to yield 3-acetyl-4-isothiazolecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:30][C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]2[S:20][CH:21]([CH2:24][C:25](OCC)=[O:26])[CH2:22][N:23]=2)=[CH:15]3)[CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.CCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:30][C:31]3[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]2[S:20][CH:21]([CH2:24][CH2:25][OH:26])[CH2:22][N:23]=2)=[CH:15]3)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4cccc(Cl)n4)c3[nH]2)S1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C4=NCC(CCO)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 20.2 %

Procedure:
Ethyl (2-{7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (400 mg) was dissolved in tetrahydrofuran (8 mL), lithium borohydride (43 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 17 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=40:60 to 100:0, volume ratio) to give the title compound (75 mg, yield 20%) as an amorphous solid. The amorphous solid was crystallized from diethyl ether to give pale-yellow crystals. melting point 93-94° C. MS 558 (MH+).
Reaction SMILES: [Li].[CH2:2]([O:4][C@@H:5]1[C@:13]2([CH2:14][CH3:15])[C@H:8]([C@@H:9]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([O:24]C)[CH:18]=[CH:17][C:16]=4[C@H:10]3[CH2:11][CH2:12]2)[CH2:7][CH2:6]1)[CH3:3].COCC(O)C.N>COCCOC>[CH2:2]([O:4][C@@H:5]1[C@:13]2([CH2:14][CH3:15])[C@H:8]([C@@H:9]3[CH2:23][CH2:22][C:21]4[C@H:16]([CH2:17][CH2:18][C:19](=[O:24])[CH:20]=4)[C@H:10]3[CH2:11][CH2:12]2)[CH2:7][CH2:6]1)[CH3:3]
Reactant: CCO[C@H]1CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12CC
Agent: N
Agent: [Li]
Solvent: COCCOC
Solvent: COCC(C)O
Product: CCO[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12CC
Reaction time: 1 h

Procedure:
Add 2.0 g. of lithium to a suspension of 2.0 g. of dl-17β-ethoxy-13-ethyl-3-methoxygona-1,3,5(10)-triene, 90 ml. of 1,2-dimethoxyethane, 100 ml. of 1-methoxy-2-propanol, and 300 ml. of ammonia while stirring. Treat with 2.0 g. of ammonium chloride and water, filter off the precipitate and add it to 80 ml. of methanol, 4 ml. of water, and 5 ml. of conc. hydrochloric acid. Stir for one hour and dilute with water. Extract the product with ether and recrystallize it successively from methanol-water and petroleum ether-ether to obtain the title substance, m.p. 95°-97°; ultraviolet peak at 244 mμ (15,900); infrared peak at 6.0 μ.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.B(F)(F)F.[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>C(OCC)C>[CH2:19]([O:18][C:16]([CH:15]1[CH2:6][CH2:7][CH:2]([NH2:1])[CH2:3][CH2:4][C:5]1=[O:8])=[O:17])[CH3:20]
Reactant: NC1CCC(=O)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)C1CCC(N)CCC1=O

Procedure:
The appropriate 4-aminocyclohexanone in an appropriate solvent, for example diethyl ether, is treated with an appropriate Lewis acid such as boron trifluoride for about 20 minutes to about an hour at room temperature. To this solution is then added ethyl diazoacetate and the resulting mixture is stirred for about 1 hour to about 24 hours at room temperature. The resulting 2-ethoxycarbonyl-5-aminocycloheptanone is isolated by diluting the reaction mixture with aqueous sodium carbonate and extracting with a water immiscible solvent such as diethyl ether. The reaction product is then directly dissolved in dimethylsulfoxide which contains sodium chloride and water. The reaction mixture is heated to about 170° for from about 1 to about 24 hours to effect the decarboxylation. The desired 4-aminocycloheptanone is recovered by diluting the reaction mixture with water and extracting with an appropriate solvent such as diethyl ether. The reaction product may be purified by column chromatography, if desired, prior to further reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([Cl:25])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CC(=O)C2)C(=O)O)cc1Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CC(=O)C2)C(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionic acid (0.12 g, 0.36 mmol) in methylene chloride (10 ml) was cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 0.22 ml, 0.43 mmol) and N,N-dimethylfomamide (two drops) which produced gas evolution and then it was stirred at 0° C. for 20 minutes and 40 min at 25° C. After this time, the reaction was concentrated in vacuo and azeotroped with methylene chloride (10 ml). The reaction was redissolved in methylene chloride (10 ml) to afford the crude 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionyl chloride as a 0.012M solution which was used in the following step with no further purification.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([O:12][CH3:13])=[N:10][CH:9]=[CH:8][N:7]3[C:14]=2I)[CH2:3][CH2:2]1.[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]>>[CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([O:12][CH3:13])=[N:10][CH:9]=[CH:8][N:7]3[C:14]=2[CH:35]([OH:36])[C:33]2[CH:32]=[CH:31][C:25]3/[C:26](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:37][C:21]=4[O:22][CH2:23][C:24]=3[CH:34]=2)[CH2:3][CH2:2]1
Reactant: COc1nccn2c(I)c(C3CC3)nc12
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: COc1nccn2c(C(O)c3ccc4c(c3)COc3cc(F)ccc3/C4=C(\C)C#N)c(C3CC3)nc12
Yield: 104.8 %

Procedure:
[step 3] Using 2-cyclopropyl-3-iodo-8-methoxyimidazo[1,2-a]pyrazine (9.2 g, 29 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (5.3 g, 18 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 14A, step 3, (E)-2-{8-[(2-cyclopropyl-8-methoxyimidazo[1,2-a]pyrazin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (9.1 g, quantitative) was obtained.
Reaction SMILES: S(Br)([Br:3])=O.[Cl:5][C:6]1[C:7]([CH:15](O)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[CH:14]=1>C1(C)C=CC=CC=1>[Br:3][CH:15]([C:7]1[C:6]([Cl:5])=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=S(Br)Br
Reactant: COC(=O)C(O)c1cc2c(cc1Cl)OCO2
Solvent: Cc1ccccc1
Product: COC(=O)C(Br)c1cc2c(cc1Cl)OCO2

Procedure:
Thionyl bromide (3.7 ml) was added to a stirred solution of methyl 2-(6-chloro-1,3-benzodioxol-5-yl)-2-hydroxyacetate from step (a) (7.8 g, 32 mmol) in toluene (50 ml) at ambient temperature. After 6 hours the reaction mixture was evaporated in vacuo, and the residue was flash chromatographed using dichloromethane as eluant, followed by crystallisation from diisopropylether to give the subtitle compound (7.6 g).
Reaction SMILES: Br[C:2]1[C:3]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:16][CH:17]([SH:19])[CH3:18].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:15][C:14]1[C:3]2[C:2]([S:19][CH:17]([CH3:18])[CH3:16])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[S:5][C:4]=2[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1sc2cccc(Cl)c2c1Br
Reactant: CC(C)S
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1sc2cccc(Cl)c2c1SC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 3-bromo-4-chlorobenzo[b]thiophene-2-carboxylate (0.62 g, 2.0 mmol) , 2-propanethiol (0.30 mL, 0.25 g, 3.2 mmol) , and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL, 0.34 g, 2.2 mmol) in 5.0 mL of N,N-dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is partitioned between 150 mL of cold 1.0N HCl and 75 mL of dichloromethane, and the aqueous layer is extracted several times with fresh dichloromethane. The combined organic layers are washed with 1.0N HCl and brine, then dried (anhydrous sodium sulfate) and evaporated to yield methyl 4-chloro-3-[(1-methylethyl)thio]benzo[b]thiophene-2-carboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH3:35])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:50][C:51]1[CH2:55][O:54][C:53](=[O:56])[CH:52]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:38])[F:39])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]([CH3:35])[CH2:50][C:51]4[CH2:55][O:54][C:53](=[O:56])[CH:52]=4)[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C1C=C(CBr)CO1
Reactant: CNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CC1=CC(=O)OC1)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(methylamino)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.18 mmol) in DMF (4 mL) was added DIEA (46 mg, 0.36 mmol), 4-(bromomethyl)-2,5-dihydrofuran-2-one (63 mg, 0.36 mmol). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (40.0% up to 48.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 40.0% in 2 min); Detector, UV 254/220 nm. This resulted in 15.5 mg (13%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-[methyl[(5-oxo-2,5-dihydrofuran-3-yl)methyl]amino]piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 20) [M+H]+=655.2, RT=1.91 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.09 (t, 1H, J=73.2 Hz), 6.04 (s, 1H), 5.24-5.22 (m, 2H), 4.86 (d, 2H, J=1.2 Hz), 4.39-3.37 (m, 1H), 4.01-3.93 (m, 1H), 3.47 (s, 2H), 3.10-3.01 (m, 1H), 2.67-2.62 (m, 2H), 2.20 (s, 3H), 1.76-1.73 (m, 2H), 1.56-1.42 (m, 1H), 1.40-1.29 (m, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[CH2:27](N)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N(OCC(C)C)=O>C(#N)C.CC(N(C)C)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([O:14][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: NCc1ccccc1
Agent: CC(C)CON=O
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CC(=O)OCC1=C(C(=O)OCc2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
To a solution of 3-acetoxymethyl-7β-(2-thienylacetamido) ceph-3-em-4-carboxylic acid (3.96 g., 10 m. moles) in acetonitrile (70 ml) and dimethylacetamide (5 ml) was added benzylamine (1.28 g., 12 m. moles) and isobutyl nitrite (2.47 g., 24 m. moles) and the mixture heated to 45° over 2 hours. Initially a solid formed in the mixture but with vigorous stirring it had all dissolved after 1-1.25 hours as the reaction proceeded. After removal of the solvent in vacuo, the gum was taken up in ethyl acetate (50 ml) washed with dilute H2SO4 (25 ml.), 5% NaHCO3 solution (50 ml.) and water (50 ml.), and the organic residue after evaporation of the organic solvent crystallised from hot isopropanol to yield the title ester (2.40 g., 42% based on the input acid) m.pt. 135° - 139°. T.l.c. indicated the presence of some trace impurities.